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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01597973
Recruitment Status : Recruiting
First Posted : May 15, 2012
Last Update Posted : September 26, 2019
Information provided by (Responsible Party):
Keith Kaye, University of Michigan

Brief 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.



•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.


•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.

Condition or disease Intervention/treatment Phase
Pneumonia Blood Stream Infection Drug: colistin and meropenem Drug: colistin and placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 444 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli
Study Start Date : October 2012
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia

Arm Intervention/treatment
Active Comparator: colistin and meropenem Drug: colistin and meropenem
colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function
Other Names:
  • Colistimethate
  • Meropenem

Active Comparator: colistin and placebo Drug: colistin and placebo
colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)
Other Name: Colstimethate

Primary Outcome Measures :
  1. mortality [ Time Frame: participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks ]
    Determine whether the treatment regimen of colistin combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for all-cause mortality during the 30 day post-enrollment period compared to colistin alone for subjects with bloodstream infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).

Secondary Outcome Measures :
  1. resistance [ Time Frame: patients resistance data will be collected at 28 days ]
    Determine what treatment regimen (colistin monotherapy or colistin combined a carbapenem (imipenem or meropenem)is more likely to reduce the frequency of emergence of colistin resistance among XDR-GNB isolates during therapy.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01597973

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Contact: Jolene Daniel, CCRP 734-615-1901

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United States, Florida
Jackson Memorial Hospital-Jackson Health System Terminated
Miami, Florida, United States, 33136
United States, Michigan
Wayne State University Recruiting
Detroit, Michigan, United States, 48201
Contact: Sorabh (Rob) Dhar, MD    313-966-0045   
Principal Investigator: Sorabh (Rob) Dhar, MD         
Henry Ford Health System Terminated
Detroit, Michigan, United States, 48202
Beaumont Health System Terminated
Royal Oak, Michigan, United States, 48073
United States, New York
Mount Sinai Hospital Terminated
New York, New York, United States, 10029
New York Presbyterian-Weill Cornell Medical Center Withdrawn
New York, New York, United States, 10065
United States, Ohio
The Ohio State University Wexner Medical Center Terminated
Columbus, Ohio, United States, 43210
University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov" Recruiting
Sofia, Bulgaria, 1606
Contact: Dora Tancheva, MD    +359 2 915 4414   
Contact: Emil Aleksiev, MD    +359 898 660 034   
Thriassio General Hospital of Elefsina "Latsio" Not yet recruiting
Magoula-Elefsina, Elefsina, Greece, 19018
Contact: Styliani Sympardi, MD    +30 21 3202 8497   
Contact: Nikolaos Markou, MD    +30 69 764 0 4627   
Evangelismos General Hospital of Athens Recruiting
Athens, Greece, 10676
Contact: Anastasia Kotanidou, MD    +30 69 7707 7105   
Contact: Edison Jahaj, MD    +30 69 4688 0747   
General Hospital of Athens "Laiko" 1st Department of Medicine Recruiting
Athens, Greece, 11527
Contact: George Daikos, MD    +30 21 3206 1821   
Contact: Eirini Daikou    +30 69 4598 5395   
Attikon University General Hospital of Athens Recruiting
Athens, Greece, 12461
Contact: Sotirios Tsiodras, MD    +302105831935   
Contact: Georgia Dougekou, MD    306937107054   
University Hospital of Heraklion Recruiting
Crete, Greece, 71110
Contact: Achilleas Gikas, MD    +30 28 1037 5050   
Contact: Vangelis Maridakis    +30 28 1037 5050   
Hippokration General Hospital of Thessaloniki Recruiting
Thessaloníki, Greece, 54642
Contact: Emmanuel Roilides, M.D    30 231 089 2444   
Contact: Elias Iosifidis, MD, MSc, PhD    30 231 089 2444   
Assaf Harofeh Medical Center Recruiting
Zerifin, Beer Yaakov, Israel, 70300
Contact: Dror Marchaim, MD   
Rabin Medical Centre, Beilinson Campus Recruiting
Petach Tikva, Central District, Israel, 49100
Contact: Leonard Leibovici, MD    972-3-937-6501   
Contact: Vered Daitch    972-3-937-7358   
Rambam Health Care Campus Recruiting
Haifa, Israel, 31096
Contact: Mical Paul, MD    972-5-206-2140   
Contact: Yael Dishon    972-4-777-1373   
Tel-Aviv Sourasky Medical Center Recruiting
Tel Aviv, Israel, 64239
Contact: Yehuda Carmeli, MD    972-3-697-3625   
Contact: Racheli Shvartz    972-3-694-7597   
Universita della Campania 'Luigi Vanvitelli' Recruiting
Naples, Italy, 80131
Contact: Emanuele Durante-Mangoni, MD    +39 08 1706 5184   
Contact: Fabiana D'Amico    +39 08 1706 2475   
Chang Gung Memorial Hospital Recruiting
Tao-Yuan, Kwei-San, Taiwan, 33305
Contact: Cheng-Hsun Chiu, MD   
Siriraj Hospital Recruiting
Bangkoknoi, Bangkok, Thailand, 10700
Contact: Visanu Thamlikitkul, MD   
Principal Investigator: Visanu Thamlikitkul, MD         
Sponsors and Collaborators
University of Michigan
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Principal Investigator: Keith S Kaye, MD, MPH University of Michigan

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Responsible Party: Keith Kaye, Keith Kaye, M.D.,M.P.H Study PI, University of Michigan Identifier: NCT01597973     History of Changes
Other Study ID Numbers: NIH 10-0065
First Posted: May 15, 2012    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Anti-Bacterial Agents
Anti-Infective Agents