Polymyxin Monotherapy vs. Combination Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Bloodstream Infection: A National Cohort Study

Carbapenem-resistant Enterobacteriaceae (CRE) represent an emerging and urgent public health threat. CRE bloodstream infections (CRE-BSI) are associated with high mortality yet optimal treatment remains unclear. Previous studies comparing polymyxin monotherapy vs. combination therapy have largely been limited to single-center or small multicenter analyses. The objective of this study was to compare clinical outcomes between polymyxin monotherapy vs. combination therapy with various carbapenem agents for CRE-BSI in a national cohort of hospitalized Veterans Affairs (VA) patients. We conducted a national retrospective cohort study of patients admitted to any VA hospital from 2003 through 2015. Inclusion criteria were: i) hospital admission; ii) age ≥ 18 years; and iii) ≥ 1 blood culture positive for a CRE pathogen. Patients treated with a polymyxin agent < 48 hours were excluded. The primary outcome was 28-day survival, evaluated by Cox regression. A total of 312 patients met study criteria (polymyxin monotherapy, n = 96; polymyxin/carbapenem combination therapy, n = 216). Combination carbapenem agents included imipenem (n = 140), meropenem (n = 56), doripenem (n = 12), and ertapenem (n = 8). Overall, 28-day mortality was 36.5% (n = 114/312). Polymyxin/carbapenem combination therapy was significantly associated with improved 28-day survival compared with polymyxin monotherapy (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.39–0.85; P = 0.005). With regard to individual carbapenem agents, both combination meropenem (HR, 0.38; 95% CI, 0.20–0.71; P = 0.002) and imipenem (HR, 0.64; 95% CI, 0.42–0.96; P = 0.034) were associated with significantly improved 28-day survival compared with polymyxin monotherapy. There were no significant differences in survival between combination therapies with other carbapenem agents vs. polymyxin monotherapy. Combination polymyxin/carbapenem therapy was associated with significantly improved 28-day survival compared with polymyxin monotherapy in the treatment of CRE-BSI. This survival benefit was most pronounced when combination meropenem or imipenem were used. N. S. Britt, Merck & Co., Inc.: Grant Investigator, Consulting fee; Gilead Sciences, Inc.: Grant Investigator, Consulting fee; N. Patel, Gilead Sciences, Inc.: Grant Investigator, Research grant; Merck & Co., Inc.: Grant Investigator, Consulting fee; Theravance Biopharma US, Inc.: Board Member and Speaker’s Bureau, Speaker honorarium; M. E. Steed, Merck & Co., Inc.: Grant Investigator, Research grant