S3-Leitlinie: Lungenerkrankung bei Mukoviszidose – Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa

Zusammenfassung

Mukoviszidose (Cystic Fibrosis, CF) ist die häufigste, autosomal-rezessiv vererbte Multisystemerkrankung. In Deutschland sind ca. 8000 Menschen betroffen.

Die Erkrankung wird durch Mutationen im Cystic Fibrosis Transmembrane Conductance Regulator (CFTR-) Gen verursacht; diese führen zu einer Fehlfunktion des Chloridkanals CFTR. Dadurch kommt es in den Atemwegen zu einer unzureichenden Hydrierung des epithelialen Flüssigkeitsfilms und somit zu einer chronischen Inflammation.

Rezidivierende Infektionen der Atemwege sowie pulmonale Exazerbationen der Lunge führen im Verlauf zu zunehmender Inflammation, pulmonaler Fibrose und fortschreitender Lungendestruktion bis hin zur respiratorischen Globalinsuffizienz, die für über 90 % der Mortalität verantwortlich ist.

Das Ziel der medikamentösen Therapie ist die pulmonale Inflammation und v. a. die Infektion der Atemwege zu reduzieren.

Der Kolonisation und chronischen Infektion mit Pseudomonas aeruginosa (Pa) kommt die größte Bedeutung zu. Diese führt zu weiterem Verlust an Lungenfunktion.

Für die medikamentöse Therapie der chronischen Pa-Infektion stehen viele unterschiedliche Therapieoptionen zur Verfügung.

Mit dieser S3-Leitlinie wird eine einheitliche Definition für die chronische Pa-Infektion implementiert sowie eine evidenzbasierte Diagnostik und Therapie dargelegt, um eine Orientierung bei der individuellen Therapieentscheidung zu geben.

Abstract

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways.

Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients.

The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection.

Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection.

This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

^a Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin e. V. (DGP), federführende Fachgesellschaft

^b Gesellschaft für Pädiatrische Pneumologie e. V. (GPP), federführende Fachgesellschaft

^c Paul-Ehrlich Gesellschaft für Chemotherapie e. V. (PEG)

^d Deutsche Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ)

^e Deutsche Gesellschaft für Hygiene und Mikrobiologie e. V. (DGHM)

^f Deutsche Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie e. V. (HNO)

^g Deutsche Gesellschaft für pädiatrische Infektiologie e. V. (DGPI)

^h Allianz Chronischer Seltener Erkrankungen (ACHSE) e. V.

ⁱ Österreichische Gesellschaft für Kinder- und Jugendheilkunde (ÖGKJ)

^j Deutsche Gesellschaft für Infektiologie e. V. (DGI)

^k Deutsche Röntgengesellschaft e. V. (DRG)

^l Deutscher Verband für Physiotherapie (ZVK) e. V.

^m Swiss Working Group for Cystic Fibrosis (SWGCF)

ⁿ Mukoviszidose e. V.

^o Mukoviszidose Institut gGmbH (MI)

^p Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF)

• Literatur

• 1 Elborn JS. Cystic fibrosis. Lancet 2016; 388: 2519-2531
• 2 Konstan MW, Berger M. Current understanding of the inflammatory process in cystic fibrosis: onset and etiology. Pediatr Pulmonol 1997; 24: 137-142 ; discussion 159-161
• 3 Müller F-M, Bend J, Rietschel E. et al. S3-Leitlinie „Lungenerkrankung bei Mukoviszidose“, Modul 1: Diagnostik und Therapie nach dem ersten Nachweis von Pseudomonas aeruginosa. Zugriff: 7. November 2016
• 4 Pressler T, Bohmova C, Conway S. et al. Chronic Pseudomonas aeruginosa infection definition: EuroCareCF Working Group report. J Cyst Fibros 2011; 10 (Suppl. 02) S75-S78
• 5 Lee TW, Brownlee KG, Conway SP. et al. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros 2003; 2: 29-34
• 6 Mainz JG, Naehrlich L, Schien M. et al. Concordant genotype of upper and lower airways P aeruginosa and S aureus isolates in cystic fibrosis. Thorax 2009; 64: 535-540
• 7 Deschaght P, De Baere T, Van Simaey L. et al. Comparison of the sensitivity of culture, PCR and quantitative real-time PCR for the detection of Pseudomonas aeruginosa in sputum of cystic fibrosis patients. BMC Microbiol 2009; 9: 244
• 8 Curran B, Jonas D, Grundmann H. et al. Development of a multilocus sequence typing scheme for the opportunistic pathogen Pseudomonas aeruginosa. J Clin Microbiol 2004; 42: 5644-5649
• 9 Wiehlmann L, Wagner G, Cramer N. et al. Population structure of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 2007; 104: 8101-8106
• 10 Hansen SK, Rau MH, Johansen HK. et al. Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection. The ISME journal 2012; 6: 31-45
• 11 Douglas TA, Brennan S, Berry L. et al. Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis. Thorax 2010; 65: 985-990
• 12 Anstead M, Heltshe SL, Khan U. et al. Pseudomonas aeruginosa serology and risk for re-isolation in the EPIC trial. J Cyst Fibros 2013; 12: 147-153
• 13 Lee VT, Smith RS, Tummler B. et al. Activities of Pseudomonas aeruginosa effectors secreted by the Type III secretion system in vitro and during infection. Infect Immun 2005; 73: 1695-1705
• 14 Mauch RM, Levy CE. Serum antibodies to Pseudomonas aeruginosa in cystic fibrosis as a diagnostic tool: A systematic review. J Cyst Fibros 2014;
• 15 Ratjen F, Walter H, Haug M. et al. Diagnostic value of serum antibodies in early Pseudomonas aeruginosa infection in cystic fibrosis patients. Pediatr Pulmonol 2007; 42: 249-255
• 16 Pressler T, Karpati F, Granstrom M. et al. Diagnostic significance of measurements of specific IgG antibodies to Pseudomonas aeruginosa by three different serological methods. J Cyst Fibros 2009; 8: 37-42
• 17 Kappler M, Nagel F, Feilcke M. et al. Predictive values of antibodies against Pseudomonas aeruginosa in patients with cystic fibrosis one year after early eradication treatment. J Cyst Fibros 2014; 13: 534-541
• 18 Johansen HK, Norregaard L, Gotzsche PC. et al. 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
• 19 Wainwright CE, Vidmar S, Armstrong DS. et al. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA 2011; 306: 163-171
• 20 Aaron SD, Kottachchi D, Ferris WJ. et al. Sputum versus bronchoscopy for diagnosis of Pseudomonas aeruginosa biofilms in cystic fibrosis. Eur Respir J 2004; 24: 631-637
• 21 Kabra SK, Alok A, Kapil A. et al. Can throat swab after physiotherapy replace sputum for identification of microbial pathogens in children with cystic fibrosis?. Indian journal of pediatrics 2004; 71: 21-23
• 22 Moskowitz SM, Garber E, Chen Y. et al. Colistin susceptibility testing: evaluation of reliability for cystic fibrosis isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. J Antimicrob Chemother 2010; 65: 1416-1423
• 23 Nelson A, De Soyza A, Bourke SJ. et al. Assessment of sample handling practices on microbial activity in sputum samples from patients with cystic fibrosis. Letters in applied microbiology 2010; 51: 272-277
• 24 Pye A, Hill SL, Bharadwa P. et al. Effect of storage and postage on recovery and quantitation of bacteria in sputum samples. J Clin Pathol 2008; 61: 352-354
• 25 Hogardt M, Häußler S, Balke B. et al. MIQ 24 Atemwegsinfektionen bei Mukoviszidose. In: Mikrobiologisch-infektiologische Qualitätsstandards. Im Auftrag der Deutschen Gesellschaft für Hygiene und Mikrobiologie München Jena: Elsevier: Urban & Fischer; 2006
• 26 Fehlberg LC, Andrade LH, Assis DM. et al. Performance of MALDI-ToF MS for species identification of Burkholderia cepacia complex clinical isolates. Diagnostic microbiology and infectious disease 2013; 77: 126-128
• 27 Alby K, Gilligan PH, Miller MB. Comparison of matrix-assisted laser desorption ionization-time of flight (maldi-tof) mass spectrometry platforms for the identification of gram-negative rods from patients with cystic fibrosis. J Clin Microbiol 2013; 51: 3852-3854
• 28 Desai AP, Stanley T, Atuan M. et al. Use of matrix assisted laser desorption ionisation-time of flight mass spectrometry in a paediatric clinical laboratory for identification of bacteria commonly isolated from cystic fibrosis patients. J Clin Pathol 2012; 65: 835-838
• 29 Schneider M, Muhlemann K, Droz S. et al. Clinical characteristics associated with isolation of small-colony variants of Staphylococcus aureus and Pseudomonas aeruginosa from respiratory secretions of patients with cystic fibrosis. J Clin Microbiol 2008; 46: 1832-1834
• 30 Com G, Carroll JL, Castro MM. et al. Predictors and outcome of low initial forced expiratory volume in 1 second measurement in children with cystic fibrosis. J Pediatr 2014; 164: 832-838
• 31 Kidd TJ, Grimwood K, Ramsay KA. et al. Comparison of three molecular techniques for typing Pseudomonas aeruginosa isolates in sputum samples from patients with cystic fibrosis. J Clin Microbiol 2011; 49: 263-268
• 32 Ballarini A, Scalet G, Kos M. et al. Molecular typing and epidemiological investigation of clinical populations of Pseudomonas aeruginosa using an oligonucleotide-microarray. BMC Microbiol 2012; 12: 152
• 33 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
• 34 Hurley MN, Ariff AH, Bertenshaw C. et al. Results of antibiotic susceptibility testing do not influence clinical outcome in children with cystic fibrosis. J Cyst Fibros 2012; 11: 288-292
• 35 Moskowitz SM, Emerson JC, McNamara S. et al. Randomized trial of biofilm testing to select antibiotics for cystic fibrosis airway infection. Pediatr Pulmonol 2011; 46: 184-192
• 36 Foweraker JE, Laughton CR, Brown DF. et al. Comparison of methods to test antibiotic combinations against heterogeneous populations of multiresistant Pseudomonas aeruginosa from patients with acute infective exacerbations in cystic fibrosis. Antimicrob Agents Chemother 2009; 53: 4809-4815
• 37 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: 463-471
• 38 Doring G, Flume P, Heijerman H. et al. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros 2012; 11: 461-479
• 39 Morosini MI, Garcia-Castillo M, Loza E. et al. Breakpoints for predicting Pseudomonas aeruginosa susceptibility to inhaled tobramycin in cystic fibrosis patients: use of high-range Etest strips. J Clin Microbiol 2005; 43: 4480-4485
• 40 Kerem E, Conway S, Elborn S. et al. Standards of care for patients with cystic fibrosis: a European consensus. J Cyst Fibros 2005; 4: 7-26
• 41 (RKI) KfKuIKbRK-I. Hygienemaßnahmen bei Infektionen oder Besiedlung mit multiresistenten gramnegativen Stäbchen. 2012; 55: 1311-1354
• 42 Burns JL, Saiman L, Whittier S. et al. Comparison of two commercial systems (Vitek and MicroScan-WalkAway) for antimicrobial susceptibility testing of Pseudomonas aeruginosa isolates from cystic fibrosis patients. Diagnostic microbiology and infectious disease 2001; 39: 257-260
• 43 Balke B, Hoy L, Weissbrodt H. et al. Comparison of the Micronaut Merlin automated broth microtiter system with the standard agar dilution method for antimicrobial susceptibility testing of mucoid and nonmucoid Pseudomonas aeruginosa isolates from cystic fibrosis patients. Eur J Clin Microbiol Infect Dis 2004; 23: 765-771
• 44 Burns JL, Saiman L, Whittier S. et al. Comparison of agar diffusion methodologies for antimicrobial susceptibility testing of Pseudomonas aeruginosa isolates from cystic fibrosis patients. J Clin Microbiol 2000; 38: 1818-1822
• 45 Bradbury RS, Tristram SG, Roddam LF. et al. Antimicrobial susceptibility testing of cystic fibrosis and non-cystic fibrosis clinical isolates of Pseudomonas aeruginosa: a comparison of three methods. British journal of biomedical science 2011; 68: 1-4
• 46 Dales L, Ferris W, Vandemheen K. et al. Combination antibiotic susceptibility of biofilm-grown Burkholderia cepacia and Pseudomonas aeruginosa isolated from patients with pulmonary exacerbations of cystic fibrosis. Eur J Clin Microbiol Infect Dis 2009; 28: 1275-1279
• 47 Waters V, Ratjen F. Combination antimicrobial susceptibility testing for acute exacerbations in chronic infection of Pseudomonas aeruginosa in cystic fibrosis. Cochrane Database Syst Rev 2008; CD006961
• 48 Moskowitz SM, Foster JM, Emerson JC. et al. Use of Pseudomonas biofilm susceptibilities to assign simulated antibiotic regimens for cystic fibrosis airway infection. J Antimicrob Chemother 2005; 56: 879-886
• 49 Waters V, Ratjen F. Standard versus biofilm antimicrobial susceptibility testing to guide antibiotic therapy in cystic fibrosis. Cochrane Database Syst Rev 2012; 11: CD009528
• 50 Kirchner S, Fothergill JL, Wright EA. et al. Use of artificial sputum medium to test antibiotic efficacy against Pseudomonas aeruginosa in conditions more relevant to the cystic fibrosis lung. Journal of visualized experiments : JoVE 2012; e3857
• 51 Macia MD, Borrell N, Perez JL. et al. Detection and susceptibility testing of hypermutable Pseudomonas aeruginosa strains with the Etest and disk diffusion. Antimicrob Agents Chemother 2004; 48: 2665-2672
• 52 Mowat E, Paterson S, Fothergill JL. et al. Pseudomonas aeruginosa population diversity and turnover in cystic fibrosis chronic infections. Am J Respir Crit Care Med 2011; 183: 1674-1679
• 53 Simon A. Anforderungen an die Hygiene bei der medizinischen Versorgung von Patienten mit Cystischer Fibrose (Mukoviszidose). Sonderdruck mhp-Verlag 2012
• 54 Deschaght P, Schelstraete P, Van Simaey L. et al. Is the improvement of CF patients, hospitalized for pulmonary exacerbation, correlated to a decrease in bacterial load?. PLoS One 2013; 8: e79010
• 55 Stressmann FA, Rogers GB, Marsh P. et al. Does bacterial density in cystic fibrosis sputum increase prior to pulmonary exacerbation?. J Cyst Fibros 2011; 10: 357-365
• 56 Fodor AA, Klem ER, Gilpin DF. et al. The adult cystic fibrosis airway microbiota is stable over time and infection type, and highly resilient to antibiotic treatment of exacerbations. PLoS One 2012; 7: e45001
• 57 Breen L, Aswani N. Elective versus symptomatic intravenous antibiotic therapy for cystic fibrosis. Cochrane Database Syst Rev 2012; 7: CD002767
• 58 Vandevanter DR, Yegin A, Morgan WJ. et al. Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint. J Cyst Fibros 2011; 10: 453-459
• 59 Chuchalin A, Csiszer E, Gyurkovics K. et al. 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. 01) 21-31
• 60 Wainwright CE, Quittner AL, Geller DE. et al. Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa. J Cyst Fibros 2011; 10: 234-242
• 61 Schuster A, Haliburn C, Doring G. et al. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax 2013; 68: 344-350
• 62 Retsch-Bogart GZ, Burns JL, Otto KL. et al. 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
• 63 Retsch-Bogart GZ, Quittner AL, Gibson RL. et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest 2009; 135: 1223-1232
• 64 Oermann CM, Retsch-Bogart GZ, Quittner AL. et al. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. Pediatr Pulmonol 2010; 45: 1121-1134
• 65 McCoy KS, Quittner AL, Oermann CM. et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med 2008; 178: 921-928
• 66 Clancy JP, Dupont L, Konstan MW. et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax 2013; 68: 818-825
• 67 Galeva I, Konstan MW, Higgins M. et al. Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial. Current medical research and opinion 2013; 29: 947-956
• 68 Herrmann G, Yang L, Wu H. et al. Colistin-tobramycin combinations are superior to monotherapy concerning the killing of biofilm Pseudomonas aeruginosa. J Infect Dis 2010; 202: 1585-1592
• 69 Konstan MW, Flume PA, Kappler M. et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros 2011; 10: 54-61
• 70 Lenoir G, Antypkin YG, Miano A. et al. Efficacy, safety, and local pharmacokinetics of highly concentrated nebulized tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Paediatr Drugs 2007; 9 (Suppl. 01) 11-20
• 71 Littlewood KJ, Higashi K, Jansen JP. et al. A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis. J Cyst Fibros 2012; 11: 419-426
• 72 Ryan G, Singh M, Dwan K. Inhaled antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev 2011; CD001021
• 73 Sawicki GS, Signorovitch JE, Zhang J. et al. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatr Pulmonol 2012; 47: 44-52
• 74 Geller DE, Konstan MW, Smith J. et al. Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety. Pediatr Pulmonol 2007; 42: 307-313
• 75 Elborn JS, Geller DE, Conrad D. et al. A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients. J Cyst Fibros 2015; 14: 507-514
• 76 Okusanya OO, Bhavnani SM, Hammel JP. et al. Evaluation of the pharmacokinetics and pharmacodynamics of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infections using data from two phase 2 clinical studies. Antimicrob Agents Chemother 2014; 58: 5005-5015
• 77 Page MG, Dantier C, Desarbre E. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli. Antimicrob Agents Chemother 2010; 54: 2291-2302
• 78 Hubert D, Leroy S, Nove-Josserand R. et al. Pharmacokinetics and safety of tobramycin administered by the PARI eFlow rapid nebulizer in cystic fibrosis. J Cyst Fibros 2009; 8: 332-337
• 79 Lenney W, Edenborough F, Kho P. et al. Lung deposition of inhaled tobramycin with eFlow rapid/LC Plus jet nebuliser in healthy and cystic fibrosis subjects. J Cyst Fibros 2011; 10: 9-14
• 80 Govoni M, Poli G, Acerbi D. et al. Pharmacokinetic and tolerability profiles of tobramycin nebuliser solution 300 mg/4 ml administered by PARI eFlow((R)) rapid and PARI LC Plus((R)) nebulisers in cystic fibrosis patients. Pulmonary pharmacology & therapeutics 2013; 26: 249-255
• 81 Konstan MW, Geller DE, Minic P. et al. Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol 2011; 46: 230-238
• 82 Edenborough FP, Borgo G, Knoop C. et al. Guidelines for the management of pregnancy in women with cystic fibrosis. J Cyst Fibros 2008; 7 (Suppl. 01) S2-S32
• 83 Remmington T, Jahnke N, Harkensee C. Oral anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2013; 10: CD005405
• 84 Smyth A, Elborn JS. Exacerbations in cystic fibrosis: 3--Management. Thorax 2008; 63: 180-184
• 85 Mayer-Hamblett N, Kronmal RA, Gibson RL. et al. Initial Pseudomonas aeruginosa treatment failure is associated with exacerbations in cystic fibrosis. Pediatr Pulmonol 2012; 47: 125-134
• 86 Smyth AR, Bhatt J. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2014; 2: CD002009
• 87 Riethmueller J, Junge S, Schroeter TW. et al. Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis. Infection 2009; 37: 418-423
• 88 Flume PA, Robinson KA, O'Sullivan BP. et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care 2009; 54: 522-537
• 89 Elphick HE, Jahnke N. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis. Cochrane Database Syst Rev 2014; CD002007
• 90 Blumer JL, Saiman L, Konstan MW. et al. The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Chest 2005; 128: 2336-2346
• 91 Hubert D, Le Roux E, Lavrut T. et al. Continuous versus intermittent infusions of ceftazidime for treating exacerbation of cystic fibrosis. Antimicrob Agents Chemother 2009; 53: 3650-3656
• 92 Madsen V, Lind A, Rasmussen M. et al. Determination of tobramycin in saliva is not suitable for therapeutic drug monitoring of patients with cystic fibrosis. J Cyst Fibros 2004; 3: 249-251
• 93 Parkins MD, Rendall JC, Elborn JS. Incidence and risk factors for pulmonary exacerbation treatment failures in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. Chest 2012; 141: 485-493
• 94 Sanders DB, Bittner RC, Rosenfeld M. et al. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010; 182: 627-632
• 95 Keays T, Ferris W, Vandemheen KL. et al. A retrospective analysis of biofilm antibiotic susceptibility testing: a better predictor of clinical response in cystic fibrosis exacerbations. J Cyst Fibros 2009; 8: 122-127
• 96 Tascini C, Gemignani G, Ferranti S. et al. Microbiological activity and clinical efficacy of a colistin and rifampin combination in multidrug-resistant Pseudomonas aeruginosa infections. Journal of chemotherapy 2004; 16: 282-287
• 97 Falagas ME, Kastoris AC, Karageorgopoulos DE. et al. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents 2009; 34: 111-120
• 98 Mikuniya T, Kato Y, Kariyama R. et al. Synergistic effect of fosfomycin and fluoroquinolones against Pseudomonas aeruginosa growing in a biofilm. Acta medica Okayama 2005; 59: 209-216
• 99 McCaughey G, McKevitt M, Elborn JS. et al. Antimicrobial activity of fosfomycin and tobramycin in combination against cystic fibrosis pathogens under aerobic and anaerobic conditions. J Cyst Fibros 2012; 11: 163-172
• 100 Roehmel JF, Schwarz C, Mehl A. et al. Hypersensitivity to antibiotics in patients with cystic fibrosis. J Cyst Fibros 2014; 13: 205-211
• 101 Burrows JA, Nissen LM, Kirkpatrick CM. et al. Beta-lactam allergy in adults with cystic fibrosis. J Cyst Fibros 2007; 6: 297-303
• 102 Legere 3rd HJ, Palis RI, Rodriguez BouzaT. et al. A safe protocol for rapid desensitization in patients with cystic fibrosis and antibiotic hypersensitivity. J Cyst Fibros 2009; 8: 418-424
• 103 Whitaker P, Shaw N, Gooi J. et al. Rapid desensitization for non-immediate reactions in patients with cystic fibrosis. J Cyst Fibros 2011; 10: 282-285
• 104 Southern KW, Barker PM, Solis-Moya A. et al. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2012; 11: CD002203
• 105 Nick JA, Moskowitz SM, Chmiel JF. et al. Azithromycin may antagonize inhaled tobramycin when targeting Pseudomonas aeruginosa in cystic fibrosis. Annals of the American Thoracic Society 2014; 11: 342-350
• 106 VanDevanter DR, O'Riordan MA, Blumer JL. et al. Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. Respir Res 2010; 11: 137
• 107 Adeboyeku D, Jones AL, Hodson ME. Twice vs three-times daily antibiotics in the treatment of pulmonary exacerbations of cystic fibrosis. J Cyst Fibros 2011; 10: 25-30
• 108 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
• 109 Taccetti G, Campana S, Neri AS. et al. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis. Journal of chemotherapy 2008; 20: 166-169
• 110 Thornton J, Elliott RA, Tully MP. et al. 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
• 111 Tam J, Nash EF, Ratjen F. et al. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev 2013; 7: CD007168
• 112 Balfour-Lynn IM, Lees B, Hall P. et al. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 2006; 173: 1356-1362
• 113 Cheng K, Ashby D, Smyth RL. Oral steroids for long-term use in cystic fibrosis. Cochrane Database Syst Rev 2013; 6: CD000407
• 114 Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database Syst Rev 2013; 6: CD001505
• 115 Halfhide C, Evans HJ, Couriel J. Inhaled bronchodilators for cystic fibrosis. Cochrane Database Syst Rev 2005; CD003428
• 116 Valverde-Molina J, Sanchez-Solis M, Pastor-Vivero MD. et al. [Association between chronic colonization or infection with Pseudomonas aeruginosa and bronchial hyperreactivity in patients with cystic fibrosis]. Archivos de bronconeumologia 2008; 44: 180-184
• 117 Mogayzel Jr. PJ, Naureckas ET, Robinson KA. et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013; 187: 680-689
• 118 Cai Y, Chai D, Wang R. et al. Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review. J Antimicrob Chemother 2011; 66: 968-978
• 119 Steinkamp G, Schmitt-Grohe S, Doring G. et al. Once-weekly azithromycin in cystic fibrosis with chronic Pseudomonas aeruginosa infection. Respir Med 2008; 102: 1643-1653
• 120 Kabra SK, Pawaiya R, Lodha R. et al. Long-term daily high and low doses of azithromycin in children with cystic fibrosis: a randomized controlled trial. J Cyst Fibros 2010; 9: 17-23
• 121 Renna M, Schaffner C, Brown K. et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest 2011; 121: 3554-3563
• 122 Wozniak DJ, Keyser R. Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa. Chest 2004; 125: 62S-69S ; quiz 69S
• 123 Hebestreit H, Kieser S, Junge S. et al. Long-term effects of a partially supervised conditioning programme in cystic fibrosis. Eur Respir J 2010; 35: 578-583
• 124 Kriemler S, Kieser S, Junge S. et al. Effect of supervised training on FEV1 in cystic fibrosis: a randomised controlled trial. J Cyst Fibros 2013; 12: 714-720
• 125 Gruber W, Orenstein DM, Braumann KM. et al. Health-related fitness and trainability in children with cystic fibrosis. Pediatr Pulmonol 2008; 43: 953-964
• 126 Griese M, Busch P, Caroli D. et al. Rehabilitation Programs for Cystic Fibrosis - View from a CF Center. Open Respir Med J 2010; 4: 1-8
• 127 del Campo RR, Garriga M, Perez-Aragon A. et al. Improvement of digestive health and reduction in proteobacterial populations in the gut microbiota of cystic fibrosis patients using a Lactobacillus reuteri probiotic preparation: a double blind prospective study. J Cyst Fibros 2014; 13: 716-722
• 128 Hurley MN, Forrester DL, Smyth AR. Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis. Cochrane Database Syst Rev 2013; 6: CD008037
• 129 Muhlebach MS, Miller MB, Moore C. et al. Are lower airway or throat cultures predictive of sinus bacteriology in cystic fibrosis?. Pediatr Pulmonol 2006; 41: 445-451
• 130 Johansen HK, Aanaes K, Pressler T. et al. Colonisation and infection of the paranasal sinuses in cystic fibrosis patients is accompanied by a reduced PMN response. J Cyst Fibros 2012; 11: 525-531
• 131 Mainz JG, Hentschel J, Schien C. et al. Sinonasal persistence of Pseudomonas aeruginosa after lung transplantation. J Cyst Fibros 2012; 11: 158-161
• 132 Gottlieb J, Mattner F, Weissbrodt H. et al. Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis. Respir Med 2009; 103: 743-749
• 133 Vital D, Hofer M, Boehler A. et al. Posttransplant sinus surgery in lung transplant recipients with cystic fibrosis: a single institutional experience. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies 2013; 270: 135-139
• 134 Ciofu O, Johansen HK, Aanaes K. et al. P. aeruginosa in the paranasal sinuses and transplanted lungs have similar adaptive mutations as isolates from chronically infected CF lungs. J Cyst Fibros 2013; 12: 729-736
• 135 Hentschel J, Muller U, Doht F. et al. Influences of nasal lavage collection-, processing- and storage methods on inflammatory markers – evaluation of a method for non-invasive sampling of epithelial lining fluid in cystic fibrosis and other respiratory diseases. Journal of immunological methods 2014; 404: 41-51
• 136 Mainz JG, Schadlich K, Schien C. et al. Sinonasal inhalation of tobramycin vibrating aerosol in cystic fibrosis patients with upper airway Pseudomonas aeruginosa colonization: results of a randomized, double-blind, placebo-controlled pilot study. Drug design, development and therapy 2014; 8: 209-217
• 137 Aanaes K, von Buchwald C, Hjuler T. et al. The effect of sinus surgery with intensive follow-up on pathogenic sinus bacteria in patients with cystic fibrosis. Am J Rhinol Allergy 2013; 27: e1-4
• 138 Vital D, Hofer M, Benden C. et al. Impact of sinus surgery on pseudomonal airway colonization, bronchiolitis obliterans syndrome and survival in cystic fibrosis lung transplant recipients. Respiration 2013; 86: 25-31
• 139 Fokkens WJ, Lund VJ, Mullol J. et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012; 50: 1-12
• 140 Mainz JG, Schien C, Schiller I. et al. Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial. J Cyst Fibros 2014; 13: 461-470
• 141 Beer H, Southern KW, Swift AC. Topical nasal steroids for treating nasal polyposis in people with cystic fibrosis. Cochrane Database Syst Rev 2013; CD008253
• 142 Mainz JG, Koitschev A. Management of chronic rhinosinusitis in CF. J Cyst Fibros 2009; 8 (Suppl. 01) S10-S14
• 143 de Jong PA, Nakano Y, Lequin MH. et al. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J 2004; 23: 93-97
• 144 de Jong PA, Lindblad A, Rubin L. et al. Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis. Thorax 2006; 61: 80-85
• 145 Wielputz MO, Puderbach M, Kopp-Schneider A. et al. Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease. Am J Respir Crit Care Med 2014; 189: 956-965
• 146 Sly PD, Gangell CL, Chen L. et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013; 368: 1963-1970
• 147 Farrell PM, Collins J, Broderick LS. et al. Association between mucoid Pseudomonas infection and bronchiectasis in children with cystic fibrosis. Radiology 2009; 252: 534-543
• 148 Loeve M, Gerbrands K, Hop WC. et al. Bronchiectasis and pulmonary exacerbations in children and young adults with cystic fibrosis. Chest 2011; 140: 178-185
• 149 Rosenfeld M, Ratjen F, Brumback L. et al. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307: 2269-2277
• 150 Nasr SZ, Sakmar E, Christodoulou E. et al. The use of high resolution computerized tomography (HRCT) of the chest in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis lung disease. Pediatr Pulmonol 2010; 45: 440-449
• 151 Davis SD, Fordham LA, Brody AS. et al. Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis. Am J Respir Crit Care Med 2007; 175: 943-950
• 152 Ball R, Southern KW, McCormack P. et al. Adherence to nebulised therapies in adolescents with cystic fibrosis is best on week-days during school term-time. J Cyst Fibros 2013; 12: 440-444
• 153 George M, Rand-Giovannetti D, Eakin MN. et al. Perceptions of barriers and facilitators: self-management decisions by older adolescents and adults with CF. J Cyst Fibros 2010; 9: 425-432
• 154 Modi AC, Quittner AL. Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way?. Journal of pediatric psychology 2006; 31: 846-858
• 155 Eakin MN, Bilderback A, Boyle MP. et al. Longitudinal association between medication adherence and lung health in people with cystic fibrosis. J Cyst Fibros 2011; 10: 258-264
• 156 Dibonaventura M, Gabriel S, Dupclay L. et al. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC psychiatry 2012; 12: 20
• 157 Quittner AL, Zhang J, Marynchenko M. et al. Pulmonary medication adherence and health-care use in cystic fibrosis. Chest 2014; 146: 142-151