<p>Association Between the Phenotype and Genotype of Isoniazid Resistance Among <em>Mycobacterium tuberculosis</em> Isolates in Thailand</p>

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 fluoroquinoloneresistant 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.

Molecular Detection of Drug-Resistant Mycobacterium tuberculosis in Sputum Specimens from the New and Previously Treated Tuberculosis Cases at the National Reference Chest Diseases Laboratory in Lusaka, Zambia

“…It has been projected that in 2021, Zambia will have a high burden of MDR and rifampicin-resistant TB cases [24]. Drug-resistant TB types include mono drug-resistant (resistance to any single anti-TB drug), poly drug-resistant (resistance to more than one anti-TB drug, other than both Rifampicin (RIF) and Isoniazid (INH) [25], MDR (resistance to at least INH and RIF), pre-XDR (resistance to INH, RIF, plus any one Fluoroquinolone (FLQ) (levofl oxacin, ofl oxacin, moxifl oxacin or gatifl oxacin) or any one of the Second-Line Injectable Drugs (SLIDs) (Kanamycin, Amikacin or Capreomycin), XDR (resistance to INH, RIF, plus any FLQ, plus any SLIDs) [26][27][28][29][30]. Poorly managed XDR-TB cases can progress to Totally Drug-Resistant TB (TDR-TB).…”

“…Mutations in the rpoB gene, specifi cally in an 81 base pair region called the Rifampicin-Resistance Determining Region (RRDR) confer resistance to RIF [36,37]. The four most frequent mutations that confer resistance to RIF are Ser531Leu, His526Tyr, His526Asp, and Asp516Val [25]. Mutations in the katG and/or inhA gene cause resistance to INH frequently [36].…”

“…The most frequent mutation in the katG gene that confers resistance to INH is the Ser315Thr mutation [37]. The four most frequent mutations in the inhA gene that confer resistance to INH are Cys15Thr, Ala16Gly, Thr8Cys and Thr8Ala [25]. Mutations occurring in the katG cause high-level resistance to INH, while those in the inhA cause low-level resistance [38].…”

“…The most frequent mutations in the gyrA gene that confer resistance to the FLQs are Gly88Ala, Gly88Cys, Ala90Val, Ser91Pro, Asp94Ala, Asp94Asp, Asp94Tyr, Asp94Gly, and Asp94His. While those in the gyrB gene are Asp538Asp, Glu540Val [25]. It is worth noting that mutations in the gyrA gene confer a high-level resistance to FLQs, while those in the gyrB gene confer low-level resistance [41].…”

“…Mutations in the rrs, eis and tlyA genes cause resistance to the aminoglycosides and cyclic polypeptide antibiotics [40]. The most frequent mutations in the rrs gene are Ala1401Gly, Cys1402Thr and Gly1484Thr [25,39]. While those in the eis gene are Gly37Thr, Cys14Thr, Cys12Thr, Gly10Ala, Cys2Ala [25].…”