RCT Meropenem vs Piperacillin-Tazobactam for Definitive Treatment of BSI's Due to Ceftriaxone Non-susceptible Escherichia Coli and Klebsiella Spp.
Information source: The University of Queensland
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Bloodstream Infections
Intervention: Meropenem (Drug); Piperacillin-tazobactam combination product (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: The University of Queensland Official(s) and/or principal investigator(s): David L Paterson, MD, PhD, Principal Investigator, Affiliation: UQCCR, RBWH
Summary
No randomized controlled trials (RCTs) have yet been performed comparing different treatment
options for AmpC or ESBL-producing Enterobacteriaceae. During the last 10 years we have seen
an exponentially increasing rate of carbapenem resistance worldwide, including Australia and
New Zealand. The investigators urgently need data from well-designed RCTs to guide
clinicians in the treatment of antibiotic resistant Gram-negative infections. The
investigators face a situation where a commonly used antibiotic for these infections
(meropenem) may be driving carbapenem resistance. For this reason, the investigators are
seeking to compare a carbapenem-sparing regimen with a carbapenem for the treatment of these
infections. Formal evaluation of safety and efficacy of generic antibiotics in the
treatment of infection is of immense clinical and public health importance, and no formal
trial has yet been conducted to address these issues. The international collaboration
between teams of clinician researchers, some of whom are leaders in their field, makes it
highly likely that the outcomes of this trial will have a significant impact on clinical
practice.
The investigators' hypothesis is that piperacillin/tazobactam (a carbapenem-sparing regimen)
is non-inferior to meropenem (a widely used carbapenem) for the definitive treatment of
bloodstream infections due to third-generation cephalosporin non-susceptible E. coli or
Klebsiella species.
Clinical Details
Official title: Randomized Controlled Trial of Meropenem Versus Piperacillin-Tazobactam for Definitive Treatment of Bloodstream Infections Due to Ceftriaxone Non-susceptible E. Coli and Klebsiella Species.
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Mortality at 30 days
Secondary outcome: Time to clinical and microbiologic resolution of infectionClinical and microbiologic success Microbiologic resolution of infection Microbiologic relapse Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium Difficile
Detailed description:
Escherichia coli and Klebsiella spp. are common causes of bacteraemia, and may acquire genes
encoding extended-spectrum beta-lactamases (ESBLs) or AmpC beta-lactamases (1). ESBL or AmpC
producers are typically resistant to third generation cephalosporins such as ceftriaxone,
but susceptible to carbapenems (1). Observational studies have been performed evaluating
antibiotic choices for ESBL producers (2-9). In no study has the outcome of treatment for
serious infections for ESBL producers been significantly surpassed by carbapenems (2-9).
Despite the potential advantages of carbapenems for treatment of ceftriaxone non-susceptible
organisms, widespread use of carbapenems may cause selection pressure leading to
carbapenem-resistant organisms. This is a significant issue since carbapenem-resistant
organisms are treated with "last-line" antibiotics such as colistin. Some new beta-lactam
antibiotics and beta-lactamase inhibitors, which are active against ESBL, AmpC and some
carbapenemase producing organisms, are in advanced clinical development (10). However, these
antibiotics are likely to be expensive and may best be held in reserve for infections where
there are no alternatives. Therefore, we see a need for establishing the efficacy of a
generically available alternative to carbapenems for serious infections.
The susceptibility of ESBL producers and AmpC producers to piperacillin/tazobactam is less
predictable than that of carbapenems. By definition, ESBLs are inhibited by beta-lactamase
inhibitors such as tazobactam (1). However, E. coli or Klebsiella may produce multiple
beta-lactamase types some of which are resistant to inhibition by tazobactam. Additionally,
in some cases outer membrane protein loss may contribute to resistance to tazobactam. By
definition, AmpC is not inhibited by beta-lactamase inhibitors such as tazobactam. However,
despite these limitations, approximately 50% or more of ceftriaxone non-susceptible E. coli
or Klebsiellae remain susceptible in vitro to piperacillin/tazobactam (1).
No randomised controlled trials have yet been performed comparing different treatment
options for ceftriaxone resistant Enterobacteriaceae. The largest observational study with
an analysis by treatment outcome was published in February 2012 by Rodriguez-Bano and
colleagues (9). They performed a post-hoc analysis of six published cohorts of patients with
bacteraemia due to ESBL producing E. coli. Two nonmutually exclusive cohorts (empirical
therapy and definitive therapy) were constructed and analysed separately. In both cohorts,
carbapenems were not superior to beta-lactam/beta-lactamase inhibitor combinations (BLBLIC).
Specifically, in the definitive therapy cohort, mortality rates at 30 days were not
significantly different - 9. 3% for those who received a BLBLIC and 16. 7% for those who
received a carbapenem (p>0. 20) (9).
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Bloodstream infection with E. coli or Klebsiella spp. with proven non-susceptibility
to third generation cephalosporins and susceptibility to meropenem and
piperacillin-tazobactam from at least one blood culture draw. This will be determined
in accordance with laboratory methods and susceptibility breakpoints defined by
EUCAST standards (www. eucast. org). Bacterial identification to species level will
be performed using standard laboratory methods (e. g. MALDI-TOF) and susceptibility
testing (e. g. Vitek2)
- No more than 72 hours has elapsed since the first positive blood culture collection.
- Patient is aged 18 years and over
- The patient or approved proxy is able to provide informed consent.
Exclusion Criteria:
- Patient not expected to survive more than 4 days
- Patient allergic to a penicillin or a carbapenem
- Patient with significant polymicrobial bacteraemia (that is, a Gram positive skin
contaminant in one set of blood cultures is not regarded as significant polymicrobial
bacteraemia).
- Treatment is not with the intent to cure the infection (that is, palliative care is
an exclusion).
- Pregnancy or breast-feeding.
- Use of concomitant antimicrobials in the first 4 days after enrolment with known
activity against Gram-negative bacilli (except trimethoprim/sulfamethoxazole may be
continued as Pneumocystis prophylaxis).
Locations and Contacts
Middlemore Hospital, Papatoetoe 2025, New Zealand; Not yet recruiting Stephen McBride, MD, Email: 4Stephen.McBride@middlemore.co.nz Stephen McBride, MD, Principal Investigator
The North Shore Hospital, Westlake 0622, New Zealand; Recruiting Hasan Bhally, Dr., Email: Hasan.Bhally@waitematadhb.govt.nz Hasan Bhally, MD, Principal Investigator
National University Hospital, Singapore 119074, Singapore; Recruiting Paul Paul Anantharajah Tambyah, Professor, Email: paul_anantharajah_tambyah@nuhs.edu.sg Paul Paul Anantharajah Tambyah, MD, Principal Investigator
Tan Tock Seng Hospital, Singapore 308433, Singapore; Recruiting David Lye, Dr., Email: david_lye@ttsh.com.sg David Lye, MD, PhD, Principal Investigator
Westmead Hospital, Westmead, New South Wales 2145, Australia; Recruiting Jonathan Iredell, Professor, Email: jonathan.iredell@sydney.edu.au Jonathan Iredell, MD, PhD, Principal Investigator
Wollongong Hospital, Wollongong, New South Wales 2500, Australia; Recruiting Spiros Miyakis, Associate Professor, Email: smiyakis@uow.edu.au Spiros Miyakis, MD, PhD, Principal Investigator
Brisbane Private Hospital, Brisbane, Queensland 4000, Australia; Recruiting David L Paterson, MD, PhD, Email: david.antibiotics@gmail.com David L Paterson, MD, PhD, Principal Investigator
St. Andrew's War Memorial Hospital, Brisbane, Queensland 4001, Australia; Recruiting David L Paterson, MD, PhD, Email: david.antibiotics@gmail.com David L Paterson, MD, PhD, Principal Investigator
Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia; Recruiting David L Paterson, Professor, Email: david.antiobiotics@gmail.com David L Paterson, MD, PhD, Principal Investigator Patrick Harris, Dr., Sub-Investigator
Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia; Recruiting David Looke, Dr., Email: David_Looke@health.qld.gov.au David Looke, MD, Principal Investigator
Monash Health, Clayton, Victoria 3168, Australia; Recruiting Benjamin Rogers, Dr., Email: b.rogers1@uq.edu.au Benjamin Rogers, MD, PhD, Principal Investigator
Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Recruiting Amy Crowe, Dr., Email: amylcrowe@hotmail.com Amy Crowe, MD, Principal Investigator
Barwon Health, Geelong, Victoria 3220, Australia; Not yet recruiting Eugene Athan, Assoc. Professor, Email: EUGENE@BarwonHealth.org.au Eugene Athan, MD, PhD, Principal Investigator
The Alfred Hospital, Melbourne, Victoria 3004, Australia; Recruiting Anton Peleg, Assoc. Professor, Email: anton.peleg@monash.edu Anton Peleg, MD, PhD, Principal Investigator
Royal Perth Hospital, Perth, Western Australia 6000, Australia; Recruiting Paul Ingram, Doctor, Email: Paul.Ingram@health.wa.gov.au
Additional Information
Starting date: February 2014
Last updated: April 20, 2015
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