title: From Bench-Top to Bedside: A Prospective In Vitro Antibiotic Combination Testing (iACT) Service to Guide the Selection of Rationally Optimized Antimicrobial Combinations against Extensively Drug Resistant (XDR) Gram Negative Bacteria (GNB).
abstract: BACKGROUND
  Combination therapy is increasingly utilized against extensively-drug resistant (XDR) Gram negative bacteria (GNB). However, choosing a combination can be problematic as effective combinations are often strain-specific. An in vitro antibiotic combination testing (iACT) service, aimed to guide the selection of individualized and rationally optimized combination regimens within 48 hours, was developed. We described the role and feasibility of the iACT service in guiding individualized antibiotic combination selection in patients with XDR-GNB infections.
  
  
  METHODS
  A retrospective case review was performed in two Singapore hospitals from April 2009-June 2014. All patients with XDR-GNB and antibiotic regimen guided by iACT for clinical management were included. The feasibility and role of the prospective iACT service was evaluated. The following patient outcomes were described: (i) 30-day in-hospital all-cause and infection-related mortality, (ii) clinical response, and (iii) microbiological eradication in patients with bloodstream infections.
  
  
  RESULTS
  From 2009-2014, the iACT service was requested by Infectious Disease physicians for 39 cases (20 P. aeruginosa, 13 A. baumannii and 6 K. pneumoniae). Bloodstream infection was the predominant infection (36%), followed by pneumonia (31%). All iACT recommendations were provided within 48h from request for the service. Prior to iACT-guided therapy, most cases were prescribed combination antibiotics empirically (90%). Changes in the empiric antibiotic regimens were recommended in 21 (54%) cases; in 14 (36%) cases, changes were recommended as the empiric regimens were found to be non-bactericidal in vitro. In 7 (18%) cases, the number of antibiotics used in combination empirically was reduced by the iACT service. Overall, low 30-day infection-related mortality (15%) and high clinical response (82%) were observed. Microbiological eradication was observed in 79% of all bloodstream infections.
  
  
  CONCLUSIONS
  The iACT service can be feasibly employed to guide the timely selection of rationally optimized combination regimens, and played a role in reducing indiscreet antibiotic use.
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.|Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.|Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: Nathalie Grace
authors.initials: NG
authors.lastname: Chua
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.|SingHealth Duke-NUS Medicine Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Tze-Peng
authors.initials: TP
authors.lastname: Lim
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.
authors.forename: Jocelyn Qi-Min
authors.initials: JQ
authors.lastname: Teo
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.
authors.forename: Winnie
authors.initials: W
authors.lastname: Lee
authors.affiliation: Infectious Diseases Care, Mount Elizabeth Hospital, Singapore, Singapore.
authors.forename: Asok
authors.initials: A
authors.lastname: Kurup
authors.affiliation: Department of Microbiology, Singapore General Hospital, Singapore, Singapore.
authors.forename: Tse-Hsien
authors.initials: TH
authors.lastname: Koh
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
authors.forename: Thuan-Tong
authors.initials: TT
authors.lastname: Tan
authors.affiliation: Department of Pharmacy, Singapore General Hospital, Singapore, Singapore.|Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.|Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Kwa
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003710:Demography; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology* / Q000401:mortality; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D057170:Translational Research, Biomedical
chemical_list: D000900:Anti-Bacterial Agents