INH is a crucial first-line drug for treating TB due to its strong ability to kill the bacteria in the early stages of infection.
1 Unfortunately, resistance to
INH has become the most widespread form of resistance to anti-TB drugs, whether on its own or in combination with other medications.
1 According to global statistics (2018),
INH resistance without concurrent RIF resistance was observed in 7.1% of new TB cases and 7.9% of previously treated TB cases.
2 INH mono-resistance refers to the resistance of TB bacteria to only one of the first-line drugs, specifically INH, while remaining susceptible to other anti-TB drugs.
3 The most common causes of
INH resistance are mutations in genes such as katG or inhA and less common in other genes such as ahpC32 gene.
4,5 INH is converted into an active form by an enzyme called catalase-peroxidase, which is regulated by the katG gene.
1 Mutations in katG, particularly at the Ser315Thr location, lead to a high level of
INH resistance.(6,7) The inhA gene encodes an enzyme that plays a role in fatty acid synthesis in TB bacteria, which is the target of the active derivative of INH.
1 Mutations in inhA or its promoter region prevent
INH from binding, resulting in low-level resistance to the drug.
8 Resistance to
Ethionamide and
Prothionamide is also typically seen in isolates with inhA mutations.
9 WHO recommendation in
INH resistant TB is treatment with rifampicin, pyrazinamide,
Ethambutol and
Levofloxacin for duration of 6 months.
3 The use of high dose
Isoniazid (10-15 mg/kg/day) is not reviewed due to insufficient data however Guideline Development Group discussed the effect of increased dosing depending on the type of molecular mutations seen.
3 In vitro studies suggest that in inhA mutations and in absence of KatG mutations high dose
Isoniazid could be effective and can be considered as part of treatment.
3 National Tuberculosis Elimination Programme (NTEP) recommendation is similar to the WHO guidelines. The regimen addition of
Levofloxacin vs the use of high dose
Isoniazid needs to be further evaluated but looking at the scientific approach high dose
Isoniazid would be effective and should be considered in such a patient. In our patient, we continued a regime without
INH as per the NTEP recommendations.
| References : |
- Jhun BW, Koh WJ. Treatment of Isoniazid-Resistant Pulmonary Tuberculosis. Tuberc Respir Dis (Seoul). 2020 Jan;83(1):20-30.
- World Health Organization. Global tuberculosis report 2018 [Internet] Geneva: World Health Organization;2018. [cited 2018 Dec 18]. https://www.who.int/tb/publications/global_report/en/
- World Health Organization. WHO treatment guidelines for isoniazid-resistant tuberculosis: supplement to the WHO treatment guidelines for drug-resistant tuberculosis [Internet] Geneva: World Health Organization; 2018. https://www.who.int/tb/publications/2018/WHO_guidelines_isoniazid_resistant_TB/en/
- Zhang Y, Heym B, Allen B, Young D, Cole S. The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature. 1992;358:591-593.
- Piatek AS, Telenti A, Murray MR, El-Hajj H, Jacobs WR, Jr, Kramer FR, et al. Genotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular beacons: implications for rapid susceptibility testing. Antimicrob Agents Chemother. 2000;44:103 110.
- Ramaswamy SV, Reich R, Dou SJ, Jasperse L, Pan X, Wanger A, et al. Single nucleotide polymorphisms in genes associated with isoniazid resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2003;47:1241-1250.
- Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 1998;79:3-29.
- Dalla Costa ER, Ribeiro MO, Silva MS, Arnold LS, Rostirolla DC, Cafrune PI, et al. Correlations of mutations in katG, oxyRahpC and inhA genes and in vitro susceptibility in Mycobacterium tuberculosis clinical strains segregated by spoligotype families from tuberculosis prevalent countries in South America. BMC Microbiol. 2009;9:39.
- Banerjee A, Dubnau E, Quemard A, Balasubramanian V,Um KS, Wilson T, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263:227-230.
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