Abstract
ObjectivesTo demonstrate how phenotypic cell viability data can provide insight into antimycobacterial effects for the isoniazid/rifampicin treatment backbone.MethodsData 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.ResultsIsoniazid/rifampicin combination therapy displayed a decreasing overall antimicrobial effect with time ( = 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 ( = 28.9 h, = 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.ConclusionsCell 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.
Highlights
Many infectious diseases require a combination of antimicrobial drugs to ensure complete pathogen clearance from the body
Little is known about how such combinations contribute to bacillary killing even though understanding this phenomenon in a quantitative manner would provide important insights into the activity of existing and novel drug combinations
Drug levels generated in the hollow-fibre model of infection were adjusted for protein binding, namely 42% for isoniazid and 83% for rifampicin (Table 1).[24]
Summary
Many infectious diseases require a combination of antimicrobial drugs to ensure complete pathogen clearance from the body. TB is a good example; it infects 9 million people worldwide each year and TB causes about 1.5 million deaths, which is more than any other infectious disease.[1] Even standard treatment of drugsusceptible TB is complex, with daily oral administration of four antibiotics during the first 2 months, followed by daily oral administration of two antibiotics during a 4 month continuation phase.[2]. Current treatment evolved from a series of clinical trials over a period of 60 years.[3] During this period, drugs and dosing regimens used in randomized controlled trial protocols were empirical with the evidence from one trial being used to plan the next. Little is known about how such combinations contribute to bacillary killing even though understanding this phenomenon in a quantitative manner would provide important insights into the activity of existing and novel drug combinations
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