Multi-drug therapy is the standard-of-care treatment for tuberculosis. Despite this, virtually all studies of the\npharmacodynamics (PD) of mycobacterial drugs employed for the design of treatment protocols are restricted to single\nagents. In this report, mathematical models and in vitro experiments with Mycobacterium marinum and five\nantimycobacterial drugs are used to quantitatively evaluate the pharmaco-, population and evolutionary dynamics of\ntwo-drug antimicrobial chemotherapy regimes. Time kill experiments with single and pairs of antibiotics are used to\nestimate the parameters and evaluate the fit of Hill-function-based PD models. While Hill functions provide excellent fits for\nthe PD of each single antibiotic studied, rifampin, amikacin, clarithromycin, streptomycin and moxifloxacin, two-drug Hill\nfunctions with a unique interaction parameter cannot account for the PD of any of the 10 pairs of these drugs. If we assume\ntwo antibiotic-concentration dependent functions for the interaction parameter, one for sub-MIC and one for supra-MIC\ndrug concentrations, the modified biphasic Hill function provides a reasonably good fit for the PD of all 10 pairs of\nantibiotics studied. Monte Carlo simulations of antibiotic treatment based on the experimentally-determined PD functions\nare used to evaluate the potential microbiological efficacy (rate of clearance) and evolutionary consequences (likelihood of\ngenerating multi-drug resistance) of these different drug combinations as well as their sensitivity to different forms of nonadherence\nto therapy. These two-drug treatment simulations predict varying outcomes for the different pairs of antibiotics\nwith respect to the aforementioned measures of efficacy. In summary, Hill functions with biphasic drug-drug interaction\nterms provide accurate analogs for the PD of pairs of antibiotics and M. marinum. The models, experimental protocols and\ncomputer simulations used in this study can be applied to evaluate the potential microbiological and evolutionary efficacy\nof two-drug therapy for any bactericidal antibiotics and bacteria that can be cultured in vitro.
Loading....