Carbapenem-Sparing Therapy for Extended-Spectrum β-Lactamase-Producing E coli and Klebsiella pneumoniae Bloodstream Infection: The Search Continues.

Bloodstream infections due to Escherichia coli and Klebsiella pneumoniae are associated with significant morbidity, mortality, and financial costs.1 Resistance to third-generation cephalosporins is increasing in these species both in the community and in health care settings.2 The most common mechanism of third-generation cephalosporin resistance is production of an extendedspectrum β-lactamase (ESBL). 3 These enzymes render E coli and K pneumoniae nonsusceptible to nearly all cephalosporins and penicillins. Carbapenems, such as meropenem, remain active and are considered preferred agents for treatment of bloodstream infections due to ESBL-producing organisms. However, treatment with carbapenems creates selective pressure for development of carbapenem resistance, which is arguably the greatest contemporary antibiotic resistance threat. Thus, there is intense interest both in the development of new antibiotics and in the reassessment of older antibiotics for use as carbapenem alternatives. By definition, ESBLs are inhibited by β-lactamase inhibitors such as clavulanate and tazobactam. Because of this characteristic, β-lactam/β-lactamase inhibitors (BLBLIs) have been evaluated in several observational studies as carbapenem-sparing therapy for ESBL-producing bacterial infection. Results of these studies have been conflicting. In a large multinational cohort study, 30-day mortality was similar in patients with ESBL-producing bacteremia who were treated with either a BLBLI or a carbapenem for empirical therapy (ie, treatment before antibiotic susceptibility results are known, n = 365 patients) or definitive therapy (ie, treatment targeted to known antibiotic susceptibility, n = 601 patients), with mortality rates of 17.6% vs 20% (empirical therapy) and 9.8% vs 13.9% (definitive therapy), for BLBI and carbapenem treatment, respectively.4 A systematic review and meta-analysis of 14 studies comparing BLBLIs or carbapenems for treatment of ESBL-producing bacterial bloodstream infections did not identify a significant difference in mortality between treatment groups. Mortality rates were 20.5% (109/531) vs 22.1% (121/547) in the empirical treatment group and 16.2% (32/199) vs 15.2% (115/ 767) in the definitive treatment group for BLBLI and carbapenem therapy, respectively, although heterogeneity among studies of definitive therapy was high.5 In contrast, a large single-center, retrospective cohort study of 331 patients with ESBL-producing bacteremia found that the risk of 14-day mortality was greater in patients treated empirically with piperacillin-tazobactam (17% mortality) compared with those treated with a carbapenem (8% mortality). 6 Additional concerns from in vitro and animal models include the reduced activity of piperacillin-tazobactam in the presence of higher bacterial inoculums,7,8 as can be seen in infections such as pneumonia. The discrepancies between outcomes of these and other studies have led to debate about the appropriate clinical uses of BLBLIs.9 The MERINO trial, results of which are reported in this issue of JAMA, was designed to help resolve this controversy.10 In this study, Harris and colleagues10 conducted an international noninferiority open-label randomized clinical trial to compare the effects of piperacillin-tazobactam (4.5 g every 6 hours) vs meropenem (1 g every 8 hours) given intravenously as definitive therapy on 30-day mortality for adult patients with ceftriaxone-resistant E coli or K pneumoniae bacteremia. Patients were randomized within 72 hours of blood culture collection and received study drug for a minimum of 4 days and a maximum of 14 days after randomization, with length of therapy determined by the treating physician. A conservative 5% noninferiority margin was used. As reported in the article by Harris et al,10 a decision to terminate the study was made “by the study management team, after discussion with site investigators” on the grounds of harm and futility when the third prespecified interim review determined that it was highly unlikely that noninferiority could be demonstrated. Results of the study are striking. A total of 391 patients were randomized and 378 were evaluable. Overall, the groups were balanced for baseline characteristics. Most episodes of bacteremia (86.2%) were due to E coli, 43.8% were community associated, and 54.8% had a urinary tract source. In the primary analysis population, all-cause 30-day mortality was 12.3% (23/187) in the piperacillin-tazobactam group and 3.7% (7/191) in the meropenem group, for an absolute risk difference of 8.6% (1-sided 97.5% CI, − to 14.5%; P = .90 for noninferiority) and a number needed to harm of 12. Results were consistent in the per-protocol population, and adjustment for source of infection and Charlson Comorbidity Index score did not alter results significantly. No subgroup met the noninferiority margin (although the study was not powered for these analyses) Related article page 984 Opinion