Emergence of Mycobacterium tuberculosis with Extensive Resistance to Second-Line Drugs --- Worldwide, 2000--2004

During the 1990s, multidrug-resistant (MDR) tuberculosis (TB), defined as resistance to at least isoniazid and rifampin, emerged as a threat to TB control, both in the United States (1) and worldwide (2). MDR TB treatment requires the use of second-line drugs (SLDs) that are less effective, more toxic, and costlier than first-line isoniazid- and rifampin-based regimens (3). In 2000, the Stop TB Partnership's Green Light Committee was created to increase access to SLDs worldwide while ensuring their proper use to prevent increased drug resistance. While assisting MDR TB treatment programs worldwide, the committee encountered reports of multiple cases of TB with resistance to virtually all SLDs. To assess the frequency and distribution of extensively drug-resistant (XDR) TB cases,* CDC and the World Health Organization (WHO) surveyed an international network of TB laboratories. This report summarizes the results of that survey, which determined that, during 2000--2004, of 17,690 TB isolates, 20% were MDR and 2% were XDR. In addition, population-based data on drug susceptibility of TB isolates were obtained from the United States (for 1993--2004), Latvia (for 2000--2002), and South Korea (for 2004), where 4%, 19%, and 15% of MDR TB cases, respectively, were XDR. XDR TB has emerged worldwide as a threat to public health and TB control, raising concerns of a future epidemic of virtually untreatable TB. New anti-TB drug regimens, better diagnostic tests, and international standards for SLD-susceptibility testing are needed for effective detection and treatment of drug-resistant TB.

During November 2004--November 2005, CDC and WHO surveyed the WHO/International Union Against Tuberculosis and Lung Disease Global Supranational TB Reference Laboratory (SRL) Network. The SRL Network consists of 25 reference laboratories on six continents that collaborate with national reference laboratories (NRLs) to increase culture and drug-susceptibility testing capacity and provide quality control for global surveys to assess anti-TB drug resistance (4). All SRL directors were invited to participate in this survey, but not all SRLs test for susceptibility to SLDs, and certain laboratories test for only one or two SLDs. In addition, SRLs use different (but generally accepted) media and methods to test for SLD susceptibility. Using a standardized reporting form, CDC and WHO requested anonymous, individual-level data on all isolates tested for susceptibility to at least three SLD classes during 2000--2004 and maintained in a computerized registry. SRLs receive varying proportions of isolates from countries for surveillance, diagnosis, and quality assurance. Thus, SLD-susceptibility data from SRLs are based on a convenience sample and are not population-based, with one exception: South Korea's NRL routinely performs an extended diagnostic panel of drug-susceptibility testing of isolates from all culture-positive TB patients in South Korea. To complement the SRL survey, additional population-based data were analyzed from 1) the U.S. national TB surveillance system, which contains data on all reported TB cases during 1993--2004, and 2) Latvia's national MDR TB registry from the 2000--2002 cohort of MDR TB patients.

The study sample for the SRL analysis consisted of 17,690 isolates from the period 2000--2004 that were tested for susceptibility to at least three of the six SLD classes. Of these, 11,939 were from South Korea, of which 1,298 (11%) were MDR. From the other SRLs, 2,222 (39%) of 5,751 isolates were MDR (Table 1). Of the 3,520 MDR isolates, 347 (10%) were XDR, including 200 (15%) of 1,298 from South Korea and 147 (7%) of 2,222 from other SRLs. The drug-susceptibility testing results were tabulated by year and geographic region (on the basis of the country of origin of the isolates) (Table 1). XDR TB was identified in all regions but was most common in South Korea (n = 200; 15% of all MDR TB isolates) and countries of eastern Europe/western Asia^† (n = 55; 14% of all MDR TB isolates). The total number and proportion of XDR TB isolates observed worldwide (excluding South Korea) increased from 14 (5% of MDR TB isolates) in 2000 to 34 (7% of MDR TB isolates) in 2004 (Table 1). Year-specific proportions were stratified by geographic region. Increasing proportions of XDR TB were found among isolates from countries of eastern Europe/western Asia (n = five [9%] in 2000; n = 11 [17%] in 2003) and the group of industrialized nations^§ (n = three [3%] in 2000; n = 25 [11%] in 2004).

U.S. national TB surveillance data included 169,654 patients with drug-susceptibility testing results. During 1993--2004, a total of 2,689 (1.6%) MDR TB cases were identified, of which 1,814 (67%) had results reported for three or more SLD classes. Of these, 74 (4.1%) had resistance to three or more SLD classes and thus met the criteria for XDR TB. Despite an overall decline in MDR TB incidence in the United States, the proportion of XDR TB increased slightly, from 37 (3.9%) of 944 cases during 1993--1996 to 20 (4.1%) of 489 during 1997--2000, to 17 (4.5%) of 381 in 2001--2004 (chi-square test for trend = 0.20; p = 0.66). During 1993--2002, patients with XDR TB were 64% more likely to die during treatment (relative risk [RR] = 1.6; 95% confidence interval [CI] = 1.2--2.2) than patients with MDR TB (Table 2).

Among 605 MDR TB patients in Latvia who initiated therapy during 2000--2002, 115 (19%) had XDR TB. The proportion with XDR TB increased from 30 (15%) of 204 in 2000, to 46 (21%) of 215 in 2001, to 39 (21%) of 186 in 2002 (chi-square test for trend = 2.57; p = 0.11). Patients with XDR were 54% more likely to die or have treatment failure (RR = 1.5; CI = 1.1--2.2) (Table 2).

Reported by: A Wright, MPH, Stop TB Dept, WHO; G Bai, PhD, L Barrera, MS, F Boulahbal, PhD, N Martín-Casabona, MD, PhD, C Gilpin, PhD, F Drobniewski, MD, PhD, M Havelková, MD, PhD, R Lepe, PhD, R Lumb, MAppSc, B Metchock, DrPH, F Portaels, PhD, M Rodrigues, PhD, S Rüsch-Gerdes, PhD, A Van Deun, MD, V Vincent, PhD, WHO/International Union Against Tuberculosis and Lung Disease Network of Supranational Reference Laboratories. V Leimane, MD, V Riekstina, MD, PhD, G Skenders, MD, State Agency for Tuberculosis and Lung Diseases, Riga, Latvia. T Holtz, MD, R Pratt, K Laserson, ScD, C Wells, MD, P Cegielski, MD, Div of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention; NS Shah, MD, EIS Officer, CDC.

Editorial Note:

This report presents the first data regarding the occurrence of XDR TB worldwide. The proposed definition of XDR TB was based on new WHO guidelines for programmatic management of drug-resistant TB, which recommend treatment with at least four drugs known to be effective (6). Therefore, with three or fewer remaining classes of SLDs to which the infecting organism is susceptible, treatment of these patients is unlikely to meet international standards. The findings in this report indicate that XDR TB has a wide geographic distribution, including within the United States, and is associated with worse treatment outcomes than MDR TB. A growing number and proportion of XDR TB cases could seriously hamper TB control globally.

The numerous outbreaks of MDR TB during the early 1990s were harbingers of a global epidemic. During 1994--2002, the WHO Global Project on Anti-TB Drug Resistance Surveillance coordinated data collection on more than 250,000 patients from 109 countries (or regions within large countries), representing 42% of the world's population (2). On this basis, WHO estimated the annual burden of MDR TB to be approximately 300,000--600,000 cases and the prevalence of MDR TB to be threefold higher than the annual incidence, primarily in low- and middle-income countries.^¶ The emergence of XDR TB, coupled with increased use of SLDs, suggests that urgent measures are needed to establish population-based surveillance for SLD resistance and to plan public health responses. However, existing tests for susceptibility to SLDs are less reproducible than tests for susceptibility to isoniazid and rifampin, and better methods are needed (7).

Implementation of effective TB-control programs after the resurgence of TB during the 1990s improved TB treatment outcomes and reduced TB and MDR TB transmission and incidence (8). Building upon the WHO DOTS framework and the initial implementation of MDR TB management under programmatic conditions (DOTS-Plus), the new Stop TB Strategy provides a comprehensive program against MDR TB with demonstrated feasibility and effectiveness in both low- and middle-income countries (9,10). However, SLDs are available worldwide and are not dispersed only by well-organized TB-control programs. Improper treatment of patients with drug-resistant TB (e.g., use of too few drugs or drugs for too short a time or relying on limited access to poor quality SLDs) might lead to increases in XDR TB. Management of MDR TB in DOTS-Plus programs that rely on quality-assured and internationally recommended treatment regimens administered under strict supervision must be scaled up and strengthened to stem further SLD resistance and spread of XDR TB.

The findings in this report are subject to at least two limitations. First, SLD testing methods and results have varied because of the lack of international standards and the limited reproducibility of drug-susceptibility testing for certain drugs (6). For this survey, testing methods and specific drugs tested varied by SRL. Second, the SRL data were drawn from a convenience sample of isolates and might reflect a referral bias; SRLs are likely to receive isolates from retreatment cases, treatment failures, or other complex TB cases. Regardless, these data indicate that XDR TB is geographically widespread. The population-based data from South Korea, the United States, and Latvia provide a more representative picture of XDR TB on a population level in three disparate regions of the world and confirm that XDR TB has emerged in multiple settings, including the United States where TB control has been effective for many years.

Despite these limitations, this report documents the existence of XDR TB as a serious and emerging public health threat. Population-based surveillance data are needed to describe the magnitude and trends of XDR TB worldwide. Activities to detect drug-resistant TB accurately and rapidly and treat it effectively should be expanded, including development of international standards for SLD-susceptibility testing, new anti-TB drug regimens, and better diagnostic tests. Such measures are crucial if future generations are to be protected from XDR TB.

References

1. Dooley SW, Jarvis WR, Martone WJ, Snider DE. Multidrug-resistant tuberculosis. Ann Intern Med 1992;117:257--9.
2. World Health Organization/International Union Against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Anti-tuberculosis drug resistance in the world: report no. 3. Geneva, Switzerland: World Health Organization; 2004.
3. Gupta R, Kim JY, Espinal MA, Caudron JM, Farmer PE, Raviglione MC. Responding to market failures in tuberculosis: a model to increase access to drugs and treatment. Science 2001;293:1049--51.
4. Laszlo A, Rahman M, Espinal M, et al. Quality assurance program for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994--1998. Int J Tuberc Lung Dis 2002;6:748--56.
5. Laserson KF, Thorpe LE, Leimane V, et al. Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2005;9:640--5.
6. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, Switzerland: World Health Organization; 2006. (WHO/HTM/TB/2006.361).
7. Heifets LB, Cangelosi GA. Drug susceptibility testing of Mycobacterium tuberculosis: a neglected problem at the turn of the century. Int J Tuberc Lung Dis 1999;3:564--81.
8. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City---turning the tide. N Engl J Med 1995;333:229--33.
9. Leimane V, Riekstina V, Holtz T, et al. Clinical outcome of individualized treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet 2005;365:318--26.
10. Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003; 348:119--28.

* Defined as cases in persons with TB whose isolates were resistant to isoniazid and rifampin and at least three of the six main classes of SLDs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine, and para-aminosalicyclic acid).

^† Armenia, Azerbaijan, Czech Republic, Republic of Georgia, and Russia.

^§ Australia, Belgium, Canada, France, Germany, Ireland, Japan, Portugal, Spain, United Kingdom, and United States.

^¶ According to World Bank criteria for classifying economies (available at http://www.worldbank.org).

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Date last reviewed: 3/23/2006