Multidrug-Resistant Tuberculosis Not Due to Noncompliance but to Between-Patient Pharmacokinetic Variability

Abstract

These data, based on a preclinical model, demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…This timing makes the probability of generation of mutants, or even amplifying pre-existing ones, less likely, particularly for nonreplicating persistors and semi dormant bacilli, aptly described as "fat and lazy" by Garton and colleagues 179 because of their lipid content and slow doubling times, which can take weeks. 180 The pharmacokinetic mismatch hypothesis for acquired drug resistance was directly tested for isoniazid and rifampicin in the hollow fibre model of tuberculosis, on the basis of M tuberculosis doubling times of 24 h and 240 h. 181,182 This preclinical model was chosen because of the ease in which acquired drug resistance arises in the model. Acquired drug resistance did not arise with mismatched regimens, even when the inoculum was spiked with 0·5% rifampicinresistant and isoniazid-resistant isogenic strains; rather, microbial kill was actually better with the most deliberately mismatched regimens compared with the most perfectly matched regimen, supporting a role for sequential dosing.…”

“…181 This experimental modelwhich has a forecasting accuracy of 94% for clinical therapeutic events in patients with tuberculosis, based on evidence gathered for regulatory approval by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)-enables experi ments to be done that could be too dangerous in patients (eg, the deliberate generation of acquired drug re sistance). 183 Different degrees of adherence, from 0% to 100% of doses missed, and different adherence patterns (on-off; on-off-on-off, random missed doses) were used, and population size of the resistant subpopulations was captured via repetitive sampling with treatment of up to 56 days.…”

“…191 This is because of the differential rapid elimination of some drugs in the regimen, leading to prolonged monotherapy with the drug that is not rapidly or extensively metabolised over tens to hundreds of rounds of bacterial replication. The in-silico study 181 predicted that 0·68% of patients would develop acquired drug resistance and MDR tuberculosis within 2 months despite 100% adherence, because of such differential pharmacokinetic variability of regimen components. A prospective clinical study 191 in the same population was performed, and identified suboptimal drug concentrations due to pharmacokinetic variability as the cause of failure of therapy in more than 90% of patients.…”

“…A direct association exists between acquired drug resistance and drug pharmacokinetics 181 and is best explained by use of antimicrobial pharmacokineticpharmacodynamic science. Similarly, drug exposures predict the clearing of viable M tuberculosis from the sputum.…”

“…Estimating the burden due to ineffective or poorly adherent treatment is further complicated by data that suggest that approxi mately 1% of patients will still acquire resistance despite having uninterrupted treatment. 181 Additionally, the association between treatment effectiveness (which can vary widely) and the degree of acquisition of drug resistance is not well understood.…”