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Clinical Trials to Reduce the Risk of Antimicrobial Resistance

Information source: University of Florida
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Bacterial Pneumonia

Intervention: IV meropenem; parenteral aminoglycoside (Drug); I.V. Meropenem (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Florida

Official(s) and/or principal investigator(s):
George L Drusano, MD, Principal Investigator, Affiliation: University of Florida

Overall contact:
George L. Drusano, M.D., Phone: 407-313-7060, Email: gdrusano@ufl.edu


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).

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp

Secondary outcome:

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

A pharmacodynamic relationship between meropenem exposure in plasma and extracellular lung fluid (ELF)

28 day all-cause mortality between the treatment groups.

Microbiological response at EOT, TOC and LFU between treatment groups.

Rates of pathogen response to those seen in the control arm.

Rates of resistance of other Gram-negative bacteria (non-Pseudomonas or Acinetobacter spp) between treatment groups.

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.

Clinical outcome in proportion of subjects who received prior antibiotics vs. those with no prior antibiotics

Health care resource utilization (length of ICU stay, antibiotic usage, length of hospitalization, and duration of ventilation) between treatment groups.

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.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


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.

Locations and Contacts

George L. Drusano, M.D., Phone: 407-313-7060, Email: gdrusano@ufl.edu

Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere, Paris Cedex 13, France; Recruiting
Jean Chastre, MD, Phone: 011+33 142163822, Email: jean.chastre@psl.ap-hop-paris.fr
Alain Combes, MD, Phone: 011+33 142163818, Email: alain.combes@psl.aphp.fr
Jean Chastre, MD, Principal Investigator

Hannover Clinical Trial Center GmbH, Hannover 30625, Germany; Active, not recruiting

Medizinische Hochschule, Hannover 30625, Germany; Withdrawn

Hospital Vall d'Hebron, Barcelona 08035, Spain; Recruiting
Jordi Rello, MD, Phone: 34 932746209, Email: jrello@crips.es; jrello@vhebron.net
Cristopher Mazo, MD, Phone: 34 932746209, Email: mazotorre.vhir@gmail.com
Jordi Rello, MD, Principal Investigator

InClin, Inc., San Mateo, California 94403, United States; Active, not recruiting

UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine, Gainesville, Florida 32610, United States; Recruiting
Hassan Alnuaimat,, MD, Phone: 352-273-8740, Email: alnuah@medicine.ufl.edu
Brooks E Morgan, RN, Phone: 352-273-5870, Email: Brooks.Morgan@medicine.ufl.edu
Hassan Alnuaimat, MD, Principal Investigator

Emory University, Atlanta, Georgia 30322-4250, United States; Recruiting
Kenneth Leeper, MD, Phone: 404-686-6782, Email: Ken.Leeper@emoryhealthcare.org
Mona Brown, RN, Phone: 404-686-1956, Email: Mona.Brown@emory.edu
Kenneth Leeper, MD, Principal Investigator

Northwestern University, Chicago, Illinois 60611, United States; Recruiting
Richard Wunderink, MD, Phone: 312-695-1878, Email: r-wunderink@northwestern.edu
Helen Donnelly, RN, Phone: 312-695-1881, Email: h-donnelly@northwestern.edu
Richard Wunderink, MD, Principal Investigator

JMI Laboratories, North Liberty, Iowa 52317, United States; Active, not recruiting

Washington University in St. Louis School of Medicine, St. Louis, Missouri 63130, United States; Recruiting
Marin H Kollef, MD, Phone: 314-454-8764, Email: MKOLLEF@DOM.wustl.edu
Lisa Mayfield, RN, Phone: 314 286-1550, Email: mayfieldl@wusm.wustl.edu
Marin H Kollef, MD, Principal Investigator

Weill Cornell Medical Center of Cornell University, New York, New York 10065, United States; Recruiting
Thomas J Walsh, MD, Phone: 301-693-1890, Email: thw2003@med.cornell.edu
Krisztina Skoba, RN, Phone: 301-693-1890, Email: krs2023@med.cornell.edu
Thomas J Walsh, MD, Principal Investigator

Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, United States; Recruiting
Robert D Hite, MD, Phone: 336-716-8898, Email: hited@ccf.org
Michelle Ferrari, RN, Phone: 216-444-4000, Email: FERRARM1@ccf.org
Robert D Hite, MD, Principal Investigator

Additional Information

Related publications:

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Starting date: January 2013
Last updated: January 21, 2015

Page last updated: August 23, 2015

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