Clinical Efficacy of Combination Therapy for the Treatment of Severe Infections Caused by Carbapenem Resistant Gram-Negatives. A Systematic Review of Clinical Studies

Abstract

\n Background: The combination of antibiotics has become the clinicians’ preferred strategy for the treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) although the evidence supporting its use is weak. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods: Comparative and non-comparative observational studies, randomized control trials (RCTs) and case series were considered eligible with no language restriction. Studies were included if reporting microbiologically-confirmed sepsis caused by Acinetobacter baumannii, Enterobacterales/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcome and targeted antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected to explore feasibility of pooling data on antibiotic regimens. Results: A total of 6306 records were retrieved and 134 studies (11546 patients) were included [54 studies on Acinetobacter, 52 on Enterobacterales/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas]. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective and 17 (13%) case series. Forty-one studies (31%) were multicentric. Ninety-two distinct regimens were identified with 47 (51%, 5863 patients) not reporting any details on combination. 30-day mortality was assessed in 65 (48%) studies while attributable mortality was reported only in 19 (14%).The NMAs were not applicable for any of selected outcomes given the presence of too many disconnected components. Conclusion: The existing evidence is too weak for allowing formulating any evidence-based therapeutic recommendation for combination of antibiotics to treat CR-GNB sepsis. Future studies must clearly define number, type, dosages, and in vitro activity of each antibiotic included in the regimen to drive recommendations for using combination of antibiotics that might be reliably applied into clinical practice.