Clinical Trials to Reduce the Risk of Antimicrobial Resistance
Condition: Bacterial Pneumonia
MeSH terms: Pneumonia; Pneumonia, Bacterial
Intervention: IV meropenem; I.V. Meropenem; Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h; Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.; tobramycin nebulization
Intervention description: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).; Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage; a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h); Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.; tobramycin nebulization 600mg/day
Intervention MeSH terms: Vancomycin; Gentamicins; Meropenem; Linezolid; Tobramycin; Amikacin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking description: This is an open-label study with 1:1 randomization between two active treatment groups.
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: gram negative pathogens; Pseudomonas aeruginosa; Acinetobacter; HCAP; VABP; HABP

Summary:

      The primary objective of this study is to demonstrate a low rate of emergence of antibiotic
      resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized
      patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem
      administered as a prolonged infusion in combination with a parenteral aminoglycoside plus
      tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 -
      control arm).
    

Eligibility criteria:

        Inclusion criteria:

        Written informed consent by the subject/subject's LAR.

        Hospitalized males or females ≥ 18 yrs with respiratory failure requiring mechanical
        ventilation and clinical suspicion of HABP, HCAP or VABP.

        Onset or exacerbation of pneumonia at least 48 hours after admission to any patient health
        care facility or onset of pneumonia in a nursing home or rehabilitation facility with
        subsequent transfer to an acute care facility

        Women of childbearing potential if their pregnancy test is negative

        Subjects who have received previous antibacterial therapy within 14 days of pre-treatment
        bronchoscopy entry may be entered only if the subject has not responded clinically.). While
        less than 24 hours of pre-treatment antibiotics is preferential, recovery of >104 CFU/ml in
        the quantitative Bronchoscopic BAL will be seen as primary evidence that the prior therapy
        was not efficacious and enrollment will be allowed.)

        Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP:

        Within 48 hours before starting empiric therapy a subject's chest radiograph should show
        the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of
        pneumonia

        Within 36 hours before the start of empiric study therapy, a quantitative culture of
        Bronchoscopic BAL fluid must be obtained.

        Patients with VABP should have a Clinical Pulmonary Infection Score of >/= 5.

        Exclusion Criteria:

        Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or
        equal to 16µg/ml) or a prior meropenem therapy failure.

        Subjects with contra-indications to ANY study medication, in particular with known or
        suspected allergy or hypersensitivity.

        Women who are pregnant or lactating.

        Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a
        history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled
        into the study at the discretion of the site investigator.

        Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral
        pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of
        pneumonia.

        Subjects with primary lung cancer or another malignancy metastatic to the lungs.

        Subjects who were previously enrolled in this study.

        Subjects who have had an investigational drug or have used an investigational device within
        30 days prior to entering the study.

        Subjects with another focus of infection requiring concurrent antibiotics that would
        interfere with evaluation of the response to study drug.

        Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count <200 cells/µl, neutropenia
        (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.

        Subjects with little chance of survival for the duration of study therapy.

        Subjects with an APACHE II score >35.

        Subjects with underlying condition(s) which would make it difficult to interpret response
        to the study drugs.

        Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects
        requiring ongoing treatment with vasopressors will be eligible for the study if their
        hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock
        are not eligible for enrollment.

        Subjects who have undergone bone marrow transplantation.

        Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.