The MERINO Trial is a landmark study published in September of 2018 that investigated piperacillin-tazobactam versus meropenem for the treatment of bloodstream infection caused by ceftriaxone-resistant E. coli or Klebsiella pneumoniae. In this interview the lead study investigator provides insights as to their findings and what they have learned through their work.
Interview With: Patrick Harris, BSc, MBBS, DTM&H, MRCP, FRACP, FRCPA
Interview By: Timothy P. Gauthier, Pharm.D., BCPS-AQ ID
[Last updated: 11 September 2018]
In the world of antibiotics the treatment of infections caused by drug-resistant Gram negative bacteria such as E. coli and Klebsiella pneumoniae is a topic of much interest and debate. On one hand providers want to select therapies that will give their patients the best chances for a favorable outcome. On the other hand, providers worry about unnecessarily over-using antibiotics they should be reserving for organisms exhibiting particularly high levels of drug resistance.
About two years ago to investigate some of the major challenges in the field of drug-resistant Gram negative infections, I asked one of the leading infectious diseases pharmacists in the United States to discuss some of the major unanswered questions he was pondering. One of the questions included was: What is the role of piperacillin/tazobactam for the treatment of invasive infections due to extended spectrum beta-lactamase (ESBL) producing enterobacteriaceae? Within his commentary the MERINO Trial was mentioned and this is how I first heard of it. Like many people, the efforts of the MERINO Trial investigators immediately engaged my interest. How could it not when there is even a Twitter account dedicated to it!?! You can follow them here @MERINOtrial.
Fast forward to a few months ago and the investigators of the MERINO Trial presented some of their preliminary data at the major European infectious diseases conference ECCMID. At that conference the lead investigator Dr. Harris completed an interview which was published open-access on YouTube, available here. Upon watching the video and reflecting upon the importance of their work I decided to take a chance and reach out to Dr. Harris to see if he would be willing to do an interview and share his perspectives and thoughts. He graciously accepted.
Just this week the MERINO Trial was officially published in full with JAMA:
Through corresponding with Dr. Harris and in an effort to extend the reach of the important work he and his co-investigators have undertaken, the following interview was composed. In this article the MERINO Trial is discussed and insights from the lead investigator are provided…
1. The MERINO Trial took considerable effort and resources to undertake. What made this an important project for you to pursue?
When I started training in microbiology, multi-drug resistant gram-negative bacilli were fairly unusual and tended to be seen in hospitalised patients or as part of localised outbreaks. When we encountered the occasional patient with a serious infection caused by an extended-spectrum beta-lactamase (ESBL)-producer, we tended to default to carbapenem therapy. The evidence for this was based largely on in vitro data and observational studies from the 1990s which reported improved mortality in patients treated with carbapenems, usually compared to cephalosporins or fluoroquinolones. However, in recent years there has been a global explosion in the proportion of Enterobacteriaceae which carry ESBL genes, resulting in a substantial increase in carbapenem use. Perhaps as a result, we now face the emerging phenomenon of carbapenem-reistance in common pathogens such as Klebsiella pneumoniae or Escherichia coli. It could be argued that this now presents one of the greatest threats to the safe delivery of modern healthcare.
So, we have to ask ourselves, what strategies can we use to reduce our reliance on carbapenems for these infections? Are there alternative “carbapenem-sparing” strategies available and how can we best demonstrate their efficacy?
For many years it always bothered me (and many others) that we often have to make treatment decisions in patients with these complex and difficult-to-treat infections, using fairly flimsy data. I have been frequently told that, although ESBL-producers will often test susceptible to piperacillin-tazobactam (PTZ) in vitro, their efficacy in vivo could not be trusted. However, when you looked for the clinical evidence to support this dogma, there was almost none (albeit supported by sound theoretical concerns). In 2012, a Spanish group led by Jesus Rodriguez-Bano, published an observational study, which suggested that outcomes were similar in patients with ESBL-E. coli bloodstream infections, irrespective of whether carbapenems or beta-lactam/beta-lactamase inhibitors (BLBLIs [e.g., PTZ]) were used as empirical or targeted therapy. Additional studies, including a meta-analysis of published studies and a large international prospective observational cohort (the INCREMENT study) reached similar conclusions. There certainly seemed to be increasing support for the concept that BLBLIs might prove a worthwhile carbapenem-sparing strategy in these patients. However, observational studies are prone to bias and occasionally demonstrated conflicting results.
While there seemed to be clinical equipoise for the role of BLBLIs in this context, a large randomised controlled trial seemed to be the optimal method to answer the question. As such, the MERINO trial was developed to specifically address this important clinical problem. This idea came out of a survey of infectious diseases and microbiology specialists who are part of the Australasian Society for Infectious Diseases (ASID). The concept of the MERINO trial was voted as the number one study our members wanted to see completed – hence we knew there was significant “buy-in” from specialists in our region and a desire to see this question formally addressed.
2. Based upon the data generated from your research, what are the main points you would want antimicrobial stewards to know about the MERINO Trial?
The MERINO trial tested two treatment strategies, reflecting a decision-point that we often make in clinical practice. Specifically we wanted to answer this question: when you have an ESBL-producer growing in blood cultures, and the isolate tests susceptible to PTZ, can you use this drug as directed therapy once susceptibilities are known, or is “standard” therapy with meropenem (MER) more reliable. It is important to note that this trial did not specifically address questions relating to empirical therapy, which is a separate issue.
This was a pragmatic study that aimed to reflect “real-world” practice, using a protocol that aligned with normal care as closely as possible. We chose an unambiguous primary endpoint that probably matters most to clinicians and patients alike – what is the risk of dying within 1 month following this treatment?
We designed the trial as a non-inferiority trial, in other words we were testing whether PTZ was “no-worse” than MER, allowing a predetermined difference of up to 5% in the primary mortality outcome (the so called non-inferiority [NI] margin). We then recruited patients with bloodstream infections caused by ESBL-producing E. coli or K. pneumoniae from 26 hospitals in 9 countries, although most patients were recruited in Singapore, Australia, or Turkey. Patients were randomised within 72h of the initial BC collection to PTZ 4.5g Q6H or MER 1g Q8H for a minimum of 4 days. On day 5 post-randomisation, the drug could be stopped, continued for up to 14 days or stepped down to oral therapy at the treating physician’s discretion. We followed patients for up to 30 days to determine the primary outcome (alive or dead), as well as secondary measures of clinical and microbiological resolution, relapse of bloodstream infection or secondary infections with a multi-drug resistant organisms or C. difficile.
By the time we undertook the 3rd interim analysis of 340 recruited, the Data Safety Monitoring Board noticed a widening and unexpected difference in mortality between the two arms, which approached our pre-defined stopping rule of superiority. At this point recruitment had reached 391 patients and was suspended to look more carefully at data from the remaining patients. Following analysis of the full cohort, it was determined that it would be extremely unlikely for us to demonstrate non-inferiority, even if we continued to recruit up to the planned sample size of 454. As a result, and after discussion with all the site investigators, it was decided to terminate the study at that point on the grounds of both potential harm and futility.
Of the 391 randomised, 12 patients were excluded as they never received the allocated study drug and 1 patient was lost to follow up. Hence we had a total of 378 patients in the primary analysis (modified intention-to-treat) population. A total of 23/187 (12.3%) patients randomized to PTZ met the primary outcome of mortality at 30 days, compared with 7/191 (3.7%) randomized to MER. The absolute risk difference was 8.6% (falling beyond our 5% NI threshold) with an upper bound of the one-sided 97.5% CI of 14.5%. Using the topsy-turvy parlance of NI trials, we could not reject the null-hypothesis (that there was no evidence for non-inferiority) given that these differences were so far removed from our pre-determiend threshold. Effects were also consistent in an analysis of the per-protocol population. As such, the findings did not support the use of PTZ for these patients.
3. With the favorable outcomes for meropenem as compared to piperacillin-tazobactam in this trial, do you have any words of caution for clinicians who may now be quicker to pull the trigger on prescribing carbapenems?
We have to be a little careful with the terminology here. Strictly speaking, as a non-inferiority trial, we were not intending to prove “superiority” of MER, and this was not a pre-specified aim in our a priori statistical analysis plan and sample size calculations. However, we acknowledge that many might interpret the study in this way, and indeed this may be a reflection of the truth.
The low mortality rate in the MER arm (3.7%) is striking, and one might hypothesise that we are measuring the effect of a highly potent antibiotic. On the other hand, there may still be certain groups of patients in whom PTZ is appropriate, and indeed in sub-group analysis the increased risk associated with randomisation to this drug was less marked in patients with a urinary tract source, low Pitt scores or those without evidence of immune compromise. However, it is worth noting that in all sub-group analyses, the direction of risk was increased in those randomised to PTZ (although the trial was not powered to demonstrate non-inferiority in these sub-groups).
Furthermore, we also undertook a multivariable analysis which attempted to adjust for any imbalances with respect to clinical variables which may bias towards increased mortality, but the association between randomisation to PTZ and the primary outcome was maintained even after adjustment.
Whether anyone is willing to undertake a trial to identify these “lower-risk” bacteremic patients in whom a BLBLI is safe, is an interesting question. I still suspect that clinical judgement can be applied: if a patient has bacteraemia caused by an ESBL-producer, has achieved adequate source control, is not severely unwell, has few co-morbidities or other high-risk features and has improved clinically on empirical PTZ (to which the isolate has confidently been tested as susceptible – another potential variable of uncertainty), I do not believe it is mandatory that a switch to MER is required – but such subtleties are hard to define from this trial alone. However, I am fairly convinced that in patients with septic shock, immune compromise, significant co-morbidities or poor source control, a carbapenem would be a safer choice.
We are clearly concerned that the results of this trial might lead to widespread over-prescription of carbapenems and I think the search for carbapenem-sparing alternatives remains a pressing need. It was interesting that we were not able to demonstrate any increased risk of secondary detection of carbapenem-resistant gram-negative bacilli or Clostridium difficile in those randomised to MER, but the overall event rate was low. It may be that PTZ also has significant capacity to select for multi-resistant organisms, so blaming carbapenems alone for our current predicament is perhaps too narrow a view.
4. In the MERINO Trial a standard infusion of 30 minutes was used, did you consider using extended infusion times (e.g., 4-hours) and what are your thoughts on the impact infusion time may have on the study outcome?
It is an interesting thought and we did consider this approach, but in the end decided to reflect what is most commonly done in clinical practice (i.e. standard infusions). However, we tried to maximise drug exposure by using 4.5g q6-hourly dosing (as opposed the more commonly used 8-hourly interval).
There is a large international trial (BLING-3) being undertaken to compare extended infusions in patients admitted to ICU with sepsis which might go some way to address this question, although whether this specifically provides advantages in ESBL-related infection is still unclear. We have been looking at the relationships between the minimum inhibitory concentration (MIC) to PTZ or the type of ESBL/p-AmpC genes and outcome in the trial, but this analysis is ongoing.
5. If you had the opportunity to take what you learned and go back to do the trial again, is there anything you would have do differently?
One problem we did not fully anticipate is that a number of patients switched back from PTZ to ertapenem on an outpatient parenteral antimicrobial therapy program once the mandated period of trial drug was completed. This was allowed in the protocol, but did cause some “contamination” between treatment arms. However, such cross-over would tend to bias towards non-inferiority, so might be more of an issue if we had a different result.
For the future, we also need RCTs of treatments for patients with bloodstream infections that recruit as early as possible, to reduce the duration of “empirical” treatment (which is hard to standardise and proves to be extremely heterogeneous) – one would hope that incorporation of rapid molecular diagnostics could help accelerate this process, but most diagnostic laboratories are some way off using such methods in routine care.
6. What is next for the investigators of the MERINO Trial?
We are looking more closely at the effects of PTZ and MER MICs on outcome, as well as the influence of different resistance genes. This also involves testing all the isolates with multiple methods – Etest, broth dilution, Vitek etc – to see if we can tease out discrepancies in testing methodologies, and ultimately see whether a genomics-based prediction of drug response might be feasible (or even more reliable). Discerning these genotype-phenotype relationships will be essential for interpreting any future rapid WGS approaches for culture-indepdent detection of pathogens, and datasets such as the MERINO trial provide opportunities to study this in more detail.
We also have a smaller pilot study (MERINO-2) underway which includes chromosomal AmpC producers (e.g. Enterobacter, Serratia etc). We intend to collabrorate further with the fantastic group of MERINO investigators who now have proven their ability to recruit into such trials. This provides a great opportunity to address additional clinical dilemmas, evaluate new drugs or other treatment strategies in the treatment of MDR gram-negative infections.
We firmly believe that such international collaborative and pragmatic RCTs, answering “real-world” clinical questions are going to be invaluable. Furthermore, we hope we have shown that (with some effort) such trials are not an impossible task, need not be prohibitively expensive, and should be the new standard that we accept.
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About the Interviewee
Dr Patrick Harris is an Infectious Disease Physician and Medical Microbiologist, and is currently a Postgraduate Research Fellow at The University of Queensland Centre for Clinical Research (UQCCR).
Dr. Harris obtained a BSc in Psychology and Anthropology from Durham University, prior to acquiring his medical degree from University College London Medical School. Following initial postgraduate training in the UK he worked as a clinical lecturer at the College of Medicine in Malawi, prior to completing specialist training in infectious diseases and microbiology in Australia. For his final year of training he was a Senior Visiting Fellow in Infectious Disease at the National University Hospital in Singapore. He has published more than 45 peer-reviewed articles, many as first author, including recent publications in the Lancet, Lancet Infectious Diseases and Clinical Infectious Diseases. He completed his PhD in 2018 under the supervision of Prof. David Paterson, with a focus on multi-drug resistant Gram-negative bacteria.
He has been coordinating the MERINO trial: an international multicentre study to compare carbapenem-sparing treatment options for ESBL and AmpC-producing species. This has been the first large RCT to specifically address this question, using a protocol developed and endorsed by the Australasian Society for Infectious Diseases Clinical Research Network (ASID-CRN).
I would like to thank Dr. Harris for taking the time out of his day to complete this interview and share his perspective and experience with the IDstewardship audience.
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