Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study.

Abstract

OBJECTIVE:

Doripenem is an investigational carbapenem with broad-spectrum activity against gram-negative and gram-positive pathogens, including multidrug-resistant strains, commonly responsible for ventilator-associated pneumonia (VAP). This large, phase III study compared doripenem with imipenem for the treatment of ventilator-associated pneumonia.

DESIGN:

Prospective, multicenter, parallel randomized, active-controlled, open-label study.

SETTING:

Intensive care units.

PATIENTS:

Adults (N = 531) who met clinical and radiologic criteria for ventilator-associated pneumonia.

INTERVENTIONS:

Patients were stratified by duration of mechanical ventilation (< 5 vs. > or = 5 days), severity of illness (Acute Physiology and Chronic Health Evaluation II score < or = 15 vs. > 15), and geographic region and then randomly assigned to doripenem 500 mg every 8 hrs via a 4-hr intravenous infusion or imipenem 500 mg every 6 hrs or 1000 mg every 8 hrs via 30- or 60-min intravenous infusions, respectively, for 7-14 days.

MEASUREMENTS AND MAIN RESULTS:

The primary efficacy end points were the clinical cure rates in the clinical modified intent-to-treat (cMITT) and clinically evaluable populations. Doripenem was noninferior to imipenem (lower boundary of 95% confidence interval around the difference between treatments > or = -20%). Clinical cure rates were 68.3% (doripenem) and 64.2% (imipenem) in the clinically evaluable and 59.0% (doripenem) and 57.8% (imipenem) in the cMITT populations. In patients with Pseudomonas aeruginosa, clinical cure was 80.0% (doripenem) and 42.9% (imipenem) (p not significant); microbiological cure was 65.0% (doripenem) and 37.5% (imipenem). Only 18% (5 of 28) of P. aeruginosa isolates had minimum inhibitory concentration > or = 8 microg/mL at baseline or following therapy in the doripenem arm compared with 64% (16 of 25) in the imipenem treatment group (p = .001). Clinical cure rate was higher with doripenem than imipenem at higher Acute Physiology and Chronic Health Evaluation II scores and older ages. Doripenem was generally well tolerated.

CONCLUSIONS:

In this large, phase III study of patients with ventilator-associated pneumonia, a 4-hr intravenous infusion of doripenem was clinically efficacious and therapeutically noninferior to imipenem.

• Authors: Jean Chastre, Richard Wunderink, Philippe Prokocimer, Michael Lee, Koné Kaniga, Ian Friedland
• Journal: Critical care medicine (Crit Care Med) Vol. 36 Issue 4 Pg. 1089-96 (Apr 2008) ISSN: 1530-0293 [Electronic] United States
• PMID: 18379232 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Carbapenems
• Imipenem
• Doripenem

Topics

• APACHE
• Aged
• Anti-Bacterial Agents (administration & dosage, adverse effects, therapeutic use)
• Carbapenems (administration & dosage, adverse effects, therapeutic use)
• Doripenem
• Female
• Hospital Mortality
• Humans
• Imipenem (administration & dosage, adverse effects, therapeutic use)
• Infusions, Intravenous
• Male
• Microbial Sensitivity Tests
• Middle Aged
• Pneumonia, Ventilator-Associated (classification, drug therapy, microbiology)
• Treatment Outcome