Randomised Clinical Trial: Vancomycin or Metronidazole in Patients With Primary Sclerosing Cholangitis

A Pilot Study

J. H. Tabibian; E. Weeding; R. A. Jorgensen; J. L. Petz; J. C. Keach; J. A. Talwalkar; K. D. Lindor


Aliment Pharmacol Ther. 2013;37(6):604-612. 

In This Article

Abstract and Introduction


Background Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited.

Aims To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC.

Methods Thirty-five patients with PSC were randomised in a double-blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase (ALK) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects (AEs). Nonparametric tests were used for analysis.

Results The primary endpoint was reached in the low-dose (−43% change in ALK,P = 0.03) and high-dose (−40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low-dose metronidazole group (−20%, P = 0.03) and trended towards significance in the low-dose vancomycin group (−33%, P = 0.06). Mayo PSC risk score decreased significantly in the low-dose vancomycin (−0.55, P = 0.02) and low-dose metronidazole group (−0.16, P = 0.03). Pruritus decreased significantly in the high-dose metronidazole group (−3.4, P = 0.03). AEs led to medication discontinuation in six patients, four of whom were receiving metronidazole.

Conclusions Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer-term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis (clinicaltrials.gov NCT01085760).


Primary sclerosing cholangitis (PSC) is a chronic idiopathic liver disease characterised by inflammation and concentric fibrosis of the bile ducts for which there is no known effective pharmacotherapy.[1] Liver transplantation (LT) is the only existing treatment shown to prolong survival; however, PSC recurs in up to one-third of deceased donor LT and up to two-thirds of living-related donor LT patients.[2,3] The most widely studied pharmacological agent in the treatment of cholestatic liver diseases, ursodeoxycholic acid (UDCA), improves serum liver tests in PSC, but unlike in primary biliary cirrhosis, does not appear to delay disease progression.[4–6] Furthermore, a recent large randomised trial has found high-dose UDCA to be associated with serious adverse effects (AEs) in patients with PSC.[4,7] Numerous other drugs, including but not limited to azathioprine, budesonide, methotrexate and pentoxifylline, have also been evaluated in the treatment of PSC but without evidence of benefit.[4,8–14] The negative results of these clinical trials have highlighted the importance of considering treatment approaches that target alternative pathophysiological pathways.

Primary sclerosing cholangitis is now generally considered to be an idiopathic, likely immune-mediated disease with various aetiopathogenic components. One hypothesis is that enterohepatic circulation of (as of yet undetermined) bacterially derived molecules plays a critical role in eliciting pro-inflammatory, pro-fibrotic hepatobiliary responses that lead to the development of PSC (hereinafter 'PSC microbiota hypothesis').[15–17] The entry of such molecules into the enterohepatic circulation may, in some patients, be related to the enteric dysbiosis and increased intestinal permeability associated with inflammatory bowel disease (IBD), a condition diagnosed in 75% of those with PSC.[18–22] Further supporting the PSC microbiota hypothesis is the observation, for example, that patients with PSC often have a leucocyte differential exhibiting increased neutrophils, even in the absence of signs or symptoms of acute cholangitis, suggesting circulation of endotoxins or other immunoactive molecules.[23] Collectively, these and animal model[24,25] findings point toward a role for bacteria and bacterially derived molecules in the aetiopathogenesis of PSC.[2]

To date, there have been a few studies of antibiotics in patients with PSC (Table 1), some of which have yielded favourable results based primarily on reduction in serum aminotransferases or alkaline phosphatase (ALK).[26–29] Aminotransferase values are independently associated with prognosis and are a component of the Mayo PSC risk score, and ALK values have been recently associated with prognosis,[30] thus making these two readily measured liver biochemistries important end points in studies of PSC. However, the number of patients in the aforementioned antibiotic studies has been small (and often case report-based), the end points assessed relatively few and the selection of antibiotics often arbitrary or for another condition (e.g. reactive airways disease, after which incidental improvement of PSC was noted).[27,28,31–35]

Given the evidence supporting the PSC microbiota hypothesis yet the limited studies investigating the potential therapeutic effects of antibiotics, we conducted a randomised, double-blind pilot study of oral vancomycin or metronidazole as a treatment for patients with PSC. We chose these agents based on prior experience and evidence of seemingly greater therapeutic response. We assessed safety and efficacy of both antibiotics, each at two different doses, in improving liver biochemistries and liver-related symptoms in patients with PSC.