Drug discovery and resistanceCharacteristics of drug-resistant tuberculosis in Abkhazia (Georgia), a high-prevalence area in Eastern Europe
Introduction
Drug-resistant tuberculosis (TB) is a major public health problem, particularly in countries of the former Soviet Union affected by economic decline and failing health infrastructures.1, 2, 3, 4 Globally, some of these countries show the highest frequency of isolation of Mycobacterium tuberculosis complex (MTBC) strains of multidrug-resistant (MDR)-TB, defined as resistance to at least isoniazid and rifampicin. MDR-TB rates of up to 14% have been documented, making successful treatment of the disease difficult.5, 6 Inadequate treatment is the primary cause of acquired drug resistance. In most limited-resource countries, MDR-TB cases are identified when patients fail to respond to first-line TB therapy.4 Prolonged periods of sputum smear positivity might then result in enhanced transmission of MDR strains, further accelerating the increase of MDR-TB incidence.4 Consequently in countries with high prevalence of resistance, in addition to standard short-course chemotherapy, rapid diagnosis of resistance and appropriate treatment regimens are key components for the control of TB.3
Interestingly, high levels and spread of MDR-TB in Eastern Europe have been found to be associated with a specific phylogenetic lineage/genotype of the MTBC, the Beijing genotype, indicating that special properties of this pathogen might also contribute to the problem of drug resistance.7 Studies have confirmed that patients infected with Beijing genotype strains have a higher risk of MDR-TB.3, 7, 8 Furthermore, Beijing strains may also contribute to the transmission of MDR-TB.8, 9 However, studies on the consequences of Beijing genotype infection for both TB transmission and drug-resistance in high-incidence regions are only sparsely available.
Here, we present the results of a cross-sectional survey, which assessed the characteristics of drug-resistant TB in Abkhazia (Georgia). We examined the frequency of MDR-TB and XDR-TB, as well as the relationships among resistant strains, frequency of Beijing genotype strains, and clustering in the region.
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Study setting
The survey was conducted in 2003–2005 in the Guliripchi TB hospital of Abkhazia, which is the only TB diagnostic centre in the region. Abkhazia is an autonomous region of western Georgia. Since 1994, this region has been in chronic conflict with Georgia and has an approximate population estimated between 150 and 190,000 inhabitants.10 The TB case notification rate was 125/100,000 population in 2001, and 14% of the overall TB population were infected with MDR-TB strains.11 Médecins Sans
Results
Out of 405 consecutive notified smear-positive TB patients between March 2003 and September 2005, a total of 366 (90.4%) cases were screened. Of these, 326 were included in the study (Figure 1). Mean age was 41 years old (SD 14.1), 77.3% (252/326) of patients were male and 3.4% (11/326) prisoners. Twelve percent (38/324) were ex-prisoners and 39.3% (127/323) were previously treated cases (PTC).
Drug-resistance
Data on resistance of the 326 strains to first-line drugs are presented in Table 1. Drug-resistance was more frequent among PTC, 68.5% (87/127) than among new cases (NC), 54.1% (106/196), P = 0.01. Overall, MDR strains were isolated from 68 patients (21%): 8.7% from NC and 38.6% from PTC.
Data on resistance to second-line drugs among MDR-TB patients are presented in Table 2. Overall, 39 (57.3%) MDR-TB patients had isolates that were also resistant to one or more second-line drugs. PTC isolates
Molecular typing
In general, a high degree of diversity of IS6110 DNA fingerprint and spoligotyping patterns was observed among the 323 strains analysed (for three strains, DNA isolation was not successful). For 311 isolates (96.3%), single molecular typing patterns were obtained, while 12 strains (3.8%) showed mixed patterns demonstrating a double infection with two MTB strains (data not shown). Since no clear IS6110 band definition is possible in mixed-strain isolates, the patients with mixed infections were
Cluster analysis
Similarity analysis of strains genotyping patterns identified 165/311 patients (53.2%) with clustered baseline strains grouped in 44 clusters ranging in size from 2–14 strains (median of 3 strains per cluster). The Beijing genotype (OR 2.7; 95% CI 1.4–4.8) was significantly associated with clustering after multivariate analysis, which included the age, gender, the prisoner history, the TB treatment history and the MTB genotype as covariates. In general, a positive correlation exists between the
Patients' and strains' characteristics associated with MDR-TB
The results of the MDR-TB risk factors analysis are presented in Table 5. No significant difference was observed for mean age between MDR-TB (40.4, SD 12.9) and non-MDR-TB patients (43.0, SD 14.7; P = 0.17). The strong association between MDR-TB and clustering was not maintained after adjustment with Beijing infection in multivariate analysis.
The most striking association found, however, was the enhanced risk of patients with Beijing infection having MDR-TB (OR 25.9; 95% CI 10.2–66.0). In new
Discussion
Few population-based studies are available describing the molecular determinants of the TB epidemic, including clinical and genotypic strain characteristics, in countries of the former Soviet Union. None are in Georgia or neighbouring Caucasian countries. In this study, a systematic investigation of clinical, epidemiological, and bacteriological characteristics of more than 90% of all smear-positive pulmonary TB cases could be carried out over a 3-year time period in Abkhazia.
We report a high
Acknowledgements
We thank Cathy Hewison, Juliet Melzer, and the MSF team based in Sukhumi and in Tbilisi for their support in data collection. We would also like to thank I. Radzio, T. Ubben, and P. Vock for excellent technical assistance, and Oliver Yun for his support in editing the manuscript.
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These authors contributed equally to this work.