Use of piperacillin-tazobactam (Zosyn) likely less effective than meropenem for ceftriaxone-resistant gram-negative bacteremia

1. In this randomized controlled trial, piperacillin-tazobactam was not found to be non-inferior to meropenum for all-cause mortality at 30 days among patients with gram-negative bacteremia.

2. There was no difference in microbiological resolutions between the two antibiotics in ceftriaxone-resistant gram-negative bacteremia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Antibiotic resistance has become an increasing concern, especially for ceftriaxone-resistant gram-negative bacilli that produce extended-spectrum beta-lactamase enzymes (ESBL). Antibiotics such piperacillin-tazobactam has been proposed as a carbapenem alternative, though it is unclear if they as effective. In this randomized, multinational trial, non-inferiority could not be established for piperacillin-tazobactam compared to meropenum in terms of all-cause mortality at 30 days. There was no difference in the time to resolutions of symptoms of infection nor in minimum inhibitory concentration (MIC) between the two groups. Among blood culture isolates, an overwhelming majority produced ESBL enzymes and nearly all were susceptible to meropenem. After the data and safety monitoring board reviewed this study in August of 2017, the decision was made to terminate the study based on harm and futility.

Efforts to discover alternatives to carbapenems should continue despite the results from this trial. Unfortunately, in this study, empiric antibiotic therapy was not dictated by study protocol and therefore could have very well influenced the outcomes from this study. Additionally, with this being a multinational study, antibiotics may have been dosed differently in some hospitals.

Click to read the study in JAMA

Relevant Reading: Carbapenems versus alternative antibiotics for the treatment of bacteremia due to Enterobacteriaceae producing extended-spectrum beta-lactamases: a systematic review and meta-analysis

In-Depth [randomized controlled trial]: This study recruited eligible patients from 26 hospitals in 9 countries from February 2014 to July 2017. Eligible patients were those having either E coli or Klebsiella bacteremia. Patients were randomized in a 1:1 ratio to receive either piperacillin-tazobactam or meropenem. The primary outcome was all-cause mortality at 30-days. A total of 1,646 patients were screened for eligibility during the study period and 379 patients were enrolled to receive either piperacillin-tazobactam (n=187) or meropenem (n=191). There were no differences in baseline characteristics of the two groups. Overall, 30 patients met the primary outcome of all-cause mortality at 30 days, 23 in the piperacillin-tazobactam group and 7 meropenem in the meropenem group (risk difference 8.6%; p = 0.90 for non-inferiority). There was no difference in time to resolution of signs of infection between the two groups (3 vs. 2 (IQR 1,5); p = 0.18). A total of 306 resulting blood cultures were available from the primary outcome population (n=266 E coli; n=40 Klebsiella). 99.7% of isolates were susceptible to meropenem and extended spectrum beta-lactamase (ESBL) production was discovered in 86% of isolates. The study was terminated on August 10, 2017 due to reasons of harm and futility. 

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