Drug-resistance of MDR-TB in Xi'an between 2018 and 2020 and the impact of COVID-19 epidemic prevention and control on it

To analyze the drug-resistance of clinical Mycobacterium tuberculosis strains isolated from the tuberculosis(TB)patients in six provinces in China and related risk factors, and provide evidences for the effective prevention and treatment of drug resistant TB. Six provinces were selected from China. The background information of the TB patients was investigated with questionnaire survey, and the drug susceptibilities of the clinical M. tuberculosis strains to isoniazid, rifampin, ethambutol and streptomycin were tested by means of the proportional drug susceptibility test. Then the results and related risk factors were analyzed with software SPSS 20.0. The overall drug resistant rate and multi drug-resistant(MDR)rate were 23.42% and 13.51% respectively. The overall drug resistant rate and MDR rate in Beijing, Jilin, Hunan, Henan, Shaanxi, Xinjiang were 21.50%, 12.24%, 36.27%, 42.86%, 27.78%, 24.39% and 4.67%, 8.16%, 24.51%, 26.53%, 15.28%, 14.15%, respectively. The χ(2) analysis results showed that the differences in single drug-resistant rate, overall drug resistant rate and MDR rate in these provinces had significant differences(P=0.000). The univariate statistical analysis results showed that the retreatment for TB and TB treatment history were the risk factors associated with drug resistance(P<0.05). The drug resistance of TB was very serious in China, but the TB drug resistance varied with province. The preventive intervention should be strengthened against all the major risk factors associated with the drug resistance for the better prevention and control of TB.

Objective To evaluate the resistance of multidrug-resistant Mycobacterium tuberculosis (M.tb) strains to bedaquiline (BDQ) and to analyze the relationships between their genotypes and BDQ-resistant phenotypes in order to provide a scientific basis for rational use of BDQ for the treatment of multidrug-resistant tuberculosis (MDR-TB) in clinical practice. Methods A total of 387 clinical M. tb strains, including 100 pan-susceptible strains and 287 strains isolated from patients with MDR (MDR-TB strains), were enrolled in this study. Of the 287 MDR-TB strains, 77 strains were collected in Chongqing in 2015 and the other strains were collected in a national drug-resistant tuberculosis survey conducted in China during 2007 to 2008. Minimum inhibitory concentrations (MIC) of BDQ against those strains were detected. Genotypes of those strains were analyzed by Spoligotyping. Differences in the resistant rates against BDQ between Beijing genotype and non-Beijng genotype MDR-TB strains were comparatively analyzed. Results MIC50 and MIC90 of BDQ against the 287 MDR-TB strains were 0.03 μg/ml and 0.25 μg/ml, respectively. Nineteen out of the 287 MDR-TB strains (6.6%) were resistant to BDQ. Based on the Spoligotyping, 195 strains were classified into Beijing genotype, and the other 92 strains belonged to non-Beijing genotype. Statistical analysis revealed that the BDQ-resistant rate in Being genotype strains (4.6%, 9/195) was lower than that in non-Beijing genotype strains (10.9%, 10/92, χ2=3.955, P=0.047). In addition, the MIC50 and MIC90 of BDQ against pan-susceptible strains were 0.03 μg/ml and 0.12 μg/ml, respectively. Sixty-three pan-susceptible strains belonged to Beijing genotype and the other 37 strains belonged to non-Beijing genotype. None of the pan-susceptible strains was resistant to BDQ. Conclusion This study indicates that BDQ showed stronger in vitro antibacterial activity against the MDR-TB strains isolated in China. A correlation between non-Beijing genotype and BDQ resistance is observed in those MDR strains. MDR strains of Beijing genotype are more susceptible to BDQ than those of non-Beijing genotype. Key words: Mycobacterium tuberculosis; Multidrug resistance; Drug susceptibility; Bedaquiline; Genotype

To the Editor: Multidrug-resistant (MDR) tuberculosis (TB), defined as TB caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin, is threatening global control of TB. The emergence of extensively drug-resistant (XDR) TB, defined as MDR TB resistant to at least 1 quinolone and 1 of 3 injectable second-line drugs (kanamycin, amikacin, or capreomyin), further jeopardizes TB control and prevention. In the People’s Republic of China, a country in which the economic cost of TB is high, incidence of MDR TB is higher (10%) (1) than the average global incidence (4.8%) (2). Published reports of XDR TB prevalence indicate that XDR TB is probably an underestimated problem in mainland China (3–7). China is a geographically large country, and the characteristics of drug resistance of TB might vary among provinces (2). Five regional surveys reported drug-resistance patterns of XDR TB in mainland China, and 3 were conducted in eastern China (3–7). To determine prevalence of XDT TB in central China, we characterized the resistance of MDR M. tuberculosis to second-line drugs, specifically identifying XDR strains, in Henan, a major province of central China. Henan Province has the country’s third largest provincial population (94 million) and high rates of drug resistance to any agent (35.5%) (2). The bacterial population retrospectively analyzed in this study has been described (8). In brief, from 2007 through 2009, clinical isolates were collected consecutively by the Henan Center for Disease Control and Prevention TB surveillance system and screened for resistance to 4 first-line drugs. Proportion method–based drug susceptibility testing was conducted for the following critical concentrations: isoniazid 0.2 μg/mL, rifampin 40.0 μg/mL, ethambutol 2.0 μg/mL, and streptomycin 4.0 μg/mL. As a result of that study, 150 MDR TB isolates from TB patients were obtained. The genotyping of all MDR isolates was identified by variable number tandem repeat of mycobacterial interspersed repetitive units based on 16 loci with high discriminatory power. For the study reported here, we performed additional drug susceptibility testing of 4 second-line drugs at the Henan Center for Disease Control and Prevention TB reference laboratory. We used the Lowenstein-Jensen proportion method, recommended by the World Health Organization, according to the following critical drug concentrations: ofloxacin 3.0 μg/mL, kanamycin 30.0 μg/mL, amikacin 30.0 μg/mL, and capreomycin 40.0 μg/mL (9). Susceptibility results for all second-line drugs tested were reported for 143 (95.3%) of 150 MDR M. tuberculosis isolates. Among these 143 isolates, 49 (34.3%) were resistant to ofloxacin, 23 (16.1%) to kanamycin, 17 (11.9%) to amikacin, and 25 (17.5%) to capreomycin (Table). All 17 amikacin-resistant isolates were also resistant to kanamycin, and 16 were also resistant to capreomycin. Also among the 143 MDR isolates, 18 (12.6%) showed resistance to ofloxacin and at least 1 second-line injectable drug and were defined as XDR strains. All 18 XDR M. tuberculosis isolates were resistant to isoniazid, rifampin, streptomycin, and ofloxacin; 14 (77.8%), 16 (89.9%), 12 (66.7%), and 17 (94.4%) were resistant to ethambutol, kanamycin, amikacin, and caperomycin respectively. Twelve amikacin-resistant XDR isolates were also resistant to kanamycin and capreomycin (Table). Table Second-line drug resistance patterns for 143 strains of multidrug-resistant tuberculosis, Henan Province, China, 2007–2009* Genotyping results demonstrated that XDR strains were distributed diversely in the phylogenetic tree, suggesting that these strains evolved independently. Our results indicated that 12.6% of MDR TB isolates from Henan Province meet the definition of XDR TB, which is less than that found by hospital-based studies performed in Shandong (18.7%), Shanghai (30.0%), and Beijing (14.9%) (3,5,6) but higher than that found by 2 other studies conducted in Beijing and Shanghai (6.3% each) (4,7). The discrepancy between the percentages of XDR TB and MDR TB strains found in these studies might be explained by the probable inclusion of patients who had been previously treated and patients with chronic TB. Previous studies found high cross-resistance among all 3 second-line injectable drugs in MDR and XDR TB strains (5,10). Our results support these observations; capreomycin resistance of MDR and XDR strains (17.5% and 94.4%, respectively) in Henan Province were higher than the average levels (10.2%, 62.5%, respectively) reported by a worldwide study (10). Pyrazinamide is an essential drug recommended by World Health Organization guidelines for treatment of MDR TB. Among the population with MDR TB that we studied, 10 (76.9%) of 13 XDR isolates were sensitive to pyrazinamide (data not shown), suggesting that pyrazinamide is still an effective first-line anti-TB drug for most XDR TB patients in Henan Province. We restricted our investigation to 1 province. However, given the average national prevalence of XDR TB (8% of MDR TB) (1) and the magnitude of the population of Henan Province, our findings indicate that the prevalence of XDR TB might be higher in central China than previously documented.

ObjectiveTo analyze the dynamic trend of drug resistance of Mycobacterium tuberculosis in Leiyang city, Hunan province from 2013 to 2017, and to understand the local drug resistance spectrum of M. tuberculosis, so as to provide evidences for the formulation of chemotherapy regimen of tuberculosis (TB) and TB prevention and control. MethodsThe strains of M. tuberculosis collected in Leiyang from 2013 to 2017 were analyzed retrospectively. After identification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), all the M. tuberculosis strains were subjected to susceptibility tests of 8 first and second line anti-TB drugs by using microtiter plate method to understand the minimum inhibitory concentration. Statistical description and Chi-square for trend test were used to analyze the drug resistance trend. ResultsA total of 568 clinical strains of M. tuberculosis were included in this study, of which 18.49% (105/568) were from retreated TB cases, and 81.51% (463/568) form new TB cases. Overall, the drug resistance rate was 22.13% (120/568), the multi-drug resistance rate was 6.34% (36/568) and the extensively drug resistance rate was 0.35% (2/568). Drug resistance trend analysis showed that only the resistance rate to fluoroquinolones increased year by year (trend χ2＝8.585, P＝0.003), while the fluctuations of the drug resistance rate to other drugs, overall drug resistance rate and multi-drug resistance rate were not obvious, the differences were not statistically significant. ConclusionOverall, the drug resistance of tuberculosis in Leiyang was serious, the resistance rate to fluoroquinolones showed an increasing trend, and close attention should be paid on that. The standardized use of fluoroquinolones should be strengthened. Cross-drug resistance should be fully considered in the treatment of patients with drug resistant TB. In addition, the management of MDR-TB patients should be strengthened to reduce the incidence of primary drug resistant TB.

To study the status of drug-resistant Mycobacterium tuberculosis in Ningxia, and therefore to provide scientific data for tuberculosis control in this area. Drug sensitivity tests were carried out by sputum culture and the proportional method in all patients with active pulmonary tuberculosis from April 2014 to April 2013 in Ningxia. Statistical analysis was performed with χ²-test. This survey included 2 369 cases (1 177 males, 1 192 females), aged 12 to 80 years (mean 51 ± 21). There were 1 176 patients of Han nationality, 844 Hui nationality , and 349 other nationalities. Cases with initial treatment were 2 255, and those with retreatment were 114. A total of 665 isolates were obtained. The total drug resistance rate was 26.6% (177 cases); the initial drug resistant rate was 20.2% (119/590 cases), while the acquired resistant rate was 77.3% (58/75 cases). The rate of single drug resistance was 11.7%(78/665 cases), MDR was 7.8%(52/665 cases), and multiple drug resistance was 7.1%(47/665 cases). In different areas, ethnic minority, drug-resistant bacterial classification, the rate of initial and retreatment resistance were statistically different. Drug resistant tuberculosis prevention and control in Ningxia should be focused on newly diagnosed single drug-resistant cases, retreatment multiple-drug resistant cases, and drug resistant cases in minority areas.

The novel gene mtb192 is a candidate marker for the detection of multidrug-resistant Mycobacterium tuberculosis strains

Objective To study the situation of drug-resistance of Mycobacterium tuberculosis in Jincheng, in order to select more effective, scientific and reasonable anti tuberculosis drugs, and to provide evidence for the prevention and control of drug-resistant tuberculosis. Methods Drug sensitivity tests were carried out by sputum culture and the proportional method in all patients. They were active pulmonary tuberculosis and sputum smear-positive from October 2015 to October 2016 in Jincheng. Statistical analysis was performed with χ2-test. Results A total of 162 strains of Mycobacterium tuberculosis (MTB) were isolated. The total drug-resistance rate was 20.99%(34 strains), which was lower than the fifth epidemic result in 2010 for China(36.8%). The rates of single drug resistance(SDR), poly-drug resistance(PDR) and multi drug resistance (MDR) were 4.3%(7/162), 4.94%(8/162) and 11.11% (18/162). MDR was much higher than the fifth epidemic result in 2010 for China(36.8%), but they were almost the same as the level in one hospital of Taiyuan from 2011 to 2013. The initial drug-resistance was 16.15%(21/130), while the acquired resistance rate was 40.63%(13/32), there was significant difference between them(χ2=9.273, P 0.05). Conclusions The total drug resistance rate is lower than the epidemic level in 2010 for China, but MDR is higher. It is very important in drug resistance tuberculosis prevention and control in Jincheng. Key words: Tuberculosis; Mycobacterium tuberculosis; Drug sensitivity test; Drug resistance

Distinguishing Nontuberculous Mycobacteria from Multidrug-Resistant Mycobacterium tuberculosis, China

To the Editor: Global surveillance of drug resistance has shown that a substantial proportion of tuberculosis (TB) patients are infected with drug-resistant Mycobacterium tuberculosis strains (1). Earlier hospital-based surveys have been undertaken in Taiwan, but these lacked systematic sampling and testing methods, which made interpreting results difficult. The combined treatment efficiency and the actual prevalence of drug resistance were unknown. Thus the Taiwan Center for Disease Control initiated the Taiwan Surveillance of Drug Resistance in Tuberculosis program in 2002. A laboratory surveillance system was established and supervised by the national reference laboratory. The system includes 6 medical centers, 2 TB referral centers, and 1 regional hospital, distributed in 4 regions of Taiwan. The 9 laboratories provide services for healthcare facilities in their own and surrounding areas. Both the national reference laboratory and contract laboratories participated in an external quality proficiency test provided by the College of American Pathologists and the national reference laboratory. Performance was also assessed by the supranational reference laboratory in Antwerp, Belgium. The population in the first year (2003) of the survey was 22,562,663, the number of confirmed TB cases was 15,042, the estimated incidence was 66.7 per 100,000 population, and the rate of notification of new positive sputum samples was 34.6% (2). A total of 3,699 isolates, ≈50% of M. tuberculosis strains isolated, underwent antimicrobial drug susceptibility testing in the system. Since clinical data were not available, only combined (primary plus acquired) drug resistance rates were analyzed. The survey showed that the combined drug resistance rates were 9.5% to isoniazid, 5.8% to ethambutol, 6.4% to rifampin, 9.6% to streptomycin, 20.0% to any drug, and 4.0% to multiple drugs. Resistance to any single drug was 12.3%, to any 2 drugs was 4.8%, to any 3 drugs was 2.2%, and to any 4 drugs was 0.7%. In the third global drug resistance surveillance report, the median prevalence of combined drug resistance was 6.6% to isoniazid, 1.3% to ethambutol, 2.2% to rifampin, 6.1% to streptomycin, 10.4% to any drug, and 1.7% to multiple drugs (1). Available historical data from Taiwan are not directly comparable because of different sampling methods and because susceptibility testing methods have been applied in various hospital settings over time (Table), which limits our ability to monitor trends. The latest drug resistance rates obtained from Chest Hospital, a specialized TB referral hospital, showed that the combined drug resistance of any and multiple drugs were 27.6% and 15.8%, respectively, from January 2002 to June 2004 (unpub. data). Table Drug resistance patterns in Taiwan, 1960–2004 In Taiwan, isoniazid and rifampin were introduced in 1957 and 1978, respectively. Rifampin resistance was first seen in Taiwan in 1982. In recent decades, however, the rates of primary rifampin resistance have increased (Table), and primary resistance to multiple drugs has increased to 2.4% over time. Based on patient data collected from Chest Hospital, multidrug resistance occurred in 42.2% of retreated TB patients, and 1.8% of multidrug-resistant isolates were found in new TB patients from January 2002 to June 2004 (unpub. data). In the third global drug resistance surveillance report, the median prevalence of multidrug resistance was 7.0% (highest 58.3%) among retreated cases and 1.1% (highest 14.2%) among new cases. Significant declining trends were observed for any acquired resistance (67.0% to 42.6%, p<0.0001) and acquired multidrug resistance (46.0% to 24.6%, p<0.0001) at the Taiwan Provincial Chronic Disease Control Bureau from 1996 to 2001 (3,4). In addition, a decline in combined isoniazid resistance (43.1% to 16.4%, p < 0.0001), rifampin resistance (23.4% to 9.5%, p<0.0049), and multidrug resistance (18.2% to 7.8%, p<0.0113) was also reported from Kaohsiung Medical University Hospital from 1996 to 2000 (5). Taken together, data obtained from the Taiwan Surveillance of Drug Resistance in Tuberculosis and those reported previously show that rates of combined resistance to any drugs and multiple drugs has declined in Taiwan. For retreated cases, the high acquired resistance rates indicated suboptimal initial treatment and insufficient case management of new patients, which raises a challenge to the National TB Control Programme in Taiwan. The direct observed treatment, short-course (DOTS) strategy has consequently been suggested to expand to all patients with newly diagnosed cases. The Taiwan Surveillance of Drug Resistance in Tuberculosis program will be extended to collect each patient's clinical and epidemiologic data, according to principles suggested in the guidelines prepared by the World Health Organization.

Prevalence of drug resistant Mycobacterium tuberculosis among children in China

Drug resistance characteristics of Mycobacterium tuberculosis isolates to four first-line antituberculous drugs from tuberculosis patients with AIDS in Beijing, China

Background: Tuberculosis (TB) and HIV rates continue to escalate in Russia, but true rates for drug resistance, especially multidrug resistant tuberculosis (MDR TB), are unknown. A study was conducted with...

The prevalence of drug-resistant Mycobacterium tuberculosis (Mtb) strains makes disease control more complicated, which is the main cause of death in tuberculosis (TB) patients. Early detection and timely standard treatment are the key to current prevention and control of drug-resistant TB. In recent years, despite the continuous advancement in drug-resistant TB diagnostic technology, the needs for clinical rapid and accurate diagnosis are still not fully met. With the development of sequencing technology, the research of human microecology has been intensified. This study aims to use 16 rRNA sequencing technology to detect and analyze upper respiratory flora of TB patients with anti-TB drug sensitivity (DS, n = 55), monoresistance isoniazide (MR-INH, n = 33), monoresistance rifampin (MR-RFP, n = 12), multidrug resistance (MDR, n = 26) and polyresistance (PR, n = 39) in southern China. Potential microbial diagnostic markers for different types of TB drug resistance are searched by screening differential flora, which provides certain guiding significance for drug resistance diagnosis and clinical drug use of TB. The results showed that the pulmonary microenvironment of TB patients was more susceptible to infection by external pathogens, and the infection of different drug-resistant Mtb leads to changes in different flora. Importantly, seven novel microorganisms (Leptotrichia, Granulicatella, Campylobacter, Delfitia, Kingella, Chlamydophila, Bordetella) were identified by 16S rRNA sequencing as diagnostic markers for different drug resistance types of TB. Leptotrichia, Granulicatella, Campylobacter were potential diagnostic marker for TB patients with INH single-resistance. Delftia was a potential diagnostic marker for TB patients with RFP single drug-resistance. Kingella and Chlamydophila can be used as diagnostic markers for TB patients with PR. Bordetella can be used as a potential diagnostic marker for identification of TB patients with MDR.

ObjectiveTo evaluate the levels and patterns of drug resistance in initially treated smear-negative pulmonary tuberculosis (TB) patients in Ningbo, and provide scientific evidence for the prevention and control of drug-resistant TB. MethodsSputum samples of 1 434 initially treated smear-negative pulmonary TB patients enrolled from March to December 2017 were isolated by liquid culture method. Strain identification and drug susceptibility tests were performed for all culture positive samples with proportion method. ResultsA total of 378 sputum samples from the 1 434 enrolled pulmonary TB patients were culture positive, in which 60 were non-tuberculosis mycobacterium positive. Eight six of 318 pulmonary TB cases were drug-resistant, the overall drug-resistance rate was 27.04%, with the highest resistance rate to isoniazid (17.92%, 57/86), and the lowest drug-resistance rate to rifampicin (5.35%, 17/86). The resistance rate to rifampicin in pulmonary TB patients with cavitation was significantly higher than that in those without cavitation (χ2＝5.319, P＜0.05). ConclusionThe drug resistance in initially treated smear-negative pulmonary TB cases was relatively severe in Ningbo. Further efforts should be made to expand drug susceptibility test coverage to find drug-resistant patients timely and improve the treatment and management of pulmonary TB cases.

Asserts that despite progress in controlling tuberculosis (TB), the decline in incidence has been disappointing, pointing to the need for new strategies and more effective tools. HIV/AIDS is one factor that challenges effective control of TB, especially in Southern African countries. Three key elements are needed to achieve effective TB control and to meet the Sustainable Development Goals: (1) early and accurate diagnosis and drug-sensitivity testing, (2) patient access to and completion of effective treatment, and (3) prevention of progression from latent infection to disease. Prevention requires vaccination and screening of individual at high risk as well as interventions such as air disinfection and the use of masks and respirators in hospitals and other congregate settings. Recommendations stress the need to strengthen health systems in high-burden countries by emphasizing community-based care over hospital care; to improve information systems to ensure patient adherence and manage medication supply chains; and to invest in research to develop the necessary interventions. Fundamentally, current global TB control strategies must undergo revision and receive significant research funding.