Introduction
Primary sclerosing cholangitis (PSC) is a chronic disease of the liver that is characterised by persistent and progressive inflammation and fibrosis of biliary structures, as well as liver cirrhosis.1 Liver failure is common in end-stage PSC necessitating liver transplantation.1 To date, there is no effective medical therapy for PSC, with liver transplantation being the only available treatment, although recurrence is a significant obstacle.2
The aetiology and pathogenesis of PSC is not yet determined, but it is widely accepted that the development, progression, and outcome of the disease is affected by genetic and environmental risk factors.1 PSC is also strongly associated with inflammatory bowel disease (IBD), with between 70 and 80% of patients suffering from both conditions.1 Patients with PSC are also at risk of developing colon, bile-duct, and gallbladder cancers.1 PSC is also a male predominant disease, which can present at any age, with the mean age of presentation being 40.3
Clinical presentations of PSC are normally subtle, and when symptoms are present, they tend to be non-specific, for example fatigue and pruritis.3 Other symptoms of PSC can include abdominal pain in the right upper quadrant, weight loss, and outbreaks of fever and chills.3 On clinical diagnosis, the most common signs are hepatomegaly, splenomegaly and jaundice.1 Alkaline phosphatase (ALP) may characterise a prognostic biomarker in patients with PSC, and recent studies have demonstrated that a decrease in ALP was related to a better long-term prognosis.2
As there is yet to be a proven or approved therapy for PSC to exist, it is important to study possible therapies aimed at managing complications and treating the symptoms.3 New possible therapies, including antibiotics (such as vancomycin and rifaximin), bile acids and immunotherapies are presently in development.4 As PSC is still so poorly understood, it is important to explore these possibilities as much as possible. Small studies have shown that the use of antibiotics in clinical trials has demonstrated substantial favourable results.2
The likely mechanism of action for new antibiotics to treat PSC would be in the leaky gut.2 The leaky gut is a theory describing an important role in the pathogenesis of PSC, and it suggests the translocation of colonic bacteria and endotoxins to the liver by the portal vein, which consequently triggers inflammatory cytokines resulting in biliary duct inflammation.2 Antibiotics are believed to adjust the gut microbiota, therefore encouraging a decrease in the exposure of the biliary epithelium to pathogenic antigens, making the leaky gut a perfect target.2 Previous studies have found that vancomycin showed better results than metronidazole, and rifaximin didn’t show improvement of ALP.2 From these results, vancomycin seems to be the most promising antibacterial therapy to date.5 Larger and long-term studies should be undertaken.2 Another study showed a significant reduction in ALP from those who were treated with minocycline.5
The experiment conducted by Tabibian et al. (2017) illustrated that the administration of rifaximin isn’t an efficacious therapy for most PSC patients.5 Adverse effects also affected almost 20% of the patients, preventing them from continuing the medication for the remainder of the study.5 The broad-spectrum antibacterial activity of rifaximin may be the reason for its failure to produce therapeutic results for those with PSC.5 Despite these results, the microbiota are still a promising target for potential PSC therapies, and further studies should analyse their role in the pathogenesis and review properties of antibiotics, including their antimicrobial spectrum and anti-inflammatory action in order to determine their usefulness.5
An antibiotic that has not yet been explored for the potential treatment of PSC is oral teicoplanin. A prospective study found that teicoplanin, a glycopeptide antibiotic similar to vancomycin, was efficacious and safe in the treatment of pseudomembranous colitis (PMC) and Clostridium difficile associated diarrhea.6 The twice daily dose of 100mg of teicoplanin for 10 days was found to be as effective as the four times daily dose of 500mg of vancomycin.6 Therefore, if teicoplanin would be successful in treating PSC, it may mean a therapeutic treatment consisting of lower dose numbers per day, with a smaller amount of drug per dose.
Aims
The aim of this project is to investigate, using a human study, the efficacy and safety of oral teicoplanin and determine whether it has the potential to become a therapy for patients with PSC by measuring ALP levels before and after treatment, as well as adverse effects (AEs).
Approach
Participants
Patients with PSC will be enrolled in a pilot study of oral teicoplanin at a dose of 100mg twice a day. PSC will be diagnosed using ALP >1.5 times the upper limit of normal for at least 6 months.5 Exclusion criteria will be: treatment with investigational agents within three months before the study, allergies to teicoplanin, decompensated or comorbid liver disease, pregnancy or lactation, drug abuse, and a minimum age of 16 years. Informed consent will also be required from each participant.5
Study medication and monitoring
Teicoplanin is a semi-synthetic glycopeptide antibiotic, similar to vancomycin, with a mechanism of action that inhibits bacterial cell wall synthesis.6 Written material about potential AEs of teicoplanin will be provided and serum complete blood counts and liver biochemistries will be measured twice over the study, and phone calls will be made to track AEs.
Endpoints
Study endpoints will be assessed and compared to the values that will be obtained at study entry. The primary endpoint is serum ALP, and the secondary endpoint will be frequency and types of AEs.5
Data analysis
Data will be summarized as a median. Considering the varied nature of PSC, and variations in individual responses, statistical analyses will be conducted using conservative tests.5
Significance
PSC is a rare and premalignant disease which, to date, has no proven therapy that prolongs survival.4 The only approved treatment is liver transplantation, and PSC is the 5th most common reason for liver transplantation in the US.2 With recurrence also being a significant issue, finding a therapy for PSC will not only prolong survival, but will also decrease the need for liver transplantation, which benefits more than just patients with PSC.
References
1. Ingelfinger JR, Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. The New Engl Journ of Med [serial online]. 2016 [cited 2018 April 28];375(12):1161-1170. Available from: ProQuest. https://search-proquest-com.libproxy.murdoch.edu.au/docview/1822456149/abstract/18EFA1BA4246418CPQ/1?accountid=12629
2. Rodriguez EA, Carey EJ, Lindor KD. Emerging treatments for primary sclerosing cholangitis. Exp Rev of Gastroen Hepa. 2017;11(5):451-459. doi: 10.1080/17474124.2017.1293524
3. Sirpal S, Chandok N. Primary sclerosing cholangitis: diagnostic and management challenges. Clin Exp Gasroen. 2017;10:265-273. doi: 10.2147/CEG.S105872
4. Chapman RW. Update on primary sclerosing cholangitis. Clin Liv Dis. 2017;9(5):107-110. doi: 10.1002/cld.633
5. Tabibian JH, Gossard A, El-Youssef M, Eaton JE, Petz J, Jorgenson R, et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Amer journ of thera. 2017;24(1):e56-e63. doi: 10.1097/MJT.0000000000000102.
6. De Lalla F, Nicolin R, Rinaldi E, Scarpellini P, Rigoli R, Manfrin V, et al. Prospective study of oral teicoplanin versus oral vancomycin for therapy of pseudomembranous colitis and Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother. 1992 [cited 2018 April 27];36(10):2192-2196. Available from: NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC245474/?page=1