Volume 13, Number 3–March 2007

Research

Worldwide Emergence of Extensively Drug-resistant Tuberculosis

N. Sarita Shah,*¹ Abigail Wright,† Gill-Han Bai,‡² Lucia Barrera,§² Fadila Boulahbal,¶² Nuria Martín-Casabona,#² Francis Drobniewski,**² Chris Gilpin,††² Marta Havelková,‡‡² Rosario Lepe,§§² Richard Lumb,¶¶²Beverly Metchock,*² Françoise Portaels,##² Maria Filomena Rodrigues,***² Sabine Rüsch-Gerdes,†††² Armand Van Deun,##² Veronique Vincent,‡‡‡^2,3 Kayla Laserson,* Charles Wells,* and J. Peter Cegielski*
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †World Health Organization, Geneva, Switzerland; ‡Korean Institute of Tuberculosis, Seoul, Republic of Korea; §National Institute of Infectious Diseases, Buenos Aires, Argentina; ¶Institut Pasteur d'Algérie, Alger, Algeria; #Hospital Universitaris Vall d'Hebron, Barcelona, Spain; **Health Protection Agency, London, United Kingdom; ††Prince Charles Hospital, Brisbane, Queensland, Australia; ‡‡National Institute of Public Health, Scrobarova, Czech Republic; §§Institute of Public Health of Chile, Providencia Santiago, Santiago, Chile; ¶¶Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia; ##Institute of Tropical Medicine, Antwerp, Belgium; ***National Institute of Health, Porto, Portugal; †††National Reference Center for Mycobacteria, Borstel, Germany; and ‡‡‡Institut Pasteur, Paris, France

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Results

We received data for 18,462 patients from 14 (61%) of 23 eligible SRLs. We excluded those patients tested before 2000 (n = 223), tested after 2004 (n = 14), or tested for resistance to <3 classes of second-line drugs (n = 535). Our final study sample consisted of 17,690 patients whose isolates were tested for resistance to >3 second-line drugs during 2000–2004 (Figure 2). Of these, 11,939 (67.5%) patients were from the Republic of Korea and 5,751 (32.5%) were from the remaining SRLs.

First-line–Drug Susceptibility

Among isolates from patients from the 13 SRLs other than the Republic of Korea, 3,765 (65.5%) were resistant to >1 first-line TB drug (Table 1). Of these, 3,305 (58.5%) were resistant to at least INH and 2,345 (41.5%) were resistant to at least RIF. Among isolates from the Republic of Korea patients, 2,508 (21%) had resistance to any drug; most (n = 2,196; 18.4%) were resistant to INH.

Single-drug resistance was found for isolates from 884 (15.4%) patients from the 13 SRLs; 456 (8.1%) of these were resistant to INH and 99 (1.8%) to RIF. Among isolates from patients from the Republic of Korea, 952 (8%) displayed single-drug resistance, 666 (5.6%) to INH and 148 (1.2%) to RIF.

Polyresistance other than MDR TB was seen for isolates from 651 (11.5%) patients from the 13 SRLs and 258 (2.2%) from the Republic of Korea SRL. Not all SRLs routinely tested for resistance to pyrazinamide.

Multidrug resistance (i.e., MDR TB) was present in isolates from 2,222 (39.4%) patients from the 13 SRLs and 1,298 (10.9%) from the Republic of Korea. Resistance to all first-line drugs tested (i.e., MDR TB with additional resistance to ethambutol and streptomycin) was found in isolates from 1,017 (18.6%) patients from the 13 SRLs and 233 (2%) from the Republic of Korea SRL.

Second-line–Drug Susceptibility

Among patients from the 13 SRLs, resistance to aminoglycosides was detected in 489 (8.7%) isolates and to fluoroquinolones in 298 (5.3%) (Table 2). Among isolates from Republic of Korea patients, resistance was most commonly seen to fluoroquinolones (n = 524, 4.4%) and thioamides (n = 259, 2.2%).

From all SRLs, isolates that were resistant to at least INH and RIF (i.e., MDR TB; n = 3,520) and tested for susceptibility to >3 second-line drugs were combined for analysis of second-line–drug resistance patterns. Resistance to >1 class of second-line drug was present in 1,542 (43.8%) MDR TB patients (Table 3). The most commonly observed patterns were resistance to aminoglycosides (n = 630, 18.3%), fluoroquinolones (n = 673, 19.3%), and thioamides (n = 605, 19.3%).

MDR TB patients whose isolates had further resistance to >3 classes of second-line drugs were classified as XDR TB (Table 3). A total of 347 (9.9%) MDR TB patients met criteria for XDR TB. According to the revised Global XDR TB Task Force definition (www.who.int/mediacentre/news/notes/2006/np29/en/index.html), 234 (6.6%) isolates met criteria for XDR TB. Among XDR TB patients, combination drug-resistance patterns included 90 (3.4%) with resistance to aminoglycosides, capreomycin and fluoroquinolones; 102 (3.4%) with resistance to aminoglycosides, fluoroquinolones, and thioamides; and 94 (3.8%) with resistance to fluoroquinolones, thioamides, and para-aminosalicyclic acid. Nearly half (n = 167, 48.1%) of all XDR TB isolates were resistant to all 4 first-line drugs, bringing the total to >7 drugs to which the isolate was resistant.

The proportion of XDR TB patients by region is shown in Table 4. Among the group of industrialized nations, 53 (6.5%) MDR TB patients met criteria for XDR TB. Among patients from Russia and Eastern Europe, 55 (13.6%) MDR TB patients met criteria for XDR TB. Among patients from the Republic of Korea, 200 (15.4%) MDR TB patients, who accounted for 1.7% of all M. tuberculosis isolates tested, met criteria for XDR TB.

In evaluating the accuracy of second-line–drug susceptibility testing, we found that 7 (0.1%) of 11,426 patients fully susceptible to all first-line drugs were resistant to 2 second-line drugs, and 109 (1%) were resistant to 1 second-line drug. Most of these patients were resistant to fluoroquinolones.

Discussion

This study represents the first assessment of the widespread occurrence of M. tuberculosis with such extensive drug resistance as to be nearly untreatable with currently available drugs, according to international guidelines. We provide data on second-line–drug resistance for the largest sample of patients to date, including >5,000 patients from 47 countries, apart from the Republic of Korea. The definition of XDR TB in this survey is based on WHO guidelines for the programmatic management of drug-resistant TB; the guidelines recommend treatment with >4 drugs known to be effective (15). Therefore, with <3 remaining classes of second-line drugs to which the infecting organism is susceptible, treatment of these patients cannot meet international standards. XDR TB has been detected in all regions of the world. XDR TB strains in this study also have high rates of resistance to pyrazinamide and ethambutol, thereby severely limiting the treatment options available.

Analysis of combination second-line–drug resistance patterns is critical for clinicians and policymakers who design treatment regimens for these patients. Although limited data exist in the literature about second-line–drug resistance patterns among MDR TB patients, data from patients undergoing retreatment for TB in Hong Kong showed that 30 (17%) MDR TB isolates were resistant to >3 second-line drugs (17), thereby meeting criteria for XDR TB. A drug-resistance survey of 447 culture-positive new patients and patients undergoing retreatment in Abkhazia, Republic of Georgia, found that of 63 MDR TB patients, 2 (3%) had additional resistance to 3 second-line drug classes, consistent with XDR TB (18). More recently, clusters of XDR TB have been reported in South Africa and Iran (19,20) and have been associated with HIV infection and rapid and high death rates.

The emergence of new strains of TB that are resistant to second-line drugs, especially in settings where TB control programs have become unable to adequately monitor treatment regimens for MDR TB, is cause for concern. After the resurgence of TB in industrialized countries during the 1980s and increased awareness of this global problem, implementation of strong TB control programs based on the principles of the global directly observed treatment strategy, short course (DOTS) improved treatment outcomes and reduced TB and MDR TB incidence in several countries. This framework for DOTS, promulgated by WHO, and the pilot MDR TB management projects (DOTS-Plus projects) became the basis for programmatic management of MDR TB, which has demonstrated feasibility and effectiveness in low- and middle-income countries (5,15). However, second-line drugs are available worldwide outside of well-organized TB-control programs (WHO, unpub. data).

Improper treatment of drug-resistant TB, such as using too few drugs, relying on poor quality second-line drugs, and failing to ensure adherence to treatment, will likely lead to increases in XDR TB. Strengthening basic TB programs and infection control measures is crucial for preventing the selective pressure and environments in which resistant strains are transmitted from person to person. Additionally, MDR TB programs that rely on quality-assured and internationally recommended treatment regimens according to WHO guidelines must be scaled up and strengthened to stem further second-line–drug resistance and spread of XDR TB. The Green Light Committee provides a global mechanism to help affected countries achieve these steps. A commentary published in 2000 predicted that "failure to institute [the] entire DOTS-Plus package is likely to destroy the last tools available to combat [TB], and may ultimately result in the victory of the tubercle bacillus over mankind" (21). XDR TB is an indirect indicator of program failure to adequately diagnose, prevent, and treat MDR TB.

Documenting the emergence of XDR TB requires a laboratory-based diagnosis that relies on first- and second-line–drug susceptibility testing. A limitation to accurate detection of XDR TB is that existing tests for resistance to second-line drugs are not yet standardized and are less reproducible than tests for resistance to INH and RIF. Lack of international recommendations for use, as well as lack of standardization and the historical unavailability of MDR TB treatment in the public sector, has limited use of second-line–drug susceptibility testing on a wider scale. As access to treatment with second-line drugs increases, standardized methods, improved diagnostics, and quality assurance for second-line–drug susceptibility testing are urgently needed to enable reliable testing and design of appropriate treatment regimens. Although internationally accepted methods were used by all laboratories, the precise methods and drug concentrations used varied among participating SRLs (22). Because these SRLs represent some of the most highly performing laboratories on 6 continents, results of drug-susceptibility testing are credible within the context of stated limitations. Initial studies that standardized different methods for second-line–drug susceptibility testing have been completed (23–26), but more are needed.

Our study has other limitations. The numbers reported for XDR TB probably represent an underestimate of the true number of cases because not all SRLs and not all national reference laboratories test for all 6 classes of second-line drugs. In the absence of test results for all 6 classes of second-line drugs, we speculate, on the basis of a patient's TB treatment history and known patterns of drug cross-resistance, that many other unidentified patients are likely to have had and died from XDR TB. For example, an MDR TB isolate that is also resistant to an aminoglycoside and a fluoroquinolone but that has not been tested for the other second-line drug classes is very likely to be resistant to an additional second-line drug class for the following reasons: INH and ethionamide have a 15%–20% rate of cross-resistance (27); kanamycin and capreomycin cross-resistance is common, ranging from 20%–60% (CDC, unpub. data) (28,29); and in this study, isolates that were resistant to all 4 first-line drugs as well as an aminoglycoside and a fluoroquinolone were 70%–80% likely to be resistant to at least 1 additional class of second-line drug.

Another limitation is that data from most SRLs were drawn from a convenience sample of isolates and reflect referral bias. Thus, these data can not be considered representative of a patient population or region, and actual denominators are difficult to determine. For this reason, although estimates of prevalence are possible, they cannot be generalized to the local or regional population. However, our study is the first to report XDR TB patients in multiple geographic regions; future systematic surveys are needed to determine the true extent of this disease. Data from the Republic of Korea reflect a more comprehensive policy for drug-susceptibility testing and provide an estimate of the population prevalence in this setting. However, the 10.9% rate of MDR TB for the Republic of Korea is higher than rates reported from other national drug resistance surveys and may reflect other unknown referral biases (1).

Lastly, we had limited clinical information about each patient because information submitted to each SRL varied and was not reliably available for inclusion in the analysis. Data about TB treatment history, patient age and sex, or HIV status are not routinely collected by all laboratories. Genotyping data were not available to confirm whether XDR TB isolates are related to W variant of the Beijing strain, a highly drug-resistant strain of M. tuberculosis responsible for large nosocomial outbreaks in New York in the early 1990s (30).

Despite these limitations, our survey provides the first documentation of the emergence of XDR TB as a serious worldwide public health threat. XDR TB was identified on 6 continents and is significantly associated with worse treatment outcomes than MDR TB (31,32). The emergence of XDR TB, coupled with the increased use of second-line drugs, suggests that urgent measures are needed to improve rational use of quality-assured second-line drugs. In addition, population-based surveillance for second-line–drug susceptibility testing is needed to better describe the magnitude of XDR TB worldwide, track trends, and plan a public health response. Indeed, the convergence of XDR TB with the HIV epidemic may undermine gains in HIV prevention and treatment programs and requires urgent interventions. These interventions include ensuring adherence to recommended international standards of care aimed at promptly and reliably diagnosing TB, ensuring adherence to recommended treatment regimens with demonstrated efficacy, implementing infection control precautions where patients congregate, and improving laboratories' capacity to accurately and rapidly detect drug-resistant M. tuberculosis isolates so that patients can receive effective treatment (33). Other unmet needs include further development of international standards for second-line–drug susceptibility testing, new anti-TB drug regimens, and better diagnostic tests for TB and MDR TB. Such measures are crucial if future generations are to be protected from potentially untreatable TB.

Acknowledgments

We thank Kenneth G. Castro, Michael F. Iademarco, Mario Raviglione, Paul Nunn, and Ernesto Jaramillo for technical assistance and critical appraisal of the manuscript.

Dr Shah is an internist and epidemiologist with Albert Einstein College of Medicine. She is also a guest researcher with the Division of Tuberculosis Elimination at CDC, where she was an Epidemic Intelligence Service Officer at the time of this study. Her research interests focus on TB and HIV coinfection, drug resistance, and global health.

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