Clinical Trials to Reduce the Risk of Antimicrobial Resistance
- Conditions
- Bacterial Pneumonia
- Interventions
- Drug: Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24hDevice: tobramycin nebulization
- Registration Number
- NCT01570192
- Lead Sponsor
- University of Florida
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 43
Not provided
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description IV meropenem; parenteral aminoglycoside Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage. 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. IV meropenem; parenteral aminoglycoside IV meropenem 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. IV meropenem; parenteral aminoglycoside 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 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. IV meropenem; parenteral aminoglycoside tobramycin nebulization 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. I.V. Meropenem Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage. 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. I.V. Meropenem I.V. Meropenem 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.
- Primary Outcome Measures
Name Time Method Number of Participants With Suppression and Emergence of Resistance up to 28 days after enrollment The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.
- Secondary Outcome Measures
Name Time Method Clinical Response End of treatment - up to 28 days after enrollment Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Clinical Response in Subjects Who Received Prior Antibiotics End of treatment - up to 28 days after enrollment Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Overall Microbiologic Response End of treatment - up to 28 days after enrollment Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Pretreatment Pathogen Response End of treatment - up to 28 days after enrollment Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Suppression of the Emergence of Resistance in Other Gram-negative Pathogens Day 5/Early Extubation Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Occurrence of Repeat Negative Cultures Day 5/Early Extubation Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Mortality 28 days Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
Trial Locations
- Locations (11)
UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine
🇺🇸Gainesville, Florida, United States
InClin, Inc.
🇺🇸San Mateo, California, United States
Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere
🇫🇷Paris, France
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
Northwestern University
🇺🇸Chicago, Illinois, United States
Hannover Clinical Trial Center GmbH
🇩🇪Hannover, Germany
Weill Cornell Medical Center of Cornell University
🇺🇸New York, New York, United States
JMI Laboratories
🇺🇸North Liberty, Iowa, United States
Washington University in St. Louis School of Medicine
🇺🇸Saint Louis, Missouri, United States
Cleveland Clinic Lerner College of Medicine
🇺🇸Cleveland, Ohio, United States
Emory University
🇺🇸Atlanta, Georgia, United States