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

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.