Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis

Abstract

Infections caused by carbapenemase-producing, multidrug-resistant (MDR), or extensively drug-resistant (XDR) Gram-negative bacteria constitute a major therapeutic challenge. Whether combination antibiotic therapy is superior to monotherapy remains unknown. In this systematic review and meta-analysis OVID MEDLINE, EMBASE, PubMed, The Cochrane Library, and Scopus databases were searched for randomized controlled trials (RCTs) and observational studies published by December 2016 comparing mono- with combination antibiotic therapy for infections with carbapenemase-producing, MDR, or XDR Gram-negative bacteria. Mortality and clinical cure rates served as primary and secondary outcome measures, respectively. Of 8847 initially identified studies, 53 studies - covering pneumonia (n = 10 studies), blood stream (n = 15), osteoarticular (n = 1), and mixed infections (n = 27) - were included. 41% (n = 1848) of patients underwent monotherapy, and 59% (n = 2666) combination therapy. In case series/cohort studies (n = 45) mortality was lower with combination- vs. monotherapy (RR 0.83, CI 0.73-0.93, p = 0.002, I² = 24%). Subgroup analysis revealed lower mortality with combination therapy with at least two in-vitro active antibiotics, in blood stream infections, and carbapenemase-producing Enterobacteriaceae. No mortality difference was seen in case-control studies (n = 6) and RCTs (n = 2). Cure rates did not differ regardless of study type. The two included RCTs had a high and unknown risk of bias, respectively. 16.7% (1/6) of case-control studies and 37.8% (17/45) of cases series/cohort studies were of good quality, whereas quality was poor in the remaining studies. In conclusion, combination antimicrobial therapy of multidrug-resistant Gram-negative bacteria appears to be superior to monotherapy with regard to mortality.

Figure 1

Study selection.

Figure 2

Risk ratios for mortality rates of case series and cohort studies stratified by different bacteria. Data markers indicate Risk ratios and error bars indicate 95% CIs.

Figure 3

Risk ratios for mortality rates of case series and cohort studies stratified by different bacteria. Combination therapy with at least two in vitro active substances. Data markers indicate RRs and error bars indicate 95% CIs.

Figure 4

Risk ratios for clinical cure rates of case series and cohort studies stratified by different bacteria. Data markers indicate Risk ratios and error bars indicate 95% CIs.

Figure 5

Risk ratios for clinical cure rates of case series and cohort studies stratified by different bacteria. Combination therapy with at least two in vitro active substances. Data markers indicate Risk ratios and error bars indicate 95% CIs.