Review ISSN 1975-7425(Print) / ISSN: 2288-016X(Online) http://dx.doi.org/10.14777/kjutii.2014.9.1.21 Korean J Urogenit Tract Infect Inflamm 2014;9(1):21-26 만성세균성전립선염 박흥재 성균관대학교의과대학강북삼성병원비뇨기과학교실 Chronic Bacterial Prostatitis Heung Jae Park Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea Men with prostatitis-like symptoms who had uropathogenic bacteria localized to the prostate gland by elaborate collection and culturing techniques were diagnosed with chronic bacterial prostatitis. Chronic bacterial prostatitis is characterized by prolonged or recurrent symptoms and relapsing bacteriuria. Chronic bacterial prostatitis is caused mainly by Gram-negative uropathogens. For treatment, fluoroquinolones are considered the drug of choice because of their favorable pharmacokinetic properties and antimicrobial spectrum, with the best evidence supporting ciprofloxacin and levofloxacin. Despite conduct of intensive investigations, our knowledge regarding the diagnostic ability to differentiate bacterial from nonbacterial prostatitis, the relevance of nontraditional uropathogens, and the relationship between uropathogens localized to the prostate and recurrent urinary tract infection is still limited. In this paper, we reviewed the new concepts associated with chronic bacterial prostatitis and explored the evolution of our understanding of the etiology, diagnosis, and treatment of this significant urologic disease. Keywords: Prostatitis; Etiology; Therapeutics Copyright 2014, Korean Association of Urogenital Tract Infection and Inflammation. All rights reserved. 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 the original work is properly cited. Received: 16 February, 2014 Revised: 7 March, 2014 Accepted: 10 March, 2014 Correspondence to: Heung Jae Park Department of Urology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29, Saemunan-ro, Jongno-gu, Seoul 110-746, Korea Tel: +82-2-2001-2237, Fax: +82-2-2001-2247 E-mail: tigerhj@dreamwiz.com 서론 전립선염증상은약 10% 의남성이호소하며, 약 50% 의남성이평생한번은이증상을경험한다. 전립선염은북미에서 50세이하의남성에서가장흔한비뇨기과적질환이며, 전립선염의유병률은일반남성에서 5-9% 로한국인을대상으로한연구에서도비뇨기과병원을방문한환자의 15-25% 가전립선염환자였다. 1,2 이런전립선염은미국 National Institutes of Health (NIH) 의분류에따라보통 4가지범주로나누는데, 이중 Category I에해당되는급성세균성전립선염은전립선염분류에서 5% 미만으로상대적으로만성전립선염 (chronic prostatitis) 에비해발병률이낮고만성전립선염환자들이대부분을차지한다. 3 이런만성전립선염의여러범주에서도만성세균성전립선염 (Category II) 은매우드물어서 5% 만이해당된다. 4 결국급성및만성세균성전립선염의경우원인균이밝혀진경우이지만, 이러한경우는전립선염환자전체에서 10% 미만으로원인균을밝히지못하는경우가대부분이다. 또한요도에정상적으로존재하는균에대한이견도많기 21
22 Heung Jae Park. Chronic Bacterial Prostatitis 때문에만성세균성전립선염의병인에중요한역할을하는원인균이나발병기전에대해서는아직도정립되지않은부분이많고이에대한연구들도적은것이사실이다. 이에 NIH Category II로분류되는만성세균성전립선염의원인균및발생요인들에대해서정리해보고자한다. 본 론 1. 만성세균성전립선염의진단만성세균성전립선염은대개동일균에의한재발성요로감염의과거력이있으면서다른원인, 특히영상의학적으로해부학적이상이없는만성전립선염증후군을보이는경우진단한다. 만성골반통증증후군과구별하기위해서 4배분뇨법또는 2배분뇨법을시행할수있는데, 전립선마사지를통한전립선분비액또는전립선마사지후소변에서중간뇨보다 10배이상의세균이검출될때진단할수있다. 5 2. 세균성전립선염의병인및위험요소들세균성전립선염의병인과관련하여다양한발병기전들이제시되었지만, 현재까지명확하게검증된발병기전은없다. 6 일반적으로원인균에의한요도로부터의상행성감염이가장많을것으로추정되나, 직장내의균들이직장으로부터직접전파하거나림프관을통한감염혹은요도카테타와연관된혈행성감염으로발생할수도있다. 7 또한일부의환자들에서는균이전립선관내로역류가용이한해부학적이상을가지고있다는연구도있고, 아직까지임상적혹은역학적연구에서증명된것은아니지만대부분의임상의사들은포경수술을하지않은경우, 성적활동성, 요도협착이나전립선비대증과같은배뇨이상, 이전의기구사용또는도뇨관삽입등을만성세균성전립선염의위험요소들로간주하고있다. 8,9 Guo 등 10 은만성전립선염의범주에따른환자들정액의염증성사이토카인들인 (inflammatory cytokines) tumor necrosis factor-α, interleukin-1β 그리고 heat-shock protein (HSP) 70의발현정도를비교한연구에서, HSP70의경우 Category II인만성세균성전립선염환자들에서만미국국립보건원만성전립선염증상점수표 (NIH-Chronic Prostatitis Symptom Index) 정도와역의상관관계를보였다고하였다. 이런결과는스트레스단백질로도불리는 HSP70이세균성감염에의한염증성손상에서세포를보호하는역할을하기때문에, 만성세균성전립선염에서 HPS70과관련된염증반응이병인에있어중요한역할을하고있고, HSP70의발현을증가시킬수있는방법은만성세균성전립선염의치료에도움을줄수있다고하였다. 10 또한만성세균성전립선염흰쥐모델을이용한여러연구들에서셀레늄함유온천수음용, 마늘추출물, nanocatechin, 그리고전립선내아연주입등이전립선염증예방및항균, 항염효과가있다고하였다. 11-13 또한, 리코펜 (lycopene) 을만성전립선염동물모델에서 ciprofloxacin과같이투여한경우그치료효과가더우수하였다는보고도있다. 14 이런여러물질의전립선염증완화효과와병인과의관련들에대해서는추가적인연구가필요할것이다. 3. 세균성전립선염의원인균들세균성전립선염의원인균으로호기성그람음성균인 Escherichia coli가가장큰비중을차지하고있다. 이외에도장내세균 (Enterobacteriaceae) 에속하는 Klebsiella pneumonia, Proteus mirabilis, Proteus aeruginosa 등도중요한원인균이다. 15 급성세균성전립선염의경우됴뇨관삽입, 전립선조직검사, 요역동학검사와같은하부요로에대한처치를받은이후에발생하는전립선염은자연적으로발생한전립선염과비교해서원인균의차이가있다. 이런하부요로에대한처치후발생한전립선염에서 Pseudomonas 와복합성균감염은각각 20배, 9.5배더많은것으로조사되었다. 3 한국에서진행된다기관연구에서도하부요로시술후발병한전립선염에서상대적으로 E. coli의비중이낮은대신 Pseudomonas, Klebsiella가높은비중을차지하는것으로조사되었다. 16 1) Urovirulence factors Urovirulence factors는세균성전립선염에서중요한역할을하는것으로알려져있다. 특히 bacterial P-fimbria (or pili) 는요로상피세포의수용체에결합을하고, 이런결합은요로계에서상행성감염을일으키는작용을하며또한균이전립선에깊숙하게침투하게하거나요로감염발생을촉진시키는기능을한다. 특히 E. coli에의한하부요로의군체형성 (colonization) 은 mannose-sensitive fimbria로도불리는 type 1 fimbria 에의해촉진된다. 17,18 이런요소들외에도전립선염을발생시키기위해서는다양한 virulence factors 가필요하다. 전립선관에깊숙하게자리잡은균은숙주방어기전이나항생제등에의해서공격을받는경우응집되어 biofilms 을형성하게되는데이러한방어기전을통해서항생제치료에도불구하고전립선내에서균이생존하게하는역할을하는것으로알려져있다. 19,20 Hemolysin도 E. coli가전립선내에서 biofilm으로생존할수있도록도움을준다. 21 Mazzoli 22 는만성세균성전립선염환자에서동정된 150종균주들의 biofilm 생성 (in vitro) 능력을비교한연구에서, E. coli, 그람음성균, Staphylococci, Enterococci에서 strong 또는 medium의 biofilm 생성이각각 63-30%, 75-15%, 46-36%, 58-14% 였고, 전제균주에서 85% 가 strong 또는 medium의 biofilm 생성을보였다. 이런균들중에서가장높은 biofilm 생성을보인균은 Staphylococcus haemolyticus였다. 결론적
Heung Jae Park. Chronic Bacterial Prostatitis 23 으로만성세균성전립선염을일으키는균대부분이 biofilms 을생성할수있다는것을보여주는연구결과일것이다. 22 또한대상환자들에서경요도전립선절제술을통해얻은전립선석회화 (prostatic calcifications) 를전자현미경과균배양검사를통해서분석한결과전립선석회화가 biofilm 생성균들과관련이있을가능성을제시하였다. 22 2) Gram-Positive Bacteria 그람양성균에해당되는 Streptococcus faecalis (Enterococcus 계통 ), Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus들도세균성전립선염에서중요한원인균으로생각해야하는가에대해서는아직이론의여지가있다. 9 신우신염이나골반내염증과같은다른비뇨생식기계염증질환들에서보고되는것과같이원인균들의종류에있어서과거의보고들과일부다른결과들이보고되는데, 이런결과들은항생제내성균의빈도증가, 항생제감수성이있는균이제거되면서발생하는비감수성균의과증식 (overgrowth), 진단적방법의발전등이영향을준것으로볼수있다. 6 이런영향들은만성세균성전립선염에서도비슷한영향을줄것으로추론할수있다. 만성세균성전립선염환자들을대상으로 levofloxacin 과 ciprofloxacin 의치료효과를비교한 2003년연구를보면, Staphylococcus epidermidis 와같은그람양성균들이전립선염환자의전립선관련검체들에서많이확인되고있고, 실제로그람양성균이발견된환자의수가그람음성균이발견된환자보다훨씬많았다. 또한가장흔한그람음성균은 E. coli로전체대상환자의 10% 였지만, 가장흔한그람양성균은 Enterococcus faecalis로전체대상의 38% 를차지하는것으로조사되기도하였다. 23 이와유사하게만성전립선염 / 만성골반통증증후군 (chronic prostatitis/chronic pelvic pain syndrome) 환자들을대상으로한연구에서도그람양성균의발견율이높은것으로확인이되었다. 24 이런결과는전부요도 (anterior urethra) 에공생하는정상균주가전립선에군체형성을한것인지, 아니면정말이런균들이병원균으로작용을한것인지에대한의문을가지게한다. 더욱혼란스러운점은이런연구들에서증상이없는일반대조군에서도비슷한비율로그람음성균과양성균이동정되었다는점일것이다. 23,24 그람음성균에감염된전립선염환자들과마찬가지로, 최근에전립선염증상이발생된환자들에서이런종류의그람양성균을제거하였을때비슷한치료효과를보였다는연구결과들도있다. 25 하지만만성세균성전립선염환자에서반복적으로균배양을한결과에서항상일정하게그람양성균이발견되지않았다는연구결과도있기때문에 Enterococci를제외한그람양성균들의만성세균성전립선에서병원균으로서의중요성은좀더연구가필요할것이다. 26 3) Chlamydial Infection and Others 전통적인병원균이외에도다양한논문들에서 Chlamydia 균종, Ureaplasma 균종과같은균들도정상대조군에비해서많이발견되는점을근거로만성세균성전립선염의병원균으로제시되었다. 27,28 또한최근에 Ureaplasma urealyticum, Mycoplasma genitalium 등도만성세균성전립선염의병원균이지만과소평가되고있다고주장하는연구결과들도있다. 29,30 하지만이런연구들은근본적으로요도를지나서채취하는소변검체결과때문에요도오염 (urethral contamination) 의가능성이있고, 사정액이나전립선조직검사를통해서얻은검체도요도물질 (urethral material) 을포함하고있을가능성을배제할수없다는문제가있다. 또한아직까지요도에정상적으로공생하고있는균을확실하게분류할수없기때문에이런균들을병원균으로보아야하는지는그람양성균들보다더논란의여지가크다. 31 4. 만성세균성전립선염의치료및예방만성세균성전립선의성공적인치료를위해서는적절한항생제가필수적인요소이다. 효과적인항생제치료를위해서는감염부위의병원균에항생제가적절하게침투하는것이필요하다. 이전에서술한것처럼 biofilm 을형성한경우항생제의치료효과가떨어질수있는데, 일반적으로 beta-lactams 이나 aminoglycosides에비해서 fluoroquinolones이나 macrolides 가 biofilm 에더효과적인것으로알려져있다. 32 과거에는 trimethoprime-sulfamethoxazole (TMP-SMX) 이만성세균성전립선염의주요항균제였지만, 현재는 fluoroquinolone 제제를 1차적인치료약물로사용한다. 33 Fluoroquinolone 항생제는다른항생제와비교해서전립선내로잘침투하며, 넒은항균범위를가지고있다. Fluoroquinolone의치료효과는일반적으로 4주간사용시 70-90% 정도이나 6개월이상추적관찰한경우에는 60% 정도로감소하는것으로알려져있다. 34 이런이유로 TMP-SMX 등의항생제를저용량으로장기간사용해서요도내의균을억제하는억제요법이증상의재발을막는데도움이된다는주장도있지만이론적근거는명확하지않다. 33 전향적다기관연구를통해서 ciprofloxacin 500 mg 1일 2회 4주요법은만성세균성전립선염의표준요법으로확립되었고, 이후무작위대조군연구를통해서 levofloxacin 500 mg 1일 1회 4주요법도 ciprofloxacin 4주요법과동일한효과를보인다고하였다. 23,35 만성세균성전립선염에서 fluoroquinolone 제제는경구로투여하며, 4주간의투여가권장된다. 만약병원균이 fluoroquinolone 제제에내성이있을경우에는 TMP-SMX 3개월요법을고려할수있다. 5 Chlamydia tracomatis에의한만성세균성전립선염의치료는 azithromycin 1 g 1주일마다 4주요법, doxycycline 100 mg 1일 2회 4주요법, 또는 clarithromycin 500 mg 1일 2회 2-4주
24 Heung Jae Park. Chronic Bacterial Prostatitis 요법이권장된다. 5,36-38 Kolumbić Lakos 등 39 은최근 1년간 2회이상재발한만성세균성전립선염환자들을대상으로재발을줄이기위해서기존의치료법과달리 azithromycin (500 mg/day) 과 ciprofloxacin (800 mg/day) 을 3일간정맥주사후 ciprofloxacin (1 g/day) 을 25일간경구투여하는 switch-therapy 를시도해서, 90% 의균제거및 83% 치료성공률을보였다는예비연구결과를보고하기도하였다. Fluoroquinolone을이용한항생제치료에있어서내성균에대한관심도필요할것이다. 한국에서급성세균성전립선염환자를대상으로한다기관연구에서도 ciprofloxain 의감수성결과 E. coli에대한감수성이 76.2%, E. coli를제외한원인균주에대해서는 68.4% 로조사되었는데, 이는만성세균성전립선염에서도 1차치료약물로서 fluoroquinolone을선택하는데영향을줄가능성을보여주는연구결과일것이다. 16 실제한국에서이루어진내성균에대한연구에서, Lee 40 는 81명의남성환자에서분리한 81종의 Enterococcus faecalis 균주중 levofloxacin, ciprofloxacin, norfloxacin에내성을가지고있는비율이각각 46%, 47%, 58% 라고하였다. 이와같이 fluoroquinolone 에대한내성균문제는무시할수없고, 항생제선택에있어서반드시고려해야할점이다. 위에서언급한항생제들외에도 tosufloxain 은기존의퀴놀론계항생제보다높은항균력을가진항생제로 Lee 등 41 은 E. coli 및그람음성균모두에서 levofloxacin 이나 ofloxacin 에비해서더낮은최소억제농도 (minimum inhibitory concentrations) 를가지고있고기존의항생제에비해상대적으로더우수한항균력을가지고있다고하였다. Yoon 등 42 은급성세균성전립선염으로치료받은환자들에서만성세균성전립선염으로진행되는데영향을미친위험요소들을분석한연구에서 480명의급성세균성전립선염환자중에서 10.2% (49/480) 가만성세균성전립선염으로진행되었다고하였다. 또한이런경우당뇨, 이전의하부요로에대한처치, cystostomy를하지않은경우, 도뇨관삽입이위험요소들로분석되었다. 결론 재발성요로감염의과거력이있으면서전립선과관련된검체들에서병원균이확인된경우만성세균성전립선염으로진단하는데큰문제는없다. 하지만전립선염증상이있으면서 1) 전립선검체에서균이확인은되었지만재발성요로감염의과거력이없는경우, 2) 재발성요로감염의과거력은있으나균이확인되지않는경우, 3) Streptococci species나 Staphylococcus saprophyticus 와같이전통적으로비병원균으로분류되던균이확인되는경우들과같은환자들을만성세균성전립선염으로진단후항생제치료를시작해야하는가 에대해서는아직까지명확하게대답을할수없는것이사실이다. 이런문제를해결하기위해서는전립선내에존재할가능성이있는병원균을명확하게확인하는진단방법의발전과함께요도에정상적으로존재하는균이무엇인지에대해서도추가적인연구가필요할것이다. 아직까지 4배분뇨법또는 2배분뇨법에의한균배양이가장좋은진단방법이기는하지만실제임상에서여러이유들로사용하지않고경험적으로항생제치료를시작하는경우도많기때문에적절한진단방법에대한연구는필수적이다. 미국에서임질의치료에있어내성문제로 fluoroquinolone을더는일차치료약물로권장하지않는것처럼, 항생제에대한내성문제도만성세균성전립선염의치료에있어서반드시신경써야될부분이다. 한국에서 TMP-SMX, fluoroquinolone에대한내성도무시할만한수준은아니기때문에이런내성문제도지속적으로관리해야될문제이다. 만약당장내성문제로 fluoroquinolone을사용할수없다면만성세균성전립선염의치료는비뇨기과의사에게큰고민거리가될것이다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Woo YN. Prostatitis. Korean J Urol 1994;35:575-85. 2. Krieger JN, Riley DE, Cheah PY, Liong ML, Yuen KH. Epidemiology of prostatitis: new evidence for a world-wide problem. World J Urol 2003;21:70-4. 3. Millán-Rodríguez F, Palou J, Bujons-Tur A, Musquera-Felip M, Sevilla-Cecilia C, Serrallach-Orejas M, et al. Acute bacterial prostatitis: two different sub-categories according to a previous manipulation of the lower urinary tract. World J Urol 2006;24: 45-50. 4. Nickel JC, Downey J, Hunter D, Clark J. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol 2001;165:842-5. 5. The Korean Society of Infectious Diseases; The Korean Society for Chemotherapy; Korean Association of Urogenital Tract Infection and Inflammation; The Korean Society of Clinical Microbiology. Clinical guideline for the diagnosis and treatment of urinary tract infections: asymptomatic bacteriuria, uncomplicated & complicated urinary tract infections, bacterial prostatitis. Infect Chemother 2011;43:1-25. 6. Nickel JC, Moon T. Chronic bacterial prostatitis: an evolving clinical enigma. Urology 2005;66:2-8. 7. Terai A, Ishitoya S, Mitsumori K, Ogawa O. Molecular epide-
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