gastro-jРоссийский журнал гастроэнтерологии, гепатологии, колопроктологииRussian Journal of Gastroenterology, Hepatology, Coloproctology1382-43762658-6673«Gastro» LLC10.22416/1382-4376-2017-27-2-44-53gastro-j-134Research ArticleГЕПАТОЛОГИЯHEPATOLOGYВлияние инфекции Clostridium difficile на клиническое течение цирроза печениThe effect of Clostridium difficile infection on the course of liver cirrhosisДригаА. А.DrigaA. A.driga2@mail.ruМаевскаяМ. В.MayevskayaM. V.noemail@neicon.ruИвашкинВ. Т.IvashkinV. T.noemail@neicon.ruФГБОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова»РоссияThe State Education Institution of Higher Professional Training «The First Sechenov Moscow State Medical University»Russian Federation2017120820182724453Copyright © Дрига А.А., Маевская М.В., Ивашкин В.Т., 20182018Дрига А.А., Маевская М.В., Ивашкин В.Т.Driga A.A., Mayevskaya M.V., Ivashkin V.T.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gastro-j.ru/jour/article/view/134

Цель исследования. Оценить частоту выявления инфекции Clostridium difficile (C. difficile) и ее влияние на тяжесть состояния и характер осложнений у пациентов с декомпенсированным циррозом печени (ЦП). Материал и методы. В исследование были включены 47 пациентов с декомпенсированным ЦП (класс В по Child-Pugh у 27 человек и класс С - у 20). У всех пациентов проводили сбор анамнеза, ежедневное измерение артериального давления (АД) с подсчетом уровня среднего АД, анализы крови, электрокардиографическое исследование сердца, ультразвуковое исследование (УЗИ) органов брюшной полости, эзофагогастродуоденоскопию, эхокардиографию, рентгенологическое исследование органов грудной полости, водородный дыхательный тест с лактулозой, исследование кала с помощью иммуноферментного анализа для выявления C. difficile. Результаты. Инфекция С. difficile была выявлена у 26 (55,3%) из 47 пациентов с декомпенсированным ЦП. Среди больных с алкогольным ЦП среднее количество баллов по индексу Maddrey в группе пациентов, инфицированных C. difficile, достоверно превышало аналогичный показатель в группе неинфицированных пациентов. В течение последних 6 мес до момента включения в исследование 50% пациентов с инфекцией C. difficile были госпитализированы в стационар и значительно чаще получали антибактериальные препараты. Метронидазол назначали значительно чаще пациентам, инфицированным C. difficile (92,3% против 9,5%; р<0,001), а ингибиторы протонной помпы получали 69,2% пациентов с инфекцией C. difficile и 85,7% неинфицированных пациентов (p=0,3). На основании результатов лабораторных исследований выявлена тенденция к увеличению уровня фибриногена и выраженности микрогематурии у пациентов с клостридиальной инфекцией. При УЗИ брюшной полости отмечены достоверные различия в величине краниокаудального размера левой доли печени между указанными группами больных (p=0,026). Выводы. Результаты исследования свидетельствуют о высокой частоте развития инфекции C. difficile у пациентов с декомпенсированным ЦП (55,3%), при этом она протекает преимущественно бессимптомно (у 95,7% пациентов). Причины такого течения заболевания недостаточно изучены. Клостридиальная инфекция увеличивает тяжесть состояния больных с поражением печени алкогольной этиологии, что подтверждается большим количеством баллов по индексу Maddrey. Инфекция C. difficile значительно чаще развивается у пациентов, которые в течение последних 6 мес получали антибактериальную терапию метронидазолом. Несмотря на то что метронидазол является одним из препаратов выбора при эрадикации C. difficile, полученные данные свидетельствуют в пользу наличия описанной в литературе связи терапии метронидазолом с возникновением клостридиальной инфекции.

Aim of investigation. To estimate the frequency of Clostridium difficile (C. difficile) infection and its effect on severity and pattern of complications at the compensated liver cirrhosis (LC). Material and methods. The original study included overall 47 patients with decompensated LC (Child-Pugh class B - 27 patients and class C - 20 patients). All patients underwent clinical interviewing with assessment of past history, daily blood pressure (BP) measurement with calculation of the mean blood pressure level, blood tests, ECG, abdominal ultrasound, esophagogastroduodenoscopy, echocardiography, chest X-ray, lactulose hydrogen breath test, Clostridium difficile ELISA stool test. Results. Clostridium difficile infection was found in 26 (55.3%) of 47 patients with decompensated LC. Of patients with alcoholic LC the mean Maddrey score in Clostridium difficile-infected subgroup was significantly higher than the score of non-infected patients. For the last 6 months prior to the study enrollment 50% of patients with Clostridium difficile infection were hospitalized and received antibiotics significantly more frequently. Metronidazole was prescribed more frequently to Clostridium difficile-infected patients (92.3% versus 9.5%; р<0.001), 69.2% of infected patients received proton pump inhibitors vs 85.7% of non-infected patients (p=0.3). According to laboratory test results the trend to increase of fibrinogen level and microhematuria severity at clostridial infection was found. At abdominal ultrasound significant difference in craniocaudal dimension of the left liver lobe between the studied groups of patients (p=0.026) was found. Conclusions. Study results indicate high frequency of C. difficile infection at decompensated liver cirrhosis (55.3%), but it is symptomless in most of the cases (in 95.7% of patients). The causes for such course of disease is poorly understood. Clostridial infection increases severity of the patient state with the alcoholic liver disease as confirmed by higher Maddrey score. C. difficile infection develops much more frequently in patients who previously received metronidazole treatment for the last 6 months. In spite of the fact, that metronidazole is one of drugs of choice at C. difficile eradication, obtained results indicate the possible interrelation of metronidazole treatment to clostridial infection that was previously described in the literature.

цирроз печениклостридиальная инфекцияметронидазолReferencesЗдравоохраниение: некоторые важные результаты и показатели 2015 г. http://government.ru/info/2269 8/#22698=23:1:Aih,23:16:x1o 19.04.2016.Здравоохраниение: некоторые важные результаты и показатели 2015 г. http://government.ru/info/2269 8/#22698=23:1:Aih,23:16:x1o 19.04.2016.Garcia-Tsao G. Spontaneous bacterial peritonitis: a historical perspective. J. Hepatol 2004;41:522-7.Garcia-Tsao G. Spontaneous bacterial peritonitis: a historical perspective. J. Hepatol 2004;41:522-7.Морозова М.А. Дифференциальный диагноз лихорадки у больных с диффузными заболеваниями печени: Дис. … канд мед наук. М.; 2012.Морозова М.А. Дифференциальный диагноз лихорадки у больных с диффузными заболеваниями печени: Дис. … канд мед наук. М.; 2012.Wong F., Bernardi M., Balk R. et. al. Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut 2005; 54(5):718-25.Wong F., Bernardi M., Balk R. et. al. Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut 2005; 54(5):718-25.Wheeler G. Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res Health 2003; 27(4):300-6.Wheeler G. Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res Health 2003; 27(4):300-6.Navasa M., Fernandez J., Rodes J. Bacterial Infections in liver cirrhosis. Ital J Gastroenterol Hepatol 1999; 31:616-25.Navasa M., Fernandez J., Rodes J. Bacterial Infections in liver cirrhosis. Ital J Gastroenterol Hepatol 1999; 31:616-25.Garcia-Tsao G. Bacterial infection in cirrhosis: treatment and prophylaxis. J Hеpatol 2005; 42:585-92.Garcia-Tsao G. Bacterial infection in cirrhosis: treatment and prophylaxis. J Hеpatol 2005; 42:585-92.Жаркова М.С. Бактериальная транслокация в патогенезе инфекционных осложнений у больных циррозом печени. Дис. … канд мед наук. М.; 2012.Жаркова М.С. Бактериальная транслокация в патогенезе инфекционных осложнений у больных циррозом печени. Дис. … канд мед наук. М.; 2012.Nanji A.A. Role of Kupffer cells in alcoholic hepatitis. Alcohol 2002; 27:13-5.Nanji A.A. Role of Kupffer cells in alcoholic hepatitis. Alcohol 2002; 27:13-5.Ивашкин В.Т., Маевская М.В., Федосьина Е.А. Лечение осложнений цирроза печени: Метод рекомендации для врачей. М.: Литтерра; 2011.Ивашкин В.Т., Маевская М.В., Федосьина Е.А. Лечение осложнений цирроза печени: Метод рекомендации для врачей. М.: Литтерра; 2011.Fernandez J., Navasa M., Gomez J., Colmenero J., Vila J., Arroyo V. et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002; 35:140-8.Fernandez J., Navasa M., Gomez J., Colmenero J., Vila J., Arroyo V. et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002; 35:140-8.Ивашкин В.Т., Шифрин О.С., Тертычный А.С., Полуэктова Е.А., Лапина Т.Л., Ляшенко О.С., Ивашкин К.В. Clostridium difficile-ассоциированная болезнь. Рос журн гастроэнтерол гепатол колопроктол 2015;6:5-17.Ивашкин В.Т., Шифрин О.С., Тертычный А.С., Полуэктова Е.А., Лапина Т.Л., Ляшенко О.С., Ивашкин К.В. Clostridium difficile-ассоциированная болезнь. Рос журн гастроэнтерол гепатол колопроктол 2015;6:5-17.Moriarty H.J., Scobie B.A. Pseudomembranous colitis in a patient on rifampicin and ethambutol. N Z Med J 1980; 91:294-5.Moriarty H.J., Scobie B.A. Pseudomembranous colitis in a patient on rifampicin and ethambutol. N Z Med J 1980; 91:294-5.Saginur R., Fogel R., Begin L., Cohen B., Mendelson J. Splenic abscess due to Clostridium difficile. J Infect Dis 1983;147:1105.Saginur R., Fogel R., Begin L., Cohen B., Mendelson J. Splenic abscess due to Clostridium difficile. J Infect Dis 1983;147:1105.Gellad Z.F., Alexander B.D., Liu J.K. et al. Severity of Clostridium difficile-associated diarrhea in solid organ transplant patients. Transpl Infect Dis 2007; 9:276-80.Gellad Z.F., Alexander B.D., Liu J.K. et al. Severity of Clostridium difficile-associated diarrhea in solid organ transplant patients. Transpl Infect Dis 2007; 9:276-80.Wong N.A., Bathgate A.J., Bellamy C.O. Colorectal disease in liver allograft recipients a clinicopathological study with follow-up. Eur J Gastroenterol Hepatol 2002; 14:231-6.Wong N.A., Bathgate A.J., Bellamy C.O. Colorectal disease in liver allograft recipients a clinicopathological study with follow-up. Eur J Gastroenterol Hepatol 2002; 14:231-6.Vanjak D., Girault G., Branger C., Rufat P., Valla D.C., Fantin B. Risk factors for Clostridium difficile infection in a hepatology ward. Infect Control Hosp Epidemiol 2007; 28:202-4.Vanjak D., Girault G., Branger C., Rufat P., Valla D.C., Fantin B. Risk factors for Clostridium difficile infection in a hepatology ward. Infect Control Hosp Epidemiol 2007; 28:202-4.Albright J.B., Bonatti H., Mendez J. et al. Early and late onset Clostridium difficile-associated colitis following liver transplantation. Transpl Int 2007; 20:856-66.Albright J.B., Bonatti H., Mendez J. et al. Early and late onset Clostridium difficile-associated colitis following liver transplantation. Transpl Int 2007; 20:856-66.Gravel D., Miller M., Simor A. et al; Canadian Nosocomial Infection Surveillance Program. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48:568-76.Gravel D., Miller M., Simor A. et al; Canadian Nosocomial Infection Surveillance Program. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48:568-76.Bass N.M., Mullen K.D., Sanyal A. et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071-81.Bass N.M., Mullen K.D., Sanyal A. et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362:1071-81.Neff G., Zacharias V., Kaiser T.E., Gaddis A., Kemmer N. Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: A case series. Liver Transpl 2010; 16:960-3.Neff G., Zacharias V., Kaiser T.E., Gaddis A., Kemmer N. Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: A case series. Liver Transpl 2010; 16:960-3.Jump R.L., Pultz M.J., Donskey C.J. Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother 2007; 51:2883-7.Jump R.L., Pultz M.J., Donskey C.J. Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother 2007; 51:2883-7.Kalaitzakis E., Bjornsson E. Inadequate use of protonpump inhibitors in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2008; 20:512-8.Kalaitzakis E., Bjornsson E. Inadequate use of protonpump inhibitors in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2008; 20:512-8.Bajaj J.S., Ananthakrishnan A.N., Hafeezullah M. et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: A national and tertiary center perspective. Am J Gastroenterol 2010; 105:106-13.Bajaj J.S., Ananthakrishnan A.N., Hafeezullah M. et al. Clostridium difficile is associated with poor outcomes in patients with cirrhosis: A national and tertiary center perspective. Am J Gastroenterol 2010; 105:106-13.Garcia-Tsao G., Surawicz C.M. Editorial: Clostridium difficile infection: Yet another predictor of poor outcome in cirrhosis. Am J Gastroenterol 2010;105:114-6.Garcia-Tsao G., Surawicz C.M. Editorial: Clostridium difficile infection: Yet another predictor of poor outcome in cirrhosis. Am J Gastroenterol 2010;105:114-6.Loo V.G., Poirier L., Miller M.A. et al. A predominantly clonal multi-institutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-9.Loo V.G., Poirier L., Miller M.A. et al. A predominantly clonal multi-institutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-9.Ito Y., Moriwaki H., Muto Y., Kato N., Watanabe K., Ueno K. Effect of lactulose on short-chain fatty acids and lactate production and on the growth of faecal flora, with special reference to Clostridium difficile. J Med Microbiol 1997; 46:80-4.Ito Y., Moriwaki H., Muto Y., Kato N., Watanabe K., Ueno K. Effect of lactulose on short-chain fatty acids and lactate production and on the growth of faecal flora, with special reference to Clostridium difficile. J Med Microbiol 1997; 46:80-4.Gravel D., Miller M., Simor A. et al; Canadian Nosocomial Infection Surveillance Program. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48:568-76.Gravel D., Miller M., Simor A. et al; Canadian Nosocomial Infection Surveillance Program. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48:568-76.Borzio M., Salerno F., Piantoni L., Cazzaniga M., Angeli P., Bissoli F. et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33:41-8.Borzio M., Salerno F., Piantoni L., Cazzaniga M., Angeli P., Bissoli F. et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33:41-8.Singal A.K., Salameh H., Kamath P.S. Prevalence and in-hospital mortality trends of infections among patients with cirrhosis: a nationwide study of hospitalised patients in the United States. Aliment Pharmacol Ther 2014; 40:105-12.Singal A.K., Salameh H., Kamath P.S. Prevalence and in-hospital mortality trends of infections among patients with cirrhosis: a nationwide study of hospitalised patients in the United States. Aliment Pharmacol Ther 2014; 40:105-12.Barbut F., Petit J.C. Epidemiology of Clostridium difficileassociated infections. Clin Microbiol Infect 2001; 7:405-10.Barbut F., Petit J.C. Epidemiology of Clostridium difficileassociated infections. Clin Microbiol Infect 2001; 7:405-10.Brown M.R., Jones G., Nash K.L., Wright M., Guha I.N. Antibiotic prophylaxis in variceal hemorrhage: timing, effectiveness and Clostridium difficile rates. World J Gastroenterol 2010; 16:5317-23.Brown M.R., Jones G., Nash K.L., Wright M., Guha I.N. Antibiotic prophylaxis in variceal hemorrhage: timing, effectiveness and Clostridium difficile rates. World J Gastroenterol 2010; 16:5317-23.Trifan A., Stoica O., Stanciu C., Cojocariu C., Singeap A.M., Girleanu I., Miftode E. Clostridium difficile infection in patients with liver disease: a review. Eur J Clin Microbiol Infect Dis 2015; 34(12):2313-24.Trifan A., Stoica O., Stanciu C., Cojocariu C., Singeap A.M., Girleanu I., Miftode E. Clostridium difficile infection in patients with liver disease: a review. Eur J Clin Microbiol Infect Dis 2015; 34(12):2313-24.Neff G.W., Jones M., Jonas M., Ravinuthala R., Novick D., Kaiser T.E., Kemmer N. Lack of Clostridium difficile infection in patients treated with rifaximin for hepatic encephalopathy: a retrospective analysis. J Clin Gastroenterol 2013; 47:188-92. doi:10. 1097/ MCG.0b013e318276be13.Neff G.W., Jones M., Jonas M., Ravinuthala R., Novick D., Kaiser T.E., Kemmer N. Lack of Clostridium difficile infection in patients treated with rifaximin for hepatic encephalopathy: a retrospective analysis. J Clin Gastroenterol 2013; 47:188-92. doi:10. 1097/ MCG.0b013e318276be13.Dultz G., Piiper A., Zeuzem S., Kronenberger B., Waidmann O. Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis. Aliment Pharmacol Ther 2015; 41:459-66.Dultz G., Piiper A., Zeuzem S., Kronenberger B., Waidmann O. Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis. Aliment Pharmacol Ther 2015; 41:459-66.Surawicz C.M. The acid test: is proton pump inhibitor therapy an independent risk factor for Clostridium difficileassociated disease? Gastroenterology 2007;133:355-7.Surawicz C.M. The acid test: is proton pump inhibitor therapy an independent risk factor for Clostridium difficileassociated disease? Gastroenterology 2007;133:355-7.Hashimoto M., Sugawara Y., Tamura S., Kaneko J., Matsui Y., Togashi J., Makuuch M. Clostridium difficile-associated diarrhea after living donor liver transplantation. World J Gastroenterol 2007; 13:2072-6.Hashimoto M., Sugawara Y., Tamura S., Kaneko J., Matsui Y., Togashi J., Makuuch M. Clostridium difficile-associated diarrhea after living donor liver transplantation. World J Gastroenterol 2007; 13:2072-6.

The authors declare that there are no conflicts of interest present.