Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management

Abstract

Drug resistant tuberculosis contributes significantly to the global burden of antimicrobial resistance, often consuming a large proportion of the healthcare budget and associated resources in many endemic countries. The rapid emergence of resistance to newer tuberculosis therapies signals the need to ensure appropriate antibiotic stewardship, together with a concerted drive to develop new regimens that are active against currently circulating drug resistant strains. Herein, we highlight that the current burden of drug resistant tuberculosis is driven by a combination of ongoing transmission and the intra-patient evolution of resistance through several mechanisms. Global control of tuberculosis will require interventions that effectively address these and related aspects. Interrupting tuberculosis transmission is dependent on the availability of novel rapid diagnostics which provide accurate results, as near-patient as is possible, together with appropriate linkage to care. Contact tracing, longitudinal follow-up for symptoms and active mapping of social contacts are essential elements to curb further community-wide spread of drug resistant strains. Appropriate prophylaxis for contacts of drug resistant index cases is imperative to limit disease progression and subsequent transmission. Preventing the evolution of drug resistant strains will require the development of shorter regimens that rapidly eliminate all populations of mycobacteria, whilst concurrently limiting bacterial metabolic processes that drive drug tolerance, mutagenesis and the ultimate emergence of resistance. Drug discovery programs that specifically target bacterial genetic determinants associated with these processes will be paramount to tuberculosis eradication. In addition, the development of appropriate clinical endpoints that quantify drug tolerant organisms in sputum, such as differentially culturable/detectable tubercle bacteria is necessary to accurately assess the potential of new therapies to effectively shorten treatment duration. When combined, this holistic approach to addressing the critical problems associated with drug resistance will support delivery of quality care to patients suffering from tuberculosis and bolster efforts to eradicate this disease.

Pharmacological Management of Pulmonary Tuberculosis: A Century of Expert Opinions in Cecil Textbook of Medicine

“…The emphasis is on shorter regimens that will hopefully reduce the mycobacterial population and limit mutagenesis and metabolic processes that enable drug tolerance. 39 The pillars of this effort are combinations that include bedaquiline, linezolid and levofloxacin/moxifloxacin, as well as one or more of other drugs, such as clofazimine, cycloserine/terizidone, delamanid, pretomanid and rifapentine. 39 In high HIV settings, all-oral four or more drugs regimens containing bedaquilin and linezolid are also required, together with early antiretroviral treatment.…”

Multidrug-Resistant TB (MDR-TB) and Extensively Drug-Resistant TB (XDR-TB) Among Children: Where We Stand Now

“…Diagnosing DR-TB cannot be done with conventional methods but need modern drug sensitivity testing to establish the drug resistance pattern of the MT. The absence of effective and affordable rapid diagnostic techniques makes the diagnosis arduous [ 59 , 74 , 75 ]. Several phenotypic and molecular approaches have been explored to develop quick, reliable, and accurate methods for rapidly detecting drug resistance [ 66 ].…”

Tools to develop antibiotic combinations that target drug tolerance in Mycobacterium tuberculosis

“…Tuberculosis (TB) remains notoriously difficult to treat and, until the COVID-19 pandemic, was the leading cause of death by a single infectious agent, Mycobacterium tuberculosis (Mtb) ( WHO, 2021 ). TB requires lengthy combination therapy to prevent the acquisition of heritable drug resistance [addressed by others in this collection, including ( Bhagwat et al., 2022 ; Jones et al., 2022 ; Liebenberg et al., 2022 )] and to effectively target inherent heterogeneity in infection that results in drug tolerance to prevent treatment failure and subsequent disease relapse ( Fox et al., 1999 ; Kerantzas and Jacobs, 2017 ). Genotypic resistance is defined by the heritable ability to grow in the presence of high concentrations of antibiotics beyond the minimum inhibitory concentration (MIC) ( Balaban et al., 2019 ).…”