Elsevier

The Lancet

Volume 366, Issue 9484, 6–12 August 2005, Pages 463-471
The Lancet

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Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial

https://doi.org/10.1016/S0140-6736(05)67060-2Get rights and content

Summary

Background

We did a randomised, double-blind, controlled clinical trial to prospectively assess whether use of combination antibiotic susceptibility testing improved clinical outcomes in patients with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria.

Methods

251 patients with cystic fibrosis who were chronically infected with multiresistant gram negative bacteria gave sputum at 3-month intervals for conventional culture and sensitivity tests and for combination antibiotic susceptibility tests using multiple combination bactericidal antibiotic testing (MCBT). Patients who developed an exacerbation of pulmonary disease were randomised to receive a 14-day course of any two blinded intravenous antibiotics chosen on the basis of either results from conventional sputum culture and sensitivity testing or the result of MCBT. The primary outcome was time from randomisation until the patient's next pulmonary exacerbation. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN60187870.

Findings

132 patients had a pulmonary exacerbation and were randomised during the 4·5-year study period. The time to next pulmonary exacerbation was not prolonged in the MCBT-treated group (hazard ratio 0·86 in favour of the conventionally-treated group, 95% CI 0·60–1·23, p=0·40). There was no difference between the groups in treatment failure rate. After 14 days of intravenous antibiotic therapy, changes in lung function, dyspnoea, and sputum bacterial density were similar in both groups.

Interpretation

Antibiotic therapy directed by combination antibiotic susceptibility testing did not result in better clinical and bacteriological outcomes compared with therapy directed by standard culture and sensitivity techniques. The non-bactericidal effects of antibiotic therapy might play an important part in determining improvement in patients with cystic fibrosis pulmonary exacerbations.

Introduction

Antibiotic-resistant bacterial infections are becoming a major worldwide public health problem.1, 2 Few disease states have as high a prevalence of antibiotic resistant infections as does cystic fibrosis. Estimates suggest that 25–45% of adults with cystic fibrosis are chronically infected with multiresistant bacteria in their airways.3

Chronic bacterial airway infections in patients with cystic fibrosis generally follow a smouldering course punctuated by acute pulmonary exacerbations characterised by worsening cough, increased sputum production, and increased dyspnoea.4, 5 Randomised controlled trials have suggested that combination antibiotic therapy with two antipseudomonal antibiotics is better than antibiotic monotherapy or placebo for patients with cystic fibrosis pulmonary exacerbations, and that dual antibiotic therapy extends the time to next exacerbation.6, 7 Multiantibiotic therapy has therefore become the standard of care for treatment of acute cystic fibrosis pulmonary exacerbation.8

The conundrum in managing such patients has been what combination of antibiotics to select if the bacterial organisms are multiresistant or panresistant to antibiotics on routine sensitivity testing. This question has been a particular concern for cystic fibrosis patients with severe disease, in whom further loss of lung function can lead to disastrous consequences, including death.

Conventional sputum culturing and sensitivity testing represents the current standard for diagnosis and treatment of airway infections associated with cystic fibrosis. Sputum testing involves microbiological identification of the infecting bacteria, followed by conventional antibiotic susceptibility testing of the identified bacterial isolates against individual antibiotics. Unfortunately, for patients infected with multiresistant bacteria, results of conventional single antibiotic susceptibility tests can be inadequate since traditional susceptibility results almost always show resistance to many, or all, of the single antibiotics tested.

In an effort to combat multiresistant infections we developed an in-vitro method for testing and assessing combinations of double and triple antibiotics for bactericidal activity against multiresistant bacterial isolates.9, 10 The multiple combination bactericidal antibiotic test (MCBT) method allows the clinician to choose combinations of antibiotics that together have in-vitro bactericidal activity against multiresistant Burkholderia cepacia, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans organisms. This testing has been shown to yield reproducible results in in-vitro studies.9, 11

In the past decade, MCBT clinical laboratories, and antibiotic synergy clinical laboratories that do similar combination antibiotic susceptibility tests, have been established in Canada, the UK, the USA, Australia, and Europe.12, 13 These laboratories routinely handle combination antibiotic susceptibility testing of multiresistant cystic fibrosis isolates, and many also test multiresistant bacteria associated with infections in non-cystic fibrosis patients. Although this type of laboratory testing is expensive, the tests have been widely used in the hope that use of combination antibiotic susceptibility tests, or synergy tests, will lead to appropriate choice of combination antibiotics and improved bacteriological and clinical outcomes for patients infected with multiresistant bacteria.

We conducted a clinical trial in patients with cystic fibrosis who were infected with multiresistant bacteria and were experiencing acute pulmonary exacerbations. The trial was designed to assess the clinical efficacy of MCBT-directed combination antibiotic therapy compared with that of antibiotic therapy chosen on the basis of standard conventional bacterial culture and sensitivity testing. The goal was to rigorously evaluate this new laboratory test to determine whether use of the test leads to improved patient clinical outcomes and a better ability to treat multiresistant organisms.

Section snippets

Patients

We enrolled patients from ten Canadian and two Australian sites with a confirmed diagnosis of cystic fibrosis (sweat chloride value higher than 60 mmol/L or two disease-causing cystic fibrosis mutations or both), who were at least 12 years old, and who could spontaneously produce sputum for culturing. Enrolled patients were known to be chronically infected with multiresistant Burkholderia cepacia complex, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or Achromobacter xylosoxidans

Results

251 patients consented to enrol in the study and were followed up prospectively with sputum cultures done every 3 months for up to 4 years. Of these 251 patients, 95 did not have a pulmonary exacerbation requiring intravenous antibiotics during the study period, and 24 patients did have a pulmonary exacerbation during the study period but were not randomised for reasons described in figure 1.

132 patients were randomised into the study; 64 patients were assigned to the MCBT group, and 68 were

Discussion

Our study confirms that pulmonary function and dyspnoea do improve in most patients with cystic fibrosis who are treated with antimicrobial therapy for acute pulmonary exacerbations. However, treatment of exacerbations with antibiotics chosen based on in-vitro combination bactericidal susceptibility testing did not affect patients' outcomes.

The goal of this study was to rigorously evaluate a novel laboratory microbiology test to determine if use of the test would lead to improved

References (29)

  • WE Regelmann et al.

    Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone

    Am Rev Respir Dis

    (1990)
  • HE Elphick et al.

    Single versus combination intravenous antibiotic therapy for people with cystic fibrosis

    Cochrane Database Syst Rev

    (2001)
  • SD Aaron et al.

    Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with Burkholderia cepacia

    Am J Respir Crit Care Med

    (2000)
  • BJ Lang et al.

    Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa

    Am J Respir Crit Care Med

    (2000)
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