The annual number of newly diagnosed MDR and XDR TB cases decreased slightly, with minor fluctuations, during the study period. HIV infection was associated with almost one third of MDR TB cases; this proportion is 2–4× higher than that attributed by different studies to all forms of TB in the country (16,17). As previously observed (18), annual fluctuations in the numbers of total MDR/XDR TB cases during the study period paralleled closely annual fluctuations in the numbers of HIV-infected patients.

All 7 major clusters in our study were connected with particular geographic areas, institutional settings, or both. Furthermore, most patients in these clusters underwent TB treatment in health centers that had ongoing MDR TB transmission or had a household or a prison contact with persons who had MDR TB. These findings indicate that these major clusters represent true transmission events.

Many cases in this outbreak were caused by the M strain, an apparently autochthonous outbreak genotype. In a countrywide survey performed in 1998, this strain was found to be responsible for 42% of all MDR TB cases but was confined to the metropolitan area of Buenos Aires (National TB Laboratory Network, unpub. data). Since then, the M strain has been the most frequently identified in every MDR TB investigation performed in the country. We found the M strain to be the most prevalent and that its transmission was virtually restricted to the area of the initial outbreak. However, its numbers decreased by more than half within the study period, particularly among HIV-infected patients, which suggests that the epidemic curve of the M strain has entered a declining phase. The other 2 strains associated with previous MDR TB outbreaks, Ra and Rb, were found to persist with lower, fluctuating frequencies.

The expansion of M strain transmission in Argentina was initially fostered by clinical mismanagement. During the early 1990s, patients with advanced AIDS were hospitalized in large, referral treatment centers, where they shared facilities with patients who had MDR TB. At that time, virtually no respiratory protection policy was in force because it was wrongly assumed that MDR TB patients were barely infectious. After genotyping confirmed outbreaks of MDR TB among the patients with AIDS (4), hospital infection control interventions were adopted, microbiologic diagnosis and drug-resistance detection were expedited, and second-line TB drugs and highly active antiretroviral therapy became available. As a result of those interventions, hospital transmission was substantially reduced but not completely controlled (18). At the time of our study, however, the M strain had long expanded beyond the hospital environment (6).

The national M. tuberculosis genotype database in Argentina identified very few patients with non–MDR TB harboring H2 genotypes (V. Ritacco, unpub. data). Another study supported this observation (19), and the H2 genotype was found to be infrequent in other South American countries (13,20–22). The IS6110 RFLP pattern of the M strain was absent outside Argentina in the Ibero-American MDR TB genotype database (23) and was not present in the M. tuberculosis genotype database in the Netherlands (D. van Soolingen, pers. comm.). This pattern was registered in other countries, anecdotally, in 2 MDR TB patients with AIDS: a patient from Argentina who died in San Francisco, California, shortly after his arrival in the United States (24); and a patient from Asuncion, Paraguay, who visited the Hospital Muñiz in Buenos Aires each month for antiretroviral therapy (20).

Different M. tuberculosis genotypes may have affinity with certain geographic areas and ethnic groups (25), which could explain why the M strain persists in the Buenos Aires area. In addition, most persons at risk for MDR TB are underprivileged and cannot afford to travel far distances. This mobility limitation might also help to explain why this strain has remained virtually confined to the original hotspot area.

A small number of patients affected by the M strain were immigrants from neighboring countries who had settled in Buenos Aires. Cross-border and domestic migration toward large metropolitan areas is a long-observed demographic and public health concern in Argentina. More than 80% of the patients in this study were assisted in metropolises designated as MDR TB hotspots. Even though immigrants with TB have access to higher quality health care in these areas than in other parts of the country, they are also at higher risk of becoming newly infected with an outbreak MDR TB strain.

The M strain was overrepresented among patients with XDR TB; isolate resistance to >5 anti-TB drugs was found to be a strong predictor of disease caused by the M strain (4,26). The accumulation of drug resistance–conferring mutations would be expected to have reduced the epidemiologic fitness of this strain, but it has prevailed for 15 years. The epidemiologic fitness of a strain can be influenced by a range of factors, e.g., the genetic backgrounds of host and pathogen, host–pathogen interactions, and the environment (27–29). Compensatory evolution restoring in vivo fitness, as well as social and behavioral factors, might have played a role in the epidemiologic persistence of the M strain (30). These factors might also have preferentially fostered the spread of drug-resistant strains of the H2 genotype in our setting. Further studies are needed to evaluate the most critical risk factors.

Drug-resistance profiles were not uniform within the M strain clusters. The variations in susceptibility to individual drugs reflect the existence of various ongoing chains of transmission, some of which might have started before, or simultaneously with, the first documented outbreak. One limitation of our study is the failure to identify individual chains. Factors that precluded the reliable characterization of subclusters were the long time elapsed since the outbreak onset, the insufficient epidemiologic documentation in many cases, and the unavailability of additional molecular markers.

Our study has another major limitation. Incomplete demographic and clinical data on patients were retrieved, and several observations had missing values. If missing values were systematically associated with a given force or factor, results presented here would be biased. We are not aware of any association of missing values with the dependent variables under study and assume that those data were missing at random. Missing values may have affected the analyses by reducing the number of observations, which may have reduced the power of the model to detect significant associations but without necessarily biasing the associations reported. However, the possibility that bias might have resulted from missing data cannot be ruled out. Therefore, statistical significances of our analyses should be interpreted cautiously.

In the MDR TB hotspots in Argentina, the distinction between primary and acquired MDR TB on the basis of a history of previous TB treatment was not decisive because patients could have been exposed to hospital-associated MDR TB infection while being treated for community-acquired TB. This fact could explain why clustering was not more frequent among patients without previous TB treatment in our study.

The national TB network includes all the laboratories performing bacteriological TB diagnosis in the country; therefore, the patients in this study represent all newly diagnosed MDR TB cases in Argentina. The structure, geographic coverage, and personnel of the TB laboratory network are adequate to provide DST for all patients at risk for MDR TB in Argentina. However, a few MDR TB patients might remain undiagnosed because of operational factors, e.g., inefficient detection of risk factors, insufficient or delayed requests for DST, and disorganized information systems.

The geographically restricted distribution of successful MDR TB genotypes that we found has public health implications. As a result of this study, specific interventions are being reinforced, particularly in the MDR TB hotspots: implementing universal culture and strategies to expedite drug resistance detection; decentralizing specialized health care; streamlining information-sharing systems between HIV and TB programs; and strengthening administrative infection control measures in prisons and large hospitals with high TB infection load. A national advisory group on MDR TB clinical management has also been recently created. Control interventions have already started to reduce MDR TB spread in the hospital that was the epicenter of the main outbreak (17). Still, centrally coordinated actions are needed in Argentina to curb long-term transmission of MDR TB.