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- Title
Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics.
- Authors
Srivastava, Shashikant; Deshpande, Devyani; Magombedze, Gesham; Zyl, Johanna van; Cirrincione, Kayle; Martin, Katherine; Bendet, Paula; Berg, Alexander; Hanna, Debra; Romero, Klaus; Hermann, Dave; Gumbo, Tawanda; van Zyl, Johanna
- Abstract
<bold>Objectives: </bold>Animal models have suggested that the combination of pretomanid with pyrazinamide and moxifloxacin (PaMZ) may shorten TB therapy duration to 3-4 months. Here, we tested that in the hollow-fibre system model of TB (HFS-TB).<bold>Methods: </bold>A series of HFS-TB experiments were performed to compare the kill rates of the PaMZ regimen with the standard three-drug combination therapy. HFS-TB experiments were performed with bacilli in log-phase growth treated for 28 days, intracellular bacilli treated daily for 28 days and semi-dormant Mycobacterium tuberculosis treated with daily therapy for 56 days for sterilizing effect. Next, time-to-extinction equations were employed, followed by morphism transformation and Latin hypercube sampling, to determine the proportion of patients who achieved a time to extinction of 3, 4 or 6 months with each regimen.<bold>Results: </bold>Using linear regression, the HFS-TB sterilizing effect rates of the PaMZ regimen versus the standard-therapy regimen during the 56 days were 0.18 (95% credible interval=0.13-0.23) versus 0.15 (95% credible interval=0.08-0.21) log10 cfu/mL/day, compared with 0.16 (95% credible interval=0.13-0.18) versus 0.11 (95% credible interval=0.09-0.13) log10 cfu/mL/day in the Phase II clinical trial, respectively. Using time-to-extinction and Latin hypercube sampling modelling, the expected percentages of patients in which the PaMZ regimen would achieve sterilization were 40.37% (95% credible interval=39.1-41.34) and 72.30% (95% credible interval=71.41-73.17) at 3 and 4 months duration of therapy, respectively, versus 93.67% (95% credible interval=93.18-94.13) at 6 months for standard therapy.<bold>Conclusions: </bold>The kill rates of the PaMZ regimen were predicted to be insufficient to achieve cure in less than 6 months in most patients.
- Subjects
HYPERCUBES; LATIN hypercube sampling; MYCOBACTERIUM tuberculosis; MATHEMATICS; DRUG therapy for tuberculosis; RESEARCH; COMBINATION drug therapy; PYRAZINAMIDE; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; IMIDAZOLES; COMPARATIVE studies; ANTITUBERCULAR agents
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2020, Vol 75, Issue 2, p392
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkz460