In this study, we will be assessing the efficacy and safety of tigecycline compared with imipenem/cilastatin in subjects hospitalized with nosocomial pneumonia. Imipenem/cilastatin is a potent broad-spectrum intravenous (IV) antibacterial agent approved for the treatment of serious or severe infections, including lower respiratory tract infections.

The study population will consist of subjects with nosocomial pneumonia known or suspected to be caused by gram-positive and/or gram-negative bacteria.

Condition	Treatment or Intervention	Phase
Pneumonia	Drug: Tigecycline  Drug: Imipenem  Drug: Cilastatin	Phase III

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Male or female subjects ≥ 18 years of age. BULGARIA Only: Male or female subjects ≥ 18 years of age and ≤ 70 years of age.
• Subjects known or suspected to have acute hospital-acquired pneumonia. Acute hospital-acquired pneumonia is defined as pneumonia with onset of symptoms: a. ≥ 48 hours AFTER admission to an acute care hospital or chronic care facility such as a skilled nursing home facility or rehabilitation unit. b. ≤ 7 days after a subject is discharged from the hospital. The subject’s initial hospitalization must have been ≥ 3 days duration.
• Presence of a new or evolving infiltrate on a chest x-ray film. The chest xray must be obtained ≥ 48 hours after the subject was admitted to the hospital or chronic care facility. The infiltrate must not be related to another disease process or condition (for example, congestive heart failure or acute respiratory distress syndrome). If a CT scan was used to determine the presence of a new or evolving infiltrate in the lungs and a chest x-ray had not been obtained, a chest x-ray showing an infiltrate must be obtained prior to study entry.
• The presence of: a. Fever (within 24 hours prior to randomization) defined as an oral temperature > 38°C/100.4°F, tympanic temperature > 38.5°C/101.2°F, axillary temperature ≥ 38.1°C/100.6°F, or a rectal/core temperature > 39°C/102.2°F) or hypothermia defined as rectal/core body temperature < 35°C/95.2°F OR b. Leukocytosis [white blood cell count (WBC) > 10 x 109/L (> 10,000/mm3)]; or > 15% immature neutrophils [bands]; or leukopenia with total WBC < 4.5 x 109/L (< 4,500/mm3).
• Presence of at least 2 of the following: a. Cough; b. Dyspnea, tachypnea (respiratory rate ≥ 30 per minute), particularly if any or all of these are progressive; c. Pleuritic or inspiratory chest pain; d. Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony); e. Hypoxemia with a PO2 < 60 mmHg or oxygen saturation < 90% while the subject is breathing room air, as determined by pulse oximetry or arterial blood gas; f. Purulent sputum production or respiratory secretion or a change in sputum character occurring ≥ 48 hours after hospitalization; OR g. Respiratory failure requiring mechanical ventilation, in lieu of having 2 of the clinical signs and symptoms listed for criterion # 5.
• At time of randomization, all subjects should have a respiratory tract specimen obtained for Gram stain and culture. The respiratory tract specimen may be obtained by the following means listed below: a. Deep expectoration; b. Nasotracheal aspiration; c. Endotracheal aspirated/suctioned specimen; d. Bronchoscopy with bronchoalveolar lavage; e. Bronchoscopy with protected-brush sampling; f. Bronchoscopy with distal protected specimen; g. Pleurocentesis with pleural fluid specimen; h. Transtracheal aspiration; If pleural fluid is obtained, another respiratory tract specimen should also be obtained, if possible. Microscopic examination of the Gram-stained respiratory secretions obtained by deep expectoration or nasotracheal aspiration should show < 10 squamous epithelial cells and > 25 polymorphonuclear cells per field at 100X magnification (low-power, 10X objective) for suitability for culture. All specimens obtained by invasive methods should be cultured. Whenever possible, quantitative culture results (cfu/mL) should be reported for respiratory tract specimens (except for pleural fluid). If quantitative culture results are not available, semi-quantitative results will be accepted.
• Institutional Review Board or Independent Ethics Committee approved, signed and dated informed consent form. Informed consent form (ICF) will be obtained from each subject prior to participation in this research study. If any subject is unable to give consent, it may be obtained from the subject’s next of kin or legal representative in accordance with local laws and regulations.

Exclusion Criteria:

• Presence of any of the following pulmonary conditions: cystic fibrosis; pulmonary malignancy (either primary or metastatic); known bronchial-obstructive or post-obstructive pneumonia; pulmonary abscess; empyema; known or suspected active tuberculosis; bronchiectasis; sarcoidosis; known or suspected pulmonary infection caused by Pneumocystis carinii, mycobacteria, fungi, parasites, or viruses. (Subjects with COPD are not excluded).
• Suspected or known Legionella infection.
• Concurrent hemodialysis, hemofiltration, peritoneal dialysis, or plasmapheresis.
• At time of randomization, presence of sustained shock, defined as: a. systolic blood pressure < 90 mm Hg for > 2 hours despite adequate fluid replacement, with evidence of hypoperfusion or b. need for sympathomimetic agents to maintain blood pressure. Note: The use of sympathomimetic agents to maintain adequate renal perfusion is allowed.
• Known or suspected hypersensitivity to, or inability to receive, tigecycline, tetracyclines, vancomycin, ceftazidime, imipenem/cilastatin, any aminoglycoside, and penicillin or other compounds related to these classes of antibacterial agents.
• Concomitant treatment with ganciclovir.
• Presence or history of brain lesions or presence of any uncontrolled central nervous system (CNS) disease, including epilepsy or unexplained seizures that, in the opinion of the investigator, would predispose subjects to imipenem-associated CNS adverse events, such as seizures or confusional states.
• APACHE II score > 30.
• Presence of any of the following laboratory findings: a. Neutropenia defined as an absolute neutrophil count < 1 X 109/L (< 1000/mm^3). b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 10 times the upper limit of normal. c. Total bilirubin or alkaline phosphatase (AP) > 3 times the upper limit of normal, unless isolated hyperbilirubinemia was directly related to the acute process d. Calculated creatinine clearance (CLCR) < 41mL/min/1.73m^2 after adequate hydration. CLCR may be calculated from the serum creatinine concentration by the following equation, if serum creatinine is reported in mg/dL: Male: CLCR (mL/min) = (140 – age [years]) x weight [kg] 72 x serum Cr (mg/dL) Female: CLCR (mL/min) = 0.85 x CLCrmale (derived by above formula) If serum creatinine level is reported in µmol/L, the following formula will be used: Male: CLCR (mL/min) = (140 – age [years]) x weight [kg] 0.81 x serum Cr (µmol/L) Female: CLCR (mL/min) = 0.85 x CLCrmale (derived by above formula) BSA (m^2) = (weight [kg])0.425 x (height [cm])0.725 x 0.007184 (CLCR x1.73)/BSA= mL/min/1.73 m^2
• Anticipated discharge from the hospital in less than 7 days or the likelihood that the subject will not complete the course of treatment or follow-up.
• Known or suspected concomitant bacterial infection requiring additional systemic antibacterial treatment.
• Antibacterial drugs administered for > 24 hours to treat the current episode of suspected hospital-acquired pneumonia, UNLESS a repeat respiratory culture showed that a pathogen was resistant to that agent and/or the subject had worsening or no improvement in the clinical signs and symptoms of pneumonia. Note: Patient may not have failed one of the study medications or an agent of the same class.
• Any investigational drugs taken or investigational devices used within 4 weeks before the first dose of test article. An investigational product is defined as lacking FDA or regional/local regulatory approved indications.
• Known human immunodeficiency virus (HIV) infection
• Immunosuppressive therapy that, in the opinion of the investigator, would decrease the subject’s ability to eradicate the infection (including chronic treatment with >10 mg/day of systemic prednisone or equivalent for greater than 3 weeks prior to randomization).
• Life expectancy estimated at < 1 month
• Pregnant women or nursing mothers
• Female subjects of childbearing potential who do not agree to practice sexual abstinence or use a medically acceptable method of contraception throughout the duration of the study and for at least 1 month after the last dose of test article administration.
• Any other major illness/condition that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in, and completion of, the study, or could preclude the evaluation of the subject’s response.

Arizona
      St. Joseph's Hospital and Medical Center, Phoenix,  Arizona,  85013,  United States; Recruiting
      St. Lukes Medical Center, Phoenix,  Arizona,  85006,  United States; Recruiting
      Scottsdale Healthcare Osborn, Scottsdale,  Arizona,  85251-6403,  United States; Recruiting
      Scottsdale Healthcare Shea, Scottsdale,  Arizona,  85260-6709,  United States; Recruiting
California
      Paradise Valley Hospital, National City,  California,  91950,  United States; Recruiting
      Doctor's Medical Center, Modesto,  California,  95350,  United States; Recruiting
      Memorial Medical Center, Modesto,  California,  95355,  United States; Recruiting
      VA Northern California Health Care System, Martinez,  California,  94553,  United States; Recruiting
Florida
      Alachua General Hospital, Gainesville,  Florida,  32601,  United States; Recruiting
      Bay Pines VA Medical Center, Bay Pines,  Florida,  33744,  United States; Recruiting
      Seven Rivers Community Hospital, Crystal River,  Florida,  34428,  United States; Recruiting
      Department of Surgical Education, Orlando,  Florida,  32806,  United States; Recruiting
Georgia
      Joseph M. Still Burn Center at Doctors Hospital, Augusta,  Georgia,  30909,  United States; Recruiting
      North Fulton Regional Hospital, Roswell,  Georgia,  30076,  United States; Recruiting
      Northside Hospital, Atlanta,  Georgia,  30342,  United States; Recruiting
Illinois
      Jackson Park Hospital, Chicago,  Illinois,  60610,  United States; Recruiting
      St. John's Hospital, Springfield,  Illinois,  62769,  United States; Recruiting
      Memorial Medical Center, Springfield,  Illinois,  62781,  United States; Recruiting
Louisiana
      Louisiana State University Health Sciences Center- Shreveport, Shreveport,  Louisiana,  71103,  United States; Recruiting
      Medical Center of La. in N.O., New Orleans,  Louisiana,  70112,  United States; Recruiting
      Louisiana State University Health Sciences Center- Shreveport, Shreveport,  Louisiana,  71103,  United States; Recruiting
Maryland
      Baltimore VA Medical Center, Baltimore,  Maryland,  21201,  United States; Recruiting
Missouri
      University of Missouri Health Care, Columbia,  Missouri,  65212,  United States; Recruiting
Nebraska
      Nebraska Medical Center, Omaha,  Nebraska,  68198-5300,  United States; Recruiting
North Carolina
      Maria  Parham  , Henderson,  North Carolina,  27536,  United States; Recruiting
Ohio
      Genesis Bethesda Hospital, Zanesville,  Ohio,  43071,  United States; Recruiting
      University of Cincinnati Medical Center, Cincinnati,  Ohio,  45219,  United States; Recruiting
Pennsylvania
      Temple University Hospital, Philadelphia,  Pennsylvania,  19140,  United States; Recruiting
      Hahnemann Hospital, Philadelphia,  Pennsylvania,  19102,  United States; Recruiting
South Carolina
      Greenville Hospital System, Greenville,  South Carolina,  29605,  United States; Recruiting

Study ID Numbers:  3074A1-311-WW
Record last reviewed:  January 2005
Last Updated:  January 26, 2005
Record first received:  April 5, 2004
ClinicalTrials.gov Identifier:  NCT00080496
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08