• The primary endpoint of this study is to show that doripenem is as effective as imipenem with respect to clinical cure rate in clinically-evaluable patients [ Time Frame: End of Treatment (Day 10), Clinical Cure based on Clinical Evaluability. ] [ Designated as safety issue: No ]
  

• The secondary endpoint of this study is to show that doripenem is as effective as imipenem with respect to clinical cure rate microbiologically-evaluable patients. [ Time Frame: End of Treatment (Day 10): Clinical Cure based on Microbiogical Evaluability and Clinical Cure rate in those that have relatively resistant bacteria in their lung such as Pseudomonas aeruginosa. Bacterial resistance at baseline or on study drug. ] [ Designated as safety issue: No ]
  

Patients with ventilator-associated pneumonia have high morbidity and mortality. A more potent antibiotic given for a shorter amount of time would reduce overall antibiotic exposure, emergence of bacterial resistance, and medical resource utilization. This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter study designed to assess the efficacy and safety of a 7-day course of doripenem compared with a 10-day course imipenem in patients 18 years of age or older with ventilator-associated pneumonia that is documented with clinical signs and symptoms, chest X-ray or CT scan, and a suitable lower respiratory tract specimen. The study has 3 phases: a pretreatment phase with a maximum of 1-day screening/baseline visit, a treatment phase of 10 days to the end of treatment or early withdrawal, and a posttreatment (follow-up) phase consisting of an early follow-up visit to be performed 7 to 14 days after the last dose of study drug is received, and a late follow-up visit to be performed on Day 28 to 35 after the last dose of study drug is received for all subjects including those who discontinued study drug early. Patients in each treatment group will receive 2 infusions simultaneously, one active study drug and one placebo. Thus, each patient will receive imipenem or imipenem placebo for a total of 10 days and doripenem or doripenem placebo for a total of 7 days. Patients will be hospitalized for the duration of study drug treatment. Optional adjunctive therapy with aminoglycoside (amikacin) may be started empirically at the investigator's discretion for infections suspected to be caused by resistant Pseudomonas aeruginosa or Acinetobacter species. Vancomycin or linezolid may be given empirically for methicillin-resistant Staphylococcus aureus (MRSA) for a maximum of 48 hours and must be discontinued if no MRSA is isolated from either the lower respiratory tract or blood cultures.

Assessments during clinical visits will include the completion of the Modified Clinical Pulmonary Infection Scores (CPIS) and Acute Physiology and Chronic Health Evaluation (APACHE) II, which assess the severity of disease, the Sepsis Organ Failure Assessment (SOFA), which is measured at baseline and compared with later scores to assess signs of improvement, and the Charlson Comorbidity Index, which is useful to quantify baseline co-morbidity of subjects in a study and to compare outcomes based on this co-morbidity index within treatment groups and between treatment groups. Quantitative lower respiratory tract cultures and biomarkers such as Soluble Triggering Receptor Expressed on Myeloid Cells (sTREM-1) will obtained by bronchoalveolar lavage (BAL) either bronchoscopically or nonbronchoscopically (miniBAL), at baseline. Tracheal aspirates for culture while the subject is intubated will also be obtained. Safety evaluations will include monitoring of adverse events, clinical laboratory tests, pregnancy tests, electrocardiogram (ECG), vital signs measurements, chest X-rays, and a physical examination. The study hypothesis is that in patients with ventilator-associated pneumonia, the higher 1-gram dose of doripenem infused over a 4-hour period will provide a more sustained duration of free drug level above the minimum inhibitory concentration (MIC) than the previously used-500-mg dose, for most organisms that cause ventilator-associated pneumonia, including the more resistant gram-negative organisms such as P. aeruginosa and Acinetobacter species. It is hypothesized that this advantage will provide more potent and sustained antibacterial activity than that of imipenem infused over 1 hour. Therefore it would be expected that a 7-day course of 1-g doripenem would have a clinical cure rate noninferior to that of a 10-day course of 1 g imipenem.

Doripenem/doripenem placebo will be administered for 7 days as a 1-gram intravenous infusion in normal saline (0.9% NaCl solution) over 4 hours at 8-hour intervals. Imipenem/imipenem placebo will be administered for 10 days a as 1-gram intravenous infusion in normal saline (0.9% NaCl solution) over 1 hour at 8-hour intervals. Patients will receive a minimum amount of fluid to administer study drugs and placebo and will receive total of 200 milliliters over 4 hours at 8-hour intervals.