Can phenotypic data complement our understanding of antimycobacterial effects for drug combinations?
Date
12/2019Metadata
Show full item recordAbstract
Objectives : To demonstrate how phenotypic cell viability data can provide insight into antimycobacterial effects for the isoniazid/rifampicin treatment backbone. Methods : Data from a Mycobacterium komossense hollow-fibre infection model comprising a growth control group, rifampicin at three different exposures (Cmax = 0.14, 0.4 and 1.47 mg/L with t½ = 1.57 h and τ = 8 h) and rifampicin plus isoniazid (Cmax rifampicin = 0.4 mg/L and Cmax isoniazid = 1.2 mg/L with t½ = 1.57 h and τ = 8 h) were used for this investigation. A non-linear mixed-effects modelling approach was used to fit conventional cfu data, quantified using solid-agar plating. Phenotypic proportions of respiring (alive), respiring but with damaged cell membrane (injured) and 'not respiring' (dead) cells data were quantified using flow cytometry and Sytox Green™ (Sigma-Aldrich, UK) and resazurin sodium salt staining and fitted using a multinomial logistic regression model. Results : Isoniazid/rifampicin combination therapy displayed a decreasing overall antimicrobial effect with time (θTime1/2 = 438 h) on cfu data, in contrast to rifampicin monotherapy where this trend was absent. In the presence of isoniazid a phenotype associated with cell injury was displayed, whereas with rifampicin monotherapy a pattern of phenotypic cell death was observed. Bacterial killing onset time on cfu data correlated negatively (θTime50 = 28.9 h, θLAGRIF50 = 0.132 mg/L) with rifampicin concentration up to 0.165 mg/L and this coincided with a positive relationship between rifampicin concentration and the probability of phenotypic cell death. Conclusions : Cell viability data provide structured information on the pharmacodynamic interaction between isoniazid and rifampicin that complements the understanding of the antibacillary effects of this mycobacterial treatment backbone.
Citation
Kloprogge , F , Hammond , R , Copas , A , Gillespie , S H & Della Pasqua , O 2019 , ' Can phenotypic data complement our understanding of antimycobacterial effects for drug combinations? ' , Journal of Antimicrobial Chemotherapy , vol. 74 , no. 12 , pp. 3530–3536 . https://doi.org/10.1093/jac/dkz369
Publication
Journal of Antimicrobial Chemotherapy
Status
Peer reviewed
ISSN
0305-7453Type
Journal article
Description
Funding: British Society for Antimicrobial Chemotherapy Research Grant (GA2015-172R). F. K. conducted the research as part of a Medical Research Council fellowship (MR/P014534/1).Collections
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