Executive Summary

Mogayzel PJ, Naureckas ET, Robinson KA, Brady C, Guill M, Lahiri T, Lubsch L, Matsui J, Oermann CM, Ratjen F, Rosenfeld M, Simon RH, Hazle L, Sabadosa K, Marshall BC, and the Cystic Fibrosis Foundation Pulmonary Clinical Practice Guidelines Committee. Cystic Fibrosis Foundation pulmonary guideline. Pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014 11 (10): 1640-50.

Chronic infection with Pseudomonas aeruginosa (P. aeruginosa) is associated with increased morbidity and mortality. Several eradication regimens have been proven effective. PICO (population, intervention, comparator, outcome) questions were developed and a literature review was performed by an expert panel. Recommendations included antibiotic therapy for newly acquired P. aeruginosa and routine surveillance with oropharyngeal cultures. The committee recommended against P. aeruginos prophylaxis. Subsequent studies have demonstrated the efficacy of eradication regimens not considered in the original review. A key unanswered question is how best to optimize P. aeruginosa eradication therapy.

Chronic endobronchial infection with P. aeruginosa is common among patients with cystic fibrosis and often leads to exaggerated inflammatory responses in the airways. The acquisition of this microbe is associated with a more rapid decline in lung function and earlier mortality. It is hypothesized that P. aeruginosa infection initially occurs transiently and then progresses to chronic infection by developing a “mucoid” phenotype. Mucoidy is thought to contribute to the development of difficult-to-eradicate, persistent infection. Newer investigations also indicate that decreased motility plays a role in failed eradication. Several trials have demonstrated that antimicrobial eradication therapy can be used to eliminate P. aeruginosa infection when it is first identified, potentially leading to improved outcomes. Because the optimal approach to P. aeruginosa eradication is unclear, a systematic review of the medical literature was undertaken to assess prevention and eradication strategies.

Methodology

A multidisciplinary committee developed questions regarding the prevention and treatment of initial P. aeruginosa infection. Systematic reviews of relevant trials were performed in May 2012 and August 2013 from PubMed, EMBASE and the Cochrane Central Register of Controlled Trials. After the committee reviewed the evidence, final recommendation statements were graded using the U.S. Preventive Services Task Force system. Find additional information about the U.S. Preventive Services Task Force (USPSTF) grading definitions.

The database search yielded 3,547 citations that were independently screened by two reviewers. Eighteen citations citing 13 studies were eligible and seven treatment trials addressing initial or newly acquired P. aeruginosa infection and eradication were identified.

Three studies compared inhaled and oral therapy to placebo or no therapy (three weeks of inhaled colistin and oral ciprofloxacin compared with no treatment; inhaled tobramycin for 12 months with placebo; 28 days of inhaled tobramycin with placebo). These studies demonstrated that treating P. aeruginosa infection, with inhaled antibiotics with or without oral antibiotics, frequently resulted in clearance of the organism and may reduce the incidence of chronic airway infection.

The remaining studies compared different treatments to determine an optimal eradication strategy. The ELITE trial determined that 28 days of inhaled tobramycin was as beneficial as 56 days in treating first or early P. aeruginosa growth.

Twenty-eight days of inhaled tobramycin had a similar eradication rate compared with three months of inhaled colistin and oral ciprofloxacin in a randomized, open-label trial at a single center in Belgium.

Thirteen centers in Italy compared 28 days of inhaled colistin and oral ciprofloxacin with 28 days of inhaled tobramycin and oral ciprofloxacin in 223 children with first-time P. aeruginosa growth or re-growth after six months. This analysis found similar P. aeruginosa clearance and eradication rates, and also noted an increase in stenotrophomonas maltophilia in both treatment arms.

The Early Pseudomonas Infection Control (EPIC) trial found that a similar proportion of children remained free of P. aeruginosa in groups that received inhaled tobramycin with and without oral ciprofloxacin either in cycled (every three months) or culture-based therapy for 18 months. This study suggested that adding ciprofloxacin does not provide additional benefit to inhaled tobramycin for newly acquired P. aeruginosa.

Based on these studies, the committee determined there is significant evidence that inhaled antibiotics are effective in treating newly acquired P. aeruginosa infection.

Recommendations

Unanswered Questions

• Can P. aeruginosa infection be prevented?
• Are there better techniques for earlier detection of P. aeruginosa infection?
• Is there a “best” eradication approach?
• What is the optimum approach to failed eradication?
  • Studies, such as the Trial of Optimal Therapy for Pseudomonas Eradication in Cystic Fibrosis (TORPEDO-CF) and the OPTIMIZing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis (OPTIMIZE) are ongoing and may answer some of these questions.
  • Future research is required to identify optimal eradication therapies and to define treatment in individuals with early reacquisition or failed eradication.

Further Reading

Relevant manuscripts published after the original guidelines are listed below. These manuscripts have not been reviewed or endorsed by the guidelines committee.

• Tiddens HA, De Boeck K, Clancy JP, Fayon M, Arets HGM, Bresnik M, Derchak A, Lewis SA, Oermann CM, ALPINE study investigators. Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros. 2015 Jan;14(1):111-9. doi: 10.1016/j.jcf.2014.06.003. Epub 2014 Aug 1.
  • The Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) open label study showed that aztreonam for inhalation solution (AZLI) was well tolerated and effective in eradicating P. aeruginosa, with success rates similar to those reported in the literature for other antibiotic regimens.
• Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev. 2014 Nov 10;(11):CD004197. doi: 10.1002/14651858.CD004197.pub4.
  • A Cochrane analysis found that studies directly comparing P. aeruginosa eradication therapies have not demonstrated the superiority of any therapy.
• Mayer-Hamblett N, Rosenfeld M, Treggiari MM, Konstan MW, Retsch-Bogart G, Morgan W, Wagener J, Gibson RL, Khan U, Emerson J, Thompson V, Elkin EP, Ramsey BW, EPIC ESCF Investigators. Standard care versus protocol based therapy for new onset Pseudomonas aeruginosa in cystic fibrosis. Pediatr Pulmonol. 2013 Oct;48(10):943-53. doi: 10.1002/ppul.22693. Epub 2013 Jul 2.
  • Mayer-Hamblett and colleagues compared historical controls, where treatment for P. aeruginosa was determined by the presence of respiratory symptoms, compared to culture results in the EPIC observational cohort. Lower rates of P. aeruginosa were found in the EPIC cohort, but hospitalization rates were similar compared to the historical control cohort less aggressively treated with antibiotics for new onset P. aeruginosa.
• Zemanick ET, Emerson J, Thompson V, McNamara S, Morgan W, Gibson RL, Rosenfeld M, EPIC Study Group. Clinical outcomes after initial Pseudomonas acquisition in cystic fibrosis. Pediatr Pulmonol. 2015 Jan;50(1):42-8. doi: 10.1002/ppul.23036. Epub 2014 Mar 18.
  • Zemanick and colleagues evaluated the clinical impact associated with early P. aeruginosa infection in the EPIC observational cohort. There was no significant change in the decline of FEV₁% predicted, but the exacerbation rate and odds of crackles or wheeze on physical exam were greater after P. aeruginosa acquisition.
• Sanders DB, Emerson J, Ren CL, Schechter MS, Gibson RL, Morgan W, Rosenfeld M; EPIC Study Group. Early childhood risk factors for decreased FEV1 at age six to seven years in young children with cystic fibrosis. Ann Am Thorac Soc. 2015 Aug;12(8):1170-6. doi: 10.1513/AnnalsATS.201504-198OC.
  • Sanders and colleagues evaluated children enrolled in the EPIC observational cohort before age 4 and used linear regression to estimate the association between potential early childhood risk factors and the mean best FEV₁% predicted at years 6-7. P. aeruginosa positivity, as well as the presence of crackles and wheeze, were significantly associated with lower mean FEV₁% predicted at age 6-7.
• Vaccines for preventing infection with Pseudomonas aeruginosa in cystic fibrosis. Cochrane Database Syst Rev. 2015 Aug 23;(8):CD001399. doi: 10.1002/14651858.CD001399.pub4. Johansen HK, Gøtzsche PC.
  • A recent Cochrane analysis assessing the efficacy of preventing initial infection with P. aeruginosa in cystic fibrosis was published. Analysis included one large trial (483 patients) and a smaller trial (37 patients with cystic fibrosis). The risk of chronic infection with P. aeruginosa did not decrease with vaccination in the large trial (relative risk of chronic infection was 0.91, with confidence interval 0.55 to 1.49), and there were 227 adverse events reported in the vaccine group. Based on the sparse data, this review did not recommend the use of vaccines against P. aeruginosa in patients with cystic fibrosis.
• Mayer-Hamblett N, Retsch-Bogart G, Kloster M, et al. Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial. Am J  Respir Crit Care Med. 2018 Nov 1;198(9):1177-1187. doi: 10.1164/rccm.201802-0215OC. Erratum in: Am J Respir Crit Care Med. 2019 Mar  15;199(6):809. PMID: 29890086; PMCID: PMC6221579.
• Hewer SCL, Smyth AR, Brown M, et al. Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a  randomised controlled trial. Lancet Respir Med. 2020 Oct;8(10):975-986. doi: 10.1016/S2213-2600(20)30331-3. PMID: 33007285.
• Hewer SCL, Smith S, Rowbotham NJ, Yule A, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev. 2023;6(6):CD004197. Published 2023 Jun 2. doi:10.1002/14651858.CD004197.pub6. PMID: 37268599.
   

Use of These Guidelines

The CF Foundation intends for this executive summary of its guideline to summarize the published guideline. The published guideline summarizes evidence, and provides reasonable clinical recommendations based on that evidence, to clinicians, patients, and other stakeholders. Care decisions regarding individual patients should be made using a combination of these recommendations, the associated benefit-risk assessment of treatment options from the clinical team, the patient's individual and unique circumstances, as well as the goals and preferences of the patients and families that the team serves, as a part of shared decision-making between the patient and clinician.

This executive summary was prepared by:

Alvin V. Singh (Department of Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri) and Peter J. Mogayzel, Jr. (Department of Pediatrics, The Johns Hopkins Medical Institutions, Baltimore, Maryland)

The guidelines were published in December 2014, they were reviewed in July 2021 and it was determined that no update is needed at this time.