Clinical trial NCT01570192: Clinical Trials to Reduce the Risk of Antimicrobial Resistance
Official title: Impact of Aggressive Empiric Antibiotic Therapy and Duration of Therapy on the Emergence of Antimicrobial Resistance During the Treatment of Hospitalized Subjects With Pneumonia Requiring Mechanical Ventilation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Bacterial Pneumonia
Keywords: gram negative pathogens
Pseudomonas aeruginosa
Acinetobacter
HCAP
VABP
HABP
Lead sponsor: University of Florida
Sponsor class: OTHER
First posted: 2012-04-04
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Suppression and Emergence of Resistance
timeFrame: up to 28 days after enrollment
Secondary outcomes:
measure: Clinical Response
timeFrame: End of treatment - up to 28 days after enrollment
measure: Clinical Response in Subjects Who Received Prior Antibiotics
timeFrame: End of treatment - up to 28 days after enrollment
measure: Overall Microbiologic Response
timeFrame: End of treatment - up to 28 days after enrollment
measure: Pretreatment Pathogen Response
timeFrame: End of treatment - up to 28 days after enrollment
measure: Suppression of the Emergence of Resistance in Other Gram-negative Pathogens
timeFrame: Day 5/Early Extubation
measure: Occurrence of Repeat Negative Cultures
timeFrame: Day 5/Early Extubation
measure: Mortality
timeFrame: 14 days
measure: Mortality
timeFrame: 28 days
Other outcomes:
Locations:
city: San Mateo
country: United States
facility: InClin, Inc.
state: California
city: Gainesville
country: United States
facility: UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: North Liberty
country: United States
facility: JMI Laboratories
state: Iowa
city: Saint Louis
country: United States
facility: Washington University in St. Louis School of Medicine
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medical Center of Cornell University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Lerner College of Medicine
state: Ohio
city: Paris
country: France
facility: Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere
city: Hannover
country: Germany
facility: Hannover Clinical Trial Center GmbH
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
Study officials:
affiliation: University of Florida
name: George L Drusano, MD
role: PRINCIPAL_INVESTIGATOR
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