Challenging the management of drug-resistant tuberculosis – Authors' reply

It is obvious that more efforts are needed, both in research and development and in implementation, to reduce the drug-resistant tuberculosis epidemic.1Lange C Dheda K Chesov D Mandalakas AM Udwadia Z Horsburgh Jr, CR Management of drug-resistant tuberculosis.Lancet. 2019; 394: 953-966Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar Our concerns are supported by projections suggesting that the number of patients with drug-resistant tuberculosis in high-burden countries will increase in coming decades.2Sharma A Hill A Kurbatova E et al.Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.Lancet Infect Dis. 2017; 17: 707-715Summary Full Text Full Text PDF PubMed Scopus (94) Google Scholar Without an effective vaccine, identifying individuals with latent Mycobacterium tuberculosis infection and administration of preventive chemotherapy are highly effective interventions for preventing active tuberculosis when M tuberculosis is susceptible to isoniazid or rifamycin. In countries such as Belarus, Moldova, Russia, and Ukraine, where more than 25% of patients with tuberculosis have multidrug-resistant tuberculosis or rifampicin-resistant tuberculosis, offering isoniazid-based or rifamycin-based preventive chemotherapy results in a high proportion of patients receiving ineffective treatment.1Lange C Dheda K Chesov D Mandalakas AM Udwadia Z Horsburgh Jr, CR Management of drug-resistant tuberculosis.Lancet. 2019; 394: 953-966Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar The optimal regimen for preventive treatment in a high-burden setting for multidrug-resistant tuberculosis is unknown, and we strongly support that more research be done to address this question. Observational evidence suggests that fluoroquinolones can be used successfully when the index patient's isolate is fluoroquinolone-susceptible. In our experience, 2 years of strict clinical observation and close monitoring, as advocated by Katherine Gaskell and David Moore, is challenging in low-income and middle-income countries. It might not always be necessary to have proof of infection to initiate preventive chemotherapy in small children, people with HIV, or other immunocompromised close contacts of patients with multidrug-resistant tuberculosis. In such situations, decisions for preventive chemotherapy are often made on an individual basis. Where available, therapeutic drug monitoring can guide physicians to optimise drug dosing.3Lange C Aarnoutse RE Alffenaar JWC et al.Management of patients with multidrug-resistant tuberculosis.Int J Tuberc Lung Dis. 2019; 23: 645-662Crossref PubMed Scopus (48) Google Scholar Information on the minimal inhibitory concentrations from phenotypic drug susceptibility testing and on the phamacokinetics and pharmacodynamics of antituberculosis medicines, as measured in the blood or other fluids, could be useful to estimate the dose of individual drugs needed to treat a patient with low-level drug resistance effectively. Although this method is very promising, no controlled clinical trials showing an effect of therapeutic drug monitoring on treatment outcomes in multidrug-resistant tuberculosis have been done. Moreover, several technical challenges exist. No tuberculosis centres worldwide currently have an analytical platform to measure all second-line antituberculosis drugs in routine clinical practice. Before therapeutic drug monitoring can become more widely available, the analytical technology has to become affordable, reliable, and easy to use for clinical application. CL reports personal fees from Chiesi, Gilead, Janssen, Lucane, Novartis, Oxoid, Berlin Chemie, and Thermofisher outside the submitted work, and is supported by the German Center for Infection Research. KD is supported by the South African Medical Research Council (RFA-EMU-02-2017) and the European and Developing Countries Clinical Trials Partnership (TMA-2015SF-1043 and TMA-1051-TESAII). AMM reports personal fees from Janssen Pharmaceuticals outside of the submitted work. CRH Jr is supported by the Providence and Boston Center for AIDS Research, the Boston University and Rutgers Tuberculosis Research Unit, and the US–India Vaccine Action Program Initiative on Tuberculosis. All other authors declare no competing interests. Management of drug-resistant tuberculosisDrug-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%. Full-Text PDF Challenging the management of drug-resistant tuberculosisThe management of multidrug-resistant tuberculosis is notoriously difficult. Christoph Lange and colleagues1 rightly mention that therapeutic drug monitoring can guide optimal personalised care. However, since the first recommendation for therapeutic drug monitoring in multidrug-resistant tuberculosis two decades ago,2 and despite strong evidence that suboptimal drug exposure is a key contributor to drug resistance amplification, little has changed. Full-Text PDF Challenging the management of drug-resistant tuberculosisAlthough we were pleased to read the Series paper by Christoph Lange and colleagues1 on the management of drug-resistant tuberculosis, we were disappointed by the section on management of multidrug-resistant tuberculosis contacts, which we found to perpetuate unsubstantiated platitudes, confusing clinicians and misrepresenting guidance. Full-Text PDF