Epidemiology and molecular mechanisms of drug-resistant tuberculosis

INTRODUCTION — Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide, and resistance to commonly used antituberculous drugs is increasing.

Drug-resistant TB was recognized shortly after the introduction of effective chemotherapy in the late 1940s. Streptomycin was the first drug to be used widely. Patients who received this drug usually had marked and rapid clinical improvement, but treatment failures were common after the first three months of therapy. Isolates of Mycobacterium tuberculosis obtained from patients with treatment failure were invariably streptomycin resistant. The rapid development of resistance to single-agent therapy led to the principle of multiagent chemotherapy of TB that remains the cornerstone of treatment.

The epidemiology and molecular basis of drug-resistant TB will be reviewed here. The diagnosis and treatment of drug-resistant strains of M. tuberculosis are discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

TERMINOLOGY — TB terminology is inconsistent in the literature [1]. Relevant terms are defined in the table (table 1).

DEFINITIONS FOR TUBERCULOSIS DRUG RESISTANCE — Definitions for drug-resistant TB are summarized in the table (table 2).

EPIDEMIOLOGY

Drug-resistant tuberculosis

Worldwide — Precise information about the global incidence of drug-resistant TB is difficult to obtain, since routine sputum culture and drug susceptibility testing are not performed routinely in all resource-limited settings, where the disease occurs most frequently [2]. However, this situation has improved somewhat; data on drug resistance have been systematically collected from more than 160 countries by the World Health Organization (WHO), representing more than 99 percent of the global population and TB cases. In addition, a major advancement in surveillance of drug resistance has been uptake of molecular detection methods, which allow continuous monitoring of the prevalence of drug resistance (particularly rifampin resistance) in many high-burden countries (table 3).

The WHO 2021 Global Tuberculosis Report noted that globally in 2020, more than 157,000 people were diagnosed with rifampin-resistant, multidrug-resistant (MDR), or extensively-resistant TB. This was a dramatic drop from the more than 201,000 people diagnosed in 2019; the decline almost certainly represents the difficulties in maintaining surveillance activities during the coronavirus disease 2019 (COVID-19) pandemic than it does any successes in controlling the spread of drug-resistant TB. This drop is mirrored by an overall decline of 17 percent in cases of TB overall globally in 2020.

The WHO 2020 Global Tuberculosis Report had estimated that, worldwide, approximately 3.3 percent of all new TB cases and 18 percent of previously treated cases are caused by MDR or rifampin-monoresistant strains [3]. Worldwide surveys indicate that drug-resistant TB is a large problem, although the overall burden of MDR-TB relative to the number of new and treated cases is relatively stable (figure 1 and figure 2) [4,5].

In 2019, the WHO estimated that there were roughly 465,000 cases of incident MDR-TB worldwide [6]; it is estimated that 214,000 deaths from MDR-TB occurred in 2017 [6]. This number likely rose in 2020 because of the impact of COVID-19 pandemic on TB control efforts. Globally, only 71 percent of individuals with bacteriologically confirmed TB were tested for rifampin resistance, although this represents remarkable progress over the last decade; in 2017, only 51 percent were tested, and that figure represents a tremendous increase from 2012, when the figure was only 7 percent. Only about 61 percent of cases of TB in the world were bacteriologically confirmed, so in absolute terms, substantially fewer than half of all individuals with TB are tested for drug resistance [7].

MDR-TB occurs worldwide; China, India, Russia, and the countries of the former Soviet Union are estimated to carry the highest number of MDR-TB cases [4,5,8-16], while the highest proportion of MDR cases are still seen in several countries of the former Soviet Union. Of patients who received treatment, overall outcomes were poor; only about 56 percent of patients were considered cured. As improved diagnostic testing becomes available, MDR-TB will likely be recognized as the major threat to global TB control over the next several decades.

The highest-burden countries for MDR-TB include many countries of the former Soviet Union (Kazakhstan, Azerbaijan, Belarus, Moldova, Uzbekistan, Tajikistan, Ukraine, Kyrgyzstan), several Africa countries (Angola, the Democratic Republic of Congo, Mozambique, Nigeria, South Africa, Somalia, Zambia and Zimbabwe), and several Asian nations (Indonesia, Pakistan, Mongolia, Nepal, Philippines, and Bangladesh).

Many MDR cases are reported in individuals who have not received prior treatment; however, a history of prior treatment (especially if incomplete or unsupervised) is an important risk factor for the presence of MDR-TB in a given patient. However, it is increasingly recognized that the dominant mode of development of MDR-TB is transmission rather than the development of de novo resistance in patients under treatment. The presence of initial drug resistance substantially reduces treatment outcomes, since in general, most TB treatment approaches rely on standardized rather than tailored treatment regimens [17,18]. In one study including data from 103 countries where standardized regimens are used, failure and relapse rates were significantly higher in regions where the initial multidrug-resistance prevalence was ≥3 percent [18]. In these areas, retreatment was required in more than 20 percent of cases. High rates of MDR-TB among patients requiring retreatment have also been described; in one survey from the Philippines, MDR-TB was observed 76 percent of retreatment cases [19].

According to the WHO 2020 Global TB Report, rates of MDR-TB are increasing in Russia, Ukraine, and Peru. In other countries with a high burden of TB and MDR-TB, the rate of decline in MDR incidence is substantially below that of cases of drug susceptible disease.

Some resistance data for other countries in Africa have been reported. In Botswana, the rate of drug resistance is increasing, despite implementation of 100 percent coverage of directly observed therapy short course (DOTS) strategy in 1986. In a 2002 survey of drug resistance among isolates from 1182 patients with newly diagnosed TB, rates of monoresistance and MDR-TB were 10.4 and 0.8 percent, respectively [20]. Among 106 patients previously treated for TB, the respective rates were 22.8 and 10.4 percent. In Uganda, the burden of drug resistance in previously treated patients with TB is also sizeable. Among 410 patients enrolled between 2003 and 2006, the prevalence of MDR-TB was 12.7 percent [21]. A survey of resistance to pyrazinamide and quinolones in Africa, Asia, and Eastern Europe found varying rates of resistance across these regions; resistance was quite high in some areas [22].

The outcome of DOTS with a standard four-drug regimen was evaluated by the WHO retrospectively in six geographically distinct countries [23]. Not surprisingly, treatment failures were higher among new MDR-TB cases than among new susceptible cases (10 versus 0.7 percent).

United States — Substantial drug resistance began emerging in regions of the United States in the early 1990s [24,25]. The prevalence of drug-resistant TB in the United States decreased between 1991 and 2006 (3.5 to 1.1 percent) and remained stable between 2005 and 2006 (1.2 percent), even as drug-resistant disease increased worldwide [26,27]. About 12.6 percent of drug-resistant TB cases in the United States can be linked to domestic transmission [28]. Adherence to hospital infection control measures, the widespread use of an initial four-drug chemotherapy regimen, and directly observed therapy are critical for controlling the incidence rates of drug-resistant TB in the United States [27,29-31].

Single-drug resistance to isoniazid (the most common form of drug resistance in the United States) occurred in approximately 9.6 percent of cases with positive cultures in 2019, an increase from 8.4 percent of cases in 2006 [32]. The percentage of TB cases that are isoniazid resistant has risen slowly but consistently for several years [33]. In 2019, the percentage of isoniazid (INH) resistance was higher among previously treated cases than untreated cases (14 versus 9 percent). INH resistance is slightly higher among individuals born outside the United States than among individuals born within the United States. The rate is variable by region; rates of INH resistance ranged from 0 to 34 percent [34]. In 2020, only 213 (6.3 percent) of reported cases of TB in the United States were found to be INH resistant.  

Multidrug resistance has decreased overall between 1993 and 2019 (2.4 to 1.3 percent) [35]. MDR-TB disproportionately affects foreign-born individuals; this group accounted for 85 percent of cases of MDR-TB in 2019 [27]. MDR-TB cases accounted for 0.6 percent of cases occurring in individuals born in the United States and 1.6 percent of individuals born outside the United States [34]. In 2020, the number of MDR-TB cases reported in the United States fell to 213 (from 272 in 2019); it is difficult to know how much (if any) of this decrease was real or merely a reflection of the reduced surveillance efforts during the COVID-19 pandemic.

Migration of individuals with TB can alter the prevalence and resistance patterns. Among 10,000 Hmong refugees resettled from Thailand into the United States from June 2004 through January 2005, 37 were found to have active TB, including 4 with MDR-TB [36]. Among the 6000 refugees still awaiting emigration from Thailand, TB was identified in 6 percent of individuals; of these, MDR-TB was observed in 6 percent of cases, half of which were smear negative [37]. As a result, enhanced screening for all immigrants and refugees entering the United States was implemented by the Centers for Disease Control, beginning with high-priority countries as determined by TB prevalence and immigration patterns.

At the peak of the human immunodeficiency virus (HIV) epidemic in the United States, HIV infection was associated with MDR-TB [24]. Subsequently, a 2007 review of published studies and surveillance data noted that MDR-TB does not appear to cause infection or disease in individuals with HIV infection more readily than drug-susceptible strains, although HIV infection and MDR-TB may converge in some countries [38].

Extensively drug-resistant tuberculosis — The epidemiology of extensively drug-resistant TB is discussed in detail separately. (See "Epidemiology of extensively drug-resistant tuberculosis".)

RISK FACTORS FOR DEVELOPMENT OF DRUG RESISTANCE — Risk factors for multidrug-resistant TB (MDR-TB) are summarized in the following table (table 4); these include prior episodes of TB treatment, progressive clinical and/or radiographic findings while on TB therapy, residence in or travel to a region with high prevalence of drug-resistant TB (figure 1 and figure 2), and/or exposure to an individual with known or suspected infectious drug-resistant TB.

Each patient with TB harbors a mixed population of organisms with naturally occurring resistance to various drugs. Such resistance occurs by spontaneous mutation within the organism's genome as they replicate. Selection for these resistant organisms will occur if only one drug is used in treatment, since approximately 1 in 10⁶ to 10⁸ organisms exhibits intrinsic resistance to any given drug. The chance that an organism in a population is resistant to two drugs is roughly 1 in 10¹⁴, making resistance much less likely to emerge with combination therapy. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

The development of MDR-TB is favored by an inadequate course of treatment. MDR cases in the United States are uncommon; development of MDR-TB in the United States may reflect poor prescribing practices, poorly supervised treatment, and poor infection control in hospitals and prisons. However, it is also likely that as MDR cases have proliferated worldwide, cases in the United States may represent reactivation of latent infection caused by drug-resistant strains acquired prior to immigration.

The global burden of MDR-TB is large (roughly half a million individuals) and is almost completely uncontrolled. The WHO estimates that no more than 20 percent of individuals with MDR-TB are diagnosed or treated, and of those that are treated, the outcome is favorable in only slightly more than half of cases. This means that there are many patients with MDR-TB who are likely to be infectious for prolonged periods. In addition, the global HIV epidemic has fueled spread of MDR-TB in places like South Africa by creating a large reservoir of immunosuppressed individuals who are more likely to develop active TB disease following infection.

In general, the acquisition of drug resistance is thought to come at a cost of overall fitness; MDR strains are not thought to be more virulent or transmissible. However, one molecular epidemiology study from China reported that MDR strains were more transmissible than drug-susceptible strains [39]. (See "Epidemiology of tuberculosis".)

Inappropriate therapy — The American Thoracic Society/United States Centers for Disease Control and Prevention (ATS/CDC) guideline published in 1994 recommended initial treatment with four-drug therapy in areas where the rate of isoniazid resistance exceeds 4 percent [40]. Nonetheless, one 1995 report noted that approximately 25 percent of new TB cases were initially treated with two or three drug regimens [30].

Prescribing errors by physicians inexperienced in the care of patients with TB can exacerbate problems associated with drug resistance. One review of patients referred to the National Jewish Hospital in Denver for management of complex MDR-TB noted an average of nearly four prescribing errors per patient [41]. This highlights the need for expert management of drug-resistant TB in all cases.

Compliance — One study in New York City documented that patients with high rates of alcohol and drug abuse discharged from the hospital were unlikely to adhere to TB treatment regimens; among 178 patients, only 11 percent complied with therapy [42]. Drugs were taken erratically and often singly, making the emergence of drug resistance more likely.

In communities with long-standing programs of supervised or directly observed therapy (DOT), such as Baltimore, Maryland, or Tarrant County, Texas, drug resistance has not emerged as a serious problem [43,44]. Furthermore, the incidence of MDR-TB diminished in New York after DOT was implemented [45]. (See "Adherence to tuberculosis treatment".)

Patient characteristics — Individual differences in the pharmacokinetics (including absorption, disposition, and elimination of a drug) may lead to development of drug resistance [46,47]. A given dose does not lead to identical concentration-time profiles in all patients, and pharmacokinetic variability to a single drug in a regimen is significantly associated with failure of therapy in patients with acquired drug resistance [47]. The concentration achieved by a particular dose is determined in part by patient physiology, gene alleles encoding enzymes involved in drug metabolism, dietary considerations, concomitant drug administration, and comorbidities [48]. Clinical trial simulations suggest that 1 percent of TB patients with perfect adherence may develop MDR-TB due to pharmacokinetic variability alone [46].

Strain characteristics — Propagation of drug-resistant strains appears to depend on both their fitness and diversity [49]. The risk of infection with drug-resistant strains may be amplified in regions where there is reduced cross-immunity between originating strain groups. However, epidemiologic studies and TB vaccine trials indicate that cross-protective immunity to TB can be conferred by infection within the M. tuberculosis complex (eg, by Mycobacterium bovis, Mycobacterium microti) as well as by infection within the entire genus (eg, by nontuberculous mycobacteria), suggesting that antigens common to all organisms within the genus may play a dominant role in immune protection against human TB [50].

Nosocomial transmission and HIV — Several nosocomial outbreaks of MDR-TB have been reported, primarily from hospitals and prisons in New York and New Jersey [51-54]. Most of the cases occurred in individuals with HIV infection, and reported mortality is high in all series. Links between cases were found by contact tracing and confirmed using molecular biologic techniques. Restriction fragment length polymorphism (RFLP) analysis, also known as deoxyribonucleic acid (DNA) fingerprinting, can determine the clonal origin of organisms responsible for a case cluster; clonality implies transmission of TB between cases or infection from a common index case.

Genotyping of MDR-TB case-clusters has demonstrated spread among patients with HIV infection with apparently trivial exposure when proper isolation and infection control measures are not enforced [51-54]. A hierarchy of control measures has been employed to improve infection control practices in hospitals, nursing homes, and other congregate facilities. These include isolation of suspected TB cases, rapid examination of sputum smears, health care worker use of particulate respirators, and use of environmental measures such as germicidal ultraviolet irradiation, high-efficiency particulate air filters, frequent air exchanges, and negative pressure ventilation. These measures, if applied properly, may decrease transmission and nosocomial infection [55-57]. (See "Tuberculosis transmission and control in health care settings".)

In many poor countries, these infection control measures are not affordable. Furthermore, isolation of patients is impossible because of the volume of cases. Patients are often kept together in large open wards, creating significant problems with nosocomial transmission [58].

MOLECULAR BASIS OF DRUG-RESISTANT TUBERCULOSIS — Our understanding of the molecular basis for drug resistance in M. tuberculosis is improving. This knowledge is important for new drug design, development of new rapid diagnostic tools for case-tailored therapy based on specific drug resistance in the individual patient, and creating new therapeutic strategies against drug-resistant TB.

The GeneXpert system for nucleic acid amplification testing of sputum for MTb Complex DNA and molecular detection of resistance to rifampin was approved by the US Food and Drug Administration (FDA) in 2013 and is available in many United States public health and hospital laboratories. (See "Diagnosis of pulmonary tuberculosis in adults".)

In addition, the United States Centers for Disease Control and Prevention (CDC) TB laboratory performs rapid molecular testing for drug resistance for first-line and many second-line drugs on sputum sediments and isolates of MTb Complex. This service assists clinicians and public health programs in the management of potentially drug-resistant cases and contacts [59,60]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Molecular testing'.)

Molecular tests may have false-negative or false-positive results; individual data must be interpreted in the clinical context and confirmed using culture methods for isolation, identification, and drug susceptibility testing. Even in low-prevalence settings, where the proportion of false-positive cases to true-positive cases might be assumed to be higher than in high-prevalence settings, use of GeneXpert in diagnostic algorithms appears to result in significant reduction in unnecessary treatment as compared with standard clinical approaches [59].

Isoniazid resistance — The burden of mycobacteria within a pulmonary cavity is estimated to be between 10⁷ and 10⁹ colony-forming unit/mL [60]. For many years, it was believed that isoniazid (INH) kills the largest subpopulation of bacilli that are in the exponential phase of growth during the first three days of therapy and that, once this population is depleted, INH is no longer effective. An in vitro infection model has shown that, while most early bactericidal activity does decline by 72 hours, the outcome is best explained by the emergence of drug-resistant isolates, which were undergoing exponential-phase growth [61].

Resistance to INH may be conferred by alterations in the katG and/or inhA genes. Mutations to katG and/or inhA account for 85 to 90 percent of INH resistance reported by the CDC Molecular Detection of Drug Resistance (MDDR) service [62].

It was observed in the 1950s that strains of M. tuberculosis that do not produce catalase are usually resistant to INH [63]. This finding led to the hypothesis that INH is a prodrug requiring alteration by catalase into its functional form. Subsequently, it was shown that deletion or mutation in the catalase gene (katG) is responsible for 10 to 25 percent of cases of INH resistance [64,65]. Such a mutation would also decrease the survival of the organism, were it not for compensatory hyperexpression of alkyl hydroperoxidase to protect against the toxic effect of organic peroxides [66].

Strong evidence favors an integral role of inhA in determining INH susceptibility; one inhA enzyme with introduced point mutations was 17 times more resistant to inhibition by INH than the wild-type enzyme [67]. This gene encodes a protein long-chain enoyl-acyl carrier protein reductase, which is involved in the synthesis of mycolic acid, an important cell wall component of mycobacteria [68]. Presumably, INH is activated by catalase and then binds to the inhA protein to inhibit cell wall synthesis [68]. Upregulation of inhA can overwhelm the inhibitory capacity of INH, and mutations in inhA can prevent binding of INH and therefore lead to drug resistance [69].

Rifampin resistance — Rifampin is the cornerstone of short-course chemotherapy regimens, so rifampin resistance prolongs and complicates treatment. Rifampin is thought to act against M. tuberculosis by binding to ribonucleic acid (RNA) polymerase, resulting in interference with transcription and RNA prolongation. Mutations in the rpoB gene, which encodes the beta chain of mycobacterial RNA polymerase, have been found to cause clinical rifampin resistance [70,71].

In one report, a mutation in rpoB was identified in 64 of 66 resistant organisms from diverse geographic areas but in none of 56 sensitive organisms [72]. Rifampin resistance may be detected as quickly as four hours after receipt of a sputum sample by the laboratory using the GeneXpert system available in most United States public health and in many hospital TB laboratories. The CDC's MDDR service also detects rpoB mutations associated with rifampin resistance [62]. These rapid assays can facilitate institution of proper therapy for patients and contacts within days of clinical presentation [73-75].

Pyrazinamide resistance — Conventional methods used to determine pyrazinamide (PZA) resistance are complex and require acidic media (broth-based only), which may adversely affect growth [76]. PZA is a prodrug that is converted to its active form, pyrazinoic acid, by the enzyme pyrazinamidase. PZA resistance is due to any of a number of mutations in the gene pncA, which encodes this enzyme [77,78]. In one report, 33 of 38 PZA-resistant clinical isolates had pncA mutations; among the five strains that did not contain pncA mutations, four were falsely resistant and one had only borderline resistance [78].

Among nearly 80,000 cases of TB in the United States between 1999 and 2009, PZA resistance was observed in 2.7 percent of cases [79]. Associated characteristics included age 0 to 24 years, Hispanic ethnicity, extrapulmonary disease, and normal chest radiograph. Inversely associated characteristics included Asian and Black race.

Ethambutol — Ethambutol inhibits mycobacterial cell wall biosynthesis. Ethambutol resistance in approximately 60 percent of organisms is due to amino acid replacements at position 306 of an arabinosyl transferase encoded by the embB gene [80]. Arabinosyl transferase is an enzyme that polymerizes arabinose into arabinan and then arabinogalactan, a mycobacterial cell wall constituent [81,82]. Increased production of arabinosyl transferase overwhelms the effects of ethambutol. (See "Ethambutol: An overview".)

Streptomycin — Streptomycin acts by inhibiting microbial mRNA translation. Resistance is conferred by mutations in the rpsL and rrs genes, which affect ribosomal protein S12, or the 16S portion of ribosomal RNA [83,84]. Streptomycin cannot inhibit protein synthesis in mycobacteria with these alterations in ribosomal structure.

Second-line agents — Resistance has also been documented in second-line antituberculous drugs including fluoroquinolones and ethionamide.

Fluoroquinolones inhibit DNA gyrases, which are important in maintaining the proper tertiary structure of DNA. Resistance is caused by mutations in the gyrA and gyrB genes, which encode the target DNA gyrases [85,86]. Specifically, amino acid changes in a subunit of DNA gyrase cause fluoroquinolone resistance in most organisms. Fluoroquinolones are becoming increasingly important in the treatment of TB but, to date, resistance to this class of drugs is relatively uncommon in the United States [80].

Ethionamide is a nicotinic acid derivative similar in structure to INH. Mutations in the inhA gene are also associated with ethionamide resistance, although catalase mutations (eg, katG) are not [87].

NEW REGIMENS AND EMERGING RESISTANCE — New all-oral regimens for rifampin-resistant TB endorsed by the World Health Organization [88] and the United States Centers for Disease Control and Prevention/Infectious Diseases Society of America [89] are based on a bedaquiline core, as part of a multidrug combination that includes clofazimine. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

As these drug regimens are being used worldwide, concern has been raised about the emergence of resistance during treatment:

●In a study of 70 isolates from 30 patients with multidrug-resistant and extensively drug-resistant TB on bedaquiline-containing regimens who were retrospectively tested for bedaquiline resistance by minimum inhibitory concentration (MIC) and by molecular detection of relevant gene mutations, six patients developed progressive increases in bedaquiline MICs in 7H11 medium during therapy associated with increasing MICs to clofazimine and characterized by emergence of specific mutations in Rv0678, and five patients developed bedaquiline resistance during treatment by phenotypic testing using critical drug concentrations [90].

●A subsequent study characterized a wide diversity of Rv0678 mutations in the genomes of clinical isolates from hospitals in KwaZulu-Natal, South Africa, demonstrating bedaquiline and clofazimine resistance, with evidence of onward transmission [91].

These findings suggest that with use of multidrug TB treatment regimens for drug-resistant TB, routine monitoring for phenotypic and molecular resistance to bedaquiline and clofazimine should be performed where possible to prevent emergence of resistance and treatment failure, especially in patients with delayed culture conversion [92]. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY

●Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide, and resistance to commonly used antituberculous drugs is increasing. (See 'Introduction' above.)

●The term "drug-resistant TB" refers to cases of TB caused by an isolate of Mycobacterium tuberculosis that is resistant to one of the first-line anti-TB drugs: isoniazid, rifampin, pyrazinamide, ethambutol, or streptomycin. The term "multidrug-resistant TB" (MDR-TB) refers to an isolate of M. tuberculosis that is resistant to at least isoniazid and rifampin and possibly additional chemotherapeutic agents. (See 'Definitions for tuberculosis drug resistance' above.)

●Primary drug resistance is said to occur in a patient who has never received anti-TB therapy. Secondary drug resistance refers to the development of resistance during or following chemotherapy in patients who had previously had drug-susceptible TB. (See 'Definitions for tuberculosis drug resistance' above.)

●The World Health Organization has estimated at least 500,000 cases of MDR-TB occur annually worldwide; it likely that ≤30,000 are treated appropriately. China, India, and Russia (and the countries of the former Soviet Union) are estimated to carry the highest number of MDR-TB cases. (See 'Worldwide' above.)

●In the United States, drug resistance began emerging in some regions in the early 1990s. The prevalence of drug-resistant TB in the United States decreased between the 1990s and mid-2000s and since then has remained stable. Factors leading to development of resistance include inadequate course of treatment, poorly supervised treatment programs, and poor infection control programs. (See 'United States' above and 'Risk factors for development of drug resistance' above.)

●Risk factors for MDR-TB are summarized in the following table (table 4); these include prior episode of TB treatment, progressive clinical and/or radiographic findings while on TB therapy, residence in or travel to a region with high prevalence of drug-resistant TB (figure 1 and figure 2), and/or exposure to an individual with known or suspected infectious drug-resistant TB. (See 'Risk factors for development of drug resistance' above.)

●Understanding the molecular basis for drug resistance in M. tuberculosis is gaining importance in rapid diagnostic testing and development of therapeutic strategies against drug-resistant TB. The availability of tools including the GeneXpert system and molecular determination of drug resistance by the United States Centers for Disease Control and Prevention hold promise for more rapid diagnosis and tailoring of drug therapy for patients and contacts. (See 'Molecular basis of drug-resistant tuberculosis' above.)

●Monitoring for emergence of drug resistance may be critical in new treatment regimens for rifamycin and MDR/extensively drug-resistant-TB to prevent treatment failure and transmission of drug-resistant infection. (See 'New regimens and emerging resistance' above.)