We believe that prompt initiation of eradication protocols for new Pseudomonas aeruginosa infection and early, high dose intravenous antibiotic treatment of respiratory exacerbations have been the most important factors responsible for the improved outlook for people with CF (Conway et al, 1985; Smith et al, 1988; Regelmann et al, 1990; Bradley et al, 1999). All patients require regular respiratory cultures (throat/cough swabs or sputum) and appropriate antibiotic treatment to eradicate any pathogenic bacteria (Cystic Fibrosis Trust, 2002).
There are four main indications for intravenous antibiotic therapy.
To eradicate early P. aeruginosa infection
i) As an alternative to combined oral and nebulised antibiotic treatment e.g. when
treating an infant or young child
ii) As a prelude to the standard oral and nebulised antibiotic regimen when a new P. aeruginosa
culture is associated with new respiratory symptoms
iii) When a standard eradication regimen has failed
To treat a new cough that has not settled with the addition of an oral antibiotic
If new respiratory symptoms do not settle after two different oral antibiotics, or if there are significant continuing symptoms after a single oral antibiotic course, we recommend treatment with intravenous antibiotics. It is important to remember that significant new infection may be present even when careful listening with the stethoscope does not reveal any new added sounds in the chest, and in the absence of any new chest X-ray changes. There may be only a persistent or new cough.
Neglect of these early signs and symptoms may result in permanent damage to the respiratory tract and the onset of a slowly progressive deterioration in respiratory function.
It is our experience that the persistent cough “dries up” within a few days of starting intravenous antibiotic therapy. The antibiotics prescribed will depend on previous respiratory cultures for the patient.
To treat a respiratory exacerbation
Respiratory exacerbations are loosely defined in terms of more breathlessness, increased cough, change in sputum colour to more yellow or green, changes on chest x-ray and loss of appetite and weight. We have found an increased severity of two or more lower respiratory tract symptoms and a fall of 10% or more from baseline FEV1 or FVC to best reflect a new respiratory exacerbation (Pond & Conway, 1996). We recommend that respiratory exacerbations are treated with two intravenous antibiotics to minimise the risk of antibiotic resistance developing (Cheng et al, 1996; Denton et al, 1996). Combined therapy may also have an additive or synergistic effect (synergy means that the antibiotics have an antibacterial effect when given together that is greater than would be expected by simply “adding” together their individual antibiotic potencies).
The details of hospital treatment for intravenous antibiotics and intensive treatment have changed little (Conway et al, 1985) except for our policy of “no mixing” between patients. The duration of a course of intravenous therapy varies but is usually about two weeks.
Usually an aminoglycoside (tobramycin) is combined with a beta lactam (aztreonam, ceftazidime, meropenem or piperacillin-tazobactam). We try to keep colistin as a second line agent e.g. if there are concerns about allergy or bacterial aminoglycoside resistance (Conway et al, 1997). The individual patient’s history of antibiotic hypersensitivity reactions is taken into account when deciding treatment.
The initial choice of antibiotics still depends on the bacterial sensitivity pattern, although there is dispute about whether the laboratory deduced sensitivities are of any relevance in-vivo. The reliability of susceptibility testing of P. aeruginosa isolates from chronic infections in CF is uncertain. Foweraker et al showed that standard laboratory protocols often under-represented the complexity of resistance patterns and this contributed to widespread inter-laboratory variability in determining susceptibility patterns (Foweraker et al, 2005). Further evidence also suggests that the susceptibility pattern in chronic P. aeruginosa infections is poorly predictive of clinical response. As a result we have reduced the number of routine sensitivity tests done in our clinic. Isolates of P. aeruginosa obtained from patients with CF and chronic infection are only routinely tested if they have not been checked in the previous three months, or if obtained from a sample taken at the commencement of intravenous antibiotics, or if the patient is failing on their current antibiotic regimen (Etherington et al, 2007). Clinical improvement may reflect the drugs’ anti-inflammatory and/or antioxidant effects, or activity against P. aeruginosa virulence factors such as exotoxin A, total protease, elastase, phopholipase C, lipase and lecithinase, rather than its bactericidal effect (Adeboyeku et al, 1999; Ledson et al, 1999; Daveyet al, 2000).
It is established that once daily tobramycin is as effective and safe as thrice daily administration (Masters et al, 2001; Whitehead et al, 2002; Smyth et al, 2005; Smyth & Tan, 2006). Most patients find once daily dosing more convenient. Trough drug levels should be monitored before the second dose and on day eight and should be < 1 mg/litre. In a small number of patients, toxicity may still occur despite a trough level of < 1 mg/litre. Future monitoring may involve taking two blood samples at one and eight hours post dose (Coulthard et al, 2007).
Studies indicate that ceftazidime is as effective when given as two rather than three doses each day – an added convenience particularly for patients on home treatment (Conway, 1996).
Improvement during a course of intravenous treatment can be demonstrated by performing regular respiratory function tests and carefully assessing other symptoms and signs including body weight.
As a routine three-monthly treatment for patients with chronic P. aeruginosa infection
This regimen was recommended by the Copenhagen group in 1989 when they showed a significantly better five year survival when patients with chronic P. aeruginosa infection were treated with intravenous anti-pseudomonal antibiotics every three months irrespective of their clinical condition (Jensen et al, 1989; Frederiksen et al, 1996). We and others believe that the picture has changed and that only patients requiring this frequency of treatment to maintain clinical stability should be so treated. We believe that for other patients the risks of antibiotic induced toxic effects on renal function, hearing and balance outweigh the possible benefits of this treatment regimen (Al-Aloul et al, 2005; Etherington et al, 2007). The physical status of patients with CF in 2007 is totally different to that in 1989 and most patients will keep well without recourse to four intravenous antibiotic courses annually. Moreover, patients are living much longer and therefore the potential for serious adverse events from a lifetime of frequent antibiotic treatments is significantly increased. A greater frequency of antibiotic use also increases the risk of patients developing hypersensitivity reactions (allergies) to these medications (Koch et al, 1991; Burrows et al, 2007). Finally, there is the cost of treatment to the hospital and health service and the extra costs incurred by hospitalisation for the patient and relatives.
Whenever it is considered that a patient needs elective three monthly intravenous antibiotic courses all efforts should be made to minimise its intrusive effect on the patient’s and family’s life style. The family and/or patient should be offered teaching so they can administer treatment at home. Home intravenous treatment also reduces the risk of cross infection.
Antibiotic treatment of multi-resistant organisms
Increasingly we are faced with multi-resistant isolates of P. aeruginosa. Innately resistant organisms such as Burkholderia cepacia complex (Bcc), Stenotrophomonas maltophilia and Acromobacter xylosoxidans are becoming more prevalent. Methicillin resistant staphylococcus aureus (MRSA) is also a growing problem. These changing patterns probably result from greater patient longevity and increased antibiotic use for acute exacerbations and maintenance care. The optimal treatment for these resistant bacteria, or even if treatment is always necessary, is not known (Conway et al, 2003).
Multi-resistant P. aeruginosa infection may be treated successfully by using two antibiotics with different mechanisms of action. In practice antibiotic choices have usually been made on a best-guess basis. It had been hoped that better directed therapy could have been achieved through the application of multiple-combination bactericidal testing (MCBT), (Lang et al, 2000). This systematically tests isolates against different combinations of antibiotics to determine optimal sensitivity patterns. However a follow-up study showed that clinical outcomes were not significantly improved when using regimens selected on the basis of MCBT compared to standard susceptibility tests (Aaron et al, 2005).
The selection of antibiotics for pan-resistant bacteria is problematic. In practice they should be treated with the antibiotics that by experience have produced the best clinical response in that individual patient. Combination antibiotic therapy is recommended, usually tobramycin and high dose meropenem or ceftazidime, but the choice of treatment regimen should always be guided by the clinical response (Harris et al, 1999).
Aerosol delivery of Tobramycin achieves high endobronchial concentrations that may overcome bacterial resistance as defined by standard laboratory protocols (Saiman et al, 1996; Lang et al, 2000). Resistance to colistin is rare and this antibiotic should be seen as a valuable second-line intravenous drug to be reserved for multi-resistant P. aeruginosa (Goldman & Alcorn, 1993). Mechanisms of antibiotic delivery (timing, dosage, infusion rate), should be reviewed to achieve optimal bactericidal effect. The efficacy of new antibiotic groups such as the macrolides should be evaluated.
We recommend a combination of tobramycin with high dose meropenem and/or ceftazidime for patients infected with resistant Bcc as this combination appears to confer effective in-vitro bactericidal activity (Bonacorsi et al, 1999; Aaron et al, 2000). If there is intermediate or full sensitivity to ciprofloxacin, the use of this agent in combination with meropenem or piperacillin-tazobactam may increase bactericidal activity (Kumar et al, 1992). The antibiotic regimen should always be guided by clinical response and combinations altered where and when appropriate. However, when triple therapy is given, e.g. meropenem-tobramycin-ceftazidime, growth of other microorganisms is frequently found (Aaron et al, 2000).
The clinical significance of MRSA, S. maltophilia ,and A. xylosoxidans in CF lung disease remains uncertain . If patients show clinical decline and are chronically colonised/infected with either of the former two agents, treatment is recommended but efficacy data are lacking. There are defined microbiological reasons for attempting eradication of MRSA but no proven deleterious effects of this infection on lung function in CF. Various treatment protocols exist but none has been subject to a randomised control trial.
Studies examining the clinical efficacy of different agents and combinations for significant infections with S. maltophilia are lacking and data are extrapolated mainly from in-vitro studies. Co-trimoxazole (Septrin) has consistently been shown to be the most active agent in-vitro, with most isolates susceptible on initial testing. This is regarded as the treatment of choice for significant infections with S. maltophilia (Karpati et al, 1994). Because the activity of co-trimoxazole is only bacteriostatic, it has often been tried in combination with other agents such as ticarcillin-clavulanate or ceftazidime when treating significant infections in immunocompromised patients. There are no data available regarding the efficacy of co-trimoxazole, alone or in combination, for the treatment of chronic S. maltophilia colonisation in patients with CF.
There are no controlled trials investigating the treatment of patients chronically colonised with Achromobacter species. If the latter is the sole pathogen in a symptomatic patient showing a decline in respiratory function tests or worsening chest x-ray, A. xylosoxidans should be treated in a similar way to P. aeruginosa infection with antibiotic choice guided by bacterial sensitivity patterns.
Multi-resistant micro-organisms are an important and growing issue in CF care. Each patient infected with such strains should be assessed individually and antibiotic treatment planned according to any in-vitro sensitivity, patient drug tolerance, and in-vitro studies that may direct the physician to the antibiotic combinations most likely to succeed. Antibiotic choices in these difficult cases must always be guided by the patients’ clinical response.
We have treated a small number of patients with mutli-resistant pathogens with tigecycline, a new injectable glycylcycline antibiotic related to minocycline (Denton et al, 2007). Tigecycline has in-vitro activity against non-fermentative Gram negative bacteria (excluding P.aeruginosa), S.aureus (including MRSA), H. influenzae, and rapid-growing non-tuberculous mycobacteria. We have so far treated several patients with various pathogens including Bcc, Pandoraea apista, S. maltophilia, M. abscessus, and M. chelonae. Two patients were unable to tolerate the drug due to nausea while five patients showed clinical response. Properly constructed trials are required to ascertain the effectiveness of tigecycline in CF.
Desensitisation to antibiotics
On occasions when there is a multi-resistant organism, it may be necessary to use an antibiotic to which the patient has had a previous allergic reaction. The patient can undergo a desensitisation regimen. The patient will need desensitising to the drug at the start of EVERY treatment course and during any course of therapy if more than one dose is omitted.
The regimen uses a logarithmic scale, giving a total of seven doses, starting with a minute dose and increasing by a factor of ten for each subsequent dose, until the therapeutic dose for the patient is achieved. Each dose is diluted to 45 mls, given over 20 minutes and the doses are given consecutively. The whole process takes two and a half to three hours.
Once successfully completed, the full treatment course of the antibiotic can commence as normal. If any of the escalating desensitisation doses are not tolerated the process is abandoned (Etherington et al, 1998). If the desensitisation is unsuccessful it may be repeated at a later date with steroid and/or antihistamine cover prior to and following the procedure.
Aaron SD, Ferris W, Henry DA, et al. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with Burkholderia cepacia. Am J Respir & Crit Care Med 2000; 161: 1206-1212. <a href=”http://pmid.us/10764313%20″>[PubMed]</a>
Aaron SD, Ferris W, Ramotar K, et al. Single and combination antibiotic susceptibilities of planktonic, adherent, and biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with cystic fibrosis. J Clin Microbiol 2002; 40: 4172-9. <a href=”http://pmid.us/12409393%20″>[PubMed]</a>
Aaron SD, Vandemheen KL, Ferris W, et al. Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. Lancet. 2005;366(9484):463-71. <a href=”http://pmid.us/16084254%20″>[PubMed]</a>
Adeboyeku DU, Burgess JC, Hodson ME. Antibiotic sensitivity and clinical outcome of acute respiratory exacerbations in adult CF patients colonised with P. Aeruginosa. Pediatr Pulmonol 1999; Suppl 19: 264.
Al-Aloul M, Miller H, Alapati S, et al. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 2005; 39: 15-20. <a href=”http://pmid.us/15521084%20″>[PubMed]</a>
Bonacorsi S, Fitoussi F, Lhopital S, et al. Comparitive in-vitro activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime in combination with tobramycin, rifampicin, or ciprofloxacin against Burkholderia cepacia isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 1999; 43: 213-17. <a href=”http://pmid.us/9925508%20″>[PubMed]</a>
Bradley JM, Wallace ES, Elborn JS, et al. An audit of the effects of intravenous antibiotic treatment on spirometric measures of pulmonary function in cystic fibrosis. Irish J Med Sc 1999; 168: 25-28.
Burrows JA, Nissen LM, Kirkpatrick CM, et al. Beta-lactam allergy in adults with cystic fibrosis. J Cyst Fibros 2007; 6: 297-303. <a href=”http://pmid.us/17182289%20″>[PubMed]</a>
Cheng K, Smyth RL, Govan JRW, et al. Spread of Beta-lactam-resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. Lancet 1996; 348: 639-642. <a href=”http://pmid.us/8782753%20″>[PubMed]</a>
Conway SP, Miller MG, Ramsden C, et al. 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. <a href=”http://pmid.us/3885674%20″>[PubMed]</a>
Conway SP, Pond MN, Hamnett T, et al. Compliance with treatment in adult patients with cystic fibrosis. Thorax 1996; 51:29-33. <a href=”http://pmid.us/8658364%20″>[PubMed]</a>
Conway SP. Ceftazidime 3G b.d. is as effective as ceftazidime 2G t.d.s. in the treatment of respiratory exacerbations in cystic fibrosis. Israel J Med Sci 1996; 32: S256.
Conway SP, Pond MN, Watson AJ, et al. Intravenous colistin sulphamethate in acute respiratory exacerbations in adult patients with cystic fibrosis. Thorax 1997; 52: 987-993. <a href=”http://pmid.us/9487348%20″>[PubMed]</a>
Conway SP, Brownlee KG, Denton M, Peckham DG. Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis. American Journal of Respiratory Medicine 2003; 2: 321-332. <a href=”http://pmid.us/14719998%20″>[PubMed]</a>
Coulthard KP, Peckham DG, Conway SP, et al. Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis-caution ith trough concentrations. J Cyst Fibros 2007; 6: 125-130. <a href=”http://pmid.us/16829216%20″>[PubMed]</a>
Cystic Fibrosis Trust Antibiotic Group. Antibiotic Treatment for Cystic Fibrosis. 2nd Edition. London. Cystic Fibrosis Trust, September 2002. <a name=”cftrust”></a><a href=”http://www.cfmedicine.com/cfdocs/cftext/pseudomonasiv.htm#cftrust”>[link]</a>
Davey RJ, Peckham D, Etherington C, et al. Antibiotic resistance and clinical outcome following intravenous antibiotics therapy for respiratory exacerbations in cystic fibrosis. Abstract book, XIIIth International CF Congress, Stockholm, 2000: A 409.
Denton M, Littlewood JM, Brownlee KG, et al. Spread of B-lactam resistant Pseudomonas aeruginosa in a cystic fibrosis unit. Lancet 1996; 348: 1596-1597.
Denton M, Purcell N, Cunliffe H, et al. Use of tigecycline to treat difficult respiratory pathogens in cystic fibrosis – early experiences. J Cyst Fibros 2007; 6: S15.
Etherington C, Whitehead A, Conway SP, et al. Incidence of antibiotic related allergies in an adult CF unit and the success rate of a desensitisation regimen. Pediatr Pulmonol 1998; Suppl 17: A427.
Etherington C, Bosomworth M, Clifton I, et al. Measurement of 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. <a href=”http://pmid.us/16844430%20″>[PubMed]</a>
Foweraker JE, Laughton CR, Brown DF, et al. Phenotypic variability of Pseudomonas aeruginosa in sputa from patients with acute infective exacerbation of cystic fibrosis and its impact on the validity of antimicrobial susceptibility testing. J Antimicrob Chemother 2005; 55: 921-927. <a href=”http://pmid.us/15883175%20″>[PubMed]</a>
Frederiksen B, Lanng S, Koch C, et al. Improved survival in the Danish centre treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996; 21: 153-158.<a href=”http://pmid.us/8860069%20″> [PubMed]</a>
Goldman L, Alcorn M. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by colistin. 18th European Cystic Fibrosis Conference, Madrid 1993, p114, A45.
Harris A, Torres-Viera C, Venkataraman L, et al. Epidemiology and clinical outcomes of patients with multi-resistant Pseudomonas aeruginosa. Clin Infect Dis 1999; 28: 1128-1133. <a href=”http://pmid.us/10452647%20″>[PubMed]</a>
Jensen T, Pedersen SS, Hoiby N, et al. Use of antibiotics in cystic fibrosis. The Danish approach. Antibiot Chemother 1989; 42: 237-246. <a href=”http://pmid.us/2688545%20″>[PubMed]</a>
Karpati F, Malmborg AS, Alfredsson H, et al. Bacterial colonisation with Xanthomonas maltophilia – a retrospective study in a cystic fibrosis patient population. Infection 1994; 22: 258-263. <a href=”http://pmid.us/8002085%20″>[PubMed]</a>
Koch C, Hjelt K, Pedersen SS, et al. Retrospective clinical study of hypersensitivity reactions to aztreonam and six other beta-lactam antibiotics in cystic fibrosis patients receiving multiple treatment courses. Rev Infect Dis 1991; 13 (Suppl 7): S608-S611. <a href=”http://pmid.us/2068467″>[PubMed]</a>
Kumar A, Hay MB, Maier GA, et al. Post-antibiotic effect of ceftazidime, ciprofloxacin, imipenem, piperacillin and tobramycin for Pseudomonas cepacia. J Antimicrob Chemother 1992; 30: 597-602. <a href=”http://pmid.us/1283606″>[PubMed]</a>
Lang BJ, Arron SD, Ferris SW, et al. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2000; 162: 2241-2245. <a href=”http://pmid.us/11112146″>[PubMed]</a>
Ledson M, Gallagher MJ, Hart CA, et al. Differential effect of antibiotic therapy on colony counts and inflammatory markers in CF patients colonised with B. cepacia or P. aeruginosa. Pediatr Pulmonol 1999; Suppl 19: 274.
Masters V, Roberts GW, Coulthard KP, et al. Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study. Pediatr Pulmonol 2001; 31: 367-376. <a href=”http://pmid.us/11340683″>[PubMed]</a>
Pond MN, Conway SP. Towards a definition of pulmonary exacerbation for young adults with CF. Israel J Med Sci 1996; 32(Suppl): S243.
Regelmann WE, Elliott GR, Warwick WJ, et al. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. Am Rev Respir Dis 1990; 141: 914-921.<a href=”http://pmid.us/11112146″>[PubMed]</a>
Saiman L, Mehar F, Niu WW, et al. Antibiotics susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis 1996; 23: 532-537. <a href=”http://pmid.us/8879776″>[PubMed]</a>
Smith AL, Redding G, Doershuk C, et al. Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis. J Pediatr 1988; 112: 547-554. <a href=”http://pmid.us/3127569″>[PubMed]</a>
Smyth A, Tan KH, Hyman-Taylor P, et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis – the TOPIC study: a randomised controlled trial. Lancet 2005; 365: 573-578. <a href=”http://pmid.us/15708100″>[PubMed]</a>
Smyth AR, Tan KH. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2006; 3: CD002009. <a href=”http://pmid.us/16855982″>[PubMed]</a>
Whitehead A, Conway SP, Etherington C, et al. Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. Eur Respir J 2002; 19: 303-309. <a href=”http://pmid.us/11866010″>[PubMed]</a>