| Objective 1.To investigate and analyze the drug resistance and change trend of Mycobacterium tuberculosis patients in a designated tuberculosis hospital in recent years.2.To study the characteristics of drug resistance genes of Mycobacterium tuberculosis in initialy treated pulmonary tuberculosis patients and the relationship between gene mutation and drug resistance.3.To study the efficacy and pharmacoeconomic evaluation of four groups of drug regimens,including fixed-dose compound preparation,for initialy treated pulmonary tuberculosis patients.Methods 1.During the period of drug resistance surveillance in 10 districts and counties(cities)of Ningbo from 2012 to 2014 and from 2017 to 2018,3994 sputum specimens of initialy treated tuberculosis patients were collected from designated hospitals,751 cases in 2012-2014 and 3243 cases in 2017-2018.After bacteriological examination and drug susceptibility test of tuberculosis bacilli in the tuberculosis laboratory of Ningbo,tuberculosis mycobacterium was analyzed.Drug resistance and change trend in patients with bacterial infection.2.From January 2017 to December 2018,2455 cases of Mycobacterium tuberculosis preserved in the city tuberculosis laboratory,108 cases of drug-resistant Mycobacterium tuberculosis and 10 cases of fully sensitive strains were isolated,cultured and tested for drug susceptibility.The DNA of the strains was extracted,the katG,inhA,rpoB gene sequences of the strains were amplified,and the gene characteristics and mutations were analyzed to correlate with drug resistance.3.Fixed-dose compound preparation(2-ethylpyrazine rifampicin/4-rifam--picin tablet),quadruple anti-tuberculosis bulk drug(2HRZE/4HR),mixed drug group 1(2-ethylpyrazine rifampicin/4HR)and mixed drug group 2(2HRZE/4-rifampicin tablet)were collected from January 2017 to December 2018.The sputum negative conversion rate,sputum culture negative conversion rate,lesion absorption rate,adverse reaction rate and drug resistance rate of the two groups were compared,and the pharmacoeconomic evaluation of the four groups was made.Results 1.During the period of 2012-2014,590 cases of Mycobacterium tuberculosis were detected in 751 sputum samples,the detection rate was 78.56%.During the period of 2017-2018,2455 cases of Mycobacterium tuberculosis were detected in 3243 sputum samples,the detection rate was 75.70%.During the past five years,the total drug resistance rates to INH and RFP were 6.58%,8.43%,6.62%,4.06% and 4.39%,respectively;the single drug resistance rates to INH or RFP were 5.26%,6.63%,5.15%,3.26% and 2.70%,and the multi-drug resistance rates were 1.32%,1.81%,1.47%,1.15% and 1.69%,respectively.2.Among 2455 clinical isolates of Mycobacterium tuberculosis,108 cases were found to be resistant to Mycobacterium tuberculosis,including 75 cases of single drug resistance(inh51 cases,rfp24 cases),the single drug resistance rate was 3.05%,33 cases of multi drug resistance,the multi drug resistance rate was 1.34%.Among the 33 drug-resistant strains,27 of them had mutations of rpoB and katG gene,the mutation rate was 81.82%(27/33),5 of them had mutations of inhA gene,the mutation rate was 15.15%(5/33),the mutation rate of rpoB gene 450(ser450leu)was 51.52%(17/33),the mutation rate of katG gene 315(ser315thr)was 87.88%(29/33),the mutation rate of arg463 leu was 78.79%(26/33).Among the 24 rifampicin resistant strains,17(70.83%)(17/24)had mutations in rpoB gene,mainly at the 446 locus(lys446 lysarg),which was 45.83%(11/24).Among 51 isoniazid resistant strains,45 cases had katG gene missense mutation,the mutation rate was 88.23%(45/51),315(ser315thr)mutation rate was 72.55%(37/51),463(arg463leu)mutation rate was 64.71%(33/51),22 cases had inhA gene missense mutation,the mutation rate was 43.14%(22/51),145(val145valgly)mutation rate was 27.45%(14/51),5 cases had rpoB gene missense.The mutation rate was 9.80%(5/51).In addition,11 of 108 drug-resistant strains had combined mutations of rpoB,katG and InhA genes,and missense mutations occurred at most sites,the mutation rate was 10.18%(11/108).3.Fixed-dose compound preparation group,quadruple bulk drug group,mixed drug group 1 and mixed drug group 2 had similar therapeutic effects in sputum smear negative conversion rate,sputum culture negative conversion rate,focus absorption rate and cavity closure rate,and the drug resistance rate and adverse reactions rate of quadruple bulk drug group were the highest.Cost-effectiveness acceptance curve shows that the willingness-to-pay value and cost-effectiveness probability of fixed-dose compound preparation group show a decreasing curve compared with quadruple bulk charge group.When the minimum willingness-to-pay value is 8000 yuan,the maximum cost-effectiveness can be achieved.Conclusion 1.Over the past five years,the single drug resistance rate of INH or RFP,the first-line anti-tuberculosis drug,fluctuated relatively large,and the multi-drug resistance rate(both INH and RFP resistance)was controlled at a low level,which was relatively stable.The overall drug resistance showed a small fluctuating downward trend.2.The mutations of rpoB,katG and inhA genes are closely related to drug resistance in newly treated pulmonary tuberculosis patients.The mutations of these three genes at 450(ser450leu),315(ser315thr),446(lys446lysarg),463(arg463leu),145(val145valgly)loci are one of the important mechanisms of the drug resistance of Mycobacterium tubercu losis to isoniazid and rifampicin.Among them,the main mutation sites and mutation frequency of rpoB and InhA genes have obvious regional differences.3.Four groups of drug regimens have a definite effect on the treatment of newly-treated tuberculosis patients.The drug resistance rate and adverse reaction rate of the fixed-dose combination regimen(2-ethylpyrazine rifampicin/4-rifampicin tablets)are lower,the costeffectiveness ratio is the smallest,and the maximum cost-effectiveness probability can be obtained at a lower willingness to pay value.It is a relatively economical and effective optimization scheme. |
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