Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME)
Condition: Pneumonia; Blood Stream Infection
MeSH terms: Sepsis
Study type: Interventional
Phase: Phase 3

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, Enterobacter 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.
    

Detailed description: 
      The Gram-negative bacilli organisms Acinetobacter baumannii, Klebsiella spp., Escherichia
      coli, Enterobacter 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.

      Due to the growing threat of XDR-GNB around the world, several international sites were
      subsequently added including sites in Asia, Israel, and Europe.
    

Intervention name(s): colistin and meropenem; colistin and placebo
Intervention type(s): Drug; Drug
Intervention description(s): colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function; colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)
Other intervention name(s): Colistimethate; Meropenem; Colistimethate
Intervention MeSH terms: Meropenem; Colistin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment