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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


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 infection

Clinical 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).


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


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

Page last updated: August 23, 2015

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