The purpose of the study is to show that a shorter course (7 days) of doripenem is as effective as a 10-day course of imipenem in the treatment of patients with ventilator-associated pneumonia.

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.

• Pneumonia
• Pneumonia, Bacterial

• Drug: imipenem/cilastatin
  1 gram intravenously every 8 hours for 10 days.
• Drug: doripenem
  1 gram intravenously every 8 hours for 10 days.

• 001: Experimental
  doripenem 1 gram intravenously every 8 hours for 10 days.
  Intervention: Drug: doripenem
• 002: Active Comparator
  imipenem/cilastatin 1 gram intravenously every 8 hours for 10 days.
  Intervention: Drug: imipenem/cilastatin

Inclusion Criteria:

• Have new or worsening radiographic infiltrates consistent with ventilator-associated pneumonia that is not related to cardiac or other disease processes taken within 12 hours before screening
• Have at least one of the following: Fever (in the absence of fever-reducing agents): a rectal temperature greater than 39 C OR an increase in core temperature of greater than 1 C, low body temperature, defined as a rectal/core body temperature of less than 35 C, or an abnormally large number of leukocytes (a type of white blood cells), as observed in acute infections
• Have developed ventilator-associated pneumonia and have been on mechanical ventilation for >=48 hours and on mechanical ventilation at the time of randomization
• Have been hospitalized or been in a chronic care facility for a total of 5 or more days within the last 90 days
• Have a baseline Clinical Pulmonary Infection Score (CPIS) >=6 and an Acute Physiology and Chronic Health Evaluation (APACHE) II score >8 and <35

Exclusion Criteria:

• Received antibiotics for this episode of ventilator-associated pneumonia for >24 hours before randomization
• Known presence at baseline of only methicillin-resistant Staphylococcus aureus (MRSA) or Stenotrophomonas infection
• Acute respiratory distress syndrome
• Has any of the following conditions that interfere with the assessment or interpretation of the diagnosis or response to therapy: chest trauma with severe lung bruising or loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both, increased amounts of fluid in the lung cavities requiring drainage or pus in the cavity
• lung cancer-primary or secondary within the last 2 years, chronic bronchitis with an increase in severity within the last 30 days, chronic enlargement of the bronchi or bronchioles related to inflammatory disease or obstruction, lung abscess(s), anatomical bronchial obstruction, respiratory tuberculosis on treatment, suspected atypical pneumonia, chemical pneumonitis (e.g., aspiration of gastric contents, inhalation injury), cystic fibrosis, congestive heart failure, active seizure disorder within the last 2 years or brain injury such that imipenem would not be administered to the patient in usual practice, severe burns to greater than 15% of the body, evidence of severe and chronic liver disease indicating cirrhosis in the opinion of the investigator
• History of hypersensitivity reactions to carbapenems, penicillins, other beta-lactam antibiotics, or beta-lactamase inhibitors