title: Delamanid Kills Dormant MycobacteriaIn Vitroand in a Guinea Pig Model of Tuberculosis.
abstract: Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanid's activity against growing or dormant bacilliin vitroas well asin vivoCultures ofMycobacterium bovisBCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0.016 and 0.4 mg/liter, respectively. To evaluate delamanid's antituberculosis activityin vivo, we used a guinea pig model of chronic TB infection in which the lung lesions were similar to those in human TB disease. In the guinea pig TB model, a daily dose of 100 mg delamanid/kg of body weight for 4 or 8 weeks demonstrated strong bactericidal activity againstMycobacterium tuberculosisImportantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampin and pyrazinamide or delamanid with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilliin vitroand in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials with pulmonary multidrug-resistant (MDR) TB patients. Delamanid may be an important drug for consideration in the construction of new regimens to shorten TB treatment duration.
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Xiuhao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hashizume
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tomishige
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Izuru
authors.initials: I
authors.lastname: Nakamura
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Matsuba
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Ryuki
authors.initials: R
authors.lastname: Kitamoto
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Hanaki
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan Matsumoto.Makoto@otsuka.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005000:Ethionamide / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use; D064704:Levofloxacin / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity; D009593:Nitroimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011718:Pyrazinamide / Q000494:pharmacology / Q000627:therapeutic use; D012293:Rifampin / Q000494:pharmacology / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; D011718:Pyrazinamide; D064704:Levofloxacin; D005000:Ethionamide; D007538:Isoniazid; D012293:Rifampin
keywords: Mycobacterium tuberculosis; delamanid; dormant; guinea pig