대한내과학회지 : 제 77 권제 2 호 2009 특집 (Special Review) - 신종감염병의최신지견 내성결핵균의실태및치료 서울대학교의과대학내과학교실, 폐연구소 임재준 Current status of drug-resistant tuberculosis and its treatment Jae-Joon Yim, M.D. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul, Korea Drug-resistant tuberculosis (TB), especially multidrug-resistant (MDR)-TB and extensively drug resistant (XDR)-TB, poses a serious threat to global health because it requires treatment for a long duration and frequent hospitalization, and results in a considerable number of mortalities. In South Korea, MDR is observed in 2.7% of newly diagnosed TB cases and in 14% of re-treatment cases. In addition, 5~20% of MDR-TB could be categorized as XDR-TB. Treatment regimen for MDR or XDR-TB should include 4~5 drugs susceptible to isolated tuberculous bacilli and should be maintained at least 18 months after culture conversion. Pertinent combination of anti-tb drugs and solid compliance are the basis of successful treatment for MDR and XDR-TB patients. (Korean J Med 77:152-156, 2009) Key Words: Tuberculosis; Drug resistance; Treatment 결핵의현황결핵을박멸하려는국제사회의지속적인노력에도불구하고결핵은여전히인류보건에큰도전이다. 국제보건기구의통계에따르면, 지난 2005년에세계적으로약 880만명의결핵환자가발생했으며, 160만명의환자가결핵으로사망했다 1). 전체적으로결핵의유병률과결핵으로인한사망자수는다소감소하고있지만아프리카, 지중해동부지역, 동남아시아에서결핵신환자가급격한증가로인해, 결핵신환자의수는최근도리어증가하고있다 1). 우리나라의결핵문제는지난수십년간의급속한산업발전에도불구하고, 아직도매우심각하다. 최근발표된자료에의하면, 지난 2005년에우리나라에서새로발생한결핵환자가모두 46,969명이나되어, 결핵발생률이 97.3/100,000 명에이른다 2). 미국의연간결핵발생률이 5/100,000명, 일본의연간결핵발생률이 28/100,000명에지나지않는다는사실과비교해보면, 우리나라의결핵문제가얼마나심각한지알수있다 1). 결핵균에대한내성은한가지약제에대한내성부터사용가능한모든약제에대한내성까지다양하지만, 임상적으로크게문제되는내성결핵은다제내성결핵 (Multidrug-resistant tuberculosis, MDR-TB) 및광범위내성결핵 (Extensively drug-resistant tuberculosis, XDR-TB) 이다. 다제내성결핵 1. 정의및현황결핵치료의근간이되는가장중요한두가지약제인 - 152 -
- Jae-Joon Yim. Current status of drug-resistant tuberculosis and its treatment - Table 1. Proportion of anti-tuberculous drug resistance among Korean patients, 1994~2004 5 New patients Patients with prior treatment Any resistance MDR Any resistance MDR 1994 11.3% 1.6% 54.0% 27.5% 1999 10.9% 2.2% 22.3% 7.1% 2003 12.8% 2.4% 28.9% 13.0% 2004 12.8% 2.7% 27.7% 14.0% isoniazid 와 rifampicin에동시에내성이있는결핵균에의해발생한감염증을 다제내성결핵 이라고하는데, 이는 2년이상의치료기간이요구된다는점, 치료비용이많이든다는점, 장기간의값비싼치료에도불구하고다수의사망자와치료실패자가발생한다는점 3,4), 더구나공기를통해감염되는전염병이라는점등에서인류보건에심각한위협이다. 우리나라의경우지난 2004년에새로발생하는결핵의 2.7% 와재발한결핵의 14% 가다제내성결핵이었는데 5), 다제내성결핵환자수는지난 2000년에 3,708명, 2001년에 2,830 명, 2002년에 4,245명으로도리어증가하는추세이다 6). 2. 다제내성결핵의치료 1) 치료원칙다제내성결핵환자에대한약제의조합을구성할때염두에두어야할원칙은아래와같다 7,8). 환자의병력및약복용력을면밀히검토하여약제를선택할것 과거에사용하지않았던약제를최소 3~4가지는반드시포함시킬것 우선적으로아래의약제를고려할것 - Aminoglycoside (amikacin, streptomycin, kanamycin) 혹은 capreomycin - Quinolones (Moxifloxacin, gatifloxacin, levofloxcin, ciprofloxacin) - Emthambutol 혹은 pyrazinamide 중감수성이있는것 약제의총숫자가최소네가지, 바람직하게는다섯가지가되도록할것. 사용중인약제가효과적이지않은경우절대로다른약제를한가지씩추가하지말것. Table 2. Practical tips to build a treatment regimen for MDR-TB 9 Step Instruction Drugs 1 Use any available firstline oral agents Pyrazinamide, Ethambutol 2 Plus one of injectable agents 3 Plus one of fluoroquinolones 4 Pick one or more of 2 nd line oral bacteriostatic agents 5 Consider drugs of unclear role in MDR-TB treatment Kanamycin, amikacin, streptomycin, capreomycin Levofloxacin, moxifloxacin, ofloxacin p-aminosalicylic acid, cycloserine (or terizadone), ethionamide (or prothionamide) Amoxicillin/clavulanate, clarithromycin, high-dose isoniazid, clofazimine, linezolid, thioacetazone * * Contraindicated for HIV-infected individuals given the serious risk of life-threatening adverse reaction. 2) 약제선정의실제최근세계보건기구에서제시한다제내성결핵환자약제선정의실제는아래와같다. 1단계부터시작해서다섯가지약제가선정될때까지다음단계로진행하면된다 ( 표 2). 얼마나오랫동안치료해야하는지에대한명확한근거는아직없지만, 배양음전후최소 18개월, 병변이범위가넓거나폐침윤이심했던경우는 24개월정도치료를지속하는것이추천된다. 3) 약제선택할때주의사항 1 교차내성의존재다제내성결핵환자를위한약제를선택할때약제간의교차내성이존재할가능성을반드시염두에두어야한다. 일반적으로 capromycin과 aminoglycoside (kanamycin, amikacin, viomycin) 간에교차내성이존재하며 10,11), ofloxacin, ciprofloxacin 등의 quinolone 사이에도교차내성이흔하다 12). 물론 rifampicin, rifabutin, rifapentine 사이에도교차내성이관찰된다 12. 2 주사약제의선택다제내성결핵환자들에서사용되는주사약제들은 amikacin, streptomycin, kanamycin, capreomycin 등이있는데결핵균에대한실험실내활성은 amikacin이가장우수하다 13). 그러나 amikacin은근육내로주사하기힘들다는점, amikacin - 153 -
- 대한내과학회지 : 제 77 권제 2 호통권제 588 호 2009 - Table 3. The prognoses of XDR-TB from various cohort studies. Authors Year of study Site of Study Number of XDR-TB patients HIV status Outcomes Gandhi NR et al. 30) 2006 South Africa 53 Positive (44 52 patients died. patients tested) Kim HR et al. 29) 2007 South Korea 43 Negative Treatment failure in 19 patients (44.2%) Migliori GB et al. 32,33) 2007 Estonia, Germany, Italy and the Russian Federation 64 Positive in 5% of patients Treatment failure in 26 (40.6%) patients Jeon CY et al. 28) 2007 South Korea 26 Negative Higher rate of culture-positive at 6 months (Risk ratio, 13; 95% CI, 5.1~53) Banerjee R et al. 34) 2008 USA 18 Negative 5 (29.4%) out of 17 died. Kwon YS et al. 27) 2008 South Korea 27 Negative Favorable outcomes in 18 (67%) patients Blaas SH et al. 35) 2008 Germany 4 Negative 2 cured, one died, one on treatment Mitnick CD et al. 36) 2008 Peru 48 Negative Cured or treatment completed in 29 (60.4%) patients Keshavjee S et al. 37) 2008 Russia 29 Negative Treatment failure in 31% of patients Kim DH et al. 2008 South Korea 75 Negative Higher rate of TB-related mortality (Hazard ratio, 4.45; 95% CI, 2.48~8.00) 을사용하는것이실제로양호한예후를가져오는지에대한근거가없다는점에서일반적으로근육내주사로편리하게사용할수있는 streptomycin, kanamycin 등이사용된다. 3 Quinolone의선택일반적으로모든 quinolone 계통의약제가항결핵효과를가지고있지만그강도는약간씩차이가있는데, 실험실내에서는 moxifloxacin과 gatifloxacin의항결핵균효과가가장뛰어난것으로보고되고있다 11). 실험실내최소억제농도의차이가결핵에이환된폐조직에서도유지되는지혹은환자의치료결과에도영향을주는지는분명치않지만, moxifloxacin 및 levofloxacin이가장흔히사용된다. 5) 수술적치료지난 1991년 Pomerantz 등에의해다제내성결핵환자의치료에서결핵병변의성공적인수술적제거가보고된이래 14), 내과적치료로호전되지않는환자들에게수술적치료가시행되는빈도가꾸준히증가되어왔다. 비록잘고안된무작위배정대조군설정임상시험은없으나여러코호트연 구들을통해객담배양음전을기준으로한수술적치료의성공률이약 70~80% 정도로보고되어 15-24), 현재새로운 quinolone 제재의사용과더불어병변의수술적제거가다제내성결핵환자의예후를향상시킬수있는방법중의한가지로받아들여지고있다. 3. 광범위내성결핵 1) 정의및현황광범위내성결핵은다제내성결핵중특히내성이심한결핵을따로구분하는용어인데, isoniazid 와 rifampicin에대한내성에더하여퀴놀론계약제중하나이상그리고결핵치료에주로사용되는주사제인 capreomycin, kanamycin, amikacin 중하나이상에내성이있는결핵을뜻한다 25). 우리나라의전체다제내성결핵환자중광범위내성결핵이차지하는비율은아직정확히조사되지는않았는데, 지금까지보고된우리나라다제내성결핵코호트분석에따르면, 5.3~20.4% 의다제내성결핵환자가광범위내성결핵으로분류될수있었다 26-29). - 154 -
- 임재준. 내성결핵균의실태및치료 - 2) 광범위내성결핵의치료및예후광범위내성결핵역시다제내성결핵의치료원칙에따라치료하여야하는데, 감수성이있는약제가더적으므로예후는더욱나쁘다. HIV가감염된광범위내성결핵환자들의경우전원사망하였으며진단후생존의중앙값이겨우 16일에불과하였다는보고가있었고 30), HIV 감염되지않은경우에도광범위내성결핵환자들의치료실패율이다제내성결핵환자들보다 4.6배높았고 29), 결핵과연관된사망률이 4.45배높았다는보고들이있다 31). 3) 개발되고있는새로운항결핵약제광범위내성결핵을포함한다제내성결핵의저조한치료성적을고려하면, 새로운항결핵약제의개발은매우시급하다. 지난 1966년 rifampicin이개발된이후 40년이지나도록새로운항결핵약제가더개발되지않아결핵환자들과치료자들의애를태웠는데, 다행히최근몇가지약제가개발단계를거쳐임상시험중이라기대를모으고있다. 우선그람양성균치료로목표로개발된약제이나항결핵균효과역시뛰어난것으로일관되게보고되고있는 oxazolidinones계항균제인 linezolid가대표적이고 38), diarylquinoline (TMC207), nitroimidazoles (OPC67683 및 PA824), sudoterb (pyrrole LL3858), thiolactomycin, cotrimazole, econazole, 그리고 ethambutol 유도체인 diamine SQ109 등도역시유망하며현재전임상혹은임상시험단계에있다 39). 결 우리나라의다제내성결핵및광범위내성결핵문제는매우심각하며, 치료는어렵다. 담당의사의적절한약제선택및환자의꾸준하고철저한복약만이나은치료결과를담보할수있으며, 내성결핵을포함하는결핵문제의근본적인해결을위해서는정부의강력한의지와적극적인투자가무엇보다중요하다. 론 중심단어 : 결핵 ; 약제내성 ; 치료 REFERENCES 1) WHO. Global tuberculosis control: surveillance, planning, financing. World Health Organization, 2007 2) Kim HJ. Current Situation of Tuberculosis and Its Control in Korea. J Korean Med Assoc 49:762-772, 2006 3) Kang YA, Choi YJ, Cho YJ, Lee SM, Yoo CG, Kim YW, Han SK, Shim YS, Yim JJ. Cost of treatment for multidrug-resistant tuberculosis in South Korea. Respirology 11:793-798, 2006 4) Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 329:784-791, 1993 5) Bai GH, Park YK, Choi YW, Bai JI, Kim HJ, Chang CL, Lee JK, Kim SJ. Trend of anti-tuberculosis drug resistance in Korea, 1994-2004. Int J Tuberc Lung Dis 11:571-576, 2007 6) Kim BJ, Lee IH, Lee DH, Bai GH, Kong SJ, Lee SH, Moon HR, Lee KR, Lee JY, Park SK. The current status of multidrug-resistant tuberculosis in Korea. Tuber Lung Dis (In Korean) 60:404-411, 2006 7) Caminero JA. Management of multidrug-resistant tuberculosis and patients in retreatment. Eur Respir J 25:928-936, 2005 8) Mukherjee JS, Rich ML, Socci AR, Joseph JK, Viru FA, Shin SS, Furin JJ, Becerra MC, Barry DJ, Kim JY, Bayona J, Farmer P, Smith Fawzi MC, Seung KJ. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 363:474-481, 2004 9) Guidelines for the programmatic management of drug-resistant tuberculosis. Stop TB department. World Health Organization, 2008 10) Maus CE, Plikaytis BB, Shinnick TM. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 49:3192-3197, 2005 11) Sulochana S, Rahman F, Paramasivan CN. In vitro activity of fluoroquinolones against Mycobacterium tuberculosis. J Chemother 17:169-173, 2005 12) Williams DL, Spring L, Collins L, Miller LP, Heifets LB, Gangadharam PR, Gillis TP. Contribution of rpob mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 42:1853-1857, 1998 13) Rastogi N, Labrousse V, Goh KS. In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against the virulent H37Rv strain in human macrophages. Curr Microbiol 33:167-175, 1996 14) Pomerantz M, Madsen L, Goble M, Iseman M. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 52:1108-1111; discussion 1112, 1991 15) Shiraishi Y, Nakajima Y, Katsuragi N, Kurai M, Takahashi N. Resectional surgery combined with chemotherapy remains the treatment of choice for multidrug-resistant tuberculosis. J Thorac Cardiovasc Surg 128:523-528, 2004 16) Park SK, Lee CM, Heu JP, Song SD. A retrospective study for the outcome of pulmonary resection in 49 patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 6:143-149, 2002-155 -
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