Regrowth of Mycobacterium tuberculosis Populations Exposed to Antibiotic Combinations Is Due to the Presence of Isoniazid and Not Bacterial Growth Rate

Modulation of the growth rate in Mycobacterium tuberculosis is key to its survival in the host, particularly with regard to its adaptation during chronic infection, when the growth rate is very slow. The resulting physiological changes influence the way in which this pathogen interacts with the host and responds to antibiotics. Therefore, it is important that we understand how the growth rate impacts antibiotic efficacy, particularly with respect to recovery/relapse. This is the first study that has asked how growth rates influence the mycobacterial responses to combinations of the frontline antimycobacterials, isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA), using continuous cultures. The time course profiles of log-transformed total viable counts for cultures, controlled at either a fast growth rate (mean generation time [MGT], 23.1 h) or a slow growth rate (MGT, 69.3 h), were analyzed by the fitting of a mathematical model by nonlinear regression that accounted for the dilution rate in the chemostat and profiled the kill rates and recovery in culture. Using this approach, we show that populations growing more slowly were generally less susceptible to all treatments. We observed a faster kill rate associated with INH than with RIF or PZA and the appearance of regrowth. In line with this observation, regrowth was not observed with RIF exposure, which provided a slower bactericidal response. The sequential additions of RIF and PZA did not eliminate regrowth. We consider here that faster, early bactericidal activity is not what is required for the successful sterilization of M. tuberculosis, but instead, slower elimination of the bacilli followed by reduced recovery of the bacterial population is required.