scholarly journals Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection

2019 ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Sandeep Tyagi ◽  
Vikram Saini ◽  
Iwan Vervoort ◽  
...  
Keyword(s):  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Positive Control ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Sustained Activity ◽  
Short Course ◽  
Long Acting ◽  
Aerosol Infection

ABSTRACTThe potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 (B2.67), 5.33 (B5.33), or 8 (B8) mg/kg to deliver the same total bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of BLA-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

scholarly journals Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Amit Kaushik ◽  
Nicole C. Ammerman ◽  
Sandeep Tyagi ◽  
Vikram Saini ◽  
Iwan Vervoort ◽  
...  
Keyword(s):  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Positive Control ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Content Type ◽  
Control Regimen ◽  
Long Acting ◽  
Aerosol Infection

ABSTRACT The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily bedaquiline at 2.67 mg/kg (B2.67), 5.33 mg/kg (B5.33), or 8 mg/kg (B8) to deliver the same total amount of bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of BLAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively, by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

scholarly journals Analysis of Rifapentine for Preventive Therapy in the Cornell Mouse Model of Latent Tuberculosis

1999 ◽  
Vol 43 (9) ◽  
pp. 2126-2130 ◽  
Author(s):  
Eishi Miyazaki ◽  
Richard E. Chaisson ◽  
William R. Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Therapy ◽  
Mouse Model ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Preventive Therapy ◽  
Load Reduction ◽  
Short Course ◽  
Drug Regimens ◽  
Long Acting

ABSTRACT Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously withMycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.

scholarly journals Safety of the Rifampin and Pyrazinamide Short-Course Regimen for Treating Latent Tuberculosis Infection

2007 ◽  
Vol 44 (3) ◽  
pp. 464-465 ◽  
Author(s):  
K. Ijaz ◽  
P. D. McElroy ◽  
J. Jereb ◽  
T. R. Navin ◽  
K. G. Castro
Keyword(s):  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Tuberculosis Infection ◽  
Short Course

scholarly journals Safety and Completion Rate of Short‐Course Therapy for Treatment of Latent Tuberculosis Infection

2006 ◽  
Vol 43 (3) ◽  
pp. 271-275 ◽  
Author(s):  
Paul P. Cook ◽  
Ricardo A. Maldonado ◽  
Connie T. Yarnell ◽  
Don Holbert
Keyword(s):  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Completion Rate ◽  
Tuberculosis Infection ◽  
Short Course

scholarly journals Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomised controlled study

2018 ◽  
Vol 52 (6) ◽  
pp. 1801470 ◽  
Author(s):  
Lei Gao ◽  
Haoran Zhang ◽  
Henan Xin ◽  
Jianmin Liu ◽  
Shouguo Pan ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Latent Tuberculosis Infection ◽  
Latent Tuberculosis ◽  
Tuberculosis Infection ◽  
World Health ◽  
Controlled Study ◽  
Short Course ◽  
Significant Difference ◽  
Randomised Controlled ◽  
Active Disease

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50–69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27–1.43) and 0.41 (95% CI 0.15–1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279) versus 1.17% (15 out of 1279); p=0.704).The short regimens tested must be used with caution among the elderly because of the high rates of adverse effects. Further work is necessary to test the ultrashort regimens in younger people with LTBI.

scholarly journals Elevated Circulating Concentrations of Interferon-Gamma in Latent Tuberculosis Infection

2016 ◽  
Vol 1 (2) ◽  
pp. 291 ◽  
Author(s):  
Moises Arturo Huaman ◽  
George S. Deepe, Jr. ◽  
Carl J. Fichtenbaum
Keyword(s):  
Interferon Gamma ◽  
Immune Activation ◽  
Propensity Scores ◽  
Latent Tuberculosis Infection ◽  
Plasma Concentrations ◽  
Latent Tuberculosis ◽  
Negative Control ◽  
Tuberculosis Infection ◽  
Hiv Status

Background: Latent tuberculosis infection (LTBI) has been associated with increased immune activation. We assessed circulating concentrations of interferon-gamma in persons with LTBI.Methods: We used the 2011-2012 National Health Nutritional Examination Survey (NHANES) to identify adults with and without LTBI by QuantiFERON®-TB Gold In-Tube (QFT) results. Non-LTBI persons were 1:1 age-, gender- and race-matched to LTBI persons using propensity scores. We compared the plasma concentrations of interferon-gamma measured from the unstimulated, negative control QFT tube between LTBI and non-LTBI persons. We used Mann-Whitney tests and ordered logistic regressions for comparisons.Results: There were 430 LTBI and 430 non-LTBI matched persons included in the analysis. LTBI was associated with higher circulating concentrations of interferon-gamma (median, 3 pg/mL; IQR, 2 – 5) compared to non-LTBI (median, 2.5 pg/mL; IQR, 1.5 – 3.5), P<0.001. LTBI remained associated with higher interferon-gamma concentrations after adjusting for age, gender, race, diabetes, hypertension, tobacco use, HIV status, body mass index, lipid profile and lymphocyte count (odds ratio, 1.79, 95% CI, 1.26 – 2.53). Results remained similar when LTBI was defined by tuberculin skin testing.Conclusions: LTBI was associated with increased circulating interferon-gamma concentrations. Future studies are needed to further characterize immune activation in LTBI and its potential long-term consequences. 

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