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1 Nosocomial spontaneous bacterial peritonitis: broader-spectrum antibiotics 송도선가톨릭대학교의과대학성빈센트병원소화기내과 Do Seon Song Department of Internal Medicine, St. Vincent s Hospital, College of Medicine, The Catholic University of Korea Spontaneous bacterial peritonitis (SBP) is a common and frequently fatal bacterial infection in patients with cirrhosis and ascites. Third-generation cephalosporins have been considered the first-line treatment of SBP. However, nosocomial SBP, meaning infection after hours of hospital admission, has a high prevalence of multidrug resistant (MDR) bacteria and fails to respond to 3 rd cephalosporin treatment in substantial number of patients. Therefore, experts have recommended broader-spectrum antibiotics in patients with severe sepsis or shock and patients with risk factors for MDR bacteria. Considering that nosocomial infection is one of the risk factors of MDR bacterial infection, patients with nosocomial SBP should be treated with broader-spectrum antibiotics, such as carbapenem±glycopeptide. In addition, after re-evaluation of antibiotic treatment, adjustments based on microbiological results and clinical evolution are necessary. 서론 자발성세균성복막염은간경변과복수가있는환자에서뚜렷한복강내감염원인이없는상태에서발 생하는복수의세균감염을의미한다. 자발성세균성복막염의진단은복수천자결과에서다형핵호중구 (polymorphonuclear leukocyte, PMN) 250/mm 3 일때진단할수있다. 1,2 자발성세균성복막염은복수를 동반한간경변환자의 10-30% 에서발생하고, 3-5 약 30% 의사망률을보이는질환이다. 6 감염이동반된간경변환자는간경변이아닌환자에비해사망률이약 4배정도높고 7, 쇽이동반된자발성세균성복막염환자의경우는사망률이 80% 에이를정도로예후가나쁘다. 8 현재까지의가이드라인에서는자발성세균성복막염의경험적항생제로 3세대세팔로스포린을권장한 다. 1,2 하지만지역사회획득 (community-acquired) 자발성세균성복막염에비해병원감염자발성세균 성복막염은 3 세대세팔로스포린에실패할확률이높고 9,10, 사망률은약 2 배증가된다. 10,11 따라서본원고 에서는지역사회획득자발성세균성복막염과병원감염자발성세균성복막염의역학차이및병원감 62 대한간학회 The Korean Association for study of the Liver

2 송도선 Nosocomial spontaneous bacterial peritonitis: broader-spectrum antibiotics 염자발성세균성복막염환자에서적절한경험적항생제선택에대해기술하고자한다. 병원감염자발성세균성복막염의정의및특징 병원감염자발성세균성복막염은병원에입원하고 48-72시간이상경과후에발생한경우로정의한다. 9,12 병원감염자발성세균성복막염환자는지역사회획득자발성세균성복막염환자에비해사망률이높고다약제내성균에의한감염의비율이높다. 스페인에서 506명의자발성세균성복막염환자를대상으로한후향적연구에서병원감염자발성세균성복막염환자는지역사회획득자발성복막염환자에비해 30일사망률이약 2배였으며 (adjusted HR=1.966; 95% CI, ), 3세대세팔로스포린에대해내성을보이는균에감염될확률은약 2.5배높았다 (adjusted HR=2.544; 95% CI, ) 명의자발성세균성복막염환자를대상으로한국내후향적연구에서도병원감염자발성세균성복막염환자는 30일사망률이 2.18배높았으며, 3세대세팔로스포린내성균감염위험이 7.02배높았다. 11 또다른국내후향적연구에서도병원감염자발성세균성복막염환자는지역사회획득자발성세균성복막염환자보다높은 6개월사망률을보였으며 (47% vs. 26%, P=0.07), cefotaxime 내성균 (77.8% vs. 13.6%), extended-spectrum beta-lactamase (ESBL) 생성균 (66.7% vs. 13.6%), ciprofloxacin 내성균 (44.4% vs. 13.6%) 의비율이높았다. 13 ESBL 생성균주에의한감염은점차증가하는추세를보이고, 최근에는 enterococcus나 methicillinresistant staphylococcus aureus (MRSA) 와같은다약제내성그람양성균에의한자발성세균성복막염도문제가되고있다. 11,18-20 다약제내성균에의한감염의위험인자는병원내감염, 장기간의예방적항생제사용, 최근의다약제내성균감염병력, 최근의베타-락탐항생제사용, 최근의입원병력등이있다. 9,21 병원감염자발성세균성복막염환자의경험적항생제선택 자발성세균성복막염환자에서는일차경험적항생제에실패할경우사망률이매우높다. 22 또한, 쇽을동반한심한복막염환자에서는항생제투여가 1시간늦어질수록사망률이 1.86배증가한다는보고가있다. 8 따라서자발성세균성복막염환자에서는적절한경험적항생제를조기에투약하는것이중요하다. 하지만병원감염자발성세균성복막염은지역사회획득자발성세균성복막염에비해 3세대세팔로스포린내성균주및다약제내성균에의한감염의비율이높기때문에, 현재미국간학회및유럽간학회에서경험적항생제로권장하고있는 cefotaxime과같은 3세대세팔로스포린치료에실패할확률이높다. 2014년에발표된유럽간학회보고서에서는질환의중증도, 감염경로 ( 지역사회 vs. 병원 ), 지역역학에따라항생제를선택할것을권고하였다. 23 이보고서에서는지역사회획득자발성세균성복막염은 cefo- 63

3 2017 대한간학회추계 Single Topic Symposium taxime 혹은 ceftriaxone과같은 3세대세팔로스포린을사용하고, 다약제내성균의빈도가적은지역에서의병원감염인경우는 piperacillin/tazobactam, 다약제내성균의빈도가높은지역에서의병원감염이라면 meropenem ± glycopeptide 를사용할것을권장하였다. 이보고서의내용에따라병원감염자발성세균성복막염환자 32명을대상으로광범위항생제 (meropenem+daptomycin) 와 3세대세팔로스포린 (ceftazidime) 의효과를비교하는무작위대조군연구에서는광범위항생제를사용한군이높은감염소실률을보였으며 (86.7 vs. 25%, P<0.001), 1차치료약제에대한실패여부가 90일사망의중요한예후인자였다. 12 최근인도에서는병원감염자발성세균성복막염환자에서 carbapenem 계열의 imipenem과 4세대세팔로스포린인 cefepime의효과를비교한전향적연구가있었으며, 두약제사이에감염소실률과사망률은차이가 Figure 1. Empirical antibiotic algorithm suggested in critical care setting by Spanish steward program. Empirical treatment is decided according to the severity of infection, the presence of risk factors for MDR bacteria, and the local epidemiology. *previous colonization, antibiotic treatment 5 days in the last 3 months, hospitalization 5 days in the last 3 months, and nursing home/long-term care facility; **pneumonia, secondary peritonitis (high bacterial load), or high risk of severe complications (meningitis); *** 25 mg/dl, 15 mg/dl, and 10 mg/dl in Child-Pugh A, B, and C patients, respectively; #change glycopeptides by daptomycin in infections with high risk of bacteremia (catheter, endocarditis) or by linezolid in pneumonia, cellulitis, or meningitis; ## consider adding one or more of these antibiotics depending on the local epidemiology, recent antibiotic treatments (6 weeks), and source of infection; ### consider adding an echinocandin if two or more of the following criteria are present: multifocal colonization by Candida spp. (e.g., candiduria, rectal swab), antibiotic treatment or steroids, parenteral nutrition, gastroduodenal surgery or necrohemorrhagic pancreatitis, renal replacement therapy. 64 대한간학회 The Korean Association for study of the Liver

4 송도선 Nosocomial spontaneous bacterial peritonitis: broader-spectrum antibiotics Figure 2. Deescalation algorithm proposed by Spanish steward program. Antibiotic schedules are reevaluated after hours of therapy. Deescalation is decided, considering microbiological isolation and clinical evolution. 없었다. 24 Fernández 등은스페인의항생제관리프로그램을소개하며위험인자에따라치료를층화할것을제안하였다. 25 질환의중증도및다약제내성의위험인자 ( 지난 3개월간 5일이상의항생제사용이나 5일이상의입원병력, 요양시설이용, 이전의다약제내성균배양력 ) 유무에따라항생제를선택하며 (Fig. 1), 다약제내성균의발생을줄이기위해 48-72시간후에재평가를통해항생제를조정할것을제안하였다 (Fig. 2). 25 아직병원감염자발성세균성복막염의경험적항생제에대한연구가많지않지만, 병원감염자발성세균성복막염은다약제내성균의위험인자이고, 중증의감염이더흔하게발생하기때문에 carbapenem ± glycopeptide와같은광범위항생제의사용을적극적으로고려해야할것이며, 정기적인모니터링을통해각기관에서흔한균주및내성균빈도를파악하여적절하게경험적항생제를선택해야하겠다. 65

5 2017 대한간학회추계 Single Topic Symposium 결론 병원감염자발성세균성복막염은지역사회획득자발성세균성복막염에비해 3세대세팔로스포린내성및다약제내성균에의한감염비율이높아, 현재가이드라인에서권장되는경험적항생제인 3세대세팔로스포린에실패할확률이높고, 사망률또한높다. 감염의중증도, 다약제내성균감염의위험인자유무, 지역역학을고려하여경험적항생제를선택하여야하며, 병원감염이다약제내성균감염의위험인자임을고려한다면병원감염자발성세균성복막염의경험적항생제로광범위항생제를고려해야하겠다. 또한지속적인모니터링을통해각기관의흔한균주및내성을파악하여알맞은항생제를선택해야하겠다. REFERENCES 1. Runyon BA. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis Hepatology 2013;57: EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53: Caly WR, Strauss E. A prospective study of bacterial infections in patients with cirrhosis. J Hepatol 1993;18: Wong F, Bernardi M, Balk R, Christman B, Moreau R, Garcia-Tsao G, et al. Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut 2005;54: Llach J, Rimola A, Navasa M, Ginès P, Salmerón JM, Ginès A, et al. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration. Hepatology 1992;16: Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 2008;28: Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139: , 1256.e Karvellas CJ, Abraldes JG, Arabi YM, Kumar A. Appropriate and timely antimicrobial therapy in cirrhotic patients with spontaneous bacterial peritonitis-associated septic shock: a retrospective cohort study. Aliment Pharmacol Ther 2015;41: Fernández J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012;55: Ariza X, Castellote J, Lora-Tamayo J, Girbau A, Salord S, Rota R, et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis. J Hepatol 2012;56: Cheong HS, Kang CI, Lee JA, Moon SY, Joung MK, Chung DR, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clin Infect Dis 2009;48: Piano S, Fasolato S, Salinas F, Romano A, Tonon M, Morando F, et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a randomized, controlled clinical trial. Hepatology 2016;63: Song JY, Jung SJ, Park CW, Sohn JW, Kim WJ, Kim MJ, et al. Prognostic significance of infection acquisition sites in spontaneous bacterial peritonitis: nosocomial versus community acquired. J Korean Med Sci 2006;21: Park MK, Lee JH, Byun YH, Lee H, Gwak GY, Choi MS, et al. [Changes in the profiles of causative agents and antibiotic resistance rate for spontaneous bacterial peritonitis: an analysis of cultured microorganisms in recent 12 years]. Korean J Hepatol 2007;13: Park YH, Lee HC, Song HG, Jung S, Ryu SH, Shin JW, et al. Recent increase in antibiotic-resistant microorganisms in patients 66 대한간학회 The Korean Association for study of the Liver

6 송도선 Nosocomial spontaneous bacterial peritonitis: broader-spectrum antibiotics with spontaneous bacterial peritonitis adversely affects the clinical outcome in Korea. J Gastroenterol Hepatol 2003;18: Kim MJ, Song KH, Kim NH, Choe PG, Park WB, Bang JH, et al. Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae: a retrospective cohort study. Hepatol Int 2014;8: Song KH, Jeon JH, Park WB, Park SW, Kim HB, Oh MD, et al. Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species: a retrospective matched case-control study. BMC Infect Dis 2009;9: Kim JH, Jeon YD, Jung IY, Ahn MY, Ahn HW, Ahn JY, et al. Predictive Factors of Spontaneous Bacterial Peritonitis Caused by Gram-Positive Bacteria in Patients With Cirrhosis. Medicine (Baltimore) 2016;95:e Fernández J, Navasa M, Gómez J, Colmenero J, Vila J, Arroyo V, et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002;35: Campillo B, Dupeyron C, Richardet JP. Epidemiology of hospital-acquired infections in cirrhotic patients: effect of carriage of methicillin-resistant Staphylococcus aureus and influence of previous antibiotic therapy and norfloxacin prophylaxis. Epidemiol Infect 2001;127: Wiest R, Krag A, Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut 2012;61: Umgelter A, Reindl W, Miedaner M, Schmid RM, Huber W. Failure of current antibiotic first-line regimens and mortality in hospitalized patients with spontaneous bacterial peritonitis. Infection 2009;37: Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference J Hepatol 2014;60: Jindal A, Kumar M, Bhadoria AS, Maiwall R, Sarin SK. A randomized open label study of 'imipenem vs. cefepime' in spontaneous bacterial peritonitis. Liver Int 2016;36: Fernandez J, Tandon P, Mensa J, Garcia-Tsao G. Antibiotic prophylaxis in cirrhosis: Good and bad. Hepatology 2016;63:

Postgraduate Course 2012 진 단 1. 진단적복수천자의대상 SBP 환자들은임상적으로 (1) 복막염의국소증상혹은징후 : 복통, 복부압통, 구토, 설사, 장마비 ; (2) 전신감염소견 : 발열혹은저체온, 오한, 백혈구수의변화, 빈맥, 빈호흡 ; (3) 간

Postgraduate Course 2012 진 단 1. 진단적복수천자의대상 SBP 환자들은임상적으로 (1) 복막염의국소증상혹은징후 : 복통, 복부압통, 구토, 설사, 장마비 ; (2) 전신감염소견 : 발열혹은저체온, 오한, 백혈구수의변화, 빈맥, 빈호흡 ; (3) 간 PG 3 PG Course 2012 Portal Hypertension 자발성복막염의진단과치료 전북대학교의학전문대학원내과학교실 김인희 Diagnosis and Treatment of Spontaneous Bacterial Peritonitis In Hee Kim Departments of Internal Medicine, Research Institute of