Chest
Volume 123, Issue 5, May 2003, Pages 1495-1502
Journal home page for Chest

Clinical Investigations
CYSTIC FIBROSIS
Susceptibility Testing of Pseudomonas aeruginosa Isolates and Clinical Response to Parenteral Antibiotic Administration: Lack of Association in Cystic Fibrosis

https://doi.org/10.1378/chest.123.5.1495Get rights and content

Study objective:

To determine the relationship between the antibiotic susceptibility of Pseudomonas aeruginosa isolated from the sputum of patients with cystic fibrosis (CF) and the patient’s response to parenteral antibiotic administration, we performed a retrospective analysis using data from patients in the placebo arm of a phase 3 trial of tobramycin solution for inhalation. All patients were chronically infected with P aeruginosa. Seventy-seven of the 262 patients receiving placebo experienced a pulmonary exacerbation during the trial for which they received therapy with IV tobramycin and ceftazidime. The susceptibility of the P aeruginosa isolates to ceftazidime and tobramycin was determined at trial enrollment by broth microdilution.

Design:

The clinical response to combination antibiotic therapy was assessed by analyzing differences in spirometry before and after antibiotic administration. The FEV1 percent predicted at the first visit after the conclusion of antibiotic administration was compared to the FEV1 percent predicted prior to antibiotic therapy. The results were analyzed both descriptively and by regression analyses.

Results:

The conditions of 54 patients improved, and those of 9 patients worsened, and in 14 patients there was no change in FEV1 with antibiotic administration. No correlation was observed between the susceptibility of P aeruginosa to tobramycin or ceftazidime and clinical response. Only the three following variables were observed to significantly correlate with FEV1 after antibiotic treatment on regression analysis: FEV1 prior to treatment (p < 0.0001); number of days elapsed between the previous FEV1 measurement and the initiation of IV antibiotic therapy (p < 0.002); and the number of days elapsed between the determination of the minimum inhibitory concentration and the initiation of IV therapy (p < 0.03). No significant trends were observed between the antibiotic susceptibility of P aeruginosa isolates and treatment outcomes.

Conclusion:

While lack of statistical significance for a trend between bacterial susceptibilities and the response to parenteral antibiotic administration does not mean that no such trend exists, the precision of the confidence intervals allows us to conclude that even if isolate antibiotic susceptibilities affect outcome, the impact would be small and not clinically relevant.

Section snippets

Materials and Methods

Five hundred twenty CF patients with chronic P aeruginosa infection were enrolled in two identical, double-blind, simultaneously conducted, phase 3 clinical trials.14 Patients were randomized to treatment with aerosol administration of either a tobramycin solution for inhalation (n = 258) or a taste-masked placebo (n = 262). The study drug was administered in a series of cycles consisting of 28 days of drug administration followed by 28 days off drug administration. The selection criteria, the

Results

The response of 77 CF subjects receiving combination IV tobramycin and ceftazidime therapy for pulmonary exacerbations were analyzed. Treatment responses among the 77 subjects ranged from a relative decrease of 40.3% in FEV1 percent predicted to an increase of 139.9%. The mean relative change was an increase of 17.7%. This improvement, which was expressed as an average change in FEV1, is of the same order of magnitude as that seen with antibiotic treatment of a pulmonary exacerbation seen in

Discussion

At one time, antibiotic resistance was defined as the persistence of the bacterium in the infectious focus despite standard, nontoxic doses of the antibiotic.1718 Subsequently, quantitative antibiotic susceptibility testing revealed that bacteria persisting in infectious foci during antibiotic therapy had the ability to grow in vitro in antibiotic concentrations that were toxic to mammalian cells.19 In these early studies with Gram-negative bacilli, including P aeruginosa, the definition of a

ACKNOWLEDGMENT

The authors acknowledge the assistance of Xin Yu, Jill Van Dalfsen, and Dutch VanDevanter of Chiron Corporation for providing access to clinical trial data.

References (21)

  • AL Smith et al.

    Comparison of a β-lactam alone versus β-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis

    J Pediatr

    (1999)
  • PH Beaudry et al.

    Is anti-Pseudomonastherapy warranted in acute respiratory exacerbations in children with cystic fibrosis?

    J Pediatr

    (1980)
  • JRW Govan et al.

    Microbiology of lung infection in cystic fibrosis

    Br Med Bull

    (1992)
  • WE Regelmann et al.

    Reduction of sputumPseudomonas aeruginosadensity by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone

    Am Rev Respir Dis

    (1990)
  • FJ McLaughlin et al.

    Clinical and bacteriological responses to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo

    J Infect Dis

    (1983)
  • L Saiman et al.

    Evaluation of reference dilution test methods for antimicrobial susceptibility testing ofPseudomonas aeruginosastrains isolated from patients with cystic fibrosis

    J Clin Microbiol

    (1999)
  • MJ Thomassen et al.

    Multiple isolates ofPseudomonas aeruginosawith differing antimicrobial susceptibility patterns from patients with cystic fibrosis

    J Infect Dis

    (1979)
  • I Shalit et al.

    Randomized study of two dosage regimens of ciprofloxacin for treating chronic bronchopulmonary infection in patients with cystic fibrosis

    Am J Med

    (1987)
  • AL Smith et al.

    Safety of aerosol tobramycin administration for three months to patients with cystic fibrosis

    Pediatr Pulmonol

    (1989)
  • JL Burns et al.

    Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis

    J Infect Dis

    (1999)
There are more references available in the full text version of this article.

Cited by (263)

  • Antibiotic Management in Bronchiectasis

    2022, Clinics in Chest Medicine
  • Orangutan Respiratory Disease Syndrome

    2022, Fowler's Zoo and Wild Animal Medicine Current Therapy: Volume 10
View all citing articles on Scopus

Chiron Corporation provided some statistical support for the analysis of the data under the supervision of the authors. The authors of this manuscript received no financial support for its preparation, although they have received grant support and/or honoraria from Chiron for other projects. Dr. Smith is a consultant to the Chiron Corporation. This work was supported in part by a grant from the Cystic Fibrosis Foundation.

View full text