Clinical Trials to Reduce the Risk of Antimicrobial Resistance

• Efficacy(clinical outcome) and safety (numbers of SAEs) of PD optimized/combination therapy (Group 1) of meropenem (2g infused over 3 hours Q8h) plus aminoglycoside parenterally [ Time Frame: Test-of-Cure Visit (TOC, 7-14 days post therapy) and Late-Follow-Up (LFU 14 days after test of cure or up to 42 ± 3 days after study drug initiation) ] [ Designated as safety issue: No ]
  The efficacy and safety of PD optimized/combination therapy (Group 1) of meropenem (2g infused over 3 hours Q8h) plus aminoglycoside parenterally (tobramycin/or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kgIV Q 24h) plus tobramycin nebulization in the treatment of hospitalized subjects with pneumonia requiring mechanical ventilation caused by P. aeruginosa, Acinetobacter spp, (or other Gram-negative pathogens) when compared to the Group 2 (control arm) of monotherapy meropenem
• A pharmacodynamic relationship between meropenem exposure in plasma and extracellular lung fluid (ELF) [ Time Frame: Patients will participate up to 45 days ] [ Designated as safety issue: No ]
• 28 day all-cause mortality between the treatment groups. [ Time Frame: Late-Follow-Up (LFU, 30 (±2) days Post Therapy) ] [ Designated as safety issue: No ]
• Microbiological response at EOT, TOC and LFU between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
• Rates of pathogen response to those seen in the control arm. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
• Rates of resistance of other Gram-negative bacteria (non-Pseudomonas or Acinetobacter spp) between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
• The proportion of subjects whose repeat cultures are negative (e.g. rates of clearance of bacterial infection) at Day 5 between treatment groups and among fermentor and non-fermentor pathogens. [ Time Frame: Day 5/EE ] [ Designated as safety issue: No ]
• Clinical outcome in proportion of subjects who received prior antibiotics vs. those with no prior antibiotics [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
• Health care resource utilization (length of ICU stay, antibiotic usage, length of hospitalization, and duration of ventilation) between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]

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).

The goal of this clinical study is to demonstrate that the application of pharmacodynamic dosing principles to the antibiotic treatment of hospitalized subjects with culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect by β lactam antibiotics such as meropenem is the proportion of the dosing interval during which plasma drug levels are maintained above the MIC of the causative pathogen. The hypothesis of this study is that prolongation of time above MIC by increasing total meropenem dose and the duration of infusion will counter-select for the emergence of antimicrobial resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides (amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along optimal pharmacodynamic principles will further reduce the likelihood of resistance emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem will be compared across therapeutic regimens.

• Drug: IV meropenem; parenteral aminoglycoside
  Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization
  Other Names:

  • Merrem I.V.
  • Tobramycin for Injection USP
  • Tobramycin Inhalation Solution USP
  • Gentamicin Sulfate, Injection Solution Concentrate
  • Amikacin Sulfate Injection USP
• Drug: I.V. Meropenem
  Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
  Other Name: Merrem I.V.

• Experimental: IV meropenem; parenteral aminoglycoside
  Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization
  Intervention: Drug: IV meropenem; parenteral aminoglycoside
• Active Comparator: I.V. Meropenem
  Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
  Intervention: Drug: I.V. Meropenem

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Inclusion criteria:

• Written informed consent by the subject/subject's legal rep.
• Hospitalized males or females, ≥ 18 yrs with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP.
• Onset of exacerbation of pneumonia at least 72 hours after admission to an acute 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 and they are instructed to abstain from sexual intercourse for the duration of the study;or contraceptive measures are used until all follow-up procedures are complete.
• 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.
• 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 24 hours before the start of empiric study therapy, a quantitative culture of BAL fluid must be obtained.
• Patients with VABP should have a CPIS of greater than 6, and at least one of the following present at enrollment:auscultatory findings on pulmonary exam of rales and/or evidence of pulmonary consolidation; acute changes made in the ventilator support system to enhance oxygenation, as determined by arterial blood gas, or worsening PaO2/FiO2.

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 known or suspected type I hypersensitivity (e.g., anaphylaxis) to cephalosporins, penicillins, monobactams, or carbapenems.
• Women who are pregnant or lactating.
• Subjects taking anticonvulsant medications for a known seizure disorder.
• 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, acquired immune deficiency syndrome (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.