MERINO Trial, Post-Hoc Analysis: Relationship Between MIC and 30-Day Mortality

Illustration of Enterobacteriaceae bacteria. Individual bacterium are shown as pink rod shapes with multiple hair-like flagella used for motility. The Enterobacteriaceae family contains over a hundred species including Shigella, Klebsiella, Salmonella and Escherichia coli and can be found in animal guts, water and soil. Some Enterobacteriaceae members are animal and plant parasites.
Study authors assessed the association of piperacillin/tazobactam MIC, meropenem MIC, and beta-lactam resistance genes with mortality in the MERINO trial.

For the treatment of bloodstream infections caused by Escherichia coli (E coli) and Klebsiella species that do not respond to ceftriaxone, meropenem (MER) remains the drug of choice. Piperacillacin/tazobactam (PTZ) should be avoided, particularly due to the high prevalence of oxacillinase (OXA) co-harboring extended spectrum beta-lactamases (ESBL), according to results from a study published in Clinical Infectious Disease. The 30-day mortality in this post-hoc analysis was less pronounced in PTZ compared to the MERINO study.

Investigators conducted an analysis on the microbiologic assessable population from the MERINO trial to study the association of PTZ minimum inhibitory concentrations (MICs), and MER MIC, and beta-lactam resistance genes with mortality. Patients who received at least 1 dose of the study drug, who were randomized appropriately, and whom the first positive blood culture isolate was received were included.

Of the 320 primary blood culture isolates, 278 were E coli and 42 were Klebsiella pneumoniae. The overall susceptibility to PTZ and MER in the microbiologic assessable population was 94% and 100%, respectively. The CTX-M group, found in 273 isolates, was the predominant beta-lactase genes identified by whole-genome sequencing. Narrow spectrum OXA genes were found in 102 isolates, SHV ESBL genes in 12 isolates, plasmid-encoded ampC genes in 36 isolates, and E coli with chromosomal mutations in ampC found in 3 isolates. The most common E coli sequence type (ST) was ST131, found in 143 isolates. The number of ST131 isolates co-harboring OXA genes (45%) was higher than the rate among the other STs combined (21%). Isolates harboring both OXA and ESBLs were found to have significantly higher modal PTZ MICs than those with only ESBLs (8 mg/L vs 2 mg/L; P <.001)

After accounting for confounders, data suggests that the PTZ non-susceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality (odds ratio, 14.9; 95% CI, 2.8-87.2). Absolute risk of 30-day mortality between PTZ- and MER-treated patients increased 9% (95% CI, 3-15%) in the original MERINO trial and 8% (95% CI, 2-15%) in the post-hoc microbiologic assessable populations. When strains with PTZ MIC values greater than 16 mg/L were excluded, 30-day mortality between PTZ and MER was reduced to 5% (95% CI, -1 to 10%). The isolates that harbored ESBL and OXA-1 genes were associated with elevated MICs for PTZ and the highest increase in risk of 30-day mortality at 14% (95% CI, 2-28%).

All initial isolates from enrolled patients were not collected.

There was a “strong association between PTZ MIC and mortality in the MERINO trial,” investigators concluded. Findings suggest caution in using PTZ for bloodstream infections caused by ceftriaxone non-susceptible E coli and Klebsiella species.


Henderson A, Paterson DL, Chatfield MD, et al. Association between minimum inhibitory concentration, beta-lactamase genes and mortality for patients treated with piperacillin/tazobactam or meropenem from the MERINO study. Clin Infect Dis. Published online October 27, 2020. doi: 10.1093/cid/ciaa1479.