Management of drug-resistant tuberculosis

Abstract

Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts.

Figure 1:. Percentages of patients with multidrug-resistant tuberculosis globally

Figures are based on the most recent year for which data have been reported to WHO, which varies among countries. Data cover the period from 2002–18. The number of multidrug-resistant tuberculosis cases detected globally per year has tripled from about 50 000 cases in 2009 to over 150 000 cases in 2017. Reproduced from reference 1, by permission of WHO.

Figure 2:. Molecular drug resistance detection methods for Mycobacterium tuberculosis

(A) GeneXpert MTB/RIF Ultra cartridge for the detection of M tuberculosis and RIF resistance-conferring mutations, and melt curve of GeneXpert MTB/XDR assay capable of detecting M tuberculosis and resistance-conferring mutations for INH, the FLQs, and second-line injectables. (B) Portable single module GeneXpert devices Edge (left) and Omni (right), which are battery-operated and will allow for point-of-care diagnosis, thus facilitating community-based active case finding (Omni in development and not currently available for in vitro diagnostic use). (C) Hain line probe assays GenoType MTBDRplus version 2.0 (left), used to detect resistance-conferring mutations for RIF and INH, and GenoType MTBDRsI version 2.0 (right) used to detect resistance-conferring mutations for the FLQs and second-line injectables. (D) Next-generation sequencing-based methods. M tuberculosis is either amplified with primers targeting drug resistance conferring genes and lineage-specific targets or randomly fragmented. The library is then sequenced. The resulting sequences are aligned to a reference genome and known resistance-conferring and lineage mutations identified; automated pipelines can provide advice about a suggested bespoke regimen. In addition to the technologies outlined here other molecular platforms including those with standardised targeted sequencing or with multiplexed bench top molecular devices are currently in development. RIF=rifampicin. INH=isoniazid. PZA=pyrazinamide. EMB=ethambutal. FLQ=fluoroquinolone. KAN=kanamycin. AMK=amikacin. CPM=capreomycin. ETH=ethionamide. LZD=linezolid. BDQ=bedaquiline. CFZ=clofazimine.

Figure 3:. Comprehensive care of patients with multidrug-resistant tuberculosis

The modern multidisciplinary care of multidrug-resistant tuberculosis should encompass early diagnosis with expanded access to rapid molecular tools and optimal treatment with oral regimens based on group A. Programmes should provide decentralised, well resourced, high-quality care with access to comprehensive testing and evaluation, new drugs, and expanded laboratory capacity with systems that enable treatment and quality of care monitoring (often the cascade of care is suboptimal and with substantial gaps). Adherence promotion with counselling, psychosocial support, food, and financial security (patient-level costs are often too high), and access to health care is crucial. Patients should receive holistic care with treatment of comorbidities. Care should be patient focused and oriented (the first pillar of WHO’s EndTB strategy to end tuberculosis), encompassing patient choice, and be empowering, dignified, and respectful. Patients who cannot be treated successfully with medical treatment alone, or who terminate medical treatment, should have access to surgical intervention and palliative care if appropriate. Multidisciplinary, long-term, community-based residential facilities should be available to cater for patients who cannot be cured and who cannot be managed at home.