Rationale: High-dose isoniazid is recommended in short-course regimens for multidrug-resistant tuberculosis (TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown. Objectives: To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA mutations. Methods: AIDS Clinical Trials Group A5312 is a phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomized to receive isoniazid 5, 10, or 15 mg/kg daily for 7 days (inhA group), and control subjects with drug-sensitive TB received the standard dose (5 mg/kg/d). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity (EBA) of isoniazid was estimated as the average daily change in log10 cfu on solid media (EBAcfu0-7) or as time to positivity (TTP) in liquid media in hours (EBATTP0-7) using nonlinear mixed-effects models.Measurements and Main Results: Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive TB, and 43 with isoniazid-monoresistant or multidrug-resistant TB) were enrolled at one site in South Africa. The mean EBAcfu0-7 at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log10 cfu/ml/d, respectively, and 0.16 log10 cfu/ml/d in control subjects. EBATTP0-7 patterns were similar. There were no drug-related grade ≥3 adverse events.Conclusions: Isoniazid 10-15 mg/kg daily had activity against TB strains with inhA mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next.Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
Rationale: High-dose isoniazid is recommended in short-course regimens for multidrug-resistant tuberculosis (TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown. Objectives: To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA mutations. Methods: AIDS Clinical Trials Group A5312 is a phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomized to receive isoniazid 5, 10, or 15 mg/kg daily for 7 days (inhA group), and control subjects with drug-sensitive TB received the standard dose (5 mg/kg/d). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity (EBA) of isoniazid was estimated as the average daily change in log10 cfu on solid media (EBAcfu0-7) or as time to positivity (TTP) in liquid media in hours (EBATTP0-7) using nonlinear mixed-effects models.Measurements and Main Results: Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive TB, and 43 with isoniazid-monoresistant or multidrug-resistant TB) were enrolled at one site in South Africa. The mean EBAcfu0-7 at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log10 cfu/ml/d, respectively, and 0.16 log10 cfu/ml/d in control subjects. EBATTP0-7 patterns were similar. There were no drug-related grade ≥3 adverse events.Conclusions: Isoniazid 10-15 mg/kg daily had activity against TB strains with inhA mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next.Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
Authors: Kamunkhwala Gausi; Elisa H Ignatius; Xin Sun; Soyeon Kim; Laura Moran; Lubbe Wiesner; Florian von Groote-Bidlingmaier; Richard Hafner; Kathleen Donahue; Naadira Vanker; Susan L Rosenkranz; Susan Swindells; Andreas H Diacon; Eric L Nuermberger; Kelly E Dooley; Paolo Denti Journal: Am J Respir Crit Care Med Date: 2021-12-01 Impact factor: 21.405
Authors: J W C Alffenaar; S L Stocker; L Davies Forsman; A Garcia-Prats; S K Heysell; R E Aarnoutse; O W Akkerman; A Aleksa; R van Altena; W Arrazola de Oñata; P K Bhavani; N Van't Boveneind-Vrubleuskaya; A C C Carvalho; R Centis; J M Chakaya; D M Cirillo; J G Cho; L D Ambrosio; M P Dalcolmo; P Denti; K Dheda; G J Fox; A C Hesseling; H Y Kim; C U Köser; B J Marais; I Margineanu; A G Märtson; M Munoz Torrico; H M Nataprawira; C W M Ong; R Otto-Knapp; C A Peloquin; D R Silva; R Ruslami; P Santoso; R M Savic; R Singla; E M Svensson; A Skrahina; D van Soolingen; S Srivastava; M Tadolini; S Tiberi; T A Thomas; Z F Udwadia; D H Vu; W Zhang; S G Mpagama; T Schön; G B Migliori Journal: Int J Tuberc Lung Dis Date: 2022-06-01 Impact factor: 3.427
Authors: Solomon P le Roux; Caryn Upton; Naadira Vanker; Kelly E Dooley; Andreas H Diacon Journal: Am J Respir Crit Care Med Date: 2021-03-01 Impact factor: 21.405
Authors: Tom Decroo; Bouke C de Jong; Alberto Piubello; Mahamadou Bassirou Souleymane; Lutgarde Lynen; Armand Van Deun Journal: Am J Respir Crit Care Med Date: 2020-06-15 Impact factor: 21.405
Authors: Pauline Lempens; Tom Decroo; Kya J M Aung; Mohammad A Hossain; Leen Rigouts; Conor J Meehan; Armand Van Deun; Bouke C de Jong Journal: Int J Infect Dis Date: 2020-08-20 Impact factor: 3.623
Authors: Kelly E Dooley; Sachiko Miyahara; Florian von Groote-Bidlingmaier; Xin Sun; Richard Hafner; Susan L Rosenkranz; Elisa H Ignatius; Eric L Nuermberger; Laura Moran; Kathleen Donahue; Susan Swindells; Naadira Vanker; Andreas H Diacon Journal: Am J Respir Crit Care Med Date: 2020-06-15 Impact factor: 21.405
Authors: Johannes Ndambuki; Joseph Nzomo; Lucy Muregi; Chris Mutuku; Francis Makokha; Jonathan Nthusi; Clarice Ambale; Lutgarde Lynen; Tom Decroo Journal: Int Health Date: 2021-04-27 Impact factor: 2.473