The much awaited MERINO trial is finally published.
This is a pragmatic RCT which studied whether piperacillin-tazobactam was non inferior to meropenem as definitive therapy among patients with ceftriaxone resistant (and mostly pip-taz susceptible) Ecoli or Klebsiella bacteremia. The primary outcome was 30 day mortality.
This study was conducted in 9 centres (mainly Singapore and Australia, no Indian centres were included) Patients were randomised at 72 hrs when the susceptibilities were available from the microbiology lab. The non inferiority margin used was 5% Patients received the therapy between 4 and 14 days - the treating physician decided the duration of therapy.
Points to note:
- Piptaz group had more immune compromised patients (27.1 vs 20.9%)
- At resolution almost 40% of patients in both arms had no fever, elevated TC or positive blood cultures
- The trial was terminated early as per DSMB’s suggestion (391 recruited, sample size calculated was 454).
- Since the trial evaluated the role of piptaz as definitive therapy, all patients received varied therapies before randomisation
A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6%). The number needed to harm was 11.6. The effect was consistent across subgroup analyses.
Now, why did pip-taz fail? Likely the reason is due to complex resistance mechanisms exhibited by the isolates. On WGS, 67.6 % showed OXA 1 narrow spectrum oxacillinases in addition to ESBLs and ampCs. These are of course are not inactivated by tazobactam. The duration of infusion could be another reason but the investigators used a high dose. Inoculum effect is unlikely to be operational here as most of the patients were not septic at recruitment and had already received appropriate therapy.
Overall, piperacillin-tazobactam did not meet non inferiority to meropenem in patients with ESBL gram negative bacteremia and hence should be avoided in this setting!