From January 1991 to December 2000, a total of 291 HIV-negative patients treated at Muñiz Hospital were affected by MDRTB. Of these, 212 (72.9%) were acquired MDRTB cases, and 79 (27.1%) were unambiguously identified as initially MDR. The primary site of disease was pulmonary in all patients of both groups with a single exception. An accidental subcutaneous inoculation of a bacteriologist caused the only primary extrapulmonary case, which was obviously classified in the initial MDRTB group.

Figure 1

Figure 1. Trend of initial multidrug-resistant tuberculosis among HIV-negative patients at Muñiz Hospital, Buenos Aires, 1991–2000. MDRTB, multidrug-resistant tuberculosis.

Demographic, clinical, and bacteriologic characteristics of both groups are compared in Table 1. Compared with acquired-MDRTB patients, patients with initial MDRTB showed significant differences in age, gender, and chest x-ray involvement. The presence of an underlying illness was not identified as a predisposing factor for initial MDRTB. Initial MDRTB patients were significantly younger and their lung lesions less advanced. Female patients predominated in this group. Initial MDRTB increased from 15.0% of total MDR cases in 1991 to 37.8% in 2000 (test for trend, p=0.00033, odds ratio [OR] = 3.45) (Figure 1).

Figure 2

Figure 2. HIV-negative multidrug-resistant tuberculosis groups investigated. MDRTB, multidrug-resistant tuberculosis; RFLP, restriction fragment length polymorphism.

Isolates from 49 of the 79 patients with initial MDRTB were available for DNA typing. Thirty-six (73.0%) of these 49 fit in six molecular clusters with RFLP patterns of six or more bands. The M strain was responsible for the largest cluster involving 24 (49.0%) of the 49 investigated cases. All patients in the M cluster lived and were treated in Buenos Aires City area. A flow tree is shown in Figure 2.

The second largest cluster occurred in four members of a Peruvian family who had immigrated to Argentina in 1999. The remaining four clusters consisted of two cases each. Samples from cases in two of these clusters had matching fingerprints with previously documented outbreak strains; the patients’ histories were consistent with such hospital-acquired disease (7). The remaining four case-patients in the cluster were household contacts of two clearly identified index MDRTB cases.

Figure 3

Figure 3. Biennial number of initial multidrug-resistant tuberculosis cases among HIV-negative patients and restriction fragment length polymorphism findings. RFLP, restriction fragment length polymorphism.

Figure 3 shows the biennial number of initial MDRTB cases attributable to the M strain, other strains, and those unavailable for RFLP. Among those available for fingerprinting, the proportion of initial MDRTB associated with the M strain increased significantly in the period 1997–2000 when compared with previous years (21/36 vs. 3/13; p=0.03; OR= 0.21).

The putative exposure setting and RFLP findings of the 79 initial MDRTB cases are described in Table 2. Hospital-related disease attributable to the M strain was detected in 15 cases from seven different health institutions in the metropolitan area. The M strain–associated disease was significantly more frequent among hospital-exposed cases when compared with patients who acquired the disease elsewhere (15/20 vs. 9/29; p=0.002; relative risk [RR] = 2.42; 95% confidence interval [CI] 1.33 to 4.40). The proportion of isolates lost for RFLP typing did not differ significantly between the groups compared above to analyze prevalence of the M strain in different periods (p=0.52) and exposure settings (p=0.11).

Initial MDRTB is contracted from a source case, whereas acquired MDRTB is the result of a prolonged history of inadequate treatment. Therefore, patients with initial MDRTB were substantially younger and their lung lesions less advanced. Women predominated in the initial MDRTB group, which might reflect the conventional female role as caregiver in the local population.

The ascending trend of the initial MDRTB in HIV-negative patients may be explained as a consequence of the AIDS-associated outbreak that occurred in the hospital during the 1990s. The M strain was preeminent in this phenomenon. Initial MDRTB cases attributable to this strain appeared at the peak of the AIDS-related epidemic, persisted beyond its decline, and did not reach a neat plateau at the end of the study period. These dynamics reflect the normal latency of infection and hint that a further expansion of the strain is still possible.

Hospital exposure increased the risk of acquiring M strain–associated MDRTB by approximately two and a half times. Thus, the hospital seems still to be the most likely setting for acquiring the M strain of MDRTB. However, 4 of 10 case-patients with an unidentified source of exposure were also affected by this strain. These patients were thoroughly interrogated again, and a previous institutional or household contact was virtually discarded. The failure to trace the index cases for these patients indicates the presence in the community of unidentified infectious cases harboring this highly resistant strain.

However, the marked increase of initial MDRTB cannot be ascribed entirely to the M strain. Other indigenous outbreak strains and strains recently introduced to the country contributed to this emergence, adding complexity to the MDRTB problem in the metropolitan area. Approximately one in every five case-patients with both initial and acquired MDRTB had recently migrated from a neighboring country where TB prevalence is higher than in Argentina, which suggests the influence of regional migration on local MDRTB rates.

The outcome of this investigation cannot be generalized to scenarios different from that of a referral center for infectious diseases. Other possible limitations of our study should be considered. Bias caused by laboratory cross-contamination is improbable because two or more isolates were obtained from every patient and susceptibility patterns were consistent in all cases. Data loss was appreciable: over one third of the isolates were lost for fingerprinting because of inadequate culture maintenance. Therefore, TB transmission might have been underestimated in our population, as shown by computer simulation studies (17,18). Eventually, misclassification of cases might have occurred. Some observations induced the idea of misclassification. A sudden shift from fully susceptible TB (RFLP not available) to M strain–associated MDR disease was documented in six of the cases classified in the acquired MDRTB group. We suggest that these patients were actually reinfected with the M strain while still being treated with standard chemotherapy at the hospital. As demonstrated by van Rie et al., exogenous reinfection is not uncommon among HIV-negative patients in settings with high prevalence of TB and the distinction between initial and acquired MDRTB in such situations becomes ambiguous (19).

The emergence of initial MDRTB among HIV-negative persons assisted in Muñiz Hospital in the second half of the 1990s can be considered a sequel to the MDRTB epidemic that occurred among AIDS patients in Buenos Aires. The M strain has already exceeded nosocomial bounds and might be expanding in the community. The strain appears to be more prosperous than other contemporary MDR strains and is emerging as a persistent strain.