Ratchanu Charoenpak1, Wichai Santimaleeworagun2, Gompol Suwanpimolkul3,4,5, Weerawat Manosuthi6, Paweena Kongsanan6, Suthidee Petsong7, Chankit Puttilerpong8. 1. College of Pharmacotherapy Thailand, Nonthaburi, Thailand. 2. Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand. 3. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 4. Tuberculosis Research Unit, Chulalongkorn University, Bangkok, Thailand. 5. Emerging Infectious Diseases Clinical Center, Thai Red Cross, Bangkok, Thailand. 6. Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand. 7. Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. 8. Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Abstract
PURPOSE: The emergence of isoniazid-resistant tuberculosis (HR-TB) is a global public health problem, causing treatment failure and high mortality rates. This study aimed to determine the minimal inhibitory concentration (MIC) of isoniazid and detect the gene mutation in HR-TB and any association between the level of isoniazid resistance and gene mutation. METHODS: We collected 74 clinical HR-TB isolates from two tertiary-care centers in Thailand. MICs were established using broth macrodilution. A line probe assay (LPA) was used to detect gene mutations that confer resistance to isoniazid, rifampicin, aminoglycosides, and fluoroquinolones. RESULTS: Sixty-one (82.4%) isolates were monoresistant to isoniazid and 44 (72.1%) were highly resistant to isoniazid. From the clinical isolates, the range of isoniazid MICs was 0.4-16 μg/mL. The katG S315T gene mutation was the prominent mutation in both isoniazid-monoresistant TB (70.5%) and multidrug-resistant TB (72.7%) isolates. The positive predictive value (PPV) of katG was 100% in detecting high levels of isoniazid resistance. The PPV of the inhA mutation was 93.8% in detecting low levels of isoniazid resistance. Five isolates (6.8%) exhibited low-level phenotypic resistance, whereas an LPA failed to detect an isoniazid gene mutation. Our study found one HR-TB isolate with a gyrA fluoroquinolone-resistant gene mutation. CONCLUSION: Most HR-TB isolates had high isoniazid-resistance levels associated with the katG gene mutation. High-dose isoniazid should be used with caution in patients with HR-TB. Early detection of drug resistance by genotypic assay can help determine an appropriate regimen.
PURPOSE: The emergence of isoniazid-resistant tuberculosis (HR-TB) is a global public health problem, causing treatment failure and high mortality rates. This study aimed to determine the minimal inhibitory concentration (MIC) of isoniazid and detect the gene mutation in HR-TB and any association between the level of isoniazid resistance and gene mutation. METHODS: We collected 74 clinical HR-TB isolates from two tertiary-care centers in Thailand. MICs were established using broth macrodilution. A line probe assay (LPA) was used to detect gene mutations that confer resistance to isoniazid, rifampicin, aminoglycosides, and fluoroquinolones. RESULTS: Sixty-one (82.4%) isolates were monoresistant to isoniazid and 44 (72.1%) were highly resistant to isoniazid. From the clinical isolates, the range of isoniazid MICs was 0.4-16 μg/mL. The katG S315T gene mutation was the prominent mutation in both isoniazid-monoresistant TB (70.5%) and multidrug-resistant TB (72.7%) isolates. The positive predictive value (PPV) of katG was 100% in detecting high levels of isoniazid resistance. The PPV of the inhA mutation was 93.8% in detecting low levels of isoniazid resistance. Five isolates (6.8%) exhibited low-level phenotypic resistance, whereas an LPA failed to detect an isoniazid gene mutation. Our study found one HR-TB isolate with a gyrA fluoroquinolone-resistant gene mutation. CONCLUSION: Most HR-TB isolates had high isoniazid-resistance levels associated with the katG gene mutation. High-dose isoniazid should be used with caution in patients with HR-TB. Early detection of drug resistance by genotypic assay can help determine an appropriate regimen.
Authors: Justin L Kandler; Alexandra D Mercante; Tracy L Dalton; Matthew N Ezewudo; Lauren S Cowan; Scott P Burns; Beverly Metchock; Peter Cegielski; James E Posey Journal: Antimicrob Agents Chemother Date: 2018-09-24 Impact factor: 5.191