BACKGROUND
although the incidence and mortality of tuberculosis  have declined over the past decade, there were an estimated  <dig>  million incident cases of tb and  <dig>  million deaths in  <dig> according to the world health organization  <cit> .
two major factors, including the lethal association of hiv with active tb disease, and the worldwide dissemination of multidrug-resistant  and extremely drug-resistant  strains of mycobacterium tuberculosis, contribute to the severe tb epidemic  <cit> .
globally, an estimated  <dig>  % of new cases and  <dig>  % of previously treated cases have mdr-tb.
in  <dig> there were an estimated  <dig>   <dig> new cases of mdr-tb, and about  <dig>   <dig> associated deaths  <cit> .
china is one of the  <dig> mdr-tb high-burden countries.
according to the  <dig> national survey of drug-resistant tb in china,  <dig>  % of new cases and  <dig>  % of previously treated cases were diagnosed with mdr-tb.
based on these survey results, it is estimated that there are  <dig>   <dig> new cases of mdr-tb in china per year  <cit> .
in addition, xdr-tb cases were reported by over  <dig> countries in  <dig>  and up to  <dig>  % of mdr-tb cases had xdr-tb in  <dig>  <cit> .
it is therefore urgent to control the epidemic of mdr-tb and xdr-tb.
in order to understand how drug-resistant tb develops and to find better ways to control mdr-tb and xdr-tb, it is essential to determine the clinical characteristics and molecular epidemiology of mdr-tb and xdr-tb.
recently, many studies have shown that clinical features and molecular characteristics of drug-resistant strains vary in different geographical areas  <cit> , such as, for example in different provinces in china .
these studies, however, have focused on the clinical and molecular characteristics of drug-resistant m. tuberculosis strains from a single time period, and are thus unable to assess the dynamic evolution of drug-resistant tb.
comparative studies between different time periods are thus necessary to elucidate the development of drug-resistant tb.
to better understand changes in the clinical and molecular characteristics of m. tuberculosis isolates in beijing, china, we analyzed all strains collected from tb inpatients admitted to beijing chest hospital  over two time periods separated by six years .
clinical information, drug-resistant phenotypes  and first-line drug resistance-associated mutations were compared between these two time periods.
RESULTS
demographic and clinical characteristics of enrolled subjects
our purpose in this study was to evaluate changes in the clinical characteristics and molecular epidemiology of drug-resistant tb and thus assess its dynamic evolution.
we thus performed a comparative study of m. tuberculosis isolates collected at the beijing chest hospital over two time periods separated by 6 years.
the mtb strain bank at beijing chest hospital was first established in  <dig>  and complete datasets were available for each year from  <dig> to  <dig> when we initiated this project.
we reasoned that a 6-year window would reveal possible changes in the rate of occurrence of drug-resistant tb, so chose to analyze all isolates collected from inpatients in the beijing chest hospital from  <dig> to  <dig>  a total of  <dig> isolates were selected, including  <dig> and  <dig> isolates from  <dig> to  <dig>  respectively.
the mean age of patients in  <dig> and  <dig> was  <dig>  ±  <dig>  years and  <dig>  ±  <dig>  years, and the male to female ratio was  <dig>  and  <dig> , respectively.
as shown in table  <dig>  there were no significant differences in the clinical characteristics  of each subgroup  between cases in  <dig> and  <dig> .
of note, however, the proportion of previously treated cases in  <dig>  was significantly higher than that in  <dig> .table  <dig> general demographic characteristics of patients enrolled in  <dig> and 2012
drug-resistance patterns differ in  <dig> and 2012
the overall rate of resistance in the mtb strains examined to any drug was  <dig>  % in  <dig>  significantly higher than that in  <dig> , indicating the severe and worsening situation of drug-resistance in tb in china.
furthermore, the rate of resistance to any drug in  <dig> was higher than that in  <dig> in both new and previously treated cases .
the proportion of drug-resistant m. tuberculosis isolates in  <dig> was compared with that in  <dig> .
the overall resistance level to each drug was significantly higher in  <dig> .
rates of resistance to rifampicin , streptomycin , ethambutol  and ofloxacin  were significantly higher in new cases in  <dig> , while the proportion of isolates resistant to isoniazid  were marginally higher , and resistance to capreomycin  and amikacin  was not significantly changed .
the proportions of isolates resistant to inh, rif, ofx and cap in previously treated cases were significantly higher in  <dig> , but the proportions of isolates resistant to str, emb and amk were not significantly changed .table  <dig> comparison of drug susceptibility patterns between clinical m. tuberculosis isolates in  <dig> and in 2012
<dig>
the overall rate of mdr-tb was  <dig>  % in  <dig>  significantly higher than that in  <dig> .
the proportion of mdr-tb in previously treated cases was significantly higher in  <dig> compared to  <dig> , but there was no significant increase in new cases .
the overall pre-xdr rate was  <dig>  % in  <dig>  again, significantly higher than that in  <dig> .
however, the pre-xdr rate in  <dig> did not increase significantly in either new cases  or previously treated cases  compared with  <dig>  the rate of xdr-tb also increased significantly from  <dig>  to  <dig> .
while the rate of xdr was similar in new cases during the two time periods, it was marginally higher in  <dig> in previously treated cases .
factors associated with drug-resistant tb and mdr-tb
the risk factors associated with resistance to any drug and mdr-tb were analyzed based on pooled demographic data for all patients .
by univariate analysis, age and treatment history were significantly associated with resistance to any drug and mdr-tb .
multivariate analysis confirmed that age and treatment history were independently associated with resistance to any drug and mdr-tb .table  <dig> factors associated with drug-resistant tuberculosis in all patients
patients older than 64 years had a significantly lower risk of developing drug resistance relative to patients in the younger age group , with an adjusted or of  <dig>  .
this risk decreased significantly in mdr-tb cases, with an adjusted or of  <dig>  .
previously treated cases were associated with a higher risk of developing drug resistance, with an adjusted or of  <dig>  , and the risk increased significantly in mdr-tb cases, with an adjusted or of  <dig>  .
drug resistance associated mutations in  <dig> and 2012
using a combination of mutations in katg, the maba-inha promoter and the oxyr-ahpc intergenic region, dna sequencing was able to identify  <dig>  %  and  <dig>  %  of inh-resistant isolates collected in  <dig> and  <dig>  respectively.
similarly,  <dig>  %  and  <dig>  %  of rif-resistant isolates were detected based on mutations in the rrdr region of rpob,  <dig>  %  and  <dig>  %  of str-resistant isolates were detected based on mutations in rpsl, and  <dig>  %  and  <dig>  %  of emb-resistant isolates were detected based on mutations in embb.
in addition,  <dig>  %  and  <dig>  %  of emb-susceptible isolates in the  <dig> and  <dig> groups were also found to harbor mutations in the embb gene.
other target mutations were not found in inh, rif and str susceptible isolates in the  <dig> and  <dig> collections.
the frequencies of common mutations in inh, rif, str or emb resistant isolates were similar in  <dig> and in 2012: katg <dig> , maba-inha − <dig> ; rpob <dig> , rpob <dig> ; rpsl <dig> ; embb <dig> .
data on common mutation patterns in these drug-resistant isolates are shown in table  <dig>  in addition, the embb <dig> mutation was detected in  <dig>  %  and  <dig>  %  of emb-susceptible isolates in the  <dig> and  <dig> collections, respectively.
moreover, patterns of mutation in the loci examined were more diverse in  <dig> compared to  <dig> table  <dig> most frequently identified mutations within first-line drug-resistance associated loci among drug-resistant m. tuberculosis isolates
katg
rpsl
embb
discussion
in this hospital-based study, the rate of resistance to any drug and the mdr rate of m. tuberculosis isolates was found to increase significantly from  <dig> to  <dig>  reflecting the serious drug-resistant tb epidemic in china.
overall, the percentage of previously treated cases in  <dig> was higher than that in  <dig>  suggesting that treatment of previously treated cases is still a big challenge in controlling the tb epidemic in china.
furthermore, the proportion of previously treated cases among the mdr-tb cases increased to  <dig>  % in  <dig> compared to that in  <dig> .
this implies that acquired multi-drug resistance may play an increasing role in the mdr-tb epidemic in china.
among the new tb cases in this study, rates of resistance to each first-line drug in the  <dig> isolate collection were consistent with those found in the national survey of drug-resistant tb conducted in  <dig>  <cit> .
however, rates of resistance to each first-line drug were significantly increased in  <dig>  the rate of resistance to the second-line drug ofx also increased from  <dig>  % in  <dig> to  <dig>  % in  <dig> among new tb cases.
the increasing rate of ofx resistance rate should thus be considered when choosing an optimal anti-tb regimen.
as the new cases in this study had not received therapy or were in treatment for less than 1 month, the rate of drug resistance among new cases should reflect the transmission of drug-resistant tb.
among previously treated cases examined in our study, rates of resistance of m. tuberculosis isolates to inh, rif, ofx and cap were also higher in the  <dig> collection compared with the  <dig> collection.
overall rates of drug-resistance to each first-line drug in  <dig> were much higher than that in the national survey  <cit> .
this difference might be attributed to differences in sampling methods and the subjects targeted.
for the national survey, isolates were selected from across  <dig> provinces of china using a cluster-randomized sampling method  <cit> .
in contrast, in this study, patients were recruited from one tertiary tb referral hospital, i.e., most subjects were hospitalized tb patients with relatively serious symptoms.
overall, the increasing rate of drug-resistance in previously treated cases underlines the importance of standard treatment and the necessity of optimizing the treatment regimen according to the results of drug susceptibility testing.
the mdr and xdr rates in the  <dig> isolates were similar to those found in the national survey  <cit>  among new cases, but were much higher for previously treated cases.
this may also be due to differences in the patients targeted as discussed above.
moreover, the rates of mdr and xdr mtb isolates had increased in  <dig> compared to  <dig> both among new cases and previously treated cases, although the difference was not significant for new cases.
this data suggests that acquired mdr might outweigh primary resistance in the mdr epidemic in china.
this finding is different from that of gao et al.
<cit>  who found that it is recent transmission of m. tuberculosis including transmission of mdr strains, that contributes most highly to the tb epidemic in china.
this difference in findings may be due to variation in regions sampled: gao et al.
collected strains from five counties within five different provinces  <cit> , while the study population examined here came from one hospital in beijing.
previous studies have shown that drug-resistance rates vary in different provinces  <cit> .
pre-xdr rates increased significantly from  <dig> to  <dig>  since pre-xdr is an important step in the development of drug resistance from mdr to xdr, this finding presents an additional alarming indication of the worsening situation of xdr-tb in china.
previous treatment is a well-known risk factor for drug-resistant tb and mdr-tb, and the prevalence of mdr-tb can be up to  <dig> times higher after unsuccessful treatment  <cit> .
in this sense, results obtained here are consistent with previous observations: the risk of suffering mdr-tb among previously treated cases was  <dig>  times higher than that in new cases.
the implementation of dots is thus still very important for effectively controlling drug-resistant tb and mdr-tb, especially with respect to supervising patients to complete the treatment.
we also found that people older than 64 years of age had a lower risk of drug-resistant tb and mdr-tb.
this is consistent with the conclusion of a systematic review of european studies which concluded that mdr-tb cases are more likely to occur in patients younger than 65 years of age  <cit> .
the higher risk of getting mdr-tb in people under 65 years may be attributed to the use of rif for anti-tb treatment from around  <dig>  tb cases in older patients are usually considered as relapse cases, and the infecting strains may be more ancient, and carry a lower risk of becoming resistant to rif.
between  <dig> and  <dig>  there was more or less no difference in the molecular detection rate for first line drug-resistance in our study.
it should be noted that mutations in embb were also found in emb-susceptible isolates  <cit> .
here, embb <dig> mutations were found in  <dig>  % and  <dig>  % of emb-susceptible isolates in  <dig> and  <dig>  respectively.
this percentage is lower than previously reported in russia   <cit>  and singapore   <cit> , and may be due to different percentages of multi-drug resistance among emb-susceptible isolates.
hazbon et al.
collected 807 m. tuberculosis isolates from colombia, mexico, new york and texas, and found that the association between embb <dig> mutations and resistance to increasing numbers of anti-tb drugs was significant in each region, suggesting the role of embb <dig> mutations in broad drug resistance  <cit> .
the frequency of the embb <dig> mutation in one setting may thus be influenced by the percentage of multi-drug resistant isolates.
accordingly, the embb <dig> mutation does not appear to be a reliable marker for predicting emb resistance in beijing, china.
mutation rates at common loci in specific genes associated with drug-resistance were similar in  <dig> and  <dig>  it has previously been shown that antibiotic resistance associated mutations can impair bacterial fitness  <cit> .
however, acquisition of compensatory mutations in drug resistant strains can restore their ability to survive.
it is possible that the reason why the mutation rate at common loci in the drug-resistant isolates in our study was unchanged may be that mutations in these common loci are associated with other compensatory mutations that lead to lower fitness costs.
our study, however, has some limitations.
the isolates examined were collected from only one tb referral hospital in beijing.
patients admitted to this hospital tend to be severe cases or to have received therapy in other hospitals but with poor effect.
thus the incidence of drug-resistant tb may be overestimated, and may not reflect the average level of the whole country.
well-designed studies with a wide coverage of different regions in china should thus be conducted in the future.
CONCLUSIONS
results from this study indicate that the prevalence of drug resistant tb remains high in beijing, china, and suggest that increasing rates of resistance in m. tuberculosis to all anti-tb drugs should be considered when choosing optimal anti-tb regimens for treatment.
the rate of mdr and xdr in m. tuberculosis isolates was higher in  <dig> compared to  <dig>  especially in isolates from previously-treated cases, suggesting that acquired multi-drug resistance may increasingly be playing a primary role in the mdr-tb epidemic in china.
these findings highlight the importance of an earlier start on effective and supervised treatment in order to reduce the burden of retreatment.

 although the incidence and mortality of tuberculosis have declined over the past decade, there were an estimated million incident cases of tb and million deaths in according to the world health organization. two major factors, including the lethal association of hiv with active tb disease, and the worldwide dissemination of multidrug-resistant and extremely drug-resistant strains of mycobacterium tuberculosis, contribute to the severe tb epidemic. globally, an estimated  % of new cases and  % of previously treated cases have mdr-tb. in there were an estimated new cases of mdr-tb, and about associated deaths. china is one of the mdr-tb high-burden countries. according to the national survey of drug-resistant tb in china,  % of new cases and  % of previously treated cases were diagnosed with mdr-tb. based on these survey results, it is estimated that there are new cases of mdr-tb in china per year. in addition, xdr-tb cases were reported by over countries in and up to  % of mdr-tb cases had xdr-tb in. it is therefore urgent to control the epidemic of mdr-tb and xdr-tb. in order to understand how drug-resistant tb develops and to find better ways to control mdr-tb and xdr-tb, it is essential to determine the clinical characteristics and molecular epidemiology of mdr-tb and xdr-tb. recently, many studies have shown that clinical features and molecular characteristics of drug-resistant strains vary in different geographical areas, such as, for example in different provinces in china. these studies, however, have focused on the clinical and molecular characteristics of drug-resistant m. tuberculosis strains from a single time period, and are thus unable to assess the dynamic evolution of drug-resistant tb. comparative studies between different time periods are thus necessary to elucidate the development of drug-resistant tb. to better understand changes in the clinical and molecular characteristics of m. tuberculosis isolates in beijing, china, we analyzed all strains collected from tb inpatients admitted to beijing chest hospital over two time periods separated by six years. clinical information, drug-resistant phenotypes and first-line drug resistance-associated mutations were compared between these two time periods.  demographic and clinical characteristics of enrolled subjects our purpose in this study was to evaluate changes in the clinical characteristics and molecular epidemiology of drug-resistant tb and thus assess its dynamic evolution. we thus performed a comparative study of m. tuberculosis isolates collected at the beijing chest hospital over two time periods separated by 6 years. the mtb strain bank at beijing chest hospital was first established in and complete datasets were available for each year from to when we initiated this project. we reasoned that a 6-year window would reveal possible changes in the rate of occurrence of drug-resistant tb, so chose to analyze all isolates collected from inpatients in the beijing chest hospital from to a total of isolates were selected, including and isolates from to respectively. the mean age of patients in and was  ±   years and  ±   years, and the male to female ratio was and, respectively. as shown in table  there were no significant differences in the clinical characteristics of each subgroup between cases in and. of note, however, the proportion of previously treated cases in was significantly higher than that in.table general demographic characteristics of patients enrolled in and 2012 drug-resistance patterns differ in and 2012 the overall rate of resistance in the mtb strains examined to any drug was  % in significantly higher than that in, indicating the severe and worsening situation of drug-resistance in tb in china. furthermore, the rate of resistance to any drug in was higher than that in in both new and previously treated cases. the proportion of drug-resistant m. tuberculosis isolates in was compared with that in. the overall resistance level to each drug was significantly higher in. rates of resistance to rifampicin, streptomycin, ethambutol and ofloxacin were significantly higher in new cases in, while the proportion of isolates resistant to isoniazid were marginally higher, and resistance to capreomycin and amikacin was not significantly changed. the proportions of isolates resistant to inh, rif, ofx and cap in previously treated cases were significantly higher in, but the proportions of isolates resistant to str, emb and amk were not significantly changed.table comparison of drug susceptibility patterns between clinical m. tuberculosis isolates in and in 2012 the overall rate of mdr-tb was  % in significantly higher than that in. the proportion of mdr-tb in previously treated cases was significantly higher in compared to, but there was no significant increase in new cases. the overall pre-xdr rate was  % in again, significantly higher than that in. however, the pre-xdr rate in did not increase significantly in either new cases or previously treated cases compared with the rate of xdr-tb also increased significantly from to. while the rate of xdr was similar in new cases during the two time periods, it was marginally higher in in previously treated cases. factors associated with drug-resistant tb and mdr-tb the risk factors associated with resistance to any drug and mdr-tb were analyzed based on pooled demographic data for all patients. by univariate analysis, age and treatment history were significantly associated with resistance to any drug and mdr-tb. multivariate analysis confirmed that age and treatment history were independently associated with resistance to any drug and mdr-tb.table factors associated with drug-resistant tuberculosis in all patients patients older than 64 years had a significantly lower risk of developing drug resistance relative to patients in the younger age group, with an adjusted or of. this risk decreased significantly in mdr-tb cases, with an adjusted or of. previously treated cases were associated with a higher risk of developing drug resistance, with an adjusted or of, and the risk increased significantly in mdr-tb cases, with an adjusted or of. drug resistance associated mutations in and 2012 using a combination of mutations in katg, the maba-inha promoter and the oxyr-ahpc intergenic region, dna sequencing was able to identify  % and  % of inh-resistant isolates collected in and respectively. similarly,  % and  % of rif-resistant isolates were detected based on mutations in the rrdr region of rpob,  % and  % of str-resistant isolates were detected based on mutations in rpsl, and  % and  % of emb-resistant isolates were detected based on mutations in embb. in addition,  % and  % of emb-susceptible isolates in the and groups were also found to harbor mutations in the embb gene. other target mutations were not found in inh, rif and str susceptible isolates in the and collections. the frequencies of common mutations in inh, rif, str or emb resistant isolates were similar in and in 2012: katg, maba-inha −; rpob, rpob; rpsl; embb. data on common mutation patterns in these drug-resistant isolates are shown in table  in addition, the embb mutation was detected in  % and  % of emb-susceptible isolates in the and collections, respectively. moreover, patterns of mutation in the loci examined were more diverse in compared to table most frequently identified mutations within first-line drug-resistance associated loci among drug-resistant m. tuberculosis isolates katg rpsl embb discussion in this hospital-based study, the rate of resistance to any drug and the mdr rate of m. tuberculosis isolates was found to increase significantly from to reflecting the serious drug-resistant tb epidemic in china. overall, the percentage of previously treated cases in was higher than that in suggesting that treatment of previously treated cases is still a big challenge in controlling the tb epidemic in china. furthermore, the proportion of previously treated cases among the mdr-tb cases increased to  % in compared to that in. this implies that acquired multi-drug resistance may play an increasing role in the mdr-tb epidemic in china. among the new tb cases in this study, rates of resistance to each first-line drug in the isolate collection were consistent with those found in the national survey of drug-resistant tb conducted in. however, rates of resistance to each first-line drug were significantly increased in the rate of resistance to the second-line drug ofx also increased from  % in to  % in among new tb cases. the increasing rate of ofx resistance rate should thus be considered when choosing an optimal anti-tb regimen. as the new cases in this study had not received therapy or were in treatment for less than 1 month, the rate of drug resistance among new cases should reflect the transmission of drug-resistant tb. among previously treated cases examined in our study, rates of resistance of m. tuberculosis isolates to inh, rif, ofx and cap were also higher in the collection compared with the collection. overall rates of drug-resistance to each first-line drug in were much higher than that in the national survey. this difference might be attributed to differences in sampling methods and the subjects targeted. for the national survey, isolates were selected from across provinces of china using a cluster-randomized sampling method. in contrast, in this study, patients were recruited from one tertiary tb referral hospital, i.e., most subjects were hospitalized tb patients with relatively serious symptoms. overall, the increasing rate of drug-resistance in previously treated cases underlines the importance of standard treatment and the necessity of optimizing the treatment regimen according to the results of drug susceptibility testing. the mdr and xdr rates in the isolates were similar to those found in the national survey among new cases, but were much higher for previously treated cases. this may also be due to differences in the patients targeted as discussed above. moreover, the rates of mdr and xdr mtb isolates had increased in compared to both among new cases and previously treated cases, although the difference was not significant for new cases. this data suggests that acquired mdr might outweigh primary resistance in the mdr epidemic in china. this finding is different from that of gao et al. who found that it is recent transmission of m. tuberculosis including transmission of mdr strains, that contributes most highly to the tb epidemic in china. this difference in findings may be due to variation in regions sampled: gao et al. collected strains from five counties within five different provinces, while the study population examined here came from one hospital in beijing. previous studies have shown that drug-resistance rates vary in different provinces. pre-xdr rates increased significantly from to since pre-xdr is an important step in the development of drug resistance from mdr to xdr, this finding presents an additional alarming indication of the worsening situation of xdr-tb in china. previous treatment is a well-known risk factor for drug-resistant tb and mdr-tb, and the prevalence of mdr-tb can be up to times higher after unsuccessful treatment. in this sense, results obtained here are consistent with previous observations: the risk of suffering mdr-tb among previously treated cases was times higher than that in new cases. the implementation of dots is thus still very important for effectively controlling drug-resistant tb and mdr-tb, especially with respect to supervising patients to complete the treatment. we also found that people older than 64 years of age had a lower risk of drug-resistant tb and mdr-tb. this is consistent with the conclusion of a systematic review of european studies which concluded that mdr-tb cases are more likely to occur in patients younger than 65 years of age. the higher risk of getting mdr-tb in people under 65 years may be attributed to the use of rif for anti-tb treatment from around tb cases in older patients are usually considered as relapse cases, and the infecting strains may be more ancient, and carry a lower risk of becoming resistant to rif. between and there was more or less no difference in the molecular detection rate for first line drug-resistance in our study. it should be noted that mutations in embb were also found in emb-susceptible isolates. here, embb mutations were found in  % and  % of emb-susceptible isolates in and respectively. this percentage is lower than previously reported in russia and singapore, and may be due to different percentages of multi-drug resistance among emb-susceptible isolates. hazbon et al. collected 807 m. tuberculosis isolates from colombia, mexico, new york and texas, and found that the association between embb mutations and resistance to increasing numbers of anti-tb drugs was significant in each region, suggesting the role of embb mutations in broad drug resistance. the frequency of the embb mutation in one setting may thus be influenced by the percentage of multi-drug resistant isolates. accordingly, the embb mutation does not appear to be a reliable marker for predicting emb resistance in beijing, china. mutation rates at common loci in specific genes associated with drug-resistance were similar in and it has previously been shown that antibiotic resistance associated mutations can impair bacterial fitness. however, acquisition of compensatory mutations in drug resistant strains can restore their ability to survive. it is possible that the reason why the mutation rate at common loci in the drug-resistant isolates in our study was unchanged may be that mutations in these common loci are associated with other compensatory mutations that lead to lower fitness costs. our study, however, has some limitations. the isolates examined were collected from only one tb referral hospital in beijing. patients admitted to this hospital tend to be severe cases or to have received therapy in other hospitals but with poor effect. thus the incidence of drug-resistant tb may be overestimated, and may not reflect the average level of the whole country. well-designed studies with a wide coverage of different regions in china should thus be conducted in the future.  results from this study indicate that the prevalence of drug resistant tb remains high in beijing, china, and suggest that increasing rates of resistance in m. tuberculosis to all anti-tb drugs should be considered when choosing optimal anti-tb regimens for treatment. the rate of mdr and xdr in m. tuberculosis isolates was higher in compared to especially in isolates from previously-treated cases, suggesting that acquired multi-drug resistance may increasingly be playing a primary role in the mdr-tb epidemic in china. these findings highlight the importance of an earlier start on effective and supervised treatment in order to reduce the burden of retreatment. 
drug-resistance rates and mutations associated with resistance to first-line anti-tuberculosis drugs were compared. our data suggests that the prevalence of drug resistant tb remains high in beijing, china, and that increasing rates of resistance in m. tuberculosis to all anti-tb drugs should be considered when choosing an optimal anti-tb regimen. previous treatment was found to be a risk factor for drug-resistant tb, especially for mdr-tb. comparative studies between different time periods are necessary to elucidate the development of drug-resistant tb. the rate of mdr increased significantly between these two time periods in previously treated cases but not in new cases, and the rate of xdr was similar in new cases at the two time periods, but was marginally higher in in previously treated cases. recently, many studies have shown that clinical features and molecular characteristics of drug-resistant strains vary in different geographical areas, however, further information is needed to assess the dynamic evolution of drug-resistant tb. in addition, the proportion of drug resistant isolates in which katg, the maba-inha promoter, oxyr-ahpc intergenic region, rpob, rpsl, and embb were mutated was similar in and however patterns of mutation in these loci were more diverse in compared to tuberculosisdrug-resistantmolecular characteristicshttp://dx.doi.org/ /501100001809national natural science foundation of china812718898145005781541062jiao wei-wei shen a-dong infectious diseases special project, minister of china2012zx10003002009huang hai-rong issue-copyright-statement© the author 2016 moreover, acquired multi-drug resistance may play a primary role in the mdr-tb epidemic in beijing, china. a total of and strains were collected from beijing chest hospital in and in respectively. as the epidemic of mdr-tb and xdr-tb becomes increasingly severe, it is important to determine the clinical characteristics and molecular epidemiology of mdr-tb and xdr-tb. the overall rate of drug resistance among strains of tb in was  %, significantly higher than that in. rates of resistance to each first-line drug and to second-line drug ofloxacin increased significantly from to the overall mdr rate also increased significantly from to.
 as the epidemic of mdr-tb and xdr-tb becomes increasingly severe, it is important to determine the clinical characteristics and molecular epidemiology of mdr-tb and xdr-tb. recently, many studies have shown that clinical features and molecular characteristics of drug-resistant strains vary in different geographical areas, however, further information is needed to assess the dynamic evolution of drug-resistant tb. comparative studies between different time periods are necessary to elucidate the development of drug-resistant tb.  a total of and strains were collected from beijing chest hospital in and in respectively. drug-resistance rates and mutations associated with resistance to first-line anti-tuberculosis drugs were compared. the overall rate of drug resistance among strains of tb in was  %, significantly higher than that in. rates of resistance to each first-line drug and to second-line drug ofloxacin increased significantly from to the overall mdr rate also increased significantly from to. the rate of mdr increased significantly between these two time periods in previously treated cases but not in new cases, and the rate of xdr was similar in new cases at the two time periods, but was marginally higher in in previously treated cases. previous treatment was found to be a risk factor for drug-resistant tb, especially for mdr-tb. in addition, the proportion of drug resistant isolates in which katg, the maba-inha promoter, oxyr-ahpc intergenic region, rpob, rpsl, and embb were mutated was similar in and however patterns of mutation in these loci were more diverse in compared to  our data suggests that the prevalence of drug resistant tb remains high in beijing, china, and that increasing rates of resistance in m. tuberculosis to all anti-tb drugs should be considered when choosing an optimal anti-tb regimen. moreover, acquired multi-drug resistance may play a primary role in the mdr-tb epidemic in beijing, china. consequently, this highlights the importance of an earlier start to effective and supervised treatment in order to reduce the burden of retreatment. keywords tuberculosisdrug-resistantmolecular characteristicshttp://dx.doi.org/ /501100001809national natural science foundation of china812718898145005781541062jiao wei-wei shen a-dong infectious diseases special project, minister of china2012zx10003002009huang hai-rong issue-copyright-statement© the author 2016 