Drug Combo No Better for Hard-to-Treat Bloodstream Infections

Pam Harrison

September 11, 2018

Piperacillin-tazobactam, a potentially "carbapenem-sparing" option for the treatment of bloodstream infections caused by ceftriaxone-resistant Escherichia coli or Klebsiella pneumoniae has a higher 30-day mortality rate than meropenem and should not be used as a substitute for these infections, the noninferiority MERINO trial indicates.

"In patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, noninferiority of piperacillin-tazobactam for the primary outcome of 30-day mortality could not be demonstrated when compared with meropenem," Patrick Harris, MBBS, from the University of Queensland, Brisbane, Australia, and colleagues report. "These findings do not support use of piperacillin-tazobactam in this setting," they conclude. The study was published online September 11 in JAMA.

The MERINO study was an international, multicenter, randomized clinical trial comparing piperacillin-tazobactam with meropenem for the treatment of bloodstream inflections caused by ceftriaxone-resistant E coli or K pneumoniae in adults who had at least one positive blood culture for either species that were not susceptible to ceftriaxone or cefotaxime, both of which are third-generation cephalosporins. As the authors explain, extended-spectrum β-lactamases enzymes confer resistance to third-generation cephalosporins in the setting of E coli and K pneumoniae.

Most of the bacteremia (86.2%) was caused by E coli, and 54.8% of the infections had a urinary tract source. The researchers randomly assigned patients to receive meropenem 1 g intravenously every 8 hours or piperacillin-tazobactam 4.5 g intravenously every 6 hours. Patients were assigned to the study drug within 72 hours of having a blood culture taken and were treated for a minimum of 4 days and a maximum of 14 days.

"The primary efficacy outcome was all-cause mortality at 30 days after randomization," the authors note. The primary analysis included 187 patients assigned to piperacillin-tazobactam and 191 patients assigned to meropenem. At 30 days, all-cause mortality rates were 12.3% in the carbapenem-sparing group compared with 3.7% in the meropenem group (P = .90 for noninferiority).

In the slightly smaller per protocol population, 10.6% of 170 patients in the piperacillin-tazobactam group met the primary endpoint compared with 3.8% of 186 patients in the meropenem group (P = .76 for noninferiority). Adjustment for both the source of the infection and the Charlson Comorbidity Index score did not significantly change the final outcomes for either treatment group.

The investigators also documented both clinical and microbiological resolution of the infection by day 4 in 68.4% of patients treated with piperacillin-tazobactam compared with 74.6% of patients in the carbapenem group (P = .19). Importantly, "[p]atients receiving piperacillin-tazobactam did not have significantly lower rates of subsequent detection of carbapenem-resistant organisms, although this event was infrequent (3.2% vs 2.1%)," the researchers add.

Rates of serious adverse events were low in both groups.

"Striking" Results

In an accompanying editorial, Mary Hayden, MD, and Sarah Won, MD, MPH, both from Rush University Medical Center in Chicago, Illinois, called the results of the study "striking."

"The inability of the authors to demonstrate noninferiority of piperacillin-tazobactam to meropenem is particularly notable because several features of the pragmatic trial design and patient population favored a noninferiority effect," the editorialists argue.

First, patients in either group were allowed to cross over from one group to the other. This meant that 13.8% of patients randomly assigned to piperacillin-tazobactam actually received a carbapenem as empirical therapy whereas 20.2% of them received a carbapenem as step-down therapy. "Acuity of illness was lower than expected: only 10 patients met criteria for a predefined high-risk category, 40.7% of patients had resolved signs of infection by the day of randomization, and the overall mortality rate was just 7.9%," they observe.

By way of comparison, a review and meta-analysis found mortality rates of 20.5% in patients with extended-spectrum β-lactamase-producing Enterobacteriaceae treated empirically with β-lactam/β-lactamase inhibitors compared with 22.1% for those treated empirically with a carbapenem, whereas mortality rates were 16.2% for those who received definitive β-lactam/β-lactamase inhibitor therapy compared with 15.2% for those receiving a carbapenem. "In total, these results provide strong evidence against the noninferiority of piperacillin-tazobactam for definitive treatment of bacteremia due to ceftriaxone-resistant E coli and K pneumoniae," Hayden and Won write.

"The results of the MERINO trial make clear that piperacillin-tazobactam should no longer be considered an alternative to meropenem for definitive treatment of bloodstream infection due to ceftriaxone-resistant E coli or K pneumoniae," they conclude.

Harris reports receiving support to speak at an educational event sponsored by Pfizer. A number of co-investigators have multiple ties to industry which are disclosed in the publication itself. Hayden reports receiving a research grant from Clorox Inc and serving as an investigator on research that received support in the form of products from Sage Corporation, Molnlycke, Clorox, OpGen, and Medline. Won has disclosed no relevant financial relationships.

JAMA. Published online September 11, 2018.

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