A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

Abstract

The spread of extended-spectrum-␤-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether ␤-lactam/␤-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.)

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

“…More recently, Gutiérrez-Gutiérrez et al conducted a multinational, observational study investigating this question in a design similar to the Rodriguez-Baňo study [52]. In fact, some of the same patients were included in both cohorts.…”

“…Existing observational data have indicated contradictory results between outcomes of patients receiving PTZ and carbapenems for the treatment of ESBL infections (Table 5) [8,47,[48][49][50][51][52][53][54]. Rodriguez-Baňo and colleagues provided some of the earliest robust data evaluating β-lactam-β-lactamase inhibitors (βL-βLIs) and carbapenems for the treatment of ESBL bacteremia by conducting a post hoc observational study of Spanish patients from 6 cohorts [47].…”

Use of β-Lactam/β-Lactamase Inhibitors for Extended-Spectrum-β-Lactamase Infections: Defining the Right Patient Population

“…In the past, the inoculum effect observed in vitro (1,2), data from animal studies (3,4), coexpression of additional ␤-lactamases not effectively inhibited by ␤-lactamase inhibitors (␤LI) (5), and concerns regarding inadequate pharmacokinetic-pharmacodynamic drug target attainment with standard ␤-lactam (␤L)/␤LI dosing regimens (6, 7) have tempered the enthusiasm for prescribing these agents for the treatment of invasive ESBL infections. However, more recently, and in large part due to the multicenter efforts led by several Spanish investigators (8,9), such concerns have been largely alleviated. It has been shown that for many patients with invasive ESBL infections, ␤L-␤LI treatments are safe and effective options.…”

“…The investigators compared ␤L/␤LIs to carbapenems in a cohort of neutropenic patients with ESBL bacteremia and hematological malignancies. This is a subgroup that had traditionally been left unaddressed in previous observational studies (8,9,(11)(12)(13)(14)(15). The investigators used propensity-score matching to limit bias from confounding by indication.…”

Multidrug-resistant Gram-negative bacteria-resistant infections: epidemiology, clinical issues and therapeutic options

“…25,26 However, according to recent data, BLBLIs, if active in vitro, appear to be as effective as carbapenems for empirical therapy of bloodstream infections due to ESLB-Enterobacteriaceae, regardless of the source and specific species, if used at appropriate doses. 27 Therefore, high dosage with loading dose and semicontinuous administration of BLBLIs, supported by therapeutic drug monitoring should be preferred for clinically stable patients. is likely to result in treatment failure (even with in vitro susceptibility).…”