For use in: By: For: Antimicrobial Prescribing Advice for patients with Clostridium difficile Division responsible for document: Key words: Names of document authors: Job titles of document authors: Name of document author s Line Manager: Job title of document author s Line Manager: Adult patients Medical and Nursing Staff Patients who are Clostridium difficile toxin positive, previously positive or Clostridium difficile toxigenic gene positive Wards where Supportive Measures apply Surgical Prophylaxis Clinical Support Division Diarrhoea, glutamate dehydrogenase (GDH), Clostridium difficile toxin, Clostridium difficile PCR Caroline Hallam Specialist Pharmacist, Antimicrobials Dr Catherine Tremlett Consultant Microbiologist Supported by: Dr N Elumogo, Consultant Microbiologist Assessed and approved by: Clinical Guidelines Assessment Panel (CGAP), Caroline Hallam for Anti-microbial Sub Committee Date of approval: 25/01/2018 Ratified by or reported as approved to (if applicable): Clinical Standards Group and Effectiveness Sub-Board To be reviewed before: This document remains current after this date but will be under 25/01/2021 review To be reviewed by: Reference and / or Trustdocs ID No: Version No: 5 Caroline Hallam CA5116 ID No: 9400 Description of changes: Amendments made to page 9 Compliance links: (is there any NICE related to guidance) If Yes does the strategy/policy deviate from the recommendations of NICE? If so, why? No N/A Clinical Guideline recommended Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 1 of 14
Introduction Antimicrobial Prescribing Advice for patients with Clostridium difficile Section Item Page 1. Use of antibiotics in patients who are Clostridium difficile toxin positive a. Treating first occurrence b. Treating 2 nd or future recurrences c. Guidelines for prescribing antibiotics and other high risk medication in patients who are Clostridium difficile toxin positive 3 4 5-6 7 2. Management of patients who are Clostridium difficile toxigenic gene positive by PCR 8 3. Prescribing advice for patients on wards on Supportive Measures following a period of increasing incidence. 9 4. Patients who have previously been Clostridium difficile toxin positive OR Clostridium difficile toxigenic gene positive 10 5. 6. Prescribing advice for Surgical Prophylaxis in patients with previous Clostridium difficile Appendix 1: Administration of Vancomycin injection orally Appendix 2: Administration of oral metronidazole to patients who can t swallow tablets Appendix 3: Intracolonic Vancomycin Appendix 4: FMT (Faecal Microbiota Transplantation) 11 12 12 13 14 Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 2 of 14
Section 1: Antimicrobial Treatment of Clostridium difficile toxin Positive Patients Treatment of MILD TO MODERATELY SEVERE Clostridium difficile diarrhoea DEFINITION: Mild Clostridium difficile infection (CDI) not associated with a raised WCC; it is typically associated with <3 stools of type 5-7 on the Bristol Stool Chart per day. Moderate CDI associated with raised WCC that is <15 x 10 9 cells/l. It is typically associated with 3-5 stools per day 1st line: Metronidazole 400mg tds po (500mg tds IV) for 10-14 days Symptoms not improving or worsening should not normally be deemed a treatment failure until after day 7 of treatment. However, if evidence of severe CDI: WCC>15, acute rising creatinine and/or signs/symptoms of colitis switch to 2 nd line: Vancomycin 125mg qds po for 10-14 days (Use vancomycin first line if patient unable to tolerate metronidazole or is pregnant) Treatment of SEVERE Clostridium difficile diarrhoea and/or pseudomembranous colitis DEFINITION: Severe Clostridium difficile diarrhoea and colitis WCC > 15 x 10 9 cells/l Acutely rising blood creatinine (e.g. >50% increase above baseline) Temperature > 38.5ºC or Evidence of severe colitis (abdominal signs, radiology) The number of stools may be a less reliable indicator of severity. First line: Vancomycin 125mg qds po for 10 to 14 days Should not normally be deemed a treatment failure until day 7 of treatment. However, if evidence of severe CDI continues or worsens change to Vancomycin 125mg-500mg PO/NG qds +/- Metronidazole 500mg IV tds for 10 days Use higher vancomycin doses of 250-500mg qds po in patients who are critically ill, or have impending ileus, colonic dilation or fulminant pseudomembranous colitis. Consider fidaxomicin in patients with severe CDI who are considered at high risk for recurrence; these include elderly patients with multiple co-morbidities who are receiving concomitant antibiotics (Microbiologist + Drugs and Therapeutics Committee approval required) The addition of IV immunoglobulin (400mg/kg) may also be considered on advice of a Consultant Microbiologist. Treatment of LIFE THREATENING Clostridium difficile diarrhoea DEFINITION: Includes hypotension, partial or complex ileus or toxic megacolon, or CT evidence of severe disease. Vancomycin PO up to 500mg qds for 10-14 days + Metronidazole IV 500mg tds (via NG tube or rectal installation- see page 13 below for guidance on rectal installation) Monitor closely with specialist surgical input. Colectomy should be considered especially if caecal dilatation is >10cm. Measure blood lactate. Colectomy is best performed before blood lactate rises >5mmol/L, when survival is extremely poor. Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 3 of 14
1 st episode of Clostridium difficile infection (CDI) Diarrhoea AND one of the following: Positive C. difficile toxin test OR C. difficile toxin test pending AND clinical suspicion of CDI. If clinically appropriate discontinue non-c. difficile antibiotics to allow normal intestinal flora to be re-established. Suspected cases must be isolated with enteric precautions Symptoms/signs: not severe CDI (None of: WCC>15, acute rising creatinine and/or colitis) Oral metronidazole 400mg 8 -hourly 10-14 days. DAILY ASSESSMENT by clinical team Weekly review by Clostridium difficile MDT Ward Round Symptoms improving Diarrhoea should resolve in 1-2 weeks Recurrence occurs in approximately 20% -30%after 1 st episode, 50-60% after 2 nd episode. Symptoms not improving or worsening Should not normally be deemed a treatment failure until day 7 of treatment. However, if evidence of severe CDI: WCC>15, acute rising creatinine and/or signs/symptoms of colitis Switch to oral vancomycin 125mg 6-hourly 10-14 days Symptoms/signs: severe CDI WCC>15, acute rising creatinine and/or colitis Oral vancomycin 125mg 6-hourly 10-14 days DAILY ASSESSMENT by clinical team Weekly review by Clostridium difficile MDT Ward Round Symptoms not improving or worsening Should not normally be deemed a treatment failure until day 7 of treatment. However, if evidence of severe CDI continues or worsens Surgery/GI/Micro/ID consultation AND, depending on degree of ileus/prior treatment EITHER vancomycin 125-500mg PO/NG 6- hourly +/- metronidazole 500mg IV 8-hourly x 10 days OR fidaxomicin 200mg PO 12-hourly (Microbiologist AND Drugs and Therapeutics Committee approval required) PLUS CONSIDER intracolonic vancomycin Antimotility agents should not be prescribed in acute CDI Further Surgery/GI/Micro/ID consultation Depending on choice of therapy (see above) consider: 1. High dose oral/ng vancomycin (500mg QDS po) 2. IV immunoglobulin 400mg/kg 1 dose, consider repeat Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 4 of 14
Antibiotic Treatment of Recurrent Clostridium difficile Infection DEFINITION Recurrent Clostridium difficile may be due to relapse or re-infection. Recurrent Clostridium difficile is a return of diarrhoea with a positive lab test after the end of treatment, 2-8 weeks following the onset of the previous episode. Occurs in about 20-30% of patients treated initially with either metronidazole or vancomycin. Must discontinue non-c. difficile antibiotics if at all possible to allow normal intestinal flora to be re-established Review all drugs with gastrointestinal activity or side effects e.g. iron, laxatives. Stop proton pump inhibitors unless required acutely, or consider switching to a H2 receptor antagonist e.g. ranitidine. For further information, see page 7. Initial recurrence: Vancomycin 125mg qds po for 10 days If severe disease treat as per 1 st episode. Diarrhoea should resolve in 1-2 weeks Multiple Recurrences: For severe disease treat as per 1 st episode. Discuss with microbiology. Options include 1. Fidaxomicin (if not received previously) 200mg bd for 10-14 days. Microbiology and Drugs and Therapeutics Committee approval required. 2. Tapered-pulsed Vancomycin. May provide a considerable selective pressure for vancomycin resistance e.g. in enterococci consult microbiology before use. Vancomycin 125mg qds po for 7 days then Vancomcyin 125mg tds po for 7 days then Vancomycin 125mg bd po for 7 days then Vancomycin 125mg od po for 7 days then Vancomycin 125mg alt days po for 7 days then Vancomycin 125mg every 3 days po for 7 days then stop 3. IV immunoglobulin (400 mg/kg, as a single infusion), under the guidance and advice of a Consultant Gastroenterologist. Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 5 of 14
Recurrent Clostridium difficile infection (CDI) Recurrent CDI occurs in approximately 20-30% of patients treated with metronidazole or vancomycin Recurrence of diarrhoea (at least 3 consecutive type 5-7 stools) within approximately 30 days of a previous CDI episode AND positive C. difficile toxin test Must discontinue non-c. difficile antibiotics if at all possible to allow normal intestinal flora to be re-established Review all drugs with gastrointestinal activity or side effects (stop PPIs unless required acutely) Suspected cases must be isolated Symptoms/signs: not life threatening CDI Oral vancomycin 125mg 6-hourly 10-14 days OR Fidaxomicin 200mg 12 hourly for 10-14 days (approved in the Trust for patients with 3 rd episode [2 nd recurrence] of CDI on advice of a consultant microbiologist. Given its high cost, the Chairman of the Drugs, Therapeutics & Medicines Management Committee should be consulted in each case). Daily Assessment (include review of severity markers, fluid/electrolytes) Symptoms improving: Diarrhoea should resolve in 1-2 weeks IF MULTIPLE RECURRENCES ESPECIALLY IF EVIDENCE OF MALNUTRITION, WASTING ETC 1. Review ALL antibiotic and other drug therapy (consider stopping PPIs and/or other GI active drugs) 2. Consider supervised trial of anti-motility agents alone (no abdominal symptoms or signs of severe CDI) Also consider on discussion with microbiology: 3. Fidaxomicin (if not received previously) 200mg 12 hourly for 10-14 days 4. Vancomycin tapering/pulse therapy (4-6 week regimen) (Am J Gastroenterol 2002:97:1769-75) 5. IV immunoglobulin, especially if worsening albumin status (J Antimicrob Chemother 2004:53:882-4) 6. Donor stool transplant (Clin Infect Dis 2011:53:994-1002, Van Nood et al, NEJM 2013) Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 6 of 14
General Prescribing Points in Clostridium difficile toxin positive patients Non C. difficile Antibiotics Non C. difficile antibiotics should only be continued if clinically essential. High risk antibiotics e.g. ciprofloxacin, cephalosporins and clindamycin and moderate risk antibiotics e.g. amoxicillin, co-amoxiclav, tazocin and meropenem should be switched to those with a lower risk if possible. If the antibiotic is to be continued it is imperative that this is clearly documented in the medical notes. The antibiotic should be kept under regular review, both in the medical notes and on EPMA. EPMA should be regularly reviewed and the stop/review date updated every 24/48 hours. Proton Pump Inhibitors (PPIs) PPIs reduce gastro intestinal acidity which can delay resolution of CDI. Discontinue if non-essential or reduce the dose / switch to a H2 receptor antagonist e.g. ranitidine. Generally should not be withdrawn in Current or past peptic ulcer bleed Gastro protection with NSAIDs/aspirin/anticoagulants/steroids Previous oesophageal stricture Recent (< 2 weeks upper GI endoscopic or surgical intervention predisposing to ulceration) Other drugs Other medication can delay resolution of diarrhoea by altering gastrointestinal motility and/or gastric intestinal flora or affecting other defence mechanisms. The medication outlined below should be stopped or withheld where possible. 1. Anti-peristaltic agents (opioids [although it will not be possible to stop opioids in patients who have been on them long term], anti-diarrhoeal agents etc.) 2. Pro-motility / pro-kinetic agents (laxatives, stool bulking agents etc.) 3. Iron The patients should also be reviewed daily with regard to fluid resuscitation, electrolyte replacement and nutrition. Administration information Administration of Vancomycin Injection orally (Appendix 1) Administration of oral Metronidazole to patients who cannot swallow tablets / have an enteral feeding tube (Appendix 2) Administration of intracolonic vancomycin (Appendix 3) Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 7 of 14
Section 2 : Management of Clostridium difficile toxigenic gene PCR positive Patients Patients identified to be colonised with C. difficile i.e.toxigenic gene PCR positive, toxin negative are at risk of progressing to active CDI. If CDI is likely based on frequency of diarrhoea, inflammatory markers, abdominal signs and antibiotic history etc. (bearing in mind that the toxin test is not 100% sensitive), then commence treatment with metronidazole or discuss with Duty Microbiologist. Review other medication as below. To prevent progression to active CDI, review medications as below. Stop unnecessary antibiotics or choose narrow spectrum / low risk antibiotics if indicated. Prescribing Antibiotics: High risk: Quinolones e.g. ciprofloxacin Cephalosporins e.g.cefuroxime Clindamycin Moderate Risk: Amoxicillin Co-amoxiclav Meropenem Tazocin (Piperacillin/Tazobactam) If non C. difficile antibiotics are prescribed, they should be kept under regular review in the medical notes. EPMA should be reviewed daily and a regular stop/review date updated on EPMA. General Prescribing Measures: Proton Pump Inhibitors (PPIs) PPIs reduce gastro intestinal acidity which can increase the risk of active C. difficile toxin positive diarrhoea. Discontinue if non-essential or reduce the dose Generally should not be withdrawn in Current or past peptic ulcer bleed Gastro protection with NSAIDs/aspirin/anticoagulants/steroids Previous oesophageal stricture Recent (<2 weeks upper GI endoscopic or surgical intervention predisposing to ulceration) Review antiperistaltic agents (opioids [although it will not be possible to stop opioids in patients who have been on them long term], anti-diarrhoeal agents etc.) Review promotility/prokinetic agents (laxatives, stool bulking agents etc.) Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 8 of 14
Section 3: General Information and Prescribing Advice for Wards on Supportive Measures Following a period of increased incidence of Clostridium difficile infection (CDI) in a particular clinical area, supportive measures will apply for a period of time as directed by Infection Control. This document offers advice / guidance to follow during this time. Prescribing antimicrobials HIGH RISK MODERATE RISK Quinolones Co-amoxiclav Cephalosporins Meropenem Clindamycin Amoxicillin Tazocin (Piperacillin/Tazobactam) There is no evidence to support the use of Tazocin in preference to Co-amoxiclav. Both have a moderate risk of CDI and should be avoided where possible. Where oral Co-amoxiclav is considered for step down, consider alternatives. Cephalosporins, Quinolones, Clindamycin, Tazocin and Co-amoxiclav should only be prescribed on the advice of a consultant and according to policy. Review all antibiotic prescriptions with a senior doctor daily if possible. Review IV antibiotics with a view to step down to oral antibiotics at 48 hours. Respiratory o For community acquired pneumonia, use benzyl penicillin and clarithromycin. If a broad spectrum penicillin is required use co-amoxiclav unless the patient is on the Sepsis pathway. Consider doxycycline as oral stepdown or as first choice if oral therapy possible. o Use amoxicillin and metronidazole for community acquired aspiration pneumonia. o Use amoxicillin, metronidazole and gentamicin for hospital acquired pneumonia/aspiration. Consider doxycycline as oral stepdown. o Only use Tazocin if the patient has sepsis with an EWS of 4 or more or is immunocompromised. Urinary Tract o Use gentamicin for moderate / severe urinary tract infection if the patient has good renal function unless the patient is on the sepsis pathway. Only use oral co-amoxiclav for a urinary tract infection if trimethoprim and nitrofurantoin are inappropriate. NB This also applies to patients who are transferred or treated elsewhere in the hospital. Other high risk medication Proton pump inhibitors e.g. lansoprazole Laxatives Antidiarrhoeal agents e.g loperamide Iron Prokinetic agents e.g. Metoclopramide This list highlights other drugs which can increase the risk of developing CDI. This medication should be reviewed carefully in all patients on the ward, but particularly in patients on high / moderate risk antibiotics. If possible anything that is not required in the short term should be stopped / withheld. References: Public Health England, 2013043: Updated Guidance on the Management and Treatment of Clostridium difficile infection Crown: London; 2013. Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 9 of 14
Section 4: Prescribing Advice for patients who have previously had Clostridium difficile Antibiotics are an important risk factor in precipitating C. difficile and should be used cautiously in patients who have had a previous episode. Other pre-disposing factors include increasing age, underlying illness, recent gastro-intestinal surgery and nasogastric feeding. All antibiotics pose some risk but some are riskier than others. Prescribing Antibiotics High risk: Quinolones e.g. ciprofloxacin Cephalosporins e.g.cefuroxime Clindamycin Moderate Risk: Amoxicillin Co-amoxiclav Meropenem Tazocin (Piperacillin/Tazobactam) In these patients a low risk antibiotic should be prescribed where possible. The antibiotic should be kept under regular review in the medical notes. EPMA should be reviewed daily and a regular stop/review date updated on EPMA. General Prescribing Measures Proton Pump Inhibitors (PPIs) PPIs reduce gastro intestinal acidity which can increase the risk of C. difficile diarrhoea. Discontinue if non-essential or reduce the dose Generally should not be withdrawn in Current or past peptic ulcer bleed Gastro protection with NSAIDs/aspirin/anticoagulants/steroids Previous oesophageal stricture Recent (<2 weeks upper GI endoscopic or surgical intervention predisposing to ulceration) Review antiperistaltic agents (opioids [although it will not be possible to stop opioids in patients who have been on them long term], anti-diarrhoeal agents etc.) Review promotility/prokinetic agents (laxatives, stool bulking agents etc.). Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 10 of 14
Section 5: Surgical Prophylaxis Patients with a previous history of Clostridium difficile For patients with a history of C.difficile, cephalosporins and quinolones should be avoided, as should co-amoxiclav if possible. Many surgical prophylaxis regimens do not include these antibiotics. BUT in patients who have a history of CDI please use a regimen that includes the appropriate selection from gentamicin, teicoplanin and metronidazole. There will however be particular patients and procedures in whom the risk of C.difficile is outweighed by the benefit of using particular antibiotics, but this should be an explicit decision made by the consultant in charge of the patient. Microbiology can also help in these difficult cases. Wards on Supportive Measures due to a period of increased incidence of C. difficile If the ward is on Supportive Measures due to a Period of Increased Incidence (PII) of C.difficile then patients from the ward who are to be given antibiotic prophylaxis should have the same regimens as patients who have a previous history of C. difficile. References: Public Health England, 2013043: Updated Guidance on the Management and Treatment of Clostridium difficile infection Crown: London; 2013. Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 11 of 14
Section 6: Appendices Appendix 1 - Administration of Vancomycin Injection orally Vancomycin preparation for injection is now licensed for oral use and is cheaper than the capsules. It is also easier to swallow. The contents of vials for parenteral administration may be used for oral administration. After initial reconstitution of the vial, the selected dose may be diluted in 30 ml of water and given to the patient to drink, or the diluted material may be administered via an enteral feeding tube. Instructions 1. Reconstitute 500mg vial with 10mL of water for injection to give a concentration of 125mg/2.5mL. 2. Withdraw the required volume for the dose into a medicine gallipot, this may be diluted with water up to 30mLs before administration. 3. Write the patient s name on an IV additive label plus the date and time of expiry (24 hours after opening) and attach the label to the vial. 4. Store the solution in the fridge. 5. Vials are for single patient use only and should not be shared. Appendix 2 - Administration of oral Metronidazole to patients who cannot swallow tablets Metronidazole tablets should be crushed and mixed with water in preference to using the liquid. The liquid contains metronidazole benzoate and it is not clear how well it is converted to metronidazole in the stomach of C difficile positive patients (stomach acid is required for this process and in patients with severe diarrhoea, this process may be affected). The PR route for metronidazole is also available as a last resort. Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 12 of 14
Appendix 3 Intracolonic Vancomycin Intracolonic vancomycin is indicated for the treatment of SEVERE Clostridium difficile infection (CDI) in conjunction with other lines of treatment. Intracolonic vancomycin is NOT recommended for patients with toxic megacolon or peritonitis. Dose: 500 mg Diluent: Sodium chloride 0.9% Volume: 100mL Frequency: 6-12hrly at the prescribing doctors discretion. Materials required: 500mg vial of vancomycin. 100mL sodium chloride 0.9% infusion. 18 gauge Foley catheter with 30mL balloon. 30mL sterile saline or water for balloon inflation. Catheter connector. Giving set. Administration: Given as a retention enema. Procedure: 1. Reconstitute the 500mg vial of vancomycin with 10mL of sodium chloride 0.9% drawn from the 100mL bag of sodium chloride 0.9%. Shake well to dissolve. 2. Withdraw the resulting solution from the vial and add to the remaining volume of 0.9% sodium chloride in the 100mL bag. 3. Invert the infusion bag several times to ensure that the vancomycin is evenly distributed throughout the bag. 4. Attach an 18- gauge Foley catheter with a 30mL balloon to the infusion bag, using a catheter connector adaptor and a giving set. 5. Insert the catheter into the patient s rectum taking care as there is a risk of perforation with this procedure. 6. Instill the 100mL vancomycin solution into the colon and then clamp the catheter. 7. Inflate the balloon with 30mL of sterile water/ sodium chloride 0.9%. 8. The enema should be retained for as long as practically possible, up to one hour. 9. Deflate the balloon and remove the catheter. The enema should be administered in accordance with the frequency prescribed by the doctor where possible, up to a maximum of four times a day. If there is no improvement after 48-72 hours please discuss with a Consultant Microbiologist. Refererence: Anucha Apisarnthanarak et al, Adjunctive Intracolonic Vancomycin for Severe Clostridium difficile Colitis: Case Series and Review of the Literature, Clinical Infectious Diseases, 35:690-6 (2002) Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 13 of 14
Appendix 4: FMT (Faecal Microbiota Transplantation) FMT is indicated for treatment of patients who have had relapses of Clostridium difficile. Identifying/referring patients: Patients will be identified either on the Clostridium difficile ward round by the Consultant Microbiologist. For other patients who you think could benefit from FMT then the consultant in charge of the patient should discuss with a Consultant Microbiologist or DIPC. For information about criteria for FMT and procedure for administration refer to the FMT document on the Trust Intranet. Available via Trust Docs Version: 5 Trust Docs ID: 9400 Page 14 of 14