Professor of Experimental Hygiene and Experimental Microbiology Institute of General and Environmental Hygiene
University of Tübingen
European Cystic Fibrosis Society
Cystic fibrosis (CF) is the most common lethal hereditary disorder in Caucasian populations, with an incidence of ~1:2,500 live births.(1) Disease is caused by >1,000 mutations in a gene encoding a membrane-bound chloride channel.(2) The mutations affect epithelial ion and water transport mainly in cells in the respiratory, gastrointestinal, hepatobiliary and reproductive tracts. In airways this leads to impaired mucociliary clearance(2) and causes chronic bacterial infections that may start early in the life of CF patients.(3) These secondary infections have the greatest effect on CF morbidity and mortality.
While Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae remain the most common pathogens, Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Aspergillus species, nontuberculous mycobacteria and respiratory viruses are also isolated.
The vast majority of CF patients are infected with P. aeruginosa.(3) Mucoid P. aeruginosa, characterised by the formation of the exopolysaccharide alginate, is predominantly present in chronic infection.(4) The pathogenesis of chronic P. aeruginosa lung infection in CF is characterised by antibody production against many bacterial antigens, immune complexes and a large influx of neutrophils.(4,5) Neutrophils form large areas of pus around the persisting bacteria, leading to obstruction and destruction of CF airways.(5) Uncontrolled progression of infection will result in progressively severe lung damage, respiratory failure and death. Children with CF infected with P. aeruginosa have lower pulmonary function, lower chest radiograph scores and lower 10-year survival than uninfected children.(6)
Infection control policies
P. aeruginosa is a ubiquitously found water organism, and epidemiological studies suggest that transmission to CF patients may occur by direct patient-to-patient contact or via contaminated environmental reservoirs.(7) Many studies have found P. aeruginosa in the hospital environment.(7) Washbasin sinks in particular may be contaminated, and handwashing at contaminated sinks leads to contaminated hands.(8)
Hygiene measures to decontaminate environmental reservoirs of P. aeruginosa have been recommended. CF centres have separated CF patients with and without P. aeruginosa infection in order to limit cross-infection.(4) At the Copenhagen CF centre, separation of patients with and without P. aeruginosa infection, introduction of hygiene measures for patients and healthcare workers, and the move to a modern clinic have led to a decreased prevalence of P. aeruginosa infection.(9)
Hand disinfection for CF patients and hospital personnel has been emphasised.(10) Importantly, if the hands of CF patients are contaminated with respiratory secretions, transmission of P. aeruginosa is significantly prolonged.(11)
Infection control policies vary from centre to centre, and can generate controversy and anxiety among members of the CF community. Unfortunately, compliance of hospital personnel with recommended hygiene practices is generally poor.(10) Prevention of P. aeruginosa infection is also possible by vaccination.(12,13)
P. aeruginosa infections are generally diagnosed by taking sputum or throat swabs, and P. aeruginosa is easily identified by routine methods. Serological tests for P. aeruginosa antigens have been especially useful in nonexpectorating patients.(14) There is increasing evidence that early diagnosis of P. aeruginosa lung colonisation may be beneficial, since early treatment can be initiated (see below). Therefore, it is recommended that all CF patients, regardless of clinical status, should have a respiratory tract culture performed at least quarterly.(15)
Antibiotic therapy regimens
Antibiotic therapy is thought to be responsible for improved clinical condition, pulmonary function, P. aeruginosa colony counts in sputum, inflammatory parameters, quality of life, and nutritional status of patients.(16,17) Besides antibiotics, improved mucolytic therapy, airway physiotherapy and improved nutritional strategies have contributed to the increased life expectancy of CF patients (median survival 1969 – 14 years; 1996 – 31.3 years).(3) Due to the endobronchial location of mucoid P. aeruginosa in anaerobic plugs,(18) high dosages of antibiotics are recommended (see Table 1).
To obtain high antibiotic dosages, antibiotics such as tobramycin and colistin have been given by the aerosolised route. A review of five randomised controlled trials showed benefit for nebulised antipseudomonal antibiotic therapy, with no demonstrable adverse effects.(19) Consensus reports on the use of aerosolised antibiotics in CF patients have been published.(15,20) Nevertheless, several antibiotics, including aminoglycosides and cephalosporins, are still intravenously administered in high dosages (see Table 1), and therapy is generally scheduled for approximately two weeks. Combination therapy with antibiotics has been favoured because it may slow down drug resistance and may result in synergy.(15) Only fluoroquinolones are given orally,(21,22) and in children.(23)
Eradication of mucoid P. aeruginosa in the chronic infection state by antibiotic therapy is virtually impossible, and generally only a reduction of colony counts can be achieved. This implies that subinhibitory concentrations of antibiotics are present in CF airways, which may positively affect the clinical condition and lung function of CF patients.(24) However, subinhibitory concentrations of antibiotics may also increase the mutation rate of P. aeruginosa and lead to the development of resistant variants.(25)
Chronic P. aeruginosa infections in CF necessitates many antibiotic therapy courses, which carry the risk of increasing resistance towards a given drug more rapidly. Emergence of drug resistance after intravenous and aerosol therapy has been observed in several studies.(15,26,27) Antimicrobial resistance may revert to susceptibility over time, when the antibiotic selective pressure is removed.(28) To avoid resistance, combination therapy with P. aeruginosa-specific antibiotics displaying different modes of action is used in CF patients. For aerosol therapy, intermittent on–off cycles of four weeks are recommended.(15,16)
Large amounts of aerosolised antibiotics may be swallowed, and studies to investigate the effects on gastrointestinal flora during chronic administration have been recommended. (29) Antibiotics are usually aerosolised by nebulising a solution of the drug, although dry powder inhalation, which reduces administration times significantly, has also been studied.(30) Since many CF patients reuse their disposable jet nebulisers, hygiene problems related to microbial contamination may arise. Therefore patients must be instructed how to clean and dry their nebulisers. Exhaled antibiotics should be discharged through a tube to the outside air or trapped in a filter, to avoid contamination of the patient’s surroundings. In some hospitals it is recommended that inhalations are performed in a separate area.(31)
CF patients are treated with antibiotics for most of their lives, and drug side-effects may well occur. Aminoglycosides may cause ototoxicity and nephrotoxicity due to accumulation of the drug in cells, where they bind to the ribosomes.(32) beta-lactam antibiotics, particularly penicillins, may cause allergies.(33)
Prophylactic administration of antibiotics against Staph. aureus, which normally precedes P. aeruginosa, has been suggested based on the assumption that Staph. aureus paves the way for P. aeruginosa infection. Continuous prophylactic flucloxacillin in CF patients diagnosed early was associated with improved clinical progress during the first two years of life.(34) However, this treatment increased the rate of P. aeruginosa infection(35,36) and therefore is not recommended.
Antibiotic therapy, initiated shortly after the diagnosis of P. aeruginosa lung colonisation, provides a very promising concept.(37,38) Based on the observation that the bacterium exhibits a nonmucoid phenotype at the time of colonisation so sputum volumes are low, eradication may be possible early on. Indeed, combined treatment with aerosolised colistin and oral ciprofloxacin significantly reduced the onset of chronic P. aeruginosa infection in CF patients compared with untreated controls.(37) Similarly, a placebo-controlled, double-blind, randomised tobramycin inhalation study showed that, after the onset of P. aeruginosa colonisation, the time of conversion to a P. aeruginosa-negative respiratory culture was significantly shortened by active treatment, suggesting that early treatment may prevent P. aeruginosa pulmonary infection in CF.(38) In a follow-up study,(39) it was demonstrated that this regimen prevented or delayed chronic P. aeruginosa infection in 78% of the CF patients for 3.5 years. Furthermore, aggressive treatment maintained or increased pulmonary function during the year after inclusion compared with the control group, in which pulmonary function declined.(39) Recently, it was demonstrated that early antibiotic therapy eradicated the pathogen from CF airways.(40)
Home therapy permits more normal activity for the CF patient, including school attendance or continuing employment.(41,42) Home intravenous antibiotic therapy in CF patients is a feasible, cost-effective alternative to receiving therapy in hospital. However, patient guidelines concerning hygiene and physiotherapy need to be established.(43) In addition, stringent quality control and assessment of effectiveness are mandatory.
Several centres treat chronic P. aeruginosa infection in CF patients with intravenous antipseudomonal antibiotics three to four times a year and, in between these courses, give daily treatment with aerosolised antibiotics such as colistin and tobramycin. There are still concerns that this intensive and aggressive antibiotic treatment may eventually result in the occurrence of multiresistant P. aeruginosa strains or increased adverse drug effects.(44)
New antibiotic therapy regimens have improved the clinical condition and quality of life of CF patients. Based on the pathophysiology of P. aeruginosa lung infection in CF patients, early antibiotic therapy that may eradicate the pathogen is most promising. This can be achieved only with regular assessment of P. aeruginosa lung colonisation in CF patients.
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- Sheppard MN. The pathology of cystic fibrosis. In: Hodson ME, Geddes D, editors. Cystic fibrosis. London: Chapman and Hall; 1995.
- Cystic Fibrosis Foundation. Cystic Fibrosis Foundation patient registry 1999 annual data report. Bethesda (MD): Cystic Fibrosis Foundation; 2000.
- Høiby N, Koch C. Pseudomonas aeruginosa infection in cystic fibrosis and its management. Thorax 1990;45:881-4.
- Döring G, et al. Immunology of cystic fibrosis. In: Hodson ME, Geddes D, editors. Cystic fibrosis. London: Chapman and Hall; 1995.
- Hudson VL, et al. Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years. J Pediatr 1993;122:854-60.
- Botzenhart K, Döring G. Epidemiology and ecology of Pseudomonas aeruginosa. In: Campa M, et al, editors. Pseudomonas aeruginosa as an opportunistic pathogen. New York: Plenum; 1993. p. 1-18.
- Döring G, et al. Generation of Pseudomonas aeruginosa aerosols during handwashing from contaminated sink drains, transmission to hands of hospital personnel, and its prevention by use of a new heating device. Zbl Hyg 1991;191:494-505.
- Frederiksen B, et al. Changing epidemiology of Pseudomonas aeruginosa infection in Danish cystic fibrosis patients. Pediatr Pulmonol 1999;8:59-66.
- Boyce JM. Antiseptic technology: access, affordability, and acceptance. Emerg Infect Dis 2001;7:231-3.
- Döring G, et al. Distribution and transmission of Pseudomonas aeruginosa and Burkholderia cepacia in a hospital ward. Pediatr Pulmonol 1996;21:90-100.
- Cryz Jr SJ. Pseudomonas aeruginosa vaccines. In: SJ Cryz Jr, editor. Vaccines and immunotherapy. New York: Pergamon Press; 1991. p. 156-65.
- Döring G, Dorner F. A multicenter vaccine trial using the Pseudomonas aeruginosa flagella vaccine IMMUNO in patients with cystic fibrosis. Behring Inst Mitt 1997;98:338-44.
- Döring G, Høiby N. Longitudinal study of immune response to Pseudomonas aeruginosa antigens in cystic fibrosis. Infect Immun 1983;42:197-201.
- Döring G, et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 2000;16:749-67.
- Ramsey BW, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999;340:23-30.
- Regelmann WE, et al. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do broncho-dilators and chest physiotherapy alone. Am Rev Respir Dis 1990;141:914-21.
- Worlitzsch D, et al. Reduced oxygen concentrations in airway mucus cont-ribute to the early and late pathogenesis of Pseudomonas aeruginosa cystic fibrosis airways infection. J Clin Invest 2002;109:317-25.
- Mukhopadhyay S, et al. Nebulised antipseudomonal antibiotic therapy in cystic fibrosis: a meta-analysis of benefits and risks. Thorax 1996;51:364-8.
- Campbell PW 3rd, Saiman L. Use of aerosolized antibiotics in patients with cystic fibrosis. Chest 1999;116:775-88.
- Smith MJ, et al. Pharmacokinetics and sputum penetration of ciprofloxacin in patients with cystic fibrosis. Antimicrob Agents Chemother 1986;30:614-16.
- Hodson ME, et al. Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis. Lancet 1987;1:235-7.
- Schaad UB. Pediatric use of quinolones. Pediatr Infect Dis J 1999;18:469-70.
- Grimwood K, et al. Inhibition of Pseudomonas aeruginosa exoenzyme expression by subinhibitory antibiotic concentrations. Antimicrob Agents Chemother 1989;33:41-7.
- Oliver A, et al. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 2000;288:1251-4.
- Watkins J, et al. Does monotherapy of pulmonary infections in cystic fibrosis lead to early development of resistant strains of Pseudomonas aeruginosa? Scand J Gastroenterol 1988;143:81-5.
- Smith AL, et al. Safely of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol 1989;7:265–71.
- Barclay ML, et al. Adaptive resistance to tobramycin in Pseudomonas aeruginosa lung infection in cystic fibrosis. J Antimicrob Chemother 1996;37:1155-64.
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26th European Cystic Fibrosis Conference
4–7 June 2003
European Respiratory Society 13th Annual Congress
27 September– 1 October 2003
European Cystic Fibrosis Society (ECFS)
European Respiratory Society (ERS)
1 Bd de Grancy
T:+41 21 613 0202