Clinical trial NCT01570192
Conditions: Bacterial Pneumonia
Keywords: gram negative pathogens Pseudomonas aeruginosa Acinetobacter HCAP VABP HABP
Sponsor: University of Florida
Start date: 2010-09-01; Completion date: 2015-04-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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).

Detailed description:
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.

Arms: arm 1: Subjects assigned to this group will receive:

* IV meropenem (2 g infused over 3 hrs q 8 hr);
* a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
* tobramycin nebulization

Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens. arm 2: 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 to treat Gram-positive pathogens.

\*\*NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.
Interventions: intervention 1: IV meropenem intervention 2: I.V. Meropenem intervention 3: 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 intervention 4: Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage. intervention 5: tobramycin nebulization
Intervention descriptions: intervention 1: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). intervention 2: 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 intervention 3: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) intervention 4: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage. intervention 5: tobramycin nebulization 600mg/day

Protocol documents: