Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis

Objectives: The objective of this study was to summarize available data on polymyxin-based combination ther-apy or monotherapy for carbapenem-resistant Gram-negative bacteria. Methods: This is a systematic review. We included observational studies and randomized controlled trials (RCTs) comparing polymyxin monotherapy versus polymyxin-based combination therapy in adult patients with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Only named antibiotic regimens were included. The primary outcome was 30 day mortality. Unadjusted OR (uOR) and adjusted OR where available with 95% CI were pooled in random-effects meta-analyses. Results: Twenty-two studies including 28 comparisons were included. Polymyxin monotherapy was associated with a uOR of 1.58 (95% CI= 1.03-2.42) for mortality compared with polymyxin/carbapenem combination ther-apy (seven observational studies, 537 patients), without heterogeneity. Subgrouping studies to serious and crit-ical risk of bias resulted in uORs of 0.94 (95% CI= 0.42-2.09) and 1.94 (95% CI = 1.17-3.23), respectively. Mortality was significantly higher with polymyxin monotherapy compared with combination therapy with tige-cycline, aminoglycosides or fosfomycin (potentially double-coverage regimens): uOR of 1.57 (95% CI = 1.062.32) overall (10 observational studies and 1 RCT, 585 patients, no heterogeneity) and uOR of 2.09 (95% CI = 1.21-3.6) for Klebsiella pneumoniae bacteraemia (7 observational studies, 285 patients, no heterogeneity); very low quality evidence. Two RCTs and one observational study assessing rifampicin/colistin combination ther-apy for Acinetobacter baumannii infections showed no difference in mortality compared with colistin monother-apy; moderate quality evidence. Conclusions: The significant association observed in observational studies between polymyxin monotherapy and mortality cannot be taken as proof of combination therapy effects due to the lowquality of the evidence. The only three RCTs to date show no effect of rifampicin/colistin or fosfomycin/colistin on mortality for Acinetobacter infections.