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