Last week in the Journal of the American Medical Association, Harris and colleagues (including former University of Pittsburgh professor Dr. David Patterson) published the results of the MERINO trial, a randomized controlled trial involving patients with ceftriaxone-resistant Gram negative organisms in the blood, namely Klebsiella species and Escherichia coli (E coli). Publication has been anticipated since the top line results were presented last Spring in abstract form. The patients, who were recruited from Asia, Oceania, and North America, were given either intravenous meropenem or pipercillin-tazobactam for treatment of their Gram negative bloodstream infection, in order to determine if any significant differences in outcomes were noted. The assumption was that most of these pathogens would be from an extended spectrum beta-lactamase (ESBL) producer and differences would be noted amongst patients who were treated with meropenem when compared to piperacillin-tazobactam, with the authors hypothesizing that a carbapenem-based regimen would produce better outcomes overall. Specifically, the study was designed to test for non-inferiority between those patients that received piperacillin-tazobactam, when compared to those patients who received meropenem.
The study included 378 patients, who were randomized approximately 53 hours after blood cultures were obtained. At that time they were placed on either intravenous meropenem 1 g every 8 hours or intravenous piperacillin tazobactam (pip-tazo) 4.5 g every 6 hours. Neither drug used prolonged infusion time. Most of the patients had a urinary source for their bacteremia, with intra-abdominal infection listed as the second most common source. The patients’ treating team was given the option to change or discontinue antimicrobial therapy on day 5 of the study drug. The median time for treatment was 13 days.
The primary outcome, all-cause mortality at 30 days, favored those patients who were given IV meropenem (3.7%, compared to 12.3% with pip-tazo). As such, pip-tazo could not be classified as non-inferior to meropenem. This difference was maintained across the pre-specified subgroups of patients analyzed (including those patients with a low vs high Pitt bacteremia scores, those patients with a urinary vs non-urinary source, those patients who were on appropriate empiric therapy vs not, and immunocompromised vs immunocompetent patients).
There are a few important features of the trial and some key results that have implication for practice:
- Only 86% of the pathogens were identified as ESBL, 10% produced Amp-C beta-lactamases
- About 40% of patients received dual gram-negative therapy in empiric phase
- Early assessment of response (day 4 of study) tended to favor meropenem over pip-tazo (consistent with primary outcome)
- Relapse and acquisition of a new MDR organism tended to occur more frequently among those patients in the pip-tazo arm
- Inappropriate empiric therapy (before randomization) was not a statistically significant risk factor for mortality
Overall, this study showed a relatively dramatic mortality difference, favoring the use of carbapenem therapy use over pip-tazo amongst patients with ceftriaxone-resistant Klebsiella and E coli bloodstream infections. Given the high frequency of ESBL organisms, carbapenem-based regimens would be the preferred first line drug for this phenotype. Classically, carbapenems have also been used for Amp-C producing organisms, although the small numbers in this study likely do not have the power to detect a difference in treatment outcome by beta-lactamase-producing organisms other than ESBLs.
The authors were unable to assess the efficacy pip-tazo when compared to meropenem in non-bloodstream infections (e.g. simple cystitis) nor did it address extended infusion pip-tazo use. The overall outcome here suggests that carbapenems will continue to be the preferred beta-lactam antibiotic for ESBL bloodstream infections, and that pip-tazo is not the drug of choice here. Given the lack of data provided, providers should also be hesitant to use pip-tazo as first line therapy for serious ESBL infections that do not involve the bloodstream, at least until further studies are done regarding extended interval dosing in this setting.
From an antibiotic stewardship standpoint, it appears that the increased use of carbapenems can place patients at risk for carbapenem-resistant bloodstream infections, however this based on the results of this trial, the use of an alternative beta-lactam agent does not appear to be a viable option. Given that carbapenems appear to be the appropriate drug for drug-resistant Gram negative bloodstream infections, perhaps future studies could help evaluate the “right duration” for therapy— perhaps 13 days that was reported in the study may be longer than necessary for these infections if the optimal drug is prescribed.
Harris PNA et al 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.
Image: A MERINO Sheep