- Email: [email protected]
Diagnosing and managing infection in CF
PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S151–S153
Diagnosing and managing infection in CF Felix Ratjen* Hospital for Sick Children, Toronto Ontario, Canada KEYWORDS airway infection; antibiotic therapy; cystic fibrosis; P. aeruginosa; Saph. aureus
Summary Acute and chronic bacterial infections of the lower respiratory tract remain one of the hallmarks of cystic fibrosis lung disease. We here review some of the controversial areas of diagnosing airway infection in CF patients including the use of techniques such as induced sputum and bronchoalveolar lavage. Treatment strategies have evolved over the years and there is ongoing discussion as to whether to treat on the basis of symptoms, positive cultures alone or continuously regardless of clinical and laboratory findings. Prophylactic antibiotic therapy with anti-staphyloccocal antibiotics has been linked to a higher incidence of P. aeruginosa infection, but it is still unclear whether this side effect is limited to broader spectrum antibiotics such as cephalosporins. Early antibiotic therapy against P. aeruginosa has become an accepted treatment strategy as it not only delays the onset of chronic infection, but also leads to eradication of the organism in the majority of patients. So far no evidence exists that combination therapy is superior to inhaled therapy alone. In addition, the optimal duration of therapy type of inhaled antibiotic as well as the optimal dose has not been clarified. Studies are currently ongoing to resolve these issues. ß 2006 Elsevier Ltd. All rights reserved.
Acute and chronic bacterial infection of the lower respiratory tract remains one of the hallmarks of cystic fibrosis lung disease. The current pathophysiologic concept of CF lung disease assumes that depletion of airway surface liquid caused by defective chloride secretion and sodium hyperabsorption results in breakdown of mucociliary transport which favours bacterial infection and persistence.1 Bacterial infection is limited to a relatively small spectrum of pathogens of which Staphylococcus aureus and Pseudomonas aeruginosa are the most prevalent organisms. While Staph. auerus is the predominant organisms in younger children, P. aeruginosa infection may start early in infancy and becomes the most prevalent organism in older CF patients.2 If untreated, P. aeruginosa changes into a mucoid phenotype, which is more resistant to treatment. Most studies have indicated that once a mucoid phenotype has developed,
* Tel.: +1 416 813 6167; Fax: +1 416 813 6246. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.217
even aggressive antibiotic therapy fails to clear the infection permanently.3 Accurate diagnosis of airway infection forms the basis for guidance of therapy in CF. Older patients with more advanced lung disease often produce sputum and sputum reliably reflects lower airway colonization in most patients. However, bronchoalveolar lavage (BAL) may be useful in individual patients, where organisms are not detected in sputum and empiric therapy fails to improve the patient’s clinical status.4 In younger children and patients with milder disease the diagnosis often has to rely on throat or cough swabs, which have a reasonable sensitivity, but poor specificity for lower airway colonization.5,6 Induced sputum has been successfully used in patients older than 6 year of age, who cannot expectorate sputum spontaneously.7 In younger patients bronchoalveolar lavage is a more accurate technique to sample lower airways, but the technique is invasive and it remains to be demonstrated whether routine use of BAL in this age group improves outcome. In addition, regional variations in lower airway infection
S152
have been described in CF patients and a BAL performed in one region of the lung may not always be representative for infection in other areas.8 Since it is difficult to reliably diagnose airway infection and chronic P. aeruginosa infection is linked to poorer prognosis (see below) interest in growing in assessing P. aeruginosa antibodies as surrogate markers of infection. Initial reports have indicated that positivity for P. aeruginosa antibodies is characteristic for patients with chronic infection and that antibodies develop relatively late in the disease process.9–11 However, antibodies have been developed against different epitopes of the organisms, which vary in sensitivity and specificity. Recent evidence suggests that exotoxin A antibodies can be present prior to detection of the organism in throat swabs of CF patients.12 Our own studies including 15 european CF centers would indicate that P. aeruginosa antibodies directed against three different epitopes are more accurate than antibodies against one epitoe alone in delineating early P. aeruginosa infection. However, inter- and intra-individual variability is large and the diagnosis can not rely on the presence of antibodies alone. Reliable detection of bacterial pathogens depends, among other factors, upon the frequency of cultures obtained, which varies greatly among centers. Currently, most centers perform cultures routinely at every clinic visit. Since most centers see CF patients at least 4 times a year, this results in quarterly intervals of airway cultures. Transient bacterial colonization may be missed with this approach and individual centers have proposed airway culturing to be performed on a monthly basis.13 Whether this approach translates into a higher success rate in the treatment of airway infection, thereby improving lung function decline and prognosis, remains to be determined. Treatment strategies for bacterial infection in patients with CF have evolved over the years, but there are still a number of controversies regarding the optimal management of the major pathogens Staph. aureus and P. aeruginosa. There is no doubt that symptomatic patients should be treated based on the results of airway cultures. Whether a positive culture should be treated in the absence of symptoms is less clear, but BAL studies have demonstrated that the mere presence of bacterial organisms is associated with more pronounced airway inflammation.14,15 Continuous antibiotic therapy with anti-staphyloccocal antibiotics has been linked to a higher incidence of P. aeruginosa infection.16,17 Whether this side effect is limited to cephalosporins and less likely to occur with smaller spectrum antibiotics such as flucloxacillin remains to be determined.18 The relevance of P. aeruginosa for CF lung disease is well established. Multiple studies have shown that patients with chronic mucoid P. aeruginosa infection have a poorer prognosis compared to patients not infected with the pathogen.19,20 In contrast, patients with nonmucoid strains of P. aeruginosa do not differ in their annual rate of lung function decline. Since the natural history of P. aeruginosa infection is one of initial colonization with nonmucoid
F. RATJEN
phenotypes transforming to a mucoid phenotype over time, treatment strategies aim to prevent chronic airway infection by initiating treatment before chronic infection is established.21–26 Evidence is growing that this treatment approach not only delays the onset of chronic infection, but also leads to eradication of the organism in the majority of patients. Treatment protocols consist of inhaled antibiotics alone or in combination with ciprofloxacin.23–25 So far no evidence exists that combination therapy is superior to inhaled therapy alone. In addition, the optimal duration of therapy type of inhaled antibiotic as well as the optimal dose have not been clarified. Studies are currently ongoing to resolve these issues. While it appears logical that eradication of P. aeruginosa should improve lung function decline and patient’s outcome, there is still no conclusive evidence that this is the case. Due to the susceptibility of the CF lung to bacterial infections it is also possible that eradication P. aeruginosa may favor airway colonisation with other pathogens, another important aspect of early intervention therapy that needs to be addressed in future trials. Chronic infection with P. aeruginosa is defined as repeated detection of P. aeruginosa in respiratory cultures, mucoid conversion of the pathogen and the presence of P. aeruginosa antibodies.27 Eradication strategies usually fail once chronic infection is established and treatment focusses on suppression of bacterial pathogenicity as well as reduction of bacterial load. Controversy exists on the best strategy to achieve this goal. Inhaled antibiotic therapy with tobramycin has been shown to have positive effects on lung function and the rate of pulmonary exacerbations.28 Inhaled colistin is a second option, although its efficacy is less well documented.29 Limited data are available to define the adequate dose and dosing interval for inhaled antibiotic therapy.30 I.v. antibiotic therapy is usually reserved for the treatment of pulmonary exacerbation, although some centers have adopted a routine protocol of treating chronic P. aeruginosa infection with i.v. antibiotics independent of patient’s symptoms.31 Despite decades of dispute there is still insufficient evidence to support this treatment strategy and a comparative trial has failed to prove its superiority.32 In view of the increased treatment burden associated with this approach and the lack of proven benefit for the patient, most centers continue to reserve i.v. antibiotic therapy for patients with acute exacerbations.
REFERENCES 1. Ratjen F, Do¨ring G. Cystic Fibrosis. Lancet 2003; 361: 681–689. 2. Burns JL, Gibson RL, McNamara S et al. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 2001; 183: 444–452. 3. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–951. 4. Baughman RP, Keeton DA, Perez C, Wilmott RW. Use of bronchoalveolar lavage semiquantitative cultures in cystic fibrosis. Am J Respir Crit Care Med 1997; 156: 286–291.
DIAGNOSING AND MANAGING INFECTION IN CF
5. Ramsey BW, Wentz KR, Smith AL, Richardson M, Williams-Warren J, Hedges DL, Gibson R, Redding GJ, Lent K, Harris K. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis 1991; 144: 331–337. 6. Armstrong DS, Grimwood K, Carlin JB, Carzino R, Olinsky A, Phelan PD. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21: 267–275. 7. Suri R, Marshall LJ, Wallis C, Metcalfe C, Shute JK, Bush A. Safety and use of sputum induction in children with cystic fibrosis. Pediatr Pulmonol 2003; 35: 309–313. 8. Gutierrez JP, Grimwood K, Armstrong DS, Carlin JB, Carzino R, Olinsky A, Robertson CF, Phelan PD. Interlobar differences in bronchoalveolar lavage fluid from children with cystic fibrosis. Eur Respir J 2001; 17: 281–286. 9. Do¨ring G, Hoiby N. Longitudinal study of immune response to Pseudomonas aeruginosa antigens in cystic fibrosis. Infect Immun 1983; 42: 197–201. 10. Johansen HK, Norregaard L, Gotzsche PC, Pressler T, Koch C, Hoiby N. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success? A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection Pediatr Pulmonol 2004; 37: 427–432. 11. Hollsing AE, Granstro¨m M, Vasil ML, Wretlind B, Strandvik B. Prospective study of serum antibodies to Pseudomonas aeruginosa exoproteins in cystic fibrosis. J Clin Microbiol 1987; 25: 1868– 1874. 12. West SE, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, Splaingard MJ, Farrell PM. Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors. JAMA 2002; 287: 2958–2967. 13. Frederiksen B, Lanng S, Koch C et al. Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996; 21: 153. 14. Armstrong DS, Grimwood K, Carlin JB, Carzino R, Gutierrez JP, Hull J, Olinsky A, Phelan EM, Robertson CF, Phelan PD. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997; 156: 1197–1204. 15. Muhlebach MS, Stewart PW, Leigh MW, Noah TL. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. Am J Respir Crit Care Med 1999; 160: 186–191. 16. Smyth A. Prophylactic antibiotics in cystic fibrosis: a conviction without evidence? Pediatr Pulmonol 2005; 40: 471–476. 17. Ratjen F, Comes G, Paul K et al. Effect of continuous anti-staphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis. Pediatr Pulmonol 2001; 31: 13–16. 18. Stutman HR, Lieberman JM, Nussbaum E et al. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial. J Pediatr 2002; 140: 299–305. 19. Henry RL, Mellis CM, Petrovic L, Mucoid. Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992; 12: 158–161.
S153
20. Ballmann M, Rabsch P, von der Hardt H. Long-term follow up of changes in FEV1 and treatment intensity during Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Thorax 1998; 53: 732–737. 21. Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation by early treatment. Lancet 1991; 338: 725– 726. 22. Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, Do¨ring G, von der Hardt H. Placebo-controlled double-blind randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonisation in cystic fibrosis. Pediatr Pulmonol 1998; 26: 88–92; Shah PL. RhDNase trials in cystic fibrosis. Eur Respir J 1995; 8: 1786– 1791. 23. Munck A, Bonacorsi S, Mariani-Kurkdjian P, Lebourgeois M, Gerardin M, Brahimi N, Navarro J, Bingen E. Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization. Pediatr Pulmonol 2001; 32: 288–292. 24. Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol 1997; 23: 330–335. 25. Ratjen F, Do¨ring G, Nikolaizik W. Eradication of Pseudomonas aeruginosa with inhaled tobramycin in patients with cystic fibrosis. Lancet 2001; 358: 983–984. 26. Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld 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, Cystic Fibrosis Therapeutics Development Network Study Group. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med 2003; 167: 841–849. 27. Do¨ring G, Hoiby N. Longitudinal study of immune response to Pseudomonas aeruginosa antigens in cystic fibrosis. Infect Immun 1983; 42: 197–201. 28. Ramsey BW, Pepe MS, Quan JM et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340: 23–30. 29. Jensen T, Pedersen SS, Garne S et al. Colistin inhalation therapy in cystic fibrosis patients with chronic P. aeruginosa infection. J Antimicrob Chemother 1987; 19: 831–838. 30. 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 Chemother 2006; 57: 306–311. 31. Do¨ring G, Conway SP, Heijerman HG et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 2000; 16: 749–767. 32. 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.
Diagnosing and managing infection in CF Felix Ratjen* Hospital for Sick Children, Toronto Ontario, Canada KEYWORDS airway infection; antibiotic therapy; cystic fibrosis; P. aeruginosa; Saph. aureus
Summary Acute and chronic bacterial infections of the lower respiratory tract remain one of the hallmarks of cystic fibrosis lung disease. We here review some of the controversial areas of diagnosing airway infection in CF patients including the use of techniques such as induced sputum and bronchoalveolar lavage. Treatment strategies have evolved over the years and there is ongoing discussion as to whether to treat on the basis of symptoms, positive cultures alone or continuously regardless of clinical and laboratory findings. Prophylactic antibiotic therapy with anti-staphyloccocal antibiotics has been linked to a higher incidence of P. aeruginosa infection, but it is still unclear whether this side effect is limited to broader spectrum antibiotics such as cephalosporins. Early antibiotic therapy against P. aeruginosa has become an accepted treatment strategy as it not only delays the onset of chronic infection, but also leads to eradication of the organism in the majority of patients. So far no evidence exists that combination therapy is superior to inhaled therapy alone. In addition, the optimal duration of therapy type of inhaled antibiotic as well as the optimal dose has not been clarified. Studies are currently ongoing to resolve these issues. ß 2006 Elsevier Ltd. All rights reserved.
Acute and chronic bacterial infection of the lower respiratory tract remains one of the hallmarks of cystic fibrosis lung disease. The current pathophysiologic concept of CF lung disease assumes that depletion of airway surface liquid caused by defective chloride secretion and sodium hyperabsorption results in breakdown of mucociliary transport which favours bacterial infection and persistence.1 Bacterial infection is limited to a relatively small spectrum of pathogens of which Staphylococcus aureus and Pseudomonas aeruginosa are the most prevalent organisms. While Staph. auerus is the predominant organisms in younger children, P. aeruginosa infection may start early in infancy and becomes the most prevalent organism in older CF patients.2 If untreated, P. aeruginosa changes into a mucoid phenotype, which is more resistant to treatment. Most studies have indicated that once a mucoid phenotype has developed,
* Tel.: +1 416 813 6167; Fax: +1 416 813 6246. E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.217
even aggressive antibiotic therapy fails to clear the infection permanently.3 Accurate diagnosis of airway infection forms the basis for guidance of therapy in CF. Older patients with more advanced lung disease often produce sputum and sputum reliably reflects lower airway colonization in most patients. However, bronchoalveolar lavage (BAL) may be useful in individual patients, where organisms are not detected in sputum and empiric therapy fails to improve the patient’s clinical status.4 In younger children and patients with milder disease the diagnosis often has to rely on throat or cough swabs, which have a reasonable sensitivity, but poor specificity for lower airway colonization.5,6 Induced sputum has been successfully used in patients older than 6 year of age, who cannot expectorate sputum spontaneously.7 In younger patients bronchoalveolar lavage is a more accurate technique to sample lower airways, but the technique is invasive and it remains to be demonstrated whether routine use of BAL in this age group improves outcome. In addition, regional variations in lower airway infection
S152
have been described in CF patients and a BAL performed in one region of the lung may not always be representative for infection in other areas.8 Since it is difficult to reliably diagnose airway infection and chronic P. aeruginosa infection is linked to poorer prognosis (see below) interest in growing in assessing P. aeruginosa antibodies as surrogate markers of infection. Initial reports have indicated that positivity for P. aeruginosa antibodies is characteristic for patients with chronic infection and that antibodies develop relatively late in the disease process.9–11 However, antibodies have been developed against different epitopes of the organisms, which vary in sensitivity and specificity. Recent evidence suggests that exotoxin A antibodies can be present prior to detection of the organism in throat swabs of CF patients.12 Our own studies including 15 european CF centers would indicate that P. aeruginosa antibodies directed against three different epitopes are more accurate than antibodies against one epitoe alone in delineating early P. aeruginosa infection. However, inter- and intra-individual variability is large and the diagnosis can not rely on the presence of antibodies alone. Reliable detection of bacterial pathogens depends, among other factors, upon the frequency of cultures obtained, which varies greatly among centers. Currently, most centers perform cultures routinely at every clinic visit. Since most centers see CF patients at least 4 times a year, this results in quarterly intervals of airway cultures. Transient bacterial colonization may be missed with this approach and individual centers have proposed airway culturing to be performed on a monthly basis.13 Whether this approach translates into a higher success rate in the treatment of airway infection, thereby improving lung function decline and prognosis, remains to be determined. Treatment strategies for bacterial infection in patients with CF have evolved over the years, but there are still a number of controversies regarding the optimal management of the major pathogens Staph. aureus and P. aeruginosa. There is no doubt that symptomatic patients should be treated based on the results of airway cultures. Whether a positive culture should be treated in the absence of symptoms is less clear, but BAL studies have demonstrated that the mere presence of bacterial organisms is associated with more pronounced airway inflammation.14,15 Continuous antibiotic therapy with anti-staphyloccocal antibiotics has been linked to a higher incidence of P. aeruginosa infection.16,17 Whether this side effect is limited to cephalosporins and less likely to occur with smaller spectrum antibiotics such as flucloxacillin remains to be determined.18 The relevance of P. aeruginosa for CF lung disease is well established. Multiple studies have shown that patients with chronic mucoid P. aeruginosa infection have a poorer prognosis compared to patients not infected with the pathogen.19,20 In contrast, patients with nonmucoid strains of P. aeruginosa do not differ in their annual rate of lung function decline. Since the natural history of P. aeruginosa infection is one of initial colonization with nonmucoid
F. RATJEN
phenotypes transforming to a mucoid phenotype over time, treatment strategies aim to prevent chronic airway infection by initiating treatment before chronic infection is established.21–26 Evidence is growing that this treatment approach not only delays the onset of chronic infection, but also leads to eradication of the organism in the majority of patients. Treatment protocols consist of inhaled antibiotics alone or in combination with ciprofloxacin.23–25 So far no evidence exists that combination therapy is superior to inhaled therapy alone. In addition, the optimal duration of therapy type of inhaled antibiotic as well as the optimal dose have not been clarified. Studies are currently ongoing to resolve these issues. While it appears logical that eradication of P. aeruginosa should improve lung function decline and patient’s outcome, there is still no conclusive evidence that this is the case. Due to the susceptibility of the CF lung to bacterial infections it is also possible that eradication P. aeruginosa may favor airway colonisation with other pathogens, another important aspect of early intervention therapy that needs to be addressed in future trials. Chronic infection with P. aeruginosa is defined as repeated detection of P. aeruginosa in respiratory cultures, mucoid conversion of the pathogen and the presence of P. aeruginosa antibodies.27 Eradication strategies usually fail once chronic infection is established and treatment focusses on suppression of bacterial pathogenicity as well as reduction of bacterial load. Controversy exists on the best strategy to achieve this goal. Inhaled antibiotic therapy with tobramycin has been shown to have positive effects on lung function and the rate of pulmonary exacerbations.28 Inhaled colistin is a second option, although its efficacy is less well documented.29 Limited data are available to define the adequate dose and dosing interval for inhaled antibiotic therapy.30 I.v. antibiotic therapy is usually reserved for the treatment of pulmonary exacerbation, although some centers have adopted a routine protocol of treating chronic P. aeruginosa infection with i.v. antibiotics independent of patient’s symptoms.31 Despite decades of dispute there is still insufficient evidence to support this treatment strategy and a comparative trial has failed to prove its superiority.32 In view of the increased treatment burden associated with this approach and the lack of proven benefit for the patient, most centers continue to reserve i.v. antibiotic therapy for patients with acute exacerbations.
REFERENCES 1. Ratjen F, Do¨ring G. Cystic Fibrosis. Lancet 2003; 361: 681–689. 2. Burns JL, Gibson RL, McNamara S et al. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 2001; 183: 444–452. 3. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–951. 4. Baughman RP, Keeton DA, Perez C, Wilmott RW. Use of bronchoalveolar lavage semiquantitative cultures in cystic fibrosis. Am J Respir Crit Care Med 1997; 156: 286–291.
DIAGNOSING AND MANAGING INFECTION IN CF
5. Ramsey BW, Wentz KR, Smith AL, Richardson M, Williams-Warren J, Hedges DL, Gibson R, Redding GJ, Lent K, Harris K. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis 1991; 144: 331–337. 6. Armstrong DS, Grimwood K, Carlin JB, Carzino R, Olinsky A, Phelan PD. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21: 267–275. 7. Suri R, Marshall LJ, Wallis C, Metcalfe C, Shute JK, Bush A. Safety and use of sputum induction in children with cystic fibrosis. Pediatr Pulmonol 2003; 35: 309–313. 8. Gutierrez JP, Grimwood K, Armstrong DS, Carlin JB, Carzino R, Olinsky A, Robertson CF, Phelan PD. Interlobar differences in bronchoalveolar lavage fluid from children with cystic fibrosis. Eur Respir J 2001; 17: 281–286. 9. Do¨ring G, Hoiby N. Longitudinal study of immune response to Pseudomonas aeruginosa antigens in cystic fibrosis. Infect Immun 1983; 42: 197–201. 10. Johansen HK, Norregaard L, Gotzsche PC, Pressler T, Koch C, Hoiby N. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success? A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection Pediatr Pulmonol 2004; 37: 427–432. 11. Hollsing AE, Granstro¨m M, Vasil ML, Wretlind B, Strandvik B. Prospective study of serum antibodies to Pseudomonas aeruginosa exoproteins in cystic fibrosis. J Clin Microbiol 1987; 25: 1868– 1874. 12. West SE, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, Splaingard MJ, Farrell PM. Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors. JAMA 2002; 287: 2958–2967. 13. Frederiksen B, Lanng S, Koch C et al. Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996; 21: 153. 14. Armstrong DS, Grimwood K, Carlin JB, Carzino R, Gutierrez JP, Hull J, Olinsky A, Phelan EM, Robertson CF, Phelan PD. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997; 156: 1197–1204. 15. Muhlebach MS, Stewart PW, Leigh MW, Noah TL. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. Am J Respir Crit Care Med 1999; 160: 186–191. 16. Smyth A. Prophylactic antibiotics in cystic fibrosis: a conviction without evidence? Pediatr Pulmonol 2005; 40: 471–476. 17. Ratjen F, Comes G, Paul K et al. Effect of continuous anti-staphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis. Pediatr Pulmonol 2001; 31: 13–16. 18. Stutman HR, Lieberman JM, Nussbaum E et al. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial. J Pediatr 2002; 140: 299–305. 19. Henry RL, Mellis CM, Petrovic L, Mucoid. Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992; 12: 158–161.
S153
20. Ballmann M, Rabsch P, von der Hardt H. Long-term follow up of changes in FEV1 and treatment intensity during Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Thorax 1998; 53: 732–737. 21. Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation by early treatment. Lancet 1991; 338: 725– 726. 22. Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, Do¨ring G, von der Hardt H. Placebo-controlled double-blind randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonisation in cystic fibrosis. Pediatr Pulmonol 1998; 26: 88–92; Shah PL. RhDNase trials in cystic fibrosis. Eur Respir J 1995; 8: 1786– 1791. 23. Munck A, Bonacorsi S, Mariani-Kurkdjian P, Lebourgeois M, Gerardin M, Brahimi N, Navarro J, Bingen E. Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization. Pediatr Pulmonol 2001; 32: 288–292. 24. Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol 1997; 23: 330–335. 25. Ratjen F, Do¨ring G, Nikolaizik W. Eradication of Pseudomonas aeruginosa with inhaled tobramycin in patients with cystic fibrosis. Lancet 2001; 358: 983–984. 26. Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld 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, Cystic Fibrosis Therapeutics Development Network Study Group. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med 2003; 167: 841–849. 27. Do¨ring G, Hoiby N. Longitudinal study of immune response to Pseudomonas aeruginosa antigens in cystic fibrosis. Infect Immun 1983; 42: 197–201. 28. Ramsey BW, Pepe MS, Quan JM et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340: 23–30. 29. Jensen T, Pedersen SS, Garne S et al. Colistin inhalation therapy in cystic fibrosis patients with chronic P. aeruginosa infection. J Antimicrob Chemother 1987; 19: 831–838. 30. 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 Chemother 2006; 57: 306–311. 31. Do¨ring G, Conway SP, Heijerman HG et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 2000; 16: 749–767. 32. 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.