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


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


METHODS
Intensive care units.


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


METHODS
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.


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.
Chastre
Jean
J
Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie Paris 6, Paris, France. jean.chastre@psl.aphp.fr
Wunderink
Richard
R
Prokocimer
Philippe
P
Lee
Michael
M
Kaniga
Koné
K
Friedland
Ian
I
D018806:APACHE; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015780:Carbapenems / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077726:Doripenem; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000145:classification / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D015378:Imipenem; D000077726:Doripenem