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Cross-county Guideline: Medical Management Title: Medical Management of Clostridium difficile Infection (CDI) Authors: Mike Smith (Consultant Microbiologist), Tim Jobson (Consultant Gastroenterologist - MPH) Steve Gore (Consultant Gastroenterologist - YDH) Policy Lead: Dr Mike Smith Ratified by: Policy Review Group Active date: 14th May 2010 Ratification date: 13th May 2010 Review date: 14th May 2012 Applies to: Medical staff Exclusions: Paediatrics Purpose: To provide guidelines for doctors, and other health care workers, on the medical management of patients with C. difficile infection in Taunton & Somerset NHS Trust and Yeovil District Hospital NHS Trust - to be read in conjunction with the relevant Trust infection prevention and control policy. To be read in conjunction with the relevant Trust’s Infection Control Policy for Clostridium difficile (click here for MPH and here for YDH) (Click here to go straight to the two management algorithms) 1. Introduction Clostridium difficile is a major healthcare acquired infection associated with antibiotic use and environmental contamination; it mainly affects the over 65’s. The patients’ dignity is often compromised, as they may be incontinent of foul smelling diarrhoea up to 30 times a day. This infection can be life threatening, especially if pseudo-membranous colitis develops. Occasionally, severe CDI may present with abdominal distension, ileus and little or no diarrhoea. CDI can cause outbreaks in hospital. There is also a cost in excess of £4,000 per case (Wilcox et al, 1996) and increased lengths of stay. 2. What causes it? Clostridium difficile is an anaerobic Gram-positive bacterium that produces spores in adverse conditions i.e. when oxygen is present. The spores are resistant to many disinfectants and harsh environmental conditions where they can survive for several months. These bacteria may also produce toxins, which cause the symptoms of diarrhoea. The test to confirm CDI determines the presence of these toxin-producing strains. It is possible to be an asymptomatic carrier of C. difficile (about 3% of the general population and higher in the elderly and hospital populations), however there is no evidence to suggest that such carriers are sources of cross infection. Recent outbreaks of CDI, associated with increased severity, high relapse rates and significant mortality, have been reported from many UK hospitals, as well as north America, Europe and Japan. A toxin hyper-producing strain – ribotype 027 – has been implicated. 3. Signs & Symptoms of Infection (see Appendix D for Bristol Stool Chart) Signs and symptoms vary from mild self-limiting diarrhoea (ie Bristol Stool Chart Type 6-7) to severe, life-threatening pseudo-membranous colitis. Patients may present with as many as 20-30 episodes of watery, green, foul, smelling diarrhoea a day. The patients may also have fever, abdominal cramps, and blood in the stools. Occasionally, severe CDI may present with abdominal distension and tenderness, ileus or dilated colon, raised WCC and little or no diarrhoea. Complications associated with the infection include dehydration, electrolyte imbalance and toxic megacolon and perforation. 4. Vulnerable Patients & Spread 4.1 CDI mainly affects the elderly (over 65), the debilitated and the immunocompromised. The infection is particularly associated with the use of certain antibiotics, particularly cephalosporins, and also if a ‘cocktail’ of antibiotics are used. See Table 1. The fluoroquinolones (e.g. ciprofloxacin) are also regarded as high risk antibiotics due to the emergence of ribotype 027 which is resistant to these agents. Antimicrobials alter the normal gut flora, therefore allowing C. difficile to multiply and produce toxins in the absence of competition from the other organisms that make up normal gut flora. The gut flora may also be altered by aperients, enemas, acid suppressants and bowel surgery. See table 2. Table 1. Potential for antibiotics to cause CDI High Risk Clindamycin Cephalosporins Quinolones (eg ciprofloxacin, levofloxacin) Medium Risk Amoxicillin / Co-amoxiclav Piperacillin-tazobactam (Tazocin®) Macrolides (eg clarithromycin, erythromycin) Carbapenems (eg meropenem) Low Risk Gentamicin Benzyl penicillin / Flucloxacillin Tetracyclines (eg doxycycline) Vancomycin / teicoplanin Trimethoprim Metronidazole Table 2. Non-antibiotic medications in patients with CDI Drug group Proton pump inhibitors (PPIs) Tube feeds Opioids Antimotility agents Laxatives 4.2 Action Review need for PPIs Review Consider stopping for duration of diarrhoea Discontinue and do not prescribe Discontinue treatment while diarrhoea persists Reason Suppression of gastric acid can increase host susceptibility Disrupts normal gut flora May mask symptoms and may worsen course of disease Can mask symptoms and may worsen course of disease Not required and may worsen symptoms and increase spread of spores C. difficile is spread by the faecal-oral route. Spores in the faeces can contaminate the patients’ skin and hands, the hands of health care workers and the immediate environment around a symptomatic patient. Spores may remain viable in the environment for many months. 4.3 The risk associated with antibiotics remains for several weeks. It is important to know about antibiotics that may have been given in the preceding 4-6 weeks. 5. Preventing the spread of Infection (see relevant Infection Control Policy for Clostridium difficile for full details - MPH policy and YDH policy . The following are general principles that are to be utilized to help prevent the spread of C. difficile. The Infection Prevention and Control Team (IP&CT) can give specific infection control advice on an individual case basis. 5.1 Isolation - until 48 hr without diarrhoea and a return to normal bowel habit. 5.2 Hand Hygiene - strict and thorough hand washing with soap and water (NOT alcohol hand gel) 5.3 Protective Clothing - Disposable non-sterile examination gloves and apron 5.4 Cleaning - Clean room twice daily with a chlorine-containing cleaning agent (at least 1000ppm available chlorine). 6. Diagnosis of CDI Send stool for culture and C. difficile testing on ALL adult inpatients who develop diarrhoea or who are admitted with unexplained diarrhoea. Testing may also be indicated in children 2 years or older. C. difficile tests are performed 7 days a week. If the first sample is negative and CDI is strongly suspected, a second sample (48 hr later) should be tested. Following a positive test, please do not send any further samples for, at least, 28 days as toxin may persist in the faeces even after symptomatic improvement. The microbiology laboratory now uses a two-step testing method (which gives more accurate results, compared to the previous single test for toxins A & B). The initial screening test detects a clostridial enzyme “GDH”. If this GDH test is negative, it is reported as “C. difficile screening test (GDH) NEGATIVE” If the GDH screening test is “positive”, the lab then uses a PCR test to look for specific C. difficile toxin genes. If this PCR is negative it will be reported as “Toxigenic C. difficile NOT detected by PCR” If this PCR is positive it will be reported as “Toxigenic C. difficile DETECTED by PCR” - in which case the patient should be managed as C. difficile infection. In suspected cases of “silent” CDI (eg. Ileus, toxic megacolon or PMC) other diagnostic procedures such as flexible sigmoidoscopy/colonoscopy or CT scanning may be required. 7. Management & Specific Treatment (See flow chart in Appendix A for summary) Stop implicated antibiotics if possible (see Table 1). Contact Consultant Microbiologist for advice if patient still needs antibiotics. Investigate for other causes of diarrhoea e.g. tube feeds, antacids Review antimotility drugs, laxatives and proton pump inhibitors (see Table 2) Supportive measures as indicated i.e. adequate fluid and electrolyte replacement Isolate patient immediately (Do NOT wait for results of stool culture/toxin test) 7.1 Assess severity of CDI (this should be re-assessed daily) Start specific empirical antibiotic therapy for C. difficile Severity assessment Mild CDI – no rise in WCC; typically associated with < 3 stools/day of type 5-7 on Bristol Stool Chart (Appendix C) Moderate CDI – raised WCC but < 15 x 109/L; typically associated with 3-5 stools/day of types 5-7. Severe CDI – raised WCC > 15 x 109/L, or acute rising creatinine (>50% increase above baseline), or temperature > 38.5oC, or evidence of severe colitis eg.: o abdominal distension o dilated colon on AXR o pseudomembranous colitis The number of stools may be a less reliable indicator of severe disease. Life-threatening CDI – any of the following: 7.2 o hypotension o partial or complete ileus o toxic megacolon o CT evidence of severe disease Initial therapy Mild and moderate CDI Oral metronidazole 400 mg tds, for 10-14 days. o However, if <3 stools in 24 hours and systemically well (ie mild disease), supportive treatment may only be required, particularly if implicated antibiotics have just been stopped. If there is no improvement in symptoms after 7 days metronidazole, or if worsens and signs of severe disease develop, switch to oral vancomycin 125 mg qds, for 10-14 days. Severe CDI Oral vancomycin 125 mg qds, for 10-14 days. If not improving after 5-7 days, or if worsens, increase dose of oral vancomycin (up to 500 mg qds) and consider adding IV metronidazole 500 mg tds; discuss with Consultant Microbiologist. A Gastroenterologist should review all ‘severe’ cases, particularly if no/poor response to vancomycin, and will also advise on the need for a flexible sigmoidoscopy. Life-threatening CDI Oral vancomycin 500 mg qds (via NG tube if necessary) plus IV metronidazole 500 mg tds, for 10-14 days. Consider intracolonic vancomycin (refer to treatment Algorithm). These patients should be monitored closely, with specialist surgical and gastroenterology input, and should have blood lactate measured. Colectomy should be considered, especially if caecal dilation is > 10 cm. Colectomy is best performed before blood lactate rises > 5 mmol/L, when survival is extremely poor. If CDT-ve: review diagnosis and send a second stool to laboratory. Continue treatment if CDI strongly suspected, but consider other diagnoses. 8. Non-responders – further treatment options The initial treatment changes for non-responders are detailed above (Section 7). There is no consensus on treatment after failure of both metronidazole and vancomycin, and further treatment must be discussed with a gastroenterologist or microbiologist. Options are set out in Appendix C and include the addition of oral rifampicin or IV immunoglobulin. 9. Recurrence / relapse Disease recurs in approximately 20% of patients with a first episode of CDI over the following 3 months. Recurrence occurs in 50-60% after a second episode. This incidence may be higher with the 027 ribotype of C. difficile. There is no need to send a stool for C. difficile testing if a positive result has been obtained in the previous 28 days. A further course of metronidazole or vancomycin (depending on which the patient responded to previously) is recommended initially. Refer to Appendix B for the management of third, and subsequent, episodes of CDI. Some further treatment options are given in Appendix C. 10. References and further reading Clostridium difficile infection: how to deal with the problem. Department of Health and Health Protection Agency. Jan 2009. DH website. http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAnd Guidance/DH_093220 Aas J, Gessert CE, Bakken S. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003; 36: 580−585. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis 2002; 35: 690−696. Johnson S. Recurrent Clostridium difficile infection: A review of risk factors, treatments, and outcomes. J Infection 2009; 58: 403-410. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97: 1769−1775. Nelson RL. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD004610. DOI: 10.1002/14651858.CD004610.pub3. Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD004611. DOI: 10.1002/14651858.CD004611.pub2. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother 2004; 53: 882−884. Wullt M, Odenholt I. A double blind randomised controlled trial of fusidic acid and metronidazole for the treatment of an initial episode of Clostridium difficile associated diarrhoea. JAC 2004;54:211-216 Appendix A - Flow chart for the management of suspected CDI – first or second episodes of infection. Diarrhoea AND one of the following Positive C.difficile toxin PCR test OR results of C.difficile tests pending AND clinical suspicion of CDI NB. severe CDI may present with abdominal distension, ileus and little or no diarrhoea Ideally discontinue non-C.difficile-treatment antibiotics To allow normal intestinal flora to be re-established Suspected cases must be isolated Symptoms/signs of non-severe CDI Oral metronidazole 400 mg tds 10–14 days Symptoms/signs of severe CDI (WCC > 15 x 109/L, or acute rising creatinine >50% increase above baseline, or temperature > 38.5oC, or evidence of severe colitis) Oral vancomycin 125 mg qds 10–14 days DAILY ASSESSMENT Symptoms improving Diarrhoea should resolve in 1–2 weeks Recurrence occurs in ~20% after first episode, 50–60% after second episode Symptoms not improving or worsening (should not normally be Anti-motility deemedshould a treatment agents not failure until received at least one be prescribed week of treatment) DAILY ASSESSMENT Symptoms not improving (should not normally be deemed a treatment failure until received at least one week of treatment) Or, if evidence of severe CDI continues or worsens Surgery / GI / Micro / ID consultation in acute CDI Or, if there is evidence of severe CDI (WCC > 15 x 109/L, or acute rising creatinine >50% increase above baseline, or temperature > 38.5oC, or evidence of severe colitis) Switch to oral vancomycin 125 mg qds 10–14 days AND, depending on degree of ileus, vancomycin 125–500 mg PO/NG qds, +/metronidazole 500 mg iv tds 10 days PLUS CONSIDER intracolonic vancomycin (500 mg in 100–500 ml saline 4–12-hourly) given as retention enema: 18 gauge Foley catheter with 30 ml balloon inserted per rectum; vancomycin instilled; catheter clamped for 60 minutes; deflate and remove. Further surgery/GI/micro/ID consultation Anti-motility agents should not be prescribed in acute CDI Depending on choice of therapy (see above), consider: 1. high-dose oral/NG vancomycin (500 mg PO qds) +/. 2. IV immunoglobulin 400 mg/kg, one dose, and consider repeating. There is no robust evidence for the effectiveness of these approaches in severe CDI. See appendix C. Policy for the Medical Management of Clostridium difficile Infection (CDI) Page 9 05/05/2017 Appendix B - Flow chart for the management of recurrent CDI – third or subsequent episodes of infection. Diarrhoea AND one of the following: Positive C. difficile toxin PCR test OR results of C. difficile tests pending AND clinical suspicion of CDI Must discontinue non-C. difficile-treatment antibiotics if at all possible to allow normal intestinal flora to be re-established Suspected cases must be isolated Symptoms/signs of non-severe CDI Oral vancomycin 125 mg tds for 14 days DAILY ASSESSMENT (include review of severity markers, fluid/electrolytes) Symptoms improving Diarrhoea should resolve in 1–2 weeks Recurrence occurs in 40–60% of relapsing cases or third episode 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 (if NO abdominal symptoms or signs of severe CDI) Also consider (see Appendix C for details): 3. vancomycin tapering/pulse therapy (4–6-week regimen) 4. oral vancomycin 125 mg qds + oral rifampicin 300 mg bd for two weeks (no robust evidence for effectiveness) 5. iv immunoglobulin, especially if albumin status worsens 6. donor stool transplant Taunton & Somerset NHS Foundation Trust Page 9 of 12 If severe CDI see algorithm for first or second episode of CDI Policy for the Medical Management of Clostridium difficile Infection (CDI) Page 10 05/05/2017 APPENDIX C – Further treatment options in non-responders There is little consensus in this area (underpinned by a lack of evidence). Options are outlined below – the gastroenterologist will advise on which approach to use. 1. Tapering / pulsed vancomycin regimen Vancomycin 125 mg po qds for 1 week Vancomycin 125 mg po tds for 1 week Vancomycin 125 mg po bd for 1 week Vancomycin 125 mg po od for 1 week Vancomycin 125 mg po every other day for 1 week Vancomycin 125 mg po every third day for 1 week - then stop 2. Other antibiotics Rifampicin (300 mg bd orally) – some authorities recommend giving rifampicin in addition. No randomised, controlled trials have been reported; there is no robust evidence to support the use of rifampicin as an adjunctive agent. Teicoplanin (100-400mg bd orally) – the Cochrane review 2007 comes down in favour of this. It is very expensive and superiority to vancomycin/metronidazole is marginal at best. Fusidic acid (500mg tds orally) - the response rates in one randomised, double-blind trial comparing metronidazole with fusidic acid showed no significant difference. Recurrence rates were similar, but development of fusidic acid resistance was seen in 55% of recipients who remained culture-positive. Fusidic acid should not be used as a first-line treatment in CDI; its role in treating recurrences is unclear but resistance is likely to limit this use. 3. Non-antibiotic treatments Theoretically there are advantages to non-antibiotic treatments: firstly antibiotics are only able to target vegetative C. difficile cells and not spores, and secondly, antibiotics will disrupt the normal colonic flora, thereby compromising resistance to further C. difficile colonization. Probiotics These are mono- or mixed-cultures of live microorganisms which are postulated to work by a number of methods eg to enhance re-establishment of the normal flora, or to inactivate the C difficile toxin. There is a lot of published data in this area and a number of systematic reviews – meta-analyses have failed to demonstrate statistically any significant efficacy in treating or preventing CDI. So the evidence of benefit is nil to weak and further RCTs are warranted. Perhaps the most promising candidate is Saccharomyces boulardii (1g/day for 28 days) which may have some benefit in recurrent cases. There are risks (fungaemia, variable virulence, nonviability in many commercial preparations), and it is NOT recommended for widespread use. IV immunoglobulin Several case reports and small series have been published regarding the use of this method to treat refractory disease. A dosage of 400mg/kg IV as a stat dose has been beneficial in about two thirds of intractable cases. No randomized controlled clinical trials have been performed to evaluate the efficacy of immunoglobulin in recurrent or severe CDI. Taunton & Somerset NHS Foundation Trust Page 10 of 12 Policy for the Medical Management of Clostridium difficile Infection (CDI) Page 11 05/05/2017 Donor stool faecal enemas There is evidence for efficiency of faecal transplant in animal models. Although the number of human studies reported is small, the results are promising for refractory/relapsing CDI. A fresh stool from a healthy donor is administered in normal saline by enema, slurries via nasogastric tube, or flexible sigmoidoscopy / colonoscopy as advised by a Gastroenterologist (Aas et al, 2003). This is used as a last resort as there are no comparative studies to verify its effectiveness in CDI, and concerns remain about the safety of the approach. There is a randomised trial of this approach under way in the Netherlands. Adsorbents Oral cholestyramine (4 g packet tds) has been used in the treatment of refractory CDI because it is thought to bind C. difficile toxins. There is no robust evidence to support the use of cholestyramine as an adjunctive agent, and there is a risk that it may bind antibiotics used to treat CDI. It is not recommended. 4. Colectomy Colectomy is required in some patients with megacolon (dilatation >10 cm), perforation or septic shock, and should be done before the blood lactate rises above 5 mmol/L. Patients should have a total or subtotal colectomy rather than a hemicolectomy or a caecostomy. It may be preferable to preserve the rectal stump for subsequent ileo-rectal anastomosis. The rectocolonic stoma can then be perfused with vancomycin liquid if necessary (see Appendix A for details). Taunton & Somerset NHS Foundation Trust Page 11 of 12 Policy for the Medical Management of Clostridium difficile Infection (CDI) Page 12 05/05/2017 APPENDIX D – Bristol Stool Chart To ensure consistent recording of stool type please use the scale below to guide your classification of stools. Record the type on the appropriate patient record. Taunton & Somerset NHS Foundation Trust Page 12 of 12