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1 Review ISSN (Print) / ISSN: X(Online) Korean J Urogenit Tract Infect Inflamm 2014;9(1):9-13 재발성요로감염에대한비항생제예방요법 김기호 동국대학교경주병원비뇨기과 Non-Antibiotic Prophylaxis for Recurrent Urinary Tract Infections Ki Ho Kim Department of Urology, Dongguk University Gyeongju Hospital, Gyeongju, Korea Urinary tract infections (UTI) are one of the most common infections affecting women. In a recent study of college women with their first UTI, 27% experienced at least one culture-confirmed recurrence within the six months following the initial infection and 2.7% had a second recurrence during this time period. Women with recurrent UTI have an increased susceptibility to vaginal colonization with uropathogens due to a greater propensity for them to adhere to their epithelial cells. Risk factors include frequent sexual intercourse, spermicide use, first UTI at an early age, and maternal history of UTI. Effectiveness of continuous or post-coital prophylaxis with low-dose antimicrobials or intermittent self-treatment with antimicrobials in management of recurrent uncomplicated UTIs in women has been demonstrated. However, antibiotics are the main driving force in development of antibiotic resistance and can lead to resistance of not only the causative microorganisms, but also the commensal flora. The increasing prevalence of Escherichia coli isolates (the most prevalent uropathogen) that are resistant to antimicrobial agents has stimulated interest in non-antibiotic methods for prevention of UTIs. We discuss the overall use of non-antibiotic methods for prevention of recurrent UTI, including the use of immunostimulant OM-89, a vaginal vaccine or estrogen, lactobacilli prophylaxis, and cranberry. Received: 27 February, 2014 Revised: 11 March, 2014 Accepted: 11 March, 2014 Keywords: Urinary tract infections; Prevention and control; Recurrence; Immunosuppressive agents; Dietary supplements 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 ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Correspondence to: Ki Ho Kim Department of Urology, Dongguk University Gyeongju Hospital, 87, Dongdae-ro, Gyeongju , Korea Tel: , Fax: honda400uro@gmail.com 서론 요로감염은요로상피에세균이침범하여발생하는염증성반응으로주로직장내세균의상행성감염에의해발생한다. 세계적으로매년 1억 5천만건으로추정되는요로감염사례가 발생하며젊고건강한여성에서요로감염이연 50-70% 의높은발생빈도를보이고해부학적그리고생리학적으로정상요로구조를가진젊고건강한여성에서흔히재발성요로감염이발생한다. 1 적어도한번이상의요로감염을보이는 18세이상의여성은미국에서 10.8% 인것으로알려져있다. 지난 6개월 9

2 10 Ki Ho Kim. Non-Antibiotic Prophylaxis 간 2번이상, 1년간적어도 3번이상의요로감염이있었다면재발성요로감염으로정의하고이러한정의에따르면요로감염환자의 20-30% 는재발을경험하는것으로알려져있다. 2 재발성요로감염은세균의재감염이원인이며지속세균뇨는드물다. 재감염은세균뇨가완전히소실된후새로운균주에감염된것을뜻하며, 지속세균뇨는치료후소변배양검사에서무균뇨로전환된뒤단기간내에같은균에의해감염이재발되는경우를가리킨다. 이러한재발성요로감염의문제는증상으로인한불편감외에도장기간치료가필요하고의료비용이증가하며합병증으로인한신장손상이나패혈증이발생할수있다는데있다. 따라서재발성요로감염이발생하기전예방이중요하며유럽비뇨기과학회의가이드라인에따르면이러한재발성요로감염의예방에몇개월간의저용량항생제사용이매우효과적이며사용을권장하고있다. 하지만이러한저용량의항생제사용의문제점은항생제내성의증가와정상균총및원인균의내성증가를초래할수있다는것이다. 3 특히요로병인성대장균 (uropathogenic Escherichia coli) 과같은병원균이지역사회획득성요로감염의 70-95% 를차지할정도로내성이매우빠르게증가하는것이문제이다. 이러한이유로재발성요로감염의예방에저용량의항생제사용보다는항생제를사용하지않는방법을환자에게일차적으로고려해볼수있다. 아직까지명확한해답은나와있지않지만현재까지나와있는비항생제예방요법에대해서알아보고자한다. 본 론 1. 면역강화예방 (Immunoactive Prophylaxis) 다양한세균의추출물을이용해서재발성요로감염의치료에사용되고있으며이러한세균의추출물이체내에면역계를활성화시킨다. 1) OM-89 18가지의대장균주를용균한다음비용해성세포물질을여과하여제거한용균액인 OM-89 ( 유로박솜 ; Uro-Vaxom) 는수지상세포를 upregulation하여호중구와대식세포를증가시켜체내면역을활성화시킨다. 그외에 Urostim (1형 pili를나타내는요로감염대장균, 대장균의 Rc돌연변이주, Klebsiella pneumonia, Proteus mirabilis, Enterococcus faecalis 등 ) 과 Urvakol ( 요로감염대장균, K. pneumonia, P. mirabilis, Pseudomonas aeruginosa, E. faecalis 등 ) 이있다. 여기서이러한면역반응은항원제시세포의표면에존재하는 toll-like receptor (TLR) 에의해서매개된다. TLR은감염이있음을인지하는중요한감지자이며다양한숙주의면역방어를조절한다. 체내선천면역반응 (innate immune responses) 은섬모에의해유발되지만 TLR 방어기전이필요하다. TLRs 집합체는 단핵대식세포가초기세균생성물을인식하는데에중요한역할을한다. 4 최근요로계세포방어의첫단계인방광과신장상피세포에서의면역활성화는 TLRs 에의존한다는것이밝혀졌다. 5 TLRs을통한요로상피세포의활성화는 interleukin-6 와 interleukin-8 의생성을초래하고염증반응동안호중구와수지상피세포같은면역활성세포를끌어들이며, 이들도유사하게 TLRs에통해활성화된다. 신장의보우만주머니, 근위관, 원위관그리고하부비뇨기계및방광과같은신장상피에는항상 TLR2 와 TLR4 가발현되어있다. 이러한 TLR 은염증반응시발현이촉진되며, 신장의염증반응에서다양한역할을하는것으로알려져있다. 그람음성세균의지질다당체주입은 TLR4 를자극하고, 쥐나사람의수지상세포는 Th1 세포에의한세포매개면역을촉진하는 interleukin-12 와 interferon-α를생산한다. 또한 TLRs는항체의생산을자극하기도한다. OM-89는변형된세균의모든물질단백질, 아미노산, 다당체, 양가성분자, nucleotide 와적은양의 DNA가포함된세균용균액을포함하고있기때문에위장관의맥아에도달한후 TLR4 에결합하여면역계를활성화하고비뇨기계의반복감염을낮춘다. 세균의 OM-89 용균액은수지상세포의조직적합성복합체단백질과 CD40, CD86 분자의발현을조장하여항원전달능력을향상시키며, 종양괴사인자-α와 interleukin-12 같은 cytokine을분비시켜결국 T세포를활성화한다. 생체내에서 OM-89는항원제시세포의경우 interleukin-1 과종양괴사인자-α를생산하도록유도하며 T세포를활성화하여 interleukin-2와 interferon-γ의분비를촉진하고자연살해세포를활성화한다. 농도가낮은 OM-89는자연살해세포의활성과 interleukin-1 생산에강력한영향을미친다. 지속적인 OM-89 의섭취는체내혈액과요로계에 IgG 와 IgA 의농도를증가시킨다. 6 Tammen 7 은 120 명의요로감염을환자를대상으로 OM-89 를 3개월간복용시키고 6개월간 OM-89 를복용한그룹이대조군에비해서현저히낮은요로감염을보인다고하였으며항생제사용횟수나증상발현에있어서도낮게나타남을보고하였다. OM-89 경구면역자극제를이용한 5개임상시험 ( 성인 1,000 명 ) 을메타분석한결과임상시험사이에유의한이질성이존재하므로결과해석에주의가필요하지만요로감염횟수가평균 36% 줄었다고하였다. 8 국내의다기관연구에서도 3개월간투여하여방광염발생이치료전 6개월동안의 4.26 회에서치료후 6개월동안 0.35회로의미있게감소하였다고보고하였다. 9 메타분석에의하면적어도한번이상의요로감염이발생한위험도는 OM-89를복용한군이대조군에비해위험도를통계적으로의미있게낮출수있었다고하였으며요로감염의평균횟수도대조군에비해절반정도낮출수있었다고하였다. 또한유럽비뇨기과학회의가이드라인에서도재발성요로감염의경우 OM-89의사용을추천하고있고, Bauer 등 10 은 453명의환자를대상으로 90일간 OM-89 를 3개

3 Ki Ho Kim. Non-Antibiotic Prophylaxis 11 월간투여하고 3개월간휴약기간을거친후 12개월째결과를평가하였는데치료한군이요로감염발생이 34% 감소하여 OM-89가요로감염의빈도를낮출수있음을보고하였다. 여러임상시험에서 OM-89는치명적이거나중요한부작용은없었고두통이나소화장애등의가벼운부작용만관찰되었다. 11 2) Vaginal vaccine 6개다른대장균주와 Proteus vulgaris, K. pneumoneae, Morganella morganii, E. faecalis 각각의균주를용균한용균액을포함한 vaginal vaccine (Urovac) 을사용하여재발성요로감염의예방에사용하고있다. 12 경구용제재인경우드물기는하지만전신부작용이있을수있기때문에질내투여를시행함으로써이러한부작용을최소화할수있고경구용제재의효과만큼재발을예방할수있으리라생각된다. 정확한기전에대해서는아직까지알려져있지않지만경구용제재와같이요로계에 IgG와 IgA의분비를촉지시켜질과방광에 uropathogen 의 colonization 을감소시키는것으로알려져있다. 12 첫 3주동안매주질좌약으로넣고그다음 3개월동안매달 1회 75명에게 160 일동안 Urovac 을넣어재발성요로감염환자에서제2상이중맹검위약대조군시험을진행하였는데위약은 70%, 시험군은 27.5% 에서재발하여재발성요로감염에사용할경우효과적임을증명하였다. 또한이러한질좌약을추가로정기적으로투여할경우위약의 14% 에비해 50% 에서요로감염의재발을막을수있었다고하였다. 8 질좌약을넣고나서 27.8% 에서질의자극증상을보였으나매우짧았음을보고하였다 에스트로겐예방 (Estrogen Prophylaxis) 폐경후여성에서재발성요로감염의위험인자는방광탈출, 방광류, 잔뇨, 그리고요실금등이다. 이러한모든인자는에스트로겐의감소와연관되어있으며따라서폐경후여성에서에스트로겐투여가재발성요로감염의위험을줄일수있다. 질내에스트로겐투여는질상피에서유산균의증식을촉진시키며폐경전처럼산도를낮추고장내세균의질정착을억제시킨다. 14 에스트로겐경구는위약과비교하여요로감염을줄이지못하는것으로알려져있다. Kirkengen 등 15 은 estriol 3 mg을하루에한번경구로 4주간투여하고 8주간하루에 1 mg을사용하여재발성요로감염의예방에경구용에스트로겐을사용하였으며 Cardozo 등 16 은 6개월간경구용 estriol 3 mg을하루에한번사용하여연구를진행하였는데요로감염을줄이지못함을보고하였다. 또한부작용으로 19.4% 에서가슴통증과 8.3% 에서경한질출혈을보고하였으며심한부작용으로우울증, stroke, 출혈등을보고하였으며심경색, 유방암, thromboembolism 등과같은부작용도보고하여더는장기간의경구용에스트로겐사용은추천되지않는다 폐경후여성 93명을대상으로한이중맹검무작위대조시험에서질내에스트로겐투여군은위약에비해각각 0.5회 / 환자-년, 5.9회 / 환자-년으로요로감염을현저히낮추었음을보고하였으며유산균배양에있어서도치료전질배양에서유산균이두군모두에서배양되지않았지만 1개월후에스트로겐치료군에서는 61% 에서다시유산균이배양되었고위약군은아무것도배양되지않았다. 또한질의산도에서도질내에스트로겐치료군이평균 5.5에서 3.6으로낮아졌으며위약은변화가없어재발성요로감염예방에있어질내에스트로겐투여가효과가있음을보고하였다. 14 질내에스트로겐투여로생기는부작용으로유방압통, 질출혈, 질화끈거림, 가려움등이있을수있다 유산균예방 (Lactobacilli Prophylaxis) 특정유산균은 antibacterial compound인 hydrogen peroxide 와 biosurfactants 을생산하여세포표면에요로감염균의부착및성장, 집락을하지못하게한다. 21,22 요로감염예방연구에사용된유산균중에서 Lactobacillus rhamnosus GR-1과 L. reuteri RC-14 가가장효과적인균주다. Baerheim 등 17 은폐경전여성 48명에게 L. rhamnosus 질좌약을 26주동안주 2회투약하여무작위위약대조군시험을시행하였는데 6개월동안적어도 1번이상요로감염이발생한경우대조군은 50% ( 평균 0.86 회 ), 실험군은 56% ( 평균 1.24 회 ) 로차이가없었다. 폐경전여성에게 antimicrobial treatment 후 10주동안매주 1회 Lactobacillus crispatus 질좌약을적용한제 2상임상시험결과요로감염재발 (15%) 은대조군 (27%) 에비해낮았음을보고하였다. 몇몇연구에서재발성요로감염에대한유산균질좌약이효과가있는것으로보고되기도하지만무작위대조시험이이루어지지않았다는제한점이있다. 23 부작용으로질분비물이있었으며대조군은 4.5%, lactobacilli 을사용한경우는 16% 로대조군에비해서는높게나타났고그외가려움증, 중등도복통등이있었으나심한부작용은없었다. 23 유산균을경구로투여하여질로전달됨이확인되면서재발성요로감염의예방에경구용유산균을이용한연구가이루어졌다. Kontiokari 등 24 은 150명의요로감염환자에게 L. rhamnosus GG 요거트를이용한연구를진행하였는데 3군으로나누어 1군은크랜베리-링곤베리주스를 6개월간 50 ml 복용한군, 2군은 L. rhamnosus GG 요거트를 1년간 1주일에 5일간 100 ml 복용한군, 3군은치료하지않은군으로나누었다. 12개월뒤요로감염여부를확인하였는데치료하지않은군은 50명중 19명 (38%) 이재발하였으며 lactobacillus 를복용한군은 49명중 21명 (42.9%) 이요로감염이발생하여차이가없음을보고하였다.

4 12 Ki Ho Kim. Non-Antibiotic Prophylaxis 4. 크랜베리크랜베리에대한요로감염의예방에대한정확한메커니즘은알려져있지않지만요로상피에세균이부착하지않고는요로계점막표면을감염시킬수없기때문에크랜베리가가지고있는 proanthocyanidin 이라는탄닌성분이요로감염을일으키는 P-fimbriated 대장균이요로상피세포에부착하는것을억제함으로써증상성방광염의재발을줄이는것으로알려져있다 많은주스가 type 1 fimbriated 대장균의부착을억제하는것으로알려져있으나 P-fimbriated 대장균에대한효과는블루베리와크랜베리주스가유일하다. 27,29 Howell 등 25 은크랜베리의 proanthocyanidin의용량에따른대장균의요로계부착을어느정도막을수있는지에대한연구를진행하였는데최소 72 mg의 proanthocyanidin이들어있는크랜베리를매일복용해야요로에서세균의부착과병독성을억제할수있다고하였다. 또한 Kontiokari 등 24 은 150명의요로감염환자에게크랜베리-링곤베리주스를 6개월간 50 ml 복용시켜 6개월후적어도한번이상의요로감염을보이는환자가 50명중 8명 (16%) 으로치료하지않은군 (36%) 보다낮은요로감염재발을보임을보고하였다. 그러나여자대학생을대상으로무작위대조시험을시행한연구에서는크랜베리주스칵테일 240 ml를하루 2회섭취한군이대조군에비해요로감염재발률이약간높음을 (20.0% vs. 14.0%) 보고하였으며통계적으로는별차이가없지만크랜베리주스가방광염을막아준다는것을보여주지는못하였다. 또한최근 Cochrane 체계고찰에따르면크랜베리생산물은재발성요로감염이있는환자의증상을줄이지못함을보고하였다. 30 부작용에는소화장애, 체중증가, 잠재적인약물상호작용 (flavonoid가 cytochrome P450 효소계를억제 ) 등이있다. 31 크랜베리가요로감염의재발을막아주는지에대해서는아직까지확정된것은아니며지속적인대규모임상시험이필요하다. 5. 기타 1) Angocin 두가지유효성분인양고추냉이뿌리 (horseradish root) 80 mg과네스트리움 (nasturtium) 200 mg을포함한 herbal medicinal product인 Angocin을 103명의환자에게 90일간하루에두번사용하여이중맹검연구를시행하였는데재발성요로감염에대해서효과적이었다. Angocin을사용한군은요로감염이 6개월동안 0.43회, 대조군은 0.77회로유의하게요로감염을감소시켰다. 32 그러나 174명의환자를대상으로 intention-to-treat analysis를시행하면요로감염의빈도는 Angoin을사용한군은 0.65회, 대조군은 0.64회로차이가없다. 2) Acupuncture 2개의소규모무작위시험에서 4주간일주일에 2번 acupuncture를시행하였는데각각 acupuncture군은 6개월동안 85% 에서요로감염이없었으며대조군은 36% 에서요로감염이없어재발성요로감염을줄이는것으로나타났다. 33,34 결 론 재발성요로감염에대한가장효과적인방법은항생제예방요법이다. 하지만이러한항생제예방요법은항생제내성을유발하고약제부작용을일으킬수있다. 따라서비항생제에의한재발성요로감염에대한예방요법을시행하고다른예방책이실패한경우항생제예방요법을시행하는것을권장하고있다. 대장균추출물을이용한면역강화예방요법인 OM-89와에스트로겐질좌약은재발성요로감염의예방에사용할수있으며특히폐경후여성에서에스트로겐질내투여는효과적일수있다. 크랜베리주스, vaginal vaccine 및 acupuncture 에대한재발성요로감염의예방에관한것은몇몇연구에서요로감염의예방에긍정적인것은사실이나아직까지확정된것은아니기때문에지속적이고대규모임상시험이필요하다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 1993;329: Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000;182: Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke TM, et al. Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med 2012;172: Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21: Bäckhed F, Söderhäll M, Ekman P, Normark S, Richter-Dahlfors A. Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ- and cell-specific expression of Toll-like receptors within the human urinary tract. Cell Microbiol 2001;3: Huber M, Krauter K, Winkelmann G, Bauer HW, Rahlfs VW, Lauener PA, et al. Immunostimulation by bacterial compo-

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Review Article Infect Chemother 2012;44(5): pissn eissn Infection & Chemotherapy

Review Article Infect Chemother 2012;44(5): pissn eissn Infection & Chemotherapy Review Article http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 pissn 2093-2340 eissn 2092-6448 Infection & Chemotherapy 여성의재발성요로감염예방 김백남 인제대학교의과대학내과학교실 Prevention of Recurrent