First Trial Compares Treatment Options For Serious Infections Caused by ESBL-Producers Interview with:

Patrick Harris FRACP Staff Specialist Microbiology | Pathology Queensland | Health Support Queensland Postdoctoral Research Fellow University of Queensland, UQ Centre for Clinical Research (Paterson Group)

Dr. Harris

Patrick Harris FRACP
Staff Specialist
Microbiology | Pathology Queensland | Health Support Queensland
Postdoctoral Research Fellow
University of Queensland, UQ Centre for Clinical Research (Paterson Group What is the background for this study?

Response: Increasingly, common bacterial pathogens such as E. coli or Klebsiella have acquired genes known as extended-spectrum beta-lactamases (ESBLs), which mediate resistance to many of our most important antibiotics. Despite their clinical importance, we have limited information derived from randomised clinical trials on the best antibiotic treatments for life-threatening infections caused by these ESBL-producers.

We aimed to compare two readily available antibiotics, meropenem (a carbapenem drug, as the “standard of care”) and piperacillin-tazobactam (which may be an alternative to meropenem). Many ESBL-producing bacteria test susceptible to piperacillin-tazobactam in the laboratory, yet clinical efficacy has been uncertain.  Some observational studies have suggested that piperacillin-tazobactam may be effective against ESBL-producers, but the data have been contradictory.  The theory has been that piperacillin-tazobactam may be less likely to select for resistance to carbapenems – which, when it occurs, can result in infection with bacteria that are almost untreatable. What are the main findings?

Response: The MERINO study was an international randomised trial which aimed to test the hypothesis that piperacillin-tazobactam was “non-inferior” to meropenem (i.e. at least as effective) in patients with bloodstream infections caused by ESBL-producing bacteria.  Typically such infections are associated with a mortality in excess of 10%, require hospitalisation for intravenous antibiotics and may lead to admission to an intensive care unit.  The study protocol was developed by the Australasian Society for Infectious Disease (ASID) Clinical Research Network, and aimed to align as closely as possible with routine clinical care. We enrolled patients in 9 countries (Australia, New Zealand, Singapore, Italy, Turkey, Saudi Arabia, Lebanon, Canada and South Africa) from 2014 to 2017. The primary outcome measure was mortality at 30 days, with secondary outcomes measures of clinical and microbiological resolution, risk of microbiological relapse or subsequent detection of multi-resistant gram-negative organism or Clostridium difficile.

In the primary analysis, a total of 23/187 (12.3%) patients randomized to piperacillin-tazobactam died, compared with 7/191 (3.7%) randomized to meropenem.  This marked difference in the risk of mortality was in excess of the pre-specified non-inferiorty margin. There were also no significant differences in subsequent detection of multi-resistant organisms between treatment arms. What should readers take away from your report?

Response: This is the first large randomized trial to compare treatment options for serious infection caused by ESBL-producers. The study findings did not support the use of piperacillin-tazobactam for these infections.  This highlights the need for great caution in selecting the appropriate treatment for these difficult-to-treat organisms, especially in patients with a high risk of mortality. What recommendations do you have for future research as a result of this work?

Response: This demonstrates the importance of such pragmatic trials in assessing the true efficacy of treatment strategies against drug-resistant infections.  We are aiming to determine exactly why we saw these results by understanding the role of different resistance genes using whole genome sequencing and testing how the organisms respond to antibiotics in the laboratory. We also believe that new antibiotics with activity against multi-drug resistant bacteria should be subject to such pragmatic clinical trials, in order to select optimal treatment for these patients based on robust evidence. Is there anything else you would like to add?

Response: We would like to thank all the many clinical researchers around the world who participated in this study, as well as our funders who included the Australian Society for Antimicrobials (ASA), the International Society for Chemotherapy (ISC) and the National University Hospital Singapore.

I have no conflicts to disclose. 


Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone ResistanceA Randomized Clinical TrialJAMA. 2018;320(10):984–994. doi:10.1001/jama.2018.12163


Sep 12, 2018 @ 3:50 pm




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