title: Clinical Efficacy of Polymyxin Monotherapy versus Nonvalidated Polymyxin Combination Therapy versus Validated Polymyxin Combination Therapy in Extensively Drug-Resistant Gram-Negative Bacillus Infections.
abstract: Polymyxins have emerged as a last-resort treatment of extensively drug-resistant (XDR) Gram-negative Bacillus (GNB) infections, which present a growing threat. Individualized polymyxin-based antibiotic combinations selected on the basis of the results of in vitro combination testing may be required to optimize therapy. A retrospective cohort study of hospitalized patients receiving polymyxins for XDR GNB infections from 2009 to 2014 was conducted to compare the treatment outcomes between patients receiving polymyxin monotherapy (MT), nonvalidated polymyxin combination therapy (NVCT), and in vitro combination testing-validated polymyxin combination therapy (VCT). The primary and secondary outcomes were infection-related mortality and microbiological eradication, respectively. Adverse drug reactions (ADRs) between treatment groups were assessed. A total of 291 patients (patients receiving MT, n = 58; patients receiving NVCT, n = 203; patients receiving VCT, n = 30) were included. The overall infection-related mortality rate was 23.0% (67 patients). In the multivariable analysis, treatment of XDR GNB infections with MT (adjusted odds ratio [aOR], 8.49; 95% confidence interval [CI], 1.56 to 46.05) and NVCT (aOR, 5.75; 95% CI, 1.25 to 25.73) was associated with an increased risk of infection-related mortality compared to that with treatment with VCT. A higher Acute Physiological and Chronic Health Evaluation II (APACHE II) score (aOR, 1.14; 95% CI 1.07 to 1.21) and a higher Charlson comorbidity index (aOR, 1.28; 95% CI, 1.11 to 1.47) were also independently associated with an increased risk of infection-related mortality. No increase in the incidence of ADRs was observed in the VCT group. The use of an individualized antibiotic combination which was selected on the basis of the results of in vitro combination testing was associated with significantly lower rates of infection-related mortality in patients with XDR GNB infections. Future prospective randomized studies will be required to validate these findings.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Bingxuan
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore Department of Pharmacy, Singapore General Hospital, Singapore.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore.
authors.forename: Yi Xin
authors.initials: YX
authors.lastname: Liew
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore.
authors.forename: Nathalie Grace
authors.initials: NG
authors.lastname: Chua
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore.
authors.forename: Jocelyn Qi-Min
authors.identifier: 0000-0003-2508-3941
authors.initials: JQ
authors.lastname: Teo
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore.
authors.forename: Tze-Peng
authors.initials: TP
authors.lastname: Lim
authors.affiliation: Infectious Disease Care, Mount Elizabeth Hospital, Singapore.
authors.forename: Asok
authors.initials: A
authors.lastname: Kurup
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
authors.forename: Pui Lai Rachel
authors.initials: PL
authors.lastname: Ee
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, Singapore.
authors.forename: Thuan Tong
authors.initials: TT
authors.lastname: Tan
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore.
authors.forename: Winnie
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore Department of Pharmacy, Singapore General Hospital, Singapore Emerging Infectious Disease Program, Duke-National University of Singapore Medical School, Singapore andrea.kwa.l.h@sgh.com.sg.
authors.forename: Andrea Lay-Hoon
authors.initials: AL
authors.lastname: Kwa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011113:Polymyxins / Q000627:therapeutic use*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D011113:Polymyxins