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Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment

Abstracts

Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO–an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group.

Cystic fibrosis/diagnosis; Cystic fibrosis/drug therapy; Pseudomonas aeruginosa; Evidence-based medicine


As técnicas de medicina baseada em evidências são cada vez mais utilizadas para a construção de diretrizes clínicas e recomendações para a prática médica. O uso de níveis de evidências permite que o leitor identifique a qualidade da informação científica que sustenta as recomendações feitas pelos especialistas. Esta revisão teve por objetivo abordar conceitos atuais sobre o impacto clínico, diagnóstico e tratamento das infecções por Pseudomonas aeruginosa em pacientes com fibrose cística. Para a elaboração desta revisão, o grupo de autores definiu as perguntas que seriam respondidas, seguindo os preceitos de PICO, acrônimo baseado em perguntas referentes aos Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome (desfecho) de interesse. Para cada pergunta, uma revisão estruturada da literatura foi realizada nas bases de dados do Medline, buscando identificar os estudos com desenho metodológico mais adequado para responder à questão. As perguntas foram designadas para que cada um dos autores redigisse uma resposta, e um primeiro rascunho foi elaborado e discutido pelo grupo em uma reunião presencial. Após essa discussão, recomendações foram emitidas com base na força das evidências e na concordância entre os membros do grupo segundo o sistema de classificação do Oxford Centre for Evidence Based Medicine.

Fibrose cística/diagnóstico; Fibrose cística/quimioterapia; Pseudomonas aeruginosa; Medicina baseada em evidências


Introduction

Cystic fibrosis (CF) is a complex genetic disease with multisystem involvement and pulmonary manifestations of a suppurative nature.( 11. Ratjen F, Döring G. Cystic fibrosis. Lancet. 2003;361(9358):681-9. http://dx.doi.org/10.1016/S0140-6736(03)12567-6
http://dx.doi.org/10.1016/S0140-6736(03)...
) Patients with CF are born with structurally normal lungs, but develop a progressive respiratory disease with recurrent chronic infections that result in the formation of bronchiectasis and lead to respiratory failure, which is the leading cause of death in these subjects.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

The basic defect in CF is related to chlorine transport through epithelial cell membranes by the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the dysfunction of which was identified as being the principal mechanism of the disease in 1989.( 33. Ratjen FA. Cystic fibrosis: pathogenesis and future treatment strategies. Respir Care. 2009;54(5):595-605. http://dx.doi.org/10.4187/aarc0427 PMid:19393104
http://dx.doi.org/10.4187/aarc0427...
) There are more than 1,500 described mutations in the CFTR gene sequence, but most of them have very low prevalence, the Î"F508 mutation (deletion of phenylalanine residue at position 508) being the most prevalent worldwide.( 44. Lommatzsch ST, Aris R. Genetics of cystic fibrosis. Semin Respir Crit Care Med. 2009;30(5):531-8. http://dx.doi.org/10.1055/s-0029-1238911 PMid:19760540
http://dx.doi.org/10.1055/s-0029-1238911...
)

Patients with CF are peculiarly susceptible to infection and colonization of the respiratory tract with pathogens, such as Staphylococcus aureus, Haemophilus influenza, and glucose-nonfermenting gram-negative bacilli, including Pseudomonas aeruginosa, Burkholderia cepacia complex, and Stenotrophomonas maltophilia, among others.( 55. Ratjen F. Diagnosing and managing infection in CF. Paediatr Respir Rev. 2006;7 Suppl 1:S151-3. http://dx.doi.org/10.1016/j.prrv.2006.04.217 PMid:16798546
http://dx.doi.org/10.1016/j.prrv.2006.04...
, 66. Govan JR, Deretic V. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Microbiol Rev. 1996;60(3):539-74. PMid:8840786 PMCid:239456 ) The prevalence of these pathogens varies with age, with S. aureus infections usually occurring early (generally in the first months of life) and pathogens such as P. aeruginosa tending to appear a little later,( 77. Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, et al. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA. 2005;293(5):581-8. http://dx.doi.org/10.1001/jama.293.5.581 PMid:15687313
http://dx.doi.org/10.1001/jama.293.5.581...
) although this sequence of infections are greatly influenced by therapeutic and microbiological surveillance practices, as well as by hospitalizations, exposure to other patients with CF, and environmental conditions that have yet to be defined.

The etiologic diagnosis of respiratory infections in patients with CF is habitually established through culture of respiratory tract samples, such as sputum and oropharyngeal swabs, the latter method generally being used in infants and children who are unable to expectorate sputum.( 88. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168(8):918-51. http://dx.doi.org/10.1164/rccm.200304-505SO PMid:14555458
http://dx.doi.org/10.1164/rccm.200304-50...
) In recent years, some attention has been given to alternative methods of diagnosis, such as serology and molecular techniques, especially for early identification of infection with P. aeruginosa, a pathogen that has the greatest impact on this group of patients.( 99. Deschaght P, Van Daele S, De Baets F, Vaneechoutte M. PCR and the detection of Pseudomonas aeruginosa in respiratory samples of CF patients. A literature review. J Cyst Fibros. 2011;10(5):293-7. http://dx.doi.org/10.1016/j.jcf.2011.05.004 PMid:21684819
http://dx.doi.org/10.1016/j.jcf.2011.05....
)

P. aeruginosa infections typically evolve to a pattern of persistence (chronicity), and strains undergo a phenotypic change, which is characterized by the production of a polysaccharide known as alginate.( 66. Govan JR, Deretic V. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Microbiol Rev. 1996;60(3):539-74. PMid:8840786 PMCid:239456 ) This bacterial phenotype, known as the mucoid phenotype, is associated with the greater difficulty in (or near impossibility of) eradicating the pathogen, eliciting a major inflammatory response and resulting in accelerated functional loss and poorer prognosis.( 66. Govan JR, Deretic V. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Microbiol Rev. 1996;60(3):539-74. PMid:8840786 PMCid:239456 , 1010. Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr. 2001;138(5):699-704. http://dx.doi.org/10.1067/mpd.2001.112897 PMid:11343046
http://dx.doi.org/10.1067/mpd.2001.11289...
, 1111. Henry RL, Mellis CM, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol. 1992;12(3):158-61. http://dx.doi.org/10.1002/ppul.1950120306 PMid:1641272
http://dx.doi.org/10.1002/ppul.195012030...
)

Since the early 1990s, various treatment centers for patients with CF have recommended eradication therapies for initial P. aeruginosa infection, which is when strains are more susceptible to antimicrobials, in order to prevent the chronicity of the infection.( 1212. Taccetti G, Campana S, Festini F, Mascherini M, Döring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J. 2005;26(3):458-61. http://dx.doi.org/10.1183/09031936.05.00009605 PMid:16135728
http://dx.doi.org/10.1183/09031936.05.00...
) In addition, strategies to suppress P. aeruginosa (or to reduce the bacterial load) with the use of inhaled antibiotics are one of the major therapeutic resources in the management of patients chronically infected with P. aeruginosa, causing improvement in pulmonary function, reducing the frequency of respiratory exacerbations, and improving the quality of life of these patients.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

Despite the growing knowledge in the field of respiratory infections in patients with CF, there are still many questions regarding the knowledge of the actual clinical impact, the most appropriate diagnostic methods, and the evidence on the treatment of P. aeruginosa infections. Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. This type of approach allows the systematic use of available scientific information, with less emphasis on isolated experiences. The objective of the present review was to address current concepts related to the clinical impact, diagnosis, and treatment of P. aeruginosa infections in patients with CF.

Methods

For the preparation of this study, the following steps were performed:

1. Question preparation: the authors, in a preliminary meeting, defined a group of questions that would be answered in accordance with the principles of PICO–an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. The questions were designed so that one of the authors could write a response.

2. Search of the literature: an initial search of the literature was conducted using the Medline database and search terms related to each question. One of the authors, who is an expert in evidence-based medicine, made the initial selection of relevant studies, which were sent to each responsible author for preparing the responses. These authors then conducted their own search and added other references that were judged relevant.

3. First draft of responses: each author was responsible for writing responses that were subsequently discussed by the entire group at a face-to-face meeting.

4. Discussion meeting: the group had a face-to-face meeting to discuss and, if necessary, to make changes to the responses proposed by each author separately. In that meeting, new information was sought and added to the original text. In addition, there was an explicit discussion about the level of evidence (LE) of the information, in accordance with the criteria set out by the Oxford Centre for Evidence-Based Medicine in 2011,( 1313. CEBM Centre For Evidence Based Medicine [homepage on the Internet]. Oxford: University of Oxford. [cited 2013 Feb 11]. “The Oxford 2011 Levels of Evidence. Available from: http://www.cebm.net/index.aspx?o=5653
Available from: htt...
) which are shown in Chart 1.

Grade of recommendation A: More consistent experimental or observational studies B: Less consistent experimental or observational studies C: Case reports (uncontrolled studies) D: Opinion without critical appraisal, based on consensus, physiological studies, or animal models Strength of evidence Level of evidence Studies on prognosis Studies on treatment 1a Systematic review of cohort studies (inception cohort), validated in different populations Systematic review of two or more independent randomized studies rated as level 1b 1b Individual cohort studies (inception cohort) Randomized study of good methodological quality, including a sufficient number of patients 2a Systematic review of either retrospective cohort studies or untreated control groups in randomized studies Systematic review of level 2b cohort studies 2b Retrospective cohort studies or follow-up of untreated control groups in randomized studies Individual cohort studies (including poor quality randomized studies) 3a Systematic review of level 3b case-control studies 3b Case-control studies 4 Case series Case series 5 Expert opinions Expert opinions without explicit critical appraisal, or based on pathophysiology a

5. Final draft: at the end of the meeting, each author sent the consensus response to the expert in evidence-based medicine, who was responsible for reviewing the LE, revising the text, and checking the references.

6. Revision: each author revised and approved the final draft of their responses and of the manuscript.

Questions addressed in the study

1. Does early P. aeruginosa colonization worsen the prognosis of patients with CF?

2. Can serologic testing for anti-Pseudomonas antibodies be useful for early detection of infection with this agent?

3. Does eradication of initial colonization with P. aeruginosa improve the prognosis in CF?

4. How does one identify and treat acute pulmonary exacerbations (APEs) in patients colonized with P. aeruginosa?

5. When should chronic inhaled antibiotic therapy be initiated in CF? Which inhaled antibiotics can be used in the treatment of chronic P. aeruginosa infection in CF?

6. Does adherence to clinical treatment affect the prognosis of patients with CF?

7. Is azithromycin efficacious in slowing the progression of lung disease in CF patients colonized with P. aeruginosa?

8. Is there a good correlation between antibiogram results and clinical response in chronic P. aeruginosa infection?

9. Does multidrug-resistant P. aeruginosa infection worsen prognosis?

Does early P. aeruginosa colonization worsen the prognosis of patients with CF?

Definitions

Colonization means the presence of bacteria as detected by colony culture, i.e., by isolation of the bacterium in culture. Colonization can be initial (or acute)–in the first bacterial isolations–or chronic, in accordance with the referral center criteria: three or more positive cultures for P. aeruginosa within a 6-month period, with an interval of at least one month between them or more than 50% of positive cultures within 12 months.( 1414. Lee TW, Brownlee KG, Conway SP, Denton M, Littlewood JM. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros. 2003;2(1):29-34. http://dx.doi.org/10.1016/S1569-1993(02)00141-8
http://dx.doi.org/10.1016/S1569-1993(02)...
)

Various parameters are used to characterize the prognosis in CF. The most common are pulmonary function testing and median survival: pulmonary function is in turn the best predictor of survival (LE 2b).( 1515. Corey M. Survival estimates in cystic fibrosis: snapshots of a moving target. Pediatr Pulmonol. 1996;21(3):149-50. http://dx.doi.org/10.1002/1099-0496(199603)21:3<149::AID-PPUL1950210302>3.0.CO;2-C
http://dx.doi.org/10.1002/1099-0496(1996...
)

Initial colonization with P. aeruginosa in children under 2 years of age significantly increases morbidity, and its association with S. aureus from the beginning significantly increases the mortality rate in the first 10 years after diagnosis (LE 2b).( 1010. Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr. 2001;138(5):699-704. http://dx.doi.org/10.1067/mpd.2001.112897 PMid:11343046
http://dx.doi.org/10.1067/mpd.2001.11289...
, 1616. Hudson VL, Wielinski CL, Regelmann WE. Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years. J Pediatr. 1993;122(6):854-60. http://dx.doi.org/10.1016/S0022-3476(09)90007-5
http://dx.doi.org/10.1016/S0022-3476(09)...
) The radiographic score deteriorates significantly and the Tiffeneau index (FEV1/FVC ratio) falls more rapidly after P. aeruginosa acquisition in patients diagnosed by newborn screening (LE 2b).( 1717. Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-87. http://dx.doi.org/10.1002/ppul.2009.abs PMid:11568988
http://dx.doi.org/10.1002/ppul.2009.abs...
) Data from the U.S. Cystic Fibrosis Foundation national registry showed that, between 1990 and 1998, the presence of P. aeruginosa was the greatest predictor of morbidity and mortality in patients aged 1-5 years (n = 3,325)–with the risk of death being 2.6 times higher in those with than in those without P. aeruginosa respiratory infection (LE 2b).( 1818. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):91-100. http://dx.doi.org/10.1002/ppul.10127 PMid:12112774
http://dx.doi.org/10.1002/ppul.10127...
)

In a cohort study conducted in the USA, nonmucoid P. aeruginosa acquisition occurred in patients with a median age of 1 year, being observed in 29% of the patients under 6 months of age; identification of P. aeruginosa strains with a mucoid phenotype occurred in patients aged 4-16 years (median of 13 years). Eradication of nonmucoid P. aeruginosa, preventing chronicity and conversion to a mucoid phenotype, would allow a better prognosis (LE 2b).( 77. Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, et al. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA. 2005;293(5):581-8. http://dx.doi.org/10.1001/jama.293.5.581 PMid:15687313
http://dx.doi.org/10.1001/jama.293.5.581...
)

Early P. aeruginosa colonization predisposes to chronic colonization with this pathogen. A low level of chronic colonization can be achieved with intermittent use of inhaled antibiotics and less use of intravenous antibiotics. A lower level of chronic P. aeruginosa colonization improves prognosis (LE 2b).( 1919. Lebecque P, Leal T, Zylberberg K, Reychler G, Bossuyt X, Godding V. Towards zero prevalence of chronic Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros. 2006;5(4):237-44. http://dx.doi.org/10.1016/j.jcf.2006.04.001 PMid:16790367
http://dx.doi.org/10.1016/j.jcf.2006.04....
)

Recommendation

Early P. aeruginosa colonization, especially if associated with initial S. aureus colonization, worsens prognosis for morbidity and mortality (LE 2b; grade of recommendation [GR] B).

Can serologic testing for anti-Pseudomonas antibodies be useful for early detection of infection with this agent?

Early identification of P. aeruginosa infection is essential for the initiation of eradication therapy, the goal of which is to prevent or delay chronic infection with the bacterium.( 2020. Ratjen F. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis. Curr Opin Pulm Med. 2006;12(6):428-32. http://dx.doi.org/10.1097/01.mcp.0000245712.51514.a1 PMid:17053493
http://dx.doi.org/10.1097/01.mcp.0000245...
)

Respiratory infection with P. aeruginosa is routinely diagnosed by examination of sputum, oropharyngeal secretion, or laryngeal aspirates after respiratory therapy or inhalation of hypertonic sodium chloride solution (3-7%). Positive oropharyngeal secretion cultures have a high predictive value, although false-negative results can occur.( 2121. Equi AC, Pike SE, Davies J, Bush A. Use of cough swabs in a cystic fibrosis clinic. Arch Dis Child. 2001;85(5):438-9. http://dx.doi.org/10.1136/adc.85.5.438 PMid:11668115 PMCid:1718986
http://dx.doi.org/10.1136/adc.85.5.438 P...
) Other resources used for diagnosis are bronchoalveolar lavage (BAL) culture, serology for detection of specific antibodies in serum, and methods for the detection of bacterial DNA (by PCR) in respiratory secretion specimens.( 99. Deschaght P, Van Daele S, De Baets F, Vaneechoutte M. PCR and the detection of Pseudomonas aeruginosa in respiratory samples of CF patients. A literature review. J Cyst Fibros. 2011;10(5):293-7. http://dx.doi.org/10.1016/j.jcf.2011.05.004 PMid:21684819
http://dx.doi.org/10.1016/j.jcf.2011.05....
)

The difficulty in obtaining representative respiratory specimens from the airways of infants and children under 6 years of age indicates the need for the use of methods that can complement or be an alternative to culture.( 2222. da Silva Filho LV, Tateno AF, Martins KM, Azzuz Chernishev AC, Garcia Dde O, Haug M, et al. The combination of PCR and serology increases the diagnosis of Pseudomonas aeruginosa colonization/infection in cystic fibrosis. Pediatr Pulmonol. 2007;42(10):938-44. http://dx.doi.org/10.1002/ppul.20686 PMid:17722007
http://dx.doi.org/10.1002/ppul.20686...
) In the 1970s, the initial experience of a group of researchers in Denmark( 2323. Hoiby N, Flensborg EW, Beck B, Friis B, Jacobsen SV, Jacobsen L. Pseudomonas aeruginosa infection in cystic fibrosis. Diagnostic and prognostic significance of Pseudomonas aeruginosa precipitins determined by means of crossed immunoelectrophoresis. Scand J Respir Dis. 1977;58(2):65-79. PMid:404701 ) regarding the use of serum precipitins to characterize stages of pulmonary infection with P. aeruginosa was the main incentive for the use of serological resources in early identification of infections with the pathogen.( 2424. Brett MM, Ghoneim AT, Littlewood JM. Prediction and diagnosis of early Pseudomonas aeruginosa infection in cystic fibrosis: a follow-up study. J Clin Microbiol. 1988;26(8):1565-70. Erratum in: J Clin Microbiol 1989;27(1):230. PMid:3139707 PMCid:266661 )

West et al.( 2525. West SE, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, et al. Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors. JAMA. 2002;287(22):2958-67. http://dx.doi.org/10.1001/jama.287.22.2958 PMid:12052125
http://dx.doi.org/10.1001/jama.287.22.29...
) evaluated a cohort of 68 infants diagnosed by neonatal screening and described the natural history of P. aeruginosa infections over a 15-year period. The detection of anti-P. aeruginosa antibodies allowed the identification of infection with the pathogen before it was isolated from a culture, with bacterial anti-cell lysate antibodies being detected 12 months before culture. Significant P. aeruginosa anti-cell lysate antibody titers were detected before or simultaneously with the first isolation of the bacterium in approximately 60% of the patients (LE 2b).( 2525. West SE, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, et al. Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors. JAMA. 2002;287(22):2958-67. http://dx.doi.org/10.1001/jama.287.22.2958 PMid:12052125
http://dx.doi.org/10.1001/jama.287.22.29...
)

In 2006, two studies reporting conflicting serological results were published in the same journal. Kappler et al.( 2626. Kappler M, Kraxner A, Reinhardt D, Ganster B, Griese M, Lang T. Diagnostic and prognostic value of serum antibodies against Pseudomonas aeruginosa in cystic fibrosis. Thorax. 2006;61(8):684-8. http://dx.doi.org/10.1136/thx.2005.049536 PMid:16449259 PMCid:2104684
http://dx.doi.org/10.1136/thx.2005.04953...
) used commercial ELISA kits in a prospective study involving 183 patients with CF and reported a sensitivity of 86%, a specificity of 96%, and a positive predictive value of 97%. Those authors propose P. aeruginosa eradication therapy in the event of a rise in antibody titers, even in the absence of positive cultures (LE 2b).( 2626. Kappler M, Kraxner A, Reinhardt D, Ganster B, Griese M, Lang T. Diagnostic and prognostic value of serum antibodies against Pseudomonas aeruginosa in cystic fibrosis. Thorax. 2006;61(8):684-8. http://dx.doi.org/10.1136/thx.2005.049536 PMid:16449259 PMCid:2104684
http://dx.doi.org/10.1136/thx.2005.04953...
) Tramper-Stranders et al.( 2727. Tramper-Stranders GA, van der Ent CK, Slieker MG, Terheggen-Lagro SW, Teding van Berkhout F, Kimpen JL, et al. Diagnostic value of serological tests against Pseudomonas aeruginosa in a large cystic fibrosis population. Thorax. 2006;61(8):689-93. http://dx.doi.org/10.1136/thx.2005.054726 PMid:16601093 PMCid:2104678
http://dx.doi.org/10.1136/thx.2005.05472...
) used other ELISA kits in 220 CF patients with different P. aeruginosa infection status and found a sensitivity of 96% and a specificity of 79% for the combination of methods. The fact that 15 serological conversions were identified during the study period, with varying response patterns, draw attention to the possibility of failure in identifying early P. aeruginosa infection through the use of serological methods (LE 2b).( 2727. Tramper-Stranders GA, van der Ent CK, Slieker MG, Terheggen-Lagro SW, Teding van Berkhout F, Kimpen JL, et al. Diagnostic value of serological tests against Pseudomonas aeruginosa in a large cystic fibrosis population. Thorax. 2006;61(8):689-93. http://dx.doi.org/10.1136/thx.2005.054726 PMid:16601093 PMCid:2104678
http://dx.doi.org/10.1136/thx.2005.05472...
)

Subsequently, Ratjen et al.,( 2828. Ratjen F, Walter H, Haug M, Meisner C, Grasemann H, Döring G. Diagnostic value of serum antibodies in early Pseudomonas aeruginosa infection in cystic fibrosis patients. Pediatr Pulmonol. 2007;42(3):249-55. http://dx.doi.org/10.1002/ppul.20562 PMid:17243185
http://dx.doi.org/10.1002/ppul.20562...
) evaluating the usefulness of serological methods in initial P. aeruginosa infection in approximately 1,800 serum samples from 375 patients with CF, found inter-individual variability in antibody titers, but reported an association between the serological response and the intensity of the respiratory infection, which, according to the authors, suggested potential for the use of serological methods in conjunction with microbiology (LE 2b).( 2828. Ratjen F, Walter H, Haug M, Meisner C, Grasemann H, Döring G. Diagnostic value of serum antibodies in early Pseudomonas aeruginosa infection in cystic fibrosis patients. Pediatr Pulmonol. 2007;42(3):249-55. http://dx.doi.org/10.1002/ppul.20562 PMid:17243185
http://dx.doi.org/10.1002/ppul.20562...
)

In 2007 in Brazil, da Silva Filho et al.,( 2222. da Silva Filho LV, Tateno AF, Martins KM, Azzuz Chernishev AC, Garcia Dde O, Haug M, et al. The combination of PCR and serology increases the diagnosis of Pseudomonas aeruginosa colonization/infection in cystic fibrosis. Pediatr Pulmonol. 2007;42(10):938-44. http://dx.doi.org/10.1002/ppul.20686 PMid:17722007
http://dx.doi.org/10.1002/ppul.20686...
) in a study comparing single-sample PCR, culture, and serology in 87 patients with CF, reported that the combination of the three methods resulted in higher positivity, PCR being the method with the highest positivity. Because the study was cross-sectional, no further conclusions could be drawn (LE 3).( 2222. da Silva Filho LV, Tateno AF, Martins KM, Azzuz Chernishev AC, Garcia Dde O, Haug M, et al. The combination of PCR and serology increases the diagnosis of Pseudomonas aeruginosa colonization/infection in cystic fibrosis. Pediatr Pulmonol. 2007;42(10):938-44. http://dx.doi.org/10.1002/ppul.20686 PMid:17722007
http://dx.doi.org/10.1002/ppul.20686...
) Methods for molecular identification of P. aeruginosa should be viewed with caution, because they do not depend on bacterial viability and they are affected by various technical aspects, such as DNA extraction methods, primers used, sample concentration, etc.( 99. Deschaght P, Van Daele S, De Baets F, Vaneechoutte M. PCR and the detection of Pseudomonas aeruginosa in respiratory samples of CF patients. A literature review. J Cyst Fibros. 2011;10(5):293-7. http://dx.doi.org/10.1016/j.jcf.2011.05.004 PMid:21684819
http://dx.doi.org/10.1016/j.jcf.2011.05....
)

Another group of authors, seeking to establish whether it would be possible to use saliva as a tool for the detection of anti-P. aeruginosa antibodies in patients with CF and in normal individuals,( 2929. Weisner AM, Chart H, Bush A, Davies JC, Pitt TL. Detection of antibodies to Pseudomonas aeruginosa in serum and oral fluid from patients with cystic fibrosis. J Med Microbiol. 2007;56(Pt 5):670-4. http://dx.doi.org/10.1099/jmm.0.46833-0 PMid:17446292
http://dx.doi.org/10....
) described significant titers in the oral fluids from 15 of the 17 patients with CF but in none from the healthy volunteers (LE 2b).

Pressler et al.( 3030. Pressler T, Karpati F, Granström M, Knudsen PK, Lindblad A, Hjelte L, et al. Diagnostic significance of measurements of specific IgG antibodies to Pseudomonas aeruginosa by three different serological methods. J Cyst Fibros. 2009;8(1):37-42. http://dx.doi.org/10.1016/j.jcf.2008.08.002 PMid:18835753
http://dx.doi.org/10.1016/j.jcf.2008.08....
) comparatively analyzed three different serological methods (exotoxin A ELISA, CF-IgG ELISA, and counterimmunoelectrophoresis) in 791 Scandinavian patients with CF and concluded that the performance of the tests was very similar. Another relevant finding was the association between the antibody titers observed and the duration and characteristic of the infection, which means that serology could be used in characterizing the chronicity of the infection (LE 2b).( 3030. Pressler T, Karpati F, Granström M, Knudsen PK, Lindblad A, Hjelte L, et al. Diagnostic significance of measurements of specific IgG antibodies to Pseudomonas aeruginosa by three different serological methods. J Cyst Fibros. 2009;8(1):37-42. http://dx.doi.org/10.1016/j.jcf.2008.08.002 PMid:18835753
http://dx.doi.org/10.1016/j.jcf.2008.08....
)

In another study conducted in Brazil, Milagres et al.( 3131. Milagres LG, Castro TL, Garcia D, Cruz AC, Higa L, Folescu T, et al. Antibody response to Pseudomonas aeruginosa in children with cystic fibrosis. Pediatr Pulmonol. 2009;44(4):392-401. http://dx.doi.org/10.1002/ppul.21022 PMid:19283764
http://dx.doi.org/10.1002/ppul.21022...
) studied 51 patients with CF over a 2-year period, using two types of antigen (bacterial lysate and recombinant PcrV). For 44% of the patients with previously negative cultures or intermittent isolations, serology allowed the detection of P. aeruginosa, on average, 21 months before its detection by culture, suggesting that the method should be part of the routine follow-up of patients with CF (LE 2b).( 3131. Milagres LG, Castro TL, Garcia D, Cruz AC, Higa L, Folescu T, et al. Antibody response to Pseudomonas aeruginosa in children with cystic fibrosis. Pediatr Pulmonol. 2009;44(4):392-401. http://dx.doi.org/10.1002/ppul.21022 PMid:19283764
http://dx.doi.org/10.1002/ppul.21022...
)

More recently, two studies have generated more controversy on the subject. Hayes et al.,( 3232. Hayes D Jr, Farrell PM, Li Z, West SE. Pseudomonas aeruginosa serological analysis in young children with cystic fibrosis diagnosed through newborn screening. Pediatr Pulmonol. 2010;45(1):55-61. http://dx.doi.org/10.1002/ppul.21083 PMid:20025049 PMCid:2924665
http://dx.doi.org/10.1002/ppul.21083...
) in an approximately 6-year longitudinal study evaluating 69 children with CF diagnosed by newborn screening, reported that serology allowed the early identification of P. aeruginosa infection in those patients. In contrast, Douglas et al.( 3333. Douglas TA, Brennan S, Berry L, Winfield K, Wainwright CE, Grimwood K, et al. Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis. Thorax. 2010;65(11):985-90. http://dx.doi.org/10.1136/thx.2009.132845 PMid:20889526
http://dx.doi.org/10.1136/thx.2009.13284...
) described paired BAL culture and serology results and found a low positive predictive value and a high negative predictive value using BALF culture as a reference. In view of these findings, there is questioning regarding the potential of serology for monitoring P. aeruginosa infection (LE 2b), although recently, the role of BALF culture as a decision-making tool in the treatment of respiratory infection in patients with CF has also been questioned.( 3434. Wainwright CE, Vidmar S, Armstrong DS, Byrnes CA, Carlin JB, Cheney J, 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(2):163-71. http://dx.doi.org/10.1001/jama.2011.954 PMid:21750293
http://dx.doi.org/10.1001/jama.2011.954...
)

Recommendation

Positive serology results and culture-negative samples of respiratory secretion should alert health professionals to perform a more thorough search for a probable infection, by repeating the test or by using methods that are more sensitive and more specific. In contrast, increasing levels of antibodies are associated with a greater likelihood of persistent chronic infection with the bacterium. Their use in routine practice remains controversial (LE 2b; GR B).

Does eradication of initial colonization with P. aeruginosa improve the prognosis in CF?

P. aeruginosa is the most common pathogen in lung infections in patients with CF. The importance of its early detection is due to its correlation with a more pronounced reduction in pulmonary function, which results in impaired quality of life and poorer prognosis of patients chronically colonized with the bacterium. Early identification of P. aeruginosa infection is essential for the initiation of eradication therapy, the goal of which is to prevent or delay chronic infection with the bacterium at a phase in which strains are more susceptible to antibiotics.

Studies dating back to the 1980s investigated the effects of early treatment in patients infected with P. aeruginosa, suggesting that early eradication could lead to a decrease in the number of patients with chronic colonization. Since the initial studies by Littlewood et al.,( 3535. Littlewood JM, Miller MG, Ghoneim AT, Ramsden CH. Nebulised colomycin for early pseudomonas colonisation in cystic fibrosis. Lancet. 1985;1(8433):865. http://dx.doi.org/10.1016/S0140-6736(85)92222-6
http://dx.doi.org/10.1016/S0140-6736(85)...
) there has been growing evidence that the early initiation of antibiotic therapy is an effective strategy to delay chronic P. aeruginosa infection.( 3636. Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet. 1991;338(8769):725-6. http://dx.doi.org/10.1016/0140-6736(91)91446-2
http://dx.doi.org/10.1016/0140-6736(91)9...

37. Munck A, Bonacorsi S, Mariani-Kurkdjian P, Lebourgeois M, Gérardin M, Brahimi N, et al. Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization. Pediatr Pulmonol. 2001;32(4):288-92. http://dx.doi.org/10.1002/ppul.1121 PMid:11568989
http://dx.doi.org/10.1002/ppul.1121...
- 3838. Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld M, Yunker A, et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med. 2003;167(6):841-9. http://dx.doi.org/10.1164/rccm.200208-855OC PMid:12480612
http://dx.doi.org/10.1164/rccm.200208-85...
)

A broader assessment of the effects of eradication therapy was performed by Taccetti et al.,( 1212. Taccetti G, Campana S, Festini F, Mascherini M, Döring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J. 2005;26(3):458-61. http://dx.doi.org/10.1183/09031936.05.00009605 PMid:16135728
http://dx.doi.org/10.1183/09031936.05.00...
) who, in a study of 47 patients, showed that the early use of oral ciprofloxacin + inhaled colomycin resulted in reduced chronicity, causing no increase in bacterial resistance or in the emergence of other pathogens. In addition, those authors found a reduction in pulmonary function decline and in treatment costs.( 1212. Taccetti G, Campana S, Festini F, Mascherini M, Döring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J. 2005;26(3):458-61. http://dx.doi.org/10.1183/09031936.05.00009605 PMid:16135728
http://dx.doi.org/10.1183/09031936.05.00...
)

In a recently published study,( 3939. Davidson AG, Chilvers MA, Lillquist YP. Effects of a Pseudomonas aeruginosa eradication policy in a cystic fibrosis clinic. Curr Opin Pulm Med. 2012;18(6):615-21. http://dx.doi.org/10.1097/MCP.0b013e328358f5a2 PMid:22990661
http://dx.doi.org/10.1097/MCP.0b013e3283...
) the authors concluded that the implementation of an early intervention protocol led to decreased prevalence of chronic P. aeruginosa infection, improved pulmonary function, and decreased hospital costs (LE 1b). The decision on the best antimicrobial strategy for P. aeruginosa eradication remains controversial. In an open-label randomized multicenter study,( 4040. Ratjen F, Munck A, Kho P, Angyalosi G; ELITE Study Group. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2010;65(4):286-91. http://dx.doi.org/10.1136/thx.2009.121657 PMid:19996339
http://dx.doi.org/10.1136/thx.2009.12165...
) patients with CF (age ≥ 6 months) and primary infection with P. aeruginosa were treated for 28 days or 56 days with inhaled tobramycin administered twice daily. The study showed that more than 90% of patients had negative cultures for P. aeruginosa one month after the end of treatment, and that most of those patients remained free from infection for up to 27 months. There was no significant difference when the period of treatment with inhaled tobramycin was extended to 56 days (LE 1b).( 4040. Ratjen F, Munck A, Kho P, Angyalosi G; ELITE Study Group. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2010;65(4):286-91. http://dx.doi.org/10.1136/thx.2009.121657 PMid:19996339
http://dx.doi.org/10.1136/thx.2009.12165...
)

In another recent multicenter study,( 4141. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165(9):847-56. http://dx.doi.org/10.1001/archpediatrics.2011.136 PMid:21893650
http://dx.doi.org/10.1001/archpediatrics...
) the participants were randomized 1:1 to one of four treatment algorithms for 18 months. The treatment regimens were as follows: (a) intermittent courses (every 3 months) of inhaled tobramycin (300 mg twice daily) for 28 days + oral ciprofloxacin (15-20 mg/kg twice daily) for 14 days; (b) intermittent courses (every 3 months) of inhaled tobramycin for 28 days + oral placebo for 14 days; (c) inhaled tobramycin for 28 days + oral ciprofloxacin for 14 days in the presence of a positive culture for P. aeruginosa; and (d) inhaled tobramycin for 28 days + oral placebo for 14 days in the presence of a positive culture for P. aeruginosa. Those authors concluded that, after 18 months, there were no differences in the rates of exacerbation or prevalence of P. aeruginosa between prophylactic treatment and treatment based on positive cultures. There was no additional benefit from the addition of ciprofloxacin during that study (LE 1b).( 4141. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165(9):847-56. http://dx.doi.org/10.1001/archpediatrics.2011.136 PMid:21893650
http://dx.doi.org/10.1001/archpediatrics...
)

Recommendation

Evidence suggests that the early initiation of inhaled antibiotic therapy, combined or not with oral antibiotics, is an efficient strategy to delay chronic P. aeruginosa infection. Studies suggest that short-term eradication can be achieved (LE 1b; GR A).( 4242. Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev. 2009;(4):CD004197. PMid:19821321 )

How does one identify and treat acute pulmonary exacerbations (APEs) in patients colonized with P. aeruginosa?

In patients with CF, APEs are a common complication. Although there are published guidelines for the management of APEs in patients with CF, it is not possible to know for sure which are the best treatment strategies, given the insufficient data.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

Chronic P. aeruginosa infection becomes more common as patients grow older and is associated with increased morbidity and mortality. Chronic infection is interspersed with APEs, which require additional and more aggressive antibiotic therapy. There is evidence that APEs result in functional loss that often is not completely reversed by treatment.( 4343. Collaco JM, Green DM, Cutting GR, Naughton KM, Mogayzel PJ Jr. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med. 2010;182(9):1137-43. http://dx.doi.org/10.1164/rccm.201001-0057OC PMid:20581166 PMCid:3001256
http://dx.doi.org/10.1164/rccm.201001-00...
)

In APEs with no obvious precipitating factor, several questions arise:

  1. a

    How does one define an APE?

  2. b

    Should intravenous therapy for an APE be administered in the home or in the hospital?

  3. c

    Which antibiotic(s) should intravenous therapy for an APE include?

  4. d

    Can (or should) aminoglycosides be used once daily?

  5. e

    What should be the duration of intravenous therapy for an APE?

How does one define an APE?

In 1994, Fuchs et al.( 4444. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331(10):637-42. http://dx.doi.org/10.1056/NEJM199409083311003 PMid:7503821
http://dx.doi.org/10.1056/NEJM1994090833...
) established criteria for defining APEs in CF, criteria that were subsequently used in a number of scientific studies in the field. According to those authors, an APE could be defined as the clinical need for intravenous antibiotics as indicated by the presence of at least 4 of the 12 signs or symptoms described below:

  • Change in sputum volume or color

  • Hemoptysis

  • Increased cough

  • Increased dyspnea

  • Increased malaise, fatigue, or lethargy

  • Temperature over 38°C

  • Anorexia or weight loss

  • Maxillary sinus pain or sensitivity

  • Change or increase in postnasal discharge

  • Change in chest physical examination findings

  • Decrease in FEV1 of 10% or higher

  • New radiographic changes

Given that APEs have a negative impact on survival, quality of life, and costs (because of the high costs of hospitalizations and medications), they are an important outcome measure in clinical trials, and although various authors have proposed alternative methods for their objective characterization in patients with CF,( 4545. Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgomery AB, et al. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr. 2001;139(3):359-65. http://dx.doi.org/10.1067/mpd.2001.117288 PMid:11562614
http://dx.doi.org/10.1067/mpd.2001.11728...

46. Dakin C, Henry RL, Field P, Morton J. Defining an exacerbation of pulmonary disease in cystic fibrosis. Pediatr Pulmonol. 2001;31(6):436-42. http://dx.doi.org/10.1002/ppul.1072 PMid:11389576
http://dx.doi.org/10.1002/ppul.1072...
- 4747. Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802-8. http://dx.doi.org/10.1164/rccm.200812-1845PP PMid:19729669
http://dx.doi.org/10.1164/rccm.200812-18...
) this definition remains a source of controversy.( 4848. Stenbit AE, Flume PA. Pulmonary exacerbations in cystic fibrosis. Curr Opin Pulm Med. 2011;17(6):442-7. PMid:21881509 )

In 2011, a group of European experts met in Hamburg and proposed new consensus There is insufficient evidence to recommendcriteria for characterizing an APE( 4949. Bilton D, Canny G, Conway S, Dumcius S, Hjelte L, Proesmans M, et al. Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials. J Cyst Fibros. 2011;10 Suppl 2:S79-81. http://dx.doi.org/10.1016/S1569-1993(11)60012-X
http://dx.doi.org/10.1016/S1569-1993(11)...
): the need for antibiotic therapy resulting from a recent change in at least 2 of the following 7 items:

• Change in sputum volume or color

• Increased cough

• Increased malaise, fatigue, or lethargy

• Anorexia or weight loss

• Decrease in FEV1 of 10% or higher

• New radiographic changes

• Increased dyspnea

• Recommendation

The criteria for defining an APE are derived from several studies, and there is a consensus among authors that most of the criteria are adopted on the basis of accumulated experience, although the scientific basis remains flimsy (LE 2b; GR B).( 4747. Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802-8. http://dx.doi.org/10.1164/rccm.200812-1845PP PMid:19729669
http://dx.doi.org/10.1164/rccm.200812-18...
)

Should intravenous therapy for an APE be administered in the home or in the hospital?

A cohort study conducted in the USA and involving twins and siblings with CF retrospectively analyzed APEs in 1,535 patients, comparing the FEV1 outcomes of approximately 5,000 courses of intravenous antibiotics administered in the hospital with those of the same number of courses administered in the home, and concluded that there was no difference in functional outcome between the two approaches (LE 2b).( 4343. Collaco JM, Green DM, Cutting GR, Naughton KM, Mogayzel PJ Jr. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med. 2010;182(9):1137-43. http://dx.doi.org/10.1164/rccm.201001-0057OC PMid:20581166 PMCid:3001256
http://dx.doi.org/10.1164/rccm.201001-00...
)

A recent systematic review of the literature( 5050. Balaguer A, González de Dios J. Home versus hospital intravenous antibiotic therapy for cystic fibrosis. Cochrane Database Syst Rev. 2012;3:CD001917. PMid:22419283 ) evaluated whether or not home therapy can replace hospitalization in cases of APE. Although several databases were searched, only a small randomized study involving 17 patients was found. The authors concluded that the current evidence is too limited: the results of the only randomized study suggest that, in the short term, home therapy is efficient and cheaper, as well as resulting in reduced social costs. There are advantages and disadvantages in terms of quality of life. The decision to attempt treatment in the home should be made on a case-by-case basis. The authors concluded that further research is necessary (LE 3a).( 5050. Balaguer A, González de Dios J. Home versus hospital intravenous antibiotic therapy for cystic fibrosis. Cochrane Database Syst Rev. 2012;3:CD001917. PMid:22419283 )

Recommendation

There is insufficient evidence to recommend or refute intravenous home therapy for APEs, and decisions should be made on a case-by-case basis (LE 5; GR D).

Which antibiotic(s) should intravenous therapy for an APE include?

Traditionally, intravenous administration of beta-lactam antibiotics combined with aminoglycosides has been the most commonly used therapeutic regimen in the treatment of APEs in patients with CF.( 5151. Smyth A, Elborn JS. Exacerbations in cystic fibrosis: 3. Management. Thorax. 2008;63(2):180-4. http://dx.doi.org/10.1136/thx.2006.060905 PMid:18234661
http://dx.doi.org/10.1136/thx.2006.06090...
, 5252. Smyth A, Knox A. Twice vs three times daily antibiotics in the treatment of pulmonary exacerbations of cystic fibrosis. J Cyst Fibros. 2011;10(5):383. http://dx.doi.org/10.1016/j.jcf.2011.03.010 PMid:21507733
http://dx.doi.org/10.1016/j.jcf.2011.03....
) Given that P. aeruginosa is a pathogen that develops resistance to antimicrobial agents relatively easily,( 5353. Breidenstein EB, de la Fuente-Nú-ez C, Hancock RE. Pseudomonas aeruginosa: all roads lead to resistance. Trends Microbiol. 2011;19(8):419-26. http://dx.doi.org/10.1016/j.tim.2011.04.005 PMid:21664819
http://dx.doi.org/10.1016/j.tim.2011.04....
) the combination of drugs with different mechanisms of action can contribute to minimizing this risk. In a study conducted in England, the researchers reported a high prevalence of ceftazidime-resistant P. aeruginosa strains, possibly due to the practice of monotherapy with this drug in the institution (LE 4).( 5454. Cheng K, Smyth RL, Govan JR, Doherty C, Winstanley C, Denning N, et al. Spread of beta-lactam-resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. Lancet. 1996;348(9028):639-42. http://dx.doi.org/10.1016/S0140-6736(96)05169-0
http://dx.doi.org/10.1016/S0140-6736(96)...
)

A systematic review published in 2005( 5555. Elphick HE, Tan A. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis. Cochrane Database Syst Rev. 2005;(2):CD002007. PMid:15846627 ) included 27 studies comparing monotherapy with combination antibiotic therapy in the treatment of APEs in patients with CF. The studies were mostly of questionable methodological quality and were quite heterogeneous, complicating the analysis and interpretation of results. In contrast, some randomized studies have shown that combination antibiotic therapy is effective in the treatment of APEs in patients with CF (NE 2a).( 5656. Bosso JA, Saxon BA, Matsen JM. Comparative activity of cefepime, alone and in combination, against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients. Antimicrob Agents Chemother. 1991;35(4):783-4. http://dx.doi.org/10.1128/AAC.35.4.783 PMid:1906264 PMCid:245101
http://dx.doi.org/10.1128/AAC.35.4.783 P...
, 5757. Tré-Hardy M, Nagant C, El Manssouri N, Vanderbist F, Traore H, Vaneechoutte M, et al. Efficacy of the combination of tobramycin and a macrolide in an in vitro Pseudomonas aeruginosa mature biofilm model. Antimicrob Agents Chemother. 2010;54(10):4409-15. http://dx.doi.org/10.1128/AAC.00372-10 PMid:20696878 PMCid:2944582
http://dx.doi.org/10.1128/AAC.00372-10 P...
) American guidelines( 4747. Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802-8. http://dx.doi.org/10.1164/rccm.200812-1845PP PMid:19729669
http://dx.doi.org/10.1164/rccm.200812-18...
) recognize the deficiency in information but recommend that combination drug therapy be instituted.

Recommendation

There is evidence to recommend the combination of an aminoglycoside and a beta-lactam antibiotic for the treatment of APEs in patients with CF (LE 2a; GR B).

Can (or should) aminoglycosides be used once daily?

Aminoglycosides were originally studied and approved for use as a three times-daily injection regimen.( 5858. Leroy A, Humbert G, Oksenhendler G, Fillastre JP. Pharmacokinetics of aminoglycosides in subjects with normal and impaired renal function. Antibiot Chemother. 1978;25:163-80. PMid:352252 ) The recognition that the maximum bactericidal effect of aminoglycosides results from the serum peak values achieved motivated researchers in the late 1980s to evaluate once-daily aminoglycoside administration,( 5959. Kovarik JM, Hoepelman IM, Verhoef J. Once-daily aminoglycoside administration: new strategies for an old drug. Eur J Clin Microbiol Infect Dis. 1989;8(9):761-9. http://dx.doi.org/10.1007/BF02185842 PMid:2512146
http://dx.doi.org/10.1007/BF02185842...
) and this strategy was found to be effective and safe in various clinical settings.( 6060. Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother. 1997;39(6):677-86. http://dx.doi.org/10.1093/jac/39.6.677 PMid:9222035
http://dx.doi.org/10.1093/jac/39.6.677...
) In patients with CF, the results of a meta-analysis( 6161. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics. 2004;114(1):e111-8. http://dx.doi.org/10.1542/peds.114.1.e111 PMid:15231982
http://dx.doi.org/10.1542/peds.114.1.e11...
) and of a systematic review( 6262. Smyth AR, Bhatt J. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 2012;2:CD002009. PMid:22336782 ) indicate that once-daily aminoglycoside administration is effective and safer (LE 1a).

Recommendation

Aminoglycosides should be administered in a single daily dose in order to reduce side effects (LE 1a; GR A).

What should be the duration of intravenous therapy for an APE?

There are no clear guidelines on the optimal duration of intravenous antibiotic therapy in APEs in patients with CF. Treatment duration is currently based on the policies of each referral center and on individual response to treatment. Shorter treatment durations for APEs should improve the quality of life and satisfaction of patients and their families, as well as being less costly. However, this might not be sufficient to reduce the density of P. aeruginosa in the lungs significantly, potentially resulting in early recurrence of APE.

Although a systematic review( 6363. Plummer A, Wildman M. Duration of intravenous antibiotic therapy in people with cystic fibrosis. Cochrane Database Syst Rev. 2011;(1):CD006682. PMid:21249681 ) concluded that there are insufficient data to recommend an appropriate treatment duration for an APE in patients with CF, most treatment regimens, in many centers worldwide, last 10-14 days (LE 4).

Two more recent studies have provided some interesting data on the subject. VanDevanter et al.,( 6464. VanDevanter DR, O'Riordan MA, Blumer JL, Konstan MW. Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. Respir Res. 2010;11:137. http://dx.doi.org/10.1186/1465-9921-11-137 PMid:20925941 PMCid:2959026
http://dx.doi.org/10.1186/1465-9921-11-1...
) in a retrospective study involving 95 hospitalized patients treated with two distinct antimicrobial regimens, found that the average time to the highest observed FEV1 during the hospitalizations was 8.7 days (median = 10 days), and also reported that, in patients who had poor baseline pulmonary function (FEV1 < 40%), the time to the highest observed FEV1 was significantly longer (LE 3b). In another recent study (also retrospective), which evaluated more than 10,000 courses of intravenous antibiotic therapy in approximately 1,500 patients with CF, Collaco et al.( 4343. Collaco JM, Green DM, Cutting GR, Naughton KM, Mogayzel PJ Jr. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med. 2010;182(9):1137-43. http://dx.doi.org/10.1164/rccm.201001-0057OC PMid:20581166 PMCid:3001256
http://dx.doi.org/10.1164/rccm.201001-00...
) showed that clinical and functional improvement was observed between day 7 and day 8 of therapy in most cases, indicating that shorter therapy durations can be used in some cases (LE 3b).

Recommendation

There is no clear definition in the literature as to what the duration of therapy for APEs should be. However, the results suggest that antibiotics should be administered for at least 8-10 days, and patients who have worse baseline pulmonary function might require longer period of intravenous therapy (LE 3; GR C).

When should chronic inhaled antibiotic therapy be initiated in CF? Which inhaled antibiotics can be used in the treatment of chronic P. aeruginosa infection in CF?

Chronic P. aeruginosa infections have a negative impact on the prognosis of patients with CF, and, since the 1980s, there has been evidence that the use of therapies that decrease the amount of P. aeruginosa in the bronchial tree contributes to the stabilization or improvement of the disease.( 6565. Hodson ME, Penketh AR, Batten JC. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet. 1981;2(8256):1137-9. http://dx.doi.org/10.1016/S0140-6736(81)90588-2
http://dx.doi.org/10.1016/S0140-6736(81)...
, 6666. Szaff M, Høiby N, Flensborg EW. Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Acta Paediatr Scand. 1983;72(5):651-7. http://dx.doi.org/10.1111/j.1651-2227.1983.tb09789.x PMid:6637463
http://dx.doi.org/10.1111/j.1651-2227.19...
)

Tobramycin is the most studied inhaled antibiotic, since a specific formulation of tobramycin (TobiÂ(r); Novartis, São Paulo, Brazil) has been developed and tested in randomized, double-blind, placebo-controlled clinical trials involving a large number of patients with CF.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

In the initial studies, inhaled tobramycin was compared with inhaled placebo or standard therapy in patients with moderate to severe lung disease (FEV1 < 70% of predicted), and the largest of them involved a sample of 520 patients (LE 1).( 6767. Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328(24):1740-6. http://dx.doi.org/10.1056/NEJM199306173282403 PMid:8497284
http://dx.doi.org/10.1056/NEJM1993061732...
) The three most significant studies had a total number of 619 randomized patients. The results showed statistically significant improvement in FEV1 in those who received tobramycin, with a 7.8-12.0% increase in pulmonary function (FEV1; LE 1b).( 6767. Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328(24):1740-6. http://dx.doi.org/10.1056/NEJM199306173282403 PMid:8497284
http://dx.doi.org/10.1056/NEJM1993061732...

68. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1):23-30. http://dx.doi.org/10.1056/NEJM199901073400104 PMid:9878641
http://dx.doi.org/10.1056/NEJM1999010734...
- 6969. MacLusky IB, Gold R, Corey M, Levison H. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol. 1989;7(1):42-8. http://dx.doi.org/10.1002/ppul.1950070110 PMid:2505216
http://dx.doi.org/10.1002/ppul.195007011...
)

In addition, those three studies evaluated the influence of the use of inhaled tobramycin on the frequency of APEs, reporting a reduction in the number of hospitalizations and in the number of hospitalization days for the group treated with inhaled tobramycin (NE 1b).( 6767. Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328(24):1740-6. http://dx.doi.org/10.1056/NEJM199306173282403 PMid:8497284
http://dx.doi.org/10.1056/NEJM1993061732...

68. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340(1):23-30. http://dx.doi.org/10.1056/NEJM199901073400104 PMid:9878641
http://dx.doi.org/10.1056/NEJM1999010734...
- 6969. MacLusky IB, Gold R, Corey M, Levison H. Long-term effects of inhaled tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Pediatr Pulmonol. 1989;7(1):42-8. http://dx.doi.org/10.1002/ppul.1950070110 PMid:2505216
http://dx.doi.org/10.1002/ppul.195007011...
) The frequency of reported adverse events, especially those related to tinnitus, throat problems, and voice changes, was low in all studies.

These results led to inhaled tobramycin being recommended by international guidelines as the primary treatment option for such cases.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

Two studies,( 3838. Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld M, Yunker A, et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med. 2003;167(6):841-9. http://dx.doi.org/10.1164/rccm.200208-855OC PMid:12480612
http://dx.doi.org/10.1164/rccm.200208-85...
, 7070. Murphy TD, Anbar RD, Lester LA, Nasr SZ, Nickerson B, VanDevanter DR, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4):314-20. http://dx.doi.org/10.1002/ppul.20097 PMid:15334509
http://dx.doi.org/10.1002/ppul.20097...
) involving a total number of 202 patients, evaluated the use of inhaled tobramycin in patients with CF and mild lung disease (FEV1 between 70% and 89% of predicted). Gibson et al., in a sample of 21 patients under 6 years of age with CF and P. aeruginosa detected by BAL culture, reported that the use of inhaled tobramycin resulted in a reduction in the amount of P. aeruginosa in the airways (LE 2b).( 3838. Gibson RL, Emerson J, McNamara S, Burns JL, Rosenfeld M, Yunker A, et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med. 2003;167(6):841-9. http://dx.doi.org/10.1164/rccm.200208-855OC PMid:12480612
http://dx.doi.org/10.1164/rccm.200208-85...
) Another study, involving 181 patients (6-15 years of age) with mild lung disease, compared the use of inhaled tobramycin with the use of standard therapy for 56 weeks and found a significant reduction in the occurrence of exacerbations requiring hospitalization (11.0% vs. 25.6%). The study was stopped early because of the magnitude of the observed impact (LE 1b).( 7070. Murphy TD, Anbar RD, Lester LA, Nasr SZ, Nickerson B, VanDevanter DR, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4):314-20. http://dx.doi.org/10.1002/ppul.20097 PMid:15334509
http://dx.doi.org/10.1002/ppul.20097...
) There was no significant improvement in FEV1, but those treated with inhaled tobramycin showed a significant improvement (10%) in forced expiratory flow values–FEF50% (LE 1b).( 7070. Murphy TD, Anbar RD, Lester LA, Nasr SZ, Nickerson B, VanDevanter DR, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4):314-20. http://dx.doi.org/10.1002/ppul.20097 PMid:15334509
http://dx.doi.org/10.1002/ppul.20097...
)

The quality of evidence for the use of inhaled tobramycin in patients with mild lung disease remains limited by the number of studies and by sample sizes, and the largest of those studies( 7070. Murphy TD, Anbar RD, Lester LA, Nasr SZ, Nickerson B, VanDevanter DR, et al. Treatment with tobramycin solution for inhalation reduces hospitalizations in young CF subjects with mild lung disease. Pediatr Pulmonol. 2004;38(4):314-20. http://dx.doi.org/10.1002/ppul.20097 PMid:15334509
http://dx.doi.org/10.1002/ppul.20097...
) was stopped early because of the magnitude of the impact observed for respiratory exacerbations.

Other inhaled antibiotics are used in CF patients with chronic P. aeruginosa infection, but the amount of scientific evidence remains relatively sparse.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

Inhaled colomycin remains the initial drug of choice for nebulization in patients with CF and chronic respiratory infection with P. aeruginosa in the United Kingdom.( 7171. Cystic Fibrosis Trust [homepage on the Internet]. Bromley: Cystic Fibrosis Trust. [cited 2013 Feb 11]. Antibiotic treatment for cystic fibrosis 2009. [Adobe Acrobat document, 102p.]. Available from: https://www.cysticfibrosis.org.uk/media/82010/CD_Antibiotic_treatment_for_CF_May_09.pdf
Available from: htt...
) A comparative study of inhaled tobramycin (300 mg twice daily) and nebulized colomycin (1,000,000 IU twice daily) involving 115 patients showed that both therapies reduced the bacterial content of sputum samples and increased FEV1 values by 6.7% and 0.37%, respectively (NE 2b).( 7272. Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20(3):658-64. http://dx.doi.org/10.1183/09031936.02.00248102 PMid:12358344
http://dx.doi.org/10.1183/09031936.02.00...
) There have been few studies on the use of other drugs, such as gentamicin, amikacin, and ceftazidime.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
)

New drugs for inhalation have recently been tested in order to expand the range of therapeutic options, with benefits in the areas of tolerability, bacterial resistance, and practicality of administration, impacting patient safety and quality of life.

Inhaled aztreonam, a single-ring beta-lactam antibiotic (a monobactam), is one of the recently introduced drugs.( 7373. McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9):921-8. http://dx.doi.org/10.1164/rccm.200712-1804OC PMid:18658109 PMCid:2577727
http://dx.doi.org/10.1164/rccm.200712-18...
) One of the initial studies was a randomized, double-blind, placebo-controlled trial involving 211 patients over 6 years of age with CF, FEV1 between 25% and 75% of predicted, and chronic P. aeruginosa infection, all of whom were using inhaled tobramycin regularly. The patients received 75 mg inhaled aztreonam or placebo, two or three times daily for 28 days, and were then monitored for another 56 days. The reported positive effects included a 21-day increase in the mean time to next respiratory exacerbation, improvement in mean quality of life scores, a 6.3% increase in VEF1 (p = 0.001), and a reduction in sputum P. aeruginosa density. Adverse events were comparable between the groups. There was no change in susceptibility to P. aeruginosa for aztreonam (LE 2b).( 7373. McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9):921-8. http://dx.doi.org/10.1164/rccm.200712-1804OC PMid:18658109 PMCid:2577727
http://dx.doi.org/10.1164/rccm.200712-18...
) More recently, a study has been published that reports data on the use of inhaled aztreonam for a longer period of time (18 months).( 7474. Oermann CM, Retsch-Bogart GZ, Quittner AL, Gibson RL, McCoy KS, Montgomery AB, 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(11):1121-34. http://dx.doi.org/10.1002/ppul.21301 PMid:20672296
http://dx.doi.org/10....
) The study included 274 patients (mean age, 26 years) who had participated in other studies with inhaled aztreonam. It was an open-label study involving two regimens (75 mg two or three times daily) in alternate months. In addition to high adherence to treatment, pulmonary function and quality-of-life data improved with each course of the drug, there being no significant increase in bacterial resistance rates. Patients treated with three times-daily nebulization showed more significant improvement in pulmonary function and respiratory symptoms (LE 2b).( 7474. Oermann CM, Retsch-Bogart GZ, Quittner AL, Gibson RL, McCoy KS, Montgomery AB, 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(11):1121-34. http://dx.doi.org/10.1002/ppul.21301 PMid:20672296
http://dx.doi.org/10....
)

A novel dry-powder formulation of tobramycin delivered via an innovative inhaler was compared, in a non-inferiority study, with the commercially available inhaled tobramycin preparation.( 7575. Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011;10(1):54-61. http://dx.doi.org/10.1016/j.jcf.2010.10.003 PMid:21075062
http://dx.doi.org/10.1016/j.jcf.2010.10....
) The study included 517 patients over 6 years of age with CF, FEV1 between 25% and 75% of predicted, and a history of chronic P. aeruginosa infection for the last 6 months. The dry-powder formulation of tobramycin and the inhaled tobramycin preparation had similar efficacy in terms of FEV1 and microbiological effect, although the former resulted in higher rates of adverse effects, such as dysphonia, cough, and dysgeusia. However, the dry-powder formulation of tobramycin resulted in higher scores on quality-of-life questionnaires (LE 1b).( 7575. Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011;10(1):54-61. http://dx.doi.org/10.1016/j.jcf.2010.10.003 PMid:21075062
http://dx.doi.org/10.1016/j.jcf.2010.10....
)

A formulation of levofloxacin (MP-376, Aeroquin) was tested in 151 CF patients with chronic P. aeruginosa infection (LE 2b).( 7676. Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ, et al. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;183(11):1510-6. http://dx.doi.org/10.1164/rccm.201008-1293OC PMid:21471106
http://dx.doi.org/10.1164/rccm.201008-12...
) Three different doses (120 mg/day, 240 mg once daily, and 240 mg twice daily) were tested against placebo for 28 days. Sputum P. aeruginosa density was reduced by MP-376 treatment at all three different doses, and there was a dose-dependent increase (of up to 8.7%) in FEV1, as well as a significant reduction in the occurrence of APEs. The drug was generally well tolerated relative to placebo (LE 2b).( 7676. Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ, et al. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;183(11):1510-6. http://dx.doi.org/10.1164/rccm.201008-1293OC PMid:21471106
http://dx.doi.org/10.1164/rccm.201008-12...
)

A systematic review of the literature, published in 2011,( 7777. Ryan G, Singh M, Dwan K. Inhaled antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2011;(3):CD001021. PMid:21412868 ) summarized the available evidence on the use of inhaled antibiotics in patients with CF. The review made several comparisons using meta-analysis techniques. The conclusion was that inhaled antibiotics improve pulmonary function and reduce the rates of exacerbation of P. aeruginosa infection, and that the best evidence supports the use of inhaled tobramycin (LE 1a).( 7777. Ryan G, Singh M, Dwan K. Inhaled antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2011;(3):CD001021. PMid:21412868 )

Recommendation

It is recommended that inhaled tobramycin be used in patients over 6 years of age with CF, chronic P. aeruginosa infection, and moderate or severe lung disease (FEV1 < 70%; LE 1; GR A).

The use of inhaled tobramycin in patients over 6 years of age with CF, chronic P. aeruginosa infection, and mild lung disease (FEV1 between 70% and 89%) is recommended to reduce respiratory exacerbations (LE 2; GR B).

The evidence for the use of inhaled tobramycin in the younger population (those under 6 years of age) remains too poor to allow any evidence-based recommendation.

There are still few data on the use of other antibiotics, such as colomycin, gentamicin, and aztreonam, and there is no evidence to recommend that they be widely used.

Does adherence to clinical treatment affect the prognosis of patients with CF?

The treatment of patients with CF is based on the prevention structural lung injury, the management of the nutritional status, with supplementation with enzymes and nutrients, the prevention of exacerbations, and the identification and treatment of comorbidities, allowing a good quality of life.( 7878. Sawicki GS, Tiddens H. Managing treatment complexity in cystic fibrosis: challenges and opportunities. Pediatr Pulmonol. 2012;47(6):523-33. http://dx.doi.org/10.1002/ppul.22546 PMid:22467341
http://dx.doi.org/10.1002/ppul.22546...
) Among daily treatments, respiratory therapy plays a prominent role because of its complexity, since it usually requires the assistance of another individual and it is a procedure that has a significant impact on disease progression.( 7979. Robinson P. Cystic fibrosis. Thorax. 2001;56(3):237-41. http://dx.doi.org/10.1136/thorax.56.3.237 PMid:11182019 PMCid:1758774
http://dx.doi.org/10.1136/thorax.56.3.23...
, 8080. Bell SC, Robinson PJ. Exacerbations in cystic fibrosis: 2 . prevention. Thorax. 2007;62(8):723-32. http://dx.doi.org/10.1136/thx.2006.060897 PMid:17687099 PMCid:2117269
http://dx.doi.org/10.1136/thx.2006.06089...
) Given the complexity of the disease and the various objectives involved, it is clear that complex and aggressive treatment regimens are frequently used, which is very time-consuming for patients and their families.( 8181. Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros. 2009;8(2):91-6. http://dx.doi.org/10.1016/j.jcf.2008.09.007 PMid:18952504 PMCid:2680350
http://dx.doi.org/10.1016/j.jcf.2008.09....
)

In this setting of complex treatments and no set deadline for their completion, adherence to the recommended treatment is a factor that greatly impacts the clinical outcomes and prognosis of such patients.( 7878. Sawicki GS, Tiddens H. Managing treatment complexity in cystic fibrosis: challenges and opportunities. Pediatr Pulmonol. 2012;47(6):523-33. http://dx.doi.org/10.1002/ppul.22546 PMid:22467341
http://dx.doi.org/10.1002/ppul.22546...
)

Nebulizations are the most complex part of the pharmacological treatment, because they are very time-consuming and are increasingly recommended in patients with mild disease.( 22. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-69. http://dx.doi.org/10.1164/rccm.200705-664OC PMid:17761616
http://dx.doi.org/10.1164/rccm.200705-66...
) In a recent study involving adult patients with CF, the mean reported time spent on treatment activities was 108 min/day, and nebulized therapies accounted for 41 min of that time.( 8181. Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros. 2009;8(2):91-6. http://dx.doi.org/10.1016/j.jcf.2008.09.007 PMid:18952504 PMCid:2680350
http://dx.doi.org/10.1016/j.jcf.2008.09....
) Even in asthma patients, who spend much less time on drug administration, estimates of adherence to inhaled therapies range from 30% to 50%.( 8282. Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol. 1996;98(6 Pt 1):1051-7. http://dx.doi.org/10.1016/S0091-6749(96)80190-4
http://dx.doi.org/10.1016/S0091-6749(96)...
)

One of the reasons for poor adherence to treatment is lack of understanding of physician recommendations by patients and their families, who often also understand the same physician recommendation differently.( 8383. Ievers CE, Brown RT, Drotar D, Caplan D, Pishevar BS, Lambert RG. Knowledge of physician prescriptions and adherence to treatment among children with cystic fibrosis and their mothers. J Dev Behav Pediatr. 1999;20(5):335-43. http://dx.doi.org/10.1097/00004703-199910000-00008 PMid:10533992
http://dx.doi.org/10.1097/00004703-19991...
)

There is evidence that the low rates of adherence to medication use in CF are associated with poorer disease control, school absenteeism, and an increase in APEs (LE 2b).( 8484. Rau JL. Determinants of patient adherence to an aerosol regimen. Respir Care. 2005;50(10):1346-56; discussion 1357-9. PMid:16185370 ) In general, the onset of adolescence further worsens the scenario, because that is the time when the lung disease usually progresses and is precisely the time when adherence to treatment becomes poorer.( 8585. DiGirolamo AM, Quittner AL, Ackerman V, Stevens J. Identification and assessment of ongoing stressors in adolescents with a chronic illness: an application of the behavior-analytic model. J Clin Child Psychol. 1997;26(1):53-66. http://dx.doi.org/10.1207/s15374424jccp2601_6 PMid:9118176
http://dx.doi.org/10.1207/s15374424jccp2...
) There is evidence that adherence is inversely proportional to patient age, as well as being intimately related to a more optimistic view of the disease.( 8686. Gudas LJ, Koocher GP, Wypij D. Perceptions of medical compliance in children and adolescents with cystic fibrosis. J Dev Behav Pediatr. 1991;12(4):236-42. http://dx.doi.org/10.1097/00004703-199108000-00004 PMid:1939678
http://dx.doi.org/10.1097/00004703-19910...
)

Given that a study evaluating factors associated with poor adherence in children with asthma and CF identified common factors between the two diseases (forgetting, oppositional behaviors toward parents, difficulties with time management for procedures, side effects, difficulties swallowing pills, and taste of some medications), but also described many aspects that are specific to each disease, it is recommended that a disease-specific approach be applied to issues of adherence to treatment (LE 2b).( 8787. Modi AC, Quittner AL. Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way? J Pediatr Psychol. 2006;31(8):846-58. http://dx.doi.org/10.1093/jpepsy/jsj096 PMid:16401680
http://dx.doi.org/10....
)

A study involving adult CF patients and self-reported adherence that was conducted in Brazil showed high adherence rates, which were higher than that perceived by the medical staff involved in the treatment of those individuals.( 8888. Dalcin Pde T, Rampon G, Pasin LR, Ramon GM, Abrahão CL, Oliveira VZ. Adherence to treatment in patients with cystic fibrosis. J Bras Pneumol. 2007;33(6):663-70. PMid:18200366 ) Using other tools to measure adherence, such as pharmacy records, Eakin et al.( 8989. Eakin MN, Bilderback A, Boyle MP, Mogayzel PJ, Riekert KA. Longitudinal association between medication adherence and lung health in people with cystic fibrosis. J Cyst Fibros. 2011;10(4):258-64. http://dx.doi.org/10.1016/j.jcf.2011.03.005 PMid:21458391 PMCid:3114200
http://dx.doi.org/10.1016/j.jcf.2011.03....
) showed that poor adherence was associated with a higher risk of APE requiring the use of intravenous antibiotics (LE 4). Analyzing supplemental health care data on reimbursement for the purchase of inhaled tobramycin, Briesacher et al.( 9090. Briesacher BA, Quittner AL, Saiman L, Sacco P, Fouayzi H, Quittell LM. Adherence with tobramycin inhaled solution and health care utilization. BMC Pulm Med. 2011;11:5. http://dx.doi.org/10.1186/1471-2466-11-5 PMid:21251275 PMCid:3033861
http://dx.doi.org/10.1186/1471-2466-11-5...
) assessed the impact of adherence to this therapy on the clinical outcomes of patients with CF. Categorizing adherence as “low” (< 2 cycles/year), “medium” (2-3 cycles/year,) and “high” (≥ 4 cycles/year), those authors reported that high adherence was identified in only 7% of patients, and that low adherence was associated with an increased risk of hospitalization, with higher costs to the health care system (LE 3b). It is of note that the recommended treatment regimen is at least 6 cycles/year.

Recommendation

Adherence to treatment in CF is related to the great treatment load required and is poorer in adolescence. Nebulized therapies and respiratory therapy have the worst rates of adherence, and there is evidence that these therapies affect relevant clinical outcomes, such as the need for hospitalization (LE 3; GR C).

Is azithromycin efficacious in slowing the progression of lung disease in CF patients colonized with P. aeruginosa?

Macrolides are bacteriostatic drugs that act by inhibiting bacterial protein synthesis by binding to the 50S ribosomal unit.( 9191. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. 2005;6(3):227-35. http://dx.doi.org/10.1016/j.prrv.2005.06.005 PMid:16153572
http://dx.doi.org/10.1016/j.prrv.2005.06...
) In the 1980s, Japanese researchers described their experience in using low doses of erythromycin in diffuse panbronchiolitis, a disease that is accompanied by bronchiectasis and pulmonary suppuration.( 9292. Kudoh S, Uetake T, Hagiwara K, Hirayama M, Hus LH, Kimura H, et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis [Article in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1987;25(6):632-42. PMid:3682440 ) That initial experience motivated further studies using different macrolides in the treatment of respiratory diseases, such as CF, asthma, and bronchiolitis obliterans.( 9191. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. 2005;6(3):227-35. http://dx.doi.org/10.1016/j.prrv.2005.06.005 PMid:16153572
http://dx.doi.org/10.1016/j.prrv.2005.06...
)

Possible mechanisms of action of macrolides in CF include actions in the microorganism, such as reduced P. aeruginosa virulence, delayed bactericidal effects, reduced bacterial adherence to the respiratory epithelium, decreased bacterial motility, and impaired biofilm production.( 9191. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. 2005;6(3):227-35. http://dx.doi.org/10.1016/j.prrv.2005.06.005 PMid:16153572
http://dx.doi.org/10.1016/j.prrv.2005.06...
, 9393. McArdle JR, Talwalkar JS. Macrolides in cystic fibrosis. Clin Chest Med. 2007;28(2):347-60. http://dx.doi.org/10.1016/j.ccm.2007.02.005 PMid:17467553
http://dx.doi.org/10.1016/j.ccm.2007.02....
) Among the immunomodulatory actions of macrolides in the host are alteration in the neutrophil production of elastase, inhibition of alveolar macrophage production of inflammatory cytokines, and decreased mucus hypersecretion.( 9191. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. 2005;6(3):227-35. http://dx.doi.org/10.1016/j.prrv.2005.06.005 PMid:16153572
http://dx.doi.org/10.1016/j.prrv.2005.06...
, 9393. McArdle JR, Talwalkar JS. Macrolides in cystic fibrosis. Clin Chest Med. 2007;28(2):347-60. http://dx.doi.org/10.1016/j.ccm.2007.02.005 PMid:17467553
http://dx.doi.org/10.1016/j.ccm.2007.02....
)

Azithromycin is the most commonly used macrolide in patients with CF, and the first encouraging clinical trial was published in 2002: a 15-month randomized double-blind, placebo-controlled crossover trial evaluating 41 patients with CF.( 9494. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978-84. http://dx.doi.org/10.1016/S0140-6736(02)11081-6
http://dx.doi.org/10.1016/S0140-6736(02)...
) The primary outcome measure was change in FEV1, and azithromycin was dosed by body weight: ≤ 40 kg (250 mg/day) and > 40 kg (500 mg/day). The authors found significant improvement in pulmonary function (5.4%; 95% CI: 0.8-10.5%) in the group receiving azithromycin as compared with the group receiving placebo, and there was no significant difference in sputum bacterial concentration, exercise tolerance, or quality of life. In addition, treatment was well tolerated, with no significant adverse events (LE 2b).( 9494. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978-84. http://dx.doi.org/10.1016/S0140-6736(02)11081-6
http://dx.doi.org/10.1016/S0140-6736(02)...
)

Subsequently, a new, multicenter, randomized, double-blind, placebo-controlled trial involving 185 patients over 6 years of age who were chronically infected with P. aeruginosa was conducted in the USA.( 9595. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-56. http://dx.doi.org/10.1001/jama.290.13.1749 PMid:14519709
http://dx.doi.org/10.1001/jama.290.13.17...
) The dose of azithromycin was the same as that of the previous study, although it was administered only three times weekly. The primary outcome measure was also FEV1, and the authors reported a significant difference between the treatment and placebo groups (6.2%; 95% CI: 2.6-9.8%). Other encouraging results were a 35% reduction in the risk of APE and significant weight gain among the patients receiving azithromycin (LE 1b).( 9595. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-56. http://dx.doi.org/10.1001/jama.290.13.1749 PMid:14519709
http://dx.doi.org/10.1001/jama.290.13.17...
) The same group of authors assessed the effects of azithromycin in CF patients uninfected with P. aeruginosa( 9696. Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2010;303(17):1707-15. http://dx.doi.org/10.1001/jama.2010.563 PMid:20442386
http://dx.doi.org/10.1001/jama.2010.563...
); the use of azithromycin for 24 weeks did not result in significant improvement in FEV1 when compared with that of placebo, but there was a significant reduction in the occurrence of APEs in the group treated with azithromycin (LE 2b).( 9696. Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2010;303(17):1707-15. http://dx.doi.org/10.1001/jama.2010.563 PMid:20442386
http://dx.doi.org/10.1001/jama.2010.563...
)

A recent meta-analysis evaluating the use of macrolides in patients with CF included 6 randomized placebo-controlled trials (654 patients).( 9797. Cai Y, Chai D, Wang R, Bai N, Liang BB, Liu Y. Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review. J Antimicrob Chemother. 2011;66(5):968-78. http://dx.doi.org/10.1093/jac/dkr040 PMid:21393178
http://dx.doi.org/10.1093/jac/dkr040...
) Treatment with azithromycin resulted in significant improvement in FEV1 and FVC, especially in patients chronically infected with P. aeruginosa. The incidence of side effects was not significantly different between the placebo group and the azithromycin group (LE 1a).( 9797. Cai Y, Chai D, Wang R, Bai N, Liang BB, Liu Y. Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review. J Antimicrob Chemother. 2011;66(5):968-78. http://dx.doi.org/10.1093/jac/dkr040 PMid:21393178
http://dx.doi.org/10.1093/jac/dkr040...
)

A recent systematic review on the use of macrolides in CF included 10 studies (959 patients).( 9898. Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2011;(12):CD002203. PMid:22161368 ) Four clinical trials (549 patients) reported significant improvement in pulmonary function by comparing azithromycin with placebo. The mean difference at 6 months was 3.97% (95% CI: 1.74-6.19%). Patients receiving azithromycin had a reduction in the occurrence of APEs, needed oral antibiotics less frequently, had greater weight gain, and had fewer respiratory secretion cultures positive for S. aureus. Adverse effects were uncommon, although there was an increase in resistance to macrolides. The authors concluded that azithromycin has a small beneficial effect in the treatment of patients with CF using a three times-weekly regimen for periods of 6 months. However, considering the limited long-term data available and the concern about the development of bacterial resistance to macrolides, the current evidence is not strong enough to recommend that azithromycin be used in all patients with CF (LE 1a).( 9898. Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2011;(12):CD002203. PMid:22161368 )

Recommendation

The use of azithromycin in CF patients chronically infected with P. aeruginosa causes slight improvement in pulmonary function, reduces the frequency of APEs, and has no significant side effects (LE 1; GR A).cepacia complex, Achromobacter xylosoxidans, Aspergillus spp., etc.e efficacy and safety of azithromycin.

Is there a good correlation between antibiogram results and clinical response in chronic P. aeruginosa infection?

In initial infection with P. aeruginosa in patients with CF, nonmucoid forms are usually quite sensitive, there is a good correlation with antibiogram results, and treatment is usually successful. In chronic infections, mucoid forms of P. aeruginosa predominate, and higher concentrations of antibiotics are required; in addition, given the common occurrence of mixed populations of P. aeruginosa in the biofilm in the lung, the correlation between antibiogram results and clinical response might not be good.( 7171. Cystic Fibrosis Trust [homepage on the Internet]. Bromley: Cystic Fibrosis Trust. [cited 2013 Feb 11]. Antibiotic treatment for cystic fibrosis 2009. [Adobe Acrobat document, 102p.]. Available from: https://www.cysticfibrosis.org.uk/media/82010/CD_Antibiotic_treatment_for_CF_May_09.pdf
Available from: htt...
)

There are reports of clinical success in the treatment of bacteria that are resistant in vitro, and, in a study involving treatment of APEs, clinical outcomes were not associated with the minimum inhibitory concentration values for P. aeruginosa of the antimicrobial agents used (LE 2b).( 9999. Smith AL, Fiel SB, Mayer-Hamblett N, Ramsey B, Burns JL. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest. 2003;123(5):1495-502. http://dx.doi.org/10.1378/chest.123.5.1495 PMid:12740266
http://dx.doi.org/10.1378/chest.123.5.14...
)

In a study addressing multidrug-resistant P. aeruginosa isolates, Aaron et al.( 100100. Aaron SD, Vandemheen KL, Ferris W, Fergusson D, Tullis E, Haase D, 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. http://dx.doi.org/10.1016/S0140-6736(05)67060-2
http://dx.doi.org/10.1016/S0140-6736(05)...
) found no significant differences in clinical or bacteriological outcomes between the antimicrobial regimen chosen on the basis of standard sensitivity testing and that chosen on the basis of multiple combination bactericidal antibiotic testing (synergy testing; LE 2b).

Despite the lack of correlation found between antibiogram results and clinical response in the treatment of P. aeruginosa infections, the recommendation is to perform cultures of respiratory secretions from CF patients periodically to detect the initial infection, as well as to monitor changes in sensitivity patterns or the presence of other pathogens, such as B. cepacia complex, Achromobacter xylosoxidans, Aspergillus spp., etc. (LE 5).( 101101. Cantón R, Cobos N, de Gracia J, Baquero F, Honorato J, Gartner S, et al. Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients. Clin Microbiol Infect. 2005;11(9):690-703. http://dx.doi.org/10.1111/j.1469-0691.2005.01217.x PMid:16104983
http://dx.doi.org/10.1111/j.1469-0691.20...
)

Recommendation

Despite the poor correlation between antibiogram results and clinical response in chronic P. aeruginosa infection, it is recommended that cultures of respiratory secretions from CF patients be performed periodically to identify different bacterial species, although P. aeruginosa treatment should not be directed solely by the sensitivity pattern in the antibiogram (LE 5; GR D).

Does multidrug-resistant P. aeruginosa infection worsen prognosis?

As the mean survival of patients with CF increases and the population of adults with CF grows, there is increasing concern about multidrug-resistant P. aeruginosa infections. Multidrug-resistant P. aeruginosa has been defined as resistance to all drugs in at least two of the three following antimicrobial classes: fluoroquinolones; beta-lactam antibiotics; and aminoglycosides.( 102102. Saiman L, Mehar F, Niu WW, Neu HC, Shaw KJ, Miller G, et al. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis. 1996;23(3):532-7. http://dx.doi.org/10.1093/clinids/23.3.532 PMid:8879776
http://dx.doi.org/10.1093/clinids/23.3.5...
)

The major risk factors for multidrug-resistant P. aeruginosa infection are diabetes, long-term use of inhaled tobramycin, and frequent APEs requiring hospitalization or intravenous antibiotics. Receiving care at a treatment center with a high prevalence of resistant Pseudomonas spp. also increases the risk for acquiring multidrug-resistant P. aeruginosa (LE 2b).( 103103. Merlo CA, Boyle MP, Diener-West M, Marshall BC, Goss CH, Lechtzin N. Incidence and risk factors for multiple antibiotic-resistant Pseudomonas aeruginosa in cystic fibrosis. Chest. 2007;132(2):562-8. http://dx.doi.org/10.1378/chest.06-2888 PMid:17646236
http://dx.doi.org/10.1378/chest.06-2888...
)

A study following 75 adult patients with CF over a 3-year period found that multidrug-resistant P. aeruginosa infection was associated with greater lung disease severity, more rapid decline in FEV1, increased use of intravenous antibiotics, and increased frequency of medical visits (LE 2b).( 104104. Lechtzin N, John M, Irizarry R, Merlo C, Diette GB, Boyle MP. Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration. 2006;73(1):27-33. http://dx.doi.org/10.1159/000087686 PMid:16113513
http://dx.doi.org/10.1159/000087686...
)

Recommendation

Multidrug-resistant P. aeruginosa infection worsens the prognosis of patients with CF, as well as increasing the need for care and the use of medical and hospital resources (LE 2).

Final considerations

There is a body of evidence that early P. aeruginosa colonization has a significant impact on the prognosis of patients with CF, and that eradication strategies should be used, although there is controversy as to what is the best treatment regimen for this purpose. Early diagnosis of P. aeruginosa infection remains a challenge in clinical practice, and the role of P. aeruginosa serology in routine practice has yet to be established. A major problem for patients with CF, APEs are difficult to identify and treat, which often results in significant functional loss. Maintenance treatment for patients with chronic P. aeruginosa infection includes drugs such as azithromycin and inhaled antibiotics and, despite the body of evidence supporting the use of inhaled tobramycin, there is a novel formulation of this drug, as well as other antimicrobial agents with potential for use in such cases.

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Publication Dates

  • Publication in this collection
    June-August 2013

History

  • Received
    11 Feb 2013
  • Accepted
    17 Apr 2013
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