대한요로생식기감염학회지 : 제 5 권제 2 호 2010년 10월 Korean J UTII Vol. 5, No. 2, October 2010 종설 무증상세균뇨 가톨릭대학교의과대학비뇨기과학교실 한창희 조용현 [Abstract] Asymptomatic Bacteriuria Chang-Hee Han, Yong-Hyun Cho From the Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea Asymptomatic bacteriuria is common. Among healthy adults, bacteriuria increases with age, and occurs more frequently in women than men. Individuals with underlying genitourinary abnormalities, such as spinal cord injuries or with indwelling catheters also have a very high prevalence of bacteriuria. Bacteriuria per se in most population is benign. It has been shown to have adverse outcomes in pregnant women, in whom it is associated with pyelonephritis, low-birth weight and premature birth, and in patients undergoing traumatic genitourinary procedures associated with mucosal bleeding, in whom there is a high risk of bacteremia and sepsis. In other populations, clinical trials have consistently shown no benefits of screen for or treatment of asymptomatic bacteriuria. For some immunocompromised persons, such as those with neutropenia or post-renal transplant, further evaluation to describe the natural history and impact of bacteriuria is required. (Korean J UTII 2010;5:119-128) Key Words: Bacteriuria, Urinary tract infections 서 무증상세균뇨란아무런요로생식기계의증상없이소변에일정량이상의세균이존재하는상태를말한다. 무증상세균뇨는매우흔하며정상성인의 론 교신저자 : 한창희, 가톨릭대학교의정부성모병원비뇨기과경기의정부시금오동 65-1 우 480-717 Tel: 031-820-3546, Fax: 031-847-6133 E-mail: urohan@catholic.ac.kr Received: September 1, 2010 Accepted: September 30, 2010 경우나이가많아질수록, 남자보다는여자에서더흔하다. 특히요로생식기계의이상이있거나도뇨관을가지고있는환자의경우유병률은매우높다. 일반적으로무증상세균뇨는별다른문제를일으키지않는다. 그러나임산부의경우신우신염이나조산의위험성이높고, 요로계의손상을주는처치를받는환자에서는패혈증의위험이높아질수있다. 본장에서는이러한무증상세균뇨의진단과치료에대해알아보고자한다. 119
120 대한요로생식기감염학회지 : 제 5 권제 2 호 2010 년 10 월 본론 1. 역학무증상세균뇨는모든연령대에서여자에더흔하며나이가많아질수록빈도가증가한다 (Table 1). 1 젊은남자에서는드물지만 65세이상의건강한남성에서는전립선비대증으로인해그빈도가증가한다. 최근스웨덴의지역사회인구기반조사연구에서 80세이상노인인구의무증상세균뇨의유병률은여성이 20%, 남성이 5 10% 라고보고하였다. 2 특히요양원에거주하는노인의경우그빈도가더욱높아여성의경우 25 50%, 남성의경우 15 40% 정도로보고된다. 3 또한요로생식기계의기능적혹은구조적이상이있는사람의경우에도세균 뇨의빈도가높다. 척수손상환자의경우배뇨방법에관계없이약 50% 에서세균뇨가있으며, 1 30일이상장기적으로도뇨관을가지고있는환자의경우에는 100% 세균뇨가있다. 반면단기간요도카테터를유치하는경우세균뇨의빈도는매일 3 7% 씩증가한다. 4 그밖에신루관이나요관부목또한유치중에는세균뇨의발생빈도를증가시킨다. 2. 위험요소폐경전여성의경우무증상세균뇨의위험인자로는재발성요로감염의경우와마찬가지로성관계나피임목적의살정제사용등이있다. 반면폐경후여성의경우에는과거요로감염의병력이있는 nonsecretor blood group과관련이깊다. 5,6 또한폐경후질내 ph를산성으로유지시키는유산균이 Table 1. Prevalence of asymptomatic bacteriuria in selected populations Women: Prevalence of bacteriuria (%) Premenopausal 5 10 55 75 years 10 20 70 years Long-term care facility Diabetic women 15 20 25 50 5 10 Men: 70 years Long term care facility 5 10 15 40 Indwelling urinary devices Chronic indwelling catheter 100 Short-term indwelling catheter 3 7/day Ileal neobladder 57 Spinal cord injured Sphincterotomy 50 Intermittent catheterization 50 External condom catheter 50
한창희외 : 무증상세균뇨 121 감소하고 E. coli나 group B streptoccocci가증가하게된다. 7 이러한변화는에스트로겐감소에기인하며에스트로겐보충요법으로유산균의재증식및질내산성화를이룰수있다. 따라서에스트로겐결핍은노화로인한세균뇨의증가와밀접한관계가있다고할수있다. 그러나여러임상시험들의결과는논란이있다. Raz 등 8 은에스트로겐국소도포치료에대한전향적, 무작위임상실험에서지역사회와장기요양시설거주노인여성모두에서증상성뿐만아니라무증상성요로감염도감소시킨다고보고하였다. 반면 Ouslander 등 9 은요양원에거주하는여성에게전신적에스트로겐보충요법을시행한전향적, 위약대조연구에서질내산도는감소하였으나무증상세균뇨는감소시키지못하였다고보고하였다. 잔뇨량의증가또한노화에따른세균뇨증가에관여할것으로여겨지는요소이다. 그러나아직까지그인과관계를명확히규명한임상연구는없다. 6,10 요실금또한여성에서무증상세균뇨와관련이있으나그자체가원인요소는아니다. 1,3 그밖에만성신경계질환으로인한배뇨장애, 요로생식기 계의기능적혹은구조적이상으로인한배뇨장애및그에따른도뇨관유치등도세균뇨와깊은관련이있다. 3. 발생률및사망률임산부의경우무증상세균뇨가문제를일으킬수있다. 1 또한세균뇨가있는경우요로계의손상을유발하는조작이균혈증과패혈증을유발할수있다. 1 그이외의경우무증상세균뇨는별다른문제를야기하지않는다. 무증상세균뇨가발견된사람은추후증상성요로감염이발생할위험이높다. 1 그러나무증상세균뇨자체가원인은아닌것으로생각한다. 건강한젊은여성에서세균뇨가새롭게발생한후 1주일이내에 8% 에서증상성요로감염이발생한다. 11 따라서이러한여성들의경우증상이발현되기바로전약간의세균뇨기간이선행된다고할수있다. 그러나요로폐색이나손상등과같은위험요소가없다면지속적인무증상세균뇨가동일한균에의한증상성요로감염을일으키지는않는다. 일부환자에서는무증상세균뇨가 Table 2. Asymptomatic bacteriuria and mortality Population Subjects (n) Follow-up (years) Mortality Reece, older women and men institutionalized Wales and Jamaica women 15-84 years 342 10 Significantly shorter survival for bacteriuric men or women 1530 13 RR 1.5 (0.96, 2.32) adjusted for age only Sweden, men and women >70 years 2010 9 Similar mortality with and without asymptomatic bacteriuria, with stratification for risk factors Finland, men and women >85 years 561 5 Bacteriuria had no prognostic significance for mortality US, women, >80 years 1491 10 Multivariate: observational RR 1.1 clinical trial RR 0.92 (0.57, 1.47) Canada, men mean age 78 years, institutionalized 91 6 No association of bacteriuria with mortality; OR at 5 years 1.2 (0.38, 3.9) Swedish, random population based, women 1462 24 No difference in mortality ASB vs not: 95% CI RR: (0.74-2.52) ASB: asymptomatic bacteriuria
122 대한요로생식기감염학회지 : 제 5 권제 2 호 2010 년 10 월 증상성요로감염의위험을감소시키기도하는데이는방광내감염을유발하는다른세균의증식을방해하기때문으로생각된다. 12 무증상세균뇨가사망률을증가시키지는않는다 (Table 2). 13-19 무증상세균뇨가생존율을감소시킨다는일부보고가있지만세균뇨발생과사망률증가모두와관련이있는동반질환의존재여부나신체장기의기능상태등을고려하지않았다. 13,14 노인에서는무증상세균뇨가기능장애와관련이있는데이러한기능장애는그자체만으로도사망의독립적인위험요소이다. 20 이와같은가능성있는바이어스 (bias) 를보정한연구들중무증상세균뇨가사망률을증가시킨다는보고는없다. 14-19 4. 미생물학무증상세균뇨가있는여성에서가장흔히동정되는균주는 E. coli이다. 1 또한동일세균에의한지속적세균뇨의경우에도 E. coli가가장흔한원인이다. 21,22 Hooton 등 11 은젊은여성을대상으로한전향적연구에서증상의유무에관계없이동정된 E. coli의독성에는차이가없다고보고하였다. 그러나증상이없는여성에서동정된균주가증상이있는여성에서의균주보다세균독성이더낮다는일부다른연구들도있다. 23 Group B streptococcus, enterococcus 및 coagulase negative staphylococci (Staphylococcus saprophyticus 제외 ) 등과같은그람양성균주들은무증상세균뇨여성에서더흔히발견된다. 남성의경우에도무증상세균뇨의가장흔한균주는 E. coli, enterococcus 및 coagulase negative staphylococci 등이다. 24 비뇨기계의이상이동반되어있는경우에는일반적으로더광범위하게여러균주들이동정된다. 비록 E. coli가가장흔한균이지만치료를위해반복적으로항생제를투여하게되면 Pseudomonas aeruginosa, Citrobacter종및 Proteus mirabilis, Providencia stuartii와같은요소분해효소생산균과같이내성이더강한세균에의한감염위험이높아진다. 5. 진단 1) 미생물학적기준여성의무증상세균뇨진단기준은 2회연속으로채취한소변에서 10 5 cfu/ml의세균이검출될때이다. 25 처음검사에서세균뇨가발견된여성의약 10 15% 에서재검사시세균뇨음성소견을보인다. 이와같은결과는첫번째검사시채취한검체가오염되었기때문일가능성이높으나젊은여성의경우에는일시적세균뇨도흔하다. 2,11,26 따라서일차검체채취후이차검체채취까지의시간간격이길어질수록세균뇨의자연소실로인해이차검사에서음성소견을보일가능성이높아진다. 반면남성의경우에는한번의배뇨검체에서 10 5 cfu/ml의세균이검출되더라도세균뇨를진단할수있다. 27 콘돔카테터로채취한경우 28,29 나유치도뇨관을통해채취한경우에도모두 10 5 cfu/ml의세균이검출될때진단할수있다. 그러나일회도뇨로채취한소변의경우 10 2 cfu/ml의세균만검출되어도남녀모두에서세균뇨로진단할수있다. 30,31 2) 농뇨농뇨는비뇨기계에염증이있음을나타내는소견으로무증상세균뇨가있는경우흔히나타난 다. 3,11,32-34 무증상세균뇨가있을때농뇨가동반될가능성은젊은여성의경우약 30% 내외, 13 임산부는 30 70%, 33,34 당뇨병이있는여성은 70%, 32 양로원에있는노인은 90%, 3 혈액투석환자는 90%, 장기도뇨관유치환자는 50 100% 35 이다. 또한농뇨는요배양검사에서음성인환자에서다른요로생식기계의염증성질환, 예를들어요로결핵이나성병과같은감염성질환이나간질성신장염과같은비감염성질환등과동반되어나타날수있다. 따라서농뇨가있다는그자체만으로세균뇨를진단할수없으며, 농뇨의유무로증상성요로감염이냐무증상요로감염이냐를구별할수도없다. 6. 치료 1) 폐경전여성폐경전여성에서세균뇨에대한항생제치료는무
한창희외 : 무증상세균뇨 123 Table 3. Findings of comparative clinical trials of antimicrobial therapy for the treatment of asymptomatic bacteriuria in pregnancy No. of patients with pyelonephritis/total no. of patients (%) Clinical trial Design Antimicrobial therapy Initially negative result a Initially positive result a Treated patients Nontreated patients LeBlanc and McGanity 55 Brumfit and Condie et al 57 Randomized, not blinded Randomized, placebo-controlled Sulfonamide and mandelamine, nitrofurantoin, or mandelamine alone; 22/1143 (1.9) 3/69 (4.3) 8/41 (20) mandelamine to term Sulfonamides 3/150 (2) 4/67 (6.0) 55/179 (31) Wren 58 Alternating between antibiotics and no antibiotics Nitrofurantoin, ampicillin, sulfonamide, and nalidixic acid to term - NS 33/90 (37) Elder et al 59 Savage et al 52 Alternating, placebo -controlled Alternating, placebo -controlled Tetracycline for 6 weeks 6/279 (2) 4/133 (3.0) 27/148 (18) Sulfonamide to term 7/496 (1.4) 1/93 (1.1) 26/98 (26) Kincaid-Smith and Bullen 26 Cohort, sequential Various - 2/61 (3.3) 20/53 (37) Little 54 Randomized, not blinded Sulfonamide to term 19/4735 (0.4) 4/124 (3.2) 35/141 (25) NS: not specified a: microbiologic results from initial screening urine culture in pregnancy (Adopted from Smaill F. 51 ) 증상세균뇨의단기유병률은감소시키지만, 차후의증상발현을감소시키지는못한다. 1,36 수십년동안의장기간코호트연구를통해서도처음에세균뇨가있는지혹은없는지여부가다른결과를나타내지는않았다. 37-40 사실무증상세균뇨에대한항생제치료는치료직후에발생가능한증상성감염의위험성을높이는것과도관련이있을것이다. 41 이는항생제치료에의해질의세균집락이변화하기때문이라고설명할수있으며, 또다른가능성은세균뇨가항생제치료에의해서사라지게되면세균간의간섭작용이없어지기때문이라고하겠다. 따라서폐경전여성에서무증상세균뇨는치료하지말것이권장된다. 2) 임산부임신초기에무증상세균뇨가있는경우세균뇨 가없는경우에비해임신중에신우신염에이환될위험이 20 30배높으며, 34,42-50 조산이나저체중아출산의위험이높다. 여러전향적비교임상시험에서임신중무증상세균뇨의항생제치료가신우신염의위험을 20 35% 에서 1 4% 로낮출수있음을보고하였다 (Table 3). 51 또한여러코호트연구와무작위임상시험들에대한메타분석결과는무증상세균뇨에대한항생제치료가저체중아출산과조산의빈도를의미있게낮춘다는결론을뒷바침한다. 52,53 치료기간에대해서는논란이있다. 최근발표된 Cochrane systemic review에서는임산부에서항생제치료기간에대해 1회, 3일, 4일및 7일요법중어떤방법을권장할지에대한충분한근거가아직없다고결론내리고있다. 54
124 대한요로생식기감염학회지 : 제 5 권제 2 호 2010 년 10 월 3) 폐경후여성건강한폐경후여성에서무증상세균뇨에대한전향적인무작위비교연구들과전향적인코호트연구들에따르면치료의이득과치료하지않았을때의해로움모두확인할수없었다. 13,38-40 특히무증상세균뇨치료후에증상성요로감염의발생이감소하지는않았다. 36 4) 당뇨병여성무증상세균뇨를보이는당뇨병을가진모든연령의여성에대한전향적이고무작위적인이중맹검연구를통해서항생제치료가무증상세균뇨에있어서이득이없음이밝혀졌다. 26 요로감염에의한, 혹은다른원인에의한방광염이나신우신염그리고입원등도세균뇨에대해항생제치료를시행한다고해서그빈도가감소하지않았다. 그러나이세균뇨를치료한환자들은상당한항생제의노출을보였다. 제2형당뇨여성에대한전향적인코호트연구에따르면무증상세균뇨때문에신기능의감소가가속화된다는증거는없었다. 55 다른코호트연구에서도당뇨병을가진여성에서세균뇨여부에따라사망률이나당뇨병합병증의진행에있어서차이를보이지않았다. 56 따라서당뇨병여성의무증상세균뇨에대해특별히선별검사를하거나치료할필요는없을것이다. 5) 무증상세균뇨를가진남성무증상세균뇨를가진건강한남성의치료에대한전향적인무작위연구는아직없다. 하지만세균뇨를가진남성에대한전향적인코호트연구에서이후증상성감염의발생위험성은낮고항생제치료를하지않더라도대부분의경우자연적인세균뇨의소실이있다고보고하였다. 57 6) 장기간요양시설에있는노인무증상세균뇨를보이면서장기간요양시설에있는환자들에대한전향적인무작위연구를통해항생제치료가증상성요로감염의발생을줄이지못하고만성비뇨생식기계의증상을감소시킬수없으며, 생존율에영향을미치지않음이밝혀졌다. 1 그러나이런치료를통해서항생제의부작용이나내성증가로인한다른세균의재감염, 비용증가등과같은부작용을보이기도했다. 7) 도뇨관유치환자만성적으로도뇨관을가지고있는환자들에대한세균뇨치료가증상성감염을줄이지못한다. 58,59 오히려치료로짧은기간세균뇨가없어진동안항생제내성이증가된다른세균들에의해재감염이발생하기도한다. 도뇨관삽입후 3 4일동안혹은단기간유치했던도뇨관의제거직후에항생제를투여하면무증상세균뇨의유병률을줄일수있다. 1 그러나항생제사용으로인한내성증가를고려한다면도뇨관을가진환자에있어서무증상세균뇨일때항생제사용은피할것이권고된다. 8) 척수손상환자척수손상환자의무증상세균뇨에대한치료는세균뇨혹은증상성감염의유병율을감소시키지않는다. 60-62 재감염이빠르게발생하므로어떤항생제치료의효과도제한적이다. 따라서무증상세균뇨에대한치료시도는내성균에의한재감염의위험성을높이므로권장되지않는다. 9) 비뇨기과적시술세균뇨가있는경우에요로생식기계의손상은균혈증이나패혈증을일으킬위험성이높다. 63 시술직전에무증상세균뇨에대해항생제치료를시작하는것이이러한합병증들을예방할수있다. 따라서요로계의손상이가능한남성방광경이나방광점막생검, 스텐트삽입술, 경요도적전립선절제술과같은침습적인시술전에는반드시항생제를사용해야한다. 63-67 이상적으로항생제치료는감염을일으키는균주를그표적으로삼아야한다. 수많은임상연구에서경요도적전립선절제술후패혈증을막기위해예방적항생제가효과적이라고밝히고있지만다른비뇨기과적시술에대한연구는제한적이다. 1 그러나패혈증의위험성은점막출혈을유발할수있는모든시술들에서있으며항생제치료는이러한모든술기에있어서비슷한유
한창희외 : 무증상세균뇨 125 용성을가질것으로생각한다. 10) 기타환자신이식환자 : 전향적인임상연구를통해서도무증상세균뇨를가진신이식환자에있어서항생제치료가유병률이나사망률을감소시키고이식신의생존을향상시키는지에대한명쾌한답은얻지못했다. 보통이식후 6개월동안환자들은주로 trimethoprim/sulfamethoxazole을사용하는예방적항생제요법을받게된다. 1 이는증상성혹은무증상성요로감염이나다른감염의예방에있어서효과적이다. 6개월후, 코호트연구에따르면무증상세균뇨와이식신의생존의상관관계는확실하지않다. 물론무증상세균뇨가흔하지만이는반복적인요로감염을경험한환자의경우에서그렇다. 68,69 따라서이러한환자들은증상성요로감염에준해서치료를해야하며무증상세균뇨에대해선별검사또는치료는추가적인이득이없는것으로생각한다. 이러한대상군에대한추가적인연구가필요할것이다. 11) 캔디다뇨증무증상성캔디다뇨증을보이는입원환자를대상으로한전향적인무작위비교연구에따르면 fluconazole 치료만이캔디다뇨증에대해단기간의효과가있지만치료대상군에있어서임상적인효과는없는것으로밝혀졌다. 70 또한이식신환자에있어서무증상캔디다뇨증의치료는이득이없을것이라는연구결과를보이기도하였다. 71 7. 향후연구아직도풀리지않은숙제들은신이식환자나다른면역억제환자들에있어서무증상세균뇨에있어서의치료이다. 게다가앞으로의연구는노인요양보호시설등에있는환자들을대상으로한연구가필요할것이다. 결론무증상세균뇨는여성에서흔하고, 나이가들수 록증가하며남성에있어서는노인에서흔하다. 무증상세균뇨에대한선별검사나치료는임산부나비뇨기과시술전에이루어져야한다. 이외의집단에서는선별검사나치료의이득이없음이밝혀졌다. 따라서건강한남성이나여성에있어서무증상세균뇨에대한선별검사는필요치않으며, 진단이되었더라도치료할필요는없다. REFEENCES 1. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005;40(5):643-54 2. Rodhe N, Molstad S, Englund L, Svardsudd K. Asymptomatic bacteriuria in a population of elderly residents living in a community setting: prevalence, characteristics and associated factors. Fam Pract 2006;23(3):303-7 3. Nicolle LE. Asymptomatic bacteriuria in the elderly. Infect Dis Clin North Am 1997;11(3):647-62 4. Warren JW. Catheter-associated urinary tract infections. Infect Dis Clin North Am 1997:11(3):609-22 5. Jackson SL, Boyko EJ, Scholes D, Abraham L, Gupta K, Fihn SD. Predictors of urinary tract infection after menopause: a prospective study. Am J Med 2004;117(12):903-11 6. Raz R, Gennesin Y, Wasser J, Stoler Z, Rosenfeld S, Rottensterich E, et al. Recurrent urinary tract infections in postmenopausal women. Clin Infect Dis 2000;30(1):152-6 7. Pabich WL, Fihn SD, Stamm WE, Scholes D, Boyko EJ, Gupta K. Prevalence and determinants of vaginal flora alterations postmenopausal women. J Infect Dis 2003;188(7):1054-8 8. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329(11):753-6 9. Ouslander JG, Greendale GA, Uman G, Lee C, Paul W, Schnelle J. Effects of oral estrogen and progestin on the lower urinary tract among female nursing home residents. J Am Geriatr Soc 2001;49(6):803-7 10. Barabas G, Molstad S. No association between elevated post-void residual volume and bacteriuria in residents of nursing homes Scand J Prim Health Care 2005;23(1):52-6 11. Hooton TM, Scholes D, Stapleton AE, Roberts PL,
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