Antibiotics by type

AMINOGLYCOSIDES

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AMOXICILLIN/ CARBENICILLIN/ CLOXACILLIN/FLUCLOXACILLIN/METHICILLIN PENICILLIN G/ PIPERACILLIN
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GENERAL ARTICLES RELATING TO ANTIBIOTIC USE – GUIDELINES, TECNIQUES OF ADMINISTRATION, EFFECTS ETC

TECHNIQUES/ANALGESIA
TOTALLY IMPLANTABLE VENOUS ACCESS DEVICES
HOME IV ANTIBIOTICS

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AMINOGLYCOSIDES

AMIKACIN /GENTAMICIN/ NEOMYCIN/ NETILMICIN/ TOBRAMYCIN

1960 Young WF. Ototoxicity to neomycin aerosol. Lancet 1960; i: 110
This letter to the Lancet from Winifred Young (1909-1969) (figure 6), 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.). A case report of ototoxicity appeared in 1959 (Greenwood GJ. AMA Arch Otolaryngol 1959; 69:390-397.) and in a number of reports in the early Sixties although most reports of ototoxicity and CF concern the aminoglycosides.

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.

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 Pseudomonas 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) 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]).

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 the 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 that I took back to Leeds from Toronto.

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 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 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 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. 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 nebulized antibiotics. Although nebulized 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 that revived the interest in nebulized antibiotics for patients with chronic Pseudomonas infection – particularly in the UK. The nebulized 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 nebulized 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 1991 (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.

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.

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).

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 (£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).

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, 1991 above) [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.

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]
The authors suggest that inhaled antibiotics might 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 the first report of eradication of early P. aeruginosa appeared in 1985 (Littlewood et al, 1985). The 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.

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. Lancet 2005; 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.) 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. This is the first report of a lung transplant recipient who developed renal failure and vestibular injury after receiving inhaled tobramycin.

The authors 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.

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]
the authors undertook the 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. They 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

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 to 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. They concluded 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 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 (Weisemann 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. aeruginosa infection. 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 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 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.

–   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. RESULTS: 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).
CONCLUSIONS: 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 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 but 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 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).

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”.

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.

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.

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.
CONCLUSIONS: 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 is developing 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.

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 randomized to treatment with tobramycin inhalation solution for 28 days (TIS) or inhaled sodiumcolistimethate (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 regimens 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 comnclude that all the different studies on first eradicatin 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 eleiminated. 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 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 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. the authors assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing.

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.

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).
Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

2014 Al-Aloul M. Nazareth D. Walshaw M. Nebulized tobramycin in the treatment of adult cystic fibrosis pulmonary exacerbations. J Aerosol Med Pulm Drug Deliv 2014; 27(4):299-305. [PubMed]
Repeated courses of intravenous (IV) aminoglycosides in cystic fibrosis (CF) patients are associated with cumulative nephrotoxicity. Targeting their delivery through the inhaled route during acute pulmonary exacerbations may also be effective, but without systemic side effects.
Using a randomized crossover trial design, in a pilot study the authors compared 14 days of IV tobramycin with nebulized tobramycin 300mg twice a day (TNS) in acute respiratory exacerbations in 20 CF adults chronically infected with Pseudomonas aeruginosa (Psa). Patients also received IV colistin in both arms. Improvement in spirometry was similar between the two groups [mean change in FEV1 % predicted: IV group 16.4 (standard deviation 8.5) versus TNS group 19.9 (11.3), p=0.26], but there was more suppression of sputum Psa in the TNS group [mean difference between treatments 0.85 log10 colony-forming units/mL (CI 0.03 to 1.67), p=0.05]. IV tobramycin was associated with a greater urinary protein leak [mean difference between treatments 0.59mg/24hr (0.30 to 0.87), p=0.0005] and higher urinary levels of markers of acute renal tubular injury: N-acetylglucosaminidase [0.72IU/mmol (0.37 to 1.07), p=0.0004], alanine aminopeptidase [1.19IU/mmol (0.70 to 1.68), p=0.0001], and beta2-microglobulin [0.44mug/mmol (0.16 to 0.72), p=0.0046] than TNS. Compared with IV tobramycin, TNS treatment prolonged the time to next exacerbation requiring hospitalisation (p<0.001). Patient satisfaction was similar with both treatments, and no serious adverse effects were recorded. The authors concluded that nebulised tobramycin (TNS) is effective in treating acute exacerbations of Psa in CF patients, but with a renal sparing potential compared with the IV preparation.

A useful study in view of the increasing problem of renal damage resulting from so many courses of intravenous aminoglycosides over many years. The efficacy of the inhaled route would need further confirmation in a longer study but the renal sparing factor is very important although, with regard to efficacy in this trial, it should be noted that both groups also received IV colistin which is an effective anti-pseudomonal agent.

2014 Al-Malky G. Suri R. Sirimanna T. Dawson SJ. Normal hearing in a child with the m.1555A>G mutation despite repeated exposure to aminoglycosides. Has the penetrance of this pharmacogenetic interaction been overestimated?. J Pediatr Otorhinolaryngol 2014; 78(6):969-73.[PubMed]
The mtDNA m.1555A>G mutation causes increased susceptibility to aminoglycoside ototoxicity resulting in significant hearing loss in 100% of reported exposed cases. Genetic and audiological assessments were conducted in a sample of 59 children with cystic fibrosis undergoing aminoglycoside treatment. Of the two m.1555G patients identified one had severe-profound deafness. Surprisingly, the second m.1555G patient exhibited well-preserved hearing despite repeated exposure to aminoglycosides.
The authors suggest that this may be a rare case of intact hearing in an m.1555G individual with aminoglycoside use. Alternatively, its penetrance may have been previously overestimated due to recruitment bias. They suggest further studies are required to determine the true penetrance to inform m.1555A>G genetic testing in similar clinical scenarios.

It has been suggested that the rarity of this mutation would preclude the routine testing of patients receiving courses of intravenous aminoglycosides. Only 3 of 10 preterm m.1555A>G carriers who were exposed to aminoglycosides failed hearing screening (Goplel G et al, 2014.[PubMed]) and not all small preterm infants with the mutation have subsequently been found to have hearing loss. These authors suggest further research would be helpful.

2014 Di Cicco M. Alicandro G. Claut L. Cariani L. Luca N. Defilippi G. Costantini D. Colombo C. Efficacy and tolerability of a new nasal spray formulation containing hyaluronate and tobramycin in cystic fibrosis patients with bacterial rhinosinusitis. J Cyst Fibros 2014; 13(4):455-60. [PubMed]
A small study to assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF.
The formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain).
The authors suggest that the present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF.

2014 Griese M. Eismann C. Borner G. Denk O. Schierholz JM. Keller M. Mazurek H. Kappler M. A pharmacokinetics and safety comparison of a highly concentrated tobramycin solution with TOBI. J Aerosol Med Pulm D 2014; 27(3):185-92. [PubMed]
Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition was demonstrated; here, we investigated its safety and pharmacokinetics. METHODS: In a randomised, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow() nebuliser and TOBI() (300 mg/5 mL) nebulized with a PARI LC PLUS() nebuliser in 78 CF patients. RESULTS: Non-inferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulisation time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination.

The authors concluded inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics

2014 Konstan MW. Wagener JS. Pasta DJ. Millar SJ. Morgan WJ. Clinical use of tobramycin inhalation solution (TOBI) shows sustained improvement in FEV1 in cystic fibrosis. Pulmonology 2014; 49(6):529-36. [PubMed]
Tobramycin inhalation solution (TIS; TOBI) has improved forced expiratory volume in 1sec (FEV1 ) in cystic fibrosis (CF) trials. Using data from the Epidemiologic Study of CF (ESCF), the authors assessed the change in level and trend of FEV1 % predicted over a 2-year period associated with initiation of TIS during routine clinical practice.

Initiating chronic TIS therapy in the routine clinical care of patients with CF was associated with improvement in FEV1 % predicted but no change in rate of decline, indicating this benefit was sustained over the 2 years studied.

2014 Stanojevic S. Waters V. Mathew JL. Taylor L. Ratjen F. Effectiveness of inhaled tobramycin in eradicating Pseudomonas aeruginosa in children with cystic fibrosis. J Cyst Fibros 2014;13(2):172-8. [PubMed] 
Inhaled tobramycin therapy has been shown to be efficacious in clinical trials for the eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis. However, the effectiveness of different regimens in eradicating P. aeruginosa and preventing the development of chronic infection in actual clinical settings has yet to be determined. This was an observational study of children (<18 years of age) with CF with incident P. aeruginosa infection from 2005-2012 based on data collected from the Toronto CF Database and medical charts. Patients who received inhaled tobramycin (80 mg/2 ml twice daily for 365 days) were compared to those who received tobramycin inhalation solution (TIS) (300 mg/5 ml twice daily for 28 days) with respect to eradication and development of chronic infection. The authors also examined the risk factors for recurrence of infection.
During the study period, 65 patients were identified with incident P. aeruginosa, of which 7 (11%) failed eradication therapy. Eradication failure was similar between the two treatment groups. A total of 4 patients (6%) developed chronic P. aeruginosa infection in the 12 months following the end of therapy with no differences between treatment groups. Female gender, older age, pancreatic insufficiency, lower lung function and worse nutritional status were identified as risk factors for recurrence of P. aeruginosa infection.
Both regimens of inhaled tobramycin have similar effectiveness in eradicating P. aeruginosa and preventing chronic P. aeruginosa infection in CF patients in clinical practice. Further work is needed, however, to identify patient characteristics and bacterial factors that play a role in eradication failure, in order to develop more effective antimicrobial rescue treatment strategies.

2014 Ting L. Aksenov S. Bhansali SG. Ramakrishna R. Tang P. Geller DE. Population pharmacokinetics of inhaled tobramycin powder in cystic fibrosis patients.: Pharmacometrics Syst Pharmacol 2014 Feb12;3:e99.doi: 10. 1038/psp.2013.76.[PubMed]
Tobramycin powder for inhalation (TOBI Podhaler or TIP) is approved for the treatment of Pseudomonas aeruginosa airway infection in patients with cystic fibrosis. A population pharmacokinetic model for tobramycin inhalation powder (TIP) in CF patients was developed to characterise the effect of covariates including body mass index (BMI) and lung function (FEV1% predicted) at baseline on the serum exposure parameters. The results indicate that no BMI- or FEV1-based dose adjustment is needed for use of tobramycin powder (TIP) in CF patients.

This is reassuring as the serum levels associated with inhaled aminoglycosides are of some concern when the drugs are used by the patient over many years.

2014 Waters V. Ratjen F. Inhaled liposomal amikacin. Rev of Respir Med 2014; 8(4):401-9.[PubMed]
Arikace is a novel formulation of inhaled liposomal amikacin that can penetrate deep within airway secretions and within Pseudomonas aeruginosa biofilms, making it an attractive therapeutic option for the treatment of cystic fibrosis (CF) pulmonary infections. Initial Phase I and Phase II studies in CF patients with chronic P. aeruginosa infection demonstrated that Arikace was a safe drug that resulted in significant improvements in lung function after 14-28 days of treatment. Phase III studies of inhaled liposomal amikacin compared to tobramycin inhalation solution in CF patients with P. aeruginosa infection revealed a comparable increase in forced expiratory volume in 1 second at the end of three cycles. In addition, inhaled liposomal amikacin has other potential applications in the management of difficult-to-treat pulmonary infections.

A Phase II trial is currently underway to study the use of Arikace for the treatment of recalcitrant nontuberculous mycobacterial lung disease.

2014 Xue X. Mutyam V. Tang L. Biswas S. Du M. Jackson LA. Dai Y. Belakhov V. Shalev M. Chen F. Schacht J. J Bridges R. Baasov T. Hong J. Bedwell DM. Rowe SM. Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. J Respir Cell Mol Biol 2014; 50(4):805-16.[PubMed]
New drugs are needed to enhance premature termination codon (PTC) suppression to treat the underlying cause of cystic fibrosis (CF) and other diseases caused by nonsense mutations. The authors tested new synthetic aminoglycoside derivatives expressly developed for PTC suppression in a series of complementary CF models.
These results provide evidence that NB124 and other synthetic aminoglycosides provide a 10-fold improvement in therapeutic index over gentamicin and other first-generation aminoglycosides, providing a promising treatment for a wide array of CFTR nonsense mutations.

2015 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. 2015 Aug 15. pii:S1569-1993(15)00174-5.doi: 10.1016/j.jcf.2015.07.012. [Epub ahead of print]    Full text available[PubMed] 
A study 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.Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 (a biomarker of renal toxicity) was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%).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 full text is available and interesting. The authors discuss the relatively new KIM-1 marker of nephrotoxicity. Before suggesting evening dosing is definitely more toxic they advise a more extensive trial.

Summary: The now much enlarged understanding of CFTR in the kidney may permit the measurement of challenged urine HCO3- excretion as a new biomarker for CF. We suggest a new explanation for the electrolyte disorder in CF termed Pseudo-Bartter Syndrome. The hallmark electrolyte disturbance features of this can be well explained by a reduced function of collecting duct Cl-/HCO3- exchange. Eventually, we suggest the diagnostic term distal renal tubular alkalosis to cover those disturbances that causes metabolic alkalosis by a reduced collecting duct base secretion.

Dr Peder Berg is in the Department of Biomedicine, Physiology, Health, Aarhus University, Aarhus, Denmark. For this work he was awarded the Gerd Döring award of the ECFS in 2021

 Diana Bilton, Isabelle Fajac, Tacjana Pressler, John Paul Clancy, Dorota Sands, Predrag Minic, Marco Cipolli, Ivanka Galeva, Amparo Solé, Alexandra L Quittner, Zhanna Jumadilova, Monika Ciesielska, Michael W Konstan, CLEAR-110 Study Group. Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection.  J Cyst Fibros 2021 Jun 15;S1569-1993(21)00164-8. doi: 10.1016/j.jcf.2021.05.013.Online ahead of print.  [Pubmed]

Background: In CLEAR-108-a phase 3, randomised, open-label study-once-daily amikacin liposome inhalation suspension (ALIS) was noninferior to twice-daily tobramycin inhalation solution (TIS) in improving lung function in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection after 3 treatment cycles (28 days on/28 days off). The CLEAR-110 extension study (ClinicalTrials.gov: NCT01316276; EudraCT: 2011-000443-24) assessed long-term safety, tolerability, and efficacy of ALIS in eligible patients who completed CLEAR-108.
Methods: . Patients received once-daily ALIS 590 mg for 12 treatment cycles (96 weeks). Patients were grouped by prior treatment: the “prior-ALIS” cohort received ALIS in CLEAR-108, and the “ALIS-naive” cohort received TIS in CLEAR-108.
Results: . Overall, 206 patients (prior-ALIS, n=92; ALIS-naive, n=114) entered CLEAR-110 and received ≥1 dose of ALIS. Most patients (88.8%) experienced ≥1 treatment-emergent adverse event (TEAE) through day 672 (end of year 2). Most TEAEs (72.3%) were mild or moderate in severity. Severe TEAEs were reported in 31 patients (15.0%). Two life-threatening TEAEs (haemoptysis; intestinal obstruction) and 1 death (cardiac failure) were reported. Twenty-one patients (10.2%) discontinued treatment due to a TEAE (mostly infective pulmonary exacerbation of CF). Mean change from baseline in forced expiratory volume in 1 second percent predicted at day 672 was -3.1% (prior-ALIS, -4.0%; ALIS-naive, -2.3%). Mean change from baseline in sputum density of P. aeruginosa at day 672 was 0.02 (prior-ALIS, -0.16; ALIS-naive, 0.19) log CFU/g.

Conclusions: . Long-term treatment with ALIS was well tolerated with a favourable adverse event profile and demonstrated continued antibacterial activity in CF patients with chronic P. aeruginosa infection.

Dr Diana Bilton, before her retirement, was Director of the Adult CF Unit at the Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom.

Kevin J Downes , Austyn Grim, Laura Shanley, Ronald C Rubenstein, Athena F Zuppa, Marc R Gastonguay.  A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation. Antimicrob Agents Chemother 2022 Apr 28;e0237721.doi: 10.1128/aac.02377-21.Online ahead of print.   [Pubmed]

Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of C_max >25 mg/L and AUC₂₄ of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.

Kevin J Downes  is attending physician at the Division of Infectious, Diseases at the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. and other departments.

CARBAPENEMS

IMIPENEM-CILASTIN/MEROPENEM

CEPHALOSPORINS

CEFALEXIN/CEFACLOR/ CEFTAZIDIME

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 is a 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 P. aeruginosa. 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 – particularly not about long term narrower spectrum therapy with flucloxacillin.

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 recent 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.

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 result were obtained in the present study when treating resistant bacteria.

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 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.

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.

2014 Bourget P. Amin A. Dupont C. Abely M. Desmazes-Dufeu N. Dubus JC. Jouani BL. Merlette C. Nove-Josserand R. Pages J. Panzo R. Vidal F. Voge F. Hubert D. How to minimize toxic exposure to pyridine during continuous infusion of ceftazidime in patients with cystic fibrosis?. Antimicrob Agents Chemother 2014; 58:2849-55. [PubMed].
Ceftazidime is widely used in cystic fibrosis patients. Thus, the spontaneous production of pyridine, which is a toxic product, raises some concern. This study was to examine the kinetics of degradation of ceftazidime in portable infusion pumps either at 4C, 22C, or 33C and to propose some recommendations in order to reduce the pyridine exposure. Two administration models were studied in vitro. In model 1, 12 g of ceftazidime was infused over 23 h (once-daily infusion) compared to 6 g infused over 11.5 h in model 2 (twice-daily regimen). Regardless of the conditions, the production of pyridine was significantly lower in model 2, whereas the total delivery amount of ceftazidime is significantly higher at 4C and 33C compared to that in model 1.
These findings led to the authors’ three major recommendations: (i) exposing a solution of ceftazidime to over 22C should be strictly avoided, (ii) a divided dose of 6 g over 11.5 hrs instead of a once-daily administration is preferred, and (iii) infusion should be administered immediately after reconstitution.

In view of the increasing tendency to administer prolonged infusions of ceftazidime as the ideal way to achieve a recommended constant blood level, the findings reported here would appear to be of practical importance.

Taylor A Imburgia Michelle L Kussin.  A Review of Extended and Continuous Infusion Beta-Lactams in Pediatric Patients.  J Pediatr Pharmacol Ther 2022;27(3):214-227.doi: 10.5863/1551-6776-27.3.214.Epub 2022 Mar 21.   [Pubmed]

Intravenous beta-lactam antibiotics are the most prescribed antibiotic class in US hospitalized patients of all ages; therefore, optimizing their dosing is crucial. Bactericidal killing is best predicted by the time in which beta-lactam drug concentrations are maintained above the organism’s minimum inhibitory concentration (MIC), rather than achievement of a high peak concentration. As such, administration of beta-lactam antibiotics via extended or continuous infusions over a minimum of 3 hours, rather than standard infusions over approximately 30 minutes, has been associated with improved achievement of pharmacodynamic targets and improved clinical outcomes in adult medical literature.
This review summarizes the pediatric medical literature. Applicable studies include pharmacodynamic models, case series, retrospective analyses, and prospective studies on the use of extended infusion and continuous infusion penicillins, cephalosporins, carbapenems, and monobactams in neonates, infants, children, and adolescents. Specialized patient populations with unique pharmacokinetics and high-risk infections (neonates, critically ill, febrile neutropenia, cystic fibrosis) are also reviewed.

While more studies are needed to confirm prospective clinical outcomes, the current body of evidence suggests extended and continuous infusions of beta-lactam antibiotics are well tolerated in children and improve achievement of pharmacokinetic pharmacodynamic targets with similar or superior clinical outcomes, particularly in infections associated with high MICs.

Dr Taylor A Imburgia is Pediatric Pharmacy Specialist in the Department of Pharmacy (TAI), WVU Medicine Children’s, Morgantown, WV.

GLYCOPEPTIDES

TEICOPLANIN/ VANCOMYCIN

LINCOSAMIDES

CLINDAMYCIN/ LINCOMYCIN

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).

MACROLIDES

AZITHROMYCIN/CLARITHROMYCIN/ ERYTHROMYCIN

1997 Everard ML, Sly P, Brenan S, Ryan G. Macrolide antibiotics in diffuse panbronchiolitis and in cystic fibrosis. Eur Respir J 1997; 10:2926. [PubMed].
Professor 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) were the first in the UK to report an effect on sputum inflammatory markers in cystic fibrosis.

1998 Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998; 351:420. [PubMed]. 
The second very convincing observational study on macrolides and CF from the UK (first report by Everard et al, 1997 above) showing impressive improvement in the respiratory function of severely affected children given regular azithromycin in addition to their usual treatment. These impressive observations were followed by a controlled trial from the Brompton Hospital, London which confirmed the beneficial effect (Equi et al, 2002 below) and also by a multi-centre trial from the US CF Foundation (Saiman et al, 2003 below).

2002 Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002; 360:978-84. [PubMed]
A major UK trial of macrolides from the Brompton Hospital, London following the report of Jaffe et al, 1998 (above) from that hospital. 41 children with CF received azithromycin or placebo for 6 months in addition to their usual treatments. The median relative difference in FEV1 between azithromycin and placebo patients was 5.4%. However, this was made up as follows – FEV1 of 13 (31.7%) patients improved by more than 13% but five (12.2%) deteriorated by more than 13% (p=0.059). Seventeen (41.5%) of the azithromycin treated patients required fewer oral antibiotic courses but five had extra courses (p=0.005). Sputum bacterial densities, inflammatory markers, exercise tolerance, and subjective well-being did not change. There were no noticeable side-effects.

This was an important trial as it gave further support to one of the major new treatments of the Millennium which would become widely used not only in patients chronically infected with Pseudomonas but eventually also in younger uninfected patients. The clear importance of considering the effect of treatment on individual patients is apparent as the FEV1 of five children deteriorated by more than 13%.
It is interesting, and perhaps not without relevance in regard to the effects of macrolides, that Harry Shwachman used erythromycin on more severely affected patients and at times saw significant benefit; also Margaret Mearns in London used erythromycin in the young patients. Perhaps both these experienced clinicians appreciated that there was some additional effect from the macrolides? By 2010 no less than 70.2% of patients with CF in the USA were taking regular azithromycin.

2003 Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY Accurso FJ Campbell PW. Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290:1749-56. [PubMed]
This is the major CF Foundation multicentre study on azithromycin. The active group (n = 87) received 250 mg (if weight <40 kg) or 500 mg (if weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; the placebo group (n = 98) received identically packaged tablets The azithromycin group had a significant mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group. Participants in the azithromycin group had less risk of experiencing an exacerbation and at the end of the study weighed an average 0.7 kg more than participants receiving placebo.

So here was further evidence that azithromycin treatment was associated with improvement in clinically relevant end points and the authors advised the drug should be considered for patients with CF who are 6 years or older and chronically infected. Following this trial the product was licensed for use in cystic fibrosis.

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 Hansen CR, Pressler T, Koch C, Hoiby N. Long-term azithromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study. J Cyst Fibros 2005; 4:35-40. [PubMed]
In 2001 long-term, low-dose azithromycin (AZ) treatment was introduced as an integral part of the routine treatment at the Copenhagen CF centre and 45 patients completed 1-year of treatment. The authors concluded that long-term, low-dose AZ treatment in adult CF patients with chronic P. aeruginosa infection was safe and reduced the rate of decline in lung function, increased weight, and reduced the percentage of mucoid strains of P. aeruginosa in sputum samples.

This was a useful observational study from a centre where the previous standard of treatment was known to be high – even so, there was further impressive improvement with the addition of azithromycin to their usual treatment regimen (also Everard et al, 1997; Jaffe et al, 1998; Equi et al, 2002; Saiman et al, 2003 all above).

2006 Phaff SJ, Tiddens HA, Verbrugh HA, Ott A. Macrolide resistance of Staphylococcus aureus and Haemophilus species associated with long-term azithromycin use in cystic fibrosis. J Antimicrob Chemother 2006; 57:741-746. [PubMed]
The purpose of this study was to determine the association between long-term use of azithromycin, now taken by many patients with CF, and change over time in macrolide susceptibility of Staphylococcus aureus and Haemophilus spp. The authors found that erythromycin resistance in S. aureus increased from 6.9 to 53.8% and clarithromycin resistance in Haemophilus spp. from 3.7 to 37.5%. Resistance but also isolation rates were strongly related to azithromycin use.

So over a 4 year period, azithromycin maintenance therapy in the CF population was associated with an increase in macrolide resistance in S. aureus and Haemophilus spp. which was not unexpected.
There is an extensive literature on the use of macrolides in cystic fibrosis since 2006 including a Cochrane Review (Southern KW et al. Cochrane Database Syst Rev 2011; Dec 7;(12):CD002203. [PubMed]http://www.ncbi.nlm.nih.gov/pubmed/). This Cochrane Review provides evidence of improved respiratory function after six months of azithromycin. Data beyond six months were less clear, although reduction in pulmonary exacerbation was sustained. Treatment appeared safe over a six-month period; however, emergence of macrolide resistance was a concern. The authors considered a multi-centre trial examining long-term effects of this antibiotic treatment is needed, especially for infants recognised through newborn screening.

2012 Saiman L, Mayer-Hamblett N, Anstead M, Lands LC, Kloster M, Goss CH, Rose LM, Burns JL, Marshall BC, Ratjen F. AZ0004 Macrolide Study Team. Open-label follow-on study of azithromycin in pediatric patients uninfected with Pseudomonas aeruginosa. Pediatr Pulmonol 2012; 47:641-648. [PubMed]
The authors had previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6-18 years of age with cystic fibrosis uninfected with Pseudomonas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain.(Saiman L et al. JAMA 2010; 303:1707-1715 [PubMed]http://www.ncbi.nlm.nih.gov/pubmed/20442386).

The present report is of a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin-azithromycin) and participants initially on placebo who then received azithromycin (placebo-azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday-Wednesday-Friday for participants weighing 18-35.9 kg and 500 mg Monday-Wednesday-Friday for participants weighing 36 kg or greater.
Of 174 eligible participants, 146 (83.9%) enrolled in the open-label study. During the open-label study, the authors observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns.
Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6-12 months among children and adolescents with CF uninfected with P. aeruginosa.

2012 Robinson P. Schechter MS. Sly PD. Winfield K. Smith J. Brennan S. Shinkai M. Henke MO. Rubin BK. Clarithromycin therapy for patients with cystic fibrosis: a randomized controlled trial. Pediatr Pulmonol 2012; 47:551-557.[PubMed]
Two previously reported short term, open label trials of clairthromycin in small numbers of patients with CF failed to show significant benefits in modifying lung function or inflammation. The authors performed an international double blind, cross-over trial in which 63 subjects with CF were studied while receiving either placebo or 500 mg oral clarithromycin twice daily for 5 months, with a 1-month wash-out.

No significant difference in either the primary efficacy end point or any secondary end point was seen during the period of clarithromycin treatment compared to those seen during placebo administration. The authors concluded that clarithromycin is not effective in treating CF lung disease.

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.

By 2011 70.6% of eligible patients on the US CF Foundation Registry were taking azithromycin

2015 Principi N; Blasi F; Esposito S.  Azithromycin use in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis 2015; 34(6):1071-9.    [PubMed] 
Long-term treatment with azithromycin (Az) is included in the current guidelines for CF patients aged >6 years. Az has microbiological, immunomodulatory and anti-inflammatory properties that can reduce some of the biological problems that are among the causes of the progressive lung damage associated with CF. Moreover, although it is not active against Pseudomonas aeruginosa, sub-inhibitory concentrations can reduce their pathogenic role by interfering with some bacterial activities and increasing their susceptibility to antibiotics. Azithromycin also has anti-viral activity that limits the risk of the bacterial pulmonary exacerbations that frequently occur after apparently mild viral infections.
The available data seem to indicate that it is effective during its first year of administration, but the impact of longer treatment is debated. Other still undefined aspects of the use of Az include the possible emergence of antibiotic resistance in the other bacterial pathogens that usually colonise CF patients, the real incidence of adverse events and the drug’s potential interference with other routine therapies.

– A review from Milan on the present use and actions of azithromycin in CF. In the USA a median of 67.3% of eligible individuals 6 years and older are receiving longterm azithromycin – slightly more than in the UK.

Somayaji R, Russell R, Cogen JD, Goss CH, Nick SE, Saavedra MT, Taylor-Cousar JL, Nick JA, Nichols DP.Oral Azithromycin Use and the Recovery of Lung Function from Pulmonary Exacerbations Treated with Intravenous Tobramycin or Colistimethate in Adults with Cystic Fibrosis.  Ann Am Thorac Soc. 2019 Jul; 16(7):853-860. [Pubmed]

A retrospective cohort study evaluating the effect of azithromycin with IV tobramycin or colistimethate in adult CF patients treated for a pulmonary exacerbation. The primary outcome was relative lung function recovery (FEV1) following exacerbation treatment. Generalized estimating equations were applied to account for repeated events with independent correlation structures and robust standard errors, incorporating several confounders.

220 exacerbation events occurred in 121 patients in the tobramycin group (47% using azithromycin), and 207 exacerbation events occurred in 86 patients in the colistimethate group (59% using azithromycin). Azithromycin use was associated with less FEV1% recovery in patients treated with tobramycin (-3% relative FEV1% recovery [95% CI -7, 0.2] and -2.64% absolute FEV1% change [95% CI -4.52, -0.76]). Azithromycin use was associated with greater recovery of FEV1% when treated with colistimethate (+3% relative FEV1% recovery [95% CI -0.1, 7] and 2.00% absolute improvement in FEV1% [95% CI 0.13, 3.87]). The odds of 90% or 100% recovery to baseline FEV1% were lower with azithromycin use in the tobramycin cohort and higher with azithromycin use in the colistimethate cohort but were not statistically significant.

The authors concluded azithromycin use was associated with a more favourable response in patients treated with IV colistimethate but a less favourable response in patients treated with IV tobramycin.

– Not sure of the practical implications of these findings. Perhaps if it had previously been decided not to use azithromycin these results would not enourage one to start?

Denis A, Touzet S, Diabaté L, Durieu I, Lemonnier L, Poupon-Bourdy S, Iwaz J, Reynaud Q, Rabilloud M.Quantifying Long-term Changes in Lung Function and Exacerbations after Initiation of Azithromycin in Cystic Fibrosis.  Ann Am Thorac Soc. 2019 Oct 11. doi: 10.1513/AnnalsATS.201812-882OC. [Epub ahead of print][Pubmed] The study sought to quantify the changes in lung function and the number of intravenous antibiotic courses after initiation of azithromycin in patients included in the French Cystic Fibrosis Registry.   The study followed-up 1,065 children and 990 adults from 2 years before to 5 years after long-term azithromycin treatment initiated between 2001 and 2011. Mixed change-point models were used to quantify the changes in the forced expiratory volume in one second and the yearly number of intravenous antibiotic courses.

In the year of treatment initiation, the mean forced expiratory volume was significantly higher than expected (+1.6%, p=0.007 in children and +1.3%, p=0.02 in adults). The decline of the forced expiratory volume over time was less marked after than before treatment initiation (slope difference: +0.7% per year, p=0.03 in children and +0.6% per year, p=0.06 in adults). The mean increase in the yearly number of intravenous antibiotic courses was lower after than before treatment initiation. The rate ratio quantifying the effect on the mean increase was 0.93 (95% CI: [0.88; 0.99]; p=0.02) in children and 0.95 (95% CI: [0.90; 1.01]; p=0.08) in adults.

The authors concluded that in children, long-term azithromycin treatment was associated with immediate and sustained beneficial changes in lung function and sustained beneficial changes in the frequency of pulmonary exacerbations. In adults, it was associated with immediate beneficial changes in lung function.

Dr A Denise is at the Centre Hospitalier Universitaire de Lyon, 26900, Pôle de Santé Publique, Lyon, Rhône-Alpes , France.

Nichols DP, Odem-Davis K, Cogen JD, Goss CH, Ren CL, Skalland M, Somayaji R, Heltshe SL.  Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis.  Am J Respir Crit Care Med. 2019 Oct 29. doi: 10.1164/rccm.201906-1206OC. [Epub ahead of print]  [Pubmed]    
Chronic azithromycin is commonly used in cystic fibrosis (CF) based on short, controlled, clinical trials showing reductions in pulmonary exacerbations (PEx) and improved FEV1. Long term effects are unknown.
The authors examined pulmonary outcomes among chronic azithromycin users compared to matched controls over years of use, and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.  A retrospective cohort study using the U.S. CF Foundation Patient Registry. Incident chronic azithromycin users were compared to matched controls by FEV1 percent predicted rate of decline and rates of intravenous antibiotic use to treat PEx. Propensity score methods were utilized to address confounding by indication. Pre-defined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.

Across 3 years, FEV1 percent predicted per year decline was nearly 40% less in those with PA using azithromycin compared to matched controls (slopes -1.53 vs -2.41 pp/yr, difference: 0.88; 95% CI: [0.30, 1.47]). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of IV antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV1 percent predicted/year decline of -0.16 versus non-users (95% CI: [-0.44, 0.13]), while users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49 pp/year slower decline than matched controls (95% CI:[-0.11, 1.10]).

The authors conclude the results from this study provide additional rationale for chronic azithromycin use in PA positive individuals to reduce lung function decline.

Dr David P Nichols is a paedaitric pulmonologist at Seattle Childrens’s Hospital

Saiman L. Improving outcomes of infections in cystic fibrosis in the era of CFTR modulator therapy.  Pediatr Pulmonol. 2019 Nov;54 Suppl 3:S18-S26. doi: 10.1002/ppul.24522.   [Pubmed]

Currently, available single and dual-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have favorably altered the life course of individuals with cystic fibrosis (CF) by decreasing morbidities and increasing survival. However, even with CFTR modulator use, questions and challenges remain to optimize the management of lung infections. This review (a) identifies these ongoing challenges and discusses the current understanding of the potential impact of CFTR modulator therapy on infections; (b) describes ongoing research to optimize detection, diagnosis, and treatment of CF microorganisms; and (c) discusses strategies to develop new anti-infective therapies. The CF Foundation has launched the Infection Research Initiative to fund research that will improve our understanding of the complex microbial ecology within the CF lung, improve detection of CF pathogens, optimize current treatment, including long-term chronic therapies, and develop new anti-infective therapies. Ongoing clinical trials to determine the optimal duration of treatment of pulmonary exacerbations and to diagnose and treat nontuberculous mycobacteria represent clinical research paradigms that could be used to answer other complex treatment questions. The anti-infective pipeline includes both existing anti-infective and non-anti-infective agents, many of which are proposed to have unique mechanisms of action in CF. Future studies plan to evaluate short- and long-term clinical effectiveness and impact on infections, of the next generation of CFTR modulator therapy, the highly effective triple-combination therapy, for individuals with CF, homozygous or heterozygous for F508del.

Dr Lisa Saiman, is a Professor of Pediatrics at Columbia University Medical Center and an attending physician at New York-Presbyterian (NYP) Morgan Stanley Children’s Hospital.

– What will be the impact of the new modulators in individuals who already have chronic lung disease? It is likely that all CF individuals whatever the state of their lung disease will require carful “monitoring of their microbiology and anti-microbial therapy remains a cornerstone of treatment for CF”. There was a decrease in the proportion of G551D patients with positive cultures for P.aeruginosa significantly after starting ivacaftor noted by a number of authors. A number of studies suggest that existing CFTR modulators have a favourable effect on the microbiology. The effect of modulator therapy on the microbiome is discussed. The author hopes that studies will allow careful assessment of the risks and benefits of withdrawing antimicrobial therapies as may appear attractive to some individuals. An interesting review of the microbiology by an expert as treatment of CF enters a new “modulator era”.

A M Akkerman-Nijland , J E Möhlmann, O W Akkerman, H Vd Vaart, C J Majoor, B L Rottier, J G M Burgerhof, E Hak, G H Koppelman, D J Touw ^.  The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart.  Expert Opin Drug Saf 2021 May 25. doi: 10.1080/14740338.2021.1932814.Online ahead of print. [Pubmed]

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.
Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.
Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.

Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

A M Akkerman-Nijland  is at the University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, University of Groningen, Groningen, the Netherlands, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.

MONOBACTAMS

AZTREONAM

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]http://www.ncbi.nlm.nih.gov/pubmed/ [PubMed]http://www.ncbi.nlm.nih.gov/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)

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).

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])

2004 Habash MB. Park AJ. Vis EC. Harris RJ. Khursigara CM. Synergy of silver nanoparticles and aztreonam against Pseudomonas aeruginosa PAO1 biofilms. Antimicrob Agents Chemother 2014; 58:5818-30. [PubMed]
The goal of this study was to assess the efficacy of citrate-capped silver nanoparticles (AgNPs) of various sizes, alone and in combination with the monobactam antibiotic aztreonam, to inhibit Pseudomonas aeruginosa PAO1 biofilms. 10-nm nanoparticles were most effective in inhibiting the recovery of P. aeruginosa biofilm cultures and showed synergy of inhibition when combined with sub-MIC levels of aztreonam likely caused by better penetration of the small AgNPs into the biofilm matrix.
These data suggest that small AgNPs synergistically enhance the antimicrobial effects of aztreonam against P. aeruginosa in vitro, and they reveal a potential role for combinations of small AgNPs and antibiotics in treating patients with chronic infections.

There are a number of anecdotal reports of the favourable effect of silver preparations on the respiratory infections of people with cystic fibrosis (Baral VR. Colloidal silver for lung disease in cystic fibrosis. J R Soc Med. 2008;101 Suppl 1:S51-2. Free article available).

2015 Tiddens HA; De Boeck K; Clancy JP; Fayon M; H G M A; Bresnik M; Derchak A; Lewis SA; Oermann CM; ALPINE study investigators.  Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros 2015; 14(1):111-9.   [PubMed]
A single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients.
CF patients (3 months to <18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a >2-year history of Pa-negative cultures (> 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points.
A total of 105 pediatric CF patients enrolled (3 months to <2 years, n=24; 2 to <6 years, n=25; 6 to <18 years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points.

OXAZOLIDONONES

LINEZOLID

PENICILLINS

AMOXICILLIN/ CARBENICILLIN/ CLOXACILLIN/FLUCLOXACILLIN/METHICILLIN PENICILLIN G/ PIPERACILLIN
OXACILLIN

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. 
Alexander Flemming (1881-1955) (figure 1 main text) 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 main text) 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.[PubMed]http://www.ncbi.nlm.nih.gov/pubmed/
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 main text).

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.

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, where 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 – both the prevalence of chronic S. aureus infection of 14% is low (Southern et al, 1993. In: Clinical ecology of cystic fibrosis. Escobar H et al. (eds). Excerpta Medica Internat Congr Series 1034: 129-132) 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,[PubMed] below).

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.

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.

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[PubMed] above).
In our expanding clinic in Leeds in the early 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. 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 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[PubMed]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]).

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 or placebo 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 in the treated infants. 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 recommended 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.

Another trial on the use of prophylactic flucloxacillin for screened CF infants is underway  in the UK.

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.

POLYPEPTIDES

BACITRACIN/ COLISTIN/ POLYMYXIN B

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 nebulised 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).

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 was accepted in the USA (even the excellent trial of Valerius et al, 1991 with its 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)

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 (figure 7) 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 paper. With permission of the Lancet.(see main text)

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 likely to be a significant effect.

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 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)in chronic infection 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.

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. The design of the trial has been critised. It is true that the 26 of 30 families who agreed to participate and were randomly allocated to receive treatment with ciprofloxacin and inhaled colomycin for 3 weeks or no anti-pseudomonas treatment. However, the difference in chronic Pseudomonas infection bewteen the treated (14%) and the non-treated (58%), ad the clearing of the pseudomonas infection so unusual that it is difficult to understand why this data from from Copenhagen, which so 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]http://www.ncbi.nlm.nih.gov/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 (figure in main text), 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 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]; Wiesemann HG, et al. Pediatr Pulmonol 1998; 25:88-92. [PubMed]; and later Munck A et al. Pediatr Pulmonol 2001; 32:288-292. [PubMed]).

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).

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 Niels 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).

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.

A 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 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.

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.

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. These authors 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 they 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 the treatment.

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

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. The authors performed a 17-year prospective study on colistin susceptibility and compared their 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

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. 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). Also 80mg bd of tobramycin was adequate to prevent Pseudomonas infection in another study (Wiesemann HG et al. Pediatr Pulmonol 1998; 25:88-92).

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 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.

2014 W S Yapa S. Li J. Patel K. Wilson JW. Dooley MJ. George J. Clark D. Poole S. Williams E. Porter CJ. Nation RL. McIntosh MP. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration. Antimicrob Agents Chemother 2014; 58:2570-9. Free article available..[PubMed]
The purpose of this study was to define the pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following intravenous (i.v.) and inhaled administration in cystic fibrosis (CF) patients. The pharmacokinetic parameters for CMS following i.v. delivery were consistent with previously reported values. Sputum concentrations of formed colistin were maintained at <1.0 mg/liter for 12 h postdose. Nebulization of CMS resulted in relatively high sputum concentrations of CMS and formed colistin compared to those resulting from i.v. administration. The systemic availability of CMS was low following nebulisation of 2 and 4 million IU (7.93% + 4.26% and 5.37% + 1.36%, respectively), and the plasma colistin concentrations were below the limit of quantification. Less than 2 to 3% of the nebulized CMS dose was recovered in the urine samples in 24 h.
The therapeutic availability and drug targeting index for CMS and colistin following inhalation compared to i.v. delivery were significantly greater than 1. Inhalation of CMS is an effective means of targeting CMS and formed colistin for delivery to the lungs, as high lung exposure and minimal systemic exposure were achieved in CF subjects.

QUINOLONES /FLUROQUINOLONES

CIPROFLOXACIN/ENOXACIN

Also many references to oral ciprofloxacin used with inhaled colomycin in the early eradication of P. aeruginosa.

*1985 Weber AH, Scribner RK, Marks MI. In vitro activity of ciprofloxacin against pediatric pathogens. Chemotherapy. 1985;31(6):456-65. [PubMed].

Of the new quinoline derivatives tested, ciprofloxacin demonstrated consistently superior antibacterial activity. Ciprofloxacin may be particularly effective for oral administration in infections requiring prolonged antibiotic therapy, such as bone, joint, and complicated soft tissue infections, and in pulmonary infections in patients with cystic fibrosis.

The first publication on ciprofloxacin re. cystic fibrosis. Eventually over 350 publications concerned the use of the antibiotic in CF. At the time a major advance for the treatment of P. aeruginosa as an alternative to intravenous antibiotics.

*1985 Miller MG, Ghoneim AT, Littlewood JM. Use of enoxacin in a patient with cystic fibrosis.
Lancet 1985;1(8429):646. [PubMed].

We reported the successful use of another oral anti-pseudomonal antibiotic, Enoxacin, in a 12 year old boy with cystic fibrosis.

I recall there was much excitement when these drugs became available as a possible alternative to intravenous antibiotics. There was initially concern about possible bone lesions which had been observed in beagle puppies. Our patient had to be reassured that he would not get the bad legs the puppies had developed.

Enoxacin was not used in CF with no mention after 1990. The drug appeared to be eventually used for gonorrhoea and urinary tract infections and more recently it was shown to have some cancer inhibiting effect.

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.

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 Remmington T, Jahnke N, Harkensee C. Oral anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2013 Oct 29;10:CD005405. doi: 10.1002/14651858.CD005405.pub3.[PubMed].
Three trials examining pulmonary exacerbations (171 participants) and two trials examining long-term therapy (85 participants) were included. The reviewers regarded the most important outcomes as quality of life and lung function. The analysis did not identify any statistically significant difference between oral anti-pseudomonal antibiotics and other treatments for these outcome measures for either pulmonary exacerbations or long-term treatment. One of the included trials reported significantly better lung function when treating a pulmonary exacerbation with ciprofloxacin when compared with intravenous treatment; however, their analysis did not confirm this finding. They found no evidence of difference between oral anti-pseudomonal antibiotics and other treatments regarding adverse events or development of antibiotic resistance, but trials were not adequately powered to detect this.

The reviewers found no conclusive evidence that an oral anti-pseudomonal antibiotic regimen is more or less effective than an alternative treatment for either pulmonary exacerbations or long-term treatment of chronic infection with P. aeruginosa. Until results of adequately-powered future trials are available, treatment needs to be selected on a pragmatic basis, based upon any available non-RCT evidence, the clinical circumstances of the individual, the known effectiveness of drugs against local strains and upon individual preference.

SULPHONAMIDES

COTRIMOXAZOLE

TETRACYCLINES

DOXYCYCLINE/ OXYTETRACYCLINE/ TETRACYCLINE
AUREOMYCIN/TERRAMYCIN

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.

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).

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 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 116 vs. 123;
Dead 68 (57%) vs. 22 (18%)
Alive 47 (41%) vs. 101 (87%)
>5 years 15 (13%) vs. 61 (50%)

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 main text) , 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 problem (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 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 thalidomide 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]).

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).

OTHER ANTIBIOTICS

CHLORAMPHENICOL, CHLOROMYCTIN/ FUSIDIC ACID / METRONIDAZOLE/ TRIMETHOPRIM

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, were some 10 years later (Denning et al, 1963 below; Huang NN. J Pediatr 1966; 68:32-44 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).

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]http://www.ncbi.nlm.nih.gov/pubmed/13805125) 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.

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 dr

VORICONAZOLE

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.

GENERAL ARTICLES RELATING TO ANTIBIOTIC USE – GUIDELINES, TECNIQUES OF ADMINISTRATION, EFFECTS ETC

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.

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), 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.

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.

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.

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.

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.

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

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]http://www.ncbi.nlm.nih.gov/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.

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 available on the CF Trust website www.cftrust.org.uk).

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 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. aureus appears (Szaff and Hoiby,1981 above – see discussion after this entry for more on anti-Staphylococcal prophylaxis).

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).

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”.

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.

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.

 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]http://www.ncbi.nlm.nih.gov/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.

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, have no complaints.

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 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.
However, 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.

2009 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). [PubMed].
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).

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.

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 randomized to treatment with tobramycin inhalation solution for 28 days (TIS) or inhaled sodiumcolistimethate (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 comnclude that all the different studies on first eradicatin treatment of P. aeruginosa agree oon 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 eleiminated. 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.

TECHNIQUES/ANALGESIA
TOTALLY IMPLANTABLE VENOUS ACCESS DEVICES
HOME IV ANTIBIOTICS

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 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 this first very impressive report from Texas by Rucker and his colleagues in our 1988 paper from Leeds on home intravenous antibiotic treatment (Gilbert et al, 1988).

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 2008, 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).

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 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 (figures 8 & 9) 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 venepuncture.

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 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 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), who were already using the devices but had been somewhat discouraged by various serious complications including massive bleeding around the site, and our 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.

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 CF 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]http://www.ncbi.nlm.nih.gov/pubmed/).

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. 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 acce

ptable to most people. (The method was first published by Kanagasundaram et al, 2001 above).

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]http://www.ncbi.nlm.nih.gov/pubmed/

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 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]http://www.ncbi.nlm.nih.gov/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.

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.

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. aeruginosa and the recommendation to use long term prophylactic anti-staphylococcal therapy for the first three years of life.

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. It would appear there are more pressing research questions to be answered.

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 fibrosisfrom 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 Bedi P. Sidhu MK. Donaldson LS. Chalmers JD. Smith MP. Turnbull K. Pentland JL. Scott J. Hill AT. A prospective cohort study of the use of domiciliary intravenous antibiotics in bronchiectasis. Primary Care Respiratory Medicine. 24:14090, 2014. [PubMed]
116 patients with non-cystic fibrosis bronchiectasis received 196 courses of IV antibiotics either as inpatient treatment, early supported discharge or as domiciliary therapy. The authors concluded on all parameters domiciliary IV antibiotic therapy in bronchiectasis is clinically effective and safe in their cohort of patients.

Here is further welcome evidence (admittedly would be considered anecdotal by Cochrane reviewers!) of the benefit and safety of home IV antibiotics, in this case in non-CF patients. it is welcome in view of the recent rather negative Cochrane Review where most of the publications didn’t come up to standard. It is recalled that the introduction of intravenous antibiotics some 40 years ago and their administration at home, avoiding hospitalisation, were major advances for patients who had cystic fibrosis and their families. Although intravenous antibiotics were not a major component of Harry Shwachman’s treatment they did in my view represent one of the major advances in cystic fibrosis care following theiri more widespread use in the late Seventies and early Eighties.