Study Evaluating Safety and Efficacy of Tigecycline Versus Imipenem/Cilastatin Subjects With Hospital-Acquired Pneumonia

This study will compare the safety and efficacy of a tigecycline regimen versus an imipenem/cilastatin regimen for the treatment of subjects who are hospitalized with hospital-acquired pneumonia (HAP). At least 70% of enrolled subjects will have ventilator-associated pneumonia (VAP). Two dose levels of tigecycline will be assessed and compared to imipenem/cilastatin in parallel. Subjects will receive intravenous therapy from a minimum of 7 & up to 14 consecutive days, the exact duration will be at the decision of the investigator based on the subject's condition. Additional protocol specified antibiotics may be given to ensure appropriate coverage. A final assessment at test-of-cure (TOC) visit will be done 10 to 21 days after the last day of therapy. The total duration of subject participation will be between 17 and 44 days, including a follow up period of 30 days after the last day of therapy for SAEs.

Subjects will be followed for safety and efficacy. The safety assessment will include: physical examinations, vital signs, assessment of the clinical signs and symptoms of pneumonia, collection of adverse events, 12-lead ECG, collection of samples for hematology, serum chemistries, and coagulation parameters, & a serum or urine pregnancy test before study entry for women of childbearing potential. The clinical and microbiological efficacy will both be evaluated.

• Drug: tigecycline
  An initial intravenous (IV) loading dose of 150 mg of tigecycline, followed by 75 mg of IV tigecycline approximately every 12 hours (q12h), for up to 14 consecutive days. Ceftazidime 2 g IV approximately every 8 hours, an aminoglycoside (tobramycin 7mg/kg daily or amikacin 20 mg/kg daily) and vancomycin placebo given at the start of therapy (unless it is known at baseline that the subject does not have Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus [MRSA]).
• Drug: tigecycline
  An initial intravenous (IV) loading dose of 200 mg of tigecycline, followed by 100 mg of IV tigecycline approximately every 12 hours (q12h), for up to 14 consecutive days. Ceftazidime 2 g IV approximately every 8 hours, an aminoglycoside (tobramycin 7mg/kg daily or amikacin 20 mg/kg daily) and vancomycin placebo given at the start of therapy (unless it is known at baseline that the subject does not have Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus [MRSA]).
• Drug: imipenem/cilastatin
  Imipenem/cilastatin 1g intravenous (IV) will be administered approximately every 8 hours, for up to 14 consecutive days. In addition vancomycin 15 mg/kg IV approximately every 12 hours (q12h), an aminoglycoside (tobramycin 7mg/kg daily or amikacin 20 mg/kg daily) and ceftazidime placebo will be given at the start of therapy (unless it is known at baseline that the subject does not have Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus [MRSA]).

• Experimental: A
  Intervention: Drug: tigecycline
• Experimental: B
  Intervention: Drug: tigecycline
• Active Comparator: C
  Intervention: Drug: imipenem/cilastatin

Inclusion Criteria:

• Male or female subjects, greater than or equal to 18 years of age, known or suspected to have acute hospital-acquired pneumonia (HAP).

• Acute HAP is defined as pneumonia with onset of symptoms:

  1. Greater than or equal to 48 hours after admission to an acute care hospital or chronic care facility such as a skilled nursing home facility or rehabilitation unit. Or
  2. Less than or equal to 7 days after the subject was discharged from the hospital. The initial hospitalization must have been greater than or equal to 3 days duration.
• VAP is defined as: onset of symptoms of pneumonia greater than or equal to 48 hours after endotracheal intubation.
• Presence of a new or evolving infiltrate on a chest x-ray film, presence of fever or leukocytosis, respiratory failure requiring mechanical ventilation or presence of 2 of the following clinical signs and symptoms: cough, dyspnea or tachypnea, pleuritic chest pain, rales and/or evidence of pulmonary consolidation, hypoxemia, or purulent sputum production.

Exclusion Criteria:

• Subjects with other significant underlying conditions that would make it difficult to evaluate the subjects or make it unlikely to complete the therapy or that would increase their risk by participating in the study, infection with organisms known to be resistant, contraindication, or hypersensitivity to any of the test articles.