MERINO

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.”

Harris PNA, Tambyah PA, Lye DC, et al.; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN).

JAMA. 2018 Sep 11;320(10):984-994. [Full Text]

Summary by Matt Coster


Beta-lactamase enzymes are a broad category of enzymes (generally plasmid encoded) produced by gram-negative organisms that confer resistance to many beta-lactam antibiotics (i.e. penicillins and cephalosporins). The most common beta-lactamases are not effective against higher generation cephalosporins with an oxyimino side chain (i.e. cefotaxime, ceftazidime, ceftriaxone, or cefepime) and are typically blocked by beta-lactamase inhibitors, such as clavulanate, sulbactam or tazobactam.

Extended-spectrum beta-lactamase (ESBL) producing bacteria vary in their ability to hydrolyze oxyimino-cephalosporins (ceftazidime, ceftriaxone, or cefepime, and the oxyimino-monobactam aztreonam) and are unable to hydrolyze 7-alpha-methoxy-cephalosporins (cephamycins, like cefoxitin) or carbapenems. ESBL-producing bacteria even often demonstrate in vitro susceptibility to cephamycins, but in vivo resistance has developed, and there is not sufficient evidence to support their use [1] and represent a growing threat in the era of antibiotic resistance [1, 2].

In an RCT of patients with UTI caused by ESBL-producing pathogens, Cefepime was not as effective as either ertapenem or piperacillin-tazobactam [3]. A 2012 meta-analysis comparing mortality rates among carbapenems and alternative regimens, such as beta-lactam/beta-lactamase inhibitors (BLBLIs), demonstrated increased mortality in those treated with alternative regimens such as fluoroquinolones or cephalosporins, but not with not BLBLIs or carbapenems [4]. Between 2012 and 2017, six subsequent studies evaluated BLBLIs, with varying results, and controversies in study design [2].

Carbapenems remained the preferred treatment for ESBL, concerns for selective pressure towards carbapenem resistance led to MERINO – an attempt to definitively determine if Piperacillin-Tazobactam (a BLBLI) could safely treat ESBL bacteremia and effectively function as a carbapenem-sparing regimen.

Patient population and Study Design

This was an international, multicenter, open-label, parallel group, randomized clinical trial involving 26 hospitals in 9 countries (most patients were recruited in Singapore, Australia, or Turkey). Those eligible included adults with at least 1 positive blood culture with ESBL-producing E. coli or Klebsiella spp (defined as non-susceptible to ceftriaxone or cefotaxime, but remained susceptible to piperacillin-tazobactam and meropenem in vitro).

These patient were randomiszed 1:1 to treatment with either Meropenem 1g Q8 or Piperacillin-Tazobactam (PTZ) 4.5g q6 (with renal adjustment of each, if necessary). Of note, the PTZ dosing was not extended duration dosing but rather given over 30 minutes. The study drug was given for 5 days post-randomization, at which time the drug could be stopped, continued for up to 14 days or stepped down to oral therapy at the treating physician’s discretion. Patients were followed for up to 30 days.

Patients were excluded if they had polymicrobial bacteremia, required additional antibiotics with activity against gram-negative bacilli, were pregnant or breastfeeding, or were not expected to survive 96 hours.

The study was funded by grants from the Australian Society for Antimicrobials (ASA), International Society for Chemotherapy (ISC), National University Hospital Singapore Clinician Researcher Grant.

Graphic by Patrick Harris @padstamundo

Outcomes

The trial was designed to determine non-inferiority of piperacillin-tazobactam in comparison to meropenem, with a non-inferiority margin of 5% in the primary outcome pre-specified. The primary outcome was all cause mortality at 30 days after randomization.

Secondary outcomes included time to resolution of infection (absence of fever and leukocytosis, as well as sterilization of blood cultures), treatment success at day 4 (resolution of fever and leukocytosis plus sterilization of blood cultures), and microbiologic resolution of infection (sterilization of blood cultures collected on or before day 4).

Safety outcomes included relapsed bloodstream infection (after the end of the period of study drug administration but before day 30 after randomization), and secondary infection with a meropenem- or piperacillin-tazobactam–resistant gram-negative organism or Clostridium difficile infection, from day 4 after randomization to day 30.

Results

The study had a number of interim analyses and by the 3rd analysis the Data Safety Monitoring Board noticed a difference in mortality between the two arms.  Recruitment was stopped despite not reaching the goal sample size of 454 and the study terminated given the potential harm and futility.

A total of 378 patients were included in the analysis. At baseline the PTZ group had more urinary tract infections as the underlying source and more immunocompromised patients. The meropenem group had a higher baseline APACHE II scores (17.9 vs 21). Interestingly, after the 5 day required study drug period, both groups equally stepped down to a carbapenem, (20.2% vs. vs 20.4%).

The PTZ minimum inhibitory concentration (MIC) was similar across treatment groups, the median MIC was significantly greater for K pneumoniae than E coli species (4 mg/L vs 2 mg/L; P <0.001) and the PTZ group had more K pneumoniae ESBL infections.

For the primary outcome, 23 of 187 (12.3%) patients in piperacillin-tazobactam group died in 30 day period compared to 7 of 191 (3.7%) patients in the meropenem group (risk difference, 8.6% [1-sided 97.5% CI -∞ to 14.5%]; P= 0.90 for non-inferiority).

The secondary outcomes were similar for both groups.

Both groups achieved similar rates of clinical resolution of infection – resolution of fever and leukocytosis plus sterilization of blood cultures at day 4 after randomization occurred in 121 of 177 (68.4%) patients in the piperacillin-tazobactam group, compared with 138 of 185 (74.6%) in meropenem group (risk difference, -6.2% [95% CI, -15.5 to 3.1%]; P= .19)

The median number of days to resolution of fever (temperature >38.0°C), leukocytosis (white blood cell count >12 000/μL), and sterilization of blood cultures was 3 days (interquartile range [IQR], 1,5) in the piperacillin-tazobactam group, and 2 days (IQR, 1,5) in the meropenem group, but this was not significant (P = 0.18)

Almost all patients in both groups had clearance of bacteremia. 169/174 (97.1%) patients of piperacillin-tazobactam group achieved sterilization of blood cultures on or before day 4 after randomization compared to 184/185 (99.5%) patients in meropenem group (between group difference -2.3 [95% CI -6.1 to 0.4]; P= 0.23).

Few patients in each group had relapsed blood stream infections during the trial period. 9/187 (4.8%) patients in piperacillin-tazobactam group compared to 4/191(2.1%) patients in meropenem group (between group difference 2.7 [95% CI -1.1 to 7.1]; P= 0.11).

A non-significant decrease in secondary infection with a meropenem- or piperacillin-tazobactam–resistant gram-negative organism or Clostridium difficile infection was noted in meropenem group. This occurred in 15/187 (8.0%) patients in piperacillin-tazobactam group compared with 8/191 (4.2%) patients in meropenem group (between group difference 3.8 [95% CI -1.1 to 9.1]).

There were similar, and low rates of serious adverse events 5 of 188 patients (2.7%) in the piperacillin-tazobactam group compared with 3 of 191 (1.6%) in the meropenem group.

Discussion 

Based on observational data, patients with bacteremia due to ESBL-producing E. coli were expected to have approximately 16.7% mortality if treated with a carbapenem [5]. However, the overall mortality in this trial was 7.9%. This could have been due to less severe infections, as those patients who weren’t expected to survive more than 96 hours were excluded.

Other limitations include delays from identification of bacteremia to randomization due to the time it takes to perform sensitivity testing, though this would tend to decrease the mortality in the PTZ group, as 13.8% initially received a carbapenem as empiric therapy. Interestingly, as noted even those randomized to PTZ could “step-down” to a carbapenem, such as ertapenem once daily, on day 5 after randomization (likely chosen for ease of dosing rather than targeted therpay). Finally, only two patients from North America were included in this study, though the ESBL genes in the bacteria isolated in the trial were similar to prevalence reports from the United States.

That the trial was stopped early came as somewhat of a surprise in a design investigating non-inferiority of PTZ to meropenem for ESBL infections. The authors take care not to state they found “superiority” of meropenem, even if the results suggest this, because the nuance of a non-inferiority study design. Rather, they state PTZ “did not result in noninferior 30-day mortality”. This, however, might make the direct clinical implication of the results from MERINO confusing. Yet the preponderance of evidence does suggest carbapenem superiority for ESBL infection [6]. For example, in another trial looking at complicated urinary tract infection, meropenem-vaborbactam was found to be superiority over PTZ (composite end point of clinical cure or improvement and microbial eradication).

The take home point is that currently, carbapenems remain the preferred treatment regimen of bacteremia due to ESBL-producing organisms. Cephalosporin-beta-lactamase inhibitor (CLBLIs) (ceftolozane-tazobactam and ceftazidime-avibactam) could be potential alternatives. Both are approved by the FDA for use in complicated UTI and intra-abdominal infections [2].

Footnotes

1Inhibitor-resistant beta-lactamases (not ESBLs) are similar enzymes that confer resistance to inhibition by clavulanic acid and sulbactam, but normally remain susceptible to inhibition by tazobactam and therefore piperacillin/tazobactam

2AmpC-type beta-lactamases are typically encoded on the chromosome, and are therefore inducible, and confer resistance to cephamycins, as well as oxyimino-beta-lactams, and are not inhibited by beta-lactamase inhibitors (SPACE organisms – Serratia, Pseudomonas or non Mirabilis Proteus, Acinetobacter, Citrobacter, and Enterobacter) [7].

References

  1. Rupp ME, Fey PD (2003) Extended Spectrum ??-Lactamase (ESBL)-Producing Enterobacteriaceae. Drugs 63:353–365. https://doi.org/10.2165/00003495-200363040-00002
  2. Pana ZD, Zaoutis T (2018) Treatment of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBLs) infections: what have we learned until now? F1000Research 7:1347. https://doi.org/10.12688/f1000research.14822.1
  3. Seo Y Bin, Lee J, Kim YK, et al (2017) Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli. BMC Infect Dis 17:404. https://doi.org/10.1186/s12879-017-2502-x
  4. Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME (2012) Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum -lactamases: a systematic review and meta-analysis. J Antimicrob Chemother 67:2793–2803. https://doi.org/10.1093/jac/dks301
  5. Rodriguez-Bano J, Navarro MD, Retamar P, et al (2012) -Lactam/ -Lactam Inhibitor Combinations for the Treatment of Bacteremia Due to Extended-Spectrum -Lactamase-Producing Escherichia coli: A Post Hoc Analysis of Prospective Cohorts. Clin Infect Dis 54:167–174. https://doi.org/10.1093/cid/cir790
  6. Kaye KS, Bhowmick T, Metallidis S, et al (2018) Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection. JAMA 319:788. https://doi.org/10.1001/jama.2018.0438
  7. Macdougall C (2011) Beyond Susceptible and Resistant, Part I: Treatment of Infections Due to  Gram-Negative Organisms With Inducible β-Lactamases. J Pediatr Pharmacol Ther  JPPT  Off J  PPAG 16:23–30