AUTHOR=Deshpande Devyani , Srivastava Shashikant , Pasipanodya Jotam Garaimunashe , Gumbo Tawanda 

TITLE=Minocycline intra-bacterial pharmacokinetic hysteresis as a basis for pharmacologic memory and a backbone for once-a-week pan-tuberculosis therapy

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1024608

DOI=10.3389/fphar.2022.1024608

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> There is need for shorter duration regimens for the treatment of <italic>tuberculosis</italic>, that can treat patients regardless of multidrug resistance status (pan-tuberculosis).</p><p><bold>Methods:</bold> We combined minocycline with tedizolid, moxifloxacin, and rifampin, in the hollow fiber system model of <italic>tuberculosis</italic> and mimicked each drugs’ intrapulmonary pharmacokinetics for 28 days. Minocycline-tedizolid was administered either as a once-a-week or a daily regimen. In order to explore a possible explanation for effectiveness of the once-a-week regimen, we measured systemic and intra-bacterial minocycline pharmacokinetics. Standard daily therapy (rifampin, isoniazid, pyrazinamide) was the comparator. We then calculated <italic>γ</italic><sub>f</sub> or kill slopes for each regimen and ranked the regimens by time-to-extinction predicted in patients.</p><p><bold>Results:</bold> The steepest <italic>γ</italic><sub>f</sub> and shortest time-to-extinction of entire bacterial population was with daily minocycline-rifampin combination. There was no difference in <italic>γ</italic><sub>f</sub> between the minocycline-tedizolid once-a-week <italic>versus</italic> the daily therapy (<italic>p</italic> = 0.85). Standard therapy was predicted to cure 88% of patients, while minocycline-rifampin would cure 98% of patients. Minocycline concentrations fell below minimum inhibitory concentration after 2 days of once-weekly dosing schedule. The shape of minocycline intra-bacterial concentration-time curve differed from the extracellular pharmacokinetic system and lagged by several days, consistent with system hysteresis. Hysteresis explained the persistent microbial killing after hollow fiber system model of <italic>tuberculosis</italic> concentrations dropped below the minimum inhibitory concentration.</p><p><bold>Conclusion:</bold> Minocycline could form a backbone of a shorter duration once-a-week pan-tuberculosis regimen. We propose a new concept of post-antibiotic microbial killing, distinct from post-antibiotic effect. We propose system hysteresis as the basis for the novel concept of pharmacologic memory, which allows intermittent dosing.</p>