Цель: выявить факторы риска Clostridium difficile инфекции у пациентов терапевтической клиники в многопрофильном стационаре. Материалы и методы. Проведен ретроспективный анализ 110 историй болезни пациентов, находившихся на стационарном лечении в отделениях терапевтического профиля в МАУ «Городская клиническая больница №40» Екатеринбурга (МАУ «ГКБ №40») в 2014–2015 гг., у которых на фоне проведения антибактериальной терапии развилась диарея. По результатам данных, полученных при исследовании копрофильтрата на Clostridium difficile (CD), пациентов разделили на 2 группы: 60 пациентов с положительным результатом и 50 пациентов с отрицательным результатом. Результаты. Удельный вес больных с CD-инфекцией в структуре пациентов терапевтического профиля МАУ «ГКБ №40» за 2014–2015 гг. составил 0,42%. Предикторами риска развития диареи, ассоциированной с CD-инфекцией, у пациентов являются возраст старше 65 лет [отношение шансов (ОШ) 4,33, 95% доверительный интервал (ДИ) 1,15–16,20, р=0,028], индекс коморбидности Charlson более 2 баллов (ОШ 3,05, 95% ДИ 1,29–7,23, р=0,016), наличие анемии (ОШ 2,32, 95% ДИ 1,07–5,02, р=0,048), проведение хронического диализа у пациентов с хронической почечной недостаточностью (ОШ 8,64, 95% ДИ 1,05–70,81, р=0,020), пребывание пациентов в стационаре более 5 сут (ОШ 3,50, 95% ДИ 1,57–7,75, р=0,003) и госпитализация пациентов в отделение реанимации и интенсивной терапии длительностью более 1 сут (ОШ 9,80, 95% ДИ 1,20–79,47, р=0,011), применение ингибиторов протонной помпы (ОШ 2,82, 95% ДИ 1,12–7,11, р=0,041), проведение антибактериальной терапии (АБТ) более 10 сут (ОШ 39,62, 95% ДИ 10,85–144,71, р<0,001), проведение более чем 1 курса АБТ (ОШ 2,85, 95% ДИ 1,20–6,76, р=0,026), применение цефтриаксона (ОШ 3,33, 95% ДИ 1,45–7,63, р=0,006). Логистический регрессионный анализ показал связь применения цефалоспоринов III поколения (ОШ 6,55, 95% ДИ 1,18–36,40, р=0,03) и длительности АБТ (ОШ 1,89, 95% ДИ 1,50–2,38, р<0,001) с риском развития диареи, ассоциированной с CD. Заключение. Независимыми факторами риска развития диареи, ассоциированной с Clostridium difficile, у пациентов терапевтической клиники многопрофильного стационара являются применение цефалоспоринов III поколения и длительное проведение АБТ.
Aim: to identify risk factors for Clostridium difficile infection in patients of a therapeutic clinic in a multidisciplinary hospital. Materials and methods. A retrospective analysis of 110 case histories of patients who were hospitalized in therapeutic departments in the Municipal Autonomous Institution “City Clinical Hospital No. 40” in Yekaterinburg (MAU City Clinical Hospital No. 40) in 2014–2015 was conducted, in which antibiotic therapy has developed diarrhea. According to the results of the study of coprofiltrate on Clostridium difficile (CD), patients were divided into 2 groups: 60 patients with a positive result and 50 patients with a negative result. Results. The proportion of patients with CD infection in the structure of patients of the therapeutic profile of the MAU GKB No.40 for 2014–2015 amounted to 0.42%. Predictors of the risk of developing diarrhea associated with CD infection in patients are: age over 65 years (OS 4.33, 95% CI 1.15–16.20, p=0.028), Charlson comorbidity index more than 2 points (OS 3.05, 95% CI 1.29–7.23, p=0.016), the presence of anemia (OR 2.32, 95% CI 1.07–5.02, p=0.048), chronic dialysis in patients with chronic renal insufficiency (CRF) (OR 8.64, 95% CI 1.05–70.81, p=0.020), patients staying in hospital for more than 5 days (OR 3.50, 95% CI 1.57–7.75, p=0.003) and hospitalization of patients in the intensive care unit (ICU) lasting more than 1 day (OS 9.80, 95% CI 1.20–79.47, p=0.011), the use of proton pump inhibitors (PPIs) (OR 2.82, 95% CI 1.12–7.11, p=0.041), antibiotic therapy more than 10 days (OS 39.62, 95% CI 10.85–144.71, p<0.001), more than 1 course of antibacterial therapy (ABT) (OS 2.85, 95% CI 1.20–6.76, p=0.026), the use of ceftriaxone (OR 3.33, 95% CI 1.45–7.63, p=0.006). Logistic regression analysis showed a connection between the use of 3rd generation cephalosporins (OR 6.55, 95% CI 1.18–36.40, p=0.03) and ABT duration (OR 1.89, 95% CI 1.50–2.38, p<0.001) with a risk of developing diarrhea associated with CD. Conclusions. The use of cephalosporins of the 3rd generation and long-term antibacterial therapy are independent risk factors for the development of diarrhea associated with Clostridium difficile in patients of the therapeutic clinic of a multidisciplinary hospital.
Keywords: risk factors, Clostridium difficile.
Список литературы
1. Pepin J, Valiquette ME, Alary P, Villemure P, Pelletier A, Forget K, Pépin K, Chouinard D. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ. 2004;171(5):466-72. doi:10.1503/cmaj.1041104
2. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-34. doi:10.1056/NEJMoa1408913
3. Kurti Z, Lovasz BD, Mandel MD, Csima Z, Golovics PA, Csako BD, Mohas A, Gönczi L, Gecse KB, Kiss LS, Szathmari M, Lakatos PL. Burden of Clostridium difficile infection between 2010 and 2013: Trends and outcomes from an academic center in Eastern Europe. World J Gastroenterol. 2015;21(21):6728-35. doi:10.3748/wjg.v21.i21.6728
4. Shivashankar R, Khanna S, Kammer PP, Harmsen WS, Zinsmeister AR, Baddour LM, Pardi DS. Clinical factors associated with development of severe-complicated Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11(11):1466-71. doi:10.1016/j.cgh.2013.04.050
5. Shivashankar R, Khanna S, Kammer PP, Harmsen WS, Zinsmeister AR, Baddour LM, Pardi DS. Clinical predictors of recurrent Clostridium difficile infection in out-patients. Aliment Pharmacol Ther. 2014;40(5): 518-22. doi:10.1111/apt.12864
6. Gash K, Brown E, Pullyblank A. Emergency subtotal colectomy for fulminant Clostridium difficile colitis-is a surgical solution considered for all patients? Ann R Coll Surg Engl. 2010;92(1):56-60. doi:10.1308/00358 8410X12518836439164
7. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(4):881-91. doi:10.1093/jac/dkt477
8. Oh SE, Lee SM, Lee Y-K, Choi SR, Choi M-J, Kim J-K, Song YR, Kim SJ, Park TJ, Kim SG, Oh J, Suh JW, Yoon J-W, Koo J-R, Kim HJ, Noh JW. Clostridium difficile-associated diarrhea in dialysis patients. Kydney Res Clin Pract. 2013;32(1):2731. doi:10.1016/j.krcp.2012.12.002
9. Gweon TG, Choi MG, Baeg MK, Lim CH, Park JM, Lee IS, Kim SW, Lee DG, Park YJ, Lee JW. Hematologic diseases: High risk of Clostridium difficile associated diarrhea. World J Gastroenterol. 2014;20(21):6602-7. doi:10.3748/wjg.v20.i21.6602
10. Nitzan O, Elias M, Chazan B, Raz R, Saliba W. Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment. World J Gastroenterol. 2013;19(43):7577-85. doi:10.3748/wjg. v19.i43.7577
11. Hainesa СF, Moorea RD, Bartletta JG, Searsa CL, Cosgrovea SE, Carrollb K, Gebo KA. Clostridium difficile in a HIV-Infected Cohort: Incidence, Risk Factors, and Clinical Outcomes. AIDS. 2013;27(17):2799-807. doi:10.1097/01.aids.0000432450.37863.e9
12. Bone RC, Sibbald WJ, Sprung CL. The ACCPSCCM consensus conference on sepsis and organ failure. Chest. 1992;101(6):1481-3. doi:10.1378/chest.101.6.1481
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. doi:10.1016/0021-9681 (87)90171-8
14. Asempa TE, Nicolau DP. Clostridium difficile infection in the elderly: an update on management. Clinical Interventions in Aging. 2017;12:1799-809. doi:10.2147/CIA.S149089
15. Othman F, Crooks CJ, Card TR. The risk of Clostridium difficile infection in patients with pernicious anaemia: a retrospective cohort study using primary care database. United European Gastroenterology J. 2017; 5(7):959-66. doi:10.1177/2050640617695697
16. Dallman PR. Iron deficiency and the immune response. Am J Clin Nutr. 1987;46(2):329-34. doi:10.1093/ajcn/46.2.329
17. Helyar L, Sherman AR. Iron deficiency and interleukin 1 production by rat leukocytes. Am J Clin Nutr. 1987;46(2):346-52. doi: 10.1093/ajcn/46.2.346
18. Dudzicz S, Adamczak M, Więcek A. Clostridium Difficile Infection in the Nephrology Ward. Kidney Blood Press Res. 2017;42(5):844-52. doi: 10. 1159/000484428
19. Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, Tranaeus A, Stenvinkel P, Lindholm B. Aspects of Immune Dysfunction in End-stage Renal Disease. Clin J Am Soc Nephrol. 2008;3(5):1526-33. doi: 10.2215/CJN.00950208
20. Trifan A, Stanciu C, Girleanu I, Stoica OA, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol. 2017;23(35):6500-15. doi: 10.3748/wjg.v23.i35.6500
21. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107:1001-10. doi: 10.1038/ajg.2012.179
22. Khanna S, Aronson SL, Kammer PP, Baddour LM, Pardi DS. Gastric acid suppression and outcomes in Clostridium difficile infection: a population-based study. Mayo Clin Proc. 2012;87(7):636-42. doi:10.1016/j.mayocp. 2011.12.021
23. Leonard AD, Ho KM, Flexman J. Proton pump inhibitors and diarrhoea related to Clostridium difficile infection in hospitalised patients: a case-control study. Intern Med J. 2012;42(5):591-4. doi:10.1111/j.1445-5994. 2012.02770.x
24. Stevens V, Dumyati G, Fine LS, Fisher SG, Wijngaarden E. Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection. Clinical Infectious Diseases. 2011;53(1):42-8. doi:10.1093/cid/ cir301
25. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(4):881-91. doi:10.1093/jac/dkt477
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1. Pepin J, Valiquette ME, Alary P, Villemure P, Pelletier A, Forget K, Pépin K, Chouinard D. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ. 2004;171(5):466-72. doi:10.1503/cmaj.1041104
2. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-34. doi:10.1056/NEJMoa1408913
3. Kurti Z, Lovasz BD, Mandel MD, Csima Z, Golovics PA, Csako BD, Mohas A, Gönczi L, Gecse KB, Kiss LS, Szathmari M, Lakatos PL. Burden of Clostridium difficile infection between 2010 and 2013: Trends and outcomes from an academic center in Eastern Europe. World J Gastroenterol. 2015;21(21):6728-35. doi:10.3748/wjg.v21.i21.6728
4. Shivashankar R, Khanna S, Kammer PP, Harmsen WS, Zinsmeister AR, Baddour LM, Pardi DS. Clinical factors associated with development of severe-complicated Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11(11):1466-71. doi:10.1016/j.cgh.2013.04.050
5. Shivashankar R, Khanna S, Kammer PP, Harmsen WS, Zinsmeister AR, Baddour LM, Pardi DS. Clinical predictors of recurrent Clostridium difficile infection in out-patients. Aliment Pharmacol Ther. 2014;40(5): 518-22. doi:10.1111/apt.12864
6. Gash K, Brown E, Pullyblank A. Emergency subtotal colectomy for fulminant Clostridium difficile colitis-is a surgical solution considered for all patients? Ann R Coll Surg Engl. 2010;92(1):56-60. doi:10.1308/00358 8410X12518836439164
7. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(4):881-91. doi:10.1093/jac/dkt477
8. Oh SE, Lee SM, Lee Y-K, Choi SR, Choi M-J, Kim J-K, Song YR, Kim SJ, Park TJ, Kim SG, Oh J, Suh JW, Yoon J-W, Koo J-R, Kim HJ, Noh JW. Clostridium difficile-associated diarrhea in dialysis patients. Kydney Res Clin Pract. 2013;32(1):2731. doi:10.1016/j.krcp.2012.12.002
9. Gweon TG, Choi MG, Baeg MK, Lim CH, Park JM, Lee IS, Kim SW, Lee DG, Park YJ, Lee JW. Hematologic diseases: High risk of Clostridium difficile associated diarrhea. World J Gastroenterol. 2014;20(21):6602-7. doi:10.3748/wjg.v20.i21.6602
10. Nitzan O, Elias M, Chazan B, Raz R, Saliba W. Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment. World J Gastroenterol. 2013;19(43):7577-85. doi:10.3748/wjg. v19.i43.7577
11. Hainesa СF, Moorea RD, Bartletta JG, Searsa CL, Cosgrovea SE, Carrollb K, Gebo KA. Clostridium difficile in a HIV-Infected Cohort: Incidence, Risk Factors, and Clinical Outcomes. AIDS. 2013;27(17):2799-807. doi:10.1097/01.aids.0000432450.37863.e9
12. Bone RC, Sibbald WJ, Sprung CL. The ACCPSCCM consensus conference on sepsis and organ failure. Chest. 1992;101(6):1481-3. doi:10.1378/chest.101.6.1481
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. doi:10.1016/0021-9681 (87)90171-8
14. Asempa TE, Nicolau DP. Clostridium difficile infection in the elderly: an update on management. Clinical Interventions in Aging. 2017;12:1799-809. doi:10.2147/CIA.S149089
15. Othman F, Crooks CJ, Card TR. The risk of Clostridium difficile infection in patients with pernicious anaemia: a retrospective cohort study using primary care database. United European Gastroenterology J. 2017; 5(7):959-66. doi:10.1177/2050640617695697
16. Dallman PR. Iron deficiency and the immune response. Am J Clin Nutr. 1987;46(2):329-34. doi:10.1093/ajcn/46.2.329
17. Helyar L, Sherman AR. Iron deficiency and interleukin 1 production by rat leukocytes. Am J Clin Nutr. 1987;46(2):346-52. doi: 10.1093/ajcn/46.2.346
18. Dudzicz S, Adamczak M, Więcek A. Clostridium Difficile Infection in the Nephrology Ward. Kidney Blood Press Res. 2017;42(5):844-52. doi: 10. 1159/000484428
19. Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, Tranaeus A, Stenvinkel P, Lindholm B. Aspects of Immune Dysfunction in End-stage Renal Disease. Clin J Am Soc Nephrol. 2008;3(5):1526-33. doi: 10.2215/CJN.00950208
20. Trifan A, Stanciu C, Girleanu I, Stoica OA, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol. 2017;23(35):6500-15. doi: 10.3748/wjg.v23.i35.6500
21. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012;107:1001-10. doi: 10.1038/ajg.2012.179
22. Khanna S, Aronson SL, Kammer PP, Baddour LM, Pardi DS. Gastric acid suppression and outcomes in Clostridium difficile infection: a population-based study. Mayo Clin Proc. 2012;87(7):636-42. doi:10.1016/j.mayocp. 2011.12.021
23. Leonard AD, Ho KM, Flexman J. Proton pump inhibitors and diarrhoea related to Clostridium difficile infection in hospitalised patients: a case-control study. Intern Med J. 2012;42(5):591-4. doi:10.1111/j.1445-5994. 2012.02770.x
24. Stevens V, Dumyati G, Fine LS, Fisher SG, Wijngaarden E. Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection. Clinical Infectious Diseases. 2011;53(1):42-8. doi:10.1093/cid/ cir301
25. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(4):881-91. doi:10.1093/jac/dkt477