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 Urinary Tract Infections in Women Urinary tract infection (UTI) is one of the most common bacterial infections affecting women. One in four of these women will develop a recurrence. Recurrent UTIs are common among otherwise healthy women with anatomically and physiologically normal urinary tracts. These conditions have a significant effect on their quality of life and have a considerable economic impact due to health care costs. This article will review risk factors predisposing pre- and postmenopausal women to recurrent UTIs, and discuss antimicrobial prophylaxis and other non-antimicrobial preventive measures, including modification of behavioral factors, estrogen, and cranberry products. Baek-Nam Kim Department of Internal Medicine, Inje University College of Medicine, Busan, Korea Key Words: Urinary tract infections, Cystitis, Pyelonephritis, Prevention and control, Anti-bacterial agents, Antibiotic prophylaxis, Recurrence 서론 요로감염은여성에게가장흔한세균감염가운데하나다. 여성의 40-50% 는평생한번이상요로감염을앓는다 [1]. 해부학적으로생리학적으로요로계가정상이더라도젊은여성에서요로감염의재발은흔하다 [2]. 여성에게요로감염은매년 12% 발생하며, 모든여성의절반은 32세까지적어도한번요로감염을앓는다 [3]. 한번이라도걸리면요로감염재발률이증가한다 [4]. 요로감염을처음앓은미국여자대학생의 26.6% 는 6개월안에재발하고 2.7% 는다시감염된다 [5]. 일차의료기관에서보면, 55세넘은여성의 53% 와이보다젊은여성의 36% 는 1년안에재발성요로감염을경험한다 [4]. 재발성요로감염은직전요로감염이해소된후연이어발생하는, 증상이있는요로감염을말한다 [2]. 재발성요로감염은지난 12개월동안 3회이상요로감염이발생한경우로정의한다 [6]. 일부여성에게재발성요로감염은심각한고통일뿐만아니라병원방문과입원, 진단, 치료에비용이든다. 그러므로이들에게적합한예방대책이필요하다. 이고찰에서는폐경전그리고폐경후건강한여성에서단순요로감염재발에대한위험요인과예방대책에대하여논하고자한다. 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. Copyright 2012 by The Korean Society of Infectious Diseases Korean Society for Chemotherapy Submitted: October 3, 2012 Accepted: October 3, 2012 Correspondence to Baek-Nam Kim, M.D. Department of Internal Medicine, Inje University Sanggye- Paik Hospital, Nowon-gu, Seoul 139-707, Korea Tel: +82-2-950-8863, Fax: +82-2-950-1955 E-mail: kimbn@paik.ac.kr www.icjournal.org

344 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 요로감염의발병기전 여성에서재발성요로감염의원인병원체의 80% 는대장균이다. 건강한사람에서요로감염균은대부분대장의정상균무리에서기인한다. 요로감염균은요도구주위나원위요도에정착하는중간단계를거쳐요도를통해방광안으로들어간다 [7]. 질에있는유산균은요로감염균의초기정착단계를방해한다 [8]. 이러한모델은여성에서산발성 (sporadic) 요로감염이든재발성감염이든똑같이적용된다 [2, 9]. 요로감염의시작은요로감염균이배뇨로씻겨내려가는것을극복하고질이나요로상피세포에부착하는것인데, 이에가는털 (fimbiria) 과같은독성인자가관여한다. 그가운데 1형 fimbriae 는거의모든요로감염대장균에서발견되며신장에대한독성인자를가지고있지않다. 끝부분에있는 FimH adhesin 를매개로방광의요로상피세포와결합한다 [10]. P 혹은 Pap (pili associated with pyelonephritis) fimbriae 는신우신염을일으킨대장균에서두드러지게발견되는데, 적혈구의 P혈액형항원이나요로상피세포의 Gal-Gal 수용체에특이적으로결합한다 [11]. P fimbriae 는요로감염대장균중에서신우신염균주의 91%, 방광염은 19%, 무증상세균뇨균주에서는 14% 발견되었으나대장에있는대장균에는 7% 존재하였다 [12]. 동물실험에서대장균은숙주에게있는대규모세균병원소에잠재할수있으며나중에재활성화되어감염을일으킬수있다. 급성단순방광염이있는여성의중간뇨를채취하여연구한결과요로감염대장균이방광상피에서세포내에집단 (intracellular bacterial community) 을이루어존재함을확인하였다 [13]. 이런집단은숙주의면역반응기제나항생제치료로부터보호받았다가나중에재활성화되어재발성요로감염을일으킬수있다 [13]. 발병기전에대해더자세한것은다른문헌을참고하기바란다. 폐경전여성에서재발성요로감염의위험요인 요로감염이발생하는데숙주의유전적, 생물학적, 혹은행동 / 습관요소들이작용한다 (Table 1). 이가운데중요한위험요인을폐경전후로나누어기술한다. 1. 성관계와살정제습관적행동이젊은여성의요로감염발생과강하게연관있다. 성관계와살정제사용 ( 특히막사용과함께 ) 은젊은여성에서산발성요로감염의발생위험을높이는, 가장명확하게연관있는위험요인이다 [15]. 젊은여성에서는성관계나살정제와같은산발성요로감염의위험요인이재발성요로감염의위험요인이기도하다 [16]. 최근시행된대규모사례대조군연구에서다변량분석결과젊은여성에게생기는재발성요로감염의행동위험요인은지난 1개월동안성관계횟수 (odds ratio [OR] 5.8; 95% confidence interval [CI] 3.1-10.6 for 4-8 episodes), 지난 1년동안살정제사용 (OR 1.8; 95% CI 1.1-2.9), 지난 1년동안새로운사람과의성관계 (OR 1.9; 95% CI 1.2-3.2) 등이었다 [17]. 성관계는시간과횟수면에서요로감염과밀접하게연관있다 [15, 17-20]. 성적으로활발한젊은여성에서방광염의 75-90% 는성관계에기인하고, 감염횟수는성관계횟수와상관있다 [15, 17]. 성적으로활발하지않은젊은여성이단순요로감염에걸리는것은드문일이라고한다 [17, 21]. 성관계는대장균의요도주위정착과요도구에서방광안으로재발성요로감염균주의이동을촉진하는데중요한역할을한다 [18, 22, 23]. 젊은여성에서재발성요로감염과가장강하게연관된위험요인은성관계횟수다. 성관계를주3회갖는평균 24세여자대학생은성관계를갖지않은사람보다요로감염의위험이 2.6 배높았고매일갖는사람은 9배증가하였다 [15]. 다른역학연구에서지난 1개월동안성관계횟수가 4-8 회인경우교차비는 5.8 (95% CI 3.1-10.6), 9 회이상은 10.3 (95% CI 5.8-18.3) 으로확인되었다 [17]. 재발성요로감염이있는폐경전여성에서재발원인균주의요도주위정착, 세균뇨, 농뇨등과더불어성관계유병률은재발직전몇일동안급격히증가함이관찰되었다 [24]. 이연구에서대장균에의한재발성요로감염의 75% 에서성관계와재발원인균주의요도주위정착이 5일안에선행하였다. 살정제사용도요로감염의주요한행동위험요인이다. 살정제는질의생태계를바꾸어재발위험을높인다 [8]. 지난 1년동안살정제사용은젊은여성에서재발성요로감염발생과의미있게연관있었다 [17]. 살정제사용횟수는성관계횟수와무관하게재발성요로감염횟수와상관있다 [15, 17, 25]. 살정제로표면처리된콘돔을사용하는것만으로도요로감염의위험은증가한다 [26, 27]. Nonoxynol-9 살정제가묻어있는가로막도요로감염을유발하는것으로알려져있으나 [15], 가로막보다는살정제가더요로감염과연관있다. 살정제성분인 Table 1. Major Factors Predisposing Adult Women to Recurrent Urinary Tract Infections, As Related to Age [14] Age group (years) Factor 15-50 Sexual intercourse Diaphragm/spermicide Spermicide Antimicrobials Prior UTI Maternal history of UTI Childhood history of UTI Nonsecretor status 51-70 Lack of estrogen Incontinence Cystocele Postvoid residual urine Nonsecretor status Prior UTI >70 Catheterization Incontinence Urogenital surgery Diminished mental status Antimicrobials UTI, urinary tract infection

www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 345 nonoxynol-9 은시험관내에서유산균을파괴하지만대장균에는별다른영향을주지않았다 [28, 29]. 살정제는그자체로또는피임용가로막과같이사용하는경우질의유산균수를줄이고대장균의질정착을증가시킨다 [15]. 살정제는요도구주위에대장균의집락화를촉진하는데, 이런집락화는재발성요로감염이있는여성에게더자주생기고더오랜기간이루어지는것으로알려졌다 [8, 30]. 하지만, 경구피임제복용이나콘돔사용은역학연구에서요로감염의위험요인으로증명되지않았다 [19, 25]. 2. 과거항생제사용질의정상균무리에영향을미치는항생제는요로감염에대한감수성을변화시킬수있다. 요로감염에선행하는결정적인사건은질입구에장내균무리에서기인한요로감염균특히대장균의정착이다 [31]. 건강한젊은여성에서질의정상균무리의 90% 는유산균으로이루어졌는데, 이세균은과산화수소를생산하여요로감염균의정착을막는다 [8, 31]. 한사례대조군연구를보면, 재발성요로감염여성이그렇지않은여성에비해질에서대장균정착이흔하였으며 (35% vs. 11%; P<0.001), 이런위험은과산화수소를생산하는유산균이없는재발성요로감염여성에서훨씬더높았다 (OR 4.0) [8]. 정상적으로유산균이우세한질균무리가과거항생제사용으로변화가생기면요로감염균의질내정착이촉진된다 [32, 33]. 동물실험에서 β-lactam 계항생제는질의균무리를현저히억제하고대장균의질내정착가능성을높이는반면, 질의정상균무리를구성하는미생물에대한항균력이별로없는 trimethoprim-sulfamethoxazole (TMP-SMX) 은요도구주위혐기균균무리에대한영향이적었다 [33]. 실제요로감염환자를 TMP-SMX 이나 fluoroquinolone 계항생제 (ofloxacin) 로치료하였을때 β-lactam 계항생제 (amoxicillin, bacampicillin, cefadroxil) 보다치료이후요로감염균의질내정착이적었다 [34-36]. 항생제사용으로모든연령대여성에서요로감염위험이증가한다 [34, 37, 38]. 젊은여성 751 명을 6개월동안추적한결과요로감염이발생하기이전 15-28 일사이항생제를사용한경우이전 3, 7 혹은 14 일동안항생제를사용한군보다요로감염발생위험이 2.57-5.83 배높았다 [39]. 요로감염으로과거항생제치료를받은여성이나다른질환으로항생제치료를받은여성도요로감염발생위험이증가한다 [39]. 3. 가족력젊은여성에서습관과상관없는, 재발성요로감염의위험요인에는첫번째요로감염때나이가 15 세미만인경우 (OR 3.9; 95% CI 1.9-8.0) 와어머니에게요로감염병력이있는경우 (OR 2.3; 95% CI 1.5-3.7) 등이있다 [17]. 어린나이에첫요로감염을앓은것과어머니에게요로감염병력이있다는점은성관계다음으로재발성요로감염과강한연관성을나타낸변수들이다 [17]. 이런소견은유전적요소가재발성요로감염이있는일부젊은여성에게중요함을시사한다. 오래전부터재발성요로감염발생에유전적인경향이있다고알려져왔다. 재발성방광염이있는여성에서그러지않은여성에비해여 자직계가족 ( 어머니, 형제 ) 이요로감염을경험할가능성이높았다 [17, 40]. 18-49 세사이폐경전여성 1,261 명을대상으로요로감염의가족력을조사한인구집단기반사례대조군연구에서어머니에게요로감염의병력이있는경우재발성방광염 (OR 2.5; 95% CI 1.9-3.4) 과재발성신우신염 (OR 3.3; 95% CI 2.4-4.5) 의발생위험이높았다 [41]. 여자형제나딸에게요로감염이있었을때도재발성방광염 (OR 각각 4.1, 2.6) 과재발성신우신염 (OR 각각 3.5, 2.9) 의위험이증가하였다. 이연구에서친척 1명혹은 2명이상에게요로감염병력이있는경우재발성방광염의교차비는각각 3.1 (95% CI 2.1-4.7) 과 5.0 (95% CI 3.1-8.1) 이었고재발성신우신염의교차비는각각 3.3 (95% CI 2.2-5.0), 5.5 (95% CI 3.4-9.0) 이었다. 4. 유전 1) 비분비자 (nonsecretor) 비분비자는 ABH혈액형과상관없이 ABH혈액형항원을체액으로분비하지않는것을의미한다. 재발성요로감염이있는여성은 ABH혈액형항원을분비하지않는사람일가능성이 3-4 배높다 [42-44]. 요로감염원인대장균은이런항원을분비하지않는여성의요로상피세포에더잘부착한다 [45]. 이는비분비자의질과요로상피세포는분비자와다르게요로감염원인대장균에더잘결합하는당지질수용체를갖고있기때문이다 [42]. 이러한관점에서비분비자의표현형은재발성요로감염이있는여성에게과하게나타난다 [42]. 그러나대규모사례대조군연구에서혈액형이나비분비여부는젊은여성에서재발성요로감염발생과아무상관이없었다 [17]. 성관계와살정제노출이더중요한젊은여성에서비분비상태는재발성요로감염의주요한위험요인이아님은주목할만하다 [16]. 사실비분비자는폐경전여성보다폐경후여성에게더중요한재발성요로감염위험요인이다 [46]. 다른연구에서비분비자여부와재발성요로감염이연관있는여성의평균연령은학생층보다높은 35세이상이었다 [43, 44]. 2) Interleukin-8 수용체결함 lnterleukin-8 (IL-8) 는감염된요로상피세포로중성구이동을촉진하는염증성시토카인이다. 동물실험에서 IL-8 의수용체인 CXCR1 이없는쥐는신장에서세균을제거하지못해균혈증을일으킨다 [47]. 재발성신우신염이있는소아의중성구에서 CXCR1 의결함이발견되었다 [48]. 5. 골반구조골반의생김새도일부젊은여성에서재발성요로감염발생에역할을한다. 재발성요로감염이있는여성 100 명과대조군 113 명사이요도구에서항문까지거리, 배뇨후잔뇨량, 배뇨특성등에차이가있는지를비교하였을때 [49], 요도구에서항문까지거리는대조군에비해사례군이현저히짧았다 ( 각각 4.8, 5.0 cm, P=0.03). 살정제를사용하지않는사람에서는사례군의요도구에서항문까지거리가 4.5 cm 미만일가능성이높았다 ( 교차비 5.7, 95% Cl 2.0-16.6, P=0.0013). 살정

346 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 제사용자에서는그런차이가없었다. 사례군과대조군사이요도의길이, 배뇨후잔뇨량, 배뇨특성 (peak flow rate, time to peak flow) 등에는차이가없었다. 이런연구결과는골반의해부학적인차이가일부여성에게, 특히요로감염의외적인위험요인이없는사람에게, 재발성요로감염을일으키는데기여함을시사한다. 6. 습관최근시행된대규모사례대조군연구에서다변량분석결과그전연구와동일하게젊은여성에서재발성요로감염은성관계전후배뇨양상, 배뇨횟수, 소변참기 (delayed voiding), 배변후닦는방향, 질세정, 탐폰사용, 샤워나욕조목욕, 속옷의종류, 수분섭취량, 카페인이든음료섭취, 체질량지수등과상관이없었다 [17]. 이연구에서피임방법도재발성요로감염과무관하였다. 자전거타기와도상관없다 [50]. 요약하면, 폐경전여성에서교정가능한행동위험요인은가로막, 콘돔, 살정제등의사용과성관계횟수등이다 [17, 21, 25, 26, 50]. 폐경후여성에서재발성요로감염의위험요인 1. 에스트로겐결핍폐경후여성에서발생하는재발성요로감염의위험요인은많이연구되지않았다. 폐경후여성은여성호르몬감소로질의정상균무리에변화가생겨요로감염의위험이증가한다. 폐경으로에스트로겐이줄면서질표피가얇아지고포도당량이감소한다. 이런환경은유산균의생존에적합하지않아결과적으로유산균수가감소하고질의산도는증가하게된다 [31]. 이에따라대장균과같은장내세균의정착이증가한다 [46, 51]. 이런여성이재발성요로감염을많이경험하게된다 [31]. 1999 년고찰에의하면폐경후여성에서에스트로겐결핍이 -비분비자, 폐경전요로감염병력, 요실금, 방광탈출증, 배뇨후잔뇨등과마찬가지로 -재발성요로감염을일으키는중요한요인이었다 [14]. 그러나사례대조군연구결과경구에스트로겐보충으로요로감염위험이줄지는않았다 [52]. 코호트연구에서도에스트로겐경구와질내투여모두폐경후여성에게요로감염예방효과가없었다 [53]. 2. 비뇨기과적위험요인폐경후여성에서재발성요로감염의위험요인은폐경전여성과다르다. 폐경전여성에게재발성요로감염의발생은습관적위험요인이두드러진반면, 폐경후여성은방광비우기에영향을미치는기계적혹은생리적위험요인이더중요하다 [2]. 재발성요로감염의병력이있는건강한폐경후여성 149 명과그러지않은 53명을비교한최근사례대조군연구에서요실금 (41% vs. 9%; P<0.001), 방광탈출증 (19% vs. 0%; P<0.001), 배뇨후잔뇨 (28% vs. 2% P=0.00008) 등세가지비뇨기과적요인들이폐경후여성의재발성요로감염과연관있었다 [46]. 이연구에서다변량분석결과폐경후재발성요로감염과강하게연관있는위험요인은요실금 (OR 5.79; 95% CI 2.05-16.42), 폐경전요로감염병력 (OR 4.85; 95% CI 1.7-13.84), 비분비상태 (OR 2.9; 95% CI 1.28-6.25) 등이었다 [46]. 폐경후여성에서요실금은요로감염발생에기여한다. 사례대조군연구에서만성요실금은일관성있게폐경후여성에서요로감염과연관이있었다 [46, 52, 54]. 요실금이있거나상당한골반바닥탈출이있거나배뇨후잔뇨가많은폐경후여성은재발성요로감염의발생위험이높다 [31]. 배뇨후잔뇨량을측정하여비교한결과폐경후여성에서배뇨후잔뇨량이 50 ml가넘는경우는독립적으로재발성요로감염의위험요인이었다 [55]. 3. 요로감염병력전술한바와같이폐경전요로감염병력은폐경후여성에게재발성요로감염의위험요인인데 [46], 다른연구에서는과거요로감염병력이있거나 [54] 과거 6회이상요로감염을앓은 [53] 경우도폐경후여성에서요로감염의위험이증가하였다. 4. 성생활성생활은폐경후여성 [53] 혹은 40-65 세사이여성 [54] 에서요로감염발생과연관이없었다. 대조적으로다른역학연구에서는최근성관계는젊은여성과마찬가지로폐경후여성에서도요로감염발생과연관있다고한다 [52, 56]. 재발성요로감염의예방 1. 항생제예방요법요로감염이반복적으로생기는여성에게삶의질향상을위하여항생제예방요법을고려할수있다. 항생제예방요법은 12개월동안 3 회이상혹은 6개월동안 2회이상요로감염이생긴여성가운데다른예방대책이효과가없을때로제한해야한다 [57]. 유럽비뇨기과학회는 2011 년지침에서다른예방책이실패한경우항생제예방요법을권하고있다 [58]. 항생제예방요법은지속항생제예방 (continuous antimicrobial prophylaxis), 성관계후예방 (post-coital prophylaxis), 자가치료 (patient-administered self-treatment) 등세가지전략이있다 [59]. 연2회이하발생하는경우자가치료가유용하고, 연3회이상재발하는사람에게는지속항생제예방혹은성관계후예방이좋다 [60]. 항생제는지역사회내성현황, 부작용, 가격등을고려하여선택한다 (Table 2). 1) 지속항생제예방자주앓는경우, 성관계가잦은경우, 혹은재발이시간적으로성관계와무관한경우지속적인예방요법 ( 매일, 주3회, 매주 ) 이낫다 [63]. 요로감염을예방한다는목적을달성하면서항생제노출을최소화할수있다면투여횟수는환자의반응에따라조정할수있다. 그러나감염률은예방요법이시행되는기간동안만감소하며항생제를끊으면기저수준으로되돌아간다. 항생제예방을시작하기전에이전요로감염의치료 1-2 주후요배양검사로박멸을확인해야한다 [63]. 재발성요로감염이있는여성에게매일저용량항생제로예방요법

www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 347 Table 2. Antimicrobial Prophylaxis for Recurrent Urinary Tract Infections [2, 62] Antimicrobial agent Continuous prophylaxis (daily dosage) a Postcoital prophylaxis (one-time dose) b Acute self treatment Cephalexin 125 to 250 mg 250 mg - Ciprofloxacin 125 mg 125 mg 250 mg bid for 3 days Nitrofurantoin 50 to 100 mg 50 to 100 mg - Norfloxacin 200 mg 200 mg 200 mg bid for 3 days Trimethoprim 100 mg 100 mg - Trimethoprim/sulfamethoxazole 40/200 mg 40/200 to 80/400 mg 160/800 mg bid for 3 days a Typically taken at night [2]. Taken within 2 hours of intercourse [2, 61]. 을시행하는경우 95% 재발을막을수있다 [64]. 430 명여성 10 개임상시험을분석한최근 Cochrane 체계고찰에서는재발성요로감염이있는폐경전후여성에서지속항생제예방은임상적그리고미생물학적재발을줄이는데효과적이었다 [63]. 이체계분석에는성관계후예방에대한임상시험이 1개 [65] 포함되었다. 고찰결과에따르면지속항생제예방군에서임상적재발은 0-0.27 회 / 환자- 년인반면대조군은 1.12-3.6 회 / 환자- 년이었다. 지속항생제예방군에서임상적재발의비교위험도는 0.15 (95% CI 0.08-0.28) 로증상이있는재발성요로감염 1건을예방하는데필요한숫자는 2.2 (95% CI 1.80-2.80) 이었다. 미생물학적재발은각각 0-0.9 회 / 환자- 년, 0.8-3.6 회 / 환자- 년으로지속항생제예방군에서훨씬낮았다. 미생물학적재발의비교위험도는 0.21 (95% CI 0.13-0.34) 로미생물학적재발 1건을예방하는데필요한숫자는 1.85 (95% CI 1.60-2.20) 이었다. 임상시험에 fluoroquinolones (norfloxacin, ciprofloxacin, pefloxacin), cephalosporins (cephalexin, cefaclor), TMP, SMX, nitrofurantoin 등의항생제가사용되었으나특정약제가더우수하지는않았다 [63]. 저용량 TMP- SMX (40/200 mg) 매주 3회복용의경우요로감염발생률은 0.2 회 / 환자- 년미만이었다 [9, 16]. 지속항생제예방군에서치료를중단할정도의중증부작용에대한비교위험도는 1.58 (95% CI 0.47-5.28) 이었고피부발진과심한구역이가장흔하였다. 그외덜심한부작용발생의비교위험도는 1.78 (95% CI 1.06-3.00) 이었고질 / 구강칸디다증, 소화장애등이발생하였다 [63]. 항생제예방요법에가장적합한약제가무엇인지는알려지지않았으므로알레르기, 과거항생제감수성, 지역사회내성양상, 가격, 부작용등을고려하여항생제를선택한다 [63]. 환자는예방요법을시작하기전에흔한부작용에대하여이해해야하고모든항생제에드물지만중증부작용이있음을알아야한다 [66]. 6-12 개월지속예방요법으로요로감염발생률을예방기간동안줄일수있으나 [63], 이기간보다더오래투여해야할지말지에대해분명한증거는아직없다. 중단후요로감염발생률은 6개월과 12개월예방요법사이에차이가없었다 [63]. 일부전문가는재발성증상성감염이있는환자에게더오래 (2-5 년 ) 예방요법을권하기도한다. 저용량 TMP-SMX 을 5년까지시도한바는있다 [67]. 예방요법기간은증상의중증도와환자의선호에따라결정한다. 6개월예방요법후에는항생제중지후생기는재감염에대한관찰기간을갖도록권한다 [2]. 환자가오래항생제예방요법을받기를원하면장기투여에따른안전성자료가없음을충고해야하고중증부작용발생의위험과내성균에의한돌발 (breakthrough) 감염이적게나마있음을알려야한다 [66]. 이런항생제예방요법으로재발성요로감염의자연경과가수정되는것은아니므로예방요법을종료하면요로감염발생률이이전상태로되돌아간다. 항생제예방요법을중단한지 3-4 개월안에약 60% 여성에서재발감염을예상할수있다 [68]. 예방요법중지로재발성감염의양상과횟수가예방요법이전상태로돌아온다면예방요법을 6-12 개월다시시도할수있다 [31]. 2) 성관계후항생제예방성관계후항생제예방요법은시간적으로요로감염발생이성관계와연관있는여성에게사용한다 [31]. 1년에 3-4 회요로감염을앓는여성에게효율적이다. 이중맹검위약대조군무작위시험에서지난 1년동안배양으로증명된요로감염이 2회이상있는여성이 TMP-SMX 40/200 mg을성관계후복용하여감염률은환자- 년당 0.3 회이었으나대조군은 3.6 회로 92% 요로감염이감소하였다 [65]. 이연구에서미생물학적재발의비교위험도는 0.15 (95% CI 0.04-058) 이었다. 부작용은드물고사소한것이었다. 나중에 ciprofloxacin 을이용하여시행된무작위대조시험에서성관계후복용한것이나매일복용하는것이나예방효과에차이는없었다 [69]. 추가적인비대조시험에서도다른전략의항생제예방요법과비교하여효과에차이가없었다 [2]. TMP-SMX 을견디지못하거나내성이면 nitrofurantoin 이나 fluoroquinolone 계항생제등을 TMP-SMX 만큼효과적으로사용할수있다. 그러나아직성관계후예방요법과관련된임상증거는충분하지않다 [65]. 특히 fluoroquinolone 계항생제는매우효과적이나일반적으로는권장되지않으므로, 임신가능성을고려하고태아에대한위험과이득을따져결정한다. 이는다른전략의항생제예방요법에서도고려해야할요소다. 성관계후항생제예방요법을시작하기전에요배양검사로세균뇨가없음을확인해야한다 [57]. 성관계후예방요법은성관계 2시간안에복용해야비용과부작용을줄일수있다 [70]. 12개월이상임상시험이시행되지않았으며, 현재복용기간이나복용횟수에관한권고안은아직없다 [63]. 성관계횟수에달렸지만, 성관계후예방요법은항생제사용량이다른예방법보다적다. 3) 자가치료엄밀하게예방책은아니나일부여성에게도움이된다. 성관계와무관하게단순요로감염이재발하는여성에게환자시작 ( 주도 ) 치료가적합하다. 이방법은 1년에두세번재발하는경우유용하다 [31]. 장점은

348 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 예방항생제장기복용을피한다는점이다. 이예방법은확실하게증명된재발성요로감염의병력이있고동기가있으며의사의지시를잘따르고의료진과협조적인여성에국한해야한다 [2]. 증상으로요로감염시작을인지할수있는여성에게적용한다 [71-73]. 자가진단과요배양사이 86-91% 일치율을보이므로요로감염을자가로진단하고치료하는경우요배양은불필요하다 [74]. 해당여성에게는 3일분의치료항생제를제공한다 [70]. 증상이시작되면환자주도로항생제복용을시작한다. 48시간안에증상이호전되지않으면병원에오도록한다 [74]. 주기적인요배양으로요로감염존재와항생제감수성을확인해야한다 [57]. 한편, 항생제 1회복용은지속항생제예방보다재발예방에덜효과적이다 [73]. 이임상시험에서 TMP-SMX 1회복용으로방광염발생횟수는 2.2 환자- 년이었으나지속항생제예방은 0.2 환자- 년이었다 (P<0.001). 2. 에스트로겐크림에스트로겐결핍은요로감염위험증가와연관있는바에스트로겐투여로폐경후여성에서재발성요로감염의위험을줄일수있다 [75]. 에스트로겐치료는질상피에서유산균의증식을촉진하여폐경전처럼산도를낮추고장내세균의질정착을억제한다. 폐경후여성 93명을대상으로한이중맹검무작위대조시험에서질내에스트로겐투여군은요로감염발생률이 0.5 회 / 환자- 년로위약의 5.9 회 / 환자- 년 (P=0.001) 에비해요로감염발생이현저히줄었다 [75]. Cochrane 체계고찰에사용된 2개무작위시험결과에스트로겐치료군에서증상성요로감염의비교위험도는각각 0.25 (95% CI 0.13-0.50) [75], 0.64 (95% CI 0.47-0.86) [51] 로요로감염발생이줄었다 [76]. 두군모두치료전질배양에서유산균은배양되지않았으나 1개월후에스트로겐치료군에서는 61% 다시나타났으나위약군은아무도배양되지않았다 (P=0.001). 마찬가지로질의산도는평균 5.5 에서 3.6 으로낮아졌으나위약군은변화가없었다. 질내에스트로겐과항생제예방요법의효과를비교한시험은연구이질성때문에분석에사용할수없었다 [76]. 에스트로겐치료반응은에스트로겐종류와치료기간에따라다양하였다. 에스트로겐은화합물자체보다는투여경로가더중요하다 [77]. 에스트로겐경구투여는위약과비교하여요로감염을줄이지못하였다 [76]. 마찬가지로호르몬대체요법은요로감염발생에영향을미치지않았다 [78]. 국소크림과달리, 페서리형태는저용량항생제예방만큼효과적이지는않았다 [76]. 질내에스트로겐투여로생기는부작용에는유방압통, 질출혈, 비생리적인분비물, 질의화끈거림과가려움증등이있다 [70]. 에스트로겐질내투여는에스트로겐과연관된자궁내막암발생을염려할필요가없다 [79]. 임상시험에사용된에스트로겐투여방법은 2주동안크림 0.5 mg을질내에매일바른후 8개월동안매주 2회바르는것이었다 [75]. 에스트로겐치료는폐경후여성에게특히다제내성균감염으로항생제선택과효과에제한이있거나증상이위축성질염과연관된경우적응증이된다 [46]. 그러나신체활동에제약이있는여성 ( 치매나중풍등 ) 은스스로바르기어렵겠고일부여성은질내적용에거부감 이있을것같다. 요약하면, 질내국소에스트로겐은폐경후여성에게요로감염재발을줄이나일부여성에만효과가있는것같고지속항생제예방만큼효과적이지는않다. 3. 크랜베리요로상피에부착하지않고는세균이요로계점막표면을감염시킬수없다. 크랜베리는세균특히대장균이요로상피세포에부착되는과정을막는다 [80, 81]. 크랜베리의 proanthocyanidin 이라는탄닌성분이요로감염을일으키는 P fimbriated 대장균이요로상피세포에부착하는것을억제한다 [82]. 크랜베리생산품은이러한기전으로증상성방광염의재발을줄이는것으로알려졌다. Proanthocyanidin 는크랜베리, 블루베리, 링곤베리주스에서발견되나자몽, 오렌지, 구아바, 망고, 파인애플주스에서는발견되지않았다 [83]. 많은주스가 type 1 fimbriated E. coli 의부착을억제하는것으로알려졌으나 P fimbriated 대장균에대한효과는블루베리와크랜베리주스가유일하다 [81, 83]. 과거생각했던것과달리, 크랜베리주스는소변의산도를변경시키지는않는다 [84]. 크랜베리주스의항부착 (antiadherent) 효과는섭취 2시간후부터시작되어 10시간까지지속된다고한다 [85]. 2008 년 Cochrane 체계고찰에따르면크랜베리는 12개월치료기간동안유의하게요로감염발생을줄였다 [86]. 4개무작위대조시험의메타분석결과크랜베리생산물은위약에비해요로감염발생률을낮추었다 (RR 0.66; 95% CI 0.47-0.92). 크랜베리생산품 ( 주스, 알약 ) 혹은링곤베리주스를매일섭취하면재발성요로감염을 -항생제사용은 90-95% 줄이는데 -약 30% 줄인다 [87, 88]. 그러나 2011 년발표된다른무작위대조시험 (n=319) 에서는여자대학생에서크랜베리주스칵테일 240 ml 하루 2회섭취가위약에비해요로감염재발률이오히려약간높았다 (20.0% vs. 14.0%) [89]. 2012 년새로운체계고찰과메타분석에따르면크랜베리추출물복용자에서재발성요로감염의비교위험도는 -분석된연구사이중등도의통계적이질성을감안하고 -위약군과비교하면 0.62 (95% CI 0.49-0.80) 로 2008 년 Cochrane 체계고찰결과와비슷하였다 [90]. 하위그룹분석결과크랜베리추출물은다른인구집단보다는재발성요로감염있는여성 (RR 0.53; 95% CI 0.33-0.83), 여성인구집단 (RR 0.49; 95% CI 0.34-0.73), 18세이상보다는 18세미만소아 (RR 0.33; 95% CI 0.16-0.69), 크랜베리알약이나캡슐약보다는주스를복용한경우 (RR 0.47; 95% CI 0.30-0.72), 하루 1회복용한것보다는 2회이상복용한경우 (RR 0.58; 95% CI 0.40-0.84) 등에효과적이었다. 한편, 최근무작위시험에서도크랜베리주스가위약에비해폐경전여성 176 명에서재발성요로감염발생을줄이고 (adjusted hazard ratio 0.68; 95% CI 0.33-1.39; P=0.29) 소변에서 P형 fimbria 가있는대장균을감소시키는 (43.5% vs. 80.0%; P=0.07) 것으로밝혀졌다 [91]. 그러나연구자들은표본수가충분하지않아통계적검정력은떨어진다고지적하였다. 크랜베리생산물은항생제요법보다는요로감염예방효과가떨어진다. 45세이상여성 137 명을대상으로크랜베리추출물 ( 하루 500 mg) 과 trimethoprim ( 하루 100 mg) 의예방효과를비교한무작위

www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 349 대조시험에서크랜베리군의비교위험도는 1.616 (95% CI 0.93-2.79; p=0.084) 로항생제군은크랜베리군에비해제한적인이득이있었으나부작용이더많았다 [92]. 크랜베리캡슐 (500 mg 하루 2회 ) 과 TMP- SMX (480 mg 매일 1회 ) 를비교한다른무작위시험에서연구기간중한번이라도증상성요로감염이생긴사람의비율이각각 78.2%, 71.1% 로폐경전여성에서재발성요로감염을예방하는데크랜베리보다항생제가더효과적이었다 [93]. 치료 1개월후무증상세균뇨의대장균균주가크랜베리군은 28.1% 항생제군은 90.5% 가 TMP-SMX 에내성이었다. 크랜베리는노인 ( 남녀모두 ) 보다는특히성적으로활발한여성에서재발성요로감염을예방하는데도움이된다 [86]. 크랜베리섭취는노인에서세균뇨를예방하기는한다 [94]. 그러나신경인성방광이있는사람에게는도움이되는것같지않았다 [86]. 무작위대조시험에서 16 주이상임신여성에서매일크랜베리주스섭취는크랜베리는증상성요로감염과무증상세균뇨를줄이는데효과적이었다. 임신부에서순응도가떨어져이러한효과는감소하는것으로추정되었다 [95]. 크랜베리주스자체는산도가너무낮아그대로마실수없어서감미료와물, 비타민 C와혼합하여크랜베리주스칵테일형태로판매되고있다 [94]. 알약과캡슐약형태도있다. 그러나요로감염예방에효과적인섭취용량이나농도, 기간에대한분명한증거가없다 [96]. 가장많이연구된형태는크랜베리주스칵테일로여기엔순수크랜베리주스가 25% 들어있다. 주스는하루 4-32 oz ( 약 120-950 ml) 를 3회로나누어식사와함께섭취하고알약은하루 600 mg에서 1200 mg 이상을 2회혹은 3회로나누어복용한다 [97]. 소규모연구에의하면크랜베리주스하루 150-750 ml ( 혹은이와동등한농도 ) 복용이재발성요로감염예방에효과적이었다 [87, 98]. Proanthocyanidin 이 36 mg 들어있는크랜베리주스칵테일 300 ml을매일마시면임상적으로세균뇨와농뇨를줄일수있는데 [84], 최근시험관내연구에서는 proanthocyanidin 이 72 mg 들어있는정도를매일섭취해야요로에서세균의부착과병독성을억제할수있다고한다 [99]. 2012 년메타분석에포함된 2개임상시험에서는 proanthocyanidin 을하루 72 mg 이상복용한다고하여예방효과가나타나는것은아니었다 [89, 95]. 부작용에는소화장애, 체중증가 ( 과도한칼로리섭취 ), 잠재적인약물상호작용 (flavonoid 가 cytochrome P450 효소계를억제 ) 등이있다 [97]. 앞의부작용과더불어다른여러이유로임상시험에서중도탈락률이최대 55% 에달하였다. 비용도꽤든다는점을고려하면크랜베리는장기간복용에적합한예방대책은아니다 [100]. 2008 년 Cochrane 체계고찰에포함된임상연구디자인에이질성이있고적합한용량과제형에대한합의가없다는점때문에미국에서는요로감염예방에크랜베리를권하지않는것같다 [97]. 2012 년미국의사협회가권하는요로감염예방수칙에도크랜베리는빠져있다 [101]. 한편, 유럽비뇨기과학회는 2011 년지침에서크랜베리를시도하는경우하루 proanthocyanidin 36 mg 이상복용을권하고있다 [58]. 가임기여성에서요로감염예방에기여하는식이를분석한역학연구결과베리주스같은신선한주스혹은정장세균을함유한발효된유제품섭취로요로감염을예방할수있다고한다 [102]. 이에반해, 커 피, 차, 청량음료섭취뿐만아니라비타민복용혹은하루수분섭취량등은요로감염예방과상관이없었다. 이외에도요로감염치료와예방에사용되는천연물의종류는많지만아직과학적연구는부족하다 [103]. 4. 성생활과피임젊은여성에서성생활이나살정제사용등을포함한, 수정가능한요로감염위험인자에대해상담이필요하겠다 [15, 17, 27, 104]. 젊은여성에서재발성요로감염과가장강하게연관된위험요인이성관계이고기본적으로성적으로활발한인구집단일지라도대장균에의한재발성요로감염이전에성관계가늘선행하는것도아니고성관계가항상재발성요로감염을초래하지도않는다 [24]. 그러므로성적으로활발한여성에서요로감염의재발을예방하기위해막연하게금욕을권하는것은합리적이지않아보인다. 살정제가포함된피임법을사용하는여성에게는가로막과살정제대신다른피임법을권한다 [60, 105-106]. 5. 행동수정마시는물의양을늘리면방광에서세균을씻어낼수있다고믿어왔다. 병원균이방광벽에붙어야한다는사실을모르던시절인 1965 년수학적모델시험으로는잔뇨량이조금있는경우빠른증식때문에자주소변을보는것으로는세균들을씻어내기에충분하지않았다. 그보다는이러한치료로소변에서 Tamm-Horsfall glycoprotein 과같은항세균물질들이희석되어감염위험이증가될지모른다 [50]. 수분섭취량을늘려세균을씻어내리려는노력은대규모전향연구에서효과가증명되지않았다 [15]. 대규모연구에따르면, 요로감염병력이있는여성과대조군을비교하였을때하루소변보는횟수, 수분섭취량, 성관계와배뇨사이시간간격등에차이가없었다 [19]. 성관계전후요배양검사를시행한연구결과성관계직후일시적인세균뇨가종종생기는것이확인되었다 [23]. 후향적사례대조군연구결과성관계후즉시배뇨가요로감염예방에도움이되었으나 [107] 나중에시행된대규모전향연구에서는그효과가확인되지않았다 [15]. 최근체계고찰에서도성관계후배뇨가요로감염예방에도움이된다고증명한대조시험결과는없었다 [61]. 달리해롭지도않고다른예방책도없어재발성요로감염을예방에도움이될지모른다는기대때문에성관계후배뇨는성관계와요로감염사이연관관계가있는여성에게권고사항으로남아있다. 6. 프로바이오틱스 (probiotics) 프로바이오틱스는질과방광에병원성세균이정착하는것을막을수있다. 유산균이폐경전건강한여성의비뇨생식기균무리에우세하기때문에요로감염균이우세한비뇨생식기균무리를유산균으로되돌리면요로감염을예방할수있을것으로보고있다. 유산균은질에있는농도에서많은미생물에독성을나타내는젖산, bacteriocin, 과산화수소등의항균물질을생산한다 [108]. 게다가유산균은세포표면에요로감염균의부착을막는 biosurfactant 를생산하여선천면역

350 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 반응을비특이적으로증강시키는데기여한다 [108, 109]. 요로감염예방연구에사용된유산균중에서 Lactobacillus rhamnosus GR-1 과 L. reuteri RC-14 ( 과거에 L. fermentum RC-14) 이가장효과적인균주다 [110]. L. caseishirota 와 L. crispatus CTV-05 도일부연구에서효과가있었다. L. rhamnosus GG는요로감염예방에효과가없다. 지금까지연구결과로는프로바이오틱스는여성에게재발성요로감염예방에이득이있을것으로보인다 [110]. 프로바이오틱스는안전성면에서도문제없다. 그러나프로바이오틱스가이적응증으로널리사용되려면효과가확실하게증명되는무작위대조시험이필요하다 [110]. 질좌약으로유산균이재발성요로감염예방에시험되었다. 오래전무작위위약대조군시험에의하면폐경전여성에게 L. rhamnosus 질좌약을 26주동안주2회적용한결과 6개월동안증상성요로감염발생률 (0.21/ 월 ) 이대조군 (0.15/ 월 ) 과차이가나지않았다 [111]. 게다가치료군은요도구주위에서유산균이더잘발견되지도않았다. 하지만, L. crispatus GAI 98332 가들어있는질좌약을재발성요로감염있는여성 9명에게 12개월적용한예비연구에서요로감염재발이 5.0±1.6 회 / 년에서 1.3±1.2 회 / 년으로 (P=0.0007) 로줄었다 [112]. 폐경전여성에게 10 주동안매주 1회 L. crispatus 질좌약을적용한제2상임상시험 (n=100) 결과요로감염재발은 15% 위약대조군은 27% 로비교위험도는 0.5 (95% CI 0.2-1.2) 이었다 [113]. 치료군에서는질내 L. crispatus 의정착이많은경우요로감염재발이의미있게감소하였다. 폐경전여성에게 5일동안매일 L. crispatus 질좌약을사용한제1 상임상시험 (n=30) 결과심한부작용은없었으나질분비물이나가려움증을호소하였다 [114]. 다른임상시험에서도유산균질내투여의가장흔한부작용은질분비물이나가려움증, 중등도복통등이었다 [113]. 경구프로바이오틱스로요로감염위험을줄이려면유산균이위장관과비뇨생식기에정착해야한다. 실제로사람에서유산균을경구로투여하여질로전달됨이확인되었다 [115]. 재발성진균질염, 세균질염, 요로감염병력있는여성 10 명에게 L. rhamnosus GR-1 와 L. reuteri RC-14 를하루 2회 14 일동안복용하였는데치료 1주안에그들의질에서발견되었다. 그러나 149 명여성에서 L. rhamnosus GG 요거트 100 ml 1년동안주5일복용을크랜베리 -링곤베리주스 100 ml 6개월매일복용과비교하였을때유산균군은 6개월후증상성요로감염의재발률이 39% 로예방효과가전혀없었으나크랜베리 -링곤베리주스군은대조군과재발 ( 각각 8%, 36%; P=0.023) 에차이가났다 [87]. 다른무작위연구에서재발성요로감염이있는폐경후여성 252 명에게 L. rhamnosus GR-1 과 L. reuteri RC-14 하루 2회 12개월경구투여와 TMP-SMX 예방요법을비교하였을때치료의향분석 (intention-totreat analysis) 결과 12개월예방요법후증상성요로감염은각각 3.3, 2.9 건발생하였고치료법사이차이는연 0.4 건 (95% CI -0.4 to 1.5) 으로비열등성기준에충족되지않았다 [116]. 각각 79.1%, 69.3% 환자에서증상성요로감염이적어도한번발생하였다. 아직까지는재발성요로감염예방에프로바이오틱스를이용한임상시험의표본수도적고투여법이확립되지않았으며결과도상충되고결정적이지않아대규모임상시험이더시행되어야한다고한다 [117, 118]. 유럽비뇨기과학회는 2011 년지침에서프로바이오틱스도사용 가능하나예방효과가있는유산균균주가유럽에서상용화되지않았다고한다 [58]. 그러나맨나중에시행된임상시험결과를고려하면요로감염예방에프로바이오틱스사용은권할만하지않다. 7. 면역강화예방 (immunoactive prophylaxis) 요로감염세균을죽여만든용해물 (lysate) 을투여하면재발성요로감염에대한감수성을줄이고숙주의방어능력을증강시킬수있다 [119]. 열로죽인요로감염균균주를혼합하여만든, 주사나질좌약으로투여하는전세포백신은방어효과가몇주에걸쳐감소하기때문에자주투여해야한다는점에서백신이라기보다는면역자극 (immuno-stimulation) 의범주에든다. OM-89 은그런여러면역자극제 (immunostimulant) 중하나다. 면역강화예방요법의가장큰장점은항생제사용을피한다는점이다. Uro-Vaxom 은 OM-89 경구캡슐로서 18개혈청형의요로감염대장균균주를가열처리하고동결건조시켜만든균체용해물로미국식품의약품국의승인을받지는않았지만유럽의일부국가에서재발성요로감염의예방에이차적으로사용하고있다 [119]. StroVac 와 SolcoUrovac 은서로다른혈청형 6종의대장균, Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii, Enterococcus faecalis 등 10 가지세균으로만든것으로각각근육주사하거나질좌약으로투여한다. 그외에 Urostim (1 형 pili를나타내는요로감염대장균, 대장균의 Rc돌연변이주, K. pneumoniae, Proteus mirabilis, E. faecalis 등 ) 과 Urvakol ( 요로감염대장균, K. pneumoniae, P. mirabilis, P. aeruginosa, E. faecalis 등 ) 가있다. 5개위약대조군이중맹검대조시험을메타분석한결과 Uro-Vaxom 경구복용으로요로감염발생률이연 0.15-0.82 건으로요로감염예방에위약군보다효과적이었다 [120]. 이후여성 453 명이 1년동안 Uro- Vaxom 을복용한대규모대조시험에서도요로감염이 34% 감소하였다 [121]. 이임상시험에서 Uro-Vaxom 은 3개월동안하루 1회복용하고다음 3개월동안중지한후그다음 3개월동안매월첫 10 일만하루 1회복용하고다음 3개월다시중지하였다 [121]. OM-89 경구면역자극제를이용한 5개임상시험 ( 성인 1,000 명 ) 을다시메타분석한결과- 분석에포함된임상시험사이에유의한이질성이존재하므로결과해석에주의가필요하지만 -요로감염횟수가평균 36% 줄었다 [119]. 유일한국내연구에따르면재발성방광염이있는폐경전후여성 42명이 Uro-Vaxom 을 3개월복용한후 6개월추적기간동안환자당요로감염발생은 0.35 건으로치료전 6개월동안 4.26 건보다재발이훨씬줄었다 (P<0.001)[122]. 여러임상시험에서 Uro-Vaxom 은치명적이거나중요한부작용은없었고두통이나소화장애등의가벼운부작용만관찰되었다 [123]. 과거유럽비뇨기과학회는 1차전략으로항생제예방을권하고불가능한경우면역강화예방을대체요법으로권하였다 [124]. 그러나 2011 년지침에서는면역강화예방요법을항생제예방요법의대체라고기술하지는않았으나예방대책의하나로권하고있다 [58]. Uro-Vaxom 과항생제예방요법을비교한제3 상임상시험결과가앞으로발표되면면역강화예방요법의적응증이더구체화될것같다. SolcoUrovac 으로재발성요로감염여성 75명에게 160 일동안진

www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 351 행된제2상이중맹검위약대조군시험에서위약은 70% 재발하였으나시험군은 27.5% 재발하였다 [125]. SolcoUrovac 은첫 3주동안매주질좌약으로넣고그다음 3개월동안매달 1회넣는다. 최근의메타분석에의하면이런질좌약은추가로정기적으로투여하면 (booster cycle) 위약의 14% 에비해 50% 에서요로감염재발이없었다 [119]. 질좌약은안전한반면, 국소특이항체가많이증가하지도않고주기적으로투여하지않으면방어면역이감소한다 [126]. 다른제제에대해서는같은적응증으로맹검대조시험이시행된바가없다 [119]. 세균의구성성분이나전세포를이용한다른요로감염백신은개발이진행되고있으며이에대해서는다른문헌을참고하기바란다 [126]. 8. 기타 2개소규모무작위시험에서 sham acupuncture 는대조군에비해재발성하부요로감염을줄이는것으로나타났다 [127,128]. 화장실의비데설치가재발성요로감염예방에도움이되는지는알수없으나소변에서세균량이줄었거나 [129] 질의유산균이감소함으로써균무리에악영향을미쳤다는 [130] 보고가있다. 결론 기술한예방대책가운데가장효과적인것은항생제예방요법이다 (Table 3). 2011 년미국감염학회와유럽임상미생물감염학회가발표한요로감염치료지침에는재발성요로감염의예방에대한언급이없다 [132]. 유럽비뇨기과학회는 2011 년지침에서재발성요로감염의예방대책으로항생제예방, 면역강화예방, 크랜베리, 프로바이오틱스, 폐경 후여성에게에스트로겐질내투여등을제시하였다 [58]. 이유럽지침에항생제예방요법은다른예방책이실패한경우사용하기를권하고있다. 프로바이오틱스는예방효과가있는균주가나중에유럽에서상용화되었을때질내투여를고려해볼수있다고한다. 그러나다른세가지예방법은적응증이나고려순위를언급하지않았다. 요약하면, 재발성요로감염예방목적으로폐경후여성에게는에스트로겐질좌약을, 젊은여성은피임법의대체를우선권할수있겠다. 그렇지만우리나라는살정제사용이보편화된게아니므로피임법에대한권고는사실현실성이떨어진다. 앞의예방법이실패한경우항생제예방요법을폐경전후여성모두에게적용할수있겠으나장기사용에따른항생제내성유발과약제부작용이부담스럽다. 크랜베리추출물은다른예방법이효과적이지않다면적어도폐경전여성에게시도해볼수있겠다. 대장균추출물을이용한면역강화예방요법은항생제예방요법과비교한 3상임상시험결과에따라적응증이결정될것같다. 물많이마시기, 성관계후배뇨, 배뇨혹은배변후앞쪽에서뒤쪽으로닦기, 소변참지않기, 면으로만든속옷과헐렁한옷입기, 욕조에서목욕하지않기등의생활습관교정이, 역학연구에서예방효과가증명되지않았지만, 위생적인데다비용이들지않고우려할만한부작용이없어흔히권장되고있다 [101, 133-135]. 감사의글 바쁘신데도초고를읽고비평해주신가톨릭대학교의과대학내과학교실위성헌교수님께감사를표합니다. Table 3. Strategies for Prevention of Recurrent Acute Uncomplicated Urinary Tract Infection [116, 121, 131] Strategy Efficacy [131] Long-term low dose antimicrobial prophylaxis TMP/SMX 40/200 daily or every other day 95% TMP 100 mg daily 95% Nitrofurantoin 50 mg or macrocrystals 100 mg daily 95% Norfloxacin 200 mg daily or every other day 95-100% Ciprofloxacin 125 mg daily >95% Cephalexin 250 mg 500 mg daily 95% Postcoital antimicrobial prophylaxis Cephalexin 250 mg >95% TMP/SMX 40/200 mg or 80/400 mg 90-95% Trimethoprim 100 mg >95% Nitrofurantoin 50 mg or 100 mg >95% Norfloxacin 200 mg >95% Ciprofloxacin 125 mg >95% Nonantimicrobial strategies Cranberry or lingonberry juice or other products 20-30% Topical estrogen for postmenopausal infections 0-30% Immunoactive prophylaxis (with Uro-Vaxom) 34% [121] Probiotics 0% per oral [116] TMP, trimethoprim; TMP/SMX, trimethoprim-sulfamethoxazole References 1. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 2002;113 Suppl 1A: 5S-13S. 2. Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents 2001;17:259-68. 3. Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am 2003;17:227-41. 4. Ikaheimo R, Siitonen A, Heiskanen T, Karkkainen U, Kuosmanen P, Lipponen P, Makela PH. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis 1996;22:91-9. 5. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990;80:331-3. 6. O'Reilly M. Recurrent urinary tract infection. In: Stanton SL, Dwyer PL, eds. Urinary tract infection in the female. London: Martin Dunitz; 2000;227-40.

352 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 7. Brumfitt W, Gargan RA, Hamilton-Miller JM. Periurethral enterobacterial carriage preceding urinary infection. Lancet 1987;1:824-6. 8. Gupta K, Stapleton AE, Hooton TM, Roberts PL, Fennell CL, Stamm WE. Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. J Infect Dis 1998;178: 446-50. 9. Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med 2003;349:259-66. 10. Schilling JD, Mulvey MA, Hultgren SJ. Structure and function of Escherichia coli type 1 pili: new insight into the pathogenesis of urinary tract infections. J Infect Dis 2001;183 Suppl 1:S36-40. 11. Lane MC, Mobley HL. Role of P-fimbrial-mediated adherence in pyelonephritis and persistence of uropathogenic Escherichia coli (UPEC) in the mammalian kidney. Kidney international 2007;72:19-25. 12. Kallenius G, Mollby R, Svenson SB, Helin I, Hultberg H, Cedergren B, Winberg J. Occurrence of P-fimbriated Escherichia coli in urinary tract infections. Lancet 1981;2:1369-72. 13. Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection. PLoS medicine 2007;4:e329. 14. Stamm WE, Raz R. Factors contributing to susceptibility of postmenopausal women to recurrent urinary tract infections. Clin Infect Dis 1999;28:723-5. 15. Hooton TM, Scholes D, Hughes JP, Winter C, Roberts PL, Stapleton AE, Stergachis A, Stamm WE. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996;335:468-74. 16. Hooton TM. Pathogenesis of urinary tract infections: an update. J Antimicrob Chemother 2000;46 Suppl 1:1-7; discussion 63-5. 17. 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;182:1177-82. 18. Hooton TM, Hillier S, Johnson C, Roberts PL, Stamm WE. Escherichia coli bacteriuria and contraceptive method. JAMA 1991;265:64-9. 19. Remis RS, Gurwith MJ, Gurwith D, Hargrett-Bean NT, Layde PM. Risk factors for urinary tract infection. Am J Epidemiol 1987;126:685-94. 20. Nicolle LE, Harding GK, Preiksaitis J, Ronald AR. The association of urinary tract infection with sexual intercourse. J Infect Dis 1982;146:579-83. 21. Foxman B, Frerichs RR. Epidemiology of urinary tract infection: I. Diaphragm use and sexual intercourse. Am J Public Health 1985;75:1308-13. 22. Bran JL, Levison ME, Kaye D. Entrance of bacteria into the female urinary bladder. N Engl J Med 1972;286:626-9. 23. Buckley RM, Jr., McGuckin M, MacGregor RR. Urine bacterial counts after sexual intercourse. N Engl J Med 1978;298:321-4. 24. Czaja CA, Stamm WE, Stapleton AE, Roberts PL, Hawn TR, Scholes D, Samadpour M, Hultgren SJ, Hooton TM. Prospective cohort study of microbial and inflammatory events imme diately preceding Escherichia coli recurrent urinary tract infection in women. J Infect Dis 2009;200:528-36. 25. Foxman B, Frerichs RR. Epidemiology of urinary tract infection: II. Diet, clothing, and urination habits. Am J Public Health 1985;75:1314-7. 26. Fihn SD, Boyko EJ, Normand EH, Chen CL, Grafton JR, Hunt M, Yarbro P, Scholes D, Stergachis A. Association between use of spermicide-coated condoms and Escherichia coli urinary tract infection in young women. Am J Epidemiol 1996;144:512-20. 27. Fihn SD, Boyko EJ, Chen CL, Normand EH, Yarbro P, Scholes D. Use of spermicide-coated condoms and other risk factors for urinary tract infection caused by Staphylococcus saprophy ticus. Arch Intern Med 1998;158:281-7. 28. McGroarty JA, Tomeczek L, Pond DG, Reid G, Bruce AW. Hydrogen peroxide production by Lactobacillus species: correlation with susceptibility to the spermicidal compound nonoxynol-9. J Infect Dis 1992;165:1142-4. 29. Klebanoff SJ. Effects of the spermicidal agent nonoxynol-9 on vaginal microbial flora. J Infect Dis 1992;165:19-25. 30. Stamey TA, Sexton CC. The role of vaginal colonization with enterobacteriaceae in recurrent urinary infections. J Urol 1975;113:214-7. 31. Gupta K, Stamm WE. Pathogenesis and management of recurrent urinary tract infections in women. World J Urol 1999;17:415-20. 32. Herthelius BM, Hedstrom KG, Mollby R, Nord CE, Pettersson L, Winberg J. Pathogenesis of urinary tract infections--amoxicillin induces genital Escherichia coli colonization. Infection 1988;16:263-6. 33. Winberg J, Herthelius-Elman M, Mollby R, Nord CE. Pathogenesis of urinary tract infection--experimental studies of vaginal resistance to colonization. Pediatric nephrology 1993;7:509-14. 34. Reid G, Bruce AW, Cook RL, Llano M. Effect on urogenital flora of antibiotic therapy for urinary tract infection. Scand J Infect Dis 1990;22:43-7. 35. Hooton TM, Winter C, Tiu F, Stamm WE. Randomized comparative trial and cost analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women. JAMA

www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 353 1995;273:41-5. 36. Hooton TM, Johnson C, Winter C, Kuwamura L, Rogers ME, Roberts PL, Stamm WE. Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women. Antimicrob Agents Chemother 1991;35: 1479-83. 37. Engel JD, Schaeffer AJ. Evaluation of and antimicrobial therapy for recurrent urinary tract infections in women. Urol Clin North Am 1998;25:685-701, x. 38. Foxman B, Barlow R, D'Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 2000;10:509-15. 39. Smith HS, Hughes JP, Hooton TM, Roberts P, Scholes D, Stergachis A, Stapleton A, Stamm WE. Antecedent antimicrobial use increases the risk of uncomplicated cystitis in young women. Clin Infect Dis 1997;25:63-8. 40. Hopkins WJ, Uehling DT, Wargowski DS. Evaluation of a familial predisposition to recurrent urinary tract infections in women. Am J Med Genet 1999;83:422-4. 41. Scholes D, Hawn TR, Roberts PL, Li SS, Stapleton AE, Zhao LP, Stamm WE, Hooton TM. Family history and risk of recurrent cystitis and pyelonephritis in women. J Urol 2010;184:564-9. 42. Stapleton A, Hooton TM, Fennell C, Roberts PL, Stamm WE. Effect of secretor status on vaginal and rectal colonization with fimbriated Escherichia coli in women with and without recurrent urinary tract infection. J Infect Dis 1995;171:717-20. 43. Sheinfeld J, Schaeffer AJ, Cordon-Cardo C, Rogatko A, Fair WR. Association of the Lewis blood-group phenotype with re current urinary tract infections in women. N Engl J Med 1989; 320:773-7. 44. Kinane DF, Blackwell CC, Brettle RP, Weir DM, Winstanley FP, Elton RA. ABO blood group, secretor state, and susceptibility to recurrent urinary tract infection in women. Br Med J (Clin Res Ed) 1982;285:7-9. 45. Lomberg H, Cedergren B, Leffler H, Nilsson B, Carlstrom AS, Svanborg-Eden C. Influence of blood group on the availability of receptors for attachment of uropathogenic Escherichia coli. Infect Immun 1986;51:919-26. 46. Raz R, Gennesin Y, Wasser J, Stoler Z, Rosenfeld S, Rottensterich E, Stamm WE. Recurrent urinary tract infections in postmeno pausal women. Clin Infect Dis 2000;30:152-6. 47. Frendeus B, Godaly G, Hang L, Karpman D, Svanborg C. Interleukin-8 receptor deficiency confers susceptibility to acute pyelonephritis. J Infect Dis 2001;183 Suppl 1:S56-60. 48. Frendeus B, Godaly G, Hang L, Karpman D, Lundstedt AC, Svanborg C. Interleukin 8 receptor deficiency confers suscepti bility to acute experimental pyelonephritis and may have a human counterpart. J Exp Med 2000;192:881-90. 49. Hooton TM, Stapleton AE, Roberts PL, Winter C, Scholes D, Bavendam T, Stamm WE. Perineal anatomy and urinevoiding characteristics of young women with and without recurrent urinary tract infections. Clin Infect Dis 1999;29: 1600-1. 50. Reid G. Potential preventive strategies and therapies in urinary tract infection. World J Urol 1999;17:359-63. 51. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol 1999;180:1072-9. 52. Hu KK, Boyko EJ, Scholes D, Normand E, Chen CL, Grafton J, Fihn SD. Risk factors for urinary tract infections in postmenopausal women. Arch Intern Med 2004;164:989-93. 53. Jackson SL, Boyko EJ, Scholes D, Abraham L, Gupta K, Fihn SD. Predictors of urinary tract infection after menopause: a pro spective study. Am J Med 2004;117:903-11. 54. Foxman B, Somsel P, Tallman P, Gillespie B, Raz R, Colodner R, Kandula D, Sobel JD. Urinary tract infection among women aged 40 to 65: behavioral and sexual risk factors. J Clin Epidemiol 2001;54:710-8. 55. Stern JA, Hsieh YC, Schaeffer AJ. Residual urine in an elderly female population: novel implications for oral estrogen replacement and impact on recurrent urinary tract infection. J Urol 2004;171:768-70. 56. Moore EE, Hawes SE, Scholes D, Boyko EJ, Hughes JP, Fihn SD. Sexual intercourse and risk of symptomatic urinary tract infection in post-menopausal women. J Gen Intern Med 2008; 23:595-9. 57. Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med 2012;366:1028-37. 58. Grabe M, Bjerklund-Johansen TE, Botto H, Wullt B, Çek M, Naber KG, Pickard RS, Tenke P, Wagenlehner F. Guidelines on urological infections. Available at: www.uroweb.org/gls/pdf/ 15_Urological_Infections.pdf. Accessed Date Oct 01 2012. 59. Lichtenberger P, Hooton TM. Antimicrobial prophylaxis in women with recurrent urinary tract infections. Int J Antimicrob Agents 2011;38 (Suppl):36-41. 60. Stapleton A, Stamm WE. Prevention of urinary tract infection. Infect Dis Clin North Am 1997;11:719-33. 61. Sen A. Recurrent cystitis in non-pregnant women. Clin Evid (Online) 2008;2008. pii:0801. 62. Epp A, Larochelle A, Lovatsis D, Walter JE, Easton W, Farrell SA, Girouard L, Gupta C, Harvey MA, Robert M, Ross S, Schachter J, Schulz JA, Wilkie D, Ehman W, Domb S, Gagnon A, Hughes O, Konkin J, Lynch J, Marshall C, Society of O, Gynaecologists of C. Recurrent urinary tract infection. J Obstet Gynaecol Can 2010;32:1082-101.

354 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 63. Albert X, Huertas I, Pereiro, II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev 2004: CD001209. 64. Salvatore S, Cattoni E, Siesto G, Serati M, Sorice P, Torella M. Urinary tract infections in women. Eur J Obstet Gynecol Reprod Biol 2011;156:131-6. 65. Stapleton A, Latham RH, Johnson C, Stamm WE. Postcoital antimicrobial prophylaxis for recurrent urinary tract infection. A randomized, double-blind, placebo-controlled trial. JAMA 1990;264:703-6. 66. Cetti RJ, Venn S, Woodhouse CR. The risks of long-term nitrofurantoin prophylaxis in patients with recurrent urinary tract infection: a recent medico-legal case. BJU Int 2009;103: 567-9. 67. Nicolle LE, Harding GK, Thomson M, Kennedy J, Urias B, Ronald AR. Efficacy of five years of continuous, low-dose trime thoprim-sulfamethoxazole prophylaxis for urinary tract infec tion. J Infect Dis 1988;157:1239-42. 68. Nicolle LE. Prophylaxis: recurrent urinary tract infection in women. Infection 1992;20 (Suppl 3):S203-5; discussion S206-10. 69. Melekos MD, Asbach HW, Gerharz E, Zarakovitis IE, Weingaert ner K, Naber KG. Post-intercourse versus daily ciprofloxacin prophylaxis for recurrent urinary tract infections in premenopausal women. J Urol 1997;157:935-9. 70. Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women. Canadian Urological Association journal=journal de l'associa tion des urologues du Canada 2011;5:316-22. 71. Schaeffer AJ, Stuppy BA. Efficacy and safety of self-start therapy in women with recurrent urinary tract infections. J Urol 1999;161:207-11. 72. Gupta K, Hooton TM, Roberts PL, Stamm WE. Patientinitiated treatment of uncomplicated recurrent urinary tract infections in young women. Ann Intern Med 2001;135:9-16. 73. Wong ES, McKevitt M, Running K, Counts GW, Turck M, Stamm WE. Management of recurrent urinary tract infections with patient-administered single-dose therapy. Ann Intern Med 1985;102:302-7. 74. Anonymous. ACOG Practice Bulletin No. 91: Treatment of urinary tract infections in nonpregnant women. Obstet Gyne col 2008;111:785-94. 75. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329:753-6. 76. Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmen opausal women. Cochrane Database Syst Rev 2008:CD005131. 77. Cardozo L, Lose G, McClish D, Versi E, de Koning Gans H. A systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenital therapy (HUT) committee. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:15-20. 78. Brown JS, Vittinghoff E, Kanaya AM, Agarwal SK, Hulley S, Foxman B. Urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. Obstet Gynecol 2001;98:1045-52. 79. Anonymous. SOGC clinical practice guidelines. The detection and management of vaginal atrophy. Number 145, May 2004. Int J Gynaecol Obstet 2005;88:222-8. 80. Schmidt DR, Sobota AE. An examination of the anti-adherence activity of cranberry juice on urinary and nonurinary bacterial isolates. Microbios 1988;55:173-81. 81. Zafriri D, Ofek I, Adar R, Pocino M, Sharon N. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob Agents Chemother 1989;33:92-8. 82. Howell AB, Vorsa N, Der Marderosian A, Foo LY. Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med 1998;339:1085-6. 83. Ofek I, Goldhar J, Zafriri D, Lis H, Adar R, Sharon N. Anti- Escherichia coli adhesin activity of cranberry and blueberry juices. N Engl J Med 1991;324:1599. 84. Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz LA. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994;271:751-4. 85. Howell AB, Foxman B. Cranberry juice and adhesion of antibiotic-resistant uropathogens. JAMA 2002;287:3082-3. 86. Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev 2008:CD001321. 87. Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001;322:1571. 88. Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol 2002;9:1558-62. 89. Barbosa-Cesnik C, Brown MB, Buxton M, Zhang L, De Busscher J, Foxman B. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis 2011;52:23-30. 90. Wang CH, Fang CC, Chen NC, Liu SS, Yu PH, Wu TY, Chen WT, Lee CC, Chen SC. Cranberry-containing products for

www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.5.343 Infect Chemother 2012;44(5):343-356 355 preven tion of urinary tract infections in susceptible populations: A systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:988-96. 91. Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarovaya Y, Chen S, Gupta K. Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial. Mayo Clin Proc 2012;87: 143-50. 92. McMurdo ME, Argo I, Phillips G, Daly F, Davey P. Cranberry or trimethoprim for the prevention of recurrent urinary tract infections? A randomized controlled trial in older women. J Antimicrob Chemother 2009;63:389-95. 93. Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke TM, Prins JM, Koeijers J, Verbon A, Stobberingh E, Geerlings SE. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med 2011;171: 1270-8. 94. Raz R, Chazan B, Dan M. Cranberry juice and urinary tract infection. Clin Infect Dis 2004;38:1413-9. 95. Wing DA, Rumney PJ, Preslicka CW, Chung JH. Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: a randomized, controlled pilot study. J Urol 2008;180:1367-72. 96. Sen A. Recurrent cystitis in non-pregnant women. Clin Evid 2006:2558-64. 97. Guay DR. Cranberry and urinary tract infections. Drugs 2009;69:775-807. 98. Sheffield JS, Cunningham FG. Urinary tract infection in women. Obstet Gynecol 2005;106:1085-92. 99. Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L, Matsumoto T, Tenke P, Sotto A, Lavigne JP. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis 2010;10:94. 100. Hisano M, Bruschini H, Nicodemo AC, Srougi M. Cranberries and lower urinary tract infection prevention. Clinics 2012;67: 661-8. 101. Torpy JM, Schwartz LA, Golub RM. JAMA patient page. Urinary tract infection. JAMA 2012;307:1877. 102. Kontiokari T, Laitinen J, Jarvi L, Pokka T, Sundqvist K, Uhari M. Dietary factors protecting women from urinary tract infection. Am J Clin Nutr 2003;77:600-4. 103. Head KA. Natural approaches to prevention and treatment of infections of the lower urinary tract. Altern Med Rev 2008; 13:227-44. 104. Handley MA, Reingold AL, Shiboski S, Padian NS. Incidence of acute urinary tract infection in young women and use of male condoms with and without nonoxynol-9 spermicides. Epidemiology 2002;13:431-6. 105. Franco AV. Recurrent urinary tract infections. Best Pract Res Clin Obstet Gynaecol 2005;19:861-73. 106. Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997;11:551-81. 107. Strom BL, Collins M, West SL, Kreisberg J, Weller S. Sexual activity, contraceptive use, and other risk factors for symptomatic and asymptomatic bacteriuria. A case-control study. Ann Intern Med 1987;107:816-23. 108. Reid G. Probiotic agents to protect the urogenital tract against infection. Am J Clin Nutr 2001;73 (2 Suppl):437S-443S. 109. Reid G. The scientific basis for probiotic strains of Lactobacillus. Appl Environ Microbiol 1999;65:3763-6. 110. Falagas ME, Betsi GI, Tokas T, Athanasiou S. Probiotics for prevention of recurrent urinary tract infections in women: a review of the evidence from microbiological and clinical studies. Drugs 2006;66:1253-61. 111. Baerheim A, Larsen E, Digranes A. Vaginal application of lactobacilli in the prophylaxis of recurrent lower urinary tract infection in women. Scand J Prim Health Care 1994;12:239-43. 112. Uehara S, Monden K, Nomoto K, Seno Y, Kariyama R, Kumon H. A pilot study evaluating the safety and effectiveness of Lactobacillus vaginal suppositories in patients with recurrent urinary tract infection. Int J Antimicrob Agents 2006;28 Suppl 1:S30-4. 113. Stapleton AE, Au-Yeung M, Hooton TM, Fredricks DN, Roberts PL, Czaja CA, Yarova-Yarovaya Y, Fiedler T, Cox M, Stamm WE. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis 2011;52:1212-7. 114. Czaja CA, Stapleton AE, Yarova-Yarovaya Y, Stamm WE. Phase I trial of a Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in women. Infect Dis Obstet Gynecol 2007;2007:35387. 115. Reid G, Bruce AW, Fraser N, Heinemann C, Owen J, Henning B. Oral probiotics can resolve urogenital infections. FEMS Immunol Med Microbiol 2001;30:49-52. 116. Beerepoot MA, Ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke TM, Prins JM, Koeijers J, Verbon A, Stobberingh E, Geerlings SE. Lactobacilli vs antibiotics to prevent urinary tract infections: A randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med 2012;172: 704-12.

356 BN Kim Prevention of Recurrent Urinary Tract Infections www.icjournal.org 117. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clin Ther 2008;30:453-68. 118. Abad CL, Safdar N. The role of lactobacillus probiotics in the treatment or prevention of urogenital infections--a systematic review. J Chemother 2009;21:243-52. 119. Naber KG, Cho YH, Matsumoto T, Schaeffer AJ. Immunoactive prophylaxis of recurrent urinary tract infections: a metaanalysis. Int J Antimicrob Agents 2009;33:111-9. 120. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents 2002;19:451-6. 121. Bauer HW, Alloussi S, Egger G, Blumlein HM, Cozma G, Schulman CC. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur Urol 2005;47:542-8; discussion 8. 122. Kim KS, Kim JY, Jeong IG, Paick JS, Son H, Lim DJ, Shim HB, Park WH, Jung HC, Choo MS. A prospective multi-center trial of Escherichia coli extract for the prophylactic treatment of patients with chronically recurrent cystitis. J Korean Med Sci 2010;25:435-9. 123. Ha US, Cho YH. Immunostimulation with Escherichia coli extract: prevention of recurrent urinary tract infections. Int J Antimicrob Agents 2008;31 (Suppl 1):S63-7. 124. Grabe M, Bishop MC, Bjerklund-Johansen TE, Botto H, Çek M, Lobel B, Naber KG, Palou J, Tenke P, Wagenlehner F. Guide lines on urological infections. Available at: http://www. uroweb.org/professional-resources/guidelines/online/. Accessed 1 October 2012. 125. Hopkins WJ, Elkahwaji J, Beierle LM, Leverson GE, Uehling DT. Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial. J Urol 2007;177:1349-53; quiz 591. 126. Sivick KE, Mobley HL. Waging war against uropathogenic Escherichia coli: winning back the urinary tract. Infect Immun 2010;78:568-85. 127. Aune A, Alraek T, LiHua H, Baerheim A. Acupuncture in the prophylaxis of recurrent lower urinary tract infection in adult women. Scand J Prim Health Care 1998;16:37-9. 128. Alraek T, Soedal LI, Fagerheim SU, Digranes A, Baerheim A. Acupuncture treatment in the prevention of uncomplicated recurrent lower urinary tract infections in adult women. Am J Public Health 2002;92:1609-11. 129. Cohen-Mansfield J, Biddison JR. The potential of wash-anddry toilets to improve the toileting experience for nursing home residents. The Gerontologist 2005;45:694-9. 130. Ogino M, Iino K, Minoura S. Habitual use of warm-water clean ing toilets is related to the aggravation of vaginal microflora. J Obstet Gynaecol Res 2010;36:1071-4. 131. Nicolle LE. Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis. Urol Clin North Am 2008;35:1-12, v. 132. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011;52:e103-20. 133. Mayo Clinic. Prevention of urinary tract infection. Available at: http://www.mayoclinic.com/health/urinary-tract-infection/ds00286/dsection=prevention. Accessed 1 October 2012. 134. National Kidney and Urologic Diseases Information Clearinghouse. What I need to know about urinary tract infections. Available at: http://kidney.niddk.nih.gov/kudiseases/pubs/ uti_ez/index.aspx. Accessed 1 October 2012. 135. American Academy of Family Physicians. Tips on preventing urinary tract infections. Available at: http://familydoctor.org/ familydoctor/en/diseases-conditions/urinary-tract-infections/prevention.html. Accessed 1 October 2012.