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)

Yiying Cai, Nathalie Grace Chua, Tze-Peng Lim, Jocelyn Qi-Min Teo, Winnie Lee, Asok Kurup, Tse-Hsien Koh, Thuan-Tong Tan, Andrea L Kwa, Yiying Cai, Nathalie Grace Chua, Tze-Peng Lim, Jocelyn Qi-Min Teo, Winnie Lee, Asok Kurup, Tse-Hsien Koh, Thuan-Tong Tan, Andrea L Kwa

Abstract

Introduction: 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.

Conflict of interest statement

Competing Interests: ALK has received funding for research from Janssen-Cilag, Pfizer Inc. and Merck Sharp and Dome (I.A) Corp. None of the companies provided any funding for this study. All other authors have declared that no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Summary of the Work Process…
Fig 1. Summary of the Work Process of the Prospective iACT Service.
Combination antibiotic regimens recommended by the iACT service take into account both the in vitro bactericidal activity of the combinations and the probability of PK/PD target attainment, and are recommended to the attending ID physician within 48h from request. Abbreviations used in Fig 1: GNB = Gram-negative bacteria, iACT = in vitro antibiotic combination testing, ID = Infectious Diseases, MIC = minimum inhibitory concentration PDR = pan-drug resistant, PK = pharmacokinetic, XDR = extensively-drug resistant.

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