Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact Name and Job Title (author)

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1 Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact ame and Job Title (author) Directorate & Speciality Date of submission December 2015 Date on which guideline must be reviewed December 2018 Explicit definition of patient group to which it applies Version 3 Changes from previous guideline If this version supersedes another clinical guideline please be explicit about which guideline it replaces including version number Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? Evidence base: (1-5) 1 ICE Guidance, Royal College Guideline, SIG (please state which source) 2a Meta analysis of randomised control trials 2b At least one randomised controlled trial 3a at least one well-designed controlled study without 2b randomisation at least one other type of well-designed quasiexperimental study 4 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 5 expert committee reports or opinions and / or clinical experiences of respected authorities 6 recommended best practise based on the clinical experience of the guideline developer Consultation Process Ratified by: Date Target audience Guideline for the management of Clostridium difficile infection and antibiotic-associated diarrhoea in adults. Dr Vivienne Weston - Consultant Microbiologist Tim Hills - Lead Pharmacist Antimicrobials and Infection Control Heather Abdic - Gastroenterology urse Specialist Dr Kathy Teahon and Prof ash Mahida - Consultant Gastroenterologists Microbiology Diagnostics and Clinical Support For adults with suspected / proven C.difficile infection or antibiotic-associated diarrhoea. Fidaxomicin highlighted, administration of vancomycin using injection orally added to flow chart. HPA / DH ational Guidelines (2009) C. difficile How to Deal With the Problem. Available from: (accessed ). PHE ational Guidelines (2013) Updated guidance on the management and treatment of Clostridium difficile infection. Available from: (accessed ). Summary of product characteristics for Privigen 10%. Available at (accessed ). Personal correspondence with CSL Behring on Miss Walter Consultant Colorectal surgeon Members of ottingham University Hospitals Antibiotic Guidelines Committee. UH antibiotic guidelines committee ovember 2015 Doctors, Registered urses, Pharmacists Review date: December 2018 A review date of 5 years will be applied by the Trust. Directorates can choose to apply a shorter review date, however this must be managed through Directorate Governance processes. This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. ottingham Antimicrobial Guidelines Committee Page 1 of 10 Written December 2015

2 Figure 1: Antibiotic-associated diarrhoea -Empirical treatment Patient with diarrhoea currently on antibiotic(s) or received antibiotic(s) over preceding 4 weeks Send stool specimen to microbiology for Clostridium difficile toxin (CDT) and check computer for previous microbiology results, See figure 2 once results are available Stop antibiotics if possible or D/W microbiology if continuation essential for the best regimen, review indication for Proton Pump Inhibitors if prescribed (see PPI guidelines) and investigate other causes for diarrhoea e.g. tube feeds, antacids, laxatives Take a FBC, U&E and, if any abdominal pain AXR. Refer to Gastro urse Specialist cdiffgastronurses@nuh.nhs.uk or OTIS- DIARCS for assessment and clinical support Inform Infection Prevention and Control Team (City Ext or QMC Ext 63866) Isolate patient, start enteric precautions and stool chart. Mild disease Mild diarrhoea alone i.e. <4 stools in 24 hours, no features of severe disease Supportive therapy only- these cases are often self-limiting if causative antibiotics are stopped. Moderate disease > 4 stools in 24 hours, no features of severe disease Start PO Metronidazole 400mg tds for 10 days, refer to gastroenterology (nurse specialists OTIS referral Diarrhoea services / out of hours acute gastro team via switch) Severe disease Any of the following regardless of stool frequency :- WBC > 15x 10 9 /L Temp > 38.5 C Acute inc. serum creatinine (>50% baseline) Evidence of severe colitis (hypotension, ileus, pseudomembranous colitis abdominal signs, radiology-ct or Abdo. X-Ray) Start PO/G (not IV) Vancomycin (use injection orally- see page 5) 125mg-250mg qds + refer to acute gastro on-call registrar ASAP (if BM + G route /A IV Metronidazole 500mg tds). Ensure first doses are given immediately. Complicated disease Signs of severe disease complicated by hypotension or partial ileus or CT evidence of severe disease Life threatening disease Complete ileus or Toxic megacolon Start PO/G (not IV) Vancomycin (use injection orally- see page 5) 250mg (if complicated) -500mg (if life threatening) qds plus IV metronidazole 500mg tds refer to acute gastro on-call registrar ASAP plus, if fulminant disease, gastrosurgery Ensure first doses are given immediately. Recurrence of symptoms, Patients should be investigated and treated according to the protocol above with repeat samples but with a second course of whichever antibiotic regimen the original infection responded to (PO Metronidazole/PO Vancomycin or combinations). If the patient is confirmed positive for C.difficile infection and not received fidaxomicin before then start PO fidaxomicin 200mg bd for 10 days (plus stop any vancomycin/metronidazole started) after discussion with microbiology. Pharmacy must be contacted following microbiology approval for urgent supply. Further recurrences should be discussed in hours with Gastroenterology urse (Specialist in C difficile disease)- OTIS DIARCS or cdiffgastronurses@nuh.nhs.uk for both City and QMC or if acutely unwell/severe disease Acute Gastro Registrar (QMC) (City). ottingham Antimicrobial Guidelines Committee Page 2 of 10 Written December 2015

3 Figure 2: Interpretation of Stool Sample Results Stool Sample Result Toxin +ve Toxin ve PCR +ve Toxin -ve Start Treatment See Figure 3 Repeat sample Toxin +ve Review other causes for diarrhoea including medication. If diarrhoea ongoing : Repeat sample. Isolate with enteric precautions. Consider referral to gastro Review other causes of diarrhoea including medication (e.g. laxatives/ PPIs). If diarrhoea ongoing : Repeat sample. If Toxin ve on repeat, unlikely C.diff infection. Consider referral to gastro PCR +ve and Toxin ve on repeat, C.diff colonisation present, infection unlikely. Continue to isolate. Review other causes of diarrhoea. Patient does not require treatment unless severe disease. Repeat sample Toxin +ve ottingham Antimicrobial Guidelines Committee Page 3 of 10 Written December 2015

4 Figure 3: Treatment of Confirmed C.difficile Toxin +ve Cases es to either question, Discuss with microbiology for most appropriate regimen Confirmed Toxin +ve cases Does the patient require concomitant systemic antimicrobials for another infection? Or is this a recurrence of C.diff infection? o to both questions Start PO Fidaxomicin 200mg bd for 10 days following approval from microbiology. All confirmed cases should be referred to the Gastroenterology urse Specialist for assessment and clinical management support. Refer via OTIS-DIARCS or cdiffgastronurses@nuh.nhs.uk in working hours Mild or Moderate symptoms o signs of severe disease Treat if ongoing diarrhoeamay have resolved spontaneously. Start PO metronidazole 400mg tds for 10 days o improvement within 5 days or any clinical deterioration, change to PO (not IV) Vancomycin (use injection orally- see page 5) 125 mg qds for 10/7 if not already started Plus seek gastroenterology / microbiology advice regarding need for further escalation of treatment Severe disease Any of the following regardless of stool frequency:- WBC > 15x 10 9 /L Temp > 38.5 C Acute increase in serum creatinine (>50% baseline) Evidence of severe colitis (hypotension, ileus, pseudomembranous colitis abdominal signs, radiology (CT or Abdo. X-Ray)) Start PO/G (not IV) Vancomycin (use injection orally- see page 5) 125mg-250mg qds + refer to acute gastro on-call registrar ASAP (if BM + G route /A IV Metronidazole 500mg tds) Ensure first doses are given immediately. Complicated disease Signs of severe disease complicated by hypotension or partial ileus or CT evidence of severe disease Life threatening disease Complete ileus or Toxic megacolon Start PO/G (not IV) Vancomycin 250mg (use injection orally- see page 5) (if complicated) -500mg (if life threatening) qds plus IV Metronidazole 500mg tds Refer to acute gastro on-call registrar ASAP plus, if fulminant disease, gastrosurgery Ensure first doses are given immediately. Complete 10 day course, this can be increased to 14 days if on-going diarrhoea or prescribed concurrent antibiotics Once patient stabilises and has a dependable oral/g route, consider stopping IV metronidazole and weaning down vancomycin to 125mg -250mg PO/G qds. Complete a 10 day course, this can be increased to 14 days if on-going diarrhoea or concurrent antibiotics or complicated/life threatening infection. ottingham Antimicrobial Guidelines Committee Page 4 of 10 Written December 2015

5 Remember: 1 Use antibiotics and proton pump inhibitors only when indicated follow trust guidelines. 2 Follow the hospital formulary and prescribing guidelines available at 3 Use narrow spectrum antibiotics whenever possible 4 Review all antibiotics daily, intravenous antibiotics at 48 hours and oral antibiotics at 5 days. Add durations and indications to antibiotic prescriptions. 5 Review empiric treatment with microbiology results. Convert to a narrower spectrum agent if possible. 6 Consider the diagnosis of C. difficile diarrhoea in patients who develop diarrhoea having had antibiotics in the preceding 4 weeks 7 Clearance stools samples are not required. Preparation and Administration of Oral/G Vancomycin for C. difficile Treatment Vancomycin injection is licensed for oral use and is used as a treatment for Clostridium difficile associated diarrhoea at UH. It is keep as stock on the majority of adult wards. Please contact pharmacy ASAP if unavailable. Directions for preparation 1. Reconstitute vancomycin 1g vial with 20ml of Water for Injection to give a concentration of vancomycin 125mg in 2.5ml. 2. Withdraw the required volume (e.g. for 125mg withdraw 2.5ml) and place into a medicine galipot. 3. This may be further diluted with water or squash to approximately 20-30ml before administering. 4. Write the patient s name, date and time of reconstitution and date and time of expiry onto an oral vancomycin sticker (Kept on the ward, flag the vial with the sticker). 5. The solution should be stored in the fridge and is suitable for oral use for up to 24 hours. 6. Vials are for single-patient-use only and should not be shared. Stickers can be ordered from pharmacy stores using an emergency stock requisition. ottingham Antimicrobial Guidelines Committee Page 5 of 10 Written December 2015

6 ADDITIOAL IFORMATIO FOR USE O THE ADVICE OF GASTROETEROLOGISTS/ MICROBIOLOGISTS/ IFECTIOUS DISEASE PHSICIAS Initial Treatment and Assessment of Severity Assess severity of disease each day defining: (i) Mild Disease as three or fewer type 5-7 stools on Bristol Stool Chart per day and no features of severe disease. (ii) Moderate Disease > 4 stools per day and no features of severe disease. (iii) Severe Disease as a WCC >15x 10 9 /L or a temperature of > 38.5 C or acute rising serum creatinine (e.g. >50% increase above baseline) or evidence of severe colitis (abdominal or radiological signs). The number of stools may be a less reliable indicator of severity. (iv) Complicated Disease as hypotension or partial ileus or CT evidence of severe disease. (v) Life threatening Disease as complete ileus or toxic megacolon. Treat according to severity : (i) Mild and Moderate Disease - oral metronidazole 400 mg 8-hourly for 10 days. (ii) Severe Disease - oral vancomycin mg 6-hourly for days. (iii) Complicated Disease - oral vancomycin up to 500mg 6-hourly for days (check random serum vancomycin level at least once, which should be <15mg/L) plus IV metronidazole 500 mg 8-hourly. (iv) Life Threatening - oral vancomycin up to 500mg 6-hourly via naso-gastric tube (check serum vancomycin levels which should be <15mg/L) plus iv metronidazole 500 mg 8-hourly. Such patients should be monitored with serum lactate and colectomy considered especially if caecal dilatation is >10 cm (see below). Once patient stabilises and has a dependable oral/g route, consider stopping IV metronidazole and weaning down vancomycin to mg PO/G qds (usually every 3-7 days according to response). Complete at least a 14 day total course. Refractory Disease As other pathologies can be responsible for ongoing diarrhoea the diagnosis should be reviewed. A flexible sigmoidoscopy, if not contraindicated, to confirm the diagnosis should be considered particularly where the C. difficile toxin is negative or a weak positive. Oral vancomycin dosing should be increased to 250mg qds once the patient has not responded or is deteriorating despite at least a 7-day course of 125mg qds dosing or sooner if the patient is deteriorating. Sigmoidoscopy (excludes haematology and neutropaenic patients) Please contact the Acute Gastro Registrar bleep via switchboard Post-infectious diarrhoea If diarrhoea persists despite 20 days treatment but the patient is stable, the daily number of type 5-7 motions has decreased, the WCC is normal, and there is no abdominal pain or distension, the persistent diarrhoea may be due to post-infectious non-specific causes. If the sigmoidoscopy and biopsy confirms absence of inflammation, the patient may be given a trial of an anti-motility agent such as loperamide 2mg prn (instead of metronidazole or vancomycin) on the advice of gastroenterology, the patient should be reviewed if diarrhoea still persists The patient should be closely observed for evidence of a therapeutic response and to ensure there is no evidence of colonic dilatation. Severe Refractory Disease As other pathologies can be responsible for ongoing diarrhoea the diagnosis should be reviewed. A flexible sigmoidoscopy, if not contraindicated, to confirm the diagnosis should be considered particularly where the C. difficile toxin is negative or a weak positive. ottingham Antimicrobial Guidelines Committee Page 6 of 10 Written December 2015

7 1. Increase oral vancomycin up to 500mg 6-hourly for days (check random serum vancomycin level at least once, which should be <15mg/L) plus IV metronidazole 500 mg 8-hourly. IV metronidazole should be reviewed once disease is under control. Local installation of vancomycin to be considered and maybe advised by a consultant gastroenterologist especially when ileus is evident. 2. Monitor serum lactate 3. Consider referral to Gastro-surgery especially if caecal dilatation is >10 cm Consider IV immunoglobulins (IVIG) Local installation of vancomycin may be advised in severe refractory cases on the advice of a consultant gastroenterologist or colorectal surgeon. Given as a retention enema via rectal Foley catheter as 500mg in ml normal saline maximum qds instilled and clamped for 60 minutes, deflate and remove (monitor serum vancomycin levels should be <15mg/L) or 1g Vancomycin in 100mls saline as a single dose down the colonoscope at the time of colonoscopy. Surgery Best practice is that patients with severe disease should have an initial assessment by the medical and surgical GI registrars. Initial assessment of co-morbidities will identify those for whom aggressive surgical care is contra-indicated. All other patients with severe disease should be reviewed at least twice a day until there is clear evidence of improvement (Temperature, Heart rate, BP and improving WCC). In patients within the severe colitis sub group, criteria for considering surgery should include: WCC > 30x 10 9 /L or < 4x 10 9 /L (a rising WCC despite full dose oral / enteral vancomycin is a good indicator of failing medical therapy) Rising lactate (before the level rises to 5 mmol/l) Hypotension not responding to appropriate fluid resuscitation (but in this context early surgery before the need for vasopressors or intubation is essential) Toxic mega-colon Junior medical and surgical teams should be reminded that: C. diff colitis should be considered when patients present, in the right setting, with acute abdomen, fever and leucocytosis. This can occur without diarrhoea or a (+) C.difficile toxin result The colon can look normal at laparotomy in patients with severe C. difficile colitis Subtotal colectomy and ileostomy is the standard surgery. Those having a left hemicolectomy or defunctioning ileostomy for C. difficile do not usually survive. Post-operative mortality is associated with patients who have an elevated lactate or are ill enough to need pre-operative vasopressors or intubation or in whom there is a delay to surgery Use of Intravenous Immunoglobulins (IVIG) in Severe or Recurrent C.Difficile infection (B requires immunoglobulin panel approval) IVIG may be useful in the following situations For the treatment of fulminant C. difficile infection where the patient fails to respond to maximal therapy, vancomycin PO 500mg qds + IV metronidazole 500mg tds, especially in patients where surgery and Faecal Microbiota Transplant is not an option. To prevent the recurrence of C.difficile infection in patients where other therapy (e.g. tapering vancomycin and rifaximin- see page 8) has failed or is inappropriate. ationally, supplies of IVIG are limited. All potential cases for IVIG treatment should be discussed with Prof Mahida or Dr Weston in hours (or consultant colleagues if out of hours) and require approval from the Trust s immunoglobulin panel, complete the request form on the Immunoglobulin website or choose immunoglobulins on the A-Z list of the Trust intranet). Once the form is submitted supply should be sought from pharmacy (i.e. contact ward pharmacist as appropriate). Prescribing Dose Initially, 0.4 grams/kg as a one-off dose by IV infusion rounding down to the nearest 5 gram vial to conserve supplies. Repeat dose may be given on the following days if clinically required. Consider reducing the ottingham Antimicrobial Guidelines Committee Page 7 of 10 Written December 2015

8 maximum rate of infusion in patients with a history of cardiovascular/ vascular disease and/or thrombotic risk factors. Ensure all patients receive enoxaparin thromboprophylaxis as appropriate. Dosing in Obesity There is no clear guidance regarding dosing in obesity. However as immunoglobulin poorly distributes into adipose tissue using dose determined weight (DDW) to calculate immunoglobulin dosage in obese patients (>20% above their ideal body weight (IBW)) appears most appropriate: IBW for males = 50 + (2.3 x (height in inches- 60)) IBW for females (2.3 x (height in inches- 60)) DDW = IBW (actual body weight (kg) IBW) Administration CAUTIO: Different brands exist with different administration details- Discuss with Pharmacy. PRIVIGE 10% BRAD (1 st Line) Start at 0.3ml per kg /hour for the first 30 minutes, if well tolerated then the rate of administration can be doubled every 30 minutes to a maximum rate of 4.8ml / per kg /hr. Refer to table below. Privigen Infusion Table for Selected Patients Weights Weight (kg) 1 st 30 minutes 2 nd 30 minutes 3 rd 30 minutes 4 th 30 minutes Maximum rate Initial rate 0.3ml / kg /hour 0.6ml / kg /hour 1.2ml / kg /hour 2.4ml / kg /hour 4.8ml / kg /hour 40Kg 12ml/hour 24ml/hour 48ml/hour 96ml/hour 192ml/hour 50Kg 15ml/hour 30ml/hour 60ml/hour 120ml/hour 240ml/hour 60Kg 18ml/hour 36ml/hour 72ml/hour 144ml/hour 288ml/hour 70Kg 21ml/hour 42ml/hour 84ml/hour 168ml/hour 336ml/hour 80Kg 24ml/hour 48ml/hour 96ml/hour 192ml/hour 384ml/hour 90Kg 27ml/hour 54ml/hour 108ml/hour 216ml/hour 432ml/hour 100Kg 30ml/hour 60ml/hour 120ml/hour 240ml/hour 480ml/hour Side effects Allergic reactions, chills / fever, headache, nausea, vomiting, joint pains, low blood pressure and moderate low back pain - consider rate reduction of infusion. Anaphylactic / shock reactions are rare but can occur even in patients who have tolerated previous treatment with normal intravenous immunoglobulin. Rare reports of acute renal failure, aseptic meningitis, transient cutaneous reactions, haemolytic anaemia, associated with thrombotic events- MI, PE, DVT, stroke reassess VTE prophylaxis. Monitoring Monitor the patient (temperature, blood pressure, pulse, respiratory rate) before starting the infusion, throughout the infusion and for 1 hour after the first infusion or 20 minutes after subsequent infusions. Monitor urine output and serum creatinine levels. Storage CAUTIO: Different brands exist with different storage details- Discuss with Pharmacy. Privigen should be stored at room temperature (not above 25 C). General otes: There are several brands of Immunoglobulin routinely stocked at UH. Use Privigen first line. Use the same brand of Immunoglobulin per treatment course. Switching between the brands increases the risk of side effects. ottingham Antimicrobial Guidelines Committee Page 8 of 10 Written December 2015

9 Recurrent Disease Recurrences occur in 20-30% of patients, and are more common in elderly patients, the risk of a further recurrence increases to 40-60%. Patients should be investigated according to the protocol on page two above with repeat samples but should receive treatment with a second empirical course of whichever antibiotic regimen the original infection responded to (PO metronidazole/po vancomycin or combinations). If the patient is confirmed positive for C.difficile infection and has not received fidaxomicin before then start PO fidaxomicin 200mg BD for 10 days (stop any vancomycin/metronidazole started) after discussion with Microbiology. Audit data from 2014/15 confirmed a C.difficile infection recurrence rate of 14.9% when fidaxomicin was used; comparable with results from published trials. More than one recurrence or non-responsive disease If more than 1 recurrence or non-responding disease, advise referral to a gastroenterologist with a specialist interest in C.difficile disease (see below) or the infectious disease team, for confirmation of diagnosis and exclusion of other causes and consideration for the use of tapering therapy +/- Rifaximin if confirmed recurrent disease. Recurrence vancomycin tapering course over 6 weeks Week 1 vancomycin 125mg QDS for 7 days Week 2 vancomycin 125mg TDS for 7 days Week 3 vancomycin 125 mg BD for 7 days Week 4 vancomcyin 125mg OD for 7 days Week 5 vancomcyin 125 mg on alternate days for 7 days Week 6 vancomycin 125mg every third day for 1 week ote on the prescription/ drug chart that this is a tapering course. If further diarrhoea, follow with a full dose course of PO vancomycin 125 mg QDS for days. Rifaximin Rifaximin is on the formulary for the management of recurrent C.difficile on a named patient basis on the advice of Drs Teahon or Prof Mahida, after discussion at the weekly clinical C. difficile multidisciplinary meeting. It is active against C.difficile whilst causing limited disruption of GI flora and poor systemic absorption. It is administered orally, as a follow-up therapy, after a course of oral vancomycin at a dose of rifaximin 400mg BD for 14 days. It may not be held as stock at UH so contact with pharmacy should be made a few days prior to prescribing. IVIG see above Gastroenterology Opinion Consultants - Dr Kathy Teahon (city) / Prof ash Mahida (QMC) Lorraine Clark (Gastroenterology and Endoscopy urse Lead) Gastroenterology urses specialist (in c diff diarrhoea) - Heather Abdic/ Angela Copeland Microbiology Contact Dr Vivienne Weston / QMC or City Duty Medical Microbiologist ottingham Antimicrobial Guidelines Committee Page 9 of 10 Written December 2015

10 Appendix 1 Audit Tool for C.diff infection (Toxin +ve) Personal information Risks for C.diff Hosp. o. K Abx in last 4/52 Date of Audit PPIs Date of Birth Enteral Feeding Previous C.diff Toxin Previous C.diff PCR C.diff Management for each episode Date of diarrhoea onset Date of Toxin result Referral to Gastro C.diff nurse - If es, date of referral Severity according to guideline Mild Moderate Severe Complicated Life (circle) - If Severe/Complicated/Life Threatening was a referral made to the Acute Gastro Team Initial C.diff treatment: Date of referral: Time of referral: threatening - Increased to: - Changed to: Did the patient have colitis (either radiologically or via flexible sigmoidoscopy (PMC) o Evidence If on PPI was it stopped? - If no was the rationale reviewed? Antibiotics preceding C.diff result: Were they in line with guidance? - If not was clinical justification given? Did the patient receive at least 10 days C.diff treatment If first reoccurrence was Fidaxomicin naïve was it prescribed? - If not, why not? If second reoccurrence and already received Fidaxomicin, was tapering Vancomycin prescribed? If the patient died whilst receiving C.diff treatment did C.diff feature on the death certificate - If yes what part of the death certificate ottingham Antimicrobial Guidelines Committee Page 10 of 10 Written December 2015