Clinical trial NCT02176122: RCT Meropenem vs Piperacillin-Tazobactam for Definitive Treatment of BSI's Due to Ceftriaxone Non-susceptible Escherichia Coli and Klebsiella Spp.
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Bloodstream Infections
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: International Society of Chemotherapy
name: Australian Society for Antimicrobials
name: Queensland Clinical Trials & Biostatistics Centre
name: Australasian Society for Infectious Diseases
First posted: 2014-06-26
Enrollment: 391
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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 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).

Primary outcomes:
measure: Mortality at 30 days
timeFrame: 30 days
Secondary outcomes:
measure: Time to clinical and microbiologic resolution of infection
timeFrame: on or before study day 4
measure: Clinical and microbiologic success
timeFrame: day 4
measure: Microbiologic resolution of infection
timeFrame: day 4
measure: Microbiologic relapse
timeFrame: day 30
measure: Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium Difficile
timeFrame: day 30
Other outcomes:
Locations:
city: Shellharbour
country: Australia
facility: Shellharbour Hospital (Illawarra Shoalhaven Local Health District)
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Brisbane Private Hospital
state: Queensland
city: Brisbane
country: Australia
facility: St. Andrew's War Memorial Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Mater Misericordiae Health Services Brisbane Ltd.
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Geelong
country: Australia
facility: Barwon Health
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
city: Toronto
country: Canada
facility: Sunnybrook Research Institute
city: Bologna
country: Italy
facility: Teaching Hospital - Sant'Orsola Malpighi
city: Milan
country: Italy
facility: Dipartimento di Scienze Biomediche e Cliniche "L. Sacco". Azienda Ospedaliera - Polo Universitario
city: Rome
country: Italy
facility: "Sapienza" University of Rome
city: Rome
country: Italy
facility: Catholic University Rome
city: Sanremo
country: Italy
facility: Sanremo Hospital
city: Udine
country: Italy
facility: Santa Maria Misericorida University Hospital
city: Beirut
country: Lebanon
facility: The American University of Beirut
city: Papatoetoe
country: New Zealand
facility: Middlemore Hospital
city: Westlake
country: New Zealand
facility: The North Shore Hospital
city: Dammam
country: Saudi Arabia
facility: King Fahad Specialist Hospital
city: Riyadh
country: Saudi Arabia
facility: King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Cape Town
country: South Africa
facility: Groote Schuur Hospital
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesberg Academic Hospital
city: Istanbul
country: Turkey
facility: İstanbul Medipol Üniversitesi Medipol Mega Hastaneler Kompleksi (Medipol Mega Hospitals Complex)
Study officials:
affiliation: UQCCR, RBWH
name: David L Paterson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, Alenazi TH, Arabi Y, Falcone M, Bassetti M, Righi E, Rogers BA, Kanj S, Bhally H, Iredell J, Mendelson M, Boyles TH, Looke D, Miyakis S, Walls G, Al Khamis M, Zikri A, Crowe A, Ingram P, Daneman N, Griffin P, Athan E, Lorenc P, Baker P, Roberts L, Beatson SA, Peleg AY, Harris-Brown T, Paterson DL; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018 Sep 11;320(10):984-994. doi: 10.1001/jama.2018.12163.
citation: Harris PN, Peleg AY, Iredell J, Ingram PR, Miyakis S, Stewardson AJ, Rogers BA, McBryde ES, Roberts JA, Lipman J, Athan E, Paul SK, Baker P, Harris-Brown T, Paterson DL. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial. Trials. 2015 Jan 27;16:24. doi: 10.1186/s13063-014-0541-9.