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 < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 μg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 μg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis. Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.)

Intestinal microbiome composition influences the peripheral inflammatory state during treatment of human tuberculosis

“…NTZ was used as the reference level for treatment (see Methods and Supplementary Table S1) ( Figure 2B). NTZ, despite its potent in vitro activity27, did not have any significant effect on TTP after 14 days ( > 0.05) ( Figure 2B, Supplementary Table S1) 26 . This lack of NTZ efficacy was traced to a failure of the drug to penetrate the sputum, 26 and indicated that disease severity remained constant as measured by mycobacterial load.…”

“…Gut microbiome diversity is depleted after two weeks of HRZE or NTZ treatment As detailed elsewhere, the GHESKIO centers in Port au Prince, Haiti conducted a prospective, randomized, early bactericidal activity (EBA) study in treatment-naive, drug-susceptible adult patients with uncomplicated pulmonary tuberculosis (TB) (ClinicalTrials.gov Identifier: NCT02684240) 26 . Thirty-four participants were randomized to receive either NTZ, 1000 mg po (oral) twice daily, or standard oral therapy with isoniazid 300 mg daily, rifampin 600 mg daily, pyrazinamide 25 mg/kg daily, and ethambutol 15 mg/kg daily (referred to as HRZE) for 14 days ( Figure 1A).…”

“…NTZ treatment is associated with no difference in TTP between day 0 and day 14 (p > 0.05, see Supplementary Table S1), and thus no change in disease status, while HRZE is significant (p < 0.05, Supplementary Table S1), and thus a reduction in disease severity. Data for TTP where obtained from Walsh et al 2020 26 . C. Principal Coordinate analysis (PCoA) with Bray-Curtis distance showing differences in microbiome community structure between individuals before and after 14 days of either HRZE or NTZ treatment.…”

“…The first dataset ( Figure 1A,B) consists of the secondary endpoint data from a clinical trial (NCT02684240) that compared the early bactericidal effect (EBA) of standard tuberculosis (TB) therapy isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) to the antiparasitic drug nitazoxanide (NTZ), shown to possess antimycobacterial activity in vitro 25,26 . We thought this dataset to be ideal for testing our hypothesis because (1) the clinical trial demonstrated that as opposed to HRZE, NTZ did not show any antimycobacterial activity in humans 26 ( Figure 2B), and (2) preliminary microbiome analysis by our group showed that NTZ caused microbiome dysbiosis similar to that caused by HRZE, thus providing us with the desired dysbiosis in the absence of any pathogen killing or aggravation of disease. We then found that HRZE and NTZ had distinct effects on host peripheral gene expression, with HRZE causing a resolution of inflammatory gene signatures, and NTZ causing an exacerbation of them in the absence of disease progression.…”

Urinary biomarkers of mycobacterial load and treatment response in pulmonary tuberculosis

“…To independently validate our findings, we obtained and analyzed urine samples from a second cohort of 35 participants with ATB enrolled in an early bactericidal activity (EBA) study at the Groupe Haitien d'Etudes du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Centers in Port-au-Prince, Haiti. The study was designed to determine if the in vitro activity of the FDA-approved antiparasitic agent nitazoxanide (NTZ) against Mycobacterium tuberculosis (Mtb) could serve as a mycobactericidal agent for drug-sensitive pulmonary TB (24). Participants were recruited at the GHESKIO Centers and allocated into 2 treatment arms: 19 participants received NTZ for 14 days, whereas 16 participants received the standard HRZE TB treatment ( Figure 1).…”