Probiotics for the Prevention of C.difficile Infection Antibiotic Guidelines Classification: Clinical Guideline Lead Author: Antibiotic Steering Committee Additional author(s): N/A Authors Division: DCSS & Tertiary Medicine Unique ID: 144TD(C)25(A4) Issue number: 4 Expiry Date: October 2019 Contents Section Page Intro Who should read this document 2 Key practice points 2 Background/ Scope/ Definitions 2 What is new in this version 2 Policy/Procedure/Guideline 3 Standards 7 Explanation of terms 7 References and Supporting Documents 7 Roles and Responsibilities 8 Document control information (Published as separate document) 8 Document Control 8 Policy Implementation Plan 9 Monitoring and Review 9 Endorsement 9 Equality analysis 9 Page 1 of 8
Who should read this document? This policy applies to all clinical staff involved the prescribing of antimicrobials. Key Practice Points In the case where an antibiotic prescription is necessary, probiotic therapy should be considered in order to reduce the risk of C. difficile infection and antibioticassociated diarrhoea. Background/ Scope/ Definitions Antimicrobial agents are among the most commonly prescribed drugs and account for 20% of the hospital pharmacy budget. Unfortunately, the benefits of antibiotics to individual patients are compromised by the development of bacterial drug resistance. Resistance is a natural and inevitable result of exposing bacteria to antimicrobials. Good antimicrobial prescribing will help to reduce the rate at which antibiotic resistance emerges and spreads. It will also minimise the many side effects associated with antibiotic prescribing, such as Clostridium difficile infection. It should be borne in mind that antibiotics are not needed for simple coughs and colds. In some clinical situations, where infection is one of several possibilities and the patient is not showing signs of systemic sepsis, a wait and see approach to antibiotic prescribing is often justified while relevant cultures are performed. This document provides treatment guidelines for the most common situations in which antibiotic treatment is required. The products and regimens listed here have been selected by the Trust's Medicines Management Group on the basis of published evidence. Doses assume a weight of 60-80kg with normal renal and hepatic function. Adjustments may be needed for the treatment of some patients. This document provides treatment guidelines for the appropriate use of antibiotics. The recommendations that follow are for empirical therapy and do not cover all clinical circumstances. Alternative antimicrobial therapy may be needed in up to 20% of cases. Alternative recommendations will be made by the microbiologist in consultation with the clinical team. This document refers to the treatment of adult patients (unless otherwise stated). Page 2 of 8
What is new in this version? References and introduction section updated. Reminder that if being discharged on VSL#3, patients should be provided with the full course (up to a maximum of 2 weeks) and primary care not asked to supply. Patients going home on more than 2 weeks of antibiotics should be discussed with microbiology. Statement that VSL#3 should not be used in patients in critical care routinely. Policy/ Guideline/ Protocol Probiotics for the Prevention of Clostridium difficile infection Introduction Antibiotic use is the most widely recognised modifiable risk factor for C. difficile infection (CDI). Antibiotics disrupt the normal colonic flora, allowing C. difficile to multiply and release toxins that bind to receptors on intestinal epithelial cells leading to inflammation and diarrhoea. Probiotics colonise the gut temporarily, producing bactericidal acids and peptides and promoting "competition" among microbes by competing for nutrients and epithelial adhesion. These effects appear to reduce the favourability of the environment for C. difficile. Evidence for the clinical efficacy of probiotics in reducing risk of CDI has varied in the literature in recent years. A 2012 systematic review and metaanalysis 1 on probiotic use for the prevention of CDI looked at 20 trials including 3818 participants. It concluded that there was moderate quality evidence to suggest that probiotic use reduced the incidence of CDI (by up to 66%). The incidence of adverse effects was 9.3% (treatment arm) vs. 12.6%(control arm) 1. The treatment duration for the probiotic ranged from the duration of antibiotic treatment only (7 studies) to 20 days beyond antibiotic treatment (1 study). Lactobacillus acidophilus and L. casei appeared to be the best combination agent to use. Receiving more than 10 billion colony forming units (CFU) daily and using multiple species showed a greater effect. Many of these trials were then included in a 2013 Cochrane review 2 Probiotics for the prevention of Clostridium difficile-associated diarrhoea in adults and children. This concluded that there was moderate quality evidence to suggest that probiotics are safe and effective for preventing CDI. In another study 3, the impact of antibiotic therapy on the intestinal microbiota of a large cohort of elderly subjects was investigated, based on faecal microbiota analysis. It was found that the culturable Bifidobacterium spp. population in faecal samples from the antibiotic-treated group decreased 7- Page 3 of 8
fold when compared with the untreated group, while levels of Lactobacillus spp. and Enterobacteriaceae were unaffected. This data suggest that probiotic and/or prebiotic use, in particular targeting the Bifidobacterium spp. population, may be one approach to correct the altered intestinal microbial composition resulting from antibiotic therapy in the elderly. The PLACIDE trial 4, a randomised, double-blind, placebo-controlled, multicentre trial in the UK, identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. This cast significant doubt on prior literature given it was a good quality, contemporary prospective double blind placebo RCT and led to many centres deciding that probiotic therapy was not a viable preventitive option. That said some authors have suggested it may have been underpowered to detect reductions in CDI given the baseline rates, and in addition not all probiotic courses were commenced at the onset of antibiotic treatment and the probiotic course was a fixed 21 days irrespective of antibiotic duration. Most recently, Shen et al. undertook a systematic review 5, looking at 6261 patients in 19 studies. Their meta-regression analysis reported a greater effect from probiotics when administered closer to the first dose of antibiotic, and that given within 2 days of commencement of antibiotics there was a significant reduction in risk of CDI with no increased adverse events. Probiotics were introduced at Salford Royal at the same time as several other measures aimed at reducing CDI and so it is unclear what role, if any, they have played in the reduction in CDI cases. However given this reduction, the fact there have been no microbiological complications (iatrogenic bacteraemia) from their use, and their relative low cost compared with the healthcare costs of a single case of CDI, the current proposal from Antibiotic Steering Group is that VSL3 continues to be recommended as detailed in this policy. As advanced age (>65years) and hospitalisation are established risk factors for CDI, this group of patients are to be targeted for probiotic therapy. VSL#3 has been chosen as the probiotic of choice due the large number of CFU it contains (450 billion CFU) and the multiple strains, including: Streptococcus thermophilus Bifidobacterium breve Bifidobacterium longum Bifidobacterium infantis Lactobacillus acidophilus Lactobacillus plantarum Lactobacillus paracasei Lactobacillus delbrueckii subsp. Bulgaricus Page 4 of 8
Criteria for receiving probiotics All of the following criteria should be met before considering probiotic therapy: Patient is receiving antibiotic treatment. Patient is an in-patient. Patient is 65years of age. Exclusion criteria: The following patients should not be prescribed probiotics. Patients in critical care (unless discussed with microbiology) Patients with active or suspected intestinal perforation. Immunocompromised patients. This includes: patients with evidence of severe primary immunodeficiency patients receiving immunosuppressive chemotherapy or radiotherapy*. patients receiving other types of immunosuppressive drugs* (e.g. azathioprine, cyclosporin, methotrexate, cyclophosphamide, leflunomide and the newer cytokine inhibitors) patients with HIV infection and CD4 count<500 patients with asplenia or splenic dysfunction patients treated with or likely to be treated with systemic steroids for more than a month at a dose equivalent to prednisolone at 20mg or more per Treatment day *currently or within the last 6 months Treatment VSL #3 sachet 1 sachet daily Duration To be continued for the duration of antibiotic treatment only. Patients who are discharged on antibiotic treatment should continue on VSL#3 until they complete the antibiotic course UNLESS the expected duration is greater than 2 weeks post discharge. The duration of VSL#3 in this instance should be determined after discussion with the microbiology team. Where patients are discharged on VSL#3, the full supply should be provided at discharge by SRFT. Primary care should not be asked to provide the VSL#3 sachets. Page 5 of 8
Patients receiving antimicrobials for prophylaxis (short or long term) do NOT usually require VSL#3 prescribing Administration VSL#3 can be taken orally or via an nasogastric tube. Data on administration of VSL#3 via other enteral feeding tubes (e.g. PEG and RIG) is limited and should be avoided due to risk of tube blockages. It should be mixed with a cold (non-fizzy) drink, or sprinkled on cold food. Storage VSL#3 sachets should be stored in a fridge (2-8 o ). Leaving a sachet lying around in excessive heat, even for a short period, will greatly reduce the effect of the bacteria. Adverse effects When starting VSL#3 bloating may be experienced while the balance of bacteria in the digestive tract changes. If bloating occurs, the daily intake may need to be reduced to allow for this adjustment. A small number of case reports describing bacteremia or fungemia attributed to probiotics have been reported. See table above for exclusion criteria for use. Dietary considerations The VSL#3 production process has been amended and as a result, according to EU allergen labelling regulations, VSL#3 is gluten free and does not contain the following: Crustacean shellfish, molluscs, eggs, fish, peanuts, tree nuts, soybeans, milk and lactose, celery, mustard, sesame, lupin and sulphur dioxide at levels above 10mg/kg, or 10 mg/litre, expressed as SO 2 Some dairy ingredients are used to make VSL#3, but these are removed during fermentation. However, there might be trace amounts left and for this reason VSL#3 is not defined as a dairy-free product. Try a small amount first if patient intolerant of dairy products. VSL#3 is suitable for vegetarians. VSL#3 is also certified as Kosher and Halal. Page 6 of 8
Standards Document the Indication/rationale for antimicrobial therapy, including clinical criteria relevant to this. Review and document the patient s allergy status Ensure the choice of antibiotic complies with the antibiotic guidelines and you have documented any clinical criteria relevant to the choice of agent. Document a management plan including a stop or review date. Where relevant, consider drainage of pus or surgical debridement/removal of foreign material. Explanation of terms Not applicable. References and Supporting Documents 1. Bradley C. Johnston, PhD; Stephanie S. Ma, MD; Joshua Z. Goldenberg, BSc; Kristian Thorlund, PhD; Per O. Vandvik, MD, PhD; Mark Loeb, MD; and Gordon H. Guyatt, MD. Probiotics for the Prevention of Clostridium difficile associated diarrhoea: A systematic review and meta-analysis. Annals of Internal Medicine 2012;157(12):878-88 2. Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013 May 31;(5):CD006095. doi: 10.1002/14651858.CD006095.pub3 3. Orla O Sullivan, Mairead Coakley, Bhuvaneswari Lakshminarayanan, Susana Conde, Marcus J. Claesson, Siobhan Cusack, Anthony P. Fitzgerald, Paul W. O Toole, Catherine Stanton and R. Paul Ross* on behalf of the ELDERMET Consortium Alterations in intestinal microbiota of elderly Irish subjects post-antibiotic therapy J Antimicrob Chemother 2013; 68: 214 221 4. Allen, Stephen J et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebocontrolled, multicentre trial. The Lancet 2014;382:1249-1257 5. Shen N, Maw A, Tmanova LL, Pino A, Ancy K, Crawford CV, Simon M, Evans A. Timely Use of Probiotics in Hospitalised Adults Prevents Page 7 of 8
Clostridium difficile Infection: A Systematic Review With Meta- Regression Analysis. Gastroenterology 2017;152:1889-1900 Roles and responsibilities All clinical staff involved in the prescribing of antimicrobials to adhere to this policy including full documentation on EPMAR as detailed. Page 8 of 8