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

Amit Kaushik, Nicole Ammerman, Sandeep Tyagi, Vikram Saini, Iwan Vervoort, Sophie Lachau-Durand, Eric Nuermberger, Koen Andries

Research output: Contribution to journalArticle

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 (B LAI-160 ); and test regimens of daily bedaquiline at 2.67 mg/kg (B 2.67 ), 5.33 mg/kg (B 5.33 ), or 8 mg/kg (B 8 ) to deliver the same total amount of bedaquiline as one, two, or three doses of B LAI-160 , respectively. All drugs were administered orally, except for B LAI-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 B LAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log 10 CFU/lung, respectively, by week 12. Daily oral dosing with B 2.67 , B 5.33 , and B 8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log 10 , respectively. One dose of B LAI-160 exhibited activity for at least 12 weeks. The sustained activity of B LAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

Original languageEnglish (US)
Article numbere00007-19
JournalAntimicrobial agents and chemotherapy
DOIs
StatePublished - Apr 1 2019

Fingerprint

bedaquiline
Latent Tuberculosis
Injections
rifapentine
Lung
Tuberculosis
Therapeutics
Intramuscular Injections
Isoniazid
Rifampin
Mycobacterium bovis
Infection
Aerosols
Half-Life
Immunization

Keywords

  • BALB/c mice
  • Bedaquiline
  • Latent tuberculosis infection
  • Long-acting injectable

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection. / Kaushik, Amit; Ammerman, Nicole; Tyagi, Sandeep; Saini, Vikram; Vervoort, Iwan; Lachau-Durand, Sophie; Nuermberger, Eric; Andries, Koen.

In: Antimicrobial agents and chemotherapy, 01.04.2019.

Research output: Contribution to journalArticle

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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 (B LAI-160 ); and test regimens of daily bedaquiline at 2.67 mg/kg (B 2.67 ), 5.33 mg/kg (B 5.33 ), or 8 mg/kg (B 8 ) to deliver the same total amount of bedaquiline as one, two, or three doses of B LAI-160 , respectively. All drugs were administered orally, except for B LAI-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 B LAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log 10 CFU/lung, respectively, by week 12. Daily oral dosing with B 2.67 , B 5.33 , and B 8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log 10 , respectively. One dose of B LAI-160 exhibited activity for at least 12 weeks. The sustained activity of B LAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.",
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AU - Tyagi, Sandeep

AU - Saini, Vikram

AU - Vervoort, Iwan

AU - Lachau-Durand, Sophie

AU - Nuermberger, Eric

AU - Andries, Koen

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AB - 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 (B LAI-160 ); and test regimens of daily bedaquiline at 2.67 mg/kg (B 2.67 ), 5.33 mg/kg (B 5.33 ), or 8 mg/kg (B 8 ) to deliver the same total amount of bedaquiline as one, two, or three doses of B LAI-160 , respectively. All drugs were administered orally, except for B LAI-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 B LAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log 10 CFU/lung, respectively, by week 12. Daily oral dosing with B 2.67 , B 5.33 , and B 8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log 10 , respectively. One dose of B LAI-160 exhibited activity for at least 12 weeks. The sustained activity of B LAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.

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