Hotspots of multidrug-resistant tuberculosis transmission

Multidrug-resistant tuberculosis (MDR-TB) is defined by resistance to at least rifampicin (RIF) and isoniazid (INH), arising from inadequate treatment practices such as incomplete therapy, insufficient drug doses, poor drug quality, or direct transmission of resistant strains. Resistance in Mycobacterium tuberculosis (MTB) results from spontaneous chromosomal mutations, with ten key gene variants linked to resistance against first-line anti-TB medications, including katG, inhA, ahpC, kasA, and Ndh for INH, and rpoB for RIF. Drug resistance develops through two primary mechanisms: primary resistance, where individuals are infected with an already resistant strain, and secondary resistance, which occurs due to poor treatment adherence. TB drug resistance classifications range from mono-resistant TB (resistance to a single first-line drug) to extensively drug-resistant TB (XDR-TB), which is resistant to fluoroquinolones and at least one second-line injectable drug in addition to MDR-TB criteria. Pre-extensively drug-resistant TB (pre-XDR-TB) is an intermediate form, involving resistance to RIF, INH, and either fluoroquinolones or one injectable drug like amikacin or kanamycin.[3]

The primary drugs used to treat TB work through different mechanisms. Rifampicin inhibits RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase, though it can cause hepatotoxicity, immune reactions, and gastrointestinal issues. Isoniazid requires activation by the mycobacterial enzyme katG to inhibit mycolic acid synthesis, which is vital for the bacterial cell wall, but it may cause peripheral neuropathy, seizures, and lupus-like symptoms. Ethambutol disrupts cell wall synthesis by inhibiting mycobacterial arabinosyltransferase, leading to bacterial aggregation and structural changes. Pyrazinamide, a prodrug activated in acidic conditions, inhibits fatty acid synthesis in MTB. MDR-TB detection methods include phenotypic testing, which relies on culture-based methods like Lowenstein Jensen or liquid media (MGIT) and takes up to three months. Genotypic testing, such as the GeneXpert test, offers faster results, detecting TB and RIF resistance within two hours using real-time PCR. While molecular tests provide speed and convenience, culture-based methods remain the gold standard due to their high sensitivity in identifying drug-resistant TB strains.[3]

Identifying MDR-TB transmission hotspots is crucial for controlling the spread of resistant disease, as these areas require prioritized resources to interrupt transmission. Factors contributing to higher transmission may include delayed diagnosis and treatment of infectious MDR-TB cases, higher population density with increased respiratory contacts, and the circulation of particularly transmissible MDR strains. A molecular epidemiological study could further validate these findings and pinpoint specific high-risk locations. By detecting these areas, geographically targeted interventions become a viable strategy, allowing health programs to concentrate resources on early detection and treatment in the most affected regions, ultimately improving MDR-TB control efforts.[2]

A study reported a tuberculosis (TB) incidence rate of 74.12 per 100,000 people, with 12% of cases classified as multidrug-resistant (MDR). Prior TB treatment significantly increased the risk of MDR-TB (OR = 2.92, 95% CI: 2.29–3.71), identifying it as a major risk factor. The Latin American–Mediterranean (LAM) sublineage was the most prevalent among MDR cases (44%), followed by Haarlem (19%) and Beijing (4%). Within LAM, Genotype 1 was the dominant strain, strongly linked to MDR cases. The study highlighted Lima Este as a geographic hotspot, where individuals faced a 3.19-fold higher MDR risk (95% CI: 2.33–4.36). Even treatment-naïve individuals in this area had a significantly elevated risk (OR = 2.80, 95% CI: 1.62–4.85), suggesting active community transmission of resistant strains rather than acquired resistance from failed treatments.[1] See also: https://tbreadingnotes.blogspot.com/2024/08/scientific-advances-and-end-of.html

The study found significant spatial clustering of TB genotypes, with Genotype 1 disproportionately concentrated in the hotspot. While 31% of Genotype 1 cases outside the hotspot were MDR, this proportion surged to 80% within the hotspot, reinforcing localized transmission. Notably, 62% of MDR cases in the hotspot had no prior TB treatment, emphasizing direct transmission as a key driver. These findings suggest that geographically targeted interventions focusing on high-risk areas may be more effective than broad population-wide strategies. The study underscores the need for enhanced case-finding and intervention measures in hotspots, particularly addressing the spread of the LAM sublineage and Genotype 1. Further geographic and mathematical modeling studies are recommended to refine MDR-TB containment strategies.[1] See also: https://tuberculosis101.blogspot.com/2024/11/evaluation-of-xpert-mtb-host-response.html

References:

1. Zelner, J.L., Murray, M.B., Becerra, M.C., Galea, J., Lecca, L., Calderon, R., Yataco, R., Contreras, C., Zhang, Z., Manjourides, J. and Grenfell, B.T., 2016. Identifying hotspots of multidrug-resistant tuberculosis transmission using spatial and molecular genetic data. The Journal of infectious diseases, 213(2), pp.287-294.

2. Manjourides, J., Lin, H.H., Shin, S., Jeffery, C., Contreras, C., Santa Cruz, J., Jave, O., Yagui, M., Asencios, L., Pagano, M. and Cohen, T., 2012. Identifying multidrug resistant tuberculosis transmission hotspots using routinely collected data. Tuberculosis, 92(3), pp.273-279.

3. Wulandari, D.A., Hartati, Y.W., Ibrahim, A.U. and Pitaloka, D.A.E., 2024. Multidrug-resistant tuberculosis. Clinica Chimica Acta, 559, p.119701.