Effects of Antibiotic Therapy in Primary Sclerosing Cholangitis with and without Inflammatory Bowel Disease: A Systematic Review and Meta-AnalysisFunding None.
17 July 2019 (eFirst)
The authors conducted a systematic review and meta-analysis to assess the effect of antibiotic therapy in primary sclerosing cholangitis (PSC). Effect of antibiotic therapy on Mayo PSC Risk Score (MRS), serum alkaline phosphatase (ALP), total serum bilirubin (TSB), and adverse events (AEs) rates were calculated and expressed as standardized difference of means or proportions. Five studies including 124 PSC patients who received antibiotics were included. Overall, antibiotic treatment was associated with a statistically significant reduction in ALP, MRS, and TSB by 33.2, 36.1, and 28.8%, respectively. ALP reduction was greatest for vancomycin (65.6%, p < 0.002) and smallest with metronidazole (22.7%, p = 0.18). Overall, 8.9% (95% confidence interval: 3.9–13.9) of patients had AEs severe enough to discontinue antibiotic therapy. In PSC patients, antibiotic treatment results in a significant improvement in markers of cholestasis and MRS. Antibiotics, particularly vancomycin, may have a positive effect on PSC either via direct effects on the microbiome or via host-mediated mechanisms.
Keywordsvancomycin - antibiotics - primary sclerosing cholangitis - inflammatory bowel disease - ulcerative colitis - Crohn's disease - microbiome
Ayesha Shah and Gerald Holtmann: Study idea, concept and design, data extraction and interpretation of data, and drafting of the manuscript.
Darrel Crawford: Analysis and interpretation of data, input into the manuscript, and review of final manuscript.
Daniel Burger: Input into discussions and review of final manuscript.
Mark Morrison: Study idea, concept and design, drafting of the manuscript, and review of final manuscript.
Mike Jones: Data analysis and review of final manuscript.
Nicholas Talley: Study idea, data interpretation, drafting of the manuscript and review of final manuscript.
Peter Lewindon: Drafting of the manuscript and review of final manuscript.
Marjorie Walker: Drafting of the manuscript and review of final manuscript.
Katherine Stuart: Drafting of the manuscript and review of final manuscript.
Graeme Macdonald: Drafting of the manuscript and review of final manuscript.
Neal Martin: Drafting of the manuscript and review of final manuscript.
Caroline Tallis: Drafting of the manuscript and review of final manuscript.
Simon Keely: Drafting of the manuscript and review of final manuscript.
* for the Australian Gastrointestinal Research Alliance (AGIRA).
- 1 Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995; 332 (14) 924-933
- 2 Wiesner RH, Grambsch PM, Dickson ER. , et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989; 10 (04) 430-436
- 3 Broomé U, Olsson R, Lööf L. , et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996; 38 (04) 610-615
- 4 Farrant JM, Hayllar KM, Wilkinson ML. , et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991; 100 (06) 1710-1717
- 5 Bambha K, Kim WR, Talwalkar J. , et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 2003; 125 (05) 1364-1369
- 6 Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 2012; 56 (05) 1181-1188
- 7 Toy E, Balasubramanian S, Selmi C, Li CS, Bowlus CL. The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population. BMC Gastroenterol 2011; 11: 83
- 8 Olsson R, Danielsson A, Järnerot G. , et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991; 100 (5 Pt 1): 1319-1323
- 9 Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis 1991; 11 (01) 31-39
- 10 Loftus Jr EV, Sandborn WJ, Lindor KD, Larusso NF. Interactions between chronic liver disease and inflammatory bowel disease. Inflamm Bowel Dis 1997; 3 (04) 288-302
- 11 Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013; 145 (03) 521-536
- 12 Gasbarrini A, Corazza GR, Gasbarrini G. , et al; 1st Rome H2-Breath Testing Consensus Conference Working Group. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference. Aliment Pharmacol Ther 2009; 29 (Suppl. 01) 1-49
- 13 Chapman R, Fevery J, Kalloo A. , et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51 (02) 660-678
- 14 Boonstra K, Weersma RK, van Erpecum KJ. , et al; EpiPSCPBC Study Group. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013; 58 (06) 2045-2055
- 15 Visseren T, Darwish Murad S. Recurrence of primary sclerosing cholangitis, primary biliary cholangitis and auto-immune hepatitis after liver transplantation. Best Pract Res Clin Gastroenterol 2017; 31 (02) 187-198
- 16 Lindor KD, Kowdley KV, Harrison ME. ; American College of Gastroenterology. ACG clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol 2015; 110 (05) 646-659 , quiz 660
- 17 Rankin JG, Boden RW, Goulston SJ, Morrow W. The liver in ulcerative colitis; treatment of pericholangitis with tetracycline. Lancet 1959; 2 (7112): 1110-1112
- 18 Cheung AC, Lazaridis KN, LaRusso NF, Gores GJ. Emerging pharmacologic therapies for primary sclerosing cholangitis. Curr Opin Gastroenterol 2017; 33 (03) 149-157
- 19 Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF. Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 2014; 59 (06) 2263-2275
- 20 Tabibian JH, Trussoni CE, O'Hara SP, Splinter PL, Heimbach JK, LaRusso NF. Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis. Lab Invest 2014; 94 (10) 1126-1133
- 21 Kono K, Ohnishi K, Omata M. , et al. Experimental portal fibrosis produced by intraportal injection of killed nonpathogenic Escherichia coli in rabbits. Gastroenterology 1988; 94 (03) 787-796
- 22 Lichtman SN, Okoruwa EE, Keku J, Schwab JH, Sartor RB. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth. J Clin Invest 1992; 90 (04) 1313-1322
- 23 Hobson CH, Butt TJ, Ferry DM, Hunter J, Chadwick VS, Broom MF. Enterohepatic circulation of bacterial chemotactic peptide in rats with experimental colitis. Gastroenterology 1988; 94 (04) 1006-1013
- 24 Karlsen TH. Primary sclerosing cholangitis: 50 years of a gut-liver relationship and still no love?. Gut 2016; 65 (10) 1579-1581
- 25 Torres J, Palmela C, Brito H. , et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. United European Gastroenterol J 2018; 6 (01) 112-122
- 26 Tabibian JH, Ali AH, Lindor KD. Primary sclerosing cholangitis, part 1: epidemiology, etiopathogenesis, clinical features, and treatment. Gastroenterol Hepatol (N Y) 2018; 14 (05) 293-304
- 27 Buness C, Lindor KD, Miloh T. Oral vancomycin therapy in a child with primary sclerosing cholangitis and severe ulcerative colitis. Pediatr Gastroenterol Hepatol Nutr 2016; 19 (03) 210-213
- 28 Davies YK, Tsay CJ, Caccamo DV, Cox KM, Castillo RO, Cox KL. Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin. Case Rep Transplant 2013; 2013: 314292
- 29 Kozaiwa K, Tajiri H, Sawada A. , et al. Three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine. J Gastroenterol Hepatol 1998; 13 (08) 825-829
- 30 Boner AL, Peroni D, Bodini A, Delaini G, Piacentini G. Azithromycin may reduce cholestasis in primary sclerosing cholangitis: a case report and serendipitous observation. Int J Immunopathol Pharmacol 2007; 20 (04) 847-849
- 31 Tada S, Ebinuma H, Saito H, Hibi T. Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis. J Gastroenterol 2006; 41 (04) 388-389
- 32 Cox KL, Cox KM. Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998; 27 (05) 580-583
- 33 Abarbanel DN, Seki SM, Davies Y. , et al. Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J Clin Immunol 2013; 33 (02) 397-406
- 34 Silveira MG, Torok NJ, Gossard AA. , et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol 2009; 104 (01) 83-88
- 35 Färkkilä M, Karvonen AL, Nurmi H. , et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 2004; 40 (06) 1379-1386
- 36 Tabibian JH, Weeding E, Jorgensen RA. , et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther 2013; 37 (06) 604-612
- 37 Rahimpour S, Nasiri-Toosi M, Khalili H, Ebrahimi-Daryani N, Nouri-Taromlou MK, Azizi Z. A triple blinded, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of oral vancomycin in primary sclerosing cholangitis: a pilot study. J Gastrointestin Liver Dis 2016; 25 (04) 457-464
- 38 Tabibian JH, Gossard A, El-Youssef M. , et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am J Ther 2017; 24 (01) e56-e63
- 39 Rupp C, Rössler A, Halibasic E. , et al. Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis. Aliment Pharmacol Ther 2014; 40 (11-12): 1292-1301
- 40 Kim WR, Therneau TM, Wiesner RH. , et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc 2000; 75 (07) 688-694
- 41 Stroup DF, Berlin JA, Morton SC. , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283 (15) 2008-2012
- 42 Moher D, Liberati A, Tetzlaff J, Altman DG. ; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
- 43 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21 (11) 1539-1558
- 44 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (03) 177-188
- 45 Ali AH, Carey EJ, Lindor KD. Current research on the treatment of primary sclerosing cholangitis. Intractable Rare Dis Res 2015; 4 (01) 1-6
- 46 Vrieze A, Out C, Fuentes S. , et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol 2014; 60 (04) 824-831
- 47 Begley M, Hill C, Gahan CG. Bile salt hydrolase activity in probiotics. Appl Environ Microbiol 2006; 72 (03) 1729-1738
- 48 Kitahara M, Sakata S, Sakamoto M, Benno Y. Comparison among fecal secondary bile acid levels, fecal microbiota and Clostridium scindens cell numbers in Japanese. Microbiol Immunol 2004; 48 (05) 367-375
- 49 Low-Beer TS, Nutter S. Colonic bacterial activity, biliary cholesterol saturation, and pathogenesis of gallstones. Lancet 1978; 2 (8099): 1063-1065
- 50 Ajouz H, Mukherji D, Shamseddine A. Secondary bile acids: an underrecognized cause of colon cancer. World J Surg Oncol 2014; 12: 164-164
- 51 Davies YK, Cox KM, Abdullah BA, Safta A, Terry AB, Cox KL. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J Pediatr Gastroenterol Nutr 2008; 47 (01) 61-67
- 52 Ledeboer A, Sloane EM, Milligan ED. , et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005; 115 (1-2): 71-83
- 53 Van den Bogert C, Kroon AM. Effects of oxytetracycline on in vivo proliferation and differentiation of erythroid and lymphoid cells in the rat. Clin Exp Immunol 1982; 50 (02) 327-335
- 54 Sewell KL, Breedveld F, Furrie E. , et al. The effect of minocycline in rat models of inflammatory arthritis: correlation of arthritis suppression with enhanced T cell calcium flux. Cell Immunol 1996; 167 (02) 195-204
- 55 Stanich PP, Björnsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig Liver Dis 2011; 43 (04) 309-313
- 56 Lindor KD, Kowdley KV, Luketic VA. , et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009; 50 (03) 808-814
- 57 Hilscher M, Enders FB, Carey EJ, Lindor KD, Tabibian JH. Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis. Ann Hepatol 2016; 15 (02) 246-253
- 58 Silveira MG, Lindor KD. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. J Hepatol 2008; 48 (05) 692-694
- 59 Tan LZ, Reilly CR, Steward-Harrison LC, Balouch F, Muir R, Lewindon PJ. Oral vancomycin induces clinical and mucosal remission of colitis in children with primary sclerosing cholangitis-ulcerative colitis. Gut 2018; gutjnl-2018-316599