자원환경지질, 제 48 권, 제 3 호, 241-246, 2015 Econ. Environ. Geol., 48(3), 241-246, 2015 http://dx.doi.org/10.9719/eeg.2015.48.3.241 pissn 1225-7281 eissn 2288-7962 헬리코박터파일로리 (Helicobacter pylori) 감염및치료법개요 송영구 * 강남세브란스병원감염내과, 연세대학교의과대학내과학교실 Overview of Helicobacter pylori and Treatment Options Young Goo Song* Division of Infectious Diseases, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (Received: 23 June 2015 / Accepted: 28 June 2015) Helicobacter pylori is an important transmissible human pathogen found on the luminal surface of the gastric epithelium. The organism can persist in the stomach indefinitely and causes gastroduodenal inflammation that may proceed to atrophic gastritis, peptic ulcer, gastric MALT lymphoma, and gastric cancer. Standard triple therapy which consists of proton pump inhibitor (PPI) plus two antibiotics (amoxicillin and clarithromycin) is now generally used in Korea, however, eradication rates of H. pylori has been decreasing due to increasing antibiotic resistance. In this review, current second-line treatment regimens, difficult problems on treatment, necessity of local target therapy, applicability of clay minerals as a drug delivery system (DDS), and a new therapeutic strategy and its study plans will be discussed. Key word : Helicobacter pylori, amoxicillin, clarithromycin, local target therapy, drug delivery system (DDS), clay minerals Helicobacter pylori는사람의위점막에서발견되는전염성이있는중요한병원균이다. 장기간기생하면서만성위염, 소화성궤양, 위변연부 B세포림프종, 그리고위암을일으키는세균으로알려져있다. 국내에서는프로톤펌프억제제 (proton pump inhibitor, PPI) 와두가지항생제 (amoxicillin, clarithromycin) 를포함하는표준삼제요법을 1차치료로사용하여왔으나, 점점증가하고있는항생제내성으로인해제균율은점차감소하고있다. 여기서는 H. pylori의현재의치료법들과이들치료법들의문제점들을검토하고, 표적치료의필요성과표적치료에활용할수있는약물전달체로서의점토광물의가능성에대해알아보고, 이들을이용한새로운치료방향에대한향후연구계획등에대해서논하고자한다. 주요어 : Helicobacter pylori, amoxicillin, clarithromycin, 표적치료, 약물전달체, 점토광물 1. Helicobacter pylori 개요및역학 Helicobacter pylori는그람음성막대균으로 1983년 Warren 과 Marshall에의해처음으로사람의위점막표면에서식하는세균으로발견되었다 (Warren and Marshall, 1983). 이후여러연구에서사람의위점막에장기간기생하면서만성위염을일으킬뿐만아니라, 감염자의 1-10% 에서소화성궤양, 0.1-3% 에서위암, 그리고 0.01% 미만에서위변연부 B세포림프종을일으키는것으로알려져왔다 (Suerbaum and Michetti, This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided original work is properly cited. *Corresponding author: IMFELL@yuhs.ac 241
242 송영구 Table 1. Healthcare situation of H. pylori related diseases (From 2012 National Health Insurance Statistical Yearbook(8)) Disease Number of Patients Cost (Thousand won) Gastric ulcer 1,263,355 181,732,392 Duodenal ulcer 322,846 54,084,647 Gastric malignancy 140,682 429,440,301 Gastritis and Duodenitis 5,839,787 376,751,704 2002). 또한병인기전은확실하지않지만자가면역성혈소판감소증, 철결핍빈혈, 그리고만성두드러기등의질환들과도연관이있는것으로알려져있다 (Gasbarrini et al., 1999). 전세계적으로 H. pylori 감염률은성인에서약 50% 정도이며, 개발도상국이나저개발국에서높고, 성별, 연령, 지역분포, 종족간에도차이를보인다 (World Gastroenterology Organisation, 2011). 미국이나유럽과같은선진국에서의 H. pylori 유병률은 3-5세에 10-15% 정도였다가연령이높아지면서증가하지만, 개 발도상국이나저개발국의경우에는 10세이전에이미 40-60% 의높은유병률을나타낸다 (Klein et al., 1991; al-moagel et al., 1990). 중국과우리나라, 그리고일본의 H. pylori 유병률을비교해보면, 중국에서는장쑤성일대농촌지역의경우나수도베이징일대에서도아동기에감염률이높은전형적인개발도상국의유형을보이고있으며, 우리나라는 1998년조사에서는 16 세이상성인에서의혈청유병률이 66.9% 로높았으나 2005년과 2011년도조사에서는 40세미만의연령에서감염률이큰폭으로감소하는추세로선진국형으로변하고있음을알수있다 (Shiota et al., 2013). 일본의경우는우리나라보다일찍선진국형으로바뀌었는데, 2007년에서 2011년의조사에서는유아기의감염률은낮고이후점점증가하여 60대이후로는 50% 중반에이르며이전조사에비해감염률이점점감소하고있는추세로나타났다 (Shiota et al., 2013). 국내의 H. pylori 감염유병률이많이감소하고있기는하지만, 1994년 WHO에서는 H. pylori를발암인자로규정하였으며, 국내위암사망순위가여전히높은상황에서 H. pylori에대한효과적인치료법을찾아내는것은여전히중요한이슈가되고있다. 2012년도건강보험공단통계연보에의하면 (Kim and Kang, 2012), 한해동안위및십이지장궤양에소요된진료비는약 2,350억원정도로나타났으며, 연관된질환으로위의악성신생물에소요된진료비는약 4,300억원, 위염및십이지장염에소요된진료비는약 3,760여억원정도에달해, 약 1조원이넘는진료비가 H. pylori와 연관된질환에소요되고있는것으로나타났다 (Table 1). 따라서 H. pylori에대한보다효과적인치료법의개발은여러면에서국가적차원의관심이필요한분야라고할수있다. 2. Helicobacter pylori 치료현황및문제점 현재국내에서 H. pylori 감염이있는경우치료를권고하는적응증이되는질환은 Table 2와같다 (Kim et al., 2013). 그러나 2014년 1월에 Kyoto에서열린 H. pylori에대한 Global Concensus Meeting에서는소화불량증환자에서제균치료의필요성을강조한다거나, 위암의예방을위해모든 H. pylori 감염환자를제균치료의대상으로해야한다는등제균대상을확대하고있어국내에서도이에대한더많은연구가필요함을느끼게해준다 (Lee and Kim, 2014). 국내에서 H. pylori 제균치료에관한권고안이발표된이후현재까지일차치료로권고되고있는치료 Table 2. Therapeutic indication of Helicobacter pylori infection related diseases Korea 2013 Guideline Evidence level A 1) Peptic ulcer disease 2) MALToma 3) Following EMR for EGC 4) Idiopathic thrombocytopenic purpura 5) Functional dyspepsia Evidence level B 1) First-relatives of gastric cancer Evidence level C 1) Atrophic gastritis / intestinal metaplasia 2) Long-term use of low dose aspirin EMR, endoscopic mucosal resection; EGC, early gastric cancer; MALToma, mucosal associated lymphoid tissue lymphoma In Korea guideline(kim et al., 2013): Evidence level A, high-quality evidence; level B, moderate- quality evidence; level C, low-quality evidence.
헬리코박터파일로리 (Helicobacter pylori) 감염및치료법개요 243 Table 3. Current recommended regimens for Helicobacter pylori therapy Treatment Standard Triple Therapy Sequential Therapy Concomitant therapy Hybrid therapy PPI, proton pump inhibitor Regimen Amoxicillin 1 g, clarithromycin 500 mg, plus a PPI, all given twice daily for 10-14 days. Amoxicillin 1 g plus a PPI twice daily for 5 days, followed by clarithromycin 500 mg, metronidazole 500 mg, plus a PPI twice daily for further 5 days. Amoxicillin 1 g, clarithromycin 500 mg, metronidazole 500 mg, plus a PPI, all given twice daily for 7-10 days. Amoxicillin 1 g plus a PPI twice daily for 7 days, followed by amoxicillin 1 g, clarithromycin 500 mg, metronidazole 500 mg, plus a PPI all given twice daily for further 7 days. 는, 양성자펌프억제제 (Proton pump inhibitor, PPI) 와두가지항생제인 amoxicillin, clarithromycin을포함하는삼제요법이다 (Kim et al., 2013). H. pylori 제균치료로적합하기위해서는최소한 80% 이상의제균율을보여야하며부작용이 5% 이하이고가급적 1 주일간의치료기간이바람직하다고권유되어왔는데 (Tadataka et al., 1994), 최근일차치료의국내제균율은 80% 를넘지못하고있는것이현실이다 (Lee and Kim, 2014). 전세계적으로도표준삼제요법의제균율은감소하고있는추세인데 (Nishizawa et al., 2012; Oh et al., 2012; Basu et al., 2011), 2000년도초반이후대부분의국가에서치료성공률이 80% 에달하지못하게되었으며 (Rimbara et al., 2011), 제균실패의주요원인을 clarithromycin 내성증가로보고있다. 2000년이후국내 H. pylori에대한일차항생제내성률을보면, amoxicillin은 7-17%, clarithromycin은 14~37%, metronidazole은 35-66% 정도의내성률을보이고있으며, levofloxacin이나 moxifloxacin 등의 quinolone계항생제의내성률도 21-37% 정도의내성률을보이는것으로조사되었다 (Lee et al., 2014; Kim et al., 2004; Lee et al., 2013). 이와같이일차항생제의높은내성률로인한치료실패의대안으로순차치료 (sequential therapy), 동시치료 (concomitant therapy), 변형순차치료 (hybrid therapy) 등의다양한치료방법들이이용되고있는데 (Kim et al, 2013; Rimbara et al., 2011) (Table 3), 전술한바와같이우리나라의 clarithromycin과 metronidazole의내성률이이미 30% 를넘고있으며, 두약제에동시내성인경우도 10% 정도여서이들다양한치료방법의예상제균성공률은기대에미치지못하고있다. 항생제의내성증가를고려하지않더라도 H. pylori 의제균치료가어려운근본적인이유가있다. 모든 감염증치료의기본원칙은세균이존재하는감염부위에서효과적인항생제농도가적정수준으로유지되도록하는것인데, H. pylori는체내로침투하지않고위점막세포표면에만존재하고있고점막층에덮여있기때문에효과적인치료조건을맞추기가쉽지않은것이다. 전신감염증이아닌위점막세포에국한된국소감염증임에도불구하고국소치료가어려운이유는, 항생제가위내에서오래머무르지못하고, 위의낮은 ph에안정적이지못하며, 점막층을잘투과하지못하기때문이다. 결국위점막세포표면에만존재하는국소감염증의치료를위해전신적인항생제치료를할수밖에없고, 궤양치료때문에 1-2주간입원을할수는없으므로경구항생제를사용해야하며, 장에서흡수된경구항생제는전신으로퍼지게되므로그중극히일부만다시위점막세포에분포하여치료효과를봐야하므로두가지이상의항생제를병합하여고용량으로 1-2주간복용해야만하는매우비효율적인치료를해야하는것이다. 장에서흡수가잘되는경구항생제만사용해야하기때문에항생제선택의폭이그만큼줄어들었고, 2-3가지이상의항생제를병합하여 1-2주간사용해야하기때문에부작용의발생빈도가증가하여복약순응도를떨어뜨리는주요이유로도작용하여치료실패의가능성이더높아졌으며, 아울러전체의료비의증가를초래하게되는이유가되고있는것이다. 따라서항생제내성을극복할수있는방법과, 치료가어려운근본적인문제를동시에해결할수있는방안이필요한상황이다. 3. 효과적인치료를위한전략전술한바와같이표준삼제요법의치료실패율이높아지면서순차치료, 동시치료, 변형순차치료등의
244 송영구 방법들이이용되고있지만, 근본적으로내성을극복할수있는방법은아니기때문에한계가있다. 내성을극복하기위한가장확실한방법은신약을개발하는것인데, 천문학적인개발비용과오랜시간이필요한만큼당장가능한방법은못된다. 현실적으로는환자검체로부터배양한 H. pylori 균주의항생제감수성검사결과를바탕으로감수성이있는약제의적절한조합으로치료를하는것이내성으로인한치료실패를줄일수있는가장적절한방법이라고생각된다. 최근치료전항생제감수성결과를기반으로항생제를선택하여치료한경우와통상적인표준삼제요법치료를비교한무작위대조군연구에서, H. pylori 제균성공률은각각 94.7% 와 71.9% 로의미있는차이를보이는것으로나와, 치료전 H. pylori 균의배양과항생제감수성검사의유용성이보고된바있으나 (Park et al., 2014), 실제임상에서는 H. pylori 배양조건이매우까다롭기때문에적절한시설이갖추어지지않은기관에서는시행할수없다는문제가있다. 하지만현재로서는 H. pylori 배양과항생제감수성검사를통하여감수성이있는항생제조합으로치료하는방법이가장효과적인방법으로생각된다. H. pylori 감염의특성으로인한치료측면에서의근본적인문제를해결하는방안으로는국소표적치료가가장효과적인방법이될것이다. 애초에국소표적치료가우선적으로고려되었어야했지만전술한여러가지의어려움으로인해차선책인전신경구용항생제치료를해왔던만큼, 국소감염증의치료원칙에입각한국소표적치료로다시돌아가야할것이다. 국소표적치료를위해서는전술한근본적인문제들을해소시킬수있는기능을가진적절한약물전달체 (drug delivery system, DDS) 의활용이필요할것으로판단되는데, 즉위의 ph를어느정도중화시킬수있는 제산제로서의효과를가지고있고, 점성탄력이있어위점막에잘도포되어일정시간동안머물러있어야하며, 인체에해가없어야하고, 원하는항생제를위환경조건에서적절히분비할수있는기능을갖추어야할것이다. 결국국소적으로위벽에항생제를도포하여치료하는형태가될텐데 (Fig. 1), 이럴경우항생제투여용량을현저히감소시킬수있고, 항생제가굳이장에서흡수되지않아도되므로비흡수성항생제를활용할수있게되어항생제선택의폭이넓어질수있는장점이있다. 주로그람음성균에효과적인 aminoglycoside계항생제의경우 H. pylori에대한최소억제농도 (minimal inhibitory concentration, MIC) 가낮아 gentamicin은 0.125-1 ug/ml, tobramycin 0.125-1 ug/ml, netilmicin 0.125-0.5 ug/ml 정도인데도불구하고 (Brenciaglia et al., 1996, Irie et al., 1997), 장에서흡수가되지않는항생제이기때문에경구용으로사용할수없어서현재까지실제임상에서 H. pylori 감염을치료하기위해전혀사용되지못하고있는상황인데, 국소치료가가능하다면이들비흡수성항생제들도효과적으로사용이가능할수있을것이다. 장오염제거목적으로비위관을통해 tobramycin을투여하였더니 H. pylori 감염이있었던 10명중 9명이 1주일이내에제균이되었다는보고도있어서 (van der Voort PHJ et al., 2000), aminoglycoside계항생제의국소치료요법으로의사용은충분히가능성이있을것으로생각된다. 특히 aminogylcoside계항생제는그동안 H. pylori 감염치료에사용되지않았기때문에아직내성이극히드물것으로예상되어, 현재사용하고있는표준요법의항생제들의내성이증가하는시점에서신약개발에소요되는천문학적인개발비용을들이지않고도내성을극복하여치료할수있는좋은후보항생제군이될수있을것이다. 물론이들항생제 Fig. 1. Schematic model of local target therapy against Helicobacter pylori infection. Antibiotic-intercalated drug delivery system might be coated on the gastric surface and then the intercalated antibiotics could be released into the mucus gel layer where the pathogen exists.
헬리코박터파일로리 (Helicobacter pylori) 감염및치료법개요 245 를위점막세포표면까지효과적으로전달할수있는약물전달체의개발이필수적인요소가된다. 4. 지구점토광물의약물전달체로서의활용가능성 H. pylori 치료에이용할수있는이상적인약물전달체의조건을고려해보면 Table 4와같을것이다. 이와같은이상적인약물전달체의후보물질로지구점토광물을이용하겠다는아이디어는다소황당한듯하지만상당히성공가능성이높은아이디어이다. 특히하이드로탈사이트 [Mg 3/4 Al 1/4 (OH) 2 ][(CO 3 ) 1/8 (H 2 O) 1/2 ] 와스멕타이트 [X x (Mg x Al 2-x )Si 4 O 10 (OH) 2 nh 2 O, or X x (Al,Fe) 2 (Si 4-x Al x ) O 10 (OH) 2 nh 2 O] 와같은점토광물은이미소화기계약물의원료로안전하게사용되고있으며, 층구조로되어있어그층간구조사이에다른물질을삽입시킬수있는특성이있는광물로알려져있다. 이들점토광물의층간구조에 H. pylori에효과가좋은항생제를삽입시킬수있고, 적절한조건에서일정시간분비시킬수있는기술을개발한다면매우유용한약물전달체로활용할수있을것이다. 이미이들물질은소화기계약물로제산효과및위벽보호효과와함께적절한첨가물을이용하면위벽에도포가가능하며인체에해가없는물질로사용되고있어서, 특정조건에서원하는농도로항생제와의복합물을만들수있다면그동안거의시도되지않은새로운치료방법이될수도있을것이다. 특히스멕타이트는농장등에서사용되어토양이나지하수등에녹아들어간 tetacycline 같은항생제를흡착하여제거하는데이용되는등 (Li et al., 2010), 층간에양이온을띄는화학물질을잘삽입시킬수있는특성이있기때문에양전하를띄는대부분의항생제들이스멕타이트층간구조에잘삽입될것으로예상되며, 분비조절에필요한조건들만잘정립된다면매우이상적인위장관계약물전달체로서활용이가능할것으로전망되는점토광물이라고할수있다. Table 4. Requirements as ideal drug delivery system (DDS) Easily intercalated with effective antibiotics in it Well coated on the gastric surface Remained to be coated for a certain period of time Neutralizing gastric acidity Possible to control drug release Harmless to human 5. 향후연구계획및전망향후 H. pylori 감염의효과적인치료를위해서의학계에서는늘해왔던방법으로현재사용하고있는항생제들을어떻게하면더효과적으로사용하느냐에연구의초점을맞출것으로예상된다. 그러기위해서는그동안배양이까다로워서시행하지않고있었던 H. pylori 균배양및항생제감수성검사를임상환자에서통상적으로시행해야한다. 여러가지배양기술과진단기법이발달해왔기때문에이제는충분히가능할수있는방법이다. 나아가서는각항생제별내성기전에대한연구가활성화될것이며, 유전자수준에서의보다신속한내성진단이이루어진다면효과적인항생제를보다빨리투여할수있게되어치료성공률도높이고국민의건강회복과증진에도그만큼도움이될수있게될것이다. 이는지금까지대부분의난치성감염질환의효과적인치료를위해시도되어왔던일반적인방법이라고할수있고, 이분야전문가라면누구나예상할수있는전망이다. 보다창의적인전망은, 본문에서기술한바와같이, H. pylori 치료가근본적으로어려울수밖에없었던여러가지문제들을직접해결하려는시도가이루어질것이라는전망이다. 감염질환치료의가장기본원칙인 국소감염증은국소표적치료가최선이다 라는원칙에입각하여, 균이존재하고있는위점막세포주위에서적절한농도의항생제가일정시간유지될수있도록하는약물전달체를이용하는연구가시도될것이다. 이미스멕타이트와같은지구점토광물을약물전달체로이용하려는지질학분야와의학분야의융합연구가시도되고있고, 이는정부에서내세우고있는창조경제의밑바탕이될뿐만아니라전혀다른학문의융합연구라는새로운분야를개척한다는의미도매우크다고하겠다. 적절한약물전달체를이용할수있다면과거에흡수가되지않는다는이유로전혀사용하지않았던주사항생제를효과적으로이용할수있어내성극복을위해새로운신약을개발하는데소요되는천문학적인비용을절감할수있으며, 현재표준요법으로사용되고있는항생제와의상승효과도기대해볼수있고, 무엇보다항생제사용량과치료기간을현저히감소시키면서도치료에대한순응도와치료성적을향상시킬수있는일석삼조이상의효과를얻을수있을것이다. 특히국내에다량매장되어있는점토광물을정제하여의약품용약물전달체등으로활용할수있도록국산화한다면, 막대한산업-경제적효
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