RCT Meropenem vs Piperacillin-Tazobactam for Definitive Treatment of BSI's Due to Ceftriaxone Non-susceptible Escherichia Coli and Klebsiella Spp.
- Conditions
- Bloodstream Infections
- Interventions
- Registration Number
- NCT02176122
- Lead Sponsor
- The University of Queensland
- 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).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 391
- 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.
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Piperacillin-tazobactam combination product Piperacillin-tazobactam combination product Piperacillin/tazobactam 4.5g adm every 6 hours IV up to study day 4. Meropenem Meropenem Meropenem 1g adm every 8 hours IV up to study day 4.
- Primary Outcome Measures
Name Time Method Mortality at 30 days 30 days To compare the 30-day mortality post bloodstream infection of piperacillin/tazobactam and meropenem.
- Secondary Outcome Measures
Name Time Method Time to clinical and microbiologic resolution of infection on or before study day 4 defined as number of days from randomisation to resolution of fever (temperature \> 38.0o C) and leucocytosis (white blood cell count \>12x109/L) PLUS sterilisation of blood cultures.
Microbiologic relapse day 30 defined as growth of a meropenem resistant Gram negative bacillus from any clinical specimen collected or a positive stool test (according to local lab diagnostic procedures) for C. difficile, from day 4 of study drug administration to day 30
Superinfection with a carbapenem or piperacillin-tazobactam resistant organism or Clostridium Difficile day 30 To compare the risk of superinfection with a carbapenem resistant organism with each regimen.
Clinical and microbiologic success day 4 defined as survival PLUS resolution of fever and leucocytosis PLUS sterilisation of blood cultures
Microbiologic resolution of infection day 4 defined as sterility of blood cultures collected on or before day 4
Trial Locations
- Locations (31)
Catholic University Rome
🇮🇹Rome, Italy
İstanbul Medipol Üniversitesi Medipol Mega Hastaneler Kompleksi (Medipol Mega Hospitals Complex)
🇹🇷Istanbul, Turkey
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
The North Shore Hospital
🇳🇿Westlake, New Zealand
Mater Misericordiae Health Services Brisbane Ltd.
🇦🇺Brisbane, Queensland, Australia
Shellharbour Hospital (Illawarra Shoalhaven Local Health District)
🇦🇺Shellharbour, New South Wales, Australia
National University Hospital
🇸🇬Singapore, Singapore
Fiona Stanley Hospital
🇦🇺Perth, Australia
Sanremo Hospital
🇮🇹Sanremo, Italy
Middlemore Hospital
🇳🇿Papatoetoe, New Zealand
Teaching Hospital - Sant'Orsola Malpighi
🇮🇹Bologna, Italy
Sunnybrook Research Institute
🇨🇦Toronto, Canada
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
The American University of Beirut
🇱🇧Beirut, Lebanon
"Sapienza" University of Rome
🇮🇹Rome, Italy
Charlotte Maxeke Johannesberg Academic Hospital
🇿🇦Johannesburg, South Africa
Groote Schuur Hospital
🇿🇦Cape Town, South Africa
Dipartimento di Scienze Biomediche e Cliniche "L. Sacco". Azienda Ospedaliera - Polo Universitario
🇮🇹Milan, Italy
Santa Maria Misericorida University Hospital
🇮🇹Udine, Italy
Brisbane Private Hospital
🇦🇺Brisbane, Queensland, Australia
St. Andrew's War Memorial Hospital
🇦🇺Brisbane, Queensland, Australia
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
King Fahad Specialist Hospital
🇸🇦Dammam, Saudi Arabia
King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City
🇸🇦Riyadh, Saudi Arabia
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Monash Health
🇦🇺Clayton, Victoria, Australia
Peter MacCallum Cancer Centre
🇦🇺East Melbourne, Victoria, Australia
Barwon Health
🇦🇺Geelong, Victoria, Australia
Tan Tock Seng Hospital
🇸🇬Singapore, Singapore
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Wollongong Hospital
🇦🇺Wollongong, New South Wales, Australia