anti-TB Drug Resistance Research Articles

Previous use of quinolones: a surrogate marker for first line anti-tuberculosis drugs resistance in HIV-infected patients?

OBJECTIVES: Drug resistant Mycobacterium tuberculosis causes much higher rates of treatment toxicity, failure or relapse, and mortality. We determined the drug resistant profile of Mycobacterium tuberculosis strains isolated from a population of HIV-infected patients in southern Brazil and studied the potential factors associated with resistance. METHODS: We conducted a retrospective cohort study to determine the resistance profile of Mycobacterium tuberculosis isolated from HIV-infected patients and factors that could be associated with resistance from 2000 to 2005. RESULTS: 236 patients were included in the study. Resistance to at least one drug was observed in 32 (14.6%) isolates, and multi-drug resistance was observed in 4 (1.82%) isolates. On multivariate analysis, previous use of tuberculostatics and quinolones were related to any first-line drug resistance. CONCLUSIONS: In our study, previous quinolone use was significantly associated to first-line anti-TB drugs resistance. Multi-drug-resistant tuberculosis (MDR-TB) is a major problem worldwide, and we believe quinolones should be used with caution in settings where TB is endemic.

Early results of systematic drug susceptibility testing in pulmonary tuberculosis retreatment cases in Cameroon

BackgroundThe number of pulmonary tuberculosis (PTB) patients reported with resistance to first-line anti-tuberculosis drugs after a standardized retreatment regimen in Cameroon is increasing. Hence, the National Tuberculosis Control Program (NTP) implemented, in one of the ten Regions of the country, a pilot programme aimed at performing routine drug susceptibility testing (DST) for previously treated PTB cases. The objectives of the programme were to evaluate the feasibility of monitoring drug resistance among retreatment cases under programme conditions and to measure the presence and magnitude of anti-TB drug resistance in order to inform NTP policies.FindingsThis retrospective cohort study was conducted in the Littoral Region of Cameroon in 2009. It included all sputum smear positive (SM+) PTB cases registered for retreatment. TB cases were identified and classified according to World Health Organization (WHO) recommendations for national TB programs. Bacterial susceptibility testing to first-line anti-TB drugs was performed using standard culture methods. In 2009, 5,668 TB cases were reported in the Littoral Region, of which 438 (7.7%) were SM + PTB retreatment cases. DST results were available for 216 (49.4%) patients. Twenty six patients (12%) harbored multi-drug resistant (MDR) strains. Positive treatment outcome rates were particularly low in retreatment patients with MDR-TB (46.2%; 95% CI: 27.1-66.3). Thirteen MDR-TB patients were treated using a standardized MDR treatment regimen. Delivery of laboratory results took on average 17 (12-26) weeks.ConclusionsWHO-recommended routine DST in retreatment patients seems feasible in Cameroon. However, coverage needs to be improved through better management. Moreover, diagnostic delay should be shortened by introducing more rapid diagnostic tools. The high risk of MDR in standard regimen failure cases virtually rules out the standard retreatment regimen for such patients without prior DST.

Prevalence of Nontuberculous Mycobacteria Infection, China, 2004–2009

To the Editor: Pulmonary nontuberculous mycobacteria (NTM) diseases share clinical signs with tuberculosis (TB), causing a clinical dilemma with regard to therapy for patients with these diseases (1). In the past 30 years (post-AIDS era), NTM have increasingly been associated with pulmonary diseases in humans (2). Recent studies in urban areas of the People’s Republic of China have shown that the prevalence of NTM (isolation rate of NTM among all mycobacteria) is increasing; for example, prevalence in Shanghai increased from 4.26% in 2005 to 6.38% in 2008 (3). To investigate NTM prevalence in rural areas of China, we evaluated the NTM isolation rates, species distribution, and drug-resistance profiles through a population-based TB sentinel surveillance study in Shandong Province, the second largest province in China. The study protocol was approved by the Institutional Review Board of Shandong Provincial Chest Hospital (Jinan, Shandong, China). Clinical samples were collected through the ongoing sentinel TB surveillance project, which first began in 7 counties in Shandong Province in 2004 and expanded to 13 counties in 2008. Of the total surveillance population, rural populations accounted for ≈80%. Each sample collected in this study was identified only by a unique participant number. Each surveillance site sent sputum samples from all patients with suspected TB to the TB Reference Laboratory of Shandong Provincial Chest Hospital for mycobacterial culture, drug-susceptibility testing, and species identification. From January 1, 2004, through December 31, 2009, Mycobacteria spp. were isolated from sputum specimens from 3,949 patients with suspected pulmonary TB. Of these patients, mean age ± SD was 48.7 ± 20.4 years (range 1–92 years), 74.6% were male, and 300 were being re-treated for TB. Identification of Mycobacteria spp. was first conducted by conventional biochemical testing—p-nitrobenzoic acid and 2-thiophene carboxylic acid hydrazide testing—following a standard protocol (4). Mycobacteria spp. were further identified by 16S rRNA gene sequence analysis (MicroSeq ID Microbial Indentification Software, version 2.0; Applied Biosystems, Foster City, CA, USA) to the species level as described (5). Drug-susceptibility testing was performed according to standard procedures recommended by the World Health Organization, and quality control was conducted by inter-laboratory confirmation testing by reference laboratories recognized by the World Health Organization in South Korea and in Hong Kong Special Administrative Region, China (6,7). The drug panel included 4 first-line anti-TB drugs: isoniazid, rifampin, streptomycin, and ethambutol. The conventional biochemical testing of the 3,949 Mycobacteria spp. strains identified 68 NTM strains, among which the 16s rRNA gene sequence analysis confirmed 64 (1.6%) NTM strains and identified 3 M. tuberculosis complex strains and 1 Nocardia glanders strain. Among the 64 NTM strains, 52 (81.2%) were M. intracellulare, 5 (7.8%) were M. kansasii, 3 (4.7%) were M. fortuitum, 2 (3.1%) were M. chelonae, 1 (1.6%) was M. gordonae, and 1 (1.6%) was M. scrofulaceum. The first-line anti-TB drug resistance rates of the 64 NTM strains were 100% for isoniazid, 98.4% for streptomycin, 78.1% for rifampin, and 51.6% for ethambutol (Table). Among the 3,949 Mycobacteria spp. strains, 163 (4.1%) were resistant to at least isoniazid and rifampin, of which 50 (30.7%) strains were identified as NTM. Among 300 TB re-treatment cases, 12 (4.0%) were caused by clinically significant NTM infections. Over the 6 study years, NTM isolation rates among the study population did not show a substantial increasing or decreasing trend. Table Species and drug-resistance profiles of 64 nontuberculous mycobacteria strains, Shandong Province, People’s Republic of China, 2004–2009 Our data suggest that the NTM isolation rate among patients with suspected pulmonary TB in rural China (1.6%) is relatively lower and more stable than that for urban areas (mean rate 5.09% in Shanghai) and that the Mycobacterium spp. differ from those in other areas of China (3,8–10). In China and most other developing countries to which TB is endemic, the decision to initiate pulmonary TB treatment is based only on finding a positive sputum smear by microscopy examination, not on Mycobacteria culture, species identification, and drug-resistance testing results. Among our study population, NTM strains showed high drug resistance to first-line anti-TB drugs and accounted for 30.7% of suspected multidrug-resistant TB (MDR-TB) cases and 4.0% of TB re-treatment cases. These findings suggest that pulmonary NTM infections pose substantial difficulties with regard to clinical management of NTM and MDR-TB diseases in China. Laboratory species identification is imperative before proper treatment can be determined for patients with MDR-TB. Compared with conventional biochemical testing, 16S rRNA gene sequencing analysis can more accurately identify Mycobacteria spp.

Previous use of quinolones: A surrogate marker for first line anti-tuberculosis drugs resistance in HIV-infected patients?

ObjectivesDrug resistant Mycobacterium tuberculosis causes much higher rates of treatment toxicity, failure or relapse, and mortality. We determined the drug resistant profile of Mycobacterium tuberculosis strains isolated from a population of HIV-infected patients in southern Brazil and studied the potential factors associated with resistance. MethodsWe conducted a retrospective cohort study to determine the resistance profile of Mycobacterium tuberculosis isolated from HIV-infected patients and factors that could be associated with resistance from 2000 to 2005. Results236 patients were included in the study. Resistance to at least one drug was observed in 32 (14.6%) isolates, and multi-drug resistance was observed in 4 (1.82%) isolates. On multivariate analysis, previous use of tuberculostatics and quinolones were related to any first-line drug resistance. ConclusionsIn our study, previous quinolone use was significantly associated to first-line anti-TB drugs resistance. Multi-drug-resistant tuberculosis (MDR-TB) is a major problem worldwide, and we believe quinolones should be used with caution in settings where TB is endemic.

Effective Interventions and Decline of Antituberculosis Drug Resistance in Eastern Taiwan, 2004–2008

BackgroundThe Taiwan health authority recently launched several tuberculosis (TB) control interventions, which may have an impact on the epidemic of drug-resistant TB. We conducted a population-based antituberculosis drug resistance surveillance program in Eastern Taiwan to measure the proportions of notified TB patients with anti-TB drug resistance and the trend from 2004 to 2008.Methods and FindingsAll culture-positive TB patients were enrolled. Drug susceptibility testing results of the first isolate of each TB patient in each treatment course were analyzed. In total, 2688 patients were included, of which 2176 (81.0%) were new TB cases and 512 (19.0%) were previously treated cases. Among the 2176 new TB cases, 97 (4.5%) were retreated after the first episode of TB treatment within the study period. The proportion of new patients with any resistance, isoniazid resistance but not multidrug-resistant TB (resistant to at least isoniazid and rifampin, MDR-TB), and MDR-TB was 16.4%, 7.5%, and 4.0%, respectively, and that among previously treated cases was 30.9%, 7.9%, and 17.6%, respectively. The combined proportion of any resistance decreased from 23.3% in 2004 to 14.3% in 2008, and that of MDR-TB from 11.5% to 2.4%.ConclusionsThe proportion of TB patients with drug-resistant TB in Eastern Taiwan remains substantial. However, an effective TB control program has successfully driven the proportion of drug resistance among TB patients downward.

Multidrug-resistant tuberculosis today

The World Health Organization (WHO) and its partners have long conducted efforts to improve tuberculosis (TB) case surveillance and programme monitoring and evaluation. WHO’s 2011 report on global TB control1 provided the most reliable information ever generated on the burden of disease and death caused by TB and multidrug-resistant TB (i.e. disease marked by in vitro resistance to at least isoniazid and rifampicin), treatment outcomes, financing mechanisms and new TB diagnostics, drugs and vaccines. The Global Project on Anti-tuberculosis Drug Resistance Surveillance, launched in 1994, has generated reliable drug resistance estimates for 127 countries based on representative studies that followed standard methods and separately looked at resistance among new and retreatment cases.2 The article by Zignol et al. in this issue of the Bulletin3 draws on those estimates to portray the best of current knowledge on anti-TB drug resistance, multidrug-resistant TB (MDR-TB) and extensively-drug-resistant TB (XDR-TB) (i.e. MDR-TB disease marked by additional in vitro resistance to at least one fluoroquinolone and one injectable drug). Zignol et al.’s report confirms that a belt of MDR-TB exists in eastern Europe and central Asia, as suggested by a recent study describing record rates of MDR-TB in Minsk, Belarus,4 where about half of all TB cases harbour MDR-TB strains. The finding that many countries in the same area still lack reliable MDR-TB surveillance systems is therefore highly worrisome. Efforts to understand how MDR-TB is evolving in African countries, India and the Russian Federation are also critically important. XDR-TB has been identified wherever it has been studied. In countries reporting nationally representative data, 10% of MDR-TB cases are extensively drug-resistant. The availability of good data for multiple years from 51 countries has finally made it possible to study trends in anti-TB drug resistance and to objectively examine why MDR-TB is increasing in some parts of the world and decreasing in others. We must now explore the determinants of these trends, learn from model programmes and delve into poorly understood areas and into the factors that influence how fast MDR-TB is declining in different places – slowly in Russian Federation oblasts, moderately fast in Estonia and Latvia, and fast in the United States of America. Furthermore, Zignol et al.’s suggestion that in the Republic of Korea therapeutic practices within the private sector may explain the increase in MDR-TB raises challenging questions. Finally, Zignol et al.’s report shows that MDR-TB surveillance is improving and is a useful source of data for investigating the basic determinants of MDR-TB. Sex did not emerge as an important determinant, and the long-feared association between MDR-TB and human immunodeficiency virus (HIV) infection was not supported by the study findings. However, the unavailability of data on HIV serostatus for many countries – not surprising since only 34% of the world’s confirmed TB cases are tested for HIV1 – dictates caution in interpreting this finding. It also reminds us of how difficult it is to incorporate HIV testing in TB drug resistance surveys and of how far away we are from fully implementing the 12 activities for collaborative control of TB and HIV infection recommended by WHO.5,6 The mismanagement of non-drug-resistant TB cases, which leads to drug resistance, is a continuing problem everywhere, even in high-income European countries with low TB incidence.7 The resulting growing reservoir of difficult-to-treat cases poses a challenge to national TB programmes and health systems all over the world.8 The number of incurable XDR-TB cases is on the rise in several countries, and properly caring for these cases, and especially for those experiencing treatment failure, is difficult and has obvious logistical, ethical and economic implications.8 Zignol et al.’s lucid report paves the way for targeted public health action in MDR-TB prevention and control. Although new molecular technologies, including line probe assays and Xpert® MTB/RIF, can allow the rapid diagnosis of thousands of MDR-TB cases, not all countries will be ready to treat those cases in compliance with appropriate guidelines. This obviously poses some risk of generating new super-resistant strains. On the positive side, at least two new forthcoming drugs – bedaquiline and delamanid – will reinforce our treatment armamentarium. The data presented by Zignol et al. should prompt us to make every effort to ensure their proper use.

Prevalence of Drug-Resistant Tuberculosis in Mainland China: Systematic Review and Meta-Analysis

BackgroundThe spread of drug-resistant tuberculosis (TB) is one of the major public health problems in the world. Surveillance of anti-TB drug resistance is important for monitoring TB control strategies. However, the status of drug-resistant TB in China has been reported inconsistently.MethodsWe systematically reviewed published studies on drug-resistant TB in China until March 31, 2011, and quantitatively summarized prevalence and patterns of anti-TB drug resistance among new cases and previously treated cases, respectively.ResultsNinety-five eligible articles, published during 1993–2011, were included in this review. The meta-analyses showed that the prevalence of drug-resistant TB in new cases was 27.9% (95% CI, 25.6%–30.2%) (n/N = 27360/104356) and in previously treated cases was 60.3% (95% CI, 56.2%–64.2%) (n/N = 30350/45858). Furthermore, in these two study populations, the prevalence of multiple drug resistance was found to be 5.3% (95% CI, 4.4%–6.4%) (n/N = 8810/101718) and 27.4% (95% CI, 24.1%–30.9%) (n/N = 10486/44530) respectively. However, the results were found to be frequently heterogeneous (p for Q tests <0.001). The most common resistance was observed for isoniazid among both study populations. Different patterns of drug resistance were observed in the subgroup analysis with respect to geographic areas, drug susceptibility testing methods and subject enrollment time.ConclusionsResults of meta-analyses indicated a severe status of drug-resistant TB in China, which attaches an importance to strength TB prevention and control.

Mycobacterium tuberculosis complex drug resistance pattern and identification of species causing tuberculosis in the West and Centre regions of Cameroon

BackgroundData on the levels of resistance of Mycobacterium tuberculosis complex (MTBC) strains to first line anti-tuberculosis drugs in Cameroon, and on the species of MTBC circulating in the country are obsolete. The picture about 10 years after the last studies, and 6 years after the re-organisation of the National Tuberculosis (TB) Control Programme (NTBCP) is not known.MethodsThe study was conducted from February to July 2009 in the West and Centre regions of Cameroon. A total of 756 suspected patients were studied. MTBC species were detected by the standard Ziehl-Neelsen staining method. Bacterial susceptibility to the first line drugs [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (SM)] were performed on cultures using the indirect proportion method. MTBC species were identified by standard biochemical and culture methods.ResultsOf the 756 suspected patients, 154 (20.37%) were positive by smear microscopy. Of these, 20.77% were HIV patients. The growth of Mycobacterium was observed with the sputa from 149 (96.75%) subjects. All the isolates were identified as either M. tuberculosis or M. africanum. Among these, 16 (10.73%) were resistant to at least one drug (13.3% for the West region and 8.1% for the Centre). The initial resistance rates were 7.35% for the Centre region and 11.29% for the West region, while the acquired resistance rates were 16.66% (1/6) for the Centre region and 23.07% (3/13) for the West. Within the two regions, the highest total resistance to one drug was obtained with INH and SM (2.68% each). Multidrug-resistance (MDR) was observed only in the West region at a rate of 6.67%. No resistance was recorded for EMB.ConclusionsM. tuberculosis and M. africanum remain the MTBC species causing pulmonary TB in the West and Centre regions of Cameroon. Following the re-organisation of the NTBCP, resistance to all first line anti-TB drugs has declined significantly (p < 0.05 for West; and p < 0.01 for Centre) in comparison to previous studies. However, the general rates of anti-TB drug resistance remain high in the country, underscoring the need for greater enforcement of control strategies.

Mycobacterium tuberculosis spoligotypes and drug susceptibility pattern of isolates from tuberculosis patients in South-Western Uganda

BackgroundDetermination of the prevalence and drug susceptibility of the M. tuberculosis strains is important in tuberculosis control. We determined the genetic diversity and susceptibility profiles of mycobacteria isolated from tuberculosis patients in Mbarara, South Western Uganda.MethodsWe enrolled, consecutively; all newly diagnosed and previously treated smear-positive TB patients aged ≥ 18 years. The isolates were characterized using regions of difference (RD) analysis and spoligotyping. Drug resistance against rifampicin and isoniazid were tested using the Genotype® MDRTBplus assay and the indirect proportion method on Lowenstein-Jensen media. HIV-1 testing was performed using two rapid HIV tests.ResultsA total of 125 isolates from 167 TB suspects (60% males) with a mean age 33.7 years and HIV prevalence of 67.9% (55/81) were analyzed. Majority (92.8%) were new cases while only 7.2% were retreatment cases. All the 125 isolates were identified as M. tuberculosis strict sense with the majority (92.8%) of the isolates being modern strains while seven (7.2%) isolates were ancestral strains. Spoligotyping revealed 79 spoligotype patterns, with an overall diversity of 63.2%. Sixty two (49.6%) of the isolates formed 16 clusters consisting of 2-15 isolates each. A majority (59.2%) of the isolates belong to the Uganda genotype group of strains. The major shared spoligotypes in our sample were SIT 135 (T2-Uganda) with 15 isolates and SIT 128 (T2) with 3 isolates. Sixty nine (87%) of the 79 patterns had not yet been defined in the SpolDB4.0.database. Resistance mutations to either RIF or INH were detected in 6.4% of the isolates. Multidrug resistance, INH and RIF resistance was 1.6%, 3.2% and 4.8%, respectively. The rpoβ gene mutations seen in the sample were D516V, S531L, H526Y H526D and D516V, while one strain had a Δ1 mutation in the wild type probes. There were three strains with katG (codon 315) gene mutations only while one strain showed the inhA promoter gene mutation.ConclusionThe present study shows that the TB epidemic in Mbarara is caused by modern M. tuberculosis strains mainly belonging to the Uganda genotype and anti-TB drug resistance rate in the region is low.

Giving a Voice to Those Who Die Young: The Fatal Impact of Tuberculosis and HIV in South Africa

The joint epidemic of HIV and TB in southern Africa is having a profound impact on the livelihood of the general population. This study of young people dying in a general hospital, serving a big conurbation in South Africa, points to a number of problems linked to disease control in the community. These include late presentation, low uptake of efforts to treat HIV and TB, a high frequency of people with infectious TB in the community and anti-TB drug resistance. The arguments are convincingly made for an improvement in case detection and earlier institution of adequate treatment. The investigative methodology used by the authors could be more widely applied to advocate for lifesaving measures in other settings sharing similar epidemiological challenges.

Anti-TB drug resistance levels and patterns among Mycobacterium tuberculosis isolated from newly diagnosed cases of pulmonary tuberculosis in Dar es Salaam, Tanzania

Anti-TB drug resistance levels and patterns among Mycobacterium tuberculosis isolated from newly diagnosed cases of pulmonary tuberculosis in Dar es Salaam, Tanzania

Declining drug resistance of Mycobacterium tuberculosis isolates from elderly patients in Taiwan, 2000–2008

We retrospectively investigated the prevalence of drug resistance in Mycobacterium tuberculosis (MTB) isolates recovered from elderly patients and compared the drug resistance patterns between the elderly (≥65years old) and adult (15-64years old) patients. Data on the prevalence of drug resistance in clinical and non-duplicate isolates of MTB recovered from 2000 to 2008 were evaluated. Among the 3,186 non-duplicate MTB isolates found during the study period, 1,497 isolates were recovered from elderly patients. Thirty-eight (2.54%) isolates were multidrug-resistant tuberculosis (MDRTB). The rates of resistance to isoniazid (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (SM), ofloxacin, rifabutin, any one drug-resistant (ADR), and multidrug-resistant (MDR) were significantly lower in isolates from the elderly than from adults (p < 0.05). Significant decreasing trends in resistance rates to EMB, SM, at least any one of the four first-line agents (ADR), and MDRTB were observed (p < 0.05) . In conclusion, elderly patients had a lower rate of anti-TB drug resistance than adults and a decreasing overall trend of anti-TB drug resistance was found in the elderly in recent years, but the higher rate of MDRTB in Taiwan continues to present a challenge for the control of TB in the elderly.

Drug‐resistant tuberculosis: Past, present, future

In a population of Mycobacterium tuberculosis, random chromosomal mutation that results in genetic resistance to anti-tuberculosis (TB) drugs occurs at a relatively low frequency. Anti-TB drugs impose selection pressure so that mycobacterial mutants gradually outnumber susceptible bacilli and emerge as the dominant strains. Resistance to two or more anti-TB drugs represents cumulative results of sequential mutation. The fourth report on global anti-TB drug resistance provides the latest data on the extent of such problem in the world. The median prevalence of multi-drug-resistant TB (MDR-TB) in new TB cases was 1.6%, and in previously treated TB cases 11.7%. Of the half a million MDR-TB cases estimated to have emerged in 2006, 50% were in China and India. The optimal duration of any given combination of anti-TB drugs for treatment of MDR- and extensively drug-resistant TB (XDR-TB) has not been defined in controlled clinical trials. Standardized treatment may be feasible for MDR-TB patients not previously treated with second-line drugs, but a different strategy needs to be applied in the treatment of MDR-TB patients who have received second-line drugs before. Unfortunately, the reliability of drug susceptibility testing of most second-line anti-TB drugs is still questionable. Drug-resistant TB is not necessarily less virulent. Findings from modelling exercise warned that if MDR-TB case detection and treatment rates increase to the World Health Organization target of 70%, without simultaneously increasing MDR-TB cure rates, XDR-TB prevalence could increase exponentially. Prevention of development of drug resistance must be accorded the top priority in the era of MDR-/XDR-TB.

Tuberculosis – An Under-appreciated Disease

Tuberculosis Worldwide Tuberculosis (TB, as usually abbreviated) is a major cause of morbidity and mortality in many countries, and a signifi cant public health problem worldwide. The World Health Organization (WHO) estimates that there are about 8.8 million new cases of TB and 1.6 million deaths from TB every year.1 Non-compliance with anti-TB drug treatment, or inappropriate treatment, or both, has led to one of the greatest challenge facing TB control programmes worldwide, i.e. drug-resistant tuberculosis. Drug-resistant TB is much more diffi cult and costly to treat than fully drug-susceptible TB. An estimated 490,000 cases of multi-drug resistant TB (MDR-TB), causing about 110,000 deaths, occur each year among both new and previously treated cases. These cases are resistant to rifampicin and isoniazid, the 2 most effective fi rst-line anti-TB drugs. The 2008 WHO Report on Anti-TB Drug Resistance stated that the world was experiencing the highest ever recorded rates of MDR-TB, with an average proportion among all TB cases of 5.3%. There were 14 geographic areas showing MDR-TB rates greater than 6% among new TB cases. These areas were mainly in countries of the former Soviet Union and in China. The highest rate of MDR-TB was reported in Baku City, the capital of Azerbaijan, where nearly a quarter of new TB cases were reported to be MDR-TB.2 The same 2008 WHO Report also indicated that cases of extensively drug-resistant TB (XDR-TB) have been reported in 45 countries, and emphasised that this phenomenon threatens to derail 10 years of progress in TB control. XDR-TB is TB that is resistant not just to rifampicin and isoniazid, but also to a fl uoroquinolone and to 1 of 3 injectable second-line anti-TB drugs (kanamycin, amikacin or capreomycin). XDR-TB is thus very diffi cult to treat, and the success rate of treatment is only 30% at best, in contrast to 50% to 70% for MDR-TB and over 95% success for pan-sensitive tuberculosis. Another major challenge has been the impact of the pandemic of human immunodefi ciency virus (HIV). HIV

Treatment outcome of multidrug/extensively drug-resistant tuberculosis in Latvia, 2000-2004

In the present study, we characterised drug-resistance patterns, compared treatment outcome between extensively and nonextensively drug-resistant tuberculosis (non-XDR-TB) cases, and assessed risk factors for poor outcome in a high-prevalence country that screens all TB patients for first-line anti-TB drug resistance. We reviewed drug susceptibility test results among all pulmonary TB cases in Latvia diagnosed from 2000-2004, as well as demographic and clinical characteristics, drug-resistance patterns, and treatment outcomes. During the 5-yr period, 1,027 multidrug-resistant tuberculosis (MDR-TB) cases initiated treatment. Among all cases, the proportion that experienced an outcome of cure or completion increased from 66.2 to 70.2% (p = 0.06 for linear trend). Among the 48 (4.7%) XDR-TB cases, 18 (38%) were cured, four (8%) died, three (6%) defaulted, and treatment failed in 23 (48%). In proportional-hazards analysis, characteristics significantly associated with poor outcome included XDR-TB, being retired, presence of bilateral cavitation, and previous MDR-TB treatment history for those aged ≥55 yrs. Overall, treatment success among all MDR-TB cases increased over time. Strategies to prevent transmission of XDR-TB and to further improve treatment outcome are crucial for the future of TB control in Latvia.

First-line anti-tuberculosis drug resistance patterns and trends at the national TB referral center in Iran—eight years of surveillance

Resistance to anti-tuberculosis (anti-TB) drugs is becoming a major and alarming threat in most regions worldwide. This was a descriptive cross-sectional study at a tertiary hospital in Iran, using patient medical records for 2000-2003. The findings were analyzed following the same framework as that used for previous reports from this center. Among 1556 TB patients, drug susceptibility testing (DST) was performed for 548 culture-positive cases. Anti-TB drug resistance to both isoniazid and rifampin was identified in 10 (2.8%) of the new TB cases (multidrug-resistant TB; MDR-TB). Any resistance was detected in 228 (41.6%), showing an increasing trend in both new and retreatment cases. The data analysis revealed that drug-resistant TB had a statistically significant association with Afghan ethnicity, age>65 years, and the type of disease (retreatment vs. new TB case) (p<0.05). Also, assessment of the drug resistance trends showed a significant increase in resistance to any anti-TB agent, to isoniazid, and to streptomycin in new cases, and to all of the first-line anti-TB drugs in retreatment patients. There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Hence, revision of the national TB control program, reevaluation of the role of the World Health Organization category II (CAT II) regimen, as well as the conducting of a nationwide drug resistance survey, are recommended.

Paradigm shift to address drug resistant tuberculosis in people living with HIV needed, and needed now

People living with HIV have a higher risk of multi-drug resistant (MDR) (Wells et al. 2007; Dubrovina et al. 2008; WHO 2008b) and extensively drug resistant (XDR) tuberculosis (Gandhi et al. 2006) with increased mortality, and greatly reduced survival time. Only 6% (less than 30,000) of the half million estimated incident MDR cases were diagnosed and notified globally by the end of 2007. Fifty-four countries had reported at least one case of XDRTB (WHO 2009a,b). Data on the HIV prevalence among these notified cases and the extent of the problem in children are not available. In the latest global antituberculosis drug resistance survey of WHO, only seven countries, none of which have a generalized HIV epidemic, reported tuberculosis (TB) drug resistance stratified by HIV status (WHO 2008a). However, people living with HIV are particularly vulnerable to the impact of drug resistant TB due to the difficulties and delays in the diagnosis (Wells et al. 2007), complications of concomitant treatment with TB and antiretroviral therapy (ART) (Havlir et al. 2008) and poor TB infection control measures in many HIV care settings (Gandhi et al. 2006; Kawai et al. 2006). Diagnosis of drug resistant TB requires sophisticated infrastructure and expertise, which at the moment is scarcely available in most resource constrained and HIV prevalent settings. The emergence of XDR TB, and its fatal association with HIV, has exposed the failures of implementing the measures recommended in the Stop TB Strategy of WHO (Raviglione & Smith 2007). It is encouraging to note that a global momentum is building towards accelerated nationwide implementation of collaborative TB/HIV activities(WHO 2004) and the scalingup of the management of MDR-TB(WHO 2008b), critical components of the Stop TB Strategy (WHO 2009a). In this editorial, we argue that not enough attention has yet been given to the interface between MDR and XDR with HIV and a framework of priority actions is needed to address the problem and consolidate synergy between TB and HIV stakeholders at all levels. The first step is to understand the extent of the problem systematically and promptly. Although current global surveillance activities identified countries in the former Soviet Union and regions of China as having a high proportion of MDR TB cases, and nearly half of the estimated MDR cases reside in China and India (WHO 2008a) the extent of the MDR problem in people living with HIV, including children, has not been properly documented. Furthermore, the situation in subSaharan Africa is largely unknown (Ben Amor et al. 2008; Zager & McNerney 2008) due mainly to lack of laboratory infrastructure. However, the XDR-TB outbreaks affecting primarily people living with HIV in KwaZulu Natal (Gandhi et al. 2006) and other provinces of South Africa (O’Donnell et al. 2009) give cause for serious concern. New HIV infections are on the rise in those countries with higher proportions of MDR TB cases including China, the Russian Federation and Ukraine (UNAIDS 2008). Data on the risk of MDR TB among HIV positive TB patients is available from just two places in the former Soviet Union, Donetsk, Ukraine, and Latvia which showed TB patients living with HIV are almost nearly twice as likely to have MDR-TB as patients without HIV (Dubrovina et al. 2008; WHO 2008a). Therefore, an urgent and systematic review of the extent and magnitude of the convergence of the HIV and drug resistant TB epidemics is needed, particularly in Africa and Eastern Europe. High quality anti-TB drug resistance surveys are needed which include HIV testing as an essential component, and synergistic opportunities between the expansion of global HIV Tropical Medicine and International Health doi:10.1111/j.1365-3156.2009.02266.x

Surveillance of antituberculosis drug resistance among children from the Western Cape Province of South Africa--an upward trend.

We assessed the prevalence of antituberculosis drug resistance among children with tuberculosis (TB) in the Western Cape Province of South Africa. Drug susceptibility testing for isoniazid and rifampin was prospectively done on all children with culture-confirmed TB at Tygerberg Children's Hospital, Cape Town, from March 2005 through February 2007. Survey results were compared with results from 2 previous surveys. We found 291 children had culture-confirmed TB. Resistance to isoniazid or rifampin increased from 21 of 306 (6.9%) to 41 of 319 (12.9%) and 43 of 285 (15.1%) in the first to third surveys (P = .005) and multidrug resistance from 7 of 306 (2.3%) to 18 of 319 (5.6%) and 19 of 285 (6.7%; P = .033). Although previously treated children had significantly more drug resistance than did new TB cases (19 of 66 [28.8%] vs 24 of 225 [10.7%]; odds ratio = 3.39; 95% confidence interval = 1.62, 7.05), evidence suggests transmission rather than acquisition of resistance. HIV infection was not significantly associated with drug resistance. Results indicate a high and rising prevalence of anti-TB drug resistance among children in the Western Cape, which suggests ongoing transmission of drug-resistant strains within the community. Improved control of TB in adults, including early identification and treatment of drug-resistant cases, is necessary to reduce transmission to children.

PL-01 Anti-TB drug resistance surveillance in China

PL-01 Anti-TB drug resistance surveillance in China

Vigilancia de la resistencia del Mycobacterium tuberculosis a los fármacos antituberculosos, Colombia 2004-2005

Tuberculosis is an important cause of disease and death worldwide. An estimated 8.8 million new cases occurred in 2005 with 1.6 million deaths, including 195,000 among HIV-infected people. According to World Health Organization, the incidence rate was stable or in decline worldwide; however, the total number of new cases rose due to regional increases. Anti-TB drug resistance is a significant public health problem and an obstacle for its control worldwide. Therefore, measures must be taken for the adequate management of patients and the adoption of strategies to prevent TB dissemination. The prevalence of resistance of Mycobacterium tuberculosis was determined in untreated cases and in previously treated cases of pulmonary tuberculosis in Colombia. A cross-sectional study determined the prevalence of resistance of Mycobacterium tuberculosis to antituberculosis drugs in 1,189 untreated cases or previously treated cases of pulmonary tuberculosis between the years 2004 and 2005. Cultures were collected throughout the country for this one-year period. Drug susceptibility of the isolates was tested by the simplified variant of the Cannetti, Risk and Grooset multiple proportions technique. The global resistance rate of 925 untreated patients was 11.8% (95% CI: 9-14%) and the rate of multidrug-resistant tuberculosis was 2.4% (95% CI: 1.6-3.6%). Among 264 previously treated patients, the rate of global resistance was 44.3% (95% CI: 38-50%) and that of multidrug resistance was 31.4% (95%CI: 26-37%). When compared to previous studies, these data show that there has not been a significant increase in drug resistance. The findings indicate that the current treatment scheme provided by the National Tuberculosis Program is adequate.