Old drugs, new purpose: Retooling existing drugs for optimized treatment of resistant tuberculosis

Kelly E. Dooley; Carole D. Mitnick; Mary Ann DeGroote; Ekwaro Obuku; Vera Belitsky; Carol D. Hamilton; Mamodikoe Makhene; Sarita Shah; James C.M. Brust; Nadza Durakovic; Eric Nuermberger

doi:10.1093/cid/cis487

Old drugs, new purpose: Retooling existing drugs for optimized treatment of resistant tuberculosis

Kelly E. Dooley, Carole D. Mitnick, Mary Ann DeGroote, Ekwaro Obuku, Vera Belitsky, Carol D. Hamilton, Mamodikoe Makhene, Sarita Shah, James C.M. Brust, Nadza Durakovic, Eric Nuermberger

Medicine

Research output: Contribution to journal › Review article › peer-review

52 Scopus citations

Abstract

Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.

Original language	English (US)
Pages (from-to)	572-581
Number of pages	10
Journal	Clinical Infectious Diseases
Volume	55
Issue number	4
DOIs	https://doi.org/10.1093/cid/cis487
State	Published - Aug 15 2012

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Old drugs, new purpose: Retooling existing drugs for optimized treatment of resistant tuberculosis",

abstract = "Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.",

author = "Dooley, {Kelly E.} and Mitnick, {Carole D.} and DeGroote, {Mary Ann} and Ekwaro Obuku and Vera Belitsky and Hamilton, {Carol D.} and Mamodikoe Makhene and Sarita Shah and Brust, {James C.M.} and Nadza Durakovic and Eric Nuermberger",

note = "Funding Information: Financial support. This work was supported by the National Institutes of Health (grant K23AI080842 to K. E. D. and K23AI083088 to J. C. M. B.) and the Doris Duke Charitable Foundation (Clinical Scientist Development Award 2007071 to S. S.). Potential conflicts of interest. All authors: No reported conflicts.",

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doi = "10.1093/cid/cis487",

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AU - Dooley, Kelly E.

AU - Mitnick, Carole D.

AU - DeGroote, Mary Ann

AU - Obuku, Ekwaro

AU - Belitsky, Vera

AU - Hamilton, Carol D.

AU - Makhene, Mamodikoe

AU - Shah, Sarita

AU - Brust, James C.M.

AU - Durakovic, Nadza

AU - Nuermberger, Eric

N1 - Funding Information: Financial support. This work was supported by the National Institutes of Health (grant K23AI080842 to K. E. D. and K23AI083088 to J. C. M. B.) and the Doris Duke Charitable Foundation (Clinical Scientist Development Award 2007071 to S. S.). Potential conflicts of interest. All authors: No reported conflicts.

PY - 2012/8/15

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N2 - Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.

AB - Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.

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Old drugs, new purpose: Retooling existing drugs for optimized treatment of resistant tuberculosis

Abstract

ASJC Scopus subject areas

UN SDGs

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