Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli
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 six 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.
•Determine whether the treatment regimen of Colistimethate sodium (colistin) combined with Imipenem-cilistatin (imipenem) is associated with a decreased risk for mortality compared to colistin alone for patients with bloodstream infection (BSI) and/or pneumonia due to XDR-GNB.
•Determine what treatment regimen (colistin monotherapy or colistin combined with imipenem) is more likely to reduce the emergence of colistin resistance among XDR-GNB isolates during therapy.
Blood Stream Infection
Drug: colistin and imipenem
Drug: colistin and placebo
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli|
- mortality [ Time Frame: participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: Yes ]Determine whether the treatment regimen of Colistimethate sodium (colistin) combined with Imipenem-cilistatin (imipenem) is associated with a decreased risk for mortality compared to colistin alone for patients with bloodstream infection (BSI) and/or pneumonia due to XDR-GNB.
- resistance [ Time Frame: patients resistance data will be collected at 28 days ] [ Designated as safety issue: No ]Determine what treatment regimen (colistin monotherapy or colistin combined with imipenem) is more likely to reduce the emergence of colistin resistance among XDR-GNB isolates during therapy.
|Study Start Date:||October 2012|
|Estimated Study Completion Date:||September 2017|
|Estimated Primary Completion Date:||August 2016 (Final data collection date for primary outcome measure)|
|Active Comparator: colistin and imipenem||
Drug: colistin and imipenem
colistin standard loading dose, maintenance dose based on patients renal function imipenem- dose based on patients renal function
|Active Comparator: colistin and placebo||
Drug: colistin and placebo
colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic imipenem (blinded)
Other Name: Colstimethate
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 imipenem.
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 imipenem combination (as determined by E-test) and clinical outcomes; and the association between colistin plasma levels and clinical outcomes and the development of nephrotoxicity.
|Contact: Debbie DeCamillo, RN, BSNemail@example.com|
|United States, Michigan|
|Wayne State University||Recruiting|
|Detroit, Michigan, United States, 48201|
|Contact: Debbie DeCamillo, BSN, RN 313-966-0045 firstname.lastname@example.org|
|Principal Investigator: Keith Kaye, MD, MPH|
|Henry Ford Health System||Recruiting|
|Detroit, Michigan, United States, 48202|
|Contact: Laura Johnson, MD 313-916-2565 LJOHNS14@hfhs.org|
|Contact: Marc Zervos, MD 313-916-2565 MZERVOS1@hfhs.org|
|Principal Investigator: Laura Johnson, MD|
|Principal Investigator:||Keith S Kaye, MD, MPH||Wayne State University and the Detroit Medical Center|