ANTIBIOTICS – (chronological order)
1929 Flemming A. “On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenza.” Br J Exp Pathol 1929; 10: 226–36. Sir Alexander Flemming (1881-1955) (figure) was a Scottish bacteriologist, working at St Mary’s Hospital, London, whose discovery of penicillin (1928) prepared the initial step towards the highly effective practice of antibiotic therapy for infectious diseases. In 1945 Fleming shared the Nobel Prize for Physiology or Medicine with Ernst Boris Chain (1906-1979) and Howard Walter Florey (1898-1968) who both (from 1939) were responsible for carrying forward Fleming’s initial observation by further isolation, purification, testing, and quantity production of penicillin
In 1940 a report was issued describing how penicillin had been found to be a chemotherapeutic agent capable of killing sensitive germs in the living body. Thereafter great efforts were made, with government assistance, to enable sufficient quantities of the drug to be made for use in World War II to treat servicemen with war wounds.
Penicillin became available for a few patients with CF in the USA in 1943 and the results were reported by Paul di Sant’Agnese (1944 below) – prior to this virtually all children with CF died in infancy or early childhood from Staphylococcal pneumonia and malnutrition.
– It is noteworthy that Flemming failed to develop his 1929 discovery – this was done over 10 years later by Florey and Chain. Nor was Flemming the first to observe the antibacterial effects of moulds. Ernest Duchesne (1874 –1912) (figure 2) was a French physician who noted that certain moulds kill bacteria. He made this discovery thirty-two years before Alexander Fleming observed the antibiotic properties of penicillin, a substance derived from those moulds, but his research went unnoticed. Duchesne entered l’Ecole du Service de Santé Militaire de Lyon (the Military Health Service School of Lyon) in 1894. Duchesne’s thesis, “Contribution à l’étude de la concurrence vitale chez les micro-organismes: antagonisme entre les moisissures et les microbes” (Contribution to the study of vital competition in micro-organisms: antagonism between moulds and microbes), that he submitted in 1897 to get his doctorate degree, was the first study to consider the therapeutic capabilities of moulds resulting from their anti-microbial activity. Duchesne had made his breakthrough by observing how the Arab stable boys at the army hospital kept their saddles in a dark and damp room to encourage mould to grow on them. When he asked why, they told him that the mould helped to heal the saddle sores on the horses. Intrigued, Duchesne prepared a solution of the mould and injected it into a series of diseased guinea pigs. All recovered.
In a series of meticulous experiments, Duchesne studied the interaction between Escherichia coli and Penicillium glaucum, showing that the latter was able to completely eliminate the former in a culture containing only these two organisms. He also showed that an animal inoculated with a normally lethal dose of typhoid bacilli would be free of the disease if the animal was also inoculated with Penicillium glaucum.Unfortunately, as he was only 23 years old and unknown, the Institut Pasteur did not even acknowledge receipt of his dissertation! He urged more research but unfortunately his army service, after getting his degree, prevented him from doing any further work. Considerable attention has been allotted to penicillin as before the availability of penicillin few infants with CF survived infancy. It was the introduction of penicillin and later other antibiotics which was the main development that permitted survival beyond infancy.
1946 Di Sant’Agnese PA, Andersen DH. Celiac Syndrome IV Chemotherapy in infections of the respiratory tract associated with cystic fibrosis of the pancreas; observations with penicillin and drugs of the sulphonamide group, with special reference to penicillin aerosol. Am J Dis Child 1946; 72:17-61.
This is the first report of the use of penicillin in cystic fibrosis. In 1943 a small quantity of penicillin had become available from the US Army to treat three children with CF and a further 2 in 1944 with intramuscular penicillin; the results were variable. Bryson and co-workers at the Carnegie Foundation were first to investigate the use nebulised penicillin (Bryson et al, Science 1944; 100:33). In 1944 Alvan Barach of the Presbyterian Hospital was using a penicillin aerosol to treat asthma and bronchiectasis (Barach et al, Ann Int Med 1945; 22:485). Similar apparatus was used by di Sant ‘Agnese for these children with CF; it consisted of a rubber mask with re-breathing bag and nebuliser with a flow of oxygen into the nebuliser (figure 3).
– This is an interesting first report describing early treatment in CF and in particular the first use of nebulised penicillin 20,000 units seven times daily with or without intramuscular penicillin 160,000 units daily. According to di Sant’Agnese, dramatic response occurred in 15 infants and young children with CF who eventually received the treatment but little success was achieved in infants less than a year old.
From 1947 there were numerous publications on the use of the recently available penicillin in other conditions by various routes both oral, by aerosol and even powdered inhalations – no less than 18 such publications were reviewed in The 1948 Year Book of Pediatrics. (Poncher HG (ed). Year Book Publishers. Chicago). Undoubtedly a new era of treatment of infection had begun.
Di Sant’Agnese (1914 – 2005) wrote that “Penicillin is the first drug known to affect the course of fibrocystic disease after cyanosis has marked the existence of suppurative Staphylococcal bronchitis”. Later, in 2001, he recalled “In most patients the results (of penicillin treatment) were dramatic. From death’s door, slowly dying from chronic pulmonary disease while we watched helplessly, patients revived in a few days”. Sulphonamides were said to be useful in prophylaxis and for intercurrent infections but not after the stage of suppurative bronchitis.
Dr Lynn Taussig, who worked with di Sant’Agnese, later recalls that Paul di Sant’Agnese and Harry Shwachman were definite rivals but had considerable respect for each other. Di Sant’Agnese came from a noble family in Italy. His father was an obstetrician and radiotherapy expert who was physician to the Italian Royal Family. Paul went to Rome medical school and then came to USA in 1939 to study medicine in New York. He was chief resident in paediatrics and published his first paper on tick paralysis – as initially he worked in infectious disease and immunology; he studied the effect of immunisations in early life. He went to work with Dorothy Andersen at the Presbyterian Hospital in New York. In 1950 he described glycogen storage disease of the heart (Pompe’s disease) and as a gastroenterologist in the early 1950s he wrote on coeliac disease.
In 1953 di Sant’Agnese’s observation of abnormal sweat electrolytes in CF was one of the most important observations in the history of CF and provided the basis of the sweat test (Di Sant’Agnese et al, 1953 below). He wrote over 140 papers mostly on CF – physicochemical differences, mucoproteins, calcium in secretions, and with West the first report of pulmonary function tests, pneumothorax, ventilation, pancreas, duodenal contents, and measurements of absorption. He was the first to describe the liver changes – a few months before Shwachman’s group. He had an interest in every aspect of the condition. But the patient always came first and he was an outstanding clinician as well as a gifted researcher. In 1955 he was involved with the medical aspects of the CF Foundation. In 1960 in Europe he met Archie Norman, David Lawson, and the International Cystic Fibrosis and Mucoviscidosis Association (ICFMA) had 28 delegates and guests from 14 countries. Di Sant’Agnese said he was most proud of training so many associates and colleagues in CF care and research. “If your plan is for one year, plant rice, if for 10 years plant trees, if for life – educate!”
In 1946 this present paper on the use of penicillin for fibrocystic disease, with special reference to aerolised penicillin, was the first publication on the use of this new antibiotic in cystic fibrosis.
1949 Shwachman H, Crocker AC, Foley GE, Patterson PR. Aureomycin therapy for the pulmonary involvement of pancreatic fibrosis (mucoviscidosis). N Eng J Med 1949; 241:185-192. [PubMed]
The first enthusiastic report of favourable response of children with CF to the wide spectrum antibiotic aureomycin – indeed Shwachman was the first to use this broad spectrum antibiotic in cystic fibrosis. Aureomycin had been used from September 1948 –“the substitution of an orally effective antibiotic such as aureomycin for the expensive and more difficult form of aerosol therapy has obvious merits”. Nebulized penicillin and streptomycin was routine treatment at the time. Thirty five children were treated with aureomycin for up to 4.5 months with excellent results in 31 and most of the Staphylococci remained sensitive. However, diarrhoea was a frequent complication and “the appearance of Proteus vulgaris, Pseudomonas aeruginosa and fungi overgrowing or replacing the initial flora” were observed repeatedly “reminiscent as seen after prolonged penicillin and streptomycin therapy”.
– So already prolonged use of antibiotics was resulting in a change of the bacterial flora from S. aureus to gram negative organisms including Pseudomonas aeruginosa. These were early days of the use of antibiotics both for short and long periods.
1950 Koyama Y, Kurosawa A, Tsuchiya A, Takakuta K. A new antibiotic, colistin, produced by spore-forming soil bacteria. J Antibiot Tokyo. 1950; 3:457.
The antibiotic colistin was discovered by Koyama et al in 1949, as a fermentation product of the bacteria Bacillus colistinus and the discovery had a direct bearing on the treatment of CF. At first the drug was given intramuscularly (and apparently it was very painful) and in 1959 an intravenous formulation (colistimethate sodium) was released commercially; but this was temporarily abandoned in the Seventies due to reports of a high incidence of nephrotoxicity (Price et al, 1970; Koch-Weser et al, 1970) and also there was increasing use of intravenous gentamicin from 1968. Later the early clinical reports of toxicity with colistin were considered as likely to have occurred as a result of inappropriate patient selection and higher dosing than was recommended and inappropriate monitoring (Li et al, 2005). However, interest in colistin was rekindled following a rise in the prevalence of multiresistant Gram-negative strains most of which were sensitive to colomycin and particularly following the report of its use in the successful early eradication of P. aeruginosa in children with cystic fibrosis (Littlewood et al, 1985 below).
– Nebulised colistin is now widely used for the treatment of both chronic infections and the early eradication of P. aeruginosa in people with cystic fibrosis (Littlewood et al, A ten year review of colomycin. Resp Med 2000; 94:632-640. below).
1951 Poncher HG. Year Book of Pediatrics. Chicago: Year Book Publishers, 1951: 128-129.
An interesting comment from Dr Henry Poncher, the Editor of the 1951 Year Book of Pediatrics, on the increasing survival of people with CF and the more frequent isolation of Pseudomonas aeruginosa, possibly as a result of prolonged antibiotic therapy. He has prophetic comments on the likely causes – “For future progress, control of Pseudomonas infections is necessary” – an astute and relevant observation as it turned out! The interruption of therapy when immediate effects have been achieved and the use of two antibiotics having different mechanisms of action are mentioned as reasonable practices.
– So already the obvious benefits of repeated and prolonged use of antibiotics were apparent but also their adverse effects were reported particularly as they related to repeated and prolonged use, with suggestions as to how these could be reduced. The tendency to use repeated and prolonged courses of antibiotics brought new problems of bacterial resistance, toxicity, and drug allergies. The change in predominant bacterial flora from Staphylococcus aureus to P. aeruginosa appeared to be related to the frequent and prolonged use of antibiotics.
1952 Shwachman H, Silverman BK, Patterson Zheutlin LJ. Antibiotics in treatment of pancreatic fibrosis with emphasis on terramycin. JAMA 1952; 149:1101-1108. [PubMed]
Terramycin, aureomycin and mixed varied antibiotic treatments were compared. All those on terramycin, most of those on aureomycin and the mixed group responded well. Terramycin was introduced in early 1950 and well tolerated. Shwachman mentions the importance of early diagnosis and prolonged treatment also the value of nebulised penicillin and streptomycin (the value of which later he seemed to doubt). As with aureomycin, withdrawal of terramycin led to relapse and it was decided to use the drugs continuously – the subject of a subsequent report of patients so treated (Shwachman et al, 1954 below).
1952 Wallenstein L, Snyder J. Neurotoxic reactions to Chloromycetin. Ann Int Med 1952; 36:1526-1528. [PubMed]
The first report of some of the serious side effects of chloramphenicol (the antibiotic first became available in 1951) in a 24 year-old patient with ulcerative colitis after 4 months continuous treatment with the antibiotic. The lady developed loss of vision, optic and peripheral neuritis but fortunately this settled when the drug was stopped.
– This is the first of a number of reports of chloramphenicol toxicity following prolonged use (Keith CG. Arch Dis Child 1966; 41:262-266; Harley RD et al. Trans Am Acad Ophthalmol Otolaryngol 1970; 74:1011-1031). Lasky MA et al. (JAMA 1953; 151:1403-1404) reported a boy aged 14 with Staphylococcal endocarditis who had 6 g of chloramphenicol daily for 6 weeks and developed optic neuritis; later there was no recovery of vision.
The first reports of side effects in people with CF, who also required prolonged courses of antibiotics, was some 10 years later (Denning et al, 1963 below; Huang NN. J Pediatr 1966; 68:32-44 below).
1954 Shwachman H, Catzel P, Patterson PR, Stoppelman MRH. Mucoviscidosis: an evaluation of continuous and prolonged antibiotic therapy. Am J Dis Child 1954; 88: 380-382. (Meeting presentation by invitation)
One hundred and twenty three patients had received continuous antibiotic therapy (Aureomycin or Terramycin) for six months to over six years. Broad spectrum antibiotics had been introduced first in 1949. The results were least satisfactory in advanced cases. There was no evidence therapy prevented onset of chest disease but it could control symptoms for prolonged periods. The age of onset of cough influenced survival – the outlook was bad if the onset was at less than three months. During the period of antibiotic therapy 56 patients showed progressive changes (33 alive and 23 had died), 24 were unchanged and five improved . Between 1945-54 the average age of death was 45.2 months; up to 1949 the age of death was only 12.8 months.
– The discussion at this meeting ranged from concerned speculation by some delegates of patients surviving and “breeding” which would be “disastrous” (!!), to whether the patients would have done as well with discontinuous therapy – had Shwachman more “survivors” in his series a questioner asked? In reply Shwachman contrasts his figures with the UK figures reported by Martin Bodian (1952) which reflect the impressive results achieved by Shwachman and his colleagues as follows-
BODIAN SERIES vs. SHWACHMAN SERIES
Total patients 11 vs. 123;
Dead 68 (57%) vs. 22 (18%)
Alive 47 (41%) vs. 101 (87%)
>5 years 15 (13%) vs. 61 (50%)
1954 Stoppelman MR, Shwachman H. Effect of antibiotic therapy on mucoviscidosis: bacteriologic study on 140 patients. N Eng J Med 1954; 251:759-763.[PubMed]
A review of the beneficial effects of antibiotic therapy in CF – treatment which had then been available for about 10 years since the mid-Forties. Mildly affected children had chlortetracycline or oxytetracycline; the worst affected had sulphadiazine, chloramphenicol or erythromycin. The worst affected patients also had short courses of penicillin and streptomycin aerosol therapy. Most patients still had S. aureus as the main pathogen – mostly still sensitive to penicillin but resistant to chlortetracycline and oxytetracycline.
– A major difference from modern CF therapy was that intravenous (IV) antibiotic therapy was rarely used as venous access in children, and particularly repeated and prolonged venous access, was still a major technical problem. Single episodes where IV access was required were often managed by cutting down on a vein at the ankle and inserting a metal cannula which was tied into the vein; this would last for some days. Of course, the vein was lost for future use as it had been ligated so the method was unsuitable for repeated venous access for which other techniques were developed subsequently such as scalp vein needles, venous long lines and eventually totally implantable venous access devices.
1958 Shwachman H, Fekete E, Kulczycki LL, Foley GE. Effect of long term antibiotic therapy in patients with cystic fibrosis of the pancreas. Antibiot Ann 1958-59; 692-699.[PubMed]
An early (possibly the first) report of severe yellow discolouration of the teeth due to tetracycline (figure 5) , an antibiotic which had become available between 1948-1950. Discolouration of the teeth was present in 80% of young children with CF receiving long term tetracycline prophylaxis; many subsequent reports have confirmed the roblem (Zegarelli EV et al. Oral Surg Oral Med oral Pathol 1962; 15:929-933.[PubMed]; Witkop CJ, Wolf RO. JAMA 1963; 185:1008-1011. [PubMed]). Tetracycline is deposited in growing bone by forming complexes with the bone mineral.
1960 Young WF. Ototoxicity to neomycin aerosol. Lancet 1960; i: 1103.
This letter to the Lancet from Winifred Young (1909-1969), of the Queen Elizabeth Hospital for Children, London, followed closely a report from the Royal National Throat, Nose and Ear Hospital, London, of two children with CF who had received nebulised neomycin for 34 months and 26 months respectively and who had become severely deaf (Fuller A. Ototoxicity of neomycin aerosol. Lancet 1960; i: 1026). Winifred Young responded that the patients were part of a series of children treated at her CF clinic at the Queen Elizabeth Hospital for Children, London and both the children had very severe chest involvement – in fact, both had since died. Dr Young and her otological colleagues “had been able to reassure herself that neomycin aerosol can be used for many months without risk of ototoxicity”.
– Despite this reassurance, the use of long term nebulised neomycin was eventually abandoned due to ototoxicity – at that time it was not appreciated that inhaled antibiotics could be absorbed in significant amounts. Inhaled neomycin was first described as a treatment for CF in 1956 (Gibbs GE, Raskin J. Antibiotic Med Clin Therapy 1956;2:332-336.[PubMed]). A case report of ototoxicity appeared in 1959 (Greenwood GJ. AMA Arch Otolaryngol 1959; 69:390-397. [PubMed]) and in a number of reports in the early Sixties although most reports of ototoxicity and CF concern the aminoglycosides.
1960 Zegarelli EV, Denning CR, Kutscher Tuoti F, di Sant’Agnese PA. Discolouration of the teeth in patients with cystic fibrosis. Pediatrics 1960; 26:1050
There was severe discoloration of the teeth in 38 of 52 children and adolescents with CF. In 31 the deciduous teeth were involved, the permanent teeth in 18 and both in 11. The authors noted that tetracycline had been involved in animals and speculated that antibiotic therapy “might conceivably contribute to the discolouration by deposition in the teeth”.
– In 1959 Shwachman et al. had recognised tooth staining (Antibiot Ann 1958-1959, 692-699) (figure 5 in Shwachman et al, 1958 above). Subsequently Zegarelli, usually with Carolyn Denning of New York, published 11 papers on tooth discoloration. Tetracycline is deposited in growing bone and teeth by complexing with the bone mineral (Witkop CJ, Wolf RO. JAMA 1963; 185:1008-1011.[PubMed]). Subsequently tetracyclines were avoided in children under seven years of age and also by pregnant women.
The dangers of some drugs taken by the mother during pregnancy were becoming apparent at this time – particularly the thalidomide tragedy which came to light in the early Sixties after over 10,000 infants had been born with various limb deformities between 1956 and 1962 as a result of their mothers taking the drug during pregnancy.
1962 Wallman IS, Hilton HB. Teeth pigmented by tetracycline. Lancet 1962; i: 827-829.[PubMed]
A report from the Princess Margaret Hospital for Children, Perth, Australia. This is an early report of “tetracycline teeth”, although the authors noted that Shwachman had described tooth discolouration in 40 of 50 children who had long term treatment with tetracycline (Antibiotics Annual. New York. 1958:692). (also Zagaralli et al, 1960 above and 1963 below).
The present authors noted pigmentation of infant’s teeth at a maternity hospital follow-up clinic; many of those affected had not been jaundiced – the usual explanation given for tooth discolouration.
– The co-author Hilton had previously observed skeletal pigmentation with tetracycline, so the possibility of a relation to tetracycline administration was investigated. 50 out of 64 babies had received tetracycline in the newborn period and 46 had yellow or brown pigmentation of their teeth with or without enamel hypoplasia. The more tetracycline, the greater the change in tooth colour. Earlier Buyske et al had noted bone pigmentation by tetracycline and chlorotetracycline in animals (Buyske DA et al. J Pharmacol 1960; 130:150-156.[PubMed]).
1963 Pino G, Conterno G, Colongo PG. Clinical observations on the activity of aerosol colomycin and of endobronchial instillations of colomycin in patients with pulmonary suppurations. Minerva Medica 1963; 54:2117-2122.[PubMed]
One of the early reports of colomycin, administered as an aerosol, achieving “satisfactory blood levels”. Reference is also made to Mensi E (1958) in this paper. Colomycin has had three phases of popularity in treating people with cystic fibrosis.
Phase 1. As Gram negative infections, including Pseudomonas aeruginosa (Ps. pyocyanea as it was then), became more of a problem during the Sixties, intramuscular colomycin was the only effective injectable antibiotic. Robert Stern recalls how, in the early Sixties, he first started infusions of intravenous colomycin in Cleveland prompted by the extreme pain of the intramuscular injections in an emaciated girl with CF who already had an IV infusion running for hydration purposes. The IV route gradually replaced the painful IM route particularly when carbenicillin became available in 1968. However, when gentamicin became available in 1968 this drug replaced colomycin as first line treatment for P. aeruginosa in people with cystic fibrosis.
Phase 2. Interest revived in nebulised colomycin following the short report from Leeds (Littlewood et al, 1985 below) of the successful eradication of early colonisation with P. aeruginosa in CF using nebulised colomycin – an observation later confirmed in Copenhagen (Valerius et al, 1991, below) and a number of other small studies from Europe. According to Hoiby, nebulised colomycin was also introduced into the treatment of chronically infected patients in Copenhagen in 1987 on the strength of the initial 1985 report from Leeds. It is interesting that none of these early reports were accepted in the USA (even the excellent trial of Valerius et al, 1991 with its quite striking results) and it was some 15 years before early eradication of P. aeruginosa became widespread in the USA.
Phase 3. As most resistant P. aeruginosa remained sensitive to colomycin, the intravenous use was again evaluated for strains of the organism which had become resistant to other antibiotics; it was found to be effective with an acceptable level of side effects (Conway et al, 1997 below).
There was a detailed multi-author ten year review of Colomycin and its role in the treatment of CF published in 2000 (Littlewood JM et al. Respir Med 2000; 94:632-640 below)
1963 Lloyd AV, Grimes G, Khaw KT, Shwachman H. Chloramphenicol for long-term therapy of cystic fibrosis. JAMA 1963; 184:1001-6.[PubMed]
Report of more than three years of daily chloramphenicol in patients with CF without toxic effects in 50 patients studied and in post mortem records of 23 others. Later one fatal case of aplastic anaemia was encountered.(also Denning et al, 1963 above; Huang NN et al. 1966.[PubMed]below).
1963 Denning CR, Bruce GM, Spalter HF. Optic neuritis in chloramphenicol treated patients with cystic fibrosis. J Pediatr 1963; 63:878.
The first report of optic neuritis in four children with CF on long term chloramphenicol – a complication which had been reported first in 1952 by Wallstein & Snyder (1952 above) in a woman with inflammatory bowel disease who after five months developed optic neuritis and peripheral neuritis.
– Later a number of reports in people with CF were reviewed by Harley RD et al (Trans Am Acad Ophthalmol Otol 1970; 74:1011-103.[PubMed] below). Numbness and tingling of the peripheries preceded the ocular signs which appeared to be related to the total dose received. It was suggested that 25 mg/kg/day for not more than 3 months was relatively safe. Fortunately, visual acuity usually recovered soon after stopping the drug but may recur if treatment was resumed. (Also Huang N et al. J Pediatr 1966; 68:32-44.[PubMed] below).
1963 Huang NN, Sproul A, Promadhattavedi V, High RH. Long-term therapy with oxacillin in patients with cystic fibrosis. Antimicrob Agent Chemother 1963; 54:667-672. [PubMed]
A short anecdotal report of long term use of oxacillin (an anti-Staphylococcal antibiotic available since 1962) in 15 patients with CF many of whom were receiving other antibiotics – mainly chloramphenicol. However, it did show that oxacillin was safe and that resistance on the part of S. aureus did not develop even after prolonged use although the organism was eliminated in only three patients – presumably because most had “advanced pulmonary involvement” and chronic entrenched infection by the time the treatment was started. S. aureus is similar to P. aeruginosa in that that once the infection becomes “chronic” eradication is impossible but usually achievable in the early stages of the infection.
– This is the first report of long term anti-Staphylococcal therapy, a treatment with flucloxacillin now recommended in the UK for all children with CF under three years of age although its prophylactic longterm use is still the subject of debate. Essential facts which have become apparent are that resistance to the antibiotic does not develop and the frequency of S. aureus positive cultures and chronic S. aureus infection is reduced when patients are receiving long term anti-Staphylococcal therapy. The possibility of an increased likelihood of culturing P. aeruginosa becomes less relevant when a policy of early Pseudomonas eradication is routine the clinic – unfortunately this was not the case in North America until recently. Also less likely when a broad spectrum antibiotic is not used. However, In Leeds, lifelong long term flucloxacillin for most patients has been the policy since 1975 and early eradication of P. aeruginosa has been practised since around 1984 (Southern et al, 1993. In: Clinical ecology of cystic fibrosis. Escobar H et al. (eds). Excerpta Medica Internat Congr Series 1034: 129-132). Even so both the prevalence of chronic S. aureus infection of 14% is low and chronic P.aeruginosa infection is well below average at 18.1% for the whole clinic and only 4.3% for those children less than 11 years of age (Lee et al, 2004, below).
1966 Huang NN, Harley RD, Promadhattavedi V, Sproul A. Visual disturbances in cystic fibrosis following chloramphenicol administration. J Pediatr 1966; 68:32-44.[PubMed]
There were visual changes in nine (27%) of 33 patients with CF who had received chloramphenicol in total doses of 81-283 g. The authors mention another patient treated with 135 g of chloramphenicol over 4.5 months (Cocke JG, et al. J Pediatr 1966; 68:27). The authors state that although visual disturbances had been described in children with CF and advanced respiratory disease (Bruce GM et al. Arch Ophthalmol 1960; 63:391-401.[PubMed]) only advanced respiratory changes were present as an explanation; however, these authors later described four children with eye changes due to chloramphenicol (Denning et al. J Pediat 1963; 63:878. above) as did Huang et al. (3rd Interscience Conference Antimicrob Chemother 1963:79). Such patients with eye changes had always received prolonged treatment with chloramphenicol. The eye symptoms usually improved when the drug was stopped. Regular tests of vision were advised when the drug was used for prolonged periods.
1966 Keith CG, de Haller J, Young WF. Side effects to antibiotics in cystic fibrosis: 1. Ocular changes in relation to antibiotic administration and severity of pulmonary involvement. Arch Dis Child 1966; 41:262-266. [PubMed]
Experience of Winifred Young from London where only one of 42 patients had ocular changes from chloramphenicol; 425 g having been given to this patient over 15 months. Various other findings were considered unrelated to drug therapy including four with squint, nine with tortuosity of the retinal vessels, one with blurring of disk margins – appearances considered due to more severe lung disease. Eighteen children had various short course of chloramphenicol with no obvious ill-effects.
1967 Swallow JN, De Haller J, Young WF. Side-effects to antibiotics in cystic fibrosis: dental changes in relation to antibiotic administration. Arch Dis Child 1967; 42: 311-318. [PubMed]
Experience from Dr Winifred Young’s unit in London where 36.5% of 63 children with CF had discoloured teeth due to tetracycline treatment (also above Shwachman H, et al, Antibiot Ann 1958-59; 692. above; Zegarelli et al, Pediatr 1960; 26:1050 above; Wallman IS, Hilton HB. Lancet 1962; i: 827 above).
1968 Boxerbaum B, Doershuk CF, Pittman S, Leroy W Matthews. Efficacy and Tolerance of carbenicillin in patients with cystic fibrosis. Antimicrob Agents Ch 1968; 8:239-295.[PubMed]
The authors, from the Cleveland clinic, state that “effective therapy of P. aeruginosa has emerged as one of the principal needs to prevent further damage to the lung”.
– This is the first report of the use of intravenous carbenicillin in 41 people with cystic fibrosis. Pulmonary function tests improved in 80% of patients and 79% had improved X-ray appearances. There were many subsequent publications on the use of carbenicillin in CF. It is interesting that although colistin (also a polymyxin) was considered to have limited clinical value due to “renal toxicity and their disappointing activity in vivo”, colistin is now a widely used antibiotic in CF for P. aeruginosa both by inhalation and intravenously.
1969 Lawson D. Panel discussion on microbiology and chemotherapy of the respiratory tract in cystic fibrosis. Proc 5th Int CF Conference, Cambridge, 1969. Ed. Lawson D. London. Cystic Fibrosis Research Trust 1969:225. [Conference]
David Lawson was one of the first paediatricians to suggest long term anti-Staphylococcal prophylactic chemotherapy. Eventually this treatment was supported by a controlled trial in CF screened infants in East Anglia, UK (Weaver et al, 1994 below). Prophylactic flucloxacillin is now recommended for all CF infants in the first 3 years by the UK CF Trust’s Expert Antibiotic Group (2002 and 2009) although the findings are not accepted in North America.
– I was impressed by David Lawson’s approach and from 1975 all CF infants and children for whom I was responsible were on long term cloxacillin and later flucloxacillin from soon after birth, if screened (from 1975 in East Leeds), or from the time of diagnosis. The results of this policy were reported in 1993 by Kevin Southern at the Madrid ECFS meeting. Of 110 patients attending our unit for all their care at that time only 16 (14.5%) had chronic Staph. aureus infection – individual group prevalence in 0-4 years nil, 5-9 yrs 14.7%, 10-15 yrs 22%; furthermore some of those patients had been referred to our clinic already chronically infected with S. aureus. The Leeds CF centres still have most patients on continuous flucloxacillin and there is a very low prevalence of chronic Staphylococcal infection. It is also interesting that despite the publications suggesting anti-Staphylococcal prophylaxis leads to a higher prevalence of Pseudomonas infection, this does not occur if there is also a policy of regular cultures and early Pseudomonas eradication. Even so clinicians are still arguing about the wisdom of flucloxacillin prophylaxis in 2018 !!
David Lawson, whose daughter had CF, was one of the founders of the UK CF Research Trust in 1964. He maintained that earlier diagnosis, by improved neonatal screening, was essential for improvement of results as by the time the diagnosis was presently made lung damage was already present. Both David and Archie Norman were major supporters of the CF Trust from its formation in 1964. They received a special award in their retirement.
1969 Louria DB, Young L, Armstrong D, Smith JK. Gentamicin in the treatment of pulmonary infections. J Infect Dis 1969; 119:483-485. [PubMed]
An early report of the use of intravenous gentamicin in a variety of respiratory infections including 30 patients with cystic fibrosis. Intravenous gentamicin was administered over periods ranging from three weeks to 16 months and the response to treatment was classified as good in 20 patients, moderately improved in 7 and ineffective in 3. The drug was reported as often valuable in infections due to Pseudomonas aeruginosa.
1970 Harley RD, Huang NN, Macri CH, Green WR. Optic neuritis and optic atrophy following chloramphenicol in cystic fibrosis patients. Trans Am Acad Ophthalmol Otolaryngol 1070; 74:1011-1031. [PubMed]
This is a review of the literature on chloramphenicol toxicity and experience with eye complications in cystic fibrosis. The authors considered that the peripheral numbness, tingling and cramps frequently preceded the ocular signs which were often sudden. Variable ocular signs were seen including both papilloedema and normal disks. Optic neuritis and visual loss were related both to dosage and duration of treatment. 25 mg/kg/day for not more than 3 months appeared to be safe. Fortunately, most patients’ visual acuity returned soon after stopping the drug.
1970 Wright GLT, Harper J. Fusidic acid and lincomycin therapy in Staphylococcal infections in cystic fibrosis. Lancet 1979; i:9-14. [PubMed]
This report from Brisbane showed the superiority of lincomycin and fusidic acid combination in eradicating Staphylococcus aureus in 16 patients with cystic fibrosis. Later John Brown from Sydney describing 718 courses of anti-Staphylococcal treatment mentions Wright and Harper’s paper and demonstrated the superiority of clindamycin with or without fusidic acid over all other regimens (Brown J. Aust Paediatr J 1980; 16:207-209).
1971 Huang NN, Hiller EJ, Macri CM, Capitanio M, Cundy KR. Carbenicillin in patients with cystic fibrosis: clinical pharmacology and therapeutic evaluation. J Pediatr 1971; 78:338-345.[PubMed]
Further work on carbenicillin, the relatively new intravenous anti-Pseudomonal antibiotic introduced in 1968. (also Bauxerbaum et al, 1968 above). The second author, Joan Hiller from the UK, eventually developed the paediatric CF Centre in Nottingham City Hospital, England.
1972 Stern RC, Doershuk CF, Matthews LW. Use of a heparin lock to administer intermittent intravenous drugs. Clin Ped 1972; 11:521-523.[PubMed]
The first report of the use of heparin locks for giving repeated doses of intravenous antibiotics to children with CF. Robert Stern (figure 6b) was the first to use colistin intravenously in CF and was closely involved in the development of intravenous (IV) antibiotic therapy. The first of his patients were treated at home from 1973 when a 15 year old girl worked as a waitress while receiving IV antibiotics via a heparin lock. Stern writes – “an early, if not the first, pioneer who self administered IV medications while continuing to work and pursue other normal out-of-hospital activities”.
Other centres followed (Rucker & Harrison, 1974 below). Crozier in Toronto reported using IV gentamicin and carbenicillin in 1974 for Pseudomonas infections (Crozier, 1974 below).
Robert Stern gives an interesting account of his early use of the intravenous route, instead of the painful intramuscular route, for colomycin in the mid-Sixties. Colomycin, was the only parenteral antibiotic in the early Sixties, later to be replaced by intravenous gentamicin and soon after carbenicillin and piperacillin became available. He describes the early developments including the heparin lock in the early Seventies, the gradual involvement of the patients with CF in managing their own IV therapy first in hospital and eventually at home (Stern RC. Intravenous treatment: where we are and how we got there. In: Doershuk CF, editor. Cystic Fibrosis in the Twentieth Century. Cleveland: AM Publishing, Ltd, 2001:93-111.).
1974 Rucker RW, Harrison GM. Outpatient intravenous medications in the management of cystic fibrosis. Pediatrics 1974; 54:358-360. [PubMed]
One of the first reports of home intravenous antibiotic treatment from Texas – the first author was supported by a Clinical Fellowship Grant from the CF Research Foundation (later the CF Foundation). They report a scalp vein needle and tube were used as a heparin lock and usually required replacing once during the 10 to 12 day course. Mainly gentamicin but also colistin was used in 127 courses in 62 patients with a 68% success rate and no major complications. Seven of the failures subsequently died.
Robert Stern, who had already described the use of the “Heparin lock” (Stern RC et al. Clin Pediat 1972; 11:521-523.) recalls starting home IV antibiotics in the early Seventies in Cleveland when a 15 year old asked if her heparin lock could be covered with a bandage so she “could leave hospital for a few hours to work at the Pronto Room as a waitress that afternoon”!! (Stern R. In Cystic Fibrosis in the 20th Century. Doershuk CF (ed.) 2001).
These reports from N. America were considerably in advance of any from the UK, the first being that of Winter RJD et al. in adults (Lancet 1984; i:1388-1339 below) and Gilbert J et al. in children with CF (Arch Dis Child 1988; 63:512-517 below). So in some large CF centres in N. America, treatment in this respect was certainly more advanced than in the UK at that time.
– I regret we did not mention the first very impressive 1974 report from Texas by Rucker and his colleagues in our 1988 paper from Leeds on home intravenous antibiotic treatment (Gilbert et al, 1988).
1975 Baran D, Dachy A, Klastersky J. Concentration of gentamicin in bronchial secretions of children with cystic fibrosis and tracheostomy. (Comparison between the intramuscular route, the endotracheal instillation and aerosolization). Int J Clin Pharmacol 1975; 12:336-341. [PubMed]
Gentamicin levels in blood and bronchial secretions were measured after 40 mg were directly instilled or given by aerosol. High levels (> 20 mug/ml), much greater than after intramuscular injection (< 2 mug/ml); low plasma levels were found by both direct methods. It was concluded that administration of an antibiotic such as gentamicin directly into the trachea by endotracheal injection or by aerolization might prove to be helpful when infection is confined mainly to the tracheobronchial tree. Gentamicin had become available in 1968.
1976 McCrae WM, Raeburn JA, Hanson EJ. Tobramycin therapy of infections due to aeruginosa in patients with cystic fibrosis: effect and dosage and concentration of antibiotic in sputum. J Inf Dis 1976; 134 Suppl: S191-193.[PubMed]
An early report of Pseudomonas aeruginosa infection treated in 17 patients with conventional and larger than conventional doses of intravenous tobramycin. Infection was eradicated in four and it appeared that treatment was most successful in those on the highest doses (12mg/kg/day) who achieved the highest peak serum values than in those on conventional doses (5mg/kg/day).
Most paediatricians were not using IV tobramycin for P. aeruginosa at this time although there had been one previous report using conventional doses (Hawley HB et al. Curr Ther Res 1974; 16:414-415.[PubMed]) and a subsequent one using conventional doses plus carbenicillin – the latter both IV and inhaled (Crozier DN, Khan SR. J Inf Dis 1976; 134:187-190.[PubMed]).
– This present paper from Morris McCrae and Sandy Raeburn, the physician looking after adults in Edinburgh at the time, was the first to suggest that higher doses of IV tobramycin were required for people with CF. Apparently intravenous gentamicin (available since the late Sixties see above) with carbenicillin had proved disappointing (Marks MI et al. J Pediatr 1971; 79:822-828. [PubMed]; Huang NN et al. J Pediatr 1971; 78:338-345.[PubMed]).
1979 Loening-Baucke VA, Mischler E, Myers MG. A placebo-controlled trial of cephalexin therapy in the ambulatory management of patients with cystic fibrosis. J Pediatr 1979; 95:630-637.[PubMed]
This trial is often quoted as supporting the view that prophylactic anti-Staphylococcal therapy predisposes to Pseudomonas infection – although most patients included in this trial were already chronically infected with P. aeruginosa at the start of the trial!! Patients received alternate four months of oral cephalexin or placebo over two years. Initially no less than 15 of 17 patients had P. aeruginosa(4 mucoid and 11 non-mucoid) and 10 of 17 had Staphylococcus aureus. Mucoid strains increased (six patients) and disease severity increased in those initially colonised with P. aeruginosa but cephalexin did reduce the frequency of respiratory illnesses and colonisation in patients initially colonised with S. aureus and H. influenzae. Authors concluded that “The long term administration….may be associated with an accelerated rate of colonisation with mucoid strains of P. aeruginosa and the potential for deterioration…”
– This small study of 17 patients (of whom 15/17 were already infected with P. aeruginosa!) subsequently has been quoted repeatedly, and in my view quite inappropriately, as showing that long term anti-Staphylococcal therapy causes an increase in chronic P. aeruginosa infection. Certainly some of the patients with non-mucoid P. aeruginosa converted to the mucoid form during the study, but this would be expected as these were the days before early eradication was thought possible or attempted; but essentially this was a small series of children already chronically infected with P. aeruginosa and certainly no conclusions can be drawn regarding long term anti-Staphylococcal therapy – certainly not about long term narrower spectrum therapy with flucloxacillin.
Of the authors only Dr. Elaine Mischler went on to publish extensively on cystic fibrosis on various aspects of CF – in recent years involved with various aspects of the Wisconsin Neonatal CF screening programme. She was one time Director of the CF/Pulmonary Center at the University Wisconsin and most recently CMO of Fiserv Health having been responsible for a spectrum of Health Management Programmes since 1998.
1980 Rabin HR, Harley FL, Bryan LE, Elfring GL. Evaluation of high dose tobramycin and ticarcillin treatment protocol in cystic fibrosis based on improved susceptibility criteria and antibiotic pharmacokinetics. In Perspectives in Cystic Fibrosis. Ed: Sturgess JM. 8th International Cystic Fibrosis Congress, Toronto, Canada 1980; 370-375.
This paper, although not widely quoted, had a major influence on our approach to intravenous antibiotic treatment in Leeds – indeed to our whole more intensive approach to treating people with cystic fibrosis.
At this 1980 Toronto meeting I was very impressed by the team approach and the significant involvement of all the members of the CF team and their obvious professional approach. With Archie Norman and his wife, who were also attending the meeting, I had an opportunity to visit Henry Levison, the paediatrician in charge of the CF Unit at the Hospital for Sick Children, Toronto.
The whole format of the conference at the Royal York Hotel, Toronto was quite new to me. This paper by Rabin and colleagues on intravenous antibiotic therapy was typical of the more professional approach to IV antibiotic therapy appropriate for CF which had been developed during the Seventies in some of the larger North American CF Centres (Stern RC. Intravenous treatment: Where we are and how we got there. In: Doershuk CF, (Ed.). Cystic fibrosis in the twentieth Century. Cleveland: AM Publishing Ltd, 2001:93-111).
– The frequent use of intravenous antibiotics for children with CF was not usual practice in most of the UK hospitals in 1980 where the majority of children with CF were still treated by their local general paediatricians.
Certainly this meeting at the Royal York Hotel, Toronto was the start of an increasingly serious involvement in Leeds with the whole field of cystic fibrosis – both research and clinical care. In retrospect, it was undoubtedly the centre/team approach first started by Leroy Matthews in Cleveland and the “Not so fatal disease” Toronto approach of Douglas Crozier (Crozier, 1974 above), that were the central lessons which I took back to Leeds from Toronto.
Dr. Harvey Rabin MD, FRCPC, is Professor, Faculty of Medicine, Departments of Medicine and Microbiology and Infectious Diseases, University of Calgary. He is the director of the adult cystic fibrosis clinic in Calgary. He has a wealth of knowledge of all clinical aspects of CF and fully supports the notion that research is key to finding a control for CF.
1981 Martin AJ, Smalley CA, George RH, Healing DE, Anderson CM. Gentamicin and tobramycin compared in the treatment of mucoid Pseudomonas lung infections in cystic fibrosis. Arch Dis Child 1980; 55:604 – 607.[PubMed]
A small straightforward and practically useful clinical comparison from Charlotte Anderson’s Birmingham unit, showing the two intravenous antibiotics, when combined with carbenicillin, gave similar results when used for treating respiratory exacerbations in cystic fibrosis. Subsequently gentamicin was shown to be less effective in vitro against Pseudomonas and was definitely the more nephrotoxic and ototoxic of these two aminoglycosides. Therefore tobramycin became the preferred aminoglycoside in most CF clinics. This was a useful review of the use of intravenous aminoglycosides in CF at the time – then a relatively new practice to most UK paediatricians.
– It is perhaps a poor reflection on our UK National Health Service that some CF Centres in the UK, against advice, were still using the more toxic IV gentamicin in 2008 apparently as their laboratory would only estimate blood levels of gentamicin and not tobramycin. A survey of renal failure in CF in 2007 showed virtually all those with episodes of acute renal failure had received intravenous gentamicin rather than tobramycin (Bertenshaw et al, 2007 below).
1981 Szaff M, Hoiby N. Antibiotic treatment of Staphylococcus aureus infection in cystic fibrosis. Monogr Paediatr 1981; 14:108-114. [PubMed]
This was a helpful practical account of the Danish regimen for treating S. aureus based on 15 years experience with 209 patients. If the organism was cultured from the airways of a person with CF “anti-Staphylococcal therapy was given whether there were clinical symptoms or not – usually courses of oxacillin and dioxacillin with fusidic acid for 14 days. Chronic infections were given long term treatment for one to three months”.
The authors noted no increase in P. aeruginosa from eradicating S. aureus and only 10% of patients in the Danish clinic had developed chronic S. aureus infection – in contrast to the usual 50% prevalence in many CF clinics. Each patient required an average of two courses of anti-staphylococcal antibiotics per year. Only a small increase in the number of S. aureus precipitins was observed.
In the UK David Lawson in London had also prevented the development of precipitins by long term cloxacillin treatment (Lawson D. Arch Dis Child 1976; 51:890-891 above).
– In our expanding clinic in Leeds in the Eighties, we found this Copenhagen paper to be a very useful as it gave clear guidance on antibiotics and dosages and also showed that chronic Staphylococcal infection could be prevented by close frequent microbiological monitoring and early treatment with short courses of antibiotics as an alternative to David Lawson’s long term cloxacillin – for some doctors and families were hesitant about long term antibiotic treatment. However, we eventually went for long term flucloxacillin for all patients as recommended by David Lawson and this is still the unit policy resulting in a low overall prevalence of chronic S. aureus infection (14%) compared to many centres (40-50%) and in only 8.3% (5/60) of children under 10 years of age – none in children below 5 years.
It is difficult to understand how chronic infection with S. aureus, a known harmful pathogen shown by bronchial lavage studies to result in an inflammatory reaction within the airways, is allowed to remain in so many patients when chronic infection can be prevented.
With regard to the influence of this treatment on the prevalence of P. aeruginosa infection, the prevalence of chronic P. aeruginosa in our clinic, where all patients are on long term flucloxacillin, is less than 4% in children under 12 years with CF (Lee et al, 2004 below). However, there has been a policy of early eradication treatment since 1984 and neonatal screening from 1975 neither of which are present in the centres reporting an increase in Pseudomonas with anti-Staphylococcal treatment (Stutman HR et al. J Pediatr 2002; 140:299-305. [PubMed]).
1981 Hodson ME, Penketh ARL, Batten JC. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa in patients with cystic fibrosis. Lancet 1981; i: 1137-1139. [PubMed]
Another definite landmark paper from the Adult CF Unit at the Royal Brompton Hospital, London by Dr Margaret Hodson, (later Professor of Cystic Fibrosis there), Dr Andrea Penketh and Sir John Batten who founded the adult CF centre there.. Professor Hodson was to make many major contributions to the treatment of people with CF from her vast experience at the Brompton Hospital treating many hundreds of adult patients with CF.
– This early paper had a major influence on treatment although there had been many earlier concerns about increasing the incidence of bacterial resistance from nebulised antibiotics. Although nebulised penicillin had been used in the Forties when S. aureus was the main pathogen (di Sant’Agnese, et al, 1946 above) it was undoubtedly this present paper of Margarte Hodson’s that revived the interest in nebulised antibiotics for patients with chronic Pseudomonas infection – particularly in the UK. The nebulised anti-Pseudomonal antibiotics obviously stabilised the condition of some patients with relapsing chronic P, aeruginosa infection who were requiring increasingly frequent courses of IV antibiotics and represented a major milestone in treatment (see entry in main text)
As a result of this paper nebulised anti-Pseudomonal antibiotics became widely used in the UK for patients with chronic Pseudomonas infection. In this respect the UK was well in advance of North America where, even in 1986, McLusky and colleagues from Toronto advised that, “until additional well-controlled trials were completed their routine use (of inhaled antibiotics) was not justified because of cost, potential side effects and the propensity to select resistant organisms” (McLusky et al, 1986 below).
As it turned out, both the routine use of anti-Pseudomonal antibiotics to suppress chronic infection as recommended by Margaret Hodson in 1981 (Ramsay BW et al, 1999) and the early use of colomycin to eradicate early infection (Littlewood et al, 1985; Valerius et al, 1991) both proved to be effective, proven and eventually widely used treatments for people with CF on both sides of the Atlantic.
1983 Knight RK. Antibiotic doses for bronchiectasis of cystic fibrosis. Lancet 1983; 2:970-971. [PubMed
One of many publications on CF and various respiratory topics by Dr Ron Knight a chest physician who worked at the Brompton Hospital, and subsequently developed his own unit – The Knight Centre – at Frimley Park Hospital, Surrey. Ron had a reputation for intensive treatment at a time when intravenous antibiotic treatment was not so widely or frequently used. His personal involvement, intensive treatment and good results were greatly appreciated to the extent that the patients and families raised the funds for the Knight Centre at Frimley Park Hospital. The recommendation in this letter to use much larger doses of antibiotics is characteristic of his approach, so appropriate for CF, which has persisted to the present day.
1983 Szaff M, Hoiby N, Flensborg EW. Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Acta Paediatr Scand 1983; 72; 651-657.[PubMed]
This is one of the main reports of improved survival at the Danish CF Centre since starting 3-monthly courses of intravenous anti-Pseudomonal antibiotics for chronically infected patients. During the period 1971-75, 51 chronically infected CF patients were treated with IV antibiotics but only when their condition deteriorated. During the period 1976-80, 58 chronically infected CF patients were treated with regular courses of intravenous antibiotics every three months.
The five year survival of patients from the time of the onset of their chronic P. aeruginosa infection increased from 54% in the first period to 82% in the second period. The authors concluded that intensive “maintenance” chemotherapy against P. aeruginosa improves survival and quality of life of CF patients although permanent eradication of chronic P. aeruginosa is not accomplished.
These results were largely ignored outside Denmark even in Europe. True, this was not a controlled trial and there were problems with the cost of the antibiotics, drug allergies, the patients’ time and quality of life and there were other treatments which could have favourably affected the outcome. It is also particularly relevant that long term nebulised antibiotics, that frequently stabilise the respiratory function of chronically infected patients, were not used at the time of this study.
Unfortunately, (even in 2018), there is still no totally adequate controlled trial of this form of regular IV antibiotic treatment although many clinicians have increasingly adopted a policy of very early intervention – which in practice almost amounts to 3-monthly treatments for some patients. One study from the UK comparing 3-monthly elective with symptomatic treatment showed no advantage in elective treatment but even the “treat when symptomatic” group received 3 courses of IV antibiotics annually (Elborn et al, Thorax 2000; 55:355-358 below).
Perhaps the frequency of intravenous antibiotic treatments is best left to the judgement of the clinician and the CF team who know the patient – and last, but not least, to the patient’s opinion! Certainly the availability of effective inhaled antibiotic therapy has influenced the management of the patients with chronic P. aeruginosa infection and reduced the need for intravenous antibiotic treatments in some patients.
1984 Winter RJ, George RJ, Deacock SJ, Shee CD, Geddes DM. Self-administered home intravenous antibiotic therapy in bronchiectasis and adult cystic fibrosis. Lancet 1984; i: 1338-1339. [PubMed]
One of the early UK reports of home intravenous antibiotic treatment in cystic fibrosis. Ten patients, eight with CF, and two with advanced bronchiectasis without CF, while being treated in hospital for exacerbations of Pseudomonas infection, were taught how to continue to give themselves intravenous antibiotics at home. In the eight patients, with two or more infective exacerbations within a 12-month period, there was no difference between home and hospital treatments in clinical improvement or in relapse time.
– This was a new treatment arrangement and the potential risks of treatment at home caused some people concern at the time. What about the medico legal risks? However, the giving of IV antibiotics at home was a major advance in patient care and a new step in treatment in the UK. Home IV antibiotics had been used in the USA in a few centres some years previously from the early Seventies (Rucker et al, 1974 above; Stern RC. Intravenous treatment: where are we and how we got there? In, Doershuk CF, Ed. Cystic Fibrosis in the 20th Century. AM Publishing Cleveland 2001; 93-111).
1985 Littlewood JM, Miller MG, Ghoneim AT, Ramsden CH. Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis. Lancet 1985; I: 865. [PubMed]
The first report of the use of nebulised colomycin to eradicate early Pseudomonas infection and, although only a modest letter, was undoubtedly the most important publication of my career!. Eradication of P. aeruginosa had previously been thought to be impossible.
– Subsequently, and according to Niels Hoiby, as a result of this short letter to the Lancet, in Copenhagen they started a controlled trial of early eradication therapy (Valerius et al, 1991 below) and found their results “confirm and extend the preliminary report by Littlewood and colleagues”. We had been using nebulised colomycin since about 1983/84 when Pseudomonas was first isolated to attempt eradication and after treating seven patients it was quite apparent that in some cases the organism was cleared from the sputum contrary to current teaching; so we reported our anecdotal experience in this letter to the Lancet. Table from the letter in the main text in Eighties Clinical.
Dr Michael Miller was one of the first CF Research Fellows in the UK funded by the Cystic Fibrosis Trust in 1983. He was with us in Leeds for over 2 years and, with our first CF Nurse Specialist, Teresa Robinson, played an important part in establishing our Regional Paediatric CF Centre at St James University Hospital. Mike subsequently was consultant paediatrician in Hudderfield, Yorkshire and eventually consultant in Paediatric Palliative Medicine at the Martin House Hospice, Boston Spa, Wetherby, Yorkshire.
The slow introduction of early eradication therapy, particularly in North America, is difficult to understand although perhaps one reason was that, in the early Eighties, the serious long term consequences of chronic Pseudomonas infection were only just being clearly described; most publications documenting the unfavorable outlook for patients with chronic Pseudomonas infection did not appear until the early Nineties (Kerem E et al, 1990; Henry et al, 1992; Hudson et al, 1993; Pamucku et al, 1995; Frederiksen et al, 1996; Kosorok et al, 2001). However, it is surprising that in a Cochrane Systematic Review of early Pseudomonas eradication treatment as late as 2006, the reviewers, while noting that the organism was eradicated in some patients, were still reluctant to admit that eradicating the organism had a favorable long term effect – presumably ignoring a great deal of published work attesting to the adverse effects of chronic P. aeruginosa infection mentioned above. The other lesson to take from this episode is that if a clinical course following a new intervention is so very different from the usual expected course, it is very likely to be a significant effect.
1985 Conway SP, Miller MG, Ramsden C, Littlewood JM. Intensive treatment of Pseudomonas chest infection in cystic fibrosis: a comparison of tobramycin and ticarcillin, and netilmicin and ticarcillin. Acta Paediatr Scand 1985; 74:107-113. [PubMed]
Seventeen cystic fibrosis patients aged 3.1 years to 19.8 years had 30 courses of intensive intravenous antibiotic treatment for exacerbations of their chronic Pseudomonas chest infection. The combination of netilmicin and ticarcillin was compared with tobramycin and ticarcillin in an open study. A significant subjective and objective improvement occurred in all patients. Pseudomonas was cleared temporarily from the sputum in 11 out of the 30 courses of treatment (37%) but, as expected, soon returned in all. There was no significant difference between the netilmicin and tobramycin groups, nor evidence of sustained renal or ototoxicity. Intensive therapy of Pseudomonas chest infection in cystic fibrosis patients is described in detail.
– The main purpose of our publishing this paper, in addition to the trial, was to document the fine details of a course of intravenous antibiotic therapy for those UK paediatricians who, like ourselves, were learning all the time how to best treat children with cystic fibrosis. At this time many children with CF in the UK were still cared for at their local hospitals by general paediatricians and had no contact with a CF centre. We hoped this detailed account of treatment would be of help in treating their CF patients.
1986 David TJ. Potential practical and legal problems with home administration of intravenous antibiotics for children with cystic fibrosis. In: David TJ, ed. Cystic fibrosis in children. Practical and legal aspects of intravenous antibiotic administration in the home. Amsterdam: Excerpta Medica, 1986:3-14.[Meeting report].
Report of a meeting organised by Professor Tim David of Manchester to discuss the practical and legal details of home intravenous antibiotic treatment which was increasingly used by CF centres in the UK for the giving treatment at home by parents or patients. The legal situation surrounding such treatment was not entirely clear at the time.(also Rucker et al, 1974 above; Winter et al, 1984 above; Gilbert et al, 1988 below; Stern RC. Intravenous treatment: where are we and how we got there? In, Doershuk CF. (Ed.) Cystic Fibrosis in the 20th Century. AM Publishing Cleveland 2001; 93-111).
1986 MacLusky I, Levison H, Gold R, McLaughlin FJ. Inhaled antibiotics in cystic fibrosis: Is there a therapeutic effect? J Pediatr 1986; 108:861-865. [PubMed]
The staff at the Toronto CF centre, under the leadership of Henry Levison, critically examined a number of the treatments used at the time confirming the value of some (physiotherapy – Reisman JJ 1988 below) and failing to confirm the benefit of others (nocturnal mist tents – Chang N et al. 1973 above).
This present study reviewed the evidence for the use of aerosol antibiotics and concluded that many studies were unsatisfactory and the results contradictory and that until additional well-controlled trials were completed their routine use was not justified because of cost, potential side effects and the propensity to select resistant organisms.
– At this time in the UK there was increasing use of inhaled antibiotics following the very convincing 1981 paper on nebulised gentamicin and carbenicillin which had a quite obvious significant beneficial effect in individual patients chronically infected with Pseudomonas (Hodson et al, 1981. above). Also the preliminary observation that inhaled colomycin would eradicate early Pseudomonas infection (Littlewood et al, 1985 above) had already been published but was not even mentioned by MacLusky et al.
As it turned out, both the routine used of anti-Pseudomonas antibiotics to suppress chronic infection as recommended by Margaret Hodson in 1981 was later shown to be effective using a special preparation of tobramycin for inhalation (Ramsey BW et al, 1999) as was the early use of colomycin to eradicate early infection (Littlewood et al, 1985; Valerius et al, 1991). Both proved to be effective, valuable, proven treatments and eventually widely accepted and used for people with CF on both sides of the Atlantic.
1986 Maunuksela EL, Korpela R. Double blind evaluation of lignocaine-prilocaine (EMLA) in children. Effect on the pain associated with venous cannulation. Brit J Anaesth 1986; 58:1242-1245. [PubMed]
The application of EMLA (Eutectic Mixture for Local Anaesthetic) local anaesthetic cream (lignocaine-prilocaine cream) to the skin and its occlusion for an hour before venepuncture was a major advance and was subsequently widely used permitting virtually painless venepuncture in the majority of children. This report was of a trial in 60 children (who did not have CF), using EMLA cream on the skin prior to venous cannulation before surgery; EMLA was clearly superior to placebo cream in preventing the pain of venipuncture.
– The introduction of this cream was a very welcome major advance both for the children with CF, who required frequent venepuncture for blood specimens and also for insertion of IV lines for antibiotic treatment; also it was welcomed by the doctors regularly inserting the IV needles – at times a very stressful business for both child, parents and the doctor!! Some children would even come to the clinic with EMLA cream already applied to both arms “just in case” someone decided on a blood test!! (Also Hallen B & Upfield A. Anaesthesiology 1982; 57:340; Clarke S & Radford M. Arch Dis Child 1986; 61:1132-1134; Halperin DL et al. Pediatrics 1989; 84:281-284 were studies all supporting the effect of EMLA cream).
Later nitrous oxide inhalations (Entonox) were used in some units for children before venepuncture (Mills HL et al. 2001 below; Kanagasundaram SA et al, 2001 below; Williams V et al. 2006 below).
These measures developed in view of the need for life long repeated venepuncture in children with CF either for the administration of antibiotics or to obtain blood specimens for investigations and annual assessments. So EMLA was undoubtedly one of the major advances in patient care of the decade!!
1986 McDowell HP, Hart CA, Martin J. Implantable subcutaneous venous catheters. Arch Dis Child 1986; 61:1037-1038.[PubMed]
The first report of the use of the Port-A-Cath totally implantable venous access device in 12 child oncology patients from Dr John Martin’s paediatric oncology unit in Liverpool; there were fewer complications than with the other central venous catheters and long lines currently in use.
At this time increasing numbers of children with CF were having repeated courses of two weeks intravenous antibiotics; problems with venous access were an increasing and major problem. This report from Liverpool prompted us in Leeds to combine with our paediatric oncology unit colleagues at St James University Hospital, to use the Port-A-Cath both in children with CF and those with oncology problems (Essex-Cater et al, 1989 below).
– Eventually Port-A-Caths and other implantable venous access devices became widely used in all CF Centres for both children and adults requiring regular course of intravenous antibiotics. They were undoubtedly a major advance in treatment.
1987 Hodson ME, Roberts CM, Butland RJA, Smith MJ, Batten JC. Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in cystic fibrosis. Lancet 1987; i: 235-7.[PubMed]
Early study of the first oral anti-Pseudomonal antibiotic ciprofloxacin showing benefit. Not surprisingly the oral treatment was preferred to IV treatment by 17 of the 20 ciproxin-treated patients! An oral anti-Pseudomonal drug was a major advance in treatment – all previous systemic anti-Pseudomonal antibiotics had required either intravenous or intramuscular administration. Eventually, combined with inhaled colomycin, ciprofloxacin became the standard eradication treatment for early Pseudomonas infection (Valerius et al, 1991).
– Undoubtedly an oral anti-Pseudomonas drug was a major advance in treatment. We also reported the successful use of another oral anti-pseudomonal antibiotic, Enoxacin, in a 12 year old boy with cystic fibrosis (Miller MG et al. Lancet 1985; i:646).
1987 Jensen T, Pedersen SS, Garne S, Heilmann C, Hoiby N, Koch C. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother 1987; 19:831-838. [PubMed]
One million units of inhaled colistin twice daily were compared with isotonic saline over three months in patients chronically infected with P. aeruginosa. More patients in the colistin group completed the study (18 vs.11). In terms of symptom scores, maintenance of pulmonary function (but only limited to the FVC) and inflammatory parameters, colistin was superior to placebo.
– The Danish group apparently started to use nebulised colistin on their chronically infected patients following the Leeds letter to the Lancet reporting its use in eradicating early Pseudomonas infection (Littlewood et al, 1985 above).
Although the results in this present study in chronically infected patients were not impressive, inhaled colistin came into widespread use in the UK and Europe to stabilise patients with chronic Pseudomonas chest infection – as it turned out, on the relatively modest published evidence in this paper! Eventually studies showed it to be less effective than inhaled tobramycin (TOBI) but both treatments were definitely associated with a significant fall in the numbers of bacteria in the sputum (Hodson ME et al. Eur Respir J 2002; 20:658-664. [PubMed]). However, in this comparison the patients had received colistin previously but were TOBI (tobramycin) naive and hence were more likely to improve.
It is of interest that on relatively little published evidence that colomycin became the most widely used inhaled anti-Pseudomonal antibiotic in Europe and still remains so and remains the mainstay of effective early P. aeruginosa eradication therapy.
1987 Pedersen SS, Jensen T, Hoiby N, Koch C, Flensborg EW. Management of Pseudomonas aeruginosa lung infection in Danish cystic fibrosis patients. Acta Paediatr Scand 1987; 76:955-961.[PubMed]
This is one of the main publications justifying the Danish policy of 3-monthly courses of intravenous antibiotics for patients chronically infected with Pseudomonas – a policy which has never been subjected to an acceptable clinical trial and as mentioned above was initiated before the advent of inhaled antibiotics. The annual mortality rate of cystic fibrosis patients with chronic P. aeruginosa lung infection at the Danish CF-centre ranged from 10 to 20% in the years 1970-1975 – in this period the patients received anti-Pseudomonal chemotherapy only during acute exacerbations of infection. From 1976-1979 patients who acquired chronic P. aeruginosa infection were given regular and intensive anti-Pseudomonal treatment three to four times per year. The patients were followed for 6-12 patient-years; seven died and the 10-year survival rate after onset of P. aeruginosa infection was 90% (+/- 4%). The annual mortality rate is now only 1-2%. Although precipitating antibodies against P. aeruginosa increased significantly, pulmonary function did not deteriorate with duration of infection.
– An unwelcome consequence was an increase in cross-infection between patients associated with more frequent hospitalisation and an increased incidence of new P. aeruginosa infection in 1976 which was steadily reduced, starting in the late Seventies, by improved hygienic measures and a new ward in the CF centre.
1987 Stead RJ, Davidson TI, Duncan FR, Hodson ME, Batten JC. Use of a totally implantable system for venous access in cystic fibrosis. Thorax 1987; 42:149-150. [PubMed]
One of the first reports of experience with this excellent device (Port-A–Cath) for adults with CF requiring frequent intravenous treatment but whose peripheral veins were becoming increasingly difficult to access (also McDowell et al, 1986 above; Essex-Cater et al, 1989 below).
1988 Gilbert J, Robinson T, Littlewood JM. Home intravenous antibiotic treatment in cystic fibrosis. Arch Dis Child 1988; 63:512-517.[PubMed]
An early study of home intravenous antibiotic therapy for CF children showing that, with adequate support, home IV treatment was as effective as hospital treatment, and preferred by families and considerably less expensive. A subsequent unpublished study showed that 2 weeks of home IV antibiotics cost approximately £1.5K and the same treatment in hospital £2.5K.
In this paper we describe our experience during the first 20 months of using a system of home intravenous antibiotic treatment in which a cystic fibrosis liaison nurse (Teresa Robinson) had a central role. Thirteen patients received 40 courses of treatment. There were highly significant improvements in weight, respiratory function, and white cell count during home treatment. There was no significant difference in weight and forced expiratory volume in one second between the end of home treatment and the end of hospital treatment while forced vital capacity was better after home treatment. All patients preferred home treatment. The advantages of home visits by the CF liaison nurse during treatment were emphasised.
– Subsequently numerous studies were published attesting to the feasibility, effectiveness and patient acceptability of home intravenous antibiotic therapy – an obvious major advance in treatment. However, surprisingly, a Cochrane Review in 2000, updated in 2006, considered only one small study as suitable for inclusion which showed home therapy did not harm the patients! The most recent update in 2012 found – “Current evidence is restricted to a single randomized clinical trial. It suggests that, in the short term, home therapy does not harm individuals, entails fewer investigations, reduces social disruptions and can be cost-effective. There were both advantages and disadvantages in terms of quality of life. The decision to attempt home treatment should be based on the individual situation and appropriate local resources. More research is urgently required”. This seems reasonable advice.
1989 Essex-Cater A, Gilbert J, Robinson T, Littlewood JM. Totally implantable venous access systems in paediatric practice. Arch Dis Child 1989; 64:119-123.[PubMed]
One of the first reports from Leeds of successful use of totally implantable venous access devices (TIVAD) in UK children with CF; this followed a report of the successful use of these devices in children from the Liverpool paediatric oncology unit (McDowell et al, 1986 above).
This present study was a combined effort of the paediatric oncologists at St James University Hospital in Leeds (Alison Essex-Cater – figure), who were already using the devices but had been somewhat discouraged by various serious complications including massive bleeding around the site, and our second CF Research Fellow (John Gilbert) and specialist CF Nurse (Teresa Robinson). This paper records our early experience with TIVADs and discusses the problems we encountered over the first three years. Forty seven TIVADs were inserted in 45 patients for the management of malignant disease (n = 29), haematological disorders (n = 5), and cystic fibrosis (n = 11).
– Subsequently TIVADs (figures in main text) became widely used in CF centres as intravenous antibiotic treatment increasingly became a major component of treatment. It became apparent that a surgeon with experience in their insertion was essential to minimise complications. Meticulous management to avoid infection of the device was important – often better given by conscientious well-trained parents than by inexperienced overworked medical and nursing staff! The teaching about TIVADs and their management became the responsibility of the CF Nurse Specialist who was also closely involved in organising home intravenous antibiotic therapy.
1989 Smith AL, Ramsey BW, Hedges DL, Hack B, Williams-Warren J, Weber A, Gore EJ, Redding GJ. Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol 1989; 7:265-271.[PubMed]
Arnold Smith had noted tobramycin in urine samples after nebulised administration hence the present study to assess safety of 12 weeks of thrice daily inhalations of 0.6gm of preservative free tobramycin. There was no detectable laboratory evidence of nephrotoxicity, neither a decrease in auditory acuity (range 250-20,000 Hz) nor vestibular dysfunction. Pulmonary function tests significantly improved during the first month in all subjects but returned to enrolment values by the end of the 12th week of administration of the tobramycin aerosol. Sputum P. aeruginosa density initially decreased and remained significantly below the enrolment value throughout. Coincident with the reduced bacterial density, a reduction in cough frequency and sputum production, as well as a weight gain was observed. However, seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrolment yielded resistant organisms during aerosol administration although 1 year later all sputum P. aeruginosa isolates were susceptible to tobramycin. The authors concluded that thrice daily aerosol tobramycin administration for three months was safe although transient emergence of tobramycin resistant P. aeruginosa may occur.
– The favourable results of this study eventually led to the development, trial and introduction of TOBI – the tobramycin preparation specifically for inhalation – one of the major treatment advances of the Nineties (Ramsay BW et al. N Eng J Med 1999; 340:23-30 below).
1990 Regelmann WE, Elliot GR, Warwick WI, Clawson CC. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and physiotherapy alone. Am Rev Respir Dis 1990; 141:914-921. [PubMed]
This widely quoted paper provided definite objective evidence of the beneficial effect of anti antibiotics over and above the other measures used when patients with chronic Pseudomonas aeruginosa infection were treated for a pulmonary exacerbation. The study has a rather complex design but is generally accepted as providing evidence of the beneficial effect of intravenous antibiotics and so it is described here in some detail.
For the first 4 days of study, all patients received bronchodilating aerosols and chest physiotherapy but no antibiotics. During this time, the patients showed significant improvement in mean FVC, FEV1, and maximal midexpiratory flow rate (FEF25-75). In 12 of 13 trials, the patients showed no significant increases in the density of Pseudomonas aeruginosa during these first four days. In these 12 trials, the patients were stratified by their initial FVC and randomized to receive either parenteral tobramycin and ticarcillin (n = 7) or placebo (n = 5), and in addition to continuing aerosol and chest physiotherapy. In the remaining trial, the patient had a significant rise in the density of P. aeruginosa during the run in and therefore was assigned to the antibiotic group.
During the next 14 days of therapy, the antibiotic group showed significantly (p < 0.01) greater reductions in log10 colony-forming units (cfu) of P. aeruginosa per gram of sputum and greater increases in FVC, FEV1, and FEF25-75 than did the placebo group. The degree of decrease in log10 cfu P. aeruginosa/g sputum correlated significantly (p < 0.001) with the degree of improvement in FVC, FEV1, and FEF25-75.
– The favourable effect of antibiotics had been questioned in a previous trial from Toronto where it was stated “there was no difference in the course during the 6 to 24 months after the study period. Intravenous antibiotics are not essential in the management of all acute respiratory exacerbations of mild to moderate severity in patients with cystic fibrosis” (Gold R et al. J Pediatr 1987; 111:907-913.[PubMed]). This was a finding quite out of keeping with the experience of most experienced CF clinicians who, fortunately, did not heed the Toronto advice.
1991 Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa infection in cystic fibrosis by early treatment. Lancet 1991; 338:725-726.[ PubMed
A randomised controlled trial from Copenhagen confirming that early P. aeruginosa infection could be eradicated in 80% of patients with CF by three weeks treatment with oral ciprofloxacin and nebulised colistin. The infection became chronic in only 2 of 14 (14%) of treated patients but in 7 of 12 (58%) of the controls. The authors comment – “Our results thus confirm and extend the preliminary report by Littlewood et al, colleagues (1995 above) who used colistin inhalations Since chronic colonisation with Ps aeruginosa is associated with increased morbidity and mortality we recommend the use of anti-Pseudomonas treatment whenever Ps aeruginosa is isolated from the sputum of cystic fibrosis patients”.
– This was certainly one of the most important papers of the decade and confirmed that early Pseudomonas infection could be eradicated with nebulised colomycin. It is difficult to understand why this perfectly satisfactory trial from Copenhagen, which clearly contradicted the previous widely held belief that it was impossible to eradicate Pseudomonas once cultured, was not followed by the widespread introduction of early eradication treatment for P. aeruginosa.Fortunately a few centres did introduce early eradication treatment but they were a minority. The fact that early treatment of Pseudomonas was so slow to be introduced in the UK and much of Europe (with notable exceptions) and was still not recommended in the USA over a decade after this report, was surprising and still difficult to explain.
The authors generously refer to our short letter to the Lancet in 1985 which was the first report on the use of inhaled colomycin to eradicate early Pseudomonas infection in CF and apparently stimulated their study. (Littlewood JM, Miller MG, Ghoneim AT, Ramsden CH. Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis. Lancet 1985; i: 865. [PubMed]). Although only a letter this was undoubtedly the most important publication of my career! It was good that the Copenhagen team confirmed our observations in their controlled trial.
Prior to treating CF children with inhaled colomycin I had been impressed by a paper from the Sixties describing successful treatment of Pseudomonas aeruginosa respiratory infections in non-CF patients with a combination of IV and inhaled colistin (Halliday NP. Clinical Trials Journal. August 1967. 771-775) and also by an editorial by Wallace Herrell in Clinical Medicine (September 1968 18-19) of successful aerosolized treatment of 60 patients with gram negative pneumonia, 30 of whom were infected by P. aeruginosa, the majority of whom improved; P. aeruginosa was eliminated from their sputum. The editorial concluded – “Thus it would appear that sodium colistimethate can be administered safely as an aerosol and it appears to be quite effective in the treatment of pulmonary infections. including pneumonia, owing to sensitive organisms particulalry the Pseudomonas strains”. So after further discussions with the firm (Pharmax Ltd – now Forest Laboratories) as to the dose, nebuliser etc in 1983/4 we started to treat children with nebulised colomycin as soon as P. aeruginosa was cultured.
Even though the numbers in the present Valerius et al 1991 trial were small and the patients not formally randomised, this was certainly one of the most important papers of the decade and confirmed that early Pseudomonas infection could be eradicated with nebulised colomycin and oral ciprofloxacin. It is difficult to understand why this trial from Copenhagen, which clearly contradicted the previous widely held belief, that it was impossible to eradicate Pseudomonas once cultured, was not followed by the widespread introduction of early eradication treatment for P. aeruginosa. Fortunately a few centres in Europe did introduce early eradication treatment but they were a minority. The fact that early treatment of Pseudomonas was so slow to be introduced in the UK and much of Europe (with notable exceptions) and was still not recommended in the USA over a decade after this report, was difficult to explain. Perhaps funding was dificult to achieve if not backed by a satisfactory trial.
It was predictable that these varied approaches to early treatment of Pseudomonas were reflected gradually in the markedly different prevalence of chronic Pseudomonas infection in different CF centres- this difference in the prevalence of chronic infection became increasingly obvious first in paediatric patients as time progressed (Frederiksen et al, 1996; Lee et al, 2003; Lebecque et al, 2006 all below).
In 1997 I had the good fortune to interview the late Dr Christian Koch, then the Medical Director of the Copenhagen CF centre, for a video. When I asked him at the end of the day what aspect of CF treatment he regarded as the most important, he thought for some time and then replied –
“When I look back on what we’ve done all through the years that I’ve been involved with cystic fibrosis, I would say that the early treatment of Pseudomonas is probably the best thing that we have done for the patients. It becomes more and more clear that really what determines the long term course is whether you get Pseudomonas or not” .
It is of interest and difficult to understand that even in 1998, reviewing the history of Pseudomonas infection in people with CF, a highly regarded US CF centre director wrote – “early administration with aerosol colistin may delay colonisation with P. aeruginosa. This intriguing observation has not been verified by prospective controlled studies” (Ramsey BW. Pediatrics 1998; Supplement: 210-213) – even though by this time early eradication of P. aeruginosa was widespread practice in Europe and already supported by many publications in addition to that of Valerius et al, 1991 from Copenhagen (Brett MM et al. Arch Dis Child 1992; 67:1086-1088.[PubMed]; Frederiksen B et al, Pediatr Pulmonol 1997; 23:330-335.[PubMed]; Weisemann HG, et al. Pediatr Pulmonol 1998; 25:88-92. [PubMed]; and later Munck A et al. Pediatr Pulmonol 2001; 32:288-292. [PubMed]).
1994 Weaver LT, Green MG, Nicholson K, Mills J, Heeley ME, Kuzemko JA, et al. Prognosis in cystic fibrosis treated with continuous flucloxacillin for the neonatal period. Arch Dis Child 1994; 70:84-89. [PubMed]
This study from East Anglia provided satisfactory evidence for most people that regular prophylactic flucloxacillin during the first two years in 38 screened CF infants was associated with less cough, fewer Staphylococcus aureus isolates, a lower hospital admission rates (19 versus 5) and for shorter periods (6.4 versus 2.2 days) and the need for only half the number of additional antibiotics. The study was possible as neonatal screening had been introduced into East Anglia by Anthony Heeley and his colleagues in 1981 – the first IRT screening in the UK ( Heeley et al, 1982 above).
– Prophylactic anti-Staphylococcal therapy had been recommended many years ago by David Lawson, paediatrician at Carshalton, London and was routine practice in some large CF centres in the UK, from the mid-Seventies. Evidence from this trial provided a basis for the CF Trust Antibiotic Group’s recommendations in 2002 (and later confirmed in 2009) for all infants with CF to receive continuous flucloxacillin for the first 2 years; in fact the first 3 years was commended in 2009.
Arguments continued for the next decade as to whether this treatment increased the likelihood of Pseudomonas infection – this was not the case in centres where early eradication of Pseudomonas had been practised since the early Eighties but probably was the case in the USA where early eradication of Pseudomonas was not routine practice. As an alternative to long term flucloxacillin, the levels of chronic S. aureus infection can also be reduced by early active treatment whenever the organism was cultured as shown in Copenhagen by Szaff and Hoiby (Szaff & Hoiby, 1981 above). It is important to note that in Copenhagen respiratory cultures are performed every month so S. aureus is detected at an early stage when it can be eradicated; as with P. aeruginosa, once allowed to become chronic eradication of S. aureus is difficult if not impossible.
The very high prevalence of chronic S. aureus infection reported in recent CF Registry figures (in up to 50% of patients) and from a number of countries, including the UK, is surprising considering that S. aureus was the main cause of death in the early years and is still associated with a definite inflammatory response as shown in bronchoscopic studies of young CF infants (Armstrong et al, 1995 below) and chronic infection can be prevented.
1997 Conway SP, Pond MN, Watson A, Etherington C, Robey HL, Goldman MH. Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis. Thorax 1997; 52:987-993.[PubMed]
Intravenous colistin was shown to be an effective safe treatment for P. aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the Pseudomonas shows in vitro sensitivity. It was advised that renal function should be monitored.
– Intravenous colomycin was first used by Robert Stern who gives an interesting account of his decision to use of the intravenous route, instead of the painful intramuscular route, in a wasted girl who already had an intravenous drip running for hydration purposes. Colomycin was the only parenteral antibiotic in the early Sixties. Later an intravenous preparation became available and but was soon replaced by intravenous gentamicin and then carbenicillin and piperacillin became available. Stern describes the early developments including the heparin lock in the early Seventies, the gradual involvement of the patients with CF in managing their own IV therapy first in hospital and eventually at home (Stern RC. Intravenous treatment: where we are and how we got there. In: Doershuk CF, editor. Cystic Fibrosis in the Twentieth Century. Cleveland: AM Publishing, Ltd, 2001:93-111).
Dr Martin Goldman is an independent consultant Pharmaceutical physician with very broad hands on experience. He was responsible for taking Colobreathe from concept to authorisation when Senior Medical Advisor with Forest Laboratories (1989-2013). He has been closely associated with CF progress for many years.
1997 Frederiksen B, Koch C, Hoiby N. Antibiotic treatment at time of initial colonisation with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in patients with cystic fibrosis. Pediatr Pulmonol 1997; 23:330-335.[PubMed]`
Follow up of the important Valerius et al, 1991 study (above) showing successful eradication of early infection with P. aeruginosa with nebulised colistin and oral ciprofloxacin. Three months colistin and ciprofloxacin gave longer freedom from recurrence of infection than did three weeks treatment.
This study was criticised as historic controls were used. However, it was already clear that the treatment prevented chronic P. aeruginosa infection (Littlewood et al, 1985; Valerius et al, 1991 above) and most clinicians in Europe would have regarded it as unethical to involve a placebo group at this stage; vigorous early eradication treatment was already routine practice in many European CF clinics. But it is difficult to understand how three months treatment increases the time to further Pseudomonas infection as the next episode of infection is usually, but not always, with a different genotype presumably acquired from the environment (Munck A et al. Pediatr Pulmonol 2001; 32:288-292). However, also using genotyping, it was later shown that a minority of Pseudomonas strains were suppressed but not completely eradicated – so presumably three months treatment would make this less likely to happen
– The great delay in the general introduction of early eradication therapy for Pseudomonas to reduce the prevalence of chronic infection, particularly in North America, was difficult to understand when the results of the earlier Copenhagen study were so impressive (Valerius et al, 1991 above).
Surprisingly, a later Cochrane Systematic review on early eradication of Pseudomonas aeruginosa, almost a decade later in 2006, could only conclude that “there is some evidence that antibiotic treatment of early P. aeruginosa results in short term eradication but it remains uncertain whether there is clinical benefit to people with cystic fibrosis” – a conclusion most experienced clinicians, including Neils Hoiby would fiercely question (as he and I did in critical letters to the Cochrane reviewers!). The views of the late Christian Koch summarise the Danish experience and of most CF clinicians as to the importance of avoiding chronic Pseudomonas infection (these are quoted in the comments on Valerius et al, 1991 above).
1997 Everard ML, Sly P, Brenan S, Ryan G. Macrolides antibiotics in diffuse panbronchiolitis and in cystic fibrosis. Eur Respir J 1997; 10:2926. [PubMed]
Mark Everard confirmed with me that this was the first report from Sheffield UK and Perth Western Australia showing the anti-inflammatory effect of macrolides in people with cystic fibrosis. Four of six patients with CF had significant reduction in IL-8 sputum levels after one month treatment with low dose (200 mg tds) oral erythromycin.
– Mark Everard believes the first report of the use of macrolides in CF was in a Japanese publication by Nakanishi et al in 1995 – “A 16-year-old boy was admitted to our hospital because of coughing, sputum, and exertional dyspnoea. Seven months after birth cystic fibrosis had been diagnosed. The chest roentgenogram on admission showed diffuse reticulonodular shadows and overinflation. Pulmonary function tests revealed obstructive and restrictive impairment. Erythromycin and Lomefloxacin were administered by mouth, and aminoglycosides were administered by inhalation. His symptoms were alleviated, and he is now an outpatient. In Japan, cystic fibrosis is rare, and this patient is extremely rare because he has grown up to be a 16-year-old.
In this case, low-dose and long-term erythromycin administration was very effective”. (Nakanishi N, Ueda N, Kitade M, Moritaka T. A case of cystic fibrosis in a Japanese student. Jpn J Thoracic Dis 1995; 33:771-774.) [PubMed]
The beneficial effect of 600 mg/day of erythromycin for 1 to 12 months in chronic panbronchiolitis in Japanese patients had been reported previously (Nagai H et al. Respiration 1991; 58:145-149. [PubMed]). The effect appeared to be independent of the presence of chronic Pseudomonas infection and an anti-inflammatory action was suggested (Fujii T et al. Thorax 1995; 50:1246-52. [PubMed]; Hoiby N. Thorax 1994; 49:531-532. [PubMed]; Kudoh S et al. Jpn J Thorac Dis 1987; 25:632-42.[PubMed]; Kudoh S. et al. Am J Respir Crit Care Med 1998; 157:1829-32 [PubMed] below).
These were important developments eventually leading to a number of large clinical trials and the widespread use of azithromycin in people with CF – undoubtedly one of the major clinical treatment advances of the Nineties and new Millennium (Equi et al, 2002 [PubMed] below; Saiman et al, 2003 [PubMed] below). By 2010 70.2% the patients on the US CF Foundation Registry were taking azithromycin.
1998 Kudoh S. Azuma A. Yamamoto M. Izumi T. Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998; 157:1829-32. [PubMed]
Diffuse panbronchiolitis (DPB) is a chronic inflammatory disease of the airways with a high mortality despite treatment with a combination of antibiotics and the use of supportive therapy. Low-dose erythromycin therapy (EM) (400 to 600 mg/d) improved the survival and most patients in Japan have been treated with this regimen since 1984. The authors compared the survival rates of 498 patients with DPB after dividing them into three groups (Group a: 1970-1979, Group b: 1980-1984, Group c: 1985-1990). The survival rate of Group c was significantly higher than that of Groups a (p < 0.0001) and b (p < 0. 0001). In Group c (1985-1990), eight of 87 patients died; five (21%) died in the EM non-treated subgroup (n = 24), and three (5%) died in the EM-treated subgroup (n = 63). So treatment with erythromycin was associated with a significant improvement in the survival of patients with DPB which was more significant in the older than in the younger patients.
– These findings were the basis for the gradual evaluation of macrolide therapy in people with cystic fibrosis. The first report of the favourable effect of erythromycin in DPD was Kudoh S, et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Jpn J Thorac Dis 1987; 25:632-642.
Mark Everard et al, (1997 above) was the first in the UK to report an effect on sputum inflammatory markers in cystic fibrosis.
[please see also separate TOPIC on MACROLIDES]
1999 Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL.. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999; 340:23-30. [PubMed]
One of the most important clinical trials of the decade showing a significant benefit of inhaled preservative free tobramycin (TOBI) given during alternate four week cycles for 24 weeks to patients chronically infected with Pseudomonas aeruginosa. Treated patients had an average increase of FEV1 of 10% predicted at 20 weeks where as those on placebo had a 2% decline; also the treated patients had 23% fewer hospital admissions.
– The introduction of TOBI, supported by this excellent clinical trial, was one of the major clinical advances of the decade and the culmination of work started in the late Eighties by Arnold Smith and others (Smith AL et al. 1989 above). By 2011 65.9% of eligible people with CF in the US CFF Registry were receiving nebulised TOBI.
Although the cost at the time (£10K per annum in the UK) has restricted the use of the TOBI preparation in the UK, inhaled anti-Pseudomonal antibiotics (colistin, tobramycin for injection and gentamicin) have been widely used in the UK for CF patients with chronic Pseudomonas infection since Margaret Hodson’s important 1981 paper (Hodson et al, 1981 above).
2000 Conway SP, Etherington C, Munday J, Goldman MH, Strong JJ, Wootton M. Safety and tolerability of bolus intravenous colistin in acute respiratory exacerbations in adults with cystic fibrosis. Ann Pharmacother 2000; 34:1238-1242. [PubMed]
This study confirmed that an intravenous bolus of 2 mega-units of colistin in 10 ml of normal saline was safe and tolerated by patients with indwelling venous access systems.
– An important practically useful paper as intravenous colistin was increasingly used as bacterial resistance to other antibiotics became more common; also previously IV colistin had been considered to be associated with unacceptable side effects. Previously it had been recommended that colistin should be given as a slow infusion when given through peripheral veins to avoid thrombophlebitis.
2000 Doring G, Conway SP, Heijerman HGH, Hodson ME, Hoiby N, Smyth A, Touw DJ, for the Consensus Committee. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European Consensus. Eur Respir J 2000; 16:749-767.[PubMed]
This document was the result of one of the valuable consensus meetings organised at Artimino in northern Italy by Prof. Gerd Döring and the European CF Society of which he was President. In 2006 Gerd Döring later became editor of the Journal of Cystic Fibrosis. In this publication there were consensus answers to 24 important questions based on current evidence by a panel of 34 European CF experts. Questions addressed and answered by the group were: The diagnosis of P. aeruginosa lung colonization in CF; the impact of P. aeruginosa on the clinical state of CF patients; the assessment of P. aeruginosa susceptibility against antibiotics and the importance of these results for the clinician; the use of monotherapy versus combination therapy; the development of microbial resistance; the achievement of optimal airway concentrations; the effects of subinhibitory concentrations of antibiotics on P. aeruginosa. Statements on the pharmacokinetics of antibiotics in CF patients; recommendations for doses and dosing intervals and length of treatment regimens and toxic side effects due to repeated antibiotic therapy was addressed. The expert panel answered further questions on the use of fluoroquinolones in children with CF, on the administration of nebulized antibiotics and whether prevention of P. aeruginosa lung colonization is possible in CF using antibiotic therapy. Problems of antibiotic therapy at home and in the hospital were addressed, a consensus statement on regular maintenance treatment, or treatment on demand, was given and different routes of administration of antibiotics were recommended for different clinical situations. Finally, the factors which determine the choice of the antibiotic, the dosage, and the duration of the treatment in cystic fibrosis patients were addressed and the design of future antibiotic studies in the context of Pseudomonas aeruginosa lung infection in cystic fibrosis patients was recommended.
– The document provides a valuable summary of current antibiotic treatment used for CF in Europe at the time and is recommended reading for all concerned with treating people with CF. Most of the important topical areas of interest are highlighted in the report. Consensus documents are particularly important in an area where so many aspects of treatment are not covered by acceptable randomised controlled trials. This has resulted in important therapeutic interventions being ignored by clinicians or even dismissed as lacking high quality evidence by the authors of Cochrane Reviews.
The UK CF Trust produced its first consensus document on antibiotics in 2002 which was fully revised in 2009 (Antibiotic Treatment for Cystic Fibrosis. 2009. Full text is available on the CF Trust website www.cysticfibrosis.org.uk).
2000 Kariyawasam HH, Pepper JR, Hodson ME, Geddes DM. Experience of totally implantable venous access devices (TIVADs) in adults with cystic fibrosis over a 13-year period. Respir Med 2000; 94:1161-1165.[PubMed]
A report of extensive experience of totally implantable venous access devices (TIVADs) in patients with CF over a 13-year period. The patients were divided into those who had the device inserted at the Royal Brompton Hospital (RBH), London and those who had the device inserted elsewhere; however all the devices were cared for at the RBH. A total of 115 devices in 74 patients were reviewed. The median duration of function of 109 devices was 1429 days (range 2-3989) or 3.9 years, with a total exposure of 91,188 days or 249.8 years. Forty patients had complications in 62 devices. The incidence of complications was 34.5% at the devices inserted at RBH and 73.7% for those inserted elsewhere (P<0.001). Of the 115 devices, mechanical complications occurred in 42 (36%), infectious complications occurred in 16 (14%) and symptomatic venous thrombosis occurred in four (3.5%).
One of the early reports on TIVADs in people with CF came from the adult unit at the Brompton Hospital in 1987 (Stead RJ et al. Thorax 1987; 42:149-150. 3433239.). The authors of the present paper conclude that TIVADs provide effective and long-term intravenous access and have fewer complications if they are inserted and cared for at a CF centre with special expertise in their insertion and management. This is general experience at other large centres (Aitken ML. Tonelli MR. Chest 2000; 118:1598-1602. [PubMed]).
Dr Kariyawasam is now the Clinical Lead for Adult Allergy and Medical Rhinology at the Royal National Throat Nose Ear Hospital, London. During the time this study was performed he worked for 7 years at the Royal Brompton Hospital in London. He has subsequently undertaken extensive research in respiratory allergy.
2000 Rappaz I, Decosterd LA, Bille J, Pilet M, Belaz N, Roulet M. Continuous infusion of ceftazidime with a portable pump is as effective as thrice-a-day bolus in cystic fibrosis children. Eur J Pediatr 2000; 159:919-925.[PubMed]
Continuous intravenous infusion of ceftazidime was just as effective as thrice daily IV administration and the method is preferred by the children.
– The method of constant infusion for beta lactam antibiotics had been suggested sporadically over the past 20 years by Prof. Tim David and others (Vinks AA et al. J Antimicrob Chemother 1997; 40:125-133. [PubMed]) but never seemed to become routine in CF centres. Probably this was, in part, related to the cost of the portable infusion pumps required and also initially their reliability was a problem, yet other authors found the method acceptable and as effective as intermittent dosing (Bosso JA, et al. Pharmacotherapy 1999; 19:620-626.). [PubMed]
However, it is the logical way to administer ceftazidime where steady blood levels should be maintained rather than trying to achieve peak serum levels as is ideal with aminoglycosides.
A review of experience with the method in severe pneumonia in non-CF patients concluded that in this small, selected population of adult patients with ventilator associated pneumonia caused by gram-negative bacteria who were treated in a non-randomized, open-label manner, ceftazidime administered by continuous infusion had greater clinical efficacy than ceftazidime administered by intermittent infusion” (Lorente L. Clin Ther 2007; 29:2433-2439. [PubMed]).
In 2008 an important short report using continuous IV ceftazidime and daily IV aminoglycoside eradicated Pseudomonas aeruginosa in a 3 month old CF infant when outpatient eradication treatment had failed (Hayes D Jr et al. Novel approach to the eradication of Pseudomonas aeruginosa in an infant with CF after outpatient treatment failure. Pediatr Pulmonol 2008; 43: 511-513. [PubMed]). This was a useful report as in most eradication schemes for Pseudomonas there were still 10-20% where initial eradication therapy failed. To use both these antibiotics in their optimal manner would possibly increase the chances of eradication which, if achieved, would be well worth all the considerable effort and inconvenience to the patient and family.
2000 Littlewood JM, Koch C, Lambert PA, Hoiby N, Elborn JS, Conway SP, Dinwiddie R, Duncan-Skingle F. A ten year review of colomycin. Respir Med 2000; 94:632-640.[PubMed]
A review of colomycin use in CF up to that time. In the concluding section it was noted that colomycin had re-emerged as the first choice antibiotic treatment for nebulised treatment of both early (Littlewood et al. 1985 above; Valerius et al. 1991 above) and chronic P. aeruginosa infection (Jensen et al, 1989 above) in people with CF – certainly in Europe if not N. America where tobramycin was preferred. Colomycin was also a valuable addition to the range of IV antibiotics used for P. aeruginosa when the organism becomes resistant to the more frequently use drugs tobramycin and ceftazidime. It seemed likely to the authors of this review that the antibiotic would continue to have an important role in the treatment of people with CF during the next decade – this proved to be the case.
Prof. Peter Lambert is Professor of Microbial Chemistry at Aston University Birmingham. He is a distinguished microbiologist and has published on a wide range of microbiological subjects including, in the Nineties, cystic fibrosis.
2000 Elborn JS, Prescott RJ, Stack BH, Goodchild MC, Bates J, Pantin C. Ali N, Shale DJ, Crane M. Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs. Thorax 2000; 55:355-358.[PubMed]
A clinical report from Copenhagen had suggested that regular 3-monthly courses of IV antibiotics increased survival of patients with CF who were chronically infected with Pseudomonas species (Szaff et al. 1983 above). In this present UK multicentre study 60 patients with CF, chronically infected with P. aeruginosa, were randomised to the two treatment arms (elective or symptomatic) and followed clinically at annual reviews. Unfortunately patients in the symptomatic group (IV only if required for clinical condition) received a mean of three antibiotic treatments each year – very similar to those in the elective group who received four antibiotic treatments during each year of the study. This study failed to demonstrate an advantage of a policy of elective 3-monthly antibiotic treatment over symptomatic treatment in patients with CF chronically infected with Pseudomonas species.
– Unfortunately not an entirely satisfactory study as B.cepacia deaths complicated the results; also the symptomatic” group received almost as many courses of IV antibiotics as the treatment group – no less than 3 courses of IV antibiotic in the year compared with 4 in the elective group. So the question is still not finally answered as to whether regular 3-monthly IV treatment, irrespective of clinical state, should be given to patients with chronic P. aeruginosa infection.
An important difference to note between the two studies is the patients were receiving regular nebulised antibiotics in this UK study but these were not used by chronically infected patients at the time of the original Danish report (Szaff et al. 1983 above).
Nowadays many UK CF centres have a very low threshold for treating with IV antibiotics and many patients with chronic P. aeruginosa infection are actually receiving almost 3-monthly courses of IV antibiotics, being treated if they show even minimal signs of deterioration.
It is now, and quite correctly, a matter of clinical judgement in most CF centres – if the chronically infected patient shows slow deterioration of respiratory function they receive 3 monthly IV antibiotics, if they are absolutely stable the intervals between the courses are increased. A few remain totally stable with inhaled antibiotics, which all chronically infected patients should be receiving, and may go for many years without IV antibiotics.
2001 Kanagasundaram SA, Lane LJ, Cavalletto BP, Keneally JP, Cooper MG. Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures. Arch Dis Child 2001; 84:492-495. [PubMed]
The repeated need for venous access is a major problem for a significant proportion of children with CF – in some amounting to severe needle phobia. Another simple method of improving their quality of life was to use inhaled nitrous oxide before venepuncture as described in this study from the Royal Alexandra Hospital for Chiildren, Westmead, New South Wales, Australia.. The technique was already used successfully in Belfast (Mills et al. 2001 below) and subsequently elsewhere for children with CF undergoing painful procedures (Williams V et al. Paediatr Nurse; 2006:18:31-33)).
– This seemed an excellent form of treatment for children having distressing procedures and is obviously used successfully in a number of CF centres by experienced clinicians (Mills & Redmond, 2001 below). The method is now used in many CF Centres in the UK.
2001 Mills HL, Redmond AOB. Cystic fibrosis patients’ view of self administered nitrous oxide (Entonox) during insertion of epicutaneo-cava catheters (long lines). 24th ECFS Conference Vienna 2001. Poster 291.
The distress of some children at even the thought of an intravenous injection or insertion of a venous catheter, when they have had many such insertions before, has to be seen to be believed. It is distressing not only for the unfortunate patient and the parents but also for the unfortunate doctor inserting the needle! The use of nitrous oxide is a great idea and appears very acceptable to most people. (The method was first published by Kanagasundaram et al, 2001 above).
2001 Mulheran M, Degg C, Burr S, Morgan DW, Stableforth DE. Occurrence and risk of cochleotoxicity in cystic fibrosis patients receiving repeated high-dose aminoglycoside therapy. Antimicrob Agents Chemother 2001; 45:2502-9. [PubMed]
The primary aim of this retrospective study was to establish the incidence and severity of auditory deficit in 70 people with CF. Twelve (17%) displayed hearing loss considered to be caused by repeated exposure to aminoglycosides. There was a nonlinear relationship between the courses of aminoglycoside therapy received and the incidence of hearing loss. The severity of the loss did not appear to be related to the number of courses received. Assuming the risk of loss to be independent for each course, preliminary estimates of per course risk of hearing loss were less than 2%.
– Upon comparison with previous clinical studies and experimental work, these findings suggest that the incidence of cochleotoxicity in CF patients is considerably lower than would be expected, even suggesting that the CF condition may confer some protection against aminoglycoside cochleotoxicity.
Subsequently increased susceptibility to aminoglycoside toxicity has been related to the possession of a particular gene the mitochondrial 12S rRNA A1555G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic hearing loss (Qian Y, Guan MX. Antimicrobial Agents & Chemotherapy 2009; 53:4612-4618. [PubMed]; Bitner-Glindzicz Met al. Prevalence of mitochondrial 1555A->G mutation in European children. N Engl J Med 2009; 360:640-642. [PubMed]
2001 Ratjen F, Doring G, Nikolaizik WH. Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Lancet 2001; 358:983-984. [PubMed]
One of the early studies (the first using tobramycin) confirming that early nebulised antibiotic treatment of airway colonisation with Pseudomonas aeruginosa could delay onset of chronic lung infection in patients with cystic fibrosis. There was successful eradication of the organism in 14 of 15 patients with cystic fibrosis who had been colonised by P. aeruginosa. Patients inhaled 80 mg tobramycin twice daily for 12 months. Eradication was confirmed by sequential respiratory cultures and serum antibody titres that were negative for P. aeruginosa. The antibiotic therapy regimen maintained pulmonary function at high levels (Further support for Littlewood et al, 1985 [PubMed] above and Valerius et al, 1991above)[PubMed].
– It is of interest that a subsequent trial showed that 80 mg of nebulised injectable tobramycin twice daily on a regular basis showed similar benefit to alternate monthly cycles of 300 mg twice daily of tobramycin for inhalation (Nikolaizik WH et al. Can Respir J 2008; 15:259-262. [PubMed]).
2001 Rosenfeld M, Gibson R, McNamara S, Emerson J, McCoyd KS, Shell R, Borowitz D, Konstan MW, Retsch-Bogart G, Wilmott RW, Burns JL, Vicini P, Montgomery AB, Ramsey B. Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis. J Pediatr 2001; 139:572-577. [PubMed]
First of two important papers from Rosenfield et al. to assess the serum and lower respiratory tract tobramycin concentrations produced by a single dose of tobramycin for inhalation (TOBI) in patients with CF aged 6 months to 6 years. A 180-mg dose of inhaled tobramycin produced a mean peak serum level of 0.5 microg/ml; a 300-mg dose produced a mean peak serum level of 0.6 microg/ml both well below the accepted maximum trough concentration with parenteral dosing (2 microg/ml). The target epithelial lining fluid level in the lung was 20 microg/ml – 10-fold greater than the minimal inhibitory concentration for most Pseudomonas isolates. The mean epithelial fluid level was 90 microg/ml.
– So in patients with CF, aged 6 months to 6 years, even a single 300-mg dose of inhaled tobramycin (TOBI) appeared to produce safe serum concentrations and high drug concentrations in the bactericidal range in the lower respiratory tract. Although it is not known if these serum levels, sustained over many years, are without side effects.
2001 Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, Grimwood K. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr 2001; 138:699-704.[PubMed]
A prospective, observational cohort study of 56 children from Melbourne. All were identified as having CF by newborn screening during 1990-92 and the study involved each child having an annual bronchial lavage during the first 2 to 3 years of life. Clinical outcome was determined at 7 years of age. P. aeruginosa infection was diagnosed in 24 (43%) children. Four children died before 7 years of age, all of whom had been infected with a multi-resistant, mucoid strain of P. aeruginosa (Armstrong et al, 2002 below). In the survivors, P. aeruginosa infection was associated with significantly increased morbidity as measured by lower National Institutes of Health scores, greater variability in lung function, increased time in the hospital, and higher rates of rhDNase (Pulmozyme) therapy (P <.01)
– Despite neonatal CF screening, the acquisition of P. aeruginosa was common by 7 years of age in this CF birth cohort and was associated with increased morbidity and mortality. The high incidence of P. aeruginosa infection here is presumably a reflection of the fact the children were born between 1990 and 1992 when early eradication therapy was not routine practice outside certain European CF centres. The high prevalence (43%) of chronic Pseudomonas infection at 7 years contrasts with the much lower prevalence (of around 4%) at centres where early eradication has been the policy for some years. This paper should be read in conjunction with the following paper (Armstrong et al, 2002 below) where the unusual situation at the time is described of a particularly virulent strain of Pseudomonas in the clinic that caused the deaths of 4 children.
2002 Stutman HR, Lieberman JM, Nussbaum E, Marks MI. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomised controlled trial. J Pediatr 2002; 140:299-305.[PubMed]
A 7-year, multicenter, double-blind, placebo-controlled study of continuous anti staphylococcal therapy. Otherwise healthy children <2 years of age with CF were randomly assigned to be treated with daily cephalexin (80-100 mg/kg/day) or placebo. 119 of 209 children enrolled and completed a 5- to 7-year course of therapy. Respiratory cultures from children treated with cephalexin were significantly less likely to be positive for S. aureus (6.0% vs. 30.4%) They were, however, more likely to be positive for Pseudomonas aeruginosa (25.6% vs. 13.5%). These differences became apparent in the first year after enrolment and persisted over the duration of the study. In contrast to these microbiologic differences, there were no differences in clinical outcome measures. The authors concluded that although long-term prophylaxis with cephalexin successfully delayed the acquisition of S. aureus, it enhanced colonization with P. aeruginosa and did not lead to clinically significant improvement in major health outcomes. Hence the findings did not support routine anti staphylococcal prophylaxis in otherwise healthy infants and young children with cystic fibrosis.
– The plan of this study was reported at the 1992 N American CF Conference by Dr Stutman but the results not published until 2002. This study with cephalexin,(a broader spectrum antibiotic than flucloxacillin) does not provide useful information about the use of long term flucloxacillin (currently recommended for the first 3 years for all CF infants by the UK CF Trust Antibiotic Working group 2009). Also during the study early eradication treatment of P. aeruginosa was not practiced in the USA. In UK centres where both long term flucloxacillin AND early P. aeruginosa eradication is routine the prevalence of both chronic S. aureus and P. aeruginosa is low (Lee et al, 2004).
It seems that if an organism is eradicated from the airways of a person with CF another potential pathogen from the environment colonizes and, if not treated, infects the airway. For example when S. aureus is treated, P aeruginosa appears (a fact noted since the early days of CF treatment); when P. aeruginosa is eradicated and prevented other environmental organisms appear particularly Aspergillus fumigatus and Stenotrophomonas maltophilia (noted both in the Copenhagen and Leeds CF centres). But this is not a good reason to fail to eradicate potential pathogens as they appear which is the policy in many European and N. American CF centres, evidenced by the high prevalence of chronic S. aureus infection.
Finally, it should be noted that it is not essential to give long term flucloxacillin to achieve a very low prevalence of S aureus infection, an alternative is to culture regularly (every clinic attendance and also when unwell) as is the policy in some European centres and treat vigorously whenever S. aureusappears (Szaff and Hoiby,1981 above – see discussion after this 1981 entry for more on anti-Staphylococcal prophylaxis).
Dr Harris Stutman is a specialist in Pediatric Infectious Disease at the Memorial Health Care System in California. His interests include Health Technology Informatics and Medical Informatics Clinical information systems. He has not published on CF since this present study.
2002 Heinzl B, Eber E, Oberwaldner B, Haas G, Zach MS. Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study. Pediatr Pulmonol 2002; 33:32-37. [PubMed]
Inhaled antibiotics are an established treatment for chronic Pseudomonas aeruginosa (PA) infection in patients with cystic fibrosis (CF). The authors suggest that inhaled antibiotics might also have prophylactic potential to delay acquisition of PA in early stages of the disease. From 1986-1999, all CF patients at this center who experienced defined risk situations for acquisition of PA (28 patients) received inhaled gentamicin (80 mg BID for those < 12 months; 120 mg BID for those > 12 months) for a minimum of 3 years. Twelve patients had repeated risk situations and continued this prophylaxis without interruption during the entire study period (group 1). In the remaining 16 patients, inhaled antibiotics were discontinued at various times for a variety of reasons (group 2). None of the patients in group 1, but 7 in group 2, became chronically infected with PA (P = 0.01). Lung function and chest X-ray scores were significantly worse in those 7 infected patients, when compared to the non infected ones in both groups. This suggests that long-term-prophylaxis with inhaled gentamicin can effectively delay acquisition of PA and decrease disease progression in children with CF.
– This study from Austria appeared to start the year after our first report of eradication of early P. aeruginosa in 1985 (Littlewood et al, 1985). The gentamicin treatment appeared to be very effective in avoiding chronic infection. However, a subsequent study of urinary NAG levels suggested some renal involvement so the gentamicin was stopped (Ring E et al. Arch Dis Child 1998; 78:540-543. [PubMed]).
2003 Gibson RL, Emerson J, McNamara S, Burns LL, Rosenfield M, Yunker A, Hamblett N., Accurso F, Dovey M, Hiatt P, Konstan MW, Moss R, Retsch-Bogart G, Wagener J Waltz D, Wilmott R, Zeitlin PL, Ramsey B. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Resp Crit Care Med 2003; 167:841-849.[PubMed]
This trial of 300 mg tobramycin for inhalation twice daily (which seems to be a huge dose for young children compared to the effective 80 mg doses of inhaled tobramycin in previous studies!) in 21 children less than 6 years for early Pseudomonas infection was stopped as there was a significant microbiological effect in all the treated patients. There was no P. aeruginosa present in the 8 tobramycin-treated children but only 1 of 13 in the placebo group had cleared. The authors concluded that “28 days of tobramycin solution for inhalation, 300 mg twice daily, is safe and effective for significant reduction of lower airway Pseudomonas density in young children with CF”.
This study seemed to eventually convince many clinicians that early treatment of PA was effective in eradicating the organism – first suggested in a letter from Leeds in 1985 nearly 20 years earlier (Littlewood et al, 1985) and later confirmed in Copenhagen in 1991 in a clinical trial (Valerius et al, 1991). The delay of over a decade in adopting early eradication treatment of PA by many N. American CF centres has been difficult to understand in view of the mass of evidence supporting the obvious deleterious effect of chronic PA infection on patients’ ultimate health and survival.
2004 Doring G, Hoiby N, Consensus Study Group. Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J Cystic Fibrosis 2004; 3:67-91. [PubMed]
One of a number of valuable Artimino conference consensus reports organised by Gerd Doring, the then President of the ECFS. Delegates representing most countries in Europe were invited to a meeting in Artimino to consider a particular area of interest and produce a consensus report. This one, on early intervention, was particularly relevant in view of the increasing introduction of neonatal CF screening. The full text is available on the European CF Society website (www.ecfsoc.org).
2004 Munck A, Malbezin S, Bloch J, Gerardin M, Lebourgeois M, Derelle J, Bremont F, Sermet I, Munck MR, Navarro J. Follow-up of 452 totally implantable vascular devices in cystic fibrosis patients. Eur Respir J 2004; 23:430-434. [PubMed]
This retrospective study involved 36 CF centres. TIVADs (n = 452) were implanted in 315 patients. The mean functional time per device was 32 +/- 25 months. Long-term complications occurred with 188 devices (42%); they consisted mainly of occlusion (21%, requiring removal in 77%), infection (9.3%, requiring removal in 851%; septicaemia in 7.3%; rate 0.3 per 1,000 days, Candida in 66%), and vascular thrombosis (4.7%, removal in 58%). Multivariate survival analysis showed that removal, whatever the reason, was associated with polyurethane (versus silicone) and routine use of the device for blood sampling (versus never). No risk factors, including heparin lock, were identified for septicaemia or for removal for obstruction.
Totally implantable venous access devices appear to be safe and reliable for long-term intermittent venous access. Although retrospective, this study suggests that the characteristics of the material and blood sampling are risk factors for removal.
2004 Thornton J. Elliott R. Tully MP. Dodd M. Webb AK. Long term clinical outcome of home and hospital intravenous antibiotic treatment in adults with cystic fibrosis. Thorax 2004; 59:242-246. [PubMed]
A total of 116 patients received 454 courses of intravenous antibiotics. At the end of 1 year there had been a mean percentage decline in FEV(1) compared with the baseline “average” for patients treated mostly at home but an improvement in patients treated mostly in hospital. For all patients there was a mean percentage decline in FEV(1) from the baseline “best” value. For each course of treatment the mean percentage improvements in FEV(1) at the end of the course from the start of the course were significantly higher for patients treated in hospital than for those treated at home. Clinical outcome, as defined by spirometric parameters and body weight, was better after a course of treatment in hospital than after home treatment, and this benefit was maintained over 1 year of treatment. The results suggest that patients treated at home need closer supervision.
– This study from a large UK adult CF centre addresses the home or hospital problem. It is likely that clinicians will consider each patient’s individual case and capabilities in making these decisions. However the authors do correctly stress the importance of adequate supervision at home.
2005 Aaron SD, Vandemheen KL, Ferris W, Fergusson D, Tullis E, Haase D, Berthiaume Y, Brown N, Wilcox P, Yozghatlian V, Bye P, Bell S, Chan F, Rose B, Jeanneret A, Stephenson A, Noseworthy M, Freitag A, Paterson N, Doucette S, Harbour C, Ruel M, MacDonald N.Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double blind, controlled clinical trial. Lancet 2005; 366:463-471.[PubMed]
Antibiotic therapy directed by combination antibiotic susceptibility testing did not result in better clinical and bacteriological outcomes compared with therapy directed by standard culture and sensitivity techniques.
2005 Thornton J, Elliott RA, Tully MP, Dodd M, Webb AK. Clinical and economic choices in the treatment of respiratory infections in cystic fibrosis: comparing hospital and home care. J Cyst Fibros 2005; 4:239-247. [PubMed]
A cost-effectiveness evaluation comparing home-based and hospital-based treatment with intravenous antibiotics for respiratory exacerbations in adults with cystic fibrosis (CF) has not been previously undertaken. METHODS: The study was conducted in a UK adult CF centre from a health service perspective. Clinical outcome and resource use data were obtained from a retrospective one-year study and combined with unit cost data in an incremental economic analysis. The primary outcome measure was percentage change in FEV(1); “effectiveness” was defined as maintenance of baseline average FEV(1) over the one-year study period. RESULTS: 116 patients received 454 courses of intravenous antibiotics. At the end of 1 year, there had been a mean percentage decline in FEV(1) compared with baseline average for home-treated patients but an improvement for hospital-treated patients (Tukey’s HSD mean difference 10.1%, 95% CI 2.9 to 17.2, p = 0.003). Treatment was deemed “effective” in more hospital (58.8%) than home (42.6%) patients. The cost of hospital treatment was higher than home treatment (mean difference £9,005, 95% CI £3,507 to £14,700, p<0.001). The mean ICER was £46,098 pounds (2.5th and 97.5th percentiles -374,044 and 362,472).
The authors concluded that hospital treatment was more effective but more expensive than home treatment. Potential methods to improve outcome at home should be considered but these may have resource implications. Also same data report [PubMed]
2005 Smyth A, Tan K H-V, Hyman-Taylor P, Mulhearn M, Lewis S, Stableforth D, Knox A, for the TOPIC study group. Once versus three-time daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis – the TOPIC study: a randomised controlled trial. Lancet2005; 365:573-578.[PubMed]
An important trial the results of which had a definite influence on patient management. The trial was coordinated by Professor Alan Smyth of Nottingham. 219 patients (107 had once and 112 thrice daily tobramycin) and both regimens were of equal efficiency for treating pulmonary exacerbations. There was a suggestion that the once daily regimen might be less nephrotoxic in children.
The results of this trial allowed the once daily treatment to be confidently recommended by the CF Trust’s Antibiotic Group (2009) for both adults and children with CF and also resulted in a number of other publications on pharmacokinetics and lack of ototoxicity in the trial (Mulhearn M et al, Antimicrob Agents Chemother 2006; 50:2293-2299. [PubMed]) and nephrotoxicity (Smyth et al. Thorax 2008; 63:532-535.[PubMed]).
2005 Ahya VN, Doyle AM, Mendez JD, Lipson DA, Christie JD, Blumberg EA, Pochettino A, Nelson L, Bloom RD, Kotloff RM. Renal and vestibular toxicity due to inhaled tobramycin in a lung transplant recipient. J Heart Lung Transplant 2005; 24:932-935.[PubMed]
The safety of inhaled tobramycin in transplant recipients, however, has not been established. The authors describe the first report of a lung transplant recipient who developed renal failure and vestibular injury after receiving inhaled tobramycin. They review the literature regarding the safety of inhaled tobramycin and discuss potential mechanisms that may promote systemic toxicity in transplant recipients.
2005 Al-Aloul M, Miller H, Stockton P, Ledson MJ, Walshaw MJ. Acute renal failure in CF patients chronically infected by the Liverpool epidemic Pseudomonas aeruginosa strain (LES). J Cyst Fibros 2005; 4:197-201.[PubMed].Eight cases of acute renal failure in adult CF patients, all occurring during the use of intravenous aminoglycosides for the treatment of pulmonary exacerbations with an epidemic multi-resistant Pseudomonas aeruginosa strain. Potential contributory factors are discussed. These cases demonstrate another complication of infection by epidemic Pseudomonas strains in CF, and confirm the need for effective segregation policies to prevent this.
Dr Mohamed Al-Aloul is a consultant in Respiratory and Transplant Medicine in Manchester. On this occaision working with the Adult CF team at Liverpool.
2005 Taccetti G, Campana S, Festini F, Mascherini M, Doring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J 2005; 26:458-461.[PubMed]
Early antibiotic treatment of lung infection in people with CF has been shown to lead to eradication of Pseudomonas aeruginosa (PA). Early antibiotic therapy leads to a PA free-period of a median (range) of 18 (4-80) months. New acquisition with different PA genotypes occurs in 73% of episodes. It also delays the decline of lung function compared with chronically infected patients. The treatment substantially lowers chronic PA prevalence in CF.
– Yet more evidence that early antibiotic therapy of P. aeruginosa infection exerts beneficial effects on the patient’s clinical status and is cost-effective compared with conventional antibiotic therapy for chronically infected cystic fibrosis patients.
2005 Saiman L, Mayer-Hamblett N, Campbell P, Marshall BC. Macrolide Study Group. Heterogeneity of treatment response to azithromycin in patients with cystic fibrosis. Am J Resp Crit Care 2005; 172:1008-1012. [PubMed]
Azithromycin participants in the previous CFF azithromycin trial experienced benefits in exacerbation parameters, hospitalisations and use of additional oral antibiotics regardless of whether their FEV1 improved or not during the trial. The authors suggest that these data have implications for clinical practice and the design of clinical trials.
2005 O’Mahony M. Skehan S. Gallagher C. Percutaneous stenting of the superior vena cava syndrome in a patient with cystic fibrosis. Irish Med J 2005; 98:85-86. [PubMed]
Superior vena cava (SVC) obstruction commonly occurs in the setting of malignancy. Cases of benign SVC obstruction are being seen more frequently with the use of long-term central venous lines. This is the case particularly in Cystic Fibrosis (CF). This report concerns the successful use of intravascular stenting to treat this distressing condition in the setting of thrombotic occlusion of the SVC in a patient with CF.
– This report from MIke Mahony’s unit in Limerick is one of an increasing number of reports of complications associated with the use of totally implantable venous access devices.
2006 Mulheran M, Hyman-Taylor P, Tan KH, Lewis S, Stableforth D, Knox A, Smyth A. Absence of cochleotoxicity measured by standard and high-frequency pure tone audiometry in a trial of once- versus three-times-daily tobramycin in cystic fibrosis patients. Antimicrob Agents Ch 2006; 50:2293-9. [PubMed]
An assessment of hearing in patients with cystic fibrosis who were taking part in a large randomized controlled trial of once- versus three-times-daily tobramycin for pulmonary exacerbations of cystic fibrosis (the TOPIC study). Complete pre- and post treatment standard audiological data were obtained for 168/219 patients. We found no significant differences in hearing thresholds when they were assessed at the baseline, at the end of treatment, and at follow-up 6 to 8 weeks later were compared. In addition, no significant differences in hearing thresholds were detected between treatment regimens. Similar results were obtained for the subset of 63/168 patients who underwent high-frequency audiometry.
– The authors conclude that for a single 14-day course of tobramycin treatment in patients with cystic fibrosis with no preexisting auditory deficit, no measurable effect on hearing was apparent with either once- or three-times-daily treatment. Estimation of the cumulative cochleotoxic risk in cystic fibrosis patients due to repeated aminoglycoside therapy, as evidenced by the patients excluded from this study due to hearing loss, also requires further characterization.
2006 Garwood S, Flume PA, Ravenel J. Superior vena cava syndrome related to indwelling intravenous catheters in patients with cystic fibrosis. Pediatr Pulmonol 2006; 41:683-687.[PubMed]
Three patients with CF had superior vena cava syndrome (thrombosis in the large vein entering the heart) due to the presence in the vessel of a foreign body i.e. the implantable venous access device.
Although these devices proved to be a major overall advance since their introduction in the mid-Eighties, a variety of complications have been reported particularly if the devices are not cared for by experts – these include infection and various vascular clotting problems even paradoxical embolisation (Espiritu JD, Kleinhenz ME. Mayo Clin Proc 2000; 75:1100-1102. [PubMed]). Experience at CF centres shows that this particular complication is not rare and most have experienced one or two cases.
2006 Williams V, Riley A, Rayner R, Richardson K. Inhaled nitrous oxide during painful procedures: a satisfaction survey. Paediatric Nursing 2006; 18:31-33. [PubMed]
Inhaled nitrous oxide was safe and effective in reducing trauma and the effects of needle phobia and being offered to children with CF for procedural pain in the district general hospital at Wolverhampton.
Dr Rosie Rayner is the consultant paediatrician in Wolverhampton who developed the CF service in that city. Previously she was the CF Research Fellow in Nottingham with Dr Joan Hiller.
2006 Gibson RL, Retsch-Bogart GZ, Oermann C, Milla C, Pilewski J, Daines C, Ahrens R, Leon K, Cohen M, McNamara S, Callahan TL, Markus R, Burns JL. Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis. Pediatr Pulmonol 2006; 41:656-665. [PubMed]
Aztreonam lysinate for inhalation (AI) is a novel monobactam formulation for chronic pulmonary Pseudomonas aeruginosa infections in CF. The activity of Al was retained against multiple CF isolates after nebulisation via eFlow nebuliser, and the activity was not inhibited by CF sputum. All 12 adult subjects and 11 of 12 adolescents tolerated the inhaled antibiotic. These data were supportive of the continued development of aztreonam lysinate for treatment of patients with CF.
Original aztreonam was not tolerated as an inhalation but the lysinate is suitable for nebulisation.
– This study also confirms that nebulisation does not denature the product. Phase III trials were completed by 2008 (Retsch-Bogart et al, 2008 [PubMed] [PubMed] below) and by 2009 the product licensed in Europe and Canada; and anticipated in the USA by 2010. By 2011 35.8% of eligible people with CF in the USA were receiving inhaled aztreonam (Cayston) (CF Foundation 2011 Patient Registry)
2006 Wood DM, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database of Systematic Reviews. (1):CD004197, 2006.[PubMed]
This search identified 15 trials on the subject but the reviewers considered only 3 trials, involving 69 participants, were eligible for inclusion. The reviewers considered that there was evidence from two randomised controlled trials, of “questionable methodological quality”, that treatment of early P. aeruginosa infection with inhaled tobramycin resulted in microbiological eradication of the organism from respiratory secretions more often than placebo and that this effect may persist for up to 12 months, however incomplete data from one of the trials precluded an accurate analysis.
One randomised controlled trial of oral ciprofloxacin and nebulised colistin versus usual treatment was identified (Valerius et al, 1991 above) but the reviewers considered this trial was of “poor methodological quality”. The results suggested treatment of early infection results in microbiological eradication of P. aeruginosa more often than “usual” treatment, after two years. The reviewers considered that there was insufficient evidence to determine whether antibiotic strategies for the eradication of early P. aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. From the three trials included in this review, there was some evidence that antibiotic treatment of early P. aeruginosa results in short-term eradication but it remains uncertain whether there is clinical benefit to people with cystic fibrosis.
– The conclusions of this Cochrane review were quite out of keeping with the clinical experience of most CF clinicians and the study was soundly criticised by Prof. Neils Hoiby who regarded further trials as unwarranted. The opinion of an experienced and respected clinician such as the late Christian Koch was representative of current opinion (quoted in entry on Valerius et al, 1991 above). There was by this time of this review (2006) a wealth of evidence that avoidance of chronic P. aeruginosa infection improved clinical condition and increased survival – evidence that the reviewers did not consider (Kerem et al, 1990; Henry et al, 1992; Hudson et al, 1993; Pamucku et al, 1995 above; Frederiksen et al, 1996; CF Foundation Patient Registry 1996; Frederiksen et al, 1997 above; Kosorok et al, 2001). Presumably this evidence was ignored as it did not directly concern eradication of P. aeruginosa.
A further Cochrane review assessed as up to date in August 2009 identified 25 trials but only considered 4 eligible for inclusion. The authors concluded that “treatment with nebulised antibiotics alone or in combination with oral antibiotics was better than no treatment for early infection with P. aeruginosa. Eradication may be sustained in the short term. Overall there is insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early P. aeruginosa infection in CF”. The 2009 Review is an extensive review of the subject (SC Langton-Hewer, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD004197. DOI: 10.1002/14651858.CD004197.pub3).
It is important to stress that eradication of early P. aeruginosa infection, to prevent or delay chronic infection, is one of the most important aspects of therapy and acquisition of chronic infection should now be regarded as avoidable and represent a failure of therapy (Drittanti et al, 1996 above).
2006 Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, van Koningsbruggen S, Grasemann H. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemo2006; 57:306-311. [PubMed]
Inhaled colistin is commonly used in patients with cystic fibrosis (CF), but only limited data are available to define its pharmacokinetic profile. We performed a multicentre study in 30 CF patients to assess sputum, serum and urine concentrations after a single dose of 2 million units of colistin administered by inhalation. In a subgroup of patients we also compared the efficacy of two different nebulizers for administration of inhaled colistin. Serum concentrations of colistin reached their maximum 1.5 h after inhalation and decreased thereafter. Serum concentrations were well below those previously reported for systemic application in all patients. A mean 4.3+/-1.3% of the inhaled dose was detected in urine. Elimination characteristics did not differ significantly from those previously reported for systemic application. A positive correlation was found between forced expiratory volume in 1 s (FEV1) in per cent predicted and both AUC and maximal colistin concentrations in serum (Cmax). Maximum sputum concentrations were at least 10 times higher than the MIC breakpoint for Pseudomonas aeruginosa proposed by the British Society for Antimicrobial Chemotherapy. Although sputum drug concentrations decreased after a peak at 1 h, the mean colistin concentrations were still above 4 mg/L after 12 h. No differences were seen in polymyxin E sputum concentrations, for CF patients between the two nebulizer systems.
– The authors concluded the low systemic and high local concentrations of colistin supported the use of inhaled colistin in CF patients infected with P. aeruginosa. This was reassuring as inhaled colistin had been increasingly used since the first report of its use in eradicating early Pseudomonas infection in CF (Littlewood et al, Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis. Lancet 1985; I: 865.[PubMed]). No pharmacokinetic studies were done before we gave inhaled colomycin in the early Eighties to see if it would clear early Pseudomonas infection! However, I did write to the firm and asked if they thought it would be a reasonable treatment to try.
2007 Veenstra DL, Harris J, Gibson RL, Rosenfeld M, Burke W, Watts C. Pharmacogenomic testing to prevent aminoglycoside-induced hearing loss in cystic fibrosis patients: potential impact on clinical, patient, and economic outcomes. Genetics in Medicine 2007; 9:695-704. [PubMed]
Recently, a genetic test to identify patients with a mitochondrial mutation (A1555G) that may predispose patients aminoglycoside induced deafness has become available. Although the A1555G variant is very rare, it seems to confer a high risk of severe hearing loss in patients exposed to aminoglycosides. The authors calculated that A1555G testing decreased the risk of severe aminoglycoside-induced hearing loss by 0.12% in the cystic fibrosis population. The results of their analysis suggest that there are significant data gaps and uncertainty in the outcomes with A1555G testing, but it is not likely cost-effective, and could lead to worse patient outcomes due to avoidance of first-line therapy in the >95% of patients who are false-positives. Additional research is needed before pharmacogenetic testing for the A1555G mitochondrial mutation can be recommended, even in a population with a high likelihood of exposure to aminoglycosides.
The full methodology is described in this paper using already published data and the conclusion was that the denial of aminoglycoside therapy would overall worsen the prognosis. However, it is important to stress that inhaled and repeated course of gentamicin should be avoided in people with CF.
2007 Brochet MS, McDuff AC, Bussières JF, Caron E, Fortin G, Lebel D, Marcotte JE. Comparative efficacy of two doses of nebulized colistimethate in the eradication of Pseudomonas aeruginosa in children with cystic fibrosis. Canad Resp J 2007; 14:473-479. [PubMed]
A study to compare the efficacy of two doses of nebulized colistimethate (30 mg versus 75 mg twice daily) for the eradication of P. aeruginosa in children with CF and intermittent colonization. There was no statistically significant difference in the rate of eradication of P. aeruginosa at days 28 and 90, neither when comparing the doses of colistimethate nor duration of treatment.
– Most antibiotic regimens for eradicating early P. aeruginosa infection seem to achieve about an 80% success. The time to re-infection varies and will depend on the environmental exposure of the individual to P. aeruginosa as it has been shown that “recurrences” are usually new infections with a different strain of the organism
2007 Gibson RL, Emerson J, Mayer-Hamblett N, Burns JL, McNamara S, Accurso FJ, Konstan MW, Chatfield BA, Retsch-Bogart G, Waltz DA, Acton J, Zeitlin P, Hiatt P, Moss R, Williams J, Ramsey BW. Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis. Pediatr Pulmonol 2007; 42:610-623. [PubMed]
An open label, sequential cohort study of tobramycin for inhalation (TSI) in young children with CF to investigate duration of antimicrobial treatment effect. Culture based, lower airway Pseudomonas eradication was observed in the majority of subjects for up to 1-3 months following TSI treatment. The authors concluded that tobramycin solution for inhalation monotherapy was safe and could eradicate lower airway P. aeruginosa for up to 3 months after treatment in young children with CF.
These results are not surprising and could have been predicted, as a number of European studies studies had already shown that inhaled tobramycin, even in a more modest dose of 80 mg twice daily, was effective in eradicating P. aeruginosa (Weismann HG, et al. Pediatr Pulmonol 1998; 25:88-92.[PubMed]; Ratjen F, et al. Lancet 2001; 358:983-984. [PubMed]). The dose of inhaled tobramycin of 300mg twice daily seems formidable and perhaps unnecessarily large as judged by previous experience – particularly in view of the great cost (£10,000 per year in the UK if given on alternate months as recommended). Nevertheless this was a good study from a major CF centre in N. America which accelerated the progress to early treatment of Pseudomonas there.
2007 Chuchalin A, Csiszer E, Gyurkovics K, Bartnicka MT, Sands D, Kapranov N, Varoli G, Monici Preti PA, Mazurek H. A formulation of aerosolized tobramycin (Bramitob) in the treatment of patients with cystic fibrosis and Pseudomonas aeruginosa infection: a double-blind, placebo-controlled, multicenter study. Paediatr Drugs. 2007; 9 Suppl 1:21-31.[PubMed]
The purpose of this European trial was to assess the efficacy and tolerability of a relatively recently introduced preparation of tobramycin highly concentrated solution for inhalation (TSI) [300mg/4mL; Bramitob] when added to other anti-Pseudomonal therapies in CF patients with chronic P. aeruginosainfection. A total of 247 patients were randomized in the study. No significant changes in serum creatinine and auditory function were detected. Long-term, intermittent administration of this aerosolized tobramycin formulation (300mg/4mL) in CF patients with chronic P. aeruginosa infection significantly improved pulmonary function and microbiologic outcome, decreased hospitalizations, increased nutritional status, and was well tolerated.
– This preparation appears to be the same or similar to TOBI and therefore it is not surprising that the results are similar (Poli G, et al, 2007. [PubMed]; Lenoir G et al. 2007. [PubMed)) – hopefully the cost will be less.
2007 Bruzzese E, Raia V, Spagnuolo MI, Volpicelli M, De Marco G. Maiuri L, Guarino A. Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis. Clinical Nutrition 2007; 26:322-328.[PubMed]
Nineteen children with CF received a probiotic Lactobacillus GG (LGG) for 6 months and then changed to a placebo of oral rehydration solution (ORS) for 6 months; in parallel nineteen received ORS and then changed to LGG. Patients treated with LGG showed a reduction of pulmonary exacerbations (Median 1 vs. 2) and of hospital admissions (Median 0 vs. 1, range 3 vs. 2,). LGG resulted in a greater increase in FEV1 (3.6% +/- 5.2 vs. 0.9% +/- 5; p=0.02) and body weight (1.5 kg +/- 1.8 vs. 0.7 kg +/- 1.8; p=0.02). The authors concluded that Lactobacillus GG reduces pulmonary exacerbations and hospital admissions in patients with CF, that probiotics may delay respiratory impairment and that a relationship exists between intestinal and pulmonary inflammation.
– There is an increasing interest on the part of patients, parents and doctors in the role probiotics in treating people with CF (Borowitz D et al, J Pediatr Gastroenterol Nutr 2005; 41:273-285. [PubMed]); however, as yet, few CF clinics advise their routine use, perhaps because the evidence of their value is still sparse but also there are so many other components to treatment that there is reluctance to add yet another medicine to gain a marginal benefit.
2007 Geller DE, Konstan MW, Smith J, Noonberg SB, Conrad C. Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety. Pediatr Pulmonol 2007; 42:307-313. [PubMed]
An evaluation of the pharmacokinetics and safety of tobramycin inhalation powder (TIP), a novel dry-powder formulation designed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections.
Dr David Geller is a physician, researcher, and medical consultant, dedicated to making a significant positive impact on the health of children and adults with cystic fibrosis and chronic respiratory disease. A Pediatric Pulmonologist for over 25 years has treated CF, asthma, prematurity, ventilator-dependence, apnea, and rare disorders. He has a long-standing interest in aerosol science led to investigationin of more efficient methods of delivering inhaled drugs to the lungs, particularly small children. They have collaborated with pharmaceutical and biotech companies to improve delivery efficiency of their drugs to the lungs and reduce the time burden for the patients.
– The development of dry powder inhaled antibiotics represents an important advance in the treatment of chronic lung infections but is by no means a new idea (Krasno L et al. Inhalation of penicillin dust. Science 1947; 106:249-250. [PubMed] ;Goldman JM et al. Inhaled micronised gentamicin powder: a new delivery system. Thorax 1990; 45:939-940.[PubMed]; Watson A et al. Sputum gentamicin levels after delivery by Rotahaler and nebuliser in Escobar H et al.(eds.) Elsevier Science Publishers. 1993; 115-117).
Tobramycin inhaltion powder was approved by the UK NICE committee in 2012/13.
2007 Etherington C, Bosomworth M, Clifton I, Peckham DG, Conway SP. Measurement of urinary N-acetyl-b-D-glucosaminidase in adult patients with cystic fibrosis: before, during and after treatment with intravenous antibiotics. J Cyst Fibros 2007; 6:67-73.[PubMed]
Patients with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous antibiotics due to repeated and prolonged courses of therapy. Routine methods of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme present in the renal proximal tubular cells, with increased excretion an indicator of renal tubular dysfunction. Urinary NAG, creatinine, serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the first out-patient visit following treatment with tobramycin or colistin. Urinary NAG levels were corrected for urinary creatinine and expressed as a NAG ratio. Patients who received>1 course of intravenous antibiotics during the study period were included in a separate analysis of the cumulative effect of treatment. 88 patients (44 female, 31 with CFRD) completed a single course of intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up. A highly significant difference in NAG excretion was observed on day 14 for tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A significant difference in NAG excretion was seen in patients with CFRD at all measured time points. Patients with CFRD had a significantly worse clinical status and had received more days of intravenous antibiotics over the previous 6 years. In 20 (80%) of 25 patients who received>1 course of treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p<0.001). There was a significant correlation between previous exposure to colistin and baseline NAG levels (r=0.389, p<0.001).
Both tobramycin and colistin cause acute renal tubular injury with a significant rise in urinary NAG excretion. Patients with CFRD seem to be at greatest risk of renal tubular damage. Cumulative damage is evident with repeated dosing. Previous exposure to nephrotoxic antibiotics, especially colistin, is associated with elevated baseline NAG levels.
– The authors recommend that colistin is reserved for patients with resistant Pseudomonas aeruginosa or those who are intolerant to tobramycin. Serial longitudinal NAG measurements may be useful in patients with CF, especially those with CFRD, to identify patients at risk of developing renal disease.
Measurement of urinary NAG in relation to aminoglycoside treatment has been periodically studied since our first European conference report in 1984 (Miller MG et al. Nephrotoxicity of aminoglycosides. In: Lawson D ed. Cystic fibrosis: horizons. John Wiley & Sons Chichester 1984; 271; also Glass S et al. J Cyst Fibros 2005; 4:221-225. [PubMed]; Ring E et al. Arch Dis Child 1998; 78:540-543. [PubMed]). All previous studies have shown transient rises of urinary NAG during aminoglycoside treatment indicating some tubular injury which recovers after the treatment; although in the Miller et al study the rise in NAG was increasingly greater with each additional course of aminoglycosides.
With increasing longevity of people with CF the cumulative effect of these repeated minor renal injuries are likely to become more relevant as evidenced by the increasing problem of renal failure in people with CF (Smyth A et al. Case-control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2008; 63:532-535.). In some, the effect of repeated courses of intravenous aminoglycosides is worsened by the immunosuppressive drugs required after lung transplantation
Interestingly, urinary NAG levels were observed to rise after prolonged nebulised gentamicin used (successfully it must be added) to prevent Pseudomonas infection in children with CF and considered to present a risk of renal toxicity (Ring E et al. Arch Dis Child 1998; 78:540-543. [PubMed]). However, subsequent publications on the long term use of nebulised gentamicin in non-CF bronchiectasis consider there to be negligible absorption and the treatment suitable for children ( Twiss TJ et al, 2005 [PubMed]and adults (Murray M P, et al, 2010). [PubMed]
In the UK it is advised that both nebulised and intravenous gentamicin are avoided in people with CF (Antibiotic Treatment for Cystic Fibrosis. CF Trust 3rd edition 2009).
Dr. Christine Etherington is Associate Specialist in the Regional Adult CF Unit at St James University Hospital Leeds and a key individual both in clinical care and research.
2007 Coulthard KP, Peckham DG, Conway SP, Smith CA, Bell J, Turnidge J. Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis – caution with trough concentrations. J Cyst Fibros 2007; 6:125-130.[PubMed]
Once daily intravenous aminoglycoside dosing (ODD) is widely used to treat acute Pseudomonas aeruginosa exacerbations in patients with cystic fibrosis. Controversy exists as to what is the most appropriate method of therapeutic drug monitoring (TDM) of such therapy with recommendations including trough plasma concentrations of <1 mg/L or <2 mg/L, area under curve (AUC) and various nomograms. After the study the authors concluded that “Area under the curve (AUC) as the method of therapeutic drug monitoring may not only reduce toxicity but also optimise efficiency”.
– Professor Kingsley Coulthard was Director of Pharmacy at Adelaide Women’s and Children’s Hospital In South Australia. Kingsley has been a leader of public pharmacy, and demonstrated this commitment by his participation in State professional committees, SA Health led initiatives and ongoing leadership of pharmaceutical reform within public hospitals. He visited Leeds on number of occaisions and combined with colleagues overseas in a number of projects.
2008 Hansen CR, Pressler T, Høiby N. Early aggressive eradication therapy for intermittent Pseudomonas aeruginosa airway colonization in cystic fibrosis patients: 15 years experience. J Cyst Fibros 2008; 7:523-530.[PubMed]
Since 1989, CF-patients intermittently colonized with Pseudomonas aeruginosa have been treated with inhaled colistin and oral ciprofloxacin in the Copenhagen CF-centre. The study evaluates 15 years results of this treatment. 146 CF-patients were included in the study (1106 patient-years). 99 patients had first ever isolate during the study period. Median observation time 7 years (0.1-14.9). 12 patients developed chronic infection. A Kaplan Meyer plot showed protection from chronic infection in up to 80% of patients for up to 15 years. 613 colistin/ciprofloxacin treatments were given. There was no difference in pseudomonas-free interval comparing 3 weeks (5 months) and 3 months (10.4 months) of colistin and ciprofloxacin, but a significant difference compared to no treatment (1.9 months). Patients developing chronic infection had significantly shorter pseudomonas-free interval after treatment of first ever isolate compared to patients remaining intermittently colonized (p<0.003). Treatment failure (P. aeruginosa-positive culture immediately after ended treatment of first ever isolate) was a strong risk factor for development of chronic infection after 3-4 years, OR 5.8. 1093 pseudomonas-isolates were evaluated (86.6% non-mucoid). No colistin-resistance was found. Ciprofloxacin-resistance was found in 4% of isolates.
The authors concluded treatment of intermittent P. aeruginosa colonization in CF-patients using colistin and ciprofloxacin can protect up to 80% of patients from development of chronic infection for up to 15 years. A positive culture immediately after treatment of first ever isolate is a strong risk factor for development of chronic infection. They found no colistin-resistance and minimal ciprofloxacin-resistance.
– This valuable paper describes experience from the team in Copenhagen and is reported in full as it represents experience from one of the first European CF centres to introduce early eradication therapy for P. aeruginosa. This treatment has protected many patients from chronic P. aeruginosa infection for many years.
2008 Johansen HK, Moskowitz SM, Ciofu O, Pressler T, Høiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. J Cyst Fibros 2008; 7:391-397. [PubMed]
Colistin resistant Pseudomonas aeruginosa have rarely been reported in cystic fibrosis (CF) patients. We performed a 17-year prospective study on colistin susceptibility and compared our findings with clinical variables. The first outbreak started in 1995 and lasted 5 years. It involved 27 CF patients who had inhaled colistin twice daily for a median of 10 years. Colistin resistant isolates persisted in individual patients for a median of 75 days after colistin was withdrawn. A second outbreak started in 2004. It involved 40 patients, 17 of whom were the same as in the first outbreak. Most resistant isolates belonged to two major clones that had similar genotypes in the two outbreaks. The P. aeruginosa isolates were all non-mucoid and they appeared in a group of chronically infected patients that had been admitted to the same ward for antibiotic treatment and had been followed at the same week-days in the outpatient clinic. Patients were individually isolated to avoid cross-infection and colistin inhalation was avoided in the CF outpatient clinic and in the ward after both outbreaks.
Since 2004, no further spread has been observed. it is important that the colistin resistant clones do not spread to non-infected patients since colistin is an important antibiotic for eradication of initial and intermittent P. aeruginosa colonisation. Infrequent resistance even with widespread use of colistin in the Danish CF centre
2008 Nikolaizik WH, Vietzke D, Ratjen F. A pilot study to compare tobramycin 80 mg injectable preparation with 300mg solution for inhalation in cystic fibrosis patients. Can Respir J 2008; 15:259-262. [PubMed]
In an open crossover study of CF patients, subjects were randomly allocated to receive either 80 mg tobramycin twice-daily continuous treatment or 300 mg tobramycin twice daily in cycles of 28 days on and 28 days off treatment. After three months, patients were switched to the alternative treatment regimen. A total of 32 patients with a mean (+/- SD) age of 18.5+/-8.6 years were included in the study. Compared with the treatment period using colistin, forced expiratory volume in 1 s decreased by -2.1+/-13.8% in the 80 mg tobramycin group and increased by +2.3+/-13.0% in the 300 mg group. Similar changes were observed in forced vital capacity (-2.5+/-12.9% in the 80 mg tobramycin group versus +2.5+/-9.6% in the 300 mg tobramycin group). Variability in responses was large but the differences were not statistically significant. Personal preference indicated that the majority of patients preferred the high-dose cycle compared with the lower dose continuous inhalation, but this was not linked to objective data on efficacy. The present trial fails to provide convincing evidence for superiority in efficacy of either of the two treatment regimens of inhaled tobramycin in CF patients.
– In the UK since the Eighties injectable tobramycin was nebulised by people with CF to suppress their chronic P. aeruginosa chest infection. It is disappointing that the results in this trial were inconclusive although the dose difference appeared to tip the balance in favour of the TOBI. However, the matter is now perhaps academic as tobramycin injectable is no longer licensed for inhalation in the UK.
2008 Ghayyda SN, Roland D, Cade A. Seat belt associated central line fracture-a previously unreported complication in cystic fibrosis. J Cyst Fibros 2008; 7:448-449. [PubMed]
It is not routine practice to advise on seating position within the car in relationship to the seatbelt placement over the anterior chest wall. Line failure due to direct pressure from a seatbelt worn to prevent injury in the sudden deceleration involved during a motor vehicle accident (MVA) has not been described previously in the CF literature This report concerns the case of an 8 year old child who fractured her Vascuport(R) line secondary to seatbelt trauma following a road traffic accident. Children and adults with CF should be advised to sit in the car on the side that places the shoulder strap of the seatbelt on the opposite side to the TIVAD line.
– This is a useful practical report which will help to prevent a complication not previously reported.
2008 Retsch-Bogart GZ, Burns JL, Otto KL, Liou TG, McCoy K, Oermann C, Gibson RL. AZLI Phase II Study Group. A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol 2008; 43:47-58.[PubMed]
This double-blind, randomized, placebo-controlled Phase 2 study evaluated the safety, tolerability and efficacy of 75 mg and 225 mg aztreonam lysine (AZLI) administered twice daily for 14 days There was a statistically significant reduction, compared to placebo, in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 (P<0.001).
The planned primary analysis, percent change in FEV1 at Day 14, demonstrated no statistically significant difference. Further analysis demonstrated significant increase in FEV1 at Day 7 for the subset of patients with baseline FEV1<75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV1, as well as greater reduction in P. aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group.
The authors concluded that these data support the further development of AZLI and provide information for the design of subsequent studies (Retsch-Bogart et al, 2008 below).
Dr Retsch-Bogart is Professor; Division Chief, Pediatric Pulmonology; Co-Director, UNC Cystic Fibrosis Therapeutics Development Center; Associate Director, Clinical and Translational Research Center of NC TraCS; Medical Director, North Carolina Children’s Airway Center.
2008 Retsch-Bogart GZ, McCoy KS, Gibson RL, Oermann C, Montgomery AB. Source of improvement in lung function in patients with cystic fibrosis following treatment with aztreonam lysine for inhalation (AZLI). Pediatr Pulmonol 2008; Suppl 31: Abstract 336:320.
Phase III study of treatment with 28 days of AZLI 75mg three times daily led to significant improvements in FEV1 and FVC compared to controls. At 28 days treated group had 10.2 better FEV1% and 5 better FVC% than did controls.
– So inhaled aztreonam lysine is a valuable addition to the inhaled antibiotics available for treating people with CF and was licensed by 2010.
2009 Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, Cooper PJ. Efficacy and safety of inhaled aztreonam lysine for airway Pseudomonas in cystic fibrosis. Chest 2009; 135:1223-1232.[PubMed]
A randomized, double-blind, placebo-controlled, international study (AIR-CF1 trial; June 2005 to April 2007), patients (n = 164; >or= 6 years of age) with FEV(1) >or= 25% and <or= 75% predicted values, and no recent use of anti-Pseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI (three times daily for 28 days) or placebo (1:1 randomization), then were monitored for 14 days after study drug completion. The primary efficacy end point was change in patient-reported respiratory symptoms. Secondary end points included changes in pulmonary function (FEV1), sputum PA density, and non-respiratory CFQ-R scales. After 28 days of treatment, AZLI improved the mean CFQ-R respiratory score (9.7 points; p < 0.001), FEV1 (10.3% predicted; p < 0.001), and sputum PA density (- 1.453 log(10) cfu/g; p < 0.001), compared with placebo. The incidence of “productive cough” was reduced by half in AZLI-treated patients. PA aztreonam susceptibility at baseline and end of therapy were similar.
So in patients with CF, PA airway infection, moderate-to-severe lung disease, and no recent use of anti-Pseudomonal antibiotics or azithromycin, 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function, and was well tolerated.
(Also McCoy KS et al. Am J Respir Crit Care Med 2008; 178:921-928.[PubMed]).
2009 Antibiotic Treatment for Cystic Fibrosis. Report of the UK Cystic Fibrosis Trust Antibiotic Working Group. 3rd Edition. Cystic Fibrosis Trust. London. 2009. (CF Trust website www.cftrust.org.uk).
This group chaired by Alan Smyth produced a very detailed and liberally referenced up to date account of the current recommendations for antibiotic use in people with CF in the UK. The recommendations differ significantly from those in N. America largely in the policy of early eradication of P. aeruginosaand the recommendation to use long term prophylactic anti-staphylococcal therapy for the first three years of life.
2009 Ratjen F, Munck A, Kho P, Angyalosi G. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2009 Dec 8. [PubMed]
The EarLy Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 mL (TOBI(R)) twice daily for the treatment of early onset P. aeruginosa infection in CF patients. Children aged 6 months and over with early P. aeruginosa infection were treated for 28 days with TIS twice daily after which they were randomised to either stop or to receive a further 28 days treatment. The primary endpoint was the median time to recurrence of P. aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P. aeruginosa infection one month after cessation of therapy and safety assessments.
The median time to recurrence of P. aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P. aeruginosa infection one month after the end of treatment and 66% and 69% remained free after 27 months in the 28-day and 56-day groups, respectively.
– So treatment with inhaled tobramycin 28 days was an effective and well tolerated therapy for early P. aeruginosa infection in CF patients.
2009 Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC. Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Resp Crit Car 2009; 180:802-808. [PubMed].
The Cystic Fibrosis Foundation established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians.
2009 Hubert D, Le Roux E, Lavrut T, Wallaert B, Scheid P, Manach D, Grenet D, Sermet-Gaudelus I, Ramel S, Cracowski C, Sardet A, Wizla N, Deneuville E, Garraffo R. Continuous versus intermittent infusions of ceftazidime for treating exacerbation of cystic fibrosis. Antimicrob Agents Ch 2009; 53:3650-3656.[PubMed]
Patients with chronic Pseudomonas aeruginosa colonization received two successive courses of intravenous tobramycin and ceftazidime (200 mg/kg of body weight/day) for pulmonary exacerbation administered as thrice-daily short infusions or as a continuous infusion. The continuous infusion of ceftazidime appeared to be as efficient as short infusions in patients with cystic fibrosis as a whole, but it gave better results in patients harboring resistant isolates of P. aeruginosa.
Ideally a steady blood level of ceftazidime should be maintained during treatment in contrast to aminoglycosides where peak levels are ideal. Previous studies have shown continuous infusion of CZ to be more satisfactory and are recommend for maximum effect – for example when attempting to eradicate Pseudomonas. It is interesting that better results were obtained in the present study when treating resistant bacteria.
2009 Okusanya OO, Bhavnani SM, Hammel J, Minic P, Dupont LJ, Forrest A, Mulder GJ, Mackinson C, Ambrose PG, Gupta R. Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic Pseudomonal infection. Antimicrob Agent Ch 2009; 53:3847-3854. [PubMed].
The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log10 CFU and serum AUC/MIC ratio and change in log10 CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and were considered to warrant the further development of liposomal amikacin for inhalation.
– One of the few new antibiotic preparations which are going forward for further evaluation.
2009 Treggiari MM, Rosenfeld M, Mayer-Hamblett N, Retsch-Bogart G, Gibson RL, Williams J, Emerson J, Kronmal RA, Ramsey BW. EPIC Study Group. Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study’. Contemp Clin Trials 2009; 30:256-268.[PubMed].
The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1-12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15-20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study.
– This major N. American study into the early eradication of Pseudomonas was welcome. The dose of tobramycin would seem to be unnecessarily large as judged by experience from some previous successful European trials.
Dr. Miriam Treggiari is Director of Research ans Critical Care, Department of Epidemiology, University of Washington. She has a primary research interest in clinical and outcomes research in critically ill patients. She is an attending physician i the UW Department of Anesthesiology and Pain Medicine and has an extensive background in critical care medicine.
2010 Cheng MP, Paquette K, Lands LC, Ovetchkine P, Theoret Y, Quach C. Voriconazole inhibition of vitamin A metabolism: are adverse events increased in cystic fibrosis patients? Pediatr Pulmonol 2010; 45:661-666. [PubMed]
Five of six CF patients receiving treatment with voriconazole developed photosensitivity, and all six patients reported visual disturbances. One 7-year-old boy developed striking erythema in the face and upper thorax; a 16-year-old girl who reported unexpected visual disturbances, including scotomas and tunneling vision. So significant adverse effects of voriconazole were noted in all treated CF patients. The authors suggest that this may be due to suppression of activity of hepatic enzymes involved in all transretinonic acid metabolism coupled with vitamin A supplementation in CF. They suggest that consideration should be given to reducing vitamin A supplementation during voriconazole treatment.
– Voriconazole is used increasingly frequently to eradicate or control fungal infections such as Aspergillus which are becoming an increasing problem but the drug appears to be associated with significant side effects.
2010 Tramper-Stranders GA, Wolfs TF, van Haren Noman S, van Aalderen WM, Nagelkerke AF, Nuijsink M, Kimpen JL, van der Ent CK. Controlled trial of cycled antibiotic prophylaxis to prevent initial Pseudomonas aeruginosa infection in children with cystic fibrosis. Thorax 2010; 65:915-920. [PubMed]
This 3-year triple-blind randomised controlled trial included 65 children with CF without P. aeruginosa infection. Intervention existed of 3-monthly 3-week treatments with oral ciprofloxacin and inhaled colistin or both placebo controls. There was no difference in acquisition of P. aeruginosa infection between the control and treatment groups (annual incidence 14% vs 11%; HR 0. 738, 95% CI 0. 299 to 1. 822). Anti-Pseudomonas antibodies emerged earlier in the control group, but this difference had disappeared after 3 years. Chronic infection was observed in 19% of controls and 12% of treated patients. Decline in pulmonary function and other clinical outcomes did not differ between the two groups.
The authors concluded that this regimen of three-monthly cycled anti-P. aeruginosa prophylaxis does not reduce the risk of initial and chronic infection in P. aeruginosa-negative children with CF of all ages.
– One would not expect that 3 weeks treatment every 3 months would be effective prophylaxis against new P. aeruginosa infection as antibiotic cover would be present only 25% of the time. However, previous work from Austria with continuous inhaled gentamicin did show a significant reduction in the incidence of new P. aeruginosa isolations (Heinzl B et al. Pediatr Pulmonol 2002; 33:32-37.[PubMed]). However, there was concern over the possibility of renal damage as judged by raised urinary NAG levels in the treated children and the gentamicin treatment was discontinued in some (Ring E et al. Arch Dis Child 1998; 78:540-543. [PubMed]). Also 80mg bd of tobramycin was adequate to prevent Pseudomonas infection in another study (Wiesemann HG et al. Pediatr Pulmonol 1998; 25:88-92.[PubMed]).
Dr G A Tramper-Stranders is a paediatrician who works at The University Medical Centre, Utrecht.
2010 Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care 2010; 182:627-632. [PubMed]
Previous studies have noted that some patients’ lung function (FEV1) does recover to pre-exacerbation levels with antibiotic treatment. This cohort study using the Cystic Fibrosis Foundation Patient Registry from 2003-2006 confirms this finding – that of 8,479 pulmonary exacerbations, 25% failed to recover to baseline FEV(1). The authors identified factors associated with the failure to recover to baseline, allowing clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment.
– A number of recent studies confirm this finding which is not surprising as some additional permanent pulmonary damage is likely to be sustained with each exacerbation. The finding emphasized the need for optimal treatment of exacerbations and also the value of prevention or reducing the frequency of exacerbations particularly by the use of long term inhaled antibiotics, rhDNase and azithromycin all of which have been shown in trials to reduced the frequency of exacerbations.
2010 Guy EL, Bosomworth M, Denton M, Conway SP, Brownlee KG, Lee TW. Serum tobramycin levels following delivery of tobramycin (TOBI) via eFlow advanced nebuliser in children with cystic fibrosis. J Cyst Fibros 2010; 9:292-295. [PubMed]
Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow. Ten children (ages 2-16 years) receiving 300mg TOBI via eFlow for clinical reasons participated. Serum tobramycin levels were obtained 1 hour post nebulisation. Nine children provided samples for urinary NAG, and 10 underwent audiology. Tobramycin levels were >1mg/L in 3 children (maximum 3.8, 2 children aged 2 years). Urine NAG/creatinine levels were raised (>0. 94micromol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss.
The authors concluded that serum tobramycin levels over 1mg/L can occur 1hr post 300mg TOBI delivered by eFlow. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.
– These results are worrying in view of the fact that the inhaled aminoglycosides are given for prolonged periods of time. Whether the “month on month off” regimen allows complete recovery of the renal tissue is unclear. Also it has been known for decades that the renal effects are to some extent cumulative. To this writer 300 mg bd of inhaled tobramycin has always seemed a very high dose when other studies have shown that 80 mg bd of tobramycin will prevent P. aeruginosa infection (Wiesemann HG et al. Pediatr Pulmonol 1998; 25:88-92. [PubMed]).
2010 McPherson H, Rosenthal M, Bush A. Can mucoid Pseudomonas aeruginosa be eradicated in children with cystic fibrosis? Pediatr Pulmonol 2010; 45:566-568. [PubMed]
Whilst the non-mucoid strain can be eradicated in the early stages, it is believed that mucoid PsA is difficult, if not impossible, to eradicate. Children aged under 16 with a confirmed diagnosis of CF and mucoid PsA on respiratory tract culture during a defined 9-year period were eligible for inclusion. One hundred sixteen children had the minimum dataset, and of these patients 67 (58%) cleared mucoid PsA for more than 1 year. Of the 67 patients who cleared mucoid PsA for more than 1 year, 38 (57%) patients remained clear of mucoid PsA at the last available culture (median 30, range 2-106 clear cultures, and median 55, 12-103 months clear). The authors concluded that isolation of mucoid PsA does not necessarily equate to lifelong infection and suggest that trials of eradication of mucoid PsA at first isolation are required.
– So “Yes” is the reassuring answer – mucoid strains of P. aeruginosa can be eliminated and this conforms to experience of smaller numbers of patients.
2010 Weiss B, Bujanover Y, Yahav Y, Vilozni D, Fireman E, Efrati O. Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: a pilot study. Pediatr Pulmonol 2010; 45:536-540. [PubMed]
Probiotics reduce intestinal inflammation, and Lactobacillus GG (LGG) reduces pulmonary exacerbation rate cystic fibrosis (CF) patients. the authors intended to determine the effect of a mixed probiotic preparation on pulmonary exacerbations and inflammatory characteristics of the sputum in CF patients. A prospective pilot study of 10 CF patients with mild-moderate lung disease and Pseudomonas aeruginosa colonization, were treated with probiotics for 6 months. Pulmonary function tests (PFT’s), sputum cultures with semi-quantitative bacterial analysis, and sputum neutrophil count and interleukin-8 (IL-8) levels were compared to pre-treatment and post-treatment values. The rate of pulmonary exacerbations was compared to 2 years prior to the study. The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0. 002). PFT’s have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed. The authors concluded that probiotics reduce pulmonary exacerbations rate in patients with CF and may have a preventive potential for pulmonary deterioration in CF patients.
– The study involved few patients and there were historical controls, however there is increasing evidence that probiotics may have a favorable effect in people with CF and other conditions such as rosacea.
2010 Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, Goss CH, Rose LM, Burns JL, Marshall BC, Ratjen F. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010; 303:1707-15. [PubMed]
In children and adolescents with CF not chronically infected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function but there fewer respiratory exacerbations – in 21% of the azithromycin group and 39% of the control group. The author concluded that 24 weeks treatment with azithromycin in this group of children did not improve pulmonary function.
– This was a large multi centre trial and answered an important question as to the use of azithromycin in patients uninfected with P. aeruginosa. However, the significant reduction in exacerbations presumably may have a favourable long term effect on lung function.
2010 Ratjen F, Munck A, Kho P. Angyalosi G. ELITE Study Group. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax 2010; 65:286-291. [PubMed].
The optimal therapeutic regimen and duration for early treatment of P. aeruginosa remains unclear. The Early Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 ml twice daily for the treatment of early onset P. aeruginosa infection in patients with CF. In this open-label randomised multicentre study, patients with CF (aged > or = 6 months) with early P. aeruginosa infection were treated for 28 days with TIS twice daily administered by the PARI LC PLUS (PARI GmbH, Starnberg, Germany) jet nebuliser. After 28 days, patients were randomised 1:1 to either stop TIS (n=45) or to receive a further 28 days of TIS (n=43). The primary endpoint was the median time to recurrence of P. aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P. aeruginosa infection 1 month after cessation of therapy and safety assessments. The median time to recurrence of P aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P aeruginosa infection 1 month after the end of treatment and 66% and 69% remained free at the final visit in the 28-day and 56-day groups, respectively. TIS was well tolerated. The authors concluded that treatment with TIS for 28 days is an effective and well tolerated therapy for early P aeruginosa infection in patients with CF.
– This is useful information but two points deserve comment. This a large dose of inhaled tobramycin for small children and infants aged 6 months – 80mg would have probably been just as effective as judged by previous European experience (Weismann HG, et al. Pediatr Pulmonol 1998; 25:88-92; Ratjen F, et al. Lancet 2000; 358:983-984; Munck A et al. Pediatr Pulmonol 2001; 32:288-292.[PubMed]). Also there is now increasing evidence that inhaled aminoglycosides are absorbed in sufficient amounts to affect renal function (Guy EL et al. Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis. J Cyst Fibros 2010; 9:292-295. [PubMed]). Considerations of cost of the dose of tobramycin used will be relevant in countries where funding of treatment is a problem.
2010 Doe SJ, McSherry A, Iceless B, Earns AM, Bright-Thomas R, Brennan AL, Webb AK, Jones AM. Patient segregation and aggressive antibiotic eradication therapy can control methicillin-resistant Staphylococcus aureus at large cystic fibrosis centres. J Cyst Fibros 2010; 9:104-109.
The prevalence of MRSA in patients with CF has risen in recent years. The authors adhere to a policy of segregation and barrier nursing to manage patients with MRSA, and actively pursue eradication of MRSA. They have evaluated their experiences of MRSA infection in their large adult CF centre. A retrospective review of all MRSA-positive patients from 1998 to 2008 was undertaken. Isolates were subjected to molecular identification to elucidate possible patient-to-patient transmission events. Eradication attempts were scrutinised. They have maintained a low incidence and prevalence (below 3%) of MRSA within this large cohort. A total of 15 pulsotypes of MRSA were identified among the 24 isolates examined, epidemiological data suggested no patient-patient transmission. Based on 6 month follow-up data, successful eradication was achieved in 81% patients. This includes those who had harboured infection for some time. Twenty-one (80. 8%) required only one course of treatment, 3 (11. 6%) patients required two different regimes and 2 (7. 5%) required three courses to fully eradicate the organism. They concluded that strict infection control procedures can control MRSA infection and keep the prevalence low in CF clinics. Eradication is achievable in the majority of patients even when significant time has lapsed from initial isolation. In some instances, up to 3 courses of antibiotics were required to achieve eradication.
– Encouraging experience from the Manchester Adult CF Centre showing the prevalence of MRSA can be maintained at a low level with careful monitoring, infection control procedures and aggressive treatment.
2011 Lavie M, Vilozni D, Sokol G, Somech R, Szeinberg A, Efrati O. Hospital versus home treatment of respiratory exacerbations in cystic fibrosis. Med Sci Monitor 2011; 17:CR698-703. [PubMed]
The authors analyzed data of 139 home intravenous antibiotic treatments in 54 CF patients (age range12-47 yrs) treated for respiratory exacerbations at the hospital (n=84) and/or at home (n=55). They concluded that hospital treatment for acute respiratory exacerbations in CF may be superior to home treatment, as indicated by a shorter duration of hospitalization, better improvement in FEV1 in patients with CF-related complications, CFRDM in particular and a trend toward better weight gain.
– Intravenous antibiotic treatment has been used at home by some CF units in the USA since the Seventies (Stern RC. Intravenous treatment: where we are and how we got there. In: Doershuk CF, editor. Cystic Fibrosis in the Twentieth Century. Cleveland: AM Publishing, Ltd, 2001:93-111) and in the UK since the mid-Eighties in adults (Winter RJ et al. Lancet 1984; i: 1338-1339) and children (1988 Gilbert J, et al. Arch Dis Child 1988; 63:512-517). Subsequently numerous studies were published attesting to the feasibility, effectiveness and patient acceptability of home intravenous antibiotic therapy – an obvious major advance in treatment but the efficacy obviously will depend on the medical and nursing staff available and their experience at managing the treatment at home.
Surprisingly, a Cochrane Review in 2000, updated in 2012, considered only one small study as suitable for inclusion out of 18 they identified, which showed home therapy did not harm the patients! Despite this, undoubtedly home IV therapy was one of the major advances in treatment and remains a central and very important component of CF treatment at most major units. Failure of a CF Centre to provide this option for some patients would be regarded as a major deficiency. Obviously each patient should be assessed individually and for some home IV treatment would quite inappropriate but for many it remains a major advance.
Also home IV treatment is a major financial saving for the health care providers. As broad estimate in the mid-Nineties in the UK 2 weeks home IV antibiotic treatment cost £1500 whereas the same treatment in hospital cost £2500 (Littlewood JM. 1995 Glaxo study to evaluate the cost of hospital vs. home IV treatment in cystic fibrosis. Presented at BTS Meeting London 1995).
2011 Renna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J, Bowden AR, Newton SM, Kampmann B, Helm J, Jones A, Haworth CS, Basaraba RJ, DeGroote MA, Ordway DJ, Rubinsztein DC, Floto RA. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest 2011; 121:3554-63. [PubMed]
A recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM). This study confirms that long-term azithromycin use by adults with CF may be associated with the development of infection with NTM, particularly the multi-drug-resistant species Mycobacterium abscessus, and identifies an underlying mechanism. In primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM in mice. The findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.
Autophagy = “the segregation of part of the cell’s own protoplasmic material within an membrane and its digestion after fusion of the segregated vacuole with a lysosome”.
– As many people with CF now receive long term azithromycin treatment further information on this association will be awaited with interest.
2011 Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, Williams J, Hiatt P, Gibson RL, Spencer T, Orenstein D, Chatfield BA, Froh DK, Burns JL, Rosenfeld M, Ramsey BW. Early Pseudomonas Infection Control (EPIC) Investigators. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediat Adol Med 2011; 165:847-856. [PubMed]
A randomised controlled trial to investigate the efficacy and safety of 4 anti-pseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection. 304 children with cystic fibrosis aged 1 to 12 years within 6 months of P. aeruginosa detection. Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009.
Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P. aeruginosa cultures. The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P. aeruginosa -positive cultures.
The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups or ciprofloxacin and placebo. The odds ratios of P. aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups. The authors concluded there was no difference in the rate of exacerbation or prevalence of P. aeruginosa positivity detected between cycled and culture-based therapies; also adding ciprofloxacin produced no benefits.
– These results are interesting and perhaps could have been predicted. It is apparent that there are a variety of antibiotic regimens that will eradicate a new growth of P. aeruginosa and these have been routine in many European centres for over 20 years in some clinics. For example there is a very low rate of chronic P. aeruginosa infection in Denmark (Hansen HJ et al. J Cyst Fibros 2008; 7:523-530). where 80% are protected from chronic P. aeruginosa to the age of 15 years; in Leeds (Lee TW et al. Pediatr Pulmonol 2004; 37:104-110). where only 4.3% of children less than 11 years have chronic P. aeruginosa infection and in Brussels (Lebecque P et al. J Cyst Fibros 2006; 5:237-244.) where only 2.8% of patient under 18 years are chronically infected with P. aeruginosa. The main problem appears to be the few patients where the usual treatment fails to eradicate the organism. The optimal use of intravenous ceftazidime (by constant infusion) and tobramycin (once daily IV) appears to be reasonable regimen (Hayes et al. 2008 above and 2011 below).
2011 Whitaker P, Shaw N, Gooi J, Etherington C, Conway S, Peckham D. Rapid desensitization for non-immediate reactions in patients with cystic fibrosis. J Cyst Fibros 2011; 10:282-285. [PubMed]
Non-immediate hypersensitivity reactions to antibiotics in patients with CF represent a real-life challenge for clinicians. Desensitization is often performed in patients who have exhausted all therapeutic options. Whilst desensitization is an established procedure for immediate reactions the authors assessed the outcomes and safety of desensitization for non-immediate reactions. They retrospectively reviewed 275 desensitization procedures in 42 patients with a range of non-immediate reactions to six commonly used antibiotics. Desensitization was performed using a 7-step rapid intravenous protocol on a normal medical ward. 250 (91%) of overall desensitization procedures were successful; however, this figure incorporates certain individuals having multiple successful procedures. Individual patient success ranged from 55% with tenuously through to 88% with tobramycin. In the 25 patients who failed desensitization the reactions were mild and the majority occurred within 48 h of starting treatment. Prophylactic anti-histamines and steroids did not reduce the risk of reaction. Whilst the mechanisms remain uncertain the authors confirm that rapid desensitization is a safe and effective way of re-introducing an antibiotic to a patient with a non-immediate reaction.
– Allergic reactions are a very common and important problem for CF patients who are having repeated course of antibiotics over many years. The report provides useful information for those facing these problems.
2011 Hayes D Jr, Feola DJ, Murphy BS, Kuhn RJ, Davis GA. Eradication of Pseudomonas aeruginosa in an adult patient with cystic fibrosis. Am J Health-System Pharm 2011; 68:319-322. [PubMed]
The use of a continuous infusion of a beta-lactam antibiotic in combination with high-dose, extended-interval amino-glycoside therapy for eradication of Pseudomonas aeruginosa in an adult patient with cystic fibrosis (CF) is reported. Testing of an expectorated sputum sample taken during routine evaluation of a 32-year-old woman with CF isolated P. aeruginosa; the patient’s medical record indicated no prior episodes of P. aeruginosa colonization. In an initial attempt to eradicate the organism, the woman received outpatient therapy with oral ciprofloxacin twice daily combined with an aminoglycoside (tobramycin solution) by nebulization twice daily. After a culture four weeks later again isolated P. aeruginosa, the patient was hospitalized, and i.v. antimicrobial therapy was initiated. The inpatient treatment regimen consisted of continuous-infusion cefepime 6 g (100 mg/kg/24 hr) and i.v. tobramycin 700 mg (12 mg/kg/24 hr), with both drugs administered via a peripherally inserted central catheter, for two weeks. A bronchoalveolar lavage fluid culture performed two months after completion of the i.v. antimicrobial regimen, as well as several sputum cultures obtained during the subsequent three years, tested negative for P. aeruginosa. The administration of continuous-infusion cefepime and high-dose, extended-interval tobramycin led to the successful eradication of P. aeruginosa in an adult patient with CF.
The 10% or so of patients in whom eradication of P. aeruginosa fails remain a clinical problem and the best form of treatment for them is not clear. This form of treatment has been reported to be successful in a 3-month old infant by Dr Hayes and colleagues (Hayes D Jr, et al. Novel approach to the eradication of Pseudomonas aeruginosa in an infant with CF after outpatient treatment failure. Pediatr Pulmonol 2008; 43:511-513. [PubMed]) i.e. using both antibiotics in an optimal manner – to achieve peak levels of aminoglycoside and steady constant levels of the beta-lactam.
– It is important to leave no stone unturned when attempting to eradicate P. aeruginosa; this often involves giving intravenous antibiotics to small children with CF who do not appear unwell. In these circumstances it would seem sensible to use the antibiotics in the optimal way as in this present report.
2012 Balaguer A, Gonzalez de Dios J. Home versus hospital intravenous antibiotic therapy for cystic fibrosis. Update of Cochrane Database Syst Rev. 2008;(3):CD001917; PMID: Cochrane Database of Systematic Reviews. 3:CD001917, 2012. [PubMed]
To determine whether home intravenous antibiotic therapy in cystic fibrosis is as effective as inpatient intravenous antibiotic therapy and if it is preferred by individuals or families or both. Eighteen studies were identified by the searches. Only one study could be included. Current evidence is restricted to a single randomized clinical trial. It suggests that, in the short term, home therapy does not harm individuals, entails fewer investigations, reduces social disruptions and can be cost-effective. There were both advantages and disadvantages in terms of quality of life. The decision to attempt home treatment should be based on the individual situation and appropriate local resources. More research is urgently required.
– It is interesting that these reviewers (neither of whom have published any other papers on cystic fibrosis) considered only one study comparing home and hospital intravenous antibiotic treatment to be acceptable when there have been numerous studies reporting experience since the mid-eighties – they rejected seventeen such reports! It seems both the researchers who designed these rejected studies and the editors who accepted them for publication should examine their standards !! The present reviewers’ suggestion that the decision to undertake home intravenous antibiotic treatment should be based on “the individual situation and appropriate local resources” is obviously the answer. The decision whether to use home IVs will obviously depend on the local resources available, the advice of the CF team and the the patient’s wishes.
2012 Pittman JE, Johnson RC, Davis SD. Improvement in pulmonary function following antibiotics in infants with cystic fibrosis. Pediatr Pulmonol 2012; 47:441-446. [PubMed]
Pre- and post-antibiotics pulmonary function test (PFT) data was available on 11 infants with CF, with a mean age of 102 weeks at the time of the first PFT. The majority of infants were symptomatic prior to antibiotics, and showed statistically significant improvement in clinical parameters following treatment. Prior to antibiotics, PFTs showed evidence of substantial obstructive disease. Following antibiotics, all of the parameters showed statistically significant improvement. The authors have shown a statistically significant improvement in infant PFT measures following antibiotic therapy in a cohort of 11 infants with CF, which paralleled improvement in clinical parameters. Though infant PFTs showed improvement, they remained abnormal in the majority of subjects, with persistent air-trapping and hyperinflation after antibiotic therapy.
– So these findings suggest that infant PFTs are sensitive to acute clinical changes in children with CF, and may be a useful tool in managing infants with CF. These findings are to be expected but the increasing use of more accurate objective measurement in young CF infants is an important advance particularly as the emphasis is increasingly on very early intervention with treatment such as antibiotics, rhDNase and hypertonic saline. Once again the significant proportion of CF infants who already have changes in their respiratory function, even after antibiotic therapy, is apparent.
2012 Mayer-Hamblett N, Kronmal RA, Gibson RL, Rosenfeld M, Retsch-Bogart G, Treggiari MM, Burns JL, Khan U, Ramsey BW. EPIC Investigators. Initial Pseudomonas aeruginosa treatment failure is associated with exacerbations in cystic fibrosis. Pediatr Pulmonol 2012; 47:125-134.[PubMed]
Study to determine if failure of antibiotic therapy to eradicate Pseudomonas aeruginosa (Pa) and frequency of Pa recurrence are associated with increased exacerbation risk. The cohort included 282 children with CF who participated in the EPIC trial ages 1-12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk. Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26, 4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12, 2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).
The authors concluded that children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.
– This is interesting, valuable data but quite predictable and will be no surprise to clinicians who have been advising early eradication for the past 25 years! There has been increasing evidence that initial asymptomatic colonisation of the airways is followed by infection and a deterioration in a number of clinical parameters (Valerius et al, 1991). However, it’s good to have as much hard data as possible on such an important matter to encourage those clinicians responsible for care of children and adults with CF to eradicate P. aeruginosa even if this entails considerable and invasive treatment in patients who, at the time, may not feel ill.
2012 Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA. Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics. [Review] Minerva Anestesiol 2012; 78:94-104. [PubMed]
Beta-lactam antibiotics display time-dependant pharmacodynamics whereby constant antibiotic concentrations rather than high peak concentrations are most likely to result in effective treatment of infections caused by susceptible bacteria. Continuous administration has been suggested as an alternative strategy, to conventional intermittent dosing, to optimise beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) properties. With the availability of emerging data, the authors elected to systematically investigate the published literature describing the comparative PK/PD and clinical outcomes of beta-lactam antibiotics administered by continuous or intermittent infusion. They found that the studies have been performed in various patient populations including critically ill, cancer and cystic fibrosis patients. Available in vitro PK/PD data conclusively support the administration of beta-lactams via continuous infusion for maximizing bacterial killing from consistent attainment of pharmacodynamic end-points. In addition, clinical outcome data supports equivalence, even with the use of a lower dose by continuous infusion. However, the present clinical data is limited with small sample sizes common with insufficient power to detect advantages in favour of either dosing strategy. With abundant positive pre-clinical data as well as document in vivo PK/PD advantages, large multi-centre trials are needed to describe whether continuous administration of beta-lactams is truly more effective than intermittent dosing.
– There is increasing evidence that beta-lactam antibiotics are more effective when given as a constant infusion rather than the intermittent dosing widely practised in most clinics. This is particularly important when using the drug as part of optimal intravenous antibiotic therapy when inhaled and oral treatment has failed to eradicate early P. aeruginosa.
2012 Sawicki GS, Signorovitch JE, Zhang J, Latremouille-Viau D, von Wartburg M, Wu EQ, Shi L. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatr Pulmonol 2012; 47:44-52. [PubMed]
Though tobramycin inhalation solution has been used for over a decade to improve lung function and reduce exacerbations in patients with cystic fibrosis (CF), its effects on mortality have not been well-described. This study aimed to assess the association between use of tobramycin inhaled solution and mortality in patients with CF and chronic Pseudomonas aeruginosa (PA) infection. Adjusted mortality rates for patients reporting tobramycin inhalation solution use in all versus none of the follow-up years were 1.3% versus 2.1% at 2 years, 5.2% versus 8.0% at 5 years, and 9.9% versus 15.0% at 10 years.
The authors conclude that, after adjustment for multiple patient characteristics and known risk factors, use of tobramycin inhalation solution was associated with significantly reduced mortality among patients with CF.
– Inhaled aminoglycosides (gentamicin and later tobramycin) have been used in Europe for some 30 years since Margaret Hodson’s landmark paper on the use of inhaled gentamicin and carbenicillin. The “over a decade” mentioned in this abstract presumably refers to the 1999 paper of Ramsey and colleagues (Ramsey B W et al. N Engl J Med 1999; 340:23-30) that preceded the approval and availability of tobramycin for inhalation (TOBI) in N. America.
2012 Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M, Moorehead L, Montgomery AB, Geller DE. Phase 2 FTI Study Group. Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with Pseudomonas airway infection.
Am J Respir Crit Care 2012; 185:171-178. [PubMed]
Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF). To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted. This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI).
A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values.
The authors concluded FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.
Apparently Gilead Sciences planned to develop the combination fosfomycin/tobramycin antibiotic in which the tobramycin dose is lower in the FTI product than the usual dose of inhaled tobramycin given alone; this would potentially allow continuous dosing with a lower risk of toxicity.
2012 Whitaker P, Naisbitt D, Peckham D. Non-immediate b-lactam reactions in patients with cystic fibrosis. Curr Opin Allergy Clin Immunol 2012; 12:369-375. [PubMed]
This review discusses new developments regarding b-lactam sensitivity in people with cystic fibrosis. It is a common complication and some 30% of patients have multiple b-lactam reactions.
2012 Schuster A, Haliburn C, Doring G, Goldman MH: for Freedom Study Group. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2012 Nov 7. [Epub ahead of print] [PubMed]
To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged ≥6 years with chronic Pseudomonas aeruginosa lung infection. A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged ≥6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks.
380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV(1)% predicted) at week 24 was -0.97% (95% CI -2.74% to 0.86%) in the intention-to-treat population (n=374) and -0.56% (95% CI -2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was ≤1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as ‘very easy or easy to use’ (90.7% vs 53.9% respectively; p<0.001).
CDPI demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P aeruginosa to colistin. Overall, CDPI was well tolerated.
2012 Doring G, Flume P, Heijerman H, Elborn JS,: for the Consensus Study Group. Treatment of lung infection in patients with cystic fibrosis: Current and future strategies. J Cyst Fibros 2012; 11:461-479. [PubMed]
This group discusses the present status of antibiotic therapy for the major pathogens in CF airways and outline measures to optimize maintenance treatment for infection in the light of novel antibiotic drug formulations. They also discuss new developments in culture-independent microbiological diagnostic techniques and the use of tools for monitoring the success of antibiotic treatment courses. Finally, cost-effectiveness analyses for antibiotic treatment in CF patients are discussed.
An extremely useful well referenced review. It is disappointing that S. aureus is dealt with so briefly and that the case against antibiotic prophylaxis relies on the 2002 paper of Stutman et al (above), particulalry as so many people with CF are still allowed to become chronically infected with this damaging pathogen. For example from the CF Foundation Patient Registry 2011 over half the patients were infected by S. aureus even from early childhood. Also S. aureus is frequently isolated from an early age in bronchoscopy specimens in very young infants diagnosed after neonatal screening
2013 Schuster A, Haliburn C, Döring G, Goldman MH. Freedom Study Group. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2013; 68:344-50. [PubMed]
A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged >=6 years with chronic P. aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks. 380 patients were randomised. Colobreathe demonstrated efficacy by virtue of non-inferiority to tobramycin inhaler solution in lung function after 24 weeks of treatment. There was no emergence of resistance of P. aeruginosa to colistin. Overall, CDPI was well tolerated.
– This important study led to the approval of Colobreathe for use by people with CF in the UK. There was some discussion regarding the design of the trial as to the advisability of comparing with the tobramycin inhaler solution.
2013 Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B. Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. [Review]Am J Resp Crit Care 2013; 187:680-9 [PubMed]
A new review of the literature to update the 2007 recommendations, including consideration of new medications and additional evidence on previously reviewed therapies. Published evidence for chronic lung therapies was systematically reviewed and resulting treatment recommendations were graded based on the United States Preventive Services Task Force scheme. These guidelines provide up-to-date evidence of safety and efficacy of chronic treatments of CF lung disease, including the use of novel therapies that have not previously been included in CF pulmonary guidelines.
– These recommedations are intended for the USA, and although useful some are not entirely relevant for the UK where recommendations differ in certain respects. For example, in the use of prophylactic anti-staphylococcal antibiotics in infants and long term anti-staphylococcal treatment in older patient confirmed as having chronic infection with that organism. The group were unable to rcommend inhaled antibiotics other than aztreonam and tobramycin whereas in Europe inhaled colistin is widely used and was recently shown to be effective in powder from for patients with chonic P. aeruginosa infection. Many outstanding questions are mentioned and some are discussed such as – prioritization of therapies, interactions between medications, effect of bacterial resistance; the optimal use of medications under 6 years (who have not been included in most trials up to present). Also they mention the sequence of administration.
Dr. Peter Mogayzel has been the Director of the Cystic Fibrosis Center since 2002. His research interests include the regulatory properties of the CFTR gene, mucociliary clearance and development of new therapeutics for cystic fibrosis.
2013 Proesmans M, Vermeulen F, Boulanger L, Verhaegen J, De Boeck K. Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros 2013; 12:29-34. [PubMed]
Two eradication regimens in children with new Pseudomonas (Pa) infection were compared. Children were randomised to treatment with tobramycin inhalation solution for 28 days (TIS) or inhaled sodium colistimethate (2x2millU/day) plus oral ciprofloxacin (30 mg/kg/day) for 3 months (CC). Airway cultures were taken for 6 consecutive months, then every 3 months. The primary outcome was Pa eradication at the end of treatment. Fifty eight patients with new Pa isolation were randomized. Eradication at end of treatment was similar for both treatments: 26/29 CC and 23/29 in TOBI treated patients. Median time to recurrence of Pa was 9 months for CC and 5 months for TIS. After 1 year, the 2 groups did not differ in change in total and Pa specific IgG, FEV1 and BMI. After 2 years, 10% of patients had chronic Pa infection. The authors concluded inhalation of TIS (28 days) or CC (3 months) resulted in similar eradication success at the end of treatment (80 and 90% respectively) and similar clinical evolution during the first 2 years of follow-up.
– These results confirm the usually reported results of early eradication therapy for which a number of regimes are effective. The published work on eradication therapy for early Pa infection has been reviewed in detail recently (Schelstraete et al 2013. below).
2013 Schelstraete P, Haerynck S, Van Deal S, Deseyne S, De Baets F. Eradication therapy for Pseudomonas aeruginosa colonization episodes in cystic fibrosis patients. J Cyst Fibros 2013; 12:1-8.[PubMed]
A detailed review of previous work relating to the different eradication trials over the past 28 years. The authors conclude that all the different studies on first eradication treatment of P. aeruginosa agree on the favourable effect of antibiotics on eradication, on the recurrence frequency and on the delay in onset of chronic P. aeruginosa infection. Such early treatment is now standard care and even mucoid Pseudomonas can be eliminated. No one regimen has been shown to be superior to others.
The authors call for larger studies and also that the genotype data is included in any future trials.
Further trials in this instance may not be a high priority when it is now obvious that a number of eradication regimens are very effective in the short and medium term and also as there is a world wide shortage of CF patients to include in trials.
2013 Fleet JE, Guha K, Piper S, Banya W, Bilton D, Hodson ME. A retrospective analysis of the impact of azithromycin maintenance therapy on adults attending a UK cystic fibrosis clinic. J Cyst Fibros 2013; 12:49-53. [PubMed]
A retrospective study of 81 adult patients with CF taking continuous azithromycin. Percentage predicted FEV1 and courses of intravenous antibiotics were examined at yearly intervals two years prior to and two years after azithromycin initiation. The FEV1 deteriorated in the two years before starting azithromycin by a mean of 2.02% per year and in the year after increased by 1.15% (P=0.01) but a mean 2.58% reduction was observed in year two. There was no statistically significant effect on courses of intravenous antibiotics in these older patients.
The authors concluded azithromycin resulted in an improved FEV1 at year one but this effect was not sustained beyond the first year of treatment. The CF Foundation guidelines recommend long term azithromycin for all patients of 6 years and older chronically infected with P. aeruginosa. In contrast, in the UK the CF Trust Antibiotic Working Group recommends azithromycin only if the patient is “deteroriorating on conventional therapy”; the UK group considers there is insufficient evidence to recommend all patients with chronic P. aeruginosa should receive long term azithromycin. This present study from London would lend support to this view.
2013 Young DC, Zobell JT, Waters CD, Ampofo K, Stockmann C, Sherwin CM,, Spigarelli MG. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: IV. colistimethate sodium. Pediatr Pulmonol 2013; 48:1-7. [PubMed]
The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing the intravenous (IV) polymixin antibiotic colistimethate sodium (CMS) in the treatment of APE and to identify areas where further study is warranted. Currently, there is not an international standard on the labeling of CMS products. As a result, this has lead to confusion in the interpretation of the literature with respect to efficacy, tolerance, and optimal dosing strategy. The dosing ranges of IV CMS from the literature are 5.3-12.9 mg/kg/day, maximum 480 mg per day for 60 kg patient (Colomycin injection-European product) and 8-21.3 mg/kg/day, maximum 800 mg per day for 60 kg patient (Coly-Mycin M parenteral-US product).The literature supports a CMS dose of 8 mg/kg/day divided every 8 hr (maximum 480 mg/day) for the treatment of APE secondary to Pseudomonas aeruginosa. The maximum recommended CMS dose of 480 mg/day is less than is recommended by the FDA-approved and CFF dosing guidelines but in agreement with UK CF Trust Antibiotic Working Group recommendations.
This is helpful as there has been confusion over the dosing and designation of the various preparations.
2013 Wilson K, Jamersom PA. Comparison of central venous catheter and peripheral vein samples of antibiotics in children with cystic fibrosis. J Spec Pediatr Nurs 2013; 18:33-41. [PubMed]
A trial to determine if accurate serum antibiotic levels can be obtained from central venous catheters (CVCs) in pediatric patients with cystic fibrosis. Fifty paired CVC-peripheral vancomycin or tobramycin specimens were collected within 5 min of each other following a 5-ml flush and discard. Specimen samples were randomized by first site drawn.
Central venous catheter and peripheral antibiotic levels were highly correlated (r =.97, p <.001), with no statistically significant difference (t = 1.18, p =.25).
So accurate antibiotic concentrations can be obtained from CVCs, reducing pediatric patient trauma and stress.
A practical very useful study of great relevance to child patients!
2013 Schuster A, Haliburn C, Doring G, Goldman MH. Freedom Study Group. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2013; 68:344-50.[PubMed]
To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged >=6 years with chronic Pseudomonas aeruginosa lung infection. A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged >=6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks. 380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV1% predicted) at week 24 was -0.98% (95% CI -2.74% to 0.86%) in the intention-to-treat population (n=373) and -0.56% (95% CI -2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was <=1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as ‘very easy or easy to use’ (90.7% vs 53.9% respectively; p<0.001).
Colobreathe demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P aeruginosa to colistin. Overall, CDPI was well tolerated.
On the basis of this trial the Colobreathe was approved for use in the NHS. The trial design was required by the regulatory authorities.
2013 Zobell JT. Waters CD. Young DC. Stockmann C. Ampofo K. Sherwin CM. Spigarelli MG. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. cephalosporins and penicillins. [Review] Pediatr Pulmonol 2013; 48:107-22. [PubMed]
Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin-tazobactam and ticarcillin-clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200-400mg/kg/day divided every 6-8hr, maximum 8-12g/day, and 150-200mg/kg/day divided every 6-8hr, up to 6-8g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350-600mg/kg/day divided every 4hr, maximum 18-24g/day of piperacillin component, and 400-750mg/kg/day divided every 6hr, up to 24-30g/day of ticarcillin component, respectively.
As a large portion of CF patients will not regain their lung function following an APE, the authors suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin-clavulanate in APE. The usefulness of high dose piperacillin (>600mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed.
2013 Stockmann C. Sherwin CM. Zobell JT. Young DC. Waters CD. Spigarelli MG. Ampofo K. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: III. fluoroquinolones. [Review]. Pediatr Pulmonol 2013; 48:211-220. [PubMed]
This review is the third installment in a comprehensive State of the Art series and aims to evaluate the use of fluoroquinolones in the management of P. aeruginosa infection in both children and adults with cystic fibrosis (CF). Oral and intravenous ciprofloxacin have been shown to be well-tolerated in the treatment of acute pulmonary exacerbations (APE) secondary to P. aeruginosa. Older literature supports an oral dosing regimen of 40mg/kg/day divided every 12hr, up to 2g/day, and intravenous (IV) ciprofloxacin 30mg/kg/day divided every 8hr, maximum 1.2g/day in children, and 750mg administered orally twice a day or 400mg IV every 8hr in adults. However, a recent pharmacodynamic (PD) modeling study shows that the literature, U.S. Food and Drug Administration (FDA)-approved, and Cystic Fibrosis Foundation (CFF) guideline dosing regimens may be suboptimal for the treatment of P. aeruginosa in APE. Further study is warranted to determine if higher doses of ciprofloxacin are needed. Limited pharmacokinetic (PK), PK/PD, and efficacy studies involving levofloxacin exist in adult patients with CF. No pediatric data exists for levofloxacin in CF patients. Further study is needed to determine the tolerability and efficacy of levofloxacin in APE. The authors state that at this time, the routine use of levofloxacin in the treatment of APE in pediatric and adult patients cannot be recommended.
2013 Stenbit AE. Bullington WM. Heh JL. Flume PA. Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring. J Cyst Fibros 2013; 12:403-406.-U.S. [PubMed]
Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing. METHODS: Twenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5-9 h after the IV dose. RESULTS: Nine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin.
Trough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing.
2013 Clancy JP. Dupont L. Konstan MW. Billings J. Fustik S. Goss CH. Lymp J. Minic P. Quittner AL. Rubenstein RC. Young KR. Saiman L. Burns JL. Govan JR. Ramsey B. Gupta R. Arikace Study Group. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax 2013; 68:818-825. [PubMed]
Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R).
RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L+/-0.203 vs -0.032L+/-0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49).
CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.
2013 Zobell JT. Young DC. Waters CD. Ampofo K. Stockmann C. Sherwin CM. Spigarelli MG. Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: VI. Executive summary. Pediatr Pulmonol 2013; 48:525-37. [PubMed]
The aim of this review is to provide an overview of the classes of intravenous anti-pseudomonal antibiotics, the findings of anti-pseudomonal antibiotic utilization surveys, the current antibiotic dosing recommendations from the U.S. and Europe, and the pharmacokinetic (PK) and pharmacodynamic (PD) differences between CF and non-CF individuals. Anti-pseudomonal antibiotic classes include beta-lactams, aminoglycosides, fluoroquinolones, and colistimethate sodium. Recent surveys of antibiotic utilization in CF Foundation-accredited care centers have shown that a large number of centers are not following recommended dosing strategies despite published recommendations in the U.S. and Europe. The recommended doses for anti-pseudomonal antibiotics may be higher than FDA-approved doses due to PK and PD differences. As a large portion of CF patients will not regain their lung function following an APE, it seems possible that currently available anti-pseudomonal agents are being used sub-optimally. As new anti-pseudomonal agents are not currently available, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat pulmonary exacerbations in an effort to improve outcomes for CF patients infected with Pseudomonas aeruginosa.
2013 Horsley AR. Davies JC. Gray RD. Macleod KA. Donovan J. Aziz ZA. Bell NJ. Rainer M. Mt-Isa S. Voase N. Dewar MH. Saunders C. Gibson JS. Parra-Leiton J. Larsen MD. Jeswiet S. Soussi S. Bakar Y. Meister MG. Tyler P. Doherty A. Hansell DM. Ashby D. Hyde SC. Gill DR. Greening AP. Porteous DJ. Innes JA. Boyd AC. Griesenbach U. Cunningham S. Alton EW. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax 2013; 68:532-9. [PubMed]
A study by members of the UK Gene Therapy Consortium to evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for their forthcoming clinical trial of CFTR gene therapy. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers.
Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31).
The authors identified the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with their study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.
The UK Gene Therapy Consortium commenced their multidose major gene therapy trial in June 2012 (Alton EW et al. Pediatr Pulmonol 2013; Suppl 36: Poster 245). This study helped to determine the parameters which would be used. The primary outcome chiosen was the FEV1 and secondary outcomes the lung clearance index, CT changes and CFQ questionaire. The trial will be completed around June 2014.
2013 Byrnes CA. Vidmar S. Cheney JL. Carlin JB. Armstrong DS. Cooper PJ. Grimwood K. Moodie M. Robertson CF. Rosenfeld M. Tiddens HA. Wainwright CE. ACFBAL Study Investigators. Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age. Thorax 2013; 68:643-651. [PubMed]
Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years.
Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry.
168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05).
The authors concluded respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group. It is interesting that the exacerbation rate was 26% lower in children receiving prophylactic antibiotics – lending some support to the UK recommendation of prophylactic flucloxacillin for the first 3 years.
2014 Berkhout MC, van Velzen AJ, Touw DJ, de Kok BM, Fokkens WJ, Heijerman HG. Systemic absorption of nasally administered tobramycin and colistin in patients with cystic fibrosis. Antimicrob Chemother 2014; 69(11):3112-5. doi: 10.1093/jac/dku239. Epub 2014 Jul 11. [PubMed]
A study to investigate the systemic absorption of nasally administered tobramycin (300mg), colistin (administered as colistin sulfomethate sodium; CMS 160mg) and a combination of same doses of both drugs using systemic absorption as surrogate for safety. In addition, tolerability of the nasal irrigations was examined.
In ten adult patients nasal irrigations with tobramycin, CMS and a combination of tobramycin and CMS resulted in safe serum levels and were well tolerated. Following the tobramycin and the combined irrigation, only two patients had detectable tobramycin serum levels, with the highest being 0.054 mg/L. Serum levels of colistin A and B were not detectable.
– The possibility of absorption of topically administered aminoglycosides is a concern in patients requiring repeated or longterm administration by inhalation. Although the amount absorbed appears to be small, the repeated or chronic exposure could be a significant factor as has been shown in a number of studies.
2015 Waters V, Chiang J, Sonneveld N, Kukkar R, Tullis E, Ratjen F. Prolongation of antibiotic treatment for cystic fibrosis pulmonary exacerbations. J Cyst Fibros. 2015 Nov;14(6):770-6. doi: 10.1016/j.jcf.2015.07.010. Epub 2015 Aug 9. [Epub ahead of print] [PubMed]
A retrospective cohort study, using the Toronto CFDATABASE from 1997 to 2012, of CF individuals with pulmonary exacerbations requiring intravenous antibiotic treatment. A total of 538 pulmonary exacerbations in 253 patients were used for these analysis; 39% of these exacerbations fully recove not achieved within 14 days in all patients, and that there is continued improvement beyond this period.red lung function at follow-up. Exacerbations were more frequently treated with >14days of antibiotics in older patients with lower FEV1 at exacerbation and higher rates of B. cepacia complex infection. Subjects with exacerbations treated for >14days had a significantly greater increase in FEV1 from day 14 to follow up compared to those with ≤14days (p<0.001). This study confirms that in the treatment of pulmonary exacerbations, maximum lung function is is not achieved within 14 days in all patients, and that there is continued improvement beyond this period.
2015 Schechter MS; Regelmann WE; Sawicki GS; Rasouliyan L; VanDevanter DR; Rosenfeld M; Pasta D; Morgan W; Konstan MW. Antibiotic treatment of signs and symptoms of pulmonary exacerbations: a comparison by care site. Pulmonology 2015; 50(5):431-40.325 [PubMed] 25530325
Pediatric care sites enrolled in the Epidemiologic Study of Cystic Fibrosis (ESCF) were ranked by median FEV1 % predicted of the children they followed. Those sites in the highest quartile for FEV(1) were more likely to prescribe antibiotics when patients presented with either mild or overt evidence of a pulmonary exacerbation (PEx). While this may not be the only reason that their patients have superior median FEV(1), it is likely an important contributor.
– An interesting study confirming the importance of early treatment of even mild new symptoms and signs – one of the most important principles of CF care. A new cough needs treatment whatever the other signs and symptoms.
2015 Mayer-Hamblett N, Kloster M, Rosenfeld M, Gibson RL, Retsch-Bogart GZ, Emerson J, Thompson V, Ramsey BW. Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis. Clin Infect Dis. 2015 Sep 1;61(5):707-15. doi: 10.1093/cid/civ377. Epub 2015 May 13. [PubMed]
Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early anti-pseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response.
This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial anti-pseudomonal therapy. Associations between eradication status and outcomes were assessed.
Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17-.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25-.73) compared with non-sustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with non-sustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline.
This is the first study to quantify the long-term durability of microbiological response associated with early anti-pseudomonal therapy, demonstrating the critical importance of optimizing anti-pseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage.
Editorial Commentary: Pseudomonas aeruginosa Eradication: How Do We Measure Success? [Clin Infect Dis. 2015]PMID: 25972024 [PubMed – in process] PMCID: PMC4626753 [Available on 2016-09-
2015 Heltshe SL, Goss CH, Thompson V, Sagel SD, Sanders DB, Marshall BC, Flume PA. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax. 2015 Apr 24. pii: thoraxjnl-2014-206750. doi: 10.1136/thoraxjnl-2014-206750. [Epub ahead of print] [PubMed]
Treatment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) varies widely with no consensus on management practices or best indicators of therapeutic success. To design trials evaluating PEx treatment factors, we characterise the heterogeneity of PEx care in adults and paediatrics, and correlate it with measures of clinical response including short-term and long-term lung function changes, change in symptom severity score and time to next intravenous antibiotic therapy.
Data were used from a prospective observational study of patients with CF ≥10 years of age enrolled at six sites between 2007 and 2010. All were started on intravenous antibiotics for a clinically diagnosed PEx. Analysis of variance, logistic and Cox regression were used to examine the association of treatment factors with short-term and long-term clinical response.
Of 123 patients with CF (60% women, aged 23.1±10.2 years), 33% experienced <10% relative improvement in FEV1 during treatment, which was associated with failing to recover baseline lung function 3 months after treatment (OR=7.8, 95% CI 1.9 to 31.6, p=0.004) and a longer time to next intravenous antibiotic (HR=0.48, 95% CI 0.27 to 0.85, p=0.011). Symptom improvement was observed but was not associated with subsequent lung function or time to next antibiotic therapy, which had a median recurrence time of 143 days.
Immediate symptomatic or respiratory response to PEx treatment did not have a clear relationship with subsequent outcomes such as lung function or intravenous antibiotic-free interval. These results can inform future research of treatment regimens for PEx in terms of interventions and outcome measures.
– Such group studies are of limited value as the treatment of an exacerbation in an individual with CF is best discussed between the patient, the staff and the doctor at the start and regularly through the course of treatment (hopefully the same doctor will be seeing the patient regularly throughout the treatment). It seems unlikely that “a consensus on management practices or best indicators of therap. eutic success” would be an adequate substitute for an individualized approach.
2016 Ahmed MI; Mukherjee S. Treatment for chronic methicillin sensitive Staphylococcus aureus pulmonary infection in people with cystic firbosis. Cochrane Database of Systematic Reviews. 3:CD011581, 2016. [PubMed]
Staphylococcus aureus is a major cause of chest infection in people with cystic fibrosis. Early onset, as well as chronic, lung infection with this organism in young children and adults results in worsening lung function, poorer nutrition and increases the airway inflammatory response, thus leading to a poor overall clinical outcome. There are currently no evidence-based guidelines for chronic suppressive therapy for Staphylococcus aureus infection in cystic fibrosis such as those used for Pseudomonas aeruginosa infection. The searches identified 55 trials, but none were eligible for inclusion in the current version of this review.The authors identified no randomised controlled trials which met the inclusion criteria for this review. Although methicillin-sensitive Staphylococcus aureus is an important and common cause of lung infection in people with cystic fibrosis, there is no agreement on how best to treat long-term infection. The review highlights the need to organise well-designed trials that can provide evidence to support the best management strategy for chronic methicillin-sensitive Staphylococcus aureus infection in people with cystic fibrosis.
– S. aureus is a damaging pathogen which should be prevented in young CF children and eradicated when it appears in older patients. In this reviewer’s opinion it would be wasteful and almost unethical to arrange trials as suggested by these authors. The advice of the UK CF Trust Antibiotic Group seems reasonable i.e. using prophylactic flucloxacillin for the first 3 years then vigorous efforts to eradicate whenever the organism appears. Useful advice, based on extensive experience, has been published over the years from Copenhagen where the incidence of chronic S. aureus infection is very low (Dalbøge CS et al. A cohort study of the Copenhagen CF Centre eradication strategy against Staphylococcus aureus in patients with CF. J Cyst Fibros. 2013; 12:42-48 [PubMed]). These Danish authors conclude that their anti-S. aureus eradication strategy in CF patients resulted in a low prevalence of chronic infections and high treatment efficacy. Furthermore, anti-staphylococcal treatment may be associated with a short-term improvement in lung function. They further state that “Antibiotic treatment of any relevant micro organisms, ignoring the presence or absence of respiratory symptoms has been our policy since the establishment of our centre in 1968”. They observe that “use of a stepwise two-drug antibiotic combination therapy strategy results in a high level of eradication with a prevalence of chronic S. aureus infection of less than 15% which has been unchanged for decades”. This prevalence is much lower than the 50% reported in many patient registries.
2016 Cohen-Cymberknoh M; Gilead N; Gartner S; Rovira S; Blau H; Mussaffi H; Rivlin J; Gur M; Shteinberg M; Bentur L; Livnat G; Aviram M; Picard E; Tenenbaum A; Armoni S; Breuer O; Shoseyov D; Kerem E. Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis. J Cyst Fibrosis 2016 Apr 30. [PubMed]
A study to determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. Data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for >1year. Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultureswere older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken.The authors concluded delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.
– This study confirms the now well-established fact that it is virtually impossible to eradicate Pseudomonas aeruginosa infection when it is chronically established. Delayed diagnosis and infrequent cultures will contribute to the percentage of eradication failures.
Dr Malena Cohen-Cymberknoh (figure) is Senior Pediatrician and Specialist in Pediatric Pulmonology atHadassah Hospital, Israel.
2016 Deppisch C; Herrmann G; Graepler-Mainka U; Wirtz H; Heyder S; Engel C; Marschal M; Miller CC; Riethmuller J. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection 2016; 44(4):513-20. [PubMed]
The authors assessed feasibility and safety of inhaled NO in eight CF patients who received 160 ppm NO for 30 min, three times daily for 2 periods of 5 days. The NO treatment was safe and in none of the patients were serious drug-related adverse events observed which caused termination of the study. The intention-to-treat analysis revealed a significant mean reduction of the colony forming units of all bacteria and all fungi, while mean forced expiratory volume 1 s % predicted (FEV1) relative to baseline increased 17.3 +/- 8.9 % (P = 0.012).
The authors concluded NO treatment may improve the therapy of chronic microbial lung infections in CF patients, particularly concerning pathogens with intrinsic or acquired resistance to antibiotics.
Flume FPA; VanDevanter DR; Morgan EE; Dudley MN; Loutit JS; Bell SC; Kerem E; Fischer R; Smyth AR; Aaron SD; Conrad D; Geller DE; Elborn JS. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. J Cyst Fibros 2016; 15(4):495-502. [PubMed]
APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF. This study was to compare the safety and efficacy of a 28-day course of treatment with LIS 240mg or placebo BID in persons >12years old with CF and chronic P. aeruginosa infection.A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CF patients >12years with chronic P. aeruginosa infection. An improvement in FEV1 (% predicted) at 28days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa.
2016 Flume PA; Clancy JP; Retsch-Bogart GZ; Tullis DE; Bresnik M; Derchak PA; Lewis SA; Ramsey BW. Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis. J Cyst Fibros, 2016 May 24. [PubMed]
The use of continuous inhaled antibiotic regimens of differing combinations is growing. This double-blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3 cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS). 90 subjects were randomized over 18months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p=0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p=0.14). AZLI/TIS CAT therapy was well tolerated.This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone.
– Although the initial approval for Tobi was for use on alternate months, clinicians gradually introduced a second inhaled antibiotic (often colistin) for the off-Tobi months to maintain the improved respiratory function. This study, to look at this practice using aztronam for the alternated months, finds it to be “well tolerated and possibly providing additional clinical benefit”.
2016 Horsley A, Jones AM, Lord R Antibiotic treatment for Burkholderia cepacia complex in people with cystic fibrosis experiencing a pulmonary exacerbation. Cochrane Database Syst Rev.2016 Jan 20;1:CD009529. doi: 10.1002/14651858.CD009529.pub3. [PubMed]
This review, which is an update of a previous review, aims to assess the available trial evidence for the choice and application of treatments for these infections.There is a lack of trial evidence to guide decision making and no conclusions can be drawn from this review about the optimal antibiotic regimens for people with cystic fibrosis who have chronic Burkholderia cepacia complex infections. Clinicians must continue to assess each person individually, taking into account in vitro antibiotic susceptibility data, previous clinical responses and their own experience
.- Although the problem of B.cepacia complex has been contained by precautions to avoid cross infection, the treatment of established infection remains a major problem.
2016 Jain K, Wainwright C, Smyth AR. Bronchoscopy-guided antimicrobial therapy for cystic fibrosis. Cochrane Database Syst Rev. 2016 Jan 21;1:CD009530.doi:10.1002/14651858.CD009530.pub3. [PubMed]
This review, essentially of Claire Wainwright’s own important study – a well-designed randomized-controlled study, shows no clear evidence to support the routine use of bronchoalveolar lavage for the diagnosis and management of pulmonary infection in pre-school children with cystic fibrosis compared to the standard practice of providing treatment based on results of oropharyngeal culture and clinical symptoms. No evidence was available for adult and adolescent populations.
– A very important study answering basic question regarding management of pre-school children with CF. The study clearly failed to show an advantage in regular bronchoalveolar surveillance of such children. This is a relief for to arrange annual bronchoscopy for all young children with CF would have been a major undertaking.
2016 Kappler M; Nagel F; Feilcke M; Kroner C; Pawlita I; Naehrig S; Ripper J; Hengst M; von Both U; Forstner M; Hector A; Griese M. Eradication of methicillin resistant Staphylococcus aureus detected for the first time in cystic fibrosis: A single center observational study. Pediatr Pulmonol 2016 Jul 5. [PubMed]
To retrospectively identify CF patients with methicillin resistant Staphylococcus aureus (MRSA) and to assess the long-term success of an eradication scheme introduced in 2002 for all newly colonized patients. All microbiological results from all 505 CF patients followed between 2002 and 2012 were analyzed focusing on the detection of MRSA. Retrospective patient record analysis of MRSA positive CF patients regarding eradication and clinical outcome. They identified 57 patients with MRSA, mean age 15.3 years (range: 0.6-36.9, incidence 0.9%/year). Of these, nine patients were lost to follow-up; seven chronically colonized patients were excluded from the intervention. Eradication was suggested to all patients, 37/41 gave their consent to the following two-step approach: (i) dual iv antibiotic treatment over 3 weeks, accompanied by hygienic directives and topical therapy for 5 days followed by a 6-week period with dual oral antibiotic therapy and inhalation with vancomycin. (ii) Each new MRSA detection was treated with 6 weeks inhalation of vancomycin and topical therapy for 5 days. Long-term eradication was rated by the microbiological status in the third year after first detection. MRSA was eradicated in 31 of 37 patients (84%) whose clinical course was stable (mean FEV1 one year before MRSA 80.4%, 3 years after MRSA 81.0%).MRSA colonization mandates complex and expensive hygienic measures which are not well accepted by patients. Therefore, MRSA eradication is desirable. Intensive therapy regimens may be successful in patients with CF and might help to maintain a stable clinical course.
2016 Kitt H, Lenney W, Gilchrist FJ. Two case reports of the successful eradication of new isolates of Burkholderia cepacia complex in children with cystic fibrosis. BMC Pharmacol Toxicol. 2016 Mar 28;17(1):14. doi: 10.1186/s40360-016-0054-0. [PubMed] Burkholderia cepacia was successfully eradicated in a 14 year old boy with CF and Burkholderia gladioli successfully eradicated in a six year old girl with CF. In both children two weeks of intravenous (IV) tobramycin, ceftazidime and temocillin were used followed by three months of inhaled tobramycin. Bronchoalveolar lavage samples taken during flexible bronchoscopy were used prior to treatment to exclude spontaneous clearance as well as after treatment to confirm eradication.New isolates of BCC can be successfully eradicated in children with CF. More research is urgently required in this area to identify the best treatment regimen for BCC eradication.
– It is certainly not general experience that “New isolates of BCC can be successfully eradicated in children with CF” as stated by the authors. Horsley et al, 2011. [PubMed] reported routine use of therapies to attempt eradication of new BCC is commonly used in the UK (12/17 centers responded). This typically involves a combination of intravenous and nebulised antibiotics. Of 19 eligible cases of new BCC infection, the organism was been eradicated in 7 (37%). Three of these did not receive specific eradication therapy. Of 14 patients who have received eradication therapy and completed follow up, BCC were cleared in only 4 (29%). Once established and chronic it is usually impossible to eradicate the organism.
2016 Konstan MW, Flume PA, Galeva I, Wan R, Debonnett LM, Maykut RJ, Angyalosi G. One-year safety and efficacy of tobramycin powder for inhalation in patients with cystic fibrosis. Pediatr Pulmonol. 2016 Apr;51(4):372-8. doi: 10.1002/ppul.23358. Epub 2015 Dec 27. [PubMed]This is an integrated analysis of data from patients with cystic fibrosis (CF) aged 6-21 years who were treated with up to seven cycles of tobramycin powder for inhalation (TIP(TM) ) over a period of at least 1 year. Safety and key efficacy endpoints were analyzed. The improvement in lung function and decrease in sputum P. aeruginosa (Pa) density from baseline were sustained over the 1-year treatment period. The number of adverse events (AEs) was low and did not increase with additional cycles of TIP treatment. Some increase in tobramycin minimum inhibitory concentration (MIC) was observed, but there was no significant increase in emergence of resistant strains based on the parenteral breakpoint for tobramycin. Efficacy of TIP was maintained for up to seven cycles. Long-term treatment with TIP was generally safe and well tolerated with no increase in AEs.
2016 Nichols DP, Happoldt CL, Bratcher PE, Caceres SM, Chmiel JF, Malcolm KC, Saavedra MT, Saiman L, Taylor-Cousar JL, Nick JA. Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis. J Cyst Fibros. 2016 Dec 24. pii: S1569-1993(16)30672-5. doi: 10.1016/j.jcf.2016.12.003. [Epub ahead of print][PubMed]
Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic. Test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modeling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump. Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV1 (L) increased 0.8% during a 4-week period of inhaled tobramycin and an additional 6.4% during a subsequent 4-week period of inhaled aztreonam (P<0.005). CFQ-R respiratory symptom score decreased 1.8 points during inhaled tobramycin and increased 8.3 points during subsequent inhaled aztreonam (P<0.001). A smaller number of trial participants not using azithromycin had similar improvement in lung function and quality of life scores during inhaled tobramycin and inhaled aztreonam. In vitro, azithromycin selectively reduced the bactericidal effects tobramycin in cultures of clinical strains of P. aeruginosa, while up regulating antibiotic resistance through MexXY efflux.
The authors concluded azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients.
– Further concerns regarding the value of long term azithromycin
2016 Prayle AP; Jain K; Touw DJ; Koch BC; Knox AJ; Watson A; Smyth AR. The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison. J Cyst Fibros 2016; 15(4):510-7. 2 Free article[PubMed]
Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. The aim was to investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. The authors’ conclusions were that renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels.
– The authors sate the clinical implications of a rise in KIM1 for the individual patient is not yet known
2016 Riethmuller J; Herrmann G; Graepler-Mainka U; Hellwig D; Heuer HE; Heyder S; Koster H; Kinder B; Kroger K; Paul K; Poplawska K; Melichar VO; Smaczny C; Mellies U.Sequential Inhalational Tobramycin-Colistin-Combination in CF-Patients with Chronic P. aeruginosa Colonization – an Observational Study. Cell Physiol Biochem 2016; 39(3):1141-51. [PubMed]
In a multicentre, open-label, exploratory, non-interventional study, inhaled tobramycin (300 mg twice daily) and colistin (1 million I.U. twice daily) were sequentially combined with the aim to investigate the effect on 41 CF patients with chronic P. aeruginosa infections for six months (mean age 24 +/- 10.8y). Six patients had adverse events that were assessed as being related to treatment. Mucus production and coughing both decreased in 39%, whereas FEV1 absolute and relative to baseline increased by 4.9% and 9.1%, respectively (p = 0.004) in 29 patients, who were definitely treated sequentially.
Efficacy of the therapy was rated ‘excellent’ or ‘good’ by the physicians in 80.5% of the patients. The results indicate that treatment with inhaled antibiotics, sequentially combined, was very well tolerated by most patients and may have a beneficial effect, even if transitory on lung function and respiratory symptoms.
2016 Samson C; Tamalet A; Thien HV; Taytard J; Perisson C; Nathan N; Clement A; Boelle PY; Corvol H. Long-term effects of azithromycin in patients with cystic fibrosis. Resp Med 2016;117:1-6. [PubMed]
The aim of this retrospective study was to investigate the effects of low-dose azithromycin treatment on the progression of CF lung disease in patients treated for more than 12 months. All of the CF patients followed in a pediatric center and who had been on low-dose azithromycin for more than 12 sequential months were included. The clinical data were collected for one year before and three years after the initiation of the azithromycin treatment. A total of 68 patients were included (mean age: 9.95 yrs (3.61)).
After 12 months, significant reductions in the numbers of pulmonary exacerbations and antibiotic courses were present. However, this effect was not maintained in the subsequent periods, during which increased rates of both pulmonary exacerbations and antibiotic courses were observed. The lung function decline was not modified during the treatment, and a decreasing time-dependent trend typical of CF was observed for the various parameters. No differences in the airway colonization by pathogens such as Pseudomonas aeruginosa and methicillin-sensitive and/or -resistant Staphylococcus aureus were observed during the treatment. However, isolated Staphylococcus aureus strains became resistant to macrolides after 6 months of azithromycin and remained resistant thereafter.
The authors concluded no clinical benefits of low-doses azithromycin were present after one year of treatment in young CF patients. Selection for macrolide-resistant strains of bacteria occurred, which should lead to a reconsideration of the duration of azithromycin treatment in CF.
– The initial interest in the use of macrolides (erythromycin) in chronic P. aeruginosa infection followed impressive results from Japan in diffuse panbronchiolitis (Kudoh S et al 1998. [PubMed]). The use in CF was approved following a study from USA showing a reduction in exacerbations (Saiman L et al.2003. [PubMed]). Further experience shows the benefits are not sustained and rarely cardiac abnormalities have been described. The CF Foundation guidelines recommend long term azithromycin for all patients of 6 years and older chronically infected with P. aeruginosa. In contrast, in the UK the CF Trust Antibiotic Working Group recommends azithromycin only if the patient is “deteriorating on conventional therapy”; the UK group considers there is insufficient evidence to recommend all patients with chronic P. aeruginosa should receive long term azithromycin.[see also Topics->Antibiotics classified-> Macrolides]
2016 van Koningsbruggen-Rietschel S, Heuer HE, Merkel N, Posselt HG, Staab D, Sieder C, Ziegler J, Krippner F, Rietschel E. Pharmacokinetics and safety of an 8 week continuous treatment with once-daily versus twice-daily inhalation of tobramycin in cystic fibrosis patients J Antimicrob Chemother. 2016 Mar;71(3):711-7. doi: 10.1093/jac/dkv399. Epub 2015 Nov 30. [PubMed]
The authors evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa.In this randomised, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow(®) rapid once daily and twice daily each for 8 weeks.
For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC0-90min ratio = 1.096, 90% CI = 0.860-1.396, P = 0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC0-90min ratio = 0.608, 90% CI = 0.461-0.802, P = 0.0055). The AUC0-90min ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC0-90min ratio = 0.749, 90% CI = 0.514-1.092, P = 0.2009). The mean FEV1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted.
The authors concluded continuous treatment with TIS (once daily or twice daily) over 8 weeks appears to be safe and tolerable.
2016 Vidya P; Smith L; Beaudoin T; Yau YC; Clark S; Coburn B; Guttman DS; Hwang DM; Waters V. Chronic infection phenotypes of Pseudomonas aeruginosa are associated with failure of eradication in children with cystic fibrosis. Eur J Clin Microbiol 2016; 35(1):67-74. [PubMed]
In 10-40 % of cases, eradication fails and the reasons for this are poorly understood. The purpose of this study was to determine whether specific microbial characteristics could explain eradication treatment failure. This was a cross-sectional study of CF patients (aged 0-18 years) with incident P. aeruginosa infection from 2011 to 2014 at the Hospital for Sick Children, Toronto, Canada. Phenotypic assays were done on all incident P. aeruginosa isolates, and eradicated and persistent isolates were compared using the Mann-Whitney test or the two-sided Chi-square test. A total of 46 children with CF had 51 incident P. aeruginosa infections.
In 72 % (33/46) of the patients, eradication treatment was successful, while 28 % failed eradication therapy. Persistent isolates were less likely to be motile, with significantly less twitch motility (p=0.001), were more likely to be mucoid (p=0.002), and more likely to have a tobramycin minimum inhibitory concentration (MIC)>128 mug/mL (p=0.02) compared to eradicated isolates. Although biofilm production was similar, there was a trend towards more persistent isolates with deletions in quorum-sensing genes compared with eradicated isolates (p=0.06).
The authors concluded that the initial acquisition of P. aeruginosa with characteristics of chronic infection is associated with failure of eradication treatment.
2016 Zhu B, Padroni M, Colombo G, Phillips G, Crapper J, Young PM, Traini D. The development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of cystic fibrosis. J Pharm. 2016 Apr 5. pii: S0378-5173(16)30284-8. doi: 10.1016/j.ijpharm.2016.04.009. [Epub ahead of print] [PubMed]
The aerosol performance and delivery characteristics of tobramycin for the treatment of respiratory infection were evaluated using the Orbital™, a multi-breath, high dose, dry powder inhaler (DPI). Micronised tobramycin was prepared and tested in the Orbital and in the commercially available TOBI Podhaler (Novartis AG). Furthermore, the TOBI Podhaler formulation containing tobramycin as Pulmospheres was tested in both the commercial Podhaler device (T-326) and Orbital for comparison.The Orbital was shown to be capable of delivering high efficiency, high dose antibiotic therapy for inhalation without the need for the use of multiple capsules as used in current devices.
– This appears to be an improvement on one of the most widely used and effective methods of treatment and is likely to improve adherence, which, understandably, is a major problem.
Batchelor H; Rayner O; Nickless J; Wan M; Southern K; Rose C. Children with cystic fibrosis: understanding issues related to oral administration of liquid flucloxacillin. Arch Dis Child 2016; 101(9):e2, [Pubmed]
Palatability of flucloxacillin is poor, yet is used long-term in the management of children with cystic fibrosis (CF). Strategies to aid administration of unpalatable medicines have been reported, however there has never been a systematic approach to gathering views of many parents/carers all administering the same medication to the same population of children. This study aimed to quantify the extent of flucloxacillin palatability issues for parents/cares of children with CF and identify parent/carer and healthcare professional (HCP) reported age-specific strategies to aid administration of flucloxacillin to children with CF.
The results from this study showed that flucloxacillin is unpalatable and that parents/carers use a range of strategies to improve acceptability of this product. Although food is an obvious strategy for making flucloxacillin more palatable when treating an acute infection; it may be that this doesn’t work in longer term therapy (e.g. CF) and the wider population can learn from parents/carers with more experience with this medicine. Parents of children with CF and HCPs have provided useful age-specific strategies to ease administration of the known poorly tolerated medicine, liquid flucloxacillin.
Dr, Hannah Batchelor (figure) is Senior Lecturer in Pharmaceutics, Formulation and Drug Delivery, Institute of Clinical Sciences, University of Birmingham.
– A practically useful study by pharmacists, parents, CF Trust and a paediatrician that should be of help to parents. Hannah Batchelor’s research focuses on the design and manipulation of medicines to create age appropriate drug formulations to maximise clinical efficacy in paediatric
2017 Blanchard AC, Horton E, Stanojevic S, Taylor L, Waters V, Ratjen F. Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis. J Cyst Fibros. 2017 Feb 9. pii: S1569-1993(17)30014-0. doi: 10.1016/j.jcf.2017.01.007. [Epub ahead of print] [Pubmed]
The aim of this study was to evaluate the effectiveness of a multi-step protocol for AET (antibiotic eradication therapy) for new-onset Pseudomonas infections in children with CF. A three-step AET protocol was used which includes: (step 1) 28 days of tobramycin inhalation solution (TIS) for new-onset Pa infection; (step 2) a second course of TIS for patients with positive respiratory tract culture after step 1; (step 3) 14 days of intravenous antibiotics followed by 28 days of TIS for patients with a subsequent positive culture. During the study period, 128 patients had a total of 213 new-onset Pa infections. Of 195 asymptomatic episodes, 150 (76.9%, 95% CI 70.4; 82.6) cleared after step 1 and 12 cleared after step 2 (33.3% (95% CI 18.6; 50.9) stepwise success rate and 87.1% (95% CI 77.1; 88.1) cumulative success rate). Intravenous antibiotics followed by 28days of TIS were administered in 24 episodes; this was successful in 10 episodes (41.7%; 95% CI 22.1; 63.4). The regimen in asymptomatic patients failed in fourteen episodes (7.5%; 95% CI 4.2; 12.3) then considered chronically infected with Pa. Overall, the cumulative success rate of the asymptomatic arm was 88.2% (95% CI 82.8; 92.4).
The authors concluded the first step of the AET protocol led to the greatest eradication success. Subsequent eradication attempts have a success rate below 50%. They suggest prospective studies of eradication protocols for this population are needed to determine the most effective treatment strategy.
~ It would appear that the success in eradication is related both to the Pa strain and the time to starting treatment from first isolation. Obviously if cultures are infrequent the culture may have been positive for some time before recognised. So both regular cultures and early treatment appear to be very important. The Torpedo study from Europe is another study looking at effectiveness of eradication therapy and will assess whether ten days intravenous ceftazidime with tobramycin is superior to three months oral ciprofloxacin at eradicating P. aeruginosa from the lungs of Cystic Fibrosis patients. Both treatment regimes will be in conjunction with three months nebulised colistin.
Ana Blanchard (figure) is a Clinical Fellow at the Hospital For Sick Children, Toronto.
2017 Deppisch C, Herrmann G, Graepler-Mainka U, Wirtz H, Heyder S, Engel C, Marschal M, Miller CC, Riethmüller J. Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection. 2016 Aug;44(4):513-20. doi: 10.1007/s15010-016-0879-x. Epub 2016 Feb 9. [Pubmed]
Nitric oxide (NO) gas possesses antimicrobial activity against a wide variety of microorganisms in vitro, in vivo in animal models and a phase I study in healthy adults showed administration of intermittent 160 ppm NO to be safe.
The authors assessed feasibility and safety of inhaled NO in eight CF patients who received 160 ppm NO for 30 min, three times daily for 2 periods of 5 days. The NO treatment was safe and in none of the patients were serious drug-related adverse events observed which caused termination of the study. The intention-to-treat analysis revealed a significant mean reduction of the colony forming units of all bacteria and all fungi, while mean forced expiratory volume 1 s % predicted (FEV1) relative to baseline increased 17.3 ± 8.9 % (P = 0.012).
The authors concluded that NO treatment may improve the therapy of chronic microbial lung infections in CF patients, particularly concerning pathogens with intrinsic or acquired resistance to antibiotics.
– Antibiotic resistance is, and will continue to be, an increasing problem so approaches such as this deserve thorough evaluation.
2017 Downes KJ, Dong M, Fukuda T, Clancy JP, Haffner C, Bennett MR, Vinks AA, Goldstein SL. Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis. J Antimicrob Chemother. 2017 Jan;72(1):254-260. Epub 2016 Sep 1.[Pubmed]
The authors evaluated the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and tested the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1). They describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Their findings suggest that patient weight and urinary NGAL or RBP could be used to individualise tobramycin therapy in patients with CF
– Dr. Kevin J. Downes (figure) is an attending physician in the Division of Infectious Diseases at The Children’s Hospital of Philadelphia – previously at the Children’s Hospital Cincinnati.
2017 Handelsman JA, Nasr SZ, Pitts C2, King WM. Prevalence of hearing and vestibular loss in cystic fibrosis patients exposed to aminoglycosides. Pediatr Pulmonol. 2017 Sep;52(9):1157-1162. doi: 10.1002/ppul.23763. Epub 2017 Jul 24.[Pubmed
Of the authors’ cohort of 71 patients, 56 (79%) patients have vestibular system dysfunction while only 15 (21%) have normal vestibular system function. Overall, 16 patients (23%) have hearing loss. In considering the relationship between auditory and vestibular function, 12 (17%) demonstrated both normal hearing and normal vestibular function and 13 (18%) have both hearing loss and abnormal vestibular function. Of the 55 (78%) patients with normal hearing, 43 (61%) have vestibular dysfunction, while 3 (4%) of patients with normal vestibular function have hearing loss.
The authors consider these results suggest that monitoring hearing alone appears to be insufficient to detect ototoxicity in CF patients being treated with systemic aminoglycosides.
Dr. Jayne Handelsman (figure) is director of pediatric audiology in the Department of Otolaryngology-Head and Neck Surgery at the University of Michigan. She is President of the American Speech-Language-Hearing Association (ASHA),
2017 Langton Hewer SC; Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. [Review][Update of Cochrane Database Syst Rev. 2014 Nov 10;(11):CD004197; PMID: 25383937] Cochrane Database of Systematic Reviews. 4:CD004197, 2017 04 25. [Pubmed]
The authors’ main conclusions were that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. However, they consider there is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.
Simon Langton-Hewer (figure) is a consultant paediatrician in Bristol and currently conducting a trial (Torpedo) on the role of IV antibiotics in the eradication of early P. aeruginosa infection.
– The authors’ conclusions from this extensive Cochrane review deserve comment, in particular – “There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment”. Although trials conforming to rigorous Cochrane standards may not be available, there is now a wealth of published evidence and experience that avoidance or delay of chronic P. aeruginosa infection by eradication certainly does decrease morbidity and improve the quality of life.
For example the 2015 statement on the CF Foundation’s website is unequivocal and reads –“Chronic infection with P. aeruginosa is associated with increased morbidity and mortality. Effective regimens include antibiotic therapy for newly acquired infection and routine surveillance with oropharyngeal cultures”.
Other relevant publications include the following –
– Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr. 2001;138(5):699–704. http://dx.doi.org/10.1067/mpd.2001.112897[PubMed]
Acquisition of P aeruginosa was common by 7 years of age in this CF birth cohort and was associated with increased morbidity and mortality ’
– Hudson VL, Wielinski CL, Regelmann WE. Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years. J Pediatr. 1993;122(6):854–860. http://dx.doi.org/10.1016/S0022-3476(09)90007-5 [PubMed] P.aeruginosa in initial oropharyngeal cultures from patients ≤2 years of age with cystic fibrosis was associated with significantly increased morbidity, and the finding of P. aeruginosa and S. aureus together in initial oropharyngeal cultures with a significantly increased mortality rate during the first 10 years after diagnosis.
– Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277–287. http://dx.doi.org/10.1002/ppul.2009.abs [PubMed] “Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative.”
– Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):91–100. http://dx.doi.org/10.1002/ppul.10127 [PubMed] The authors conducted a registry-based study to determine prognostic indicators of 8-year mortality and morbidity in young children with cystic fibrosis (CF). Patients ages 1–5 years from the 1990 U.S. Cystic Fibrosis Foundation (CFF) National Patient Registry served as the study cohort (N = 3,323). Registry data provided information on baseline characteristics in 1990, 8-year mortality, and clinical outcomes in 1998. P. aeruginosa respiratory infection was found to be a major predictor of morbidity and mortality. The 8-year risk of death was 2.6 times higher in patients who had respiratory cultures positive for P. aeruginosa in 1990 (95% confidence interval 1.6, 4.1) than in children without P. aeruginosa in their respiratory cultures. Culture-positive patients in 1990 also had a significantly lower percent predicted forced expiratory volume in 1 sec (FEV1) and weight percentile at follow-up, and they had an increased risk of continued P. aeruginosa respiratory infection and hospitalisation for acute respiratory exacerbation in 1998. Among the other predictors of increased morbidity and mortality were lower baseline weight percentiles and number of CF-related hospitalisations during the baseline year.
– So one must seriously question the authors’ conclusions regarding the adverse effects following acquisition of P.
2017 Muhlebach MS, Beckett V, Popowitch E, Miller MB, Baines A, Mayer-Hamblett N, Zemanick ET, Hoover WC, VanDalfsen JM, Campbell P, Goss CH; STAR-too study team. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax. 2017 Apr;72(4):318-326. doi: 10.1136/thoraxjnl-2016-208949. Epub 2016 Nov 15.[Pubmed
To evaluate microbiological effectiveness, that is, culture negativity, of a non-blinded eradication protocol (Rx) compared with observation (Obs) in clinically stable cystic fibrosis participants with newly positive methicillin resistant Staphylococcus aureus (MRSA) cultures. This non-blinded trial randomised participants ages 4-45 years with first or early (≤2 positive cultures within 3 years) MRSA-positive culture without MRSA-active antibiotics within 4 weeks 1:1 to Rx or Obs. The Rx protocol was: oral trimethoprim-sulfamethoxazole or if sulfa-allergic, minocycline plus oral rifampin; chlorhexidine mouthwash for 2 weeks; nasal mupirocin and chlorhexidine body wipes for 5 days and environmental decontamination for 21 days. The primary end point was MRSA culture status at day 28.
Between 1 April 2011 to September 2014, 45 participants (44% female, mean age 11.5 years) were randomised (24 Rx, 21 Obs). At day 28, 82% (n=18/22) of participants in the Rx arm compared with 26% (n=5/19) in the Obs arm were MRSA-negative. Adjusted for interim monitoring, this difference was 52% (95% CI 23% to 80%, p<0.001). Limiting analyses to participants who were MRSA-positive at the screening visit, 67% (8/12) in the Rx arm and 13% (2/15) in the Obs arm were MRSA-negative at day 28, adjusted difference: 49% (95% CI 22% to 71%, p<0.001). Fifty-four per cent in the Rx arm compared with 10% participants in the Obs arm remained MRSA-negative through day 84. Mild gastrointestinal side effects were higher in the Rx arm.
The authors concluded this MRSA eradication protocol for newly acquired MRSA demonstrated microbiological efficacy with a large treatment effect.
Marianne S Muhlebach (figure) is Professor and paediatric pulmonologist at UNC School of Medicine.
Nichols DP, Happoldt CL, Bratcher PE, Caceres SM, Chmiel JF, Malcolm KC, Saavedra MT, Saiman L, Taylor-Cousar JL, Nick JA. Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis. J Cyst Fibros. 2017 May;16(3):358-366. doi: 10.1016/j.jcf.2016.12.003. Epub 2016 Dec 24.[Pubmed]
Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic. To test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modelling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump. Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV1 (L) increased 0.8% during a 4-week period of inhaled tobramycin and an additional 6.4% during a subsequent 4-week period of inhaled aztreonam (P<0.005). CFQ-R respiratory symptom score decreased 1.8 points during inhaled tobramycin and increased 8.3 points during subsequent inhaled aztreonam (P<0.001). A smaller number of trial participants not using azithromycin had similar improvement in lung function and quality of life scores during inhaled tobramycin and inhaled aztreonam. In vitro, azithromycin selectively reduced the bactericidal effects tobramycin in cultures of clinical strains of P. aeruginosa, while up regulating antibiotic resistance through MexXY efflux
The authors concluded azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients. The authors are now conducting a prospective trial to test the impact of adding oral azithromycin to inhaled tobramycin in subjects with CF and chronic P. aeruginosa infection
2017 Pauna HF, Monsanto RC, Kurata N, Paparella MM, Cureoglu S. Changes in the inner ear structures in cystic fibrosis patients. J Pediatr Otorhinolaryngol. 2017 Jan;92:108-114. doi: 10.1016/j.ijporl.2016.11.013. Epub 2016 Nov 16. [Pubmed]
The authors used human temporal bones to analyse the density of vestibular dark, transitional, and hair cells in specimens from CF patients who were exposed to several types of antibiotics, as compared with specimens from an age-matched control group with no history of ear disease or antibiotic use. Additionally, they analysed the changes in the elements of the cochlea (hair cells, spiral ganglion neurones, and the area of the stria vascularis). Data was gathered using differential interference contrast microscopy and light microscopy.
In the CF group, 83% of patients were exposed to some ototoxic drugs, such as aminoglycosides. As compared with the control group, the density of both type I and type II vestibular hair cells was significantly lower in all structures analysed; the number of dark cells was significantly lower in the lateral and posterior semicircular canals. They noted a trend toward a lower number of both inner and outer cochlear hair cells at all turns of the cochlea. The number of spiral ganglion neurones in Rosenthal’s canal at the apical turn of the cochlea was significantly lower; furthermore, the area of the stria vascularis at the apical turn of the cochlea was significantly smaller.
The authors concluded deterioration of cochlear and vestibular structures in CF patients might be related to their exposure to ototoxic antibiotics. They comment that well-designed case-control studies are necessary to rule out the effect of CF itself.
Henrique Furlan Pauna (figure) is Affiliated Staff, Department of Otorhinolaryngology, Head and Neck Surgery, University of Campinas, Brazil
~ This is an unusual study where the anatomical changes in both cochlear and peripheral vestibular systems in the ears of people with CF were examined.
2017 Schneider EK, Azad MA, Han ML, Tony Zhou Q, Wang J, Huang JX, Cooper MA, Doi Y, Baker MA, Bergen PJ, Muller MT, Li , Velkov T. An “Unlikely” Pair: The Antimicrobial Synergy of Polymyxin B in Combination with the Cystic Fibrosis Transmembrane Conductance Regulator Drugs KALYDECO and ORKAMBI. ACS Infect Dis. 2016 Jul 8;2(7):478-88. doi: 10.1021/acsinfecdis.6b00035. Epub 2016 May 17. [Pubmed]
Novel combination therapies are desperately needed for combating lung infections caused by bacterial “superbugs”. This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa isolates from the lungs of CF patients. Polymyxin B, ivacaftor, and lumacaftor were ineffective when used individually against polymyxin-resistant (MIC ≥ 4 mg/L) isolates. However, when used together, the combination of clinically relevant concentrations of polymyxin B (2 mg/L) combined with ivacaftor (8 mg/L) or ivacaftor (8 mg/L) + lumacaftor (8 mg/L) displayed synergistic killing activity against polymyxin-resistant P. aeruginosa isolates as demonstrated by a 100-fold decrease in the bacterial count (CFU/mL) even after 24 h. The combinations also displayed excellent antibacterial activity against P. aeruginosa under CF relevant conditions in a sputum medium assay. The combination of lumacaftor (alone) with polymyxin B showed additivity against P. aeruginosa. The potential antimicrobial mode of action of the combinations against P. aeruginosa was investigated using different methods. Treatment with the combinations induced cytosolic GFP release from P. aeruginosa cells and showed permeabilizing activity in the nitrocefin assay, indicating damage to both the outer and inner Gram-negative cell membranes. Moreover, scanning and transmission electron micrographs revealed that the combinations produce outer membrane damage to P. aeruginosa cells that is distinct from the effect of each compound per se. Ivacaftor was also shown to be a weak inhibitor of the bacterial DNA gyrase and topoisomerase IV with no effect on either human type I or type IIαtopoisomerases. Lumacaftor displayed the ability to increase the cellular production of damaging reactive oxygen species.
In summary, the combination of polymyxin B with KALYDECO or ORKAMBI exhibited synergistic activity against highly polymyxin-resistant P. aeruginosa CF isolates and can be potentially useful for otherwise untreatable CF lung infections.
2017 Alan R Smyth, Jayesh Bhatt, Sarah J Nevitt. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis Database of Systematic Reviews 2017 March 27, 3: CD002009 [Pubmed]
Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants (aged 5 to 50 years) were considered suitable to included in this review.
The authors conclude that once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.
2017 Smyth AR; Rosenfeld M. Prophylactic anti-staphylococcal antibiotics for cystic fibrosis. Update of Cochrane Database Syst Rev. 2014 Nov 24;(11):CD001912;PMID: 25419599 Cochrane Database of Systematic Reviews. 4:CD001912,[Pubmed]
This is an update of a previously published review. The authors included four studies, with a total of 401 randomised participants aged zero to seven years on enrolment; one study is ongoing. After the customary criticisms of methodology of a number of previous trials the authors found that fewer children receiving anti-staphylococcal antibiotic prophylaxis had one or more isolates of Staphylococcus aureus (low quality evidence). There was no significant difference between groups in infant or conventional lung function (moderate quality evidence). They found no significant effect on nutrition (low quality evidence), hospital admissions, additional courses of antibiotics (low quality evidence) or adverse effects (moderate quality evidence). There was no significant difference in the number of isolates of Pseudomonas aeruginosa between groups (low quality evidence), though there was a trend towards a lower cumulative isolation rate of Pseudomonas aeruginosa in the prophylaxis group at two and three years and towards a higher rate from four to six years. As the studies reviewed lasted six years or less, conclusions cannot be drawn about the long-term effects of prophylaxis.
The authors concluded anti-staphylococcal antibiotic prophylaxis results in fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.
– This review finds that fewer children on prophylaxis isolated S. aureus which is a good positive finding. The oft-quoted increase in P. aeruginosa in children on prophylaxis (although based on unsatisfactory evidence) is of even less significance now early eradication P. aeruginosa is so effective. Anti-staphyloccocal prophylaxis should be advised. However, for those opposed to continuous prophylaxis it should be noted Copenhagen patients are not on long-term prophylaxis but do have monthly respiratory cultures; they require two courses of anti-staphylococcal antibiotics annually to treat positive cultures to remain free of chronic S. aureus infection.
Everything possible should be done to prevent chronic S. aureus infection – which does not appear to be the policy at some CF Centres as judged by the substantial proportion of their patients who have chronic S. aureus infection.
2016 Sommerwerck U, Virella-Lowell I, Angyalosi G, Viegas A, Cao W, Debonnett L. Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study. Cur Med Res Opin. 2016 Nov;32(11):1789-1795. Epub 2016 Sep 9.[Pubmed]
Long-term treatment with inhaled antibiotics is recommended for chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients. The ETOILES study (Clinicaltrials.gov identifier: NCT01519661) evaluated the safety of tobramycin inhalation powder (TIP) for 1 year.
This single-arm, open-label, multicenter, phase IV trial, enrolled CF patients aged ≥6 years, with baseline FEV1 ≥25%-≤75% predicted and Pa infection, and assessed the safety of TIP over six cycles in terms of the incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included presence of airway reactivity, relative change in FEV1% predicted, and change in sputum Pa density (log10 colony forming units/g sputum).
A total of 157 patients were enrolled, and 96 patients (61.1%) completed the study. The most commonly reported AE was infective pulmonary exacerbation of CF (55.4%). Cough was reported as an AE in 23.6% of patients; a majority were mild or moderate and two were severe (1.3%). SAEs were reported by 31.2% of patients. No deaths were reported during the study. There were no clinically meaningful changes reported in airway reactivity. Most frequently reported post-inhalation event was cough at all time points; however, it was of short duration (<4 minutes) and decreased over the course of the study, possibly due to patients becoming more experienced with the administration of TIP. The post-inhalation events resolved without intervention in most cases. FEV1% predicted remained stable from Cycles 1 to 4 and tended to decrease thereafter, although it was not statistically significant (change from baseline to study end mean [SD] = -1.9% [14.55]; P = 0.199).
This was one of the largest studies with long-term TIP exposure. The majority of patients enrolled were adults with more advanced CF lung disease than those in previous TIP studies. No new emerging safety signals were seen and efficacy was sustained during the year.
Dr. Urte Sommerwerck (figure) works in the Department of Pneumonology, Ruhrlandklinik, West German Lung Centre, University Hospital Essen, Essen , Germany.
2017 Stanojevic S; McDonald A; Waters V; MacDonald S; Horton E; Tullis E; Ratjen F. Effect of pulmonary exacerbations treated with oral antibiotics on clinical outcomes in cystic fibrosis. Thorax. 72(4):327-332, 2017 Apr.[Pubmed]
Despite extensive knowledge regarding the effect of pulmonary exacerbations treated with intravenous antibiotics on clinical outcomes in cystic fibrosis (CF), there is little known about the role of milder pulmonary exacerbations treated with oral antibiotics (oPEx). This was a retrospective cohort study of patients with CF followed at the Hospital for Sick Children and St. Michael’s Hospital from 2009 to 2014. The authors evaluated the effect of oPEx on short-term clinical outcomes as the proportion of oPEx events in which 100% or 90% of baseline FEV1% predicted was recovered at the end of treatment. They then examined the association of the number of oPEx events in the past 12 months on lung function (FEV1% predicted) and nutritional status (body mass index (BMI) z-score) using a mixed-effects model.
There were a total of 2608 oPEx events in 570 subjects during the study period. In over half (53.4%) of oPEx events, lung function was already at 90% or higher of baseline FEV1 at the initiation of oral antibiotic therapy and 82% were at 90% or higher of baseline FEV1 at follow-up.
In individuals with CF, one or more oPex events in the previous 12 months were associated with decreased FEV1 compared with 12 months periods without oPex events. When the cumulative effect of oPExs on lung function was examined over the entire study period, patients with six or more oPEx events had the steepest rate of FEV1 decline. oPEx events were not associated with changes in BMI.
The authors concluded pulmonary exacerbations treated with oral antibiotics are associated with short-term loss of FEV1 and have a negative effect on lung function.
Dr Sanja Stanojevic (figure) is a member of the Department of Pediatrics, Hospital for Sick Children, and the Institute of Health Policy, University of Toronto.
2017 Abigail Strang, Anthony J Fischer, Aaron Chidekel. Pseudomonas eradication and clinical effectiveness of Ivacaftor in four Hispanic patients with S549N. Pediatr Pulmonol 2017; 52(7):E37-E39 April [Pubmed]
Ivacaftor was approved for rarer class-III CFTR mutations including S549N in 2014. Since these mutations are uncommon, ongoing reports of patient experiences with Ivacaftor and these mutations are important. This case series describes the clinical effectiveness (including airway infection status, lung function, and growth) of Ivacaftor therapy in four pediatric Hispanic patients with S549N and F508del over 24 months. In these patients, Ivacaftor was highly efficacious with no further Pseudomonas-positive cultures despite prior chronic colonization in three patients as well as notable improvements in lung function and growth. The remarkable improvements in lung function and growth were similar to G551D patients with more striking changes in airway infection status.2017
Dr Abigail Strang (figure) is paediatric pulmonologist at the Department of Pulmonology, A.I. du Pont Hospital for Children, Wilmington, Delaware.
2017 Waters V, Yau Y, Beaudoin T, Wettlaufer J, Tom SK, McDonald N, Rizvi L, Klingel M, Ratjen F, Tullis E. Pilot trial of tobramycin inhalation powder in cystic fibrosis patients with chronic Burkholderia cepacia complex infection. J Cyst Fibros 2017;16(4):492-495.[Pubmed]
There is no effective chronic suppressive therapy Burkholderia cepacia complex infection in cystic fibrosis (CF) patients. This was a pilot, open-label clinical trial of tobramycin inhalation powder (TIP) delivered via Podhaler twice daily for 28days in adults and children with CF and chronic B. cepacia complex infection in Toronto, Canada. A total of 10 subjects (4 pediatric, 6 adult patients) were treated. There was a mean drop of 1.4 log (CFU/ml) in sputum bacterial density (p=0.01) and sputum IL-8 levels decreased significantly after 28days of TIP (p=0.04). The mean relative change in FEV1 (L) from Day 0 to Day 28 of TIP administration was a 4.6% increase but this was not statistically significant. The majority of patients (70%) had no or mild adverse event
Dr Valerie Waters (figure 5) is an Associate Professor in the Department of Paediatrics at the University of Toronto and an infectious diseases physician at the Hospital for Sick Children.
Garcia BA, Carden JL, Goodwin DL, Smith TA, Gaggar A, Leon K, Antony VB, Rowe SM, Solomon GM. Implementation of a successful eradication protocol for Burkholderia Cepacia complex in cystic fibrosis patients.
BMC Pulm Med. 2018 Feb 14;18(1):35. doi: 10.1186/s12890-018-0594-8.2 free PMC article [Pubmed]
The authors developed and implemented a single center Bcc eradication protocol that included an intensive combination of intravenous, inhaled, and oral antibiotic therapies based on in vitro sensitivities. They conducted a retrospective cohort analysis of clinical outcomes compared to patients with chronic Bcc infection. Six patients were identified as having a newly acquired Bcc colonization and were placed on the eradication protocol. Sequential sputum samples after completion of the protocol demonstrated sustained clearance of Bcc in all patients. Lung function and nutritional status remained stable in the year following eradication.Clearance of Bcc from sputum cultures using a standardized protocol was successful at one year and was associated with clinical stability.
Details of the protocol are included in the free article available via PubMed. Essentially an induction period (21 days) of intravenous tobramycin and ceftazidime, inhaled tobramycin oral trimethoprim/sulphamethoxazole and oral azithromycin then a consolidation period (2 months) of inhaled tobramycin, oral trimethoprim/sulfamethoxazole and azithromycin.
From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, 1900 University Blvd, THT 422, Birmingham, AL, 35294, USA.
Hurley MN, Fogarty A, McKeever TM, Goss CH, Rosenfeld M, Smyth AR. Early Respiratory Bacterial Detection and Antistaphylococcal Antibiotic Prophylaxis in Young Children with Cystic Fibrosis. Ann Am Thorac Soc. 2018 Jan;15(1):42-48. doi: 10.1513/AnnalsATS.201705-376OC [PubMed]
Consensus is lacking regarding anti-staphylococcal antibiotic prophylaxis use for young children with cystic fibrosis. Prophylaxis is recommended in the United Kingdom, but it is recommended against in the United States. To test the hypothesis that anti-staphylococcal antibiotic prophylaxis is associated with a decreased risk of Staphylococcus aureus acquisition but no increased risk of Pseudomonas aeruginosa acquisition. The authors undertook a longitudinal observational study of children with cystic fibrosis who were recruited from birth (or from their first registry entry in the period) and followed until the age of 4 years (1,500 d) using 2000-2009 data from the UK Cystic Fibrosis Trust and Cystic Fibrosis Foundation registries. Children were excluded if they had a positive culture result for S. aureus or P. aeruginosa, or if they were receiving inhaled antibiotics, at the first encounter. Time to first S. aureus and P. aeruginosa detection in the UK/U.S. cohorts was compared using a Cox proportional hazards model. A UK-based analysis compared the same for those receiving flucloxacillin with those who received no prophylaxis. They included the following covariates: sex, age at registry entry, dornase alfa use, genotype, and centre size.
The primary analysis comprised 1,074 UK and 3,677 U.S. children. The risk of first detection was greater in U.S. children than in UK children for S. aureus (hazard ratio [HR], 5.79; 95% confidence interval [CI], 4.85, 6.90; P < 0.001) and P. aeruginosa (HR, 1.92; 95% CI, 1.65, 2.24; P < 0.001). In the UK analysis, we compared 278 children receiving flucloxacillin and 306 receiving no prophylaxis. Flucloxacillin was not associated with a reduced risk of S. aureus detection (HR, 1.22; 95% CI, 0.74, 2.0; P = 0.43), but it was associated with an increased risk of P. aeruginosa detection (HR, 2.53; 95% CI, 1.71, 3.74; P < 0.001). None of the covariates significantly affected the risk estimate in either analysis.
The risk of first detection of S. aureus and P. aeruginosa was greater in the United States than in the United Kingdom. In the United Kingdom, the risk of first P. aeruginosa detection was increased among those receiving flucloxacillin compared with those who received no prophylaxis. The authors consider these observational findings should be examined in randomized controlled trials.
Jain K, Wainwright C, Smyth AR.Bronchoscopy-guided antimicrobial therapy for cystic fibrosis.
Cochrane Database Syst Rev. 2018 Sep 17;9:CD009530. doi: 10.1002/14651858.CD009530.pub4. [Pubmed]
(Update of Bronchoscopy-guided antimicrobial therapy for cystic fibrosis. [Cochrane Database Syst Rev. 2016]) The authors’ summary states this review, limited to a single, well-designed randomized controlled study (of Claire Wainwright and colleagues), which shows no clear evidence to support the routine use of bronchoalveolar lavage for the diagnosis and management of pulmonary infection in pre-school children with cystic fibrosis compared to the standard practice of providing treatment based on results of oropharyngeal culture and clinical symptoms. No evidence was available for adult and adolescent populations.
Mayer-Hamblett N, Retsch-Bogart G, Kloster M, Accurso F, Rosenfeld M, Albers G, Black P, Brown P, Cairns A, Davis SD, Graff GR, Kerby GS, Orenstein D, Buckingham R, Ramsey BW; OPTIMIZE Study Group. Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis: The Optimize Randomized Trial. Am J Respir Crit Care Med. 2018 Jun 11. doi: 10.1164/rccm.201802-0215OC. [Epub ahead of print] [Pubmed]
A study to test the hypothesis that the addition of azithromycin to TIS in children with CF and early Pa decreases the risk of PEx and prolongs time to Pa recurrence.The OPTIMIZE trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF ages 6 months-18 years with early Pa. Azithromycin or placebo was given 3x weekly with standardized TIS. The primary endpoint was time to PEx requiring antibiotics and secondary endpoint time to Pa recurrence, in addition to other clinical and safety outcomes.
221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrolment was stopped early by the National Heart, Lung, and Blood Institute (NHLBI) because the trial had reached the pre-specified interim boundary for efficacy. The risk of PEx was reduced by 44% in the azithromycin group as compared to placebo (hazard ratio [HR]: 0.56, 95% CI:0.37,0.83, p=0.004). Weight increased by 1.27 kg in the azithromycin group compared to placebo (95% CI:0.01,2.52, p=0.046). No significant differences were seen in microbiologic, clinical, or safety endpoints.
The authors concluded azithromycin was associated with a significant reduction in risk of PEx and sustained improvement in weight but had no impact on microbiologic outcomes in children with early Pa.
Ratjen F, Moeller A, McKinney ML, Asherova I, Alon N, Maykut R, Angyalosi G; EARLY study group. Collaborators (12)Eradication of early P. aeruginosa infection in children <7 years of age with cystic fibrosis: The early study. J Cyst Fibros. 2018 Apr 20. pii: S1569-1993(18)30087-0. doi: 10.1016/j.jcf.2018.04.002. [Epub ahead of print] [Pubmed]
Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited. This double-blind, placebo-controlled trial randomised CF patients aged 3 months to <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29.
On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p < 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo.
The authors concluded TOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients.
– Not mentioned in the summary was the fact that at day 91 more patients receiving TOBI during the initial 28 days (the TOBI/placebo group:19/25 patients, 76%) were Pa free compared with those initially on placebo (placebo/TOBI group: 11/23 patients 47.8 %). This was unfortunate for the latter group and emphasises the point that eradication treatment must be early – the greater the delay in initiating treatment the more the risk of chronic Pa infection as occurred in these placebo-treated children. These facts were already known however apparently this trial has satisfied the regulatory requirements.
Spoletini G, Kennedy M, Flint L, Graham T, Etherington C, Shaw N, Whitaker P, Denton M, Clifton I, Peckham D. Intravenous fosfomycin for pulmonary exacerbation of cystic fibrosis: Real life experience of a large adult CF centre.Pulm Pharmacol Ther. 2018 Apr 13. pii: S1094-5539(17)30305-X. doi: 10.1016/j.pupt.2018.04.007. [Epub ahead of print] [Pubmed]
A study to describe the clinical efficacy, safety and tolerability of intravenous fosfomycin in combination with a second anti-pseudomonal antibiotic to treat pulmonary exacerbations in adult patients with CF.
A retrospective analysis of data captured prospectively. 54 patients received 128 courses of iv fosfomycin in combination with a second antibiotic, resulting in improved FEV1 (0.94 L vs 1.24 L, p < 0.01) and reduced CRP (65 mg/L vs 19.3 mg/L, p < 0.01). Renal function pre- and post-treatment remained stable. 4% (n = 5) of courses were complicated with AKI at mid treatment, which resolved at the end of the course. Electrolyte supplementation was required in 18% of cases for potassium and magnesium and 7% for phosphate. Nausea was the most common side effects (48%), but was well controlled with anti-emetics
Antibiotic regimens including fosfomycin appear to be clinically effective and safe. Fosfomycin should, therefore, be considered as an add-on therapy in patients who failed to respond to initial treatment and with multiple drug allergies.
Dr.Giulia Spoletini is Clinical Research Fellow in Leeds Teaching Hospitals.
Wright MFA, Bush A, Carr SB. Hypersensitivity reactions to intravenous antibiotics in cystic fibrosis. Paediatr Respir Rev. 2018 Apr 5. pii: S1526-0542(18)30047-2. doi: 10.1016/j.prrv.2018.01.003. [Epub ahead of print] [Pubmed]
Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required.
McKinzie CJ, Chen L, Ehlert K, Grisso AG, Linafelter A, Lubsch L, O’Brien CE, Pan AC, Wright BA, Elson EC. Off-label use of intravenous antimicrobials for inhalation in patients with cystic fibrosis.1 Pediatr Pulmonol. 2019 Nov;54 Suppl 3:S27-S45. doi: 10.1002/ppul.24511. [Pubmed]
Management of infections in patients with cystic fibrosis (CF) presents challenges for healthcare providers, including the eradication of initial acquisition, treatment of acute exacerbations, and chronic infection with suppressive therapy. Inhaled antimicrobial therapy for infections in patients with CF has been used in these capacities, often in an effort to achieve optimal concentrations in sputum for antimicrobial efficacy while mitigating potential toxicities associated with systemic therapy. Unfortunately, there are few commercially available products formulated for inhalation, resulting in the off-label use of other formulations, such as intravenous products, administered via nebulisation.
This review aims to examine the evidence supporting the efficacy of these off-label formulations for management of acute and chronic infections associated with CF, as well as adverse effects associated with their use.
Dr Cameron J McKinzie from the Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, North Carolina.
– A useful review for off-label use of many clinically useful preparations. Currently, the only commercially available formulations of inhaled antimicrobials include tobramycin, aztreonam, colistimethate, and amikacin, depending on the geographic location of the patient.
Van Stormbroek B, Zampoli M, Morrow BM. Nebulized gentamicin in combination with systemic antibiotics for eradicating early Pseudomonas aeruginosa infection in children with cystic fibrosis. Pediatr Pulmonol. 2019 Jan 18. doi: 10.1002/ppul.24254. [Epub ahead of print] Full text available [Pubmed]
Chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) can be prevented with early eradication treatment. In resource-constrained environments, low-cost, off-label nebulized antibiotics, including intravenous gentamicin solution, are often used for eradication therapy. This study aimed to describe the characteristics and clinical course of children with CF and early Pa infection, treated with a Pa eradication protocol combining inhaled gentamicin and systemic antibiotics.
All children (0-18 years) attending a CF clinic in South Africa, with early Pa infections between January 2005 and March 2015, who received nebulized gentamicin-based Pa eradication treatment. Data were described and compared between those with successful versus unsuccessful eradication, using descriptive and inferential statistics appropriate to normality of distribution.
One hundred and forty-nine children were managed in the CF Clinic over the study period, of whom 44 (29.5%; 28 [63.6%] male) had early Pa infections treated with a gentamicin-based eradication regimen. Thirty-nine (88.6%) patients had successful Pa eradication at 12 months follow-up; of which 28 (71.8%) had Pa reinfection at a median of 37.0 (21.0-101.0) months after initial treatment. Six patients (13%) acquired chronic Pa infection during the median follow-up period of 77 months. Older age was associated with Pa eradication failure and chronic Pa infection. There were no clinically significant adverse events associated with gentamicin inhalational therapy.
The authors concluded nebulized gentamicin solution combined with systemic antibiotics appears to be safe and has comparable efficacy to other strategies in eradicating early Pa infections in children with CF.
Corresponding author is Professor Brenda Morrow in the Department of Child and Adolescent Health, University of Cape Tow
– This is a useful record of experience. It is worth noting that the Heinzl B et al 2002 Austrian study of long term inhaled gentamicin from 1986-1999 (started soon after our 1985 letter to the Lancet regarding colomycin) although effective was stopped in some children due to concerns about rising urinary NAG values reflecting renal toxicity. (Ring E, et al. Urinary N-acetyl-beta-D-glucosaminidase activity in patients with cystic fibrosis on long term gentamicin inhalation. Arch Dis Child 1998; 78:540-543). Nebulised gentamicin in currently recommended by the British Thoracic Society for non-CF bronchiectasis but a serum creatinine and urea are recommended on commencing and every 12 months.
Casciaro B, d’Angelo , Zhang , Loffredo MR, Conte G, Cappiello F, Quaglia F, Di YP, Ungaro F, Mangoni ML. Poly(lactide- co-glycolide) Nanoparticles for Prolonged Therapeutic Efficacy of Esculentin-1a-Derived Antimicrobial Peptides against Pseudomonas aeruginosa Lung Infection: in Vitro and in Vivo Studies.Biomacromolecules. 2019 Apr 23. doi: 10.1021/acs.biomac.8b01829. [Epub ahead of print].[Pubmed]
Due to their excellent in vitro activity against multi-drug resistant bacteria, antimicrobial peptides (AMPs) hold promise for treatment of Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) sufferers. In this work, poly(lactide- co-glycolide) (PLGA) nanoparticles for lung delivery of AMPs deriving from the frog-skin esculentin-1a, namely, Esc(1-21) and Esc(1-21)-1c (Esc peptides), were successfully developed. Improved peptide transport through artificial CF mucus and simulated bacterial extracellular matrix was achieved in vitro. The formulations were effectively delivered through a liquid jet nebulizer already available to patients. Notably, Esc peptide-loaded nanoparticles displayed an improved efficacy in inhibiting P. aeruginosa growth in vitro and in vivo in the long term. A single intratracheal administration of Esc peptide-loaded nanoparticles in a mouse model of P. aeruginosa lung infection resulted in a 3-log reduction of pulmonary bacterial burden up to 36 h. Overall, results unravel the potential of PLGA nanoparticles as a reliable delivery system of AMPs to lungs.
Laboratory affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences “A. Rossi Fanelli” , Sapienza University of Rome ,
Waterer G, Lord J, Hofmann T, Jouhikainen T. A Phase I, dose-escalating study of safety and pharmacokinetics of inhaled dry powder vancomycin (AeroVanc) in volunteers and patients with cystic fibrosis: a new approach to therapy for methicillin-resistant Staphylococcus aureus.
Antimicrob Agents Chemother. 2020 Jan 21. pii: AAC.01776-19. doi: 10.1128/AAC.01776-19. [Epub ahead of print] [Pubmed]
Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, the authors developed a dry powder formulation suitable for inhalation (AeroVanc).
They report a Phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.
Dr Grant Waterer is Professor of Medicine, University of Western Australia is a respiratory physician at Royal Perth Hospital and is a professor of medicine at the University of Western Australia and professor of medicine at Northwestern University, Chicago, USA.
Bressan A, Rodio DM, Stangherlin F, Puggioni G, Ambrosi C, Arcari G, Carattoli A, Antonelli G, Pietropaolo V, Trancassini M. In vitro activity of fosfomycin against mucoid and non-mucoid Pseudomonas aeruginosa strains.
J Glob Antimicrob Resist. 2020 Feb 24;20:328-331. doi: 10.1016/j.jgar.2020.02.014. [Epub ahead of print] Full text [Pubmed]
P. aeruginosa resistance to first line antibiotics limits therapeutic options in CF, but the therapeutic potential of older generation antibiotics, such as fosfomycin is under investigation. Fosfomycin does not belong to any other antibiotic class and acts by inhibiting the biosynthesis of the bacterial cell wall during the initial phases. A major problem for the use of fosfomycin against P. aeruginosa is the absence of a clinical breakpoint, the last one of 32 μg/mL was proposed in 2013 by the CA-SFM (Comité de l’Antibiogramme de la Société Française de Microbiologie).
Sixty-one strains of P. aeruginosa (thirty mucoid and thirty-one non mucoid) were collected from respiratory samples of cystic fibrosis patients. All isolates were identified by MALDI-TOF (Bruker, Bremen, Germany). Fosfomycin MICs against P. aeruginosa were measured using an automated system and confirmed by the gold standard method.
There was no significant difference between mucoid and non-mucoid strains. MIC distribution and susceptibility rates were obtained by agar dilution method and from this data we measured MIC50 and MIC90 which were equal to 32 μg/mL and 64 μg/mL, respectively. From automated method results we measured a very major error (VME), major error (ME) and categorical agreement (CA) which were equal to 0%, 11% and 89%, respectively. Comparing automated and agar dilution methods, a Cohen’s kappa equal to 73% (0.726) was measured.
The authors concluded their data suggest that fosfomycin has good effect against mucoid and non-mucoid strains of P. aeruginosa and automated systems can be implemented in clinical microbiology laboratories to assess fosfomycin with rapid and reproducible results.
Dr Alessia Brassan is in the Department of Molecular Medicine, “Sapienza” University Rome, Rome, Italy.
Claire L Keating, Jonathan B Zuckerman, Pradeep K Singh, Matthew McKevitt, Oksana Gurtovaya, Mark Bresnik, Bruce C Marshall, Lisa Saiman, CFFPR-AZLI Study Group Pseudomonas aeruginosa Susceptibility Patterns and Associated Clinical Outcomes in People with Cystic Fibrosis following Approval of Aztreonam Lysine for Inhalation. Antimicrob Agents Chemother2020 Dec 14;AAC.02327-20.doi: 10.1128/AAC.02327-20.Online ahead of print. Free article [Pubmed]
Approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect susceptibility profiles of Pseudomonas aeruginosa (PA) isolates from cystic fibrosis (CF) patients. Objective: This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic PA infection.
Aztreonam susceptibility of PA remained consistent during the 5-year study. The relationship between PA isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with accelerated decline in lung function, but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure.
Dr Claire L Keating is in the Division of Pulmonary, Allergy and Critical Care, Columbia University Irving Medical Center, New York,
Simon C Langton Hewer. Alan R Smyth, Michaela Brown, Ashley P Jones, Helen Hickey, Dervla Kenna, Deborah Ashby, Alexander Thompson, Paula R Williamson, on behalf of the TORPEDO-CF study group† Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial. Lancet Respir Med 2020; 8:975-986
Background Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa.
Methods This was a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10.
Findings Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65–1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group.
Interpretation Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis.
– This formidable protracted trial certainly shows there is no advantage in using intravenous antibiotics for first infections with P. aeruginosa. With the already known effectiveness of oral ciprofloxacin and nebulised colistin, shown many years ago, it was unlikely that using intravenous antibiotics for first infections would prove superior. It is disappointing that the eradication success rate of both treatments was so modest – perhaps the multiplicity of sites and fine details of treatment delivery where the patients were treated may have contributed to the modest results.
Lindsay Jablonski, Carlton K K Lee, Beryl J Rosenstein, Peter J Mogayzel Jr, Shruti Paranjape, Alice Pan Real World Experience of Pseudomonas aeruginosa Eradication at an Urban Pediatric Cystic Fibrosis Center. J Pediatr Pharmacol Ther 2020;25(7):623-628.doi: 10.5863/1551-6776-25.7.623.[Pubmed] Free PMC article
Objectives: Clinical practice guidelines for eradication of Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) have been established, but current studies have not assessed how these guidelines translate into clinical practice. This study aimed to characterize the real-world eradication strategies, eradication rates, and microbiologic outcomes of patients with first acquisition of PA at an urban pediatric CF center.
Methods: The Cystic Fibrosis Foundation Patient Registry was used to identify patients with CF who received care between January 2014 and September 2018 and had PA isolated from an airway culture. Patients were included if they had a first positive PA culture or the first positive culture in 2 years. Data regarding patient demographics, timing and results of airway cultures, and treatment regimens were collected.
Results: Over a 3.75-year period, 75 patients had an initial positive culture for PA. Of those patients, 74 (98.7%) received eradication treatment. Tobramycin inhalation solution (TIS) monotherapy was the most common regimen prescribed (52.7%) followed by TIS plus an oral fluoroquinolone (28.4%) (TIS + FQ). Of those treated, 62 (83.8%) patients had eradication of PA at first follow-up culture (median, 58 days; IQR, 49-77 days). Eradication rates (84.6% vs 76.2%, p = 0.421) and times to recurrence (6.37 months vs 5.1 months, p = 0.726) were comparable between TIS and TIS + FQ cohorts
Jennifer A Bartell, Lea M Sommer, Rasmus L Marvig, Marianne Skov, Tacjana Pressler, Søren Molin, Helle Krogh Johansen. Omics-based tracking of Pseudomonas aeruginosa persistence in “eradicated” CF patients. Eur Respir J 2020 Oct 22;2000512. doi: 10.1183/13993003.00512-2020. Online ahead of print.[Pubmed]
Whenever Pseudomonas aeruginosa (PA) is cultured from cystic fibrosis (CF) patient airways, the primary goal is eradication by antibiotic therapy. Success is defined by at least 6 months of negative bacterial airway cultures. However, we suspect that PA persists in airways without clinical detection for long periods. Of 298 PA-infected Copenhagen CF patients, we identified 80 with complete PA monitoring records and measured their maximum PA-free eradication periods (MEP). Isolates from 72 patients were whole genome sequenced (n=567) and clone typed. Select isolate relatedness was examined through phylogenetic analysis and phenotypic multivariate modelling.
Sixty-nine patients (86%) exhibited eradication in the monitoring period (2002-2018). Sequenced isolates bridged the MEP of 42 patients, and the same clone type persisted over the MEP in 18 (43%). Patients with failed eradication were on average treated more intensively with antibiotics, but this may be linked to their more severe pre-MEP infection trajectories. Of the 42 patients, 26 also had sinus surgery; the majority (15) show MEPs adjacent to surgery, and only 5 had persisting clone types. Importantly, combined phylogenetic-phenomic evaluation suggests that persisting clone types are a result of re-emergence of the same strain rather than re-infection from the environment, and similar relatedness is exhibited by paired lower and upper airway samples and in transmission cases.
In conclusion, nearly half of CF patients with supposed eradication may not truly be cleared of their original bacteria according to omics-based monitoring. This distinct cohort that is persistently infected would likely benefit from tailored antibiotic therapy
Jennifer A Bartell is a Research Scientist at the Rigshospitalet Department of Clinical Microbiology, Copenhagen
Conclusions: The eradication rate for PA in clinical practice is similar to that published in the literature. Consistent with published guidelines, these microbiologic outcomes do not support the addition of an oral FQ to TIS for initial PA eradication.
Corresponding author is Alice Pan, PharmD; Department of Pharmacy (LJ, CKL, AP) and Eudowood Division of Pediatric Respiratory Sciences (BJR, PJM, SP), Johns Hopkins Medical Institutions, Baltimore, Maryland
Margaret Rosenfeld, Oli Rayner, Alan R Smyth. Prophylactic anti-staphylococcal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2020 Sep 30;9:CD001912.doi:10.1002/14651858.CD001912.pub5 [Pubmed]
Staphylococcus aureus causes pulmonary infection in young children with cystic fibrosis. Prophylactic antibiotics are prescribed hoping to prevent such infection and lung damage. Antibiotics have adverse effects and long-term use might lead to infection with Pseudomonas aeruginosa. This is an update of a previously published review.More detailed account of the review on Pubmed)
Authors’ conclusions: Anti-staphylococcal antibiotic prophylaxis may lead to fewer children having isolates of Staphylococcus aureus, when commenced early in infancy and continued up to six years of age. The clinical importance of this finding is uncertain. Further research may establish whether the trend towards more children with CF with Pseudomonas aeruginosa, after four to six years of prophylaxis, is a chance finding and whether choice of antibiotic or duration of treatment might influence this.
Oli Rayner is the CF Trust’s Special Adviser on Research and Patient Involvement. He has cystic fibrosis.
Margaret Rosenfield in Associate Professor and paediatric pulmonologist at Seattle Children’s
Alan Smyth is Professor Paediatrics in Nottingham UK
– The risk of anti-staphylococcal therapy encouraging the growth of Pseudomonas aeruginosa has been raised for many years on unconvincing almost now historical clinical evidence. However, it is true that once an organism has been eradicated from the CF respiratory another soon takes its place. Before the introduction of early eradication treatment for P. aeruginosa this was a concern but not since early P. aeruginosa can be eradicated. For those opposed to prophylactic anti-staphylococcal antibiotics regular monthly cultures (not less frequently) and vigorous antibiotic therapy whenever a culture is a positive is a satisfactory alternative which been the successful practice in Copenhagen under Niels Hoiby’s guidance for many years.
Christopher H Goss , Sonya L Heltshe, Natalie E West, Michelle Skalland, Don B Sanders, Raksha Jain, Tara L Barto, Barbra Fogarty, Bruce C Marshall, Donald R VanDevanter, Patrick A Flume, STOP2 Investigators. A Randomized Trial of Antimicrobial Duration for Cystic Fibrosis Pulmonary Exacerbation Treatment. Am J Respir Crit Care Med 2021 Sep 1.doi: 10.1164/rccm.202102-0461OC.Online ahead of print. [Pubmed]
Rationale: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration.
Methods: STOP2 was a multi-center, randomized, controlled, clinical trial in exacerbation among adults with CF. After 7-10-days of treatment, participants exhibiting pre-defined lung function and symptom improvements were randomized to 10- or 14-days total antimicrobial duration; all others were randomized to 14- or 21-days.
Measurements: The primary outcome was percent predicted forced expiratory volume in 1 second (ppFEV1) change from treatment initiation to two weeks after cessation. Among early responders non-inferiority of 10-days to 14-days was tested; superiority of 21-days compared to 14-days was compared for the others. Symptoms, weight, and adverse events were secondary.
Results: Among 982 randomized, 277 met improvement criteria and were randomized to 10- or 14-days treatment; the remaining 705 received 21- or 14-days. Mean ppFEV1 change was 12.8 and 13.4 for 10- and 14-days, respectively, a ‒0.65 difference [95%CI ‒3.3, 2.0], excluding the pre-defined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV1 changes, a difference of ‒0.10 [‒1.3, 1.1]. Secondary endpoints and sensitivity analyses were supportive.
Conclusions: Among CF adults with early treatment improvement during exacerbation, ppFEV1 after 10-days of intravenous antimicrobials is not inferior to 14-days. For those with less improvement after one week, 21-days is not superior to 14-days. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02781610.
Dr Christopher H Goss is at University of Washington, 7284, Medicine and Pedaitrics, Seattle, Washington, and Seattle Children’s Research Institute, 145793, CF Therapeutics Development Network Coordinating Center, Seattle, Washington, United States.
– This is an interesting study but I suspect many experienced clinicians will use their own judgement taking into account the many factors relating to the particular patient.
Carsten Schwarz, Claudio Procaccianti , Benjamin Mignot, Hosein Sadafi, Nicolas Schwenck, Xabier Murgia, Federico Bianco Deposition of Inhaled Levofloxacin in Cystic Fibrosis Lungs Assessed by Functional Respiratory Imaging. Pharmaceutics 2021 Dec 1;13(12):2051 doi: 10.3390/pharmaceutics13122051 Free PMC article [Pubmed]
Pulmonary infections caused by Pseudomonas aeruginosa (PA) represent the leading cause of pulmonary morbidity in adults with cystic fibrosis (CF). In addition to tobramycin, colistin, and aztreonam, levofloxacin has been approved in Europe to treat PA infections. Nevertheless, no lung deposition data on inhaled levofloxacin are yet available.
We conducted a Functional Respiratory Imaging (FRI) study to predict the lung deposition of levofloxacin in the lungs of patients with CF. Three-dimensional airway models were digitally reconstructed from twenty high-resolution computed tomography scans obtained from historical patients’ records. Levofloxacin aerosols generated with the corresponding approved nebuliser were characterised according to pharmacopeia. The obtained data were used to inform a computational fluid dynamics simulation of levofloxacin lung deposition using breathing patterns averaged from actual CF patients’ spirometry data.
Levofloxacin deposition in the lung periphery was significantly reduced by breathing patterns with low inspiratory times and high inspiratory flow rates. The intrathoracic levofloxacin deposition percentages for moderate and mild CF lungs were, respectively, 37.0% ± 13.6 and 39.5% ± 12.9 of the nominal dose. A significant albeit modest correlation was found between the central-to-peripheral deposition (C/P) ratio of levofloxacin and FEV1. FRI analysis also detected structural differences between mild and moderate CF airways. FRI revealed a significant intrathoracic deposition of levofloxacin aerosols, which distributed preferentially to the lower lung lobes, with an influence of the deterioration of FEV1 on the C/P ratio. The three-dimensional rendering of CF airways also detected structural differences between the airways of patients with mild and moderate CF.
Carsten Schwarz is head of the CF Center, 14467 Potsdam, Germany.