A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia

Abstract

Introduction: The aim of this study was to compare a 7-day course of doripenem to a 10-day course of imipenem-cilastatin for ventilator-associated pneumonia (VAP) due to Gram-negative bacteria.

Methods: This was a prospective, double-blinded, randomized trial comparing a fixed 7-day course of doripenem one gram as a four-hour infusion every eight hours with a fixed 10-day course of imipenem-cilastatin one gram as a one-hour infusion every eight hours (April 2008 through June 2011).

Results: The study was stopped prematurely at the recommendation of the Independent Data Monitoring Committee that was blinded to treatment arm assignment and performed a scheduled review of data which showed signals that were close to the pre-specified stopping limits. The final analyses included 274 randomized patients. The clinical cure rate at the end of therapy (EOT) in the microbiological intent-to-treat (MITT) population was numerically lower for patients in the doripenem arm compared to the imipenem-cilastatin arm (45.6% versus 56.8%; 95% CI, -26.3% to 3.8%). Similarly, the clinical cure rate at EOT was numerically lower for patients with Pseudomonas aeruginosa VAP, the most common Gram-negative pathogen, in the doripenem arm compared to the imipenem-cilastatin arm (41.2% versus 60.0%; 95% CI, -57.2 to 19.5). All cause 28-day mortality in the MITT group was numerically greater for patients in the doripenem arm compared to the imipenem-cilastatin arm (21.5% versus 14.8%; 95% CI, -5.0 to 18.5) and for patients with P. aeruginosa VAP (35.3% versus 0.0%; 95% CI, 12.6 to 58.0).

Conclusions: Among patients with microbiologically confirmed late-onset VAP, a fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin. Consideration should be given to treating patients with VAP for more than seven days to optimize clinical outcome.

Trial registration: ClinicalTrials.gov: NCT00589693.

Figure 1

Patients enrolled and analyzed. ITT, intention-to-treat; MITT, Microbiological intention-to-treat. *Prior to study termination the Marketing Authorization Holder for the study identified five study sites (three in Guatemala, one in Germany, one in the United States), following independent internal reviews and re-monitoring by a contract research organization (CRO), that were found not to have adhered to the study protocols, or the study logs could not verify protocol adherence, and thus their data were excluded from the primary analyses.

Figure 2

Clinical cure rates at end of treatment by subgroup with 95% confidence intervals.

Figure 3

Mean Clinical Pulmonary Infection Scores (CPIS) for the MITT treatment groups during antibiotic therapy. Error bars displayed are based on the 95% confidence interval around the means. As there is significant dropout over time, as can be seen by the available sample sizes at the bottom of the figure, the results have to be interpreted with caution. Nevertheless, the curves suggest that the patients' improvement is similar for the two treatment arms up to Day 8 (the last day of active doripenem treatment), where after the decreasing trend is continued for the subjects in the Imipenem-cilastatin arm (who receive active treatment up to Day 11), but remains stable for subjects in the doripenem arm (who receive only placebo from Day 9 up to Day 11).

Figure 4

Kaplan-Meier curves for the P. aeruginosa subgroup. (P = 0.040, Log-Rank Test).