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Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli

Information source: Kaye, Keith, M.D., M.P.H.
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pneumonia; Blood Stream Infection

Intervention: colistin and meropenem (Drug); colistin and placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Kaye, Keith, M.D., M.P.H.

Official(s) and/or principal investigator(s):
Keith S Kaye, MD, MPH, Principal Investigator, Affiliation: Wayne State University and the Detroit Medical Center

Overall contact:
Jolene Daniel, Phone: 3139660045, Email: jdanie@med.wayne.edu

Summary

Approximately 444 subjects who are greater than or equal to 18 to 95 years of age, are non-pregnant, and are in the inpatient setting of one of the study sites will be evaluated to treatment efficacy. Analysis will include subjects with bloodstream infection (BSI) or pneumonia due to at least one of the following gram-negative bacilli organisms: Acinetobacter baumannii, Klebsiella spp, Escherichia coli, Enterbactor spp. and/or Pseudomonas aeruginosa that demonstrates in vitro non-susceptibility defined as extensively drug-resistant Gram-negative bacilli (XDR-GNB) which includes XDR-AB, XDR-PA and CRE. If a subject has both BSI and pneumonia at the time of study enrollment, they will be included as a subject with pneumonia. Objectives: Primary: •Determine whether the treatment regimen of Colistimethate sodium (colistin) combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for mortality compared to colistin alone for subjects with bloodstream infection (BSI) and/or pneumonia due to XDR-GNB. Secondary: •Determine what treatment regimen (colistin monotherapy or colistin combined with a carbapenem (imipenem or meropenem) is more likely to reduce the emergence of colistin resistance among XDR-GNB isolates during therapy.

Clinical Details

Official title: Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: mortality

Secondary outcome: resistance

Detailed description: The Gram-negative bacilli organisms Acinetobacter baumannii, Klebsiella spp., Escherichia coli, Enterbactor spp. and Pseudomonas aeruginosa have become a frequent cause of bloodstream infection and pneumonia in the hospital and other healthcare settings. Among these pathogens, antimicrobial resistance has emerged to many classes of antimicrobial agents. Most concerning, has been the emergence of resistance to group 2 carbapenems (such as imipenem). In several regions of the world, including Southeastern Michigan, strains of extensively-drug resistant Gram-negative bacilli (XDR-GNB) that exhibit resistance to most, and in some cases all types of available antimicrobial agents, including group 2 carbapenems, have emerged and disseminated. Treatment options for XDR-GNB typically include Colistimethate sodium (referred to as colistin in this study), used alone (monotherapy) or in combination with other agents. Unfortunately, resistance to colistin has begun to emerge in some strains of XDR-GNB, which is a truly concerning development, since colistin is one of the last remaining treatment options for XDR-GNB. No prospective, randomized controlled trials have been conducted to evaluate the clinical efficacy of colistin monotherapy versus colistin-containing combination therapy or the impact of these therapeutic modalities on the emergence of colistin resistance among XDR-GNB. We plan to conduct a double-blind randomized controlled trial including patients with pneumonia and bloodstream infection due to XDR-GNB. After enrollment, subjects will be randomized to receive 14 days of either colistin monotherapy or colistin plus meropenem. In the Detroit metro area, infections due to XDR-GNB have developed into a regional challenge and common problem. We have assembled a multi-disciplinary team that includes Infectious Diseases researchers, clinicians, infectious diseases pharmacists, microbiologists, epidemiologists and statistical experts to address critically important questions and challenges regarding the management of bloodstream infection and pneumonia due to XDR-GNB. Specifically, we hypothesize that the combination of colistin and imipenem will provide superior efficacy in the treatment of XDR-GNB pneumonia and bloodstream infection and will prevent the emergence of decreased susceptibility to colistin among XDR-GNB strains. We also aim to analyze tools that could be used in "real time" to aid clinicians treating patients with infection due to XDR-GNB. For example, we aim to analyze the association between the presence of in vitro synergy of the colistin and carbapenem (imipenem or meropenem) combination (as determined by E-test) and clinical outcomes; and the association between colistin plasma levels and clinical outcomes and the development of nephrotoxicity.

Eligibility

Minimum age: 18 Years. Maximum age: 95 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Hospitalized Adults (> 18 years to 95 years of age), at one of the study sites.

- Diagnosis of BSI and/or pneumonia due to a preliminary result of gram-negative

non-lactose fermenter that is oxidase negative; or a final results of XDR-A. baumannii; carbapenem-resistant Enterobacteriaciae; or XDR- P. aeruginosa and/or patients with suspected BSI and/or HAP and who have had a prior history (within last 6 months) of XDR-GNB that was susceptible to colistin. o If final results do not indicate that the pathogen is an XDR-GNB, and identifies alternative treatment options, the patient would be eligible for the study if the subject is allergic to all the alternative treatment options.

- Patients with polymicrobial respiratory or blood infections, including XDR-GNB and

one or more pathogens, will be included in the study, as long as the XDR-GNB is determined to be a true pathogen (AB, CRE or PA). Other pathogens will be treated with antimicrobial agents as determined by the treating physician.

- If more than one XDR-GNB study pathogens is identified as a study pathogen causing

BSI and/or pneumonia, then the first study pathogen recovered will be considered as the primary study pathogen. If more than one study pathogen is recovered from the same culture, then the infection will be categorized as being caused by multiple study pathogens.

- Patients with a life expectancy of > 24 hours

- Signed written informed consent and HIPAA Authorization form (US sites)

Exclusion Criteria:

- Female patients who are pregnant

- Female patients who are nursing

- Patients who are prisoners

- Patients who are less than 18 years of age or greater than or equal to 96 years of

age

- Patients with neutropenia (WBC < 500 cells/mm3)

- The presence of any of the following known clinical syndromes involving XDR-GNB as a

pathogen which necessitate durations of antimicrobial therapies greater than 14 days: endocarditis, osteomyelitis, prosthetic joint infections, meningitis and/or other central nervous system infections.

- Patients receiving valproic acid (with or without a known seizure disorder).

- Patients who received 72 hours or more of polymyxin treatment (intravenous or inhaled

[pneumonia]) within 96 hours of enrollment.

- Patients who have end-stage renal disease requiring hemodialysis, will be excluded

from evaluation pertaining to nephrotoxicity in the per protocol population.

- Patients with known Type 1 or other severe drug allergy to either of the study drugs

or to β-lactams.

Locations and Contacts

Jolene Daniel, Phone: 3139660045, Email: jdanie@med.wayne.edu

Sirraj Hospital, Bangkoknoi, Bangkok 10700, Thailand; Recruiting
Visanu Thamlikitkul, MD, Email: sivth@mahidol.ac.th
Visanu Thamlikitkul, MD, Principal Investigator

Assaf Harofeh Medical Center, Zerifin, Beer Yaakov 70300, Israel; Recruiting
Dror Marchaim, MD, Email: drormarchaim@asaf.health.gov.il

Jackson Memorial Hospital-Jackson Health System, Miami, Florida 33136, United States; Recruiting
Daniel Kett, MD, Phone: 305-585-6820, Email: dkett@med.miami.edu
Daniel Kett, MD, Principal Investigator

Henry Ford Health System, Detroit, Michigan 48202, United States; Terminated

Wayne State University, Detroit, Michigan 48201, United States; Recruiting
Jolene Daniel, Phone: 313-966-0045, Email: jdanie@med.wayne.edu
Keith Kaye, MD, MPH, Principal Investigator

Beaumont Health System, Royal Oak, Michigan 48073, United States; Recruiting
Matt Sims, MD, PhD, Phone: 248-551-0027, Email: matthew.sims@beaumont.edu
Matthew Sims, MD, PhD, Principal Investigator

Mount Sinai Hospital, New York, New York 10029, United States; Recruiting
Gopi Patel, MD, MS, Phone: 212-659-9566, Email: gopi.patel@mssm.edu
Gopi Patel, MD, MS, Principal Investigator

New York Presbyterian-Weill Cornell Medical Center, New York, New York 10065, United States; Recruiting
David Calfee, MD, MS, Phone: 212-746-1864, Email: dpc9003@med.cornell.edu
David Calfee, MD, MS, Principal Investigator

The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, United States; Terminated

Chang Gung Memorial Hospital, Kweishan Township, Taoyuan County 33305, Taiwan; Recruiting
Cheng-Hsun Chiu, MD, Email: chchiu@admin.cgmh.org.tw

Additional Information

Starting date: October 2012
Last updated: July 28, 2015

Page last updated: August 23, 2015

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