Dataset Information

Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

ABSTRACT: This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14?days. A control group of 10 participants received standard therapy over 14?days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14?days in the NTZ group was 3.2?h?±?22.6 h and was not statistically significant (P?=?0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134?h?±?45.2 h (P?

SUBMITTER: Walsh KF

PROVIDER: S-EPMC7179618 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

Walsh K F KF McAulay K K Lee M H MH Vilbrun S C SC Mathurin L L Jean Francois D D Zimmerman M M Kaya F F Zhang N N Saito K K Ocheretina O O Savic R R Dartois V V Johnson W D WD Pape J W JW Nathan C C Fitzgerald D W DW

Antimicrobial agents and chemotherapy 20200421 5

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture ...[more]

PMID: 32071052

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Project description:Pyrazinamide (PZA) plays an essential part in the shortened six-month tuberculosis (TB) treatment course due to its activity against slow-growing and non-replicating organisms. We tested whether PZA preferentially targets slow growing cells of Mycobacterium tuberculosis that could be representative of bacteria that remain after the initial kill with isoniazid (INH), by observing the response of either slow growing or fast growing bacilli to differing concentrations of PZA.M. tuberculosis H37Rv was grown in continuous culture at either a constant fast growth rate (Mean Generation Time (MGT) of 23.1 h) or slow growth rate (69.3 h MGT) at a controlled dissolved oxygen tension of 10 % and a controlled acidity at pH 6.3?±?0.1. Cultures were exposed to step-wise increases in the concentration of PZA (25 to 500 ?gml(-1)) every two MGTs, and bacterial survival was measured. PZA-induced global gene expression was explored for each increase in PZA-concentration, using DNA microarray.At a constant pH 6.3, actively dividing mycobacteria were susceptible to PZA, with similar responses to increasing concentrations of PZA at both growth rates. Three distinct phases of drug response could be distingished for both slow growing (69.3 h MGT) and fast growing (23.1 h MGT) bacilli. A bacteriostatic phase at a low concentration of PZA was followed by a recovery period in which the culture adapted to the presence of PZA and bacteria were actively dividing in steady-state. In contrast, there was a rapid loss of viability at bactericidal concentrations. There was a notable delay in the onset of the recovery period in quickly dividing cells compared with those dividing more slowly. Fast growers and slow growers adapted to PZA-exposure via very similar mechanisms; through reduced gene expression of tRNA, 50S, and 30S ribosomal proteins.PZA had an equivalent level of activity against fast growing and slow growing M. tuberculosis. At both growth rates drug-tolerance to sub-lethal concentrations may have been due to reduced expression of tRNA, 50S, and 30S ribosomal proteins. The findings from this study show that PZA has utility against more than one phenotypic sub-population of bacilli and could be re-assessed for its early bactericidal activity, in combination with other drugs, during TB treatment.

Dataset Information

Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

Publications

Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

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