A new evolutionary and pharmacokinetic–pharmacodynamic scenario for rapid emergence of resistance to single and multiple anti-tuberculosis drugs

The current understanding of the mechanism of anti-tuberculosis drug resistance has been shaped by the history of development of anti-tuberculosis drugs in the past 60 years and was arrived at as part of inductive generalization. Recently, these standard beliefs have been tested in controlled hollow fiber systems experiments. Drug resistance in Mycobacterium tuberculosis was shown to be related to pharmacokinetic–pharmacodynamic (PK/PD) factors, and factors such as pharmacokinetic variability. Poor PK/PD exposures owing to our current non-optimized dosing regimens initiate a chain of evolution driven events, starting with induction of multi-drug efflux pumps, followed by the development of chromosomal mutations in time, which together lead to high level resistance multi-drug resistant tuberculosis and extremely drug resistant tuberculosis.

► Mycobacterium tuberculosis resistance to pyrazinamide and ethambutol are linked to % time concentration persists above MIC while resistance to rifampin is linked to Cmax/MIC ratio and isoniazid to both Cmax/MIC and AUC/MIC.
► Mutation rates are high and drug resistance emerges in Mycobacterium tuberculosis even during latency.
► In our current poorly optimized regimens, induction of efflux pumps might lead to multiple drug tolerance/resistance and emergence of MDR-TB.
► We propose a new evolutionary scenario for MDR-TB emergence that integrates PK/PD, efflux pumps, mutator genes, and standard chromosomal mutations.