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Comment on MERINO trial and EUCAST breaking new ground

05 Nov 2018

SASCM Blog November 2018 – Comment on MERINO trial and EUCAST breaking new ground

By Warren Lowman and Nelesh Govender

MERINO trial comment

The MERINO trial which aimed to compare piperacillin-tazobactam vs. meropenem in the treatment of bloodstream infections caused by ESBL-producing K. pneumoniae and E. coli was recently published in JAMA. This trial has received much publicity and critique, rightly so given its importance in providing guidance on this contentious issue.

We do not wish to summarize the specific findings and conclusions of the trial (this has been done on other forums and in the journal’s editorial), but rather to highlight some aspects of the trial which are not immediately apparent. The main finding of the trial as reported by the authors was that definitive treatment of E. coli or K. pneumoniae (ceftriaxone resistant) bloodstream infections with piperacillin-tazobactam (piptaz) compared to meropenem did not result in non-inferior 30-day mortality.

This was a non-inferiority (NI) trial and as such it is important to understand the statistical limitations associated with such a trial, especially in light of 1-sided confidence intervals. JAMA itself provides guidance on reporting of NI trials, an extension of the CONSORT statement. The main trial finding, as reported, is in fact inconclusive. For the secondary outcomes, where 2-sided confidence intervals were used, despite the trend favouring meropenem, no outcome was statistically significant. For specific details regarding statistical analysis of NI trials, please view the following YouTube clip

There are a few salient points with regard to the trial which are hidden in the detail but need to be mentioned.

First, in the subgroup analysis for the primary outcome, there were a number of notable differences between the 2 groups: (i) twice as many patients in the piptaz group had a Pitt score ≥4; (ii) a third more in the piptaz group had a non-urinary source of infection and; (iii) 25% more patients in the piptaz group were immunocompromised. A direct comparison of the baseline characteristics in the primary analysis population highlights a similar pattern but a lower mean APACHE II score in the piptaz group. Based on this, one has to ask whether the patients in the piptaz group were different at baseline to those in the meropenem group?

Second, the patients enrolled in this trial were not severely ill based on a reported median Pitt score of 1 and the pre-specified exclusion of patients who were not expected to survive 96 hours.

Third, there were only 26 and 25 Klebsiella pneumoniae isolates in the piptaz and meropenem groups, respectively.

Fourth, narrow-spectrum oxacillinases were present in two thirds of all isolates, enzymes known to reduce inhibition by tazobactam. From a microbiology perspective, one has to ask do these results apply universally to all ESBL-producing Enterobacteriaceae, or just E. coli?

Fifth, perhaps one of the biggest unanswered questions is whether continuous infusion (currently widely practiced) of piptaz would have resulted in the same outcome. Piptaz has a very short half-life (~1.0h) and a 30-minute infusion every 6 hours only provides a 90% probability of target attainment for isolates with an MIC of 1 µg/ml or less. This was the standard recommended dose in the trial and with a median piptaz MIC of 2µg/ml, the risk that patients were under-dosed is a real possibility.

In the context of antimicrobial stewardship, the MERINO trial is unfortunately a step backwards (in terms of carbapenem-sparing therapeutic options), and based on the trial data, there needs to be careful consideration for the use of piptaz in the treatment of ESBL-producing E. coli BSI. However, it is also important to pause and consider carefully what the data tells us, both statistically and in terms of limitations. A rational conclusion is that results of this trial should not be used to make blanket statements regarding use of ß-lactam-ß-lactamase inhibitors in the treatment of BSI caused by ESBL-producing Enterobacteriaceae. Is the MERINO trial the final word? We think not.

For additional comment and insight on the MERINO trial, follow this link.

 

EUCAST redefining the “boundaries” in 2019

EUCAST has made a bold move in redefining the clinical breakpoint definition for the term intermediate. This category has long been ill-defined and used with little purpose from a clinical perspective. It is recognized that in this era of increasing antimicrobial resistance with limited therapeutic options, we need to carefully choose and use the drugs at our disposal. This starts in the microbiology laboratory with appropriate reporting of antimicrobial susceptibility testing (AST) results and clinically relevant categorization.

EUCAST has recommended that the previously designated term “Intermediate”, now be called “Susceptible, increased exposure”. In terms of a definition, this means that there is a high likelihood of therapeutic success through increased exposure to the drug, either due to an adjusted dosing regimen or due to pharmacokinetic properties which increase the concentration of the drug at the site of the infection. CLSI introduced the term “susceptible dose-dependent” (SDD) which is distinct from the intermediate category (and does not replace it), and which designates an isolate as susceptible depending on the dosing regimen used- increased doses, more frequent dosing or both. To date, this has only been applied to antifungals and to cefepime for Enterobacteriaceae. The EUCAST recommendation is to redefine the intermediate category completely through evaluation of ECOFFs and Pk-Pd data which will make this category more broadly applicable.  

This is a significant step forward as it is clinically relevant and reflective of current practice. A prime example is that of the carbapenems which are widely used in higher doses and as extended infusions in the treatment of CRE/CPE infections. This despite the MICs being high and categorized as intermediate or resistant. The supporting clinical and Pk-Pd data for this practice are robust and supportive of the change. Similarly for many of the ß-lactam agents, urinary concentrations far exceed the current breakpoints and can be used successfully in the treatment of pathogens previously reported as resistant. It will also better assist in delineation of isolates that are likely to respond to conventional dosing regimens without need for aggressive dosing strategies that are more likely to be associated with adverse effects.

The importance of dosing appropriately is critical to successful use of antimicrobials and the EUCAST breakpoint table addresses these dosing considerations. These need to become part and parcel of AST reporting, with microbiology reports providing the necessary guidance on appropriate antimicrobial use. It is crucial that we provide clinically relevant results that support appropriate use of antimicrobial agents, increasing available options rather than limiting them.

This change will be implemented in the 2019 clinical breakpoint table (v 9.0) and will be reflected for a multitude of antimicrobial agents, where there are sufficient data.   (http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Consultation/2018/Breakpoint_changes_with_introducing_new_definitions_of_SIR_4OCT2018_v2.pdf).

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