초치료 폐결핵 환자들에 있어서 초회 약제내성률

공재환 ( Jae Hwan Kong ),이상석 ( Sang Seok Lee ),강하얀 ( Ha Yan Kang ),박재석 ( Jae Seuk Park ) 대한결핵 및 호흡기학회 2008 Tuberculosis and Respiratory Diseases Vol.64 No.2

연구배경: 결핵의 치료력이 없는 결핵환자에서 발생하는 초회 약제내성은 결핵관리에 있어서 심각한 문제이다. 그러나 우리나라, 특히 민간의료기관에서 치료받는 폐결핵환자들의 초회 약제내성률에 대해서 잘 알려져 있지 않다. 본 연구에서는 천안지방의 한 3차병원에서 폐결핵환자들의 초회 약제내성률과 약제내성의 위험요소에 대해서 알아보았다. 방법: 2005년 9월부터 2007년 9월까지 단국대학교병원에서 객담 결핵균 배양검사 양성인 초치료 폐결핵환자 모두에 대해서 일차약과 이차약에 대한 약제감수성 검사를 시행하고 초회 약제내성의 양상과 함께 약제내성의 위험요소을 분석하였다. 또한 약제감수성 검사 결과가 치료 처방에 미치는 영향을 분석하였다. 결과: 총 156명의 초치료 폐결핵 환자에 대해서 약제 감수성 검사를 시행하였는데 한 가지 이상의 약제에 내성을 보인 환자는 21명(15.6%)이었으며 이소니아지드와 리팜핀에 동시 내성을 보이는 다제내성 환자는 1명(0.6%)이었다. 임상소견 중 초회 약제내성을 예측할 수 있는 독립적인 위험요소는 없었다. 약제감수성 검사 결과에 의해 15명(9.6%)의 환자에서 치료처방의 변경이 있었다. 결론: 폐결핵에서 초회 약제내성은 흔히 관찰되며 초 치료 폐결핵환자에서 약제감수성 검사는 환자치료에 도움이 된다. Background: Drug resistant tuberculosis (TB) in patients who have not received previous TB treatment (initial drug resistance) is a serious problem for the control of TB. However, prevalence of initial drug resistance among pulmonary TB patients has not been well characterized in Korea, especially in the private sector. We assessed the prevalence of initial drug resistance and evaluated the risk factors for drug resistance in pulmonary TB patients, at a regional tertiary hospital in Cheonan. Methods: We performed a drug susceptibility test for both first and second line anti-TB drugs in all culture-confirmed pulmonary TB patients who had not received a previous TB treatment at Dankook University Hospital from September 2005 to September 2007. In addition, we evaluated the initial drug resistance pattern and clinical characteristics of patients to evaluate the risk factors for initial drug resistance. We also assessed the influence of the drug susceptibility test results on the treatment regimen. Results: Of the total 156 cases where the drug susceptibility test was performed, resistance to at least one anti-TB drug was found in 21 cases (15.6%) and multidrug resistance, where TB was resistant to at least isoniazid and rifampin, was found in one case (0.6%). Multivariate logistic regression showed no clinical characteristics were independently associated with initial drug resistance. Of the total 156 patients who underwent the drug susceptibility test, the treatment regimen was changed for 15 patients (9.6%) according to the results of the drug susceptibility test. Conclusion: Initial drug resistance is common and the drug susceptibility test is informative for pulmonary TB patients who have not received previous TB treatment. (Tuberc Respir Dis 2008;64:95-101)

호흡기질환 환자에서 분리한 Mycoplasma pneumoniae의 Quinolone계와 Macrolide계 항생물질에 대한 다제 저항성

전성곤,장명웅,Jun, Sung-Gon,Chang, Myung-Woong 한국생명과학회 2007 생명과학회지 Vol.17 No.3

호흡기질환 환자의 상기도 도말물로 부터 분리 동정된 M. pneumoniae 116균주의 moxifloxacin, levofloxacin, sparfloxacin, ofloxacin, ciprofloxacin, clarithromycin minocycline, erythromycin, josamycin, and tetracycline에 대한 감수성 검사를 실시하였다. 각 항생물질에 대한 저항성 균주의 기준은 $MIC{\pm}1.0$ ${\mu}g/ml$ 로 하였으며, 초기 MIC와 최종 MIC를 구분하여 다제 저항성 균주의 분포를 분석하였다. 초기 MIC의 결과로 분리된 균주의 단일 약제에 대한 저항성은 ciprofloxacin이 79.3%, ofloxacin이 53.5%, clarithromycin이 10.3%, erythromycin이 7.8%이었으며, 2가지 약제에 저항성은 ofloxacin과 ciprofloxacin이 42.2%, ciprofloracin과 clarithromycin이 9.5%이었으며, 3가지 약제에 저항성은 erythromycin, ofloxacin과 ciprofloxacin이 6.9%, ofloxacin, ciprofloxacin과 clarithromycin이 6.0%이었다. 최종 MIC의 결과로 분리균의 단일 약제에 대한 저항성은 tetracycline, ciprofloxacin, ofloxacin이 각각 91.4%, minocycline이 89.7%, erythromycin이 68.1%, josamycin이 52.6%, clarithromycin이 28.5%, sparfloxacin이 11.2%이었으며, 2가지 약제에 저항성인 균의 분포는 $20.7{\sim}91.4%$, 3가지약제에 저항성인 규의 분포는 &28.5{\sim}89.7%$, 4가지 약제에 저항성인 균의 분포는 2.6%, 5가지 약제에 저항성인 균은 $2.6{\sim}21.6%$, 6가지 약제에 저항성인 균은 $0.9{\sim}24.1%$이었으며, 7가지 약제에 저항성인 균은 $0.9{\sim}2.6%$이었으며, 8종류 약제에 저항성인 균도 1.7%있었다. 이상의 결과로 국내에서 분리된 M. pneumoniae 균주는 적게는 1-4 종류의 항생제에, 많게는 5-8 종류의 항생제에 저항성인 균주가 있으므로 마이코플라스마폐렴 환자를 치료할때는 macrolide계나 quinolone계의 항생제 선택에 신중을 기하여야 하며, 가급적이면 항생제 감수성 검사를 실시하여 적절한 항생제를 선택함으로써 저항성균의 출현율을 줄일 수 있고 효율적인 치료도 할 수 있도록 하여야 할 것으로 생각된다. Antimicrobial susceptibility test of the 116 strains of Mycoplasma pneumoniae isolates were performed by a broth micro-dilution method against to moxifloxacin, levofloxacin, sparfloxacin, ofloxacin, ciprofloxacin, clarithromycin minocycline, erythromycin, josamycin, and tetracycline. The initial-minimum inhibitory concentration (I-MIC) was evaluated as the lowest concentration of antimicrobial agents that prevented a color change in the medium at that time when the drug-free growth control, about 7 days after incubation, and the final-minimum inhibitory concentration (F-MIC) was defined a color change about 14 days after incubation. The evaluation to the drug-resistant M. pneumoniae isolates were determined the $MIC{\pm}1.0$ ${\mu}g/ml$ of each antimicrobial agent. According to the I-MIC, single drug-resistant M. pneumoniae strains to ciprofloxacin, ofloxacin, clarithromycin and erythromycin were 79.3, 53.5, 10.3, and 7.8%, respectively. Two kinds of drug-resistant M. pneumoniae strains to ofloxacin and ciprofloxacin, or ciprofloxacin and clarithromycin were 42.2 and 9.5%. Three kinds of drug-resistant M. pneumoniae strains to erythromycin, ofloxacin, and ciprofloxacin, or ofloxacin, ciprofloxacin and clarithromycin were 6.9 and 6.0% . According to the F-MIC, single drug-resistant M. pneumoniae strains to tetracycline, ciprofloxacin, ofloxacin, minocycline,erythromycin, josamycin, clarithromycin and sparfloxacin were 91.4, 91.4, 91.4, 89.7, 68.1, 52.6, 28.5, and 11.2%, respectively. The incidence of two kinds of drug-resistant M. pneumoniae strains were from 20.7% to 91.4%, three kinds of drug-resistant M. pneumoniae strains were from 28.5% to 89.7%, four kinds of drug-resistant M. pneumoniae strains were 2.6%, five kinds of drug-resistant M. pneumoniae were from 2.6% to 21.6%, six kinds of drug-resistant M. pneumoniae strains were from 0.9% to 24.1%, seven kinds of drug-resistant M. pneumoniae strains were from 0.9% to 2.6%, and eight kinds of drug-resistant M. pneumoniae strains were 1.7%. These results suggest that sparfloxacin, moxifloxacin and levofloxacin might be promising antimicrobial agents for the treatment of M. pneumoniae infection in Korea. However, most strains of M. pneumoniae isolates were single or multi-resistance pattern to the other tested antimicrobial agents. Therefore, tetracycline, minocycline, erythromycin, clarithromycin, and second-generation quinolones are more carefully used to patients with M. pneumoniae infection in Korea.

CDRgator: An Integrative Navigator of Cancer Drug Resistance Gene Signatures

장수경,윤병하,강승민,윤여가,김선영,김완규 한국분자세포생물학회 2019 Molecules and cells Vol.42 No.3

Understanding the mechanisms of cancer drug resistance is a critical challenge in cancer therapy. For many cancer drugs, various resistance mechanisms have been identified such as target alteration, alternative signaling pathways, epithelial?mesenchymal transition, and epigenetic modulation. Resistance may arise via multiple mechanisms even for a single drug, making it necessary to investigate multiple independent models for comprehensive understanding and therapeutic application. In particular, we hypothesize that different resistance processes result in distinct gene expression changes. Here, we present a web-based database, CDRgator (Cancer Drug Resistance navigator) for comparative analysis of gene expression signatures of cancer drug resistance. Resistance signatures were extracted from two different types of datasets. First, resistance signatures were extracted from transcriptomic profiles of cancer cells or patient samples and their resistanceinduced counterparts for >30 cancer drugs. Second, drug resistance group signatures were also extracted from two largescale drug sensitivity datasets representing ~1,000 cancer cell lines. All the datasets are available for download, and are conveniently accessible based on drug class and cancer type, along with analytic features such as clustering analysis, multidimensional scaling, and pathway analysis. CDRgator allows meta-analysis of independent resistance models for more comprehensive understanding of drug-resistance mechanisms that is difficult to accomplish with individual datasets alone (database URL: http://cdrgator.ewha.ac.kr).

CDRgator: An Integrative Navigator of Cancer Drug Resistance Gene Signatures

Jang, Su-Kyeong,Yoon, Byung-Ha,Kang, Seung Min,Yoon, Yeo-Gha,Kim, Seon-Young,Kim, Wankyu Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.3

Understanding the mechanisms of cancer drug resistance is a critical challenge in cancer therapy. For many cancer drugs, various resistance mechanisms have been identified such as target alteration, alternative signaling pathways, epithelial-mesenchymal transition, and epigenetic modulation. Resistance may arise via multiple mechanisms even for a single drug, making it necessary to investigate multiple independent models for comprehensive understanding and therapeutic application. In particular, we hypothesize that different resistance processes result in distinct gene expression changes. Here, we present a web-based database, CDRgator (Cancer Drug Resistance navigator) for comparative analysis of gene expression signatures of cancer drug resistance. Resistance signatures were extracted from two different types of datasets. First, resistance signatures were extracted from transcriptomic profiles of cancer cells or patient samples and their resistance-induced counterparts for >30 cancer drugs. Second, drug resistance group signatures were also extracted from two large-scale drug sensitivity datasets representing ~1,000 cancer cell lines. All the datasets are available for download, and are conveniently accessible based on drug class and cancer type, along with analytic features such as clustering analysis, multidimensional scaling, and pathway analysis. CDRgator allows meta-analysis of independent resistance models for more comprehensive understanding of drug-resistance mechanisms that is difficult to accomplish with individual datasets alone (database URL: http://cdrgator.ewha.ac.kr).

Nano carriers that enable co-delivery of chemotherapy and RNAi agents for treatment of drug-resistant cancers

Tsouris, V.,Joo, M.K.,Kim, S.H.,Kwon, I.C.,Won, Y.Y. Pergamon Press ; Elsevier Science Ltd 2014 BIOTECHNOLOGY ADVANCES Vol.32 No.5

Tumor cells exhibit drug resistant phenotypes that decrease the efficacy of chemotherapeutic treatments. The drug resistance has a genetic basis that is caused by an abnormal gene expression. There are several types of drug resistance: efflux pumps reducing the cellular concentration of the drug, alterations in membrane lipids that reduce cellular uptake, increased or altered drug targets, metabolic alteration of the drug, inhibition of apoptosis, repair of the damaged DNA, and alteration of the cell cycle checkpoints (Gottesman et al., 2002; Holohan et al., 2013). siRNA is used to silence the drug resistant phenotype and prevent this drug resistance response. Of the listed types of drug resistance, pump-type resistance (e.g., high expression of ATP-binding cassette transporter proteins such as P-glycoproteins (Pgp; also known as multi-drug resistance protein 1 or MDR1, encoded by the ATP-Binding Cassette Sub-Family B Member 1 (ABCB1) gene)) and apoptosis inhibition (e.g., expression of anti-apoptotic proteins such as Bcl-2) are the most frequently targeted for gene silencing. The co-delivery of siRNA and chemotherapeutic drugs has a synergistic effect, but many of the current projects do not control the drug release from the nanocarrier. This means that the drug payload is released before the drug resistance proteins have degraded and the drug resistance phenotype has been silenced. Current research focuses on cross-linking the carrier's polymers to prevent premature drug release, but these carriers still rely on environmental cues to release the drug payload, and the drug may be released too early. In this review, we studied the release kinetics of siRNA and chemotherapeutic drugs from a broad range of carriers. We also give examples of carriers used to co-deliver siRNA and drugs to drug-resistant tumor cells, and we examine how modifications to the carrier affect the delivery. Lastly, we give our recommendations for the future directions of the co-delivery of siRNA and chemotherapeutic drug treatments.

HBV : The Impact of rtA181T Mutation in Hepatitis B Virus Polymerase on Drug Resistance Differs by the Overlapping Mutations in Surface Gene

( Sung Hyun Ahn ),( Eun Sook Park ),( Yong Kwang Park ),( Jeong Han Kim ),( Doo Hyun Kim ),( Keo Heun Lim ),( Won Hyeok Choe ),( Soon Young Ko ),( So Young Kwon ),( Kyun Hwan Kim ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Emergence of drug-resistant hepatitis B virus (HBV) against the nucleos(t)ide analogues (NA) is a major problem for antiviral treatment in chronic hepatitis B patients. In this study, we analyzed the evolution of drug-resistant mutations and characterized the effects of rtA181T and rtI233V mutations on viral replication and drug-resistance. Methods: We performed a clonal analysis of the HBV polymerase gene from serum samples during viral breakthrough treated with lamivudine (LMV) and adefovir (ADV). Representative mutants were analyzed for in vitro drug susceptibility by southern blot. We constructed a series of mutant clones and determined the ability of replication and drug resistance. Results: Conserved mutations in rt204, rt181, rt236, and rt233 were identified during the viral breakthrough. In vitro study revealed that the effect of rtA181T mutation on viral replication and drug resistance is dependent on the mutations in overlapping surface gene. The rtA181T mutant harboring surface stop (rtA181T/sW172*) showed a decrease in viral replication and increase in drug resistance compared to the rtA181T mutant harboring surface mutation (rtA181T/sW172S). Moreover, the rtA181T/sW172* mutant exhibited a secretion defect of viral particles. The rtI233V mutation which emerged during ADV therapy reduced the viral replication and conferred resistance to ADV. However, the rtI233V mutation did not affect the viral replication and drug resistance of rtA181T/sW172* mutant. Conclusions: Our data suggest that the impact of rtA181T mutation on drug resistance is different according to the mutation status in corresponding surface gene. The rtI233V mutation affects the replication ability and drug resistance. Our observation suggests the need of genotypic analysis of overlapping surface gene to manage the antiviral drug resistance if clinical isolates harbor rtA181T mutation.

Drug - Resistant Pulmonary Tuberculosis in a Tertiary Referral Hospital in Korea

(Sun Young Kim),(Seong Su Jeong),(Keun Wha Kim),(Kyoung Sang Shin),(Sang Gee Park),(Ae Kyoung Kim),(Hai Jeong Cho),(Ju Ock Kim) 대한내과학회 1999 The Korean Journal of Internal Medicine Vol.14 No.1

N/A Objectives : To estimate the resistance rate and to correlate the clinical characteristics of resistant tuberculosis with the patients of pulmonary tuberculosis who were referred to the university hospital. Methods : We prospectively performed sensitivity tests for all patients who were diagnosed as active tuberculosis by sputum smear or sputum culture from January, 1995 to June, 1996. Patients profile, previous treatment history, patterns of drug resistance, initial chest films and other clinical findings were analysed. Results : Overall, 24(26.0%) of the 92 patients had resistance to at least one drug and 8(8.6%) had resistance to isoniazid(INH) and rifampin(RFP). Among the 66 patients without previous tuberculosis therapy, 11(16.6%) were drug-resistant and 2(3.0%) were multi-drug resistant. Among the 26 patients with previous therapy , 13(50.0%) were drug-resistant and 6(23.0%) were multi-drug resistant. For all 92, resistance to INH was most common(19.5%), followed by RFP(9.7%) and ethambutol(9.7%). Drug resistance was significantly high in previously treated patients and in cavity-positive patients. Treatment failure was also high in previously treated patients with resistant tuberculosis. In patients with primary resistance, treatment failure was not observed. Conclusion : Sensitivity tests are strongly recommended in all culture positive patients with previous therapy but, in patients with primary resistance, sensitivity tests are not required. Proper combination chemotherapy should be given under careful surveillance.

Drug Resistance Patterns of Multidrug- and Extensively Drug-Resistant Tuberculosis in Korea: Amplification of Resistance to Oral Second-line Drugs

김창기,So Youn Shin,김희진,이경원 대한진단검사의학회 2017 Annals of Laboratory Medicine Vol.37 No.4

We aimed to analyze the drug resistance patterns of multidrug-resistant and extensively drug-resistant tuberculosis (TB) and the difference of drug resistance among various settings for health care in Korea. The data of drug susceptibility testing in 2009 was analyzed in order to secure sufficient number of patients from various settings in Korea. Patients were categorized by types of institutions into four groups, which comprised new and previously treated patients from public health care centers (PHC), the private sector, and Double-barred Cross clinics (DBC). The resistance rates to first-line drugs were uniformly high in every group. While the resistance rates to second-line drugs were not as high as first-line drugs, there was a pattern that drug resistance rates were lowest for PHC and highest for DBC. The differences of the resistance rates were more prominent for oral second-line drugs. Our findings implied that drug resistance to oral second-line drugs was significantly amplified during multidrug-resistant-TB treatment in Korea. Therefore, an individualized approach is recommended for treating drug-resistant-TB based on susceptibility testing results to prevent acquisition or amplification of drug resistance.

AttDRP: 주의집중 메커니즘 기반의 항암제 약물 반응성 예측 모델

최종환,서상민,박상현 한국정보과학회 2021 정보과학회논문지 Vol.48 No.6

Resistance to anti-cancer drugs makes chemotherapy ineffective for cancer patients. Drug resistance is caused by genetic alterations in cancer cells. Many studies have investigated drug responses of diverse cancer cell lines to various anti-cancer drugs to understand drug response mechanisms. Existing studies have proposed machine learning models for drug response prediction to find effective anti-cancer drugs. However, currently there are no models to learn the relationship between anticancer drugs and genes to improve the prediction accuracy. In this paper, we proposed a predictive model AttDRP that could identify important genes associated with anti-cancer drugs and predict drug responses based on identified genes. AttDRP exhibited better predictive accuracy than existing models and we found that the attention scores of AttDRP could be effective tools to analyze molecular structures of anticancer drugs. We hope that our proposed method would contribute to the development of precision medicine for effective chemotherapy. Resistance to anti-cancer drugs makes chemotherapy ineffective for cancer patients. Drug resistance is caused by genetic alterations in cancer cells. Many studies have investigated drug responses of diverse cancer cell lines to various anti-cancer drugs to understand drug response mechanisms. Existing studies have proposed machine learning models for drug response prediction to find effective anti-cancer drugs. However, currently there are no models to learn the relationship between anticancer drugs and genes to improve the prediction accuracy. In this paper, we proposed a predictive model AttDRP that could identify important genes associated with anti-cancer drugs and predict drug responses based on identified genes. AttDRP exhibited better predictive accuracy than existing models and we found that the attention scores of AttDRP could be effective tools to analyze molecular structures of anticancer drugs. 암환자 중 일부는 항암제에 대한 약물 저항성을 보여 약물을 이용한 항암치료를 어렵게 만든다. 약물 저항성은 암세포의 유전체 이상에 기인하는 것으로 밝혀져, 암세포주 및 항암제에 대한 약물 반응성 데이터를 분석하는 연구가 활발히 이루어지고 있다. 기존 연구들은 기계학습을 이용하여 약물 민감성 또는 저항성을 예측하는 모델을 여럿 제안하였으나, 항암제와 유전자의 관계를 학습하는 모델의 부재로 인하여 예측 정확도 향상을 위한 여지가 남아있었다. 본 논문에서는 주의집중 메커니즘을 활용하여 항암제 관련 유전자들을 식별하고, 그러한 유전자들 정보에 기반하여 항암제 반응성을 예측하는 AttDRP를 제안한다. 제안하는 모델은 CCLE 데이터에서 기존 모델들보다 높은 예측 정확도를 보여주었고, AttDRP이 학습한 주의집중 스코어가 항암제의 분자구조 분석에 효과적으로 활용될 수 있음을 확인하였다.

Molecular drug resistance profiles of <i>Mycobacterium tuberculosis</i> from sputum specimens using ion semiconductor sequencing

Park, Joonhong,Jang, Woori,Kim, Myungshin,Kim, Yonggoo,Shin, So Youn,Park, Kuhn,Kim, Myung Sook,Shin, Soyoung Elsevier Biomedical 2018 Journal of microbiological methods Vol.145 No.-

<P><B>Abstract</B></P> <P>The increasing burden of multidrug resistant (MDR)-TB, defined by resistance to rifampin (RFP) and isoniazid (INH), and extensively drug resistant-TB, defined by MDR-TB with additional resistance to fluoroquinolones (FQs) and more than one second-line injectable drug, is a serious impediment to global TB control. We evaluated the feasibility of full-length gene analysis including <I>inhA</I>, <I>katG</I>, <I>rpoB</I>, <I>pncA</I>, <I>rpsL embB</I>, <I>eis</I>, and <I>gyrA</I> using a semiconductor NGS with the Ion AmpliSeq TB panel to directly analyse 34 sputum specimens confirmed by phenotypic DST: INH, RFP, ethambutol (EMB), pyrazinamide (PZA), amikacin, kanamycin, streptomycin (SM), FQs including ofloxacin, moxifloxacin, and levofloxacin. The molecular drug resistance profiles showed “very good” and “substantial” strength of agreement for the phenotypic DST results of RFP and EMB, PZA, SM, FQs resistance with specificities of 96%, and 88%, 97%, 100% and sensitivities of 100%, and 88%, 60%, 67%, respectively. The strength of agreement for the detection of resistance to INH was “substantial”, compared between <I>katG</I> mutation and phenotypic INH only. Ion semiconductor NGS could make possible detection of several uncommon or novel amino acid changes in the full coding regions of these eight genes. However, molecular drug resistant profile should be complemented and validated by subsequent phenotypic DST studies at the same time.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Molecular drug susceptibility of <I>M. tuberculosis</I> from sputum is proposed using NGS. </LI> <LI> The agreement between Molecular and phenotypic drug susceptibility is “substantial”. </LI> <LI> Molecular drug resistance profiles can be used as predictors of phenotype DST. </LI> <LI> Molecular drug resistant profile should be complemented with phenotypic DST. </LI> </UL> </P>