Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!

Abstract

Background. One approach that could increase the efficacy and reduce the duration of antituberculosis therapy is pharmacokinetics/pharmacodynamics-based optimization of doses. However, this could increase toxicity. Methods. We mimicked the concentration-time profiles achieved by human equivalent doses of moxifloxacin 800 mg/day, rifampin 1800 mg/day, and pyrazinamide 4000 mg/day (high-dose regimen) vs isoniazid 300 mg/day, rifampin 600 mg/day, and pyrazinamide 2000 mg/day (standard therapy) in bactericidal and sterilizing effect studies in the hollow fiber system model of tuberculosis (HFS-TB). In an intracellular Mycobacterium tuberculosis (Mtb) HFS-TB experiment, we added a 3-dimensional human organotypic liver to determine potential hepatotoxicity of the high-dose regimen, based on lactate dehydrogenase (LDH). Treatment lasted 28 days and Mtb bacterial burden was based on colony counts. We calculated the time to extinction (TTE) of the Mtb population in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients. Results. The kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91-.99) log 10 colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49-.59) log 10 CFU/mL/day, respectively. The highdose regimen's bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96-.99) log 10 CFU/mL/day and 0.72 (95% CI, .56-.79) log 10 CFU/mL/day, respectively. The upper confidence bound for TTE in patients was 4.5-5 months for standard therapy vs 3.7 months on the high-dose regimen. There were no differences in LDH concentrations between the 2 regimens at any time point (P > .05). Conclusions. The high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.

Artificial intelligence–derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis

“…Antagonism disappeared when gatifloxacin AUC 0-24 exceeded 42 mg*h/L. Thus, if rifampin and gatifloxacin dosing were optimized to achieve this, shorter therapy duration could be effective, which is consistent with a high-dose rifampin and moxifloxacin hollow fiber study described in this supplement [37]. Another idea could be to replace pyrazinamide, perhaps with an optimized dose of an oxazolidinone to reduce antagonism, while tapping into the synergy of fluoroquinolones and oxazolidinones identified elsewhere [13,38].…”

Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study

“…36 As with the other first-line anti-TB drugs, delineating toxicodynamic relationships will be essential to support intensified dosing strategies among high-risk patients. 37 In addition, we estimated lung tissue drug exposure relative to serum based on the rabbit model of tuberculous lung lesions, 27 which may overestimate ethambutol exposures at the centre of lung cavities 5 and under-estimate ethambutol exposures in alveolar cells. 38 Furthermore, the ethambutol MIC demonstrates regional variability in tuberculous lung lesions, 5 which adds additional complexity to the likelihood of AUC 0-24 /MIC target attainment.…”

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

“…Of the 2 penultimate articles, the first provides the derivation of an approach that could be used to predict optimal clinical therapy duration, starting in the HFS-TB, while the second applied the approach to high-dose group D drugs plus moxifloxacin HFS-TB findings to determine whether therapy duration could be shortened to <6 months [58,59]. The final article is an editorial on the supplement, which summarizes how the results could be used to advance dosing in the clinical setting [60].…”