Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis

Abstract

Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis--ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis--and increased funding to strengthen global control efforts, research, and advocacy--even more pressing.

Figure 1. Global distribution of extensively drug-resistant tuberculosis by genotype and country

The proportion of isolates with a defined genotype are shown for South Africa, Ethiopia, Argentina, Portugal, Poland, Iran, Pakistan, India, Nepal, Cambodia, China, Taiwan, and Japan. We classified Beijing genotype strains from South Africa as typical or atypical to show regional differences in the population structure of extensively drug-resistant tuberculosis. Data sources provided in the appendix. LAM=Latino-American-Mediterranean family. CAS=Central-Asian family. T=T family. EAI=East-African-Indian family. U=U family. S=S family. X=X family. H=Haarlem family.

Figure 2. The pathogenesis of drug-resistant tuberculosis

The traditional interpretation of resistance development is that sequential drug resistance develops through fragmented treatment (A), which can be fuelled by several programmatic and socioeconomic factors. However, resistance can develop despite excellent adherence. Several factors, including efflux pumps (B), between-person pharmacokinetic variability (C), and extensive immunopathology in the lung resulting in differential drug penetration into granulomas and cavities (D) might all drive site-specific drug concentrations below minimum inhibitory concentrations, thus probably enabling drug resistance. After acquired drug resistance develops, person-to-person transmission might constitute the major route of spread (E). Strain-specific genotype, newly acquired drug-encoding mutations, and compensatory mutations that can affect fitness cost (and hence transmission) might also interact (F). Compensatory mutations could be associated with changes in structure and physiological pathways, which could affect host immune response and thereby potentially subvert protective responses and drive progressive disease (G). INH=isoniazid. RIF=rifampicin. PZA=pyrazinamide. MDR-TB=multidrug-resistant tuberculosis.

Figure 3. The arrow of time of antibiotic resistance

Several factors initiate the process, the most important of which is low drug concentrations due to pharmacokinetic variability. Variability is encountered at each step of drug absorption, distribution, metabolism, and elimination, and could be due to different single-nucleotide polymorphisms in enzymes for drug transport and xenobiotic metabolism, comorbid conditions (eg, AIDS), or increased patient weight. This variability leads in some patients to low drug concentrations of one or more drugs in the regimen (effectively equivalent to monotherapy). Bacteria then adapt to these concentrations, initially through epigenetic mechanisms (eg, induction of several efflux pumps). These efflux pumps are associated with low-level multidrug resistance and enable several rounds of bacterial replication, allowing for development of mutations in canonical genes associated with drug resistance. AUC=area under the curve.

Figure 4. Molecular (A, B) and culture-based (C) tests for diagnosis of drug resistance

(A) The Xpert MTB/RIF assay, an automated real-time PCR assay that can detect genotypic resistance to rifampicin and Mycobacterium tuberculosis complex DNA. A test cartridge, four-module machine, and an example of a tuberculosis-positive rifampicin-resistant result are shown. (B) Line-probe hybridisation patterns, resulting from the detection of specific DNA fragments containing mutations associated with drug resistance, for the Hain Lifesciences MTBDRplus (top row) and Hain Lifesciences MTBDRsl(bottom row) test. (C) An example of a commercially available kit for microscopic observation drug susceptibility, in which bacteria are cultured in a microtitre-well-plate format, and visually inspected with light microscopy for distinctive cording patterns that are indicative of M tuberculosis growth in the presence of the drug of interest.

Figure 5. Kaplan-Meier survival plot by drug-resistance pattern for patients with multidrug-resistant and extensively drug-resistant tuberculosis, 2005–07 (log-rank p<0·0001)

Median survival was 182 days (95% CI 31–395) for patients with tuberculosis resistant to isoniazid and rifampicin; 50 days (95% CI 35–106) for patients with tuberculosis resistant to isoniazid and rifampicin, plus either ethambutol or streptomycin or both; 36 days (95% CI 23–74) for patients with tuberculosis resistant to isoniazid, rifampicin, ciprofloxacin, and kanamycin, alone or plus either streptomycin or ethambutol; and 27 days (95% CI 20–38) for patients with tuberculosis resistant to isoniazid, rifampicin, ethambutol, streptomycin, ciprofloxacin, and kanamycin. Figure reproduced from Gandhi and colleagues by permission of the American Thoracic Society.