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Management of Clostridium difficile infection—medical or surgical?
matter for debate
MANAGEMENT OF CLOSTRIDIUM DIFFICILE INFECTION – MEDICAL OR SURGICAL? keywords: clostridium difficile, surgery Surgeon, 1 December 2008, pp. 325-8
C. difficile infection (CDI) typically presents as diarrhoea, abdominal cramps, fever and leucocytosis, occurring several days to up to 10 weeks after antibiotic therapy. Pseudomembranous colitis (PMC) is the most severe manifestation and is usually a pancolitis, although a right-sided colitis is also described. Severely ill patients may have little or no diarrhoea due to dilation of the colon (toxic megacolon) and paralytic ileus that may result from a loss of colonic muscular tone. CDI-associated mortality varies with the population under study and has been reported as high as 30%, although attributable mortality is thought to be lower.1,2 The most common risk factors for CDI are exposure to antibiotics, advanced age and hospitalisation. The disease is particularly linked with the use of broad-spectrum antibiotics; however, nearly all other antibiotics have been associated with CDI.3 The most commonly implicated are clindamycin, the broad-spectrum cephalosporins and fluroquinolones. While CDI is a disease predominantly of older patients, other risk factors such as hospitalisation, recent gastrointestinal surgery or procedures and immunosuppressive therapy can also predispose to infection. Another proposed risk factor is exposure to proton pump inhibitors – it is thought that the increased gastric pH produced by these drugs leads to decreased destruction of spores.4,5 However, this association has not been demonstrated in other studies.6,7 In Canada, a changing pattern of CDI severity was observed from 1991 to 2003.8 The number of patients with complicated CDI (defined as having any of megacolon, perforation, colectomy, shock requiring vasopressor therapy, or death) rose significantly from around 7% in 1991-1992 to 18% in 2003. The epidemic was largely due to the emergent hyper-virulent strain PCR ribotype 027.9 C. difficile ribotype 027 outbreaks have been described in many European countries and recently, the first case of C. difficile ribotype 027 in Ireland was reported.2,10 C. difficile © 2008 Surgeon 6; 6: 325-8
F. Fitzpatrick Health Protection Surveillance Centre, Dublin Department of Clinical Microbiology, Beaumont Hospital, Dublin, Ireland Correspondence to: Dr. Fidelma Fitzpatrick, Health Protection Surveillance Centre, 25-27 Middle Gardiner Street, Dublin 1, Ireland Tel: +353 1 8765300 Fax: +353 1 8561299 Email: delma.tzpatrick@ hse.ie
ribotype 027 produces 23 and 16 times more toxins B and A than previously described C. difficile strains and is associated with fluoroquinolone resistance in vitro.3 This editorial will discuss the clinical management of CDI, including the evidence for surgical management.
Diagnosis of CDI All patients in whom a diagnosis of gastrointestinal infection is suspected should have a stool specimen sent for microbiological analysis. The diagnosis of CDI is usually made by detection of C. difficile toxins by enzyme immunoassay (EIA). The main advantage of these assays is rapid same day results. A wide variety of commercial EIAs exist which generally perform well with regard to specificity; however, recent studies demonstrate that they have significantly reduced sensitivity (65-85%).11,12 This low sensitivity can lead to increased reporting of false negative results, subsequently presenting problems with clinical diagnosis and infection control. In cases where CDI is clinically suspected and EIA results are negative, the laboratory should be informed, in order to perform culture on the specimen. In addition, CT can be a useful adjunct. CT findings in severe CDI may include colonic thickening and pericolonic stranding and can predict intra-operative findings.13-15
Management of C. difficile infection
1. Isolation of the patient and infection control precautions Prompt isolation in a single room with clinical hand washing sink and en suite facilities using standard and contract precautions is recommended for all patients with known or suspected CDI.16 Hands should be washed before and after each contact with the patient and/or patient equipment with soap (antimicrobial or non-antimicrobial) and water.17 None of the agents (including alcohols, the royal colleges of surgeons of edinburgh and ireland | 325
chlorhexidine, iodophors or triclosan) used in antiseptic hand-wash or antiseptic hand-rub preparations are reliably sporicidal against C. difficile. The physical action of rubbing and rinsing is the only way to remove spores from hands. 2. Stop the precipitating antibiotic The first approach in the treatment of CDI should be to stop the precipitating antibiotic(s), if possible. Studies have shown that CDI will resolve in 15-23% of patients if antibiotics are discontinued.18,19 However, it is often not feasible to discontinue antibiotics for clinical reasons. If antibiotics must be continued for clinical reasons, antibiotic(s) with a lower propensity to induce CDI should be substituted. 3. Supportive therapy Supportive therapy with replacement of fluids and electrolytes is also crucial at the early stage for these patients. Antiperistaltic agents should be avoided because of the theoretical risk of precipitating toxic megacolon by slowing clearance of C. difficile toxin from the intestine.20,21 4. Specic treatment Asymptomatic carriers of C. difficile should not be treated.22 Specific treatment for CDI is indicated where: • it is not possible to discontinue antibiotics because of the underlying condition • if symptoms resolve following cessation of the precipitating antibiotic • the patient has systemic symptoms (particularly if there is evidence of severe colonic inflammation or pseudomembrane formation). Initial treatment of non-severe CDI should be with oral metronidazole. A number of studies comparing oral metronidazole to oral vancomycin indicate that with the exception of severe CDI, metronidazole is as effective as vancomycin and less expensive.20,23 The mean time for diarrhoea resolution has been shown to be three to four days in prospective trials, but most patients will show some improvement of symptoms within one to two days of starting therapy.24 It should not be concluded that treatment has failed before six to seven days of therapy.24 Antibiotic therapy for 10 days is indicated for mild CDI. Therapeutic failure requires confirmation of the diagnosis and the exclusion of ileus or toxic megacolon, as both conditions may prevent the drugs from reaching sufficiently high levels in the colonic lumen. 5. Assessment of severity and management of severe CDI Oral vancomycin is recommended for the treatment of patients with severe CDI.25-27 Patients with ileus may benefit from higher doses of oral vancomycin (500mg every 6 hours).21 Intravenous vancomycin has no role in therapy as it does not achieve adequate faecal levels. This is in contrast to when metronidazole is administered intravenously. Faecal levels are at least as high as when the drug is given orally.28 The presence of complications of colitis, including septicaemia, volume depletion, hypotension, electrolyte imbalance, peritonitis, paralytic ileus and toxic megacolon are usually taken to indicate severe disease.29 A white blood cell count of greater than 20x109/l and elevated serum creatinine are also markers of severe disease.24,30 326 |
Recently, several investigators have developed scoring systems for CDI severity, including one based on variables which correlate with a higher disease severity: fever (38oC), ileus (diagnosed by clinical or radiographic findings), systolic blood pressure < 100mmHg, leucocytosis and specific CT abnormalities (thickened colonic wall, colonic dilatation, ascites).31 In a retrospective study (102 patients) a score of >2 was associated with metronidazole failure. However, validation of this score is required in a prospective study. A similar CDI severity score was developed for use in a randomised double blind, controlled trial of vancomycin versus metronidazole.25 This score combined age (>60years), temperature (>38.3oC), albumin level <2.5mg/dl and peripheral WBC count >15,000cells/mm3, giving one point for each characteristic and giving two points if endoscopic evidence of PMC was present or if the patient required admission to the intensive care unit (ICU). Patients with a score of <2 were considered to have mild CDI and those with >2 were considered to have severe CDI. Among the patients with severe CDI, treatment with metronidazole and vancomycin resulted in clinical cure in 76% and 98% of the patients respectively.25 This superiority of vancomycin in CDI was also shown in a second study.32 Pending the development of a prospectively validated scoring system, others have proposed that severe CDI is defined as occurring in any patient with a peripheral WBC count 15,000cells/mm3 or a creatinine level increased by 50% from baseline. This is meant to have high sensitivity for identifying patients at risk of complications, while accepting a lower specificity.28 In some circumstances, oral therapy cannot be given, especially in severely ill or post-operative patients. Intravenous metronidazole 500mg every six to eight hours may be given in this situation.33 However, some data report therapeutic failure of this regimen in the setting of a dynamic ileus.34 Adjunctive intracolonic vancomycin (ICV) may be an effective therapy in severe CDI.35,36 In a small study, clinical resolution of severe colitis was achieved in eight out of nine patients treated with adjunctive ICV.35 The same authors reviewed the literature and identified successful outcomes in 20 (83.3%) of 24 episodes of C. difficile colitis treated with adjunctive ICV. As ICV has not been evaluated in randomised controlled clinical trials, questions regarding efficacy, optimal dosing and duration of therapy are unanswered. Several cases reports regarding the use of intravenous immunoglobulin to treat refractory or severe CDI have been published but no randomized controlled clinical trials have been performed.37-44 Therefore, there is no published data from which to create evidencebased recommendations for its use. 6. The role of surgery in severe CDI It is generally agreed that severely ill patients should, in addition to their antibiotic therapy, have an early surgical assessment for possible colectomy.24,29,45 However, there are no clear guidelines to date to assist surgeons in making the decision on when to operate. The reported post-emergency colectomy mortality of CDI patients is high (48% to 57%) with a variety of indications for surgery including toxic megacolon, perforation, peritonitis and failure of medical therapy. Because of the poor sensitivity of EIAs, CT findings of pancolitis with an appropriate clinical history may be an indication for surgery.13,46 In the setting of an outbreak of CDI associated with ribotype 027, investigators found that among patients with CDI that required ICU admission, colectomy could be lifesaving in patients aged >65 years and with a leucocytosis of >20x109/l or serum lactate between 2.2
the royal colleges of surgeons of edinburgh and ireland
© 2008 Surgeon 6; 6: 325-8
and 4.9mmol/l.47 The results of this study also suggest that colectomy should be considered before lactate levels increase to 5mmol/l. The main indications for colectomy in these patients included shock despite vasopressors, megacolon, failed medical management and perforation. Whether these findings can be extrapolated to other non-ICU settings with other ribotypes in an endemic setting remains to be seen. A recent eight year retrospective review of 36 adult patients with severe CDI who underwent colectomy revealed that pre-operative vasopressor requirement and preoperative intubation were risk factors for post-operative mortality.14 In this series, a minority of patients with CDI had surgical management (36/3237), with no standard indication for surgery (common indications were haemodynamic instability, peritonitis and failure to respond to medical management). Interestingly, age, APACHE II score, lactate, immunosuppresion or prior metronidazole therapy had no impact on post-operative mortality in this group. Similarly, a recent 12 year retrospective review of 73 patients undergoing colectomy for CDI revealed that vasopressor requirement, mental state changes and duration of medical management of CDI pre-op were significant predictors of mortality.15 While mental state changes and vasopressor requirements are general indicators of severe infection, the longer duration of pre-operative medical therapy in patients who died supports the conclusion that post-operative mortality can be reduced by prompt surgical intervention once medical management has failed. Again, a minority of patients with CDI required surgical management (73/5718) and age, ASA score, underlying immunosuppresion, pre-existing conditions (diabetes, inflammatory bowel disease, respiratory, renal or coronary artery disease) or antibiotic treatment for C. difficile had no impact on mortality. In addition to a longer trial of medical management, patients that survived had significantly lower lactate levels than the mortality group; however this association was not borne out on multivariate analysis.
Conclusion In summary, the management of severe CDI calls for early surgical consultation and a joint medical and surgical approach. It is generally accepted that in severe infection, timely surgical management may improve survival and a variety of predictors of mortality have been described. However, most of these studies are retrospective; surgery is indicated when medical management has failed. Further prospective studies to investigate predictors of medical failure, including the role of CT, are warranted.
Copyright © 25 September 2008
© 2008 Surgeon 6; 6: 325-8
REFERENCES 1. Musher DM, Aslam S, Logan et al. Relatively poor outcome after treatment of Clostridium difcile colitis with metronidazole. Clin Infect Dis 2005;40: 1586-90 2. Koss K, Clark MA, Sanders DS et al. The outcome of surgery in fulminant Clostridium difcile colitis. Colorectal Dis 2006;8: 149-54 3. Spencer RC. The role of antimicrobial agents in the aetiology of Clostridium difcile-associated disease. J Antimicrob Chemother 1998; 41 Suppl C:21-27 4. Dial S, Alrasadi K, Manoukian C et al. Risk of Clostridium difcile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171: 33-38 5. Nakamura M, Oda M, Akiba Y et al. Autoradiographic demonstration of lansoprazole uptake sites in rat antrum and colon. J Clin Gastroenterol 1995;20 Suppl 2:S8-13 6. Pepin J, Saheb N, Coulombe MA et al. Emergence of uoroquinolones as the predominant risk factor for Clostridium difcile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41: 1254-60 7. Lowe DO, Mamdani MM, Kopp A et al. Proton pump inhibitors and hospitalization for Clostridium difcile-associated disease: a population-based study. Clin Infect Dis 2006;43: 1272-76 8. Pepin J, Valiquette L, Alary ME et al. Clostridium difcile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004; 171:466-72 9. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difcile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005;173: 1037-42 10. Long S, Fenelon L, FitzGerald S et al. First isolation and report of clusters of Clostridium difcile PCR 027 cases in Ireland. Eurosurveillance Weekly 12[4]. 26-4-0007. Ref Type: Electronic Citation 11. Poutanen SM, Simor AE. Clostridium difcile-associated diarrhea in adults. CMAJ 2004;171:51-58 12. Turgeon DK, Novicki TJ, Quick J et al. Six rapid tests for direct detection of Clostridium difcile and its toxins in fecal samples compared with the broblast cytotoxicity assay. J Clin Microbiol 2003;41: 667-70 13. Longo WE, Mazuski JE, Virgo KS et al. Outcome after colectomy for Clostridium difcile colitis. Dis Colon Rectum 2004;47: 1620-26 14. Hall JF, Berger D. Outcome of colectomy for Clostridium difcile colitis: a plea for early surgical management. Am J Surg 2008; 196(3): 884-88 15. Byrn JC, Maun DC, Gingold DS et al. Predictors of mortality after colectomy for fulminant Clostridium difcile colitis. Arch Surg 2008;143: 150-54 16. From the Public Health Service, US Department of Health and Human Services Centers for Disease Control and Prevention Atlanta Georgia. Siegel JD Rhinehart E Jackson M Chiarello L and the Healthcare Infection Control Practices Advisory Committee. Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007. 2007. Ref Type: Internet Communication
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17. SARI Infection Control Sub-committee. Guidelines for Hand Hygiene in Irish Health Care Settings. 2005. Ref Type: Report 18. Olson MM, Shanholtzer CJ, Lee JT et al. Ten years of prospective Clostridium difcile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol 1994;15: 371-81 19. Teasley DG, Gerding DN, Olson MM et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difcile-associated diarrhoea and colitis. Lancet 1983;2: 1043-46 20. Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difcile-associated disease: old therapies and new strategies. Lancet Infect Dis 2005;5: 549-57 21. Bouza E, Munoz P, Alonso R. Clinical manifestations, treatment and control of infections caused by Clostridium difcile. Clin Microbiol Infect 2005;11 Suppl 4:57-64 22. Johnson S, Homann SR, Bettin KM et al. Treatment of asymptomatic Clostridium difcile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med 1992;117: 297-302 23. Wenisch C, Parschalk B, Hasenhundl M et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difcile-associated diarrhea. Clin Infect Dis 1996;22: 813-18 24. Gerding DN. Metronidazole for Clostridium difcileassociated disease: is it okay for Mom? Clin Infect Dis 2005;40: 1598-600 25. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difcile-associated diarrhea, stratied by disease severity. Clin Infect Dis 2007;45: 302-7 26. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difcile colitis. JAMA 1993;269: 71-75 27. Kuijper EJ, van Dissel JT, Wilcox MH. Clostridium difcile: changing epidemiology and new treatment options. Curr Opin Infect Dis 2007;20: 376-83 28. Pepin J. Vancomycin for the treatment of Clostridium difcile Infection: for whom is this expensive bullet really magic? Clin Infect Dis 2008;46: 1493-98 29. Sunenshine RH, McDonald LC. Clostridium difcileassociated disease: new challenges from an established pathogen. Cleve Clin J Med 2006;73: 187-97 30. Pepin J, Alary ME, Valiquette L et al. Increasing risk of relapse after treatment of Clostridium difcile colitis in Quebec, Canada. Clin Infect Dis 2005;40: 1591-97 31. Belmares J, Gerding DN, Parada JP et al. Outcome of metronidazole therapy for Clostridium difcile disease and correlation with a scoring system. J Infect 2007;55: 495-501 32. Louie T, Gerson M, Grimard D et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difcileassociated diarrhea . ICCAC 2007. 2007. Ref Type: Conference Proceeding
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33. Friedenberg F, Fernandez A, Kaul V et al. Intravenous metronidazole for the treatment of Clostridium difcile colitis. Dis Colon Rectum 2001;44: 1176-80 34. Guzman R, Kirkpatrick J, Forward K, Lim F. Failure of parenteral metronidazole in the treatment of pseudomembranous colitis. J Infect Dis 1988;158:1 146-47 35. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difcile colitis: case series and review of the literature. Clin Infect Dis 2002;35: 690-96 36. Apisarnthanarak A, Khoury H, Reinus WR et al. Severe Clostridium difcile colitis: the role of intracolonic vancomycin? Am J Med 2002;112: 328-29 37. Leung DY, Kelly CP, Boguniewicz M et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difcile toxin. J Pediatr 1991;118: 633-37 38. Warny M, Denie C, Delmee M et al. Gamma globulin administration in relapsing Clostridium difcileinduced pseudomembranous colitis with a defective antibody response to toxin A. Acta Clin Belg 1995;50: 36-39 39. Salcedo J, Keates S, Pothoulakis C et al. Intravenous immunoglobulin therapy for severe Clostridium difcile colitis. Gut 1997;41: 366-70 40. Beales IL. Intravenous immunoglobulin for recurrent Clostridium difcile diarrhoea. Gut 2002;51:456 41. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difcile diarrhoea. J Antimicrob Chemother 2004;53: 882-84 42. Murphy C, Vernon M, Cullen M. Intravenous immunoglobulin for resistant Clostridium difcile infection. Age Ageing 2006;35:85-86 43. McPherson S, Rees CJ, Ellis R et al. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difcile diarrhea. Dis Colon Rectum 2006;49: 640-45 44. Juang P, Skledar SJ, Zgheib NK et al. Clinical outcomes of intravenous immune globulin in severe clostridium difcile-associated diarrhea. Am J Infect Control 2007;35: 131-37 45. Synnott K, Mealy K, Merry C et al. Timing of surgery for fulminating pseudomembranous colitis. Br J Surg 1998;85: 229-31 46. Dallal RM, Harbrecht BG, Boujoukas AJ et al. Fulminant Clostridium difcile: an underappreciated and increasing cause of death and complications. Ann Surg 2002;235: 363-72 47. Lamontagne F, Labbe AC, Haeck O et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difcile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007;245: 267-72
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MANAGEMENT OF CLOSTRIDIUM DIFFICILE INFECTION – MEDICAL OR SURGICAL? keywords: clostridium difficile, surgery Surgeon, 1 December 2008, pp. 325-8
C. difficile infection (CDI) typically presents as diarrhoea, abdominal cramps, fever and leucocytosis, occurring several days to up to 10 weeks after antibiotic therapy. Pseudomembranous colitis (PMC) is the most severe manifestation and is usually a pancolitis, although a right-sided colitis is also described. Severely ill patients may have little or no diarrhoea due to dilation of the colon (toxic megacolon) and paralytic ileus that may result from a loss of colonic muscular tone. CDI-associated mortality varies with the population under study and has been reported as high as 30%, although attributable mortality is thought to be lower.1,2 The most common risk factors for CDI are exposure to antibiotics, advanced age and hospitalisation. The disease is particularly linked with the use of broad-spectrum antibiotics; however, nearly all other antibiotics have been associated with CDI.3 The most commonly implicated are clindamycin, the broad-spectrum cephalosporins and fluroquinolones. While CDI is a disease predominantly of older patients, other risk factors such as hospitalisation, recent gastrointestinal surgery or procedures and immunosuppressive therapy can also predispose to infection. Another proposed risk factor is exposure to proton pump inhibitors – it is thought that the increased gastric pH produced by these drugs leads to decreased destruction of spores.4,5 However, this association has not been demonstrated in other studies.6,7 In Canada, a changing pattern of CDI severity was observed from 1991 to 2003.8 The number of patients with complicated CDI (defined as having any of megacolon, perforation, colectomy, shock requiring vasopressor therapy, or death) rose significantly from around 7% in 1991-1992 to 18% in 2003. The epidemic was largely due to the emergent hyper-virulent strain PCR ribotype 027.9 C. difficile ribotype 027 outbreaks have been described in many European countries and recently, the first case of C. difficile ribotype 027 in Ireland was reported.2,10 C. difficile © 2008 Surgeon 6; 6: 325-8
F. Fitzpatrick Health Protection Surveillance Centre, Dublin Department of Clinical Microbiology, Beaumont Hospital, Dublin, Ireland Correspondence to: Dr. Fidelma Fitzpatrick, Health Protection Surveillance Centre, 25-27 Middle Gardiner Street, Dublin 1, Ireland Tel: +353 1 8765300 Fax: +353 1 8561299 Email: delma.tzpatrick@ hse.ie
ribotype 027 produces 23 and 16 times more toxins B and A than previously described C. difficile strains and is associated with fluoroquinolone resistance in vitro.3 This editorial will discuss the clinical management of CDI, including the evidence for surgical management.
Diagnosis of CDI All patients in whom a diagnosis of gastrointestinal infection is suspected should have a stool specimen sent for microbiological analysis. The diagnosis of CDI is usually made by detection of C. difficile toxins by enzyme immunoassay (EIA). The main advantage of these assays is rapid same day results. A wide variety of commercial EIAs exist which generally perform well with regard to specificity; however, recent studies demonstrate that they have significantly reduced sensitivity (65-85%).11,12 This low sensitivity can lead to increased reporting of false negative results, subsequently presenting problems with clinical diagnosis and infection control. In cases where CDI is clinically suspected and EIA results are negative, the laboratory should be informed, in order to perform culture on the specimen. In addition, CT can be a useful adjunct. CT findings in severe CDI may include colonic thickening and pericolonic stranding and can predict intra-operative findings.13-15
Management of C. difficile infection
1. Isolation of the patient and infection control precautions Prompt isolation in a single room with clinical hand washing sink and en suite facilities using standard and contract precautions is recommended for all patients with known or suspected CDI.16 Hands should be washed before and after each contact with the patient and/or patient equipment with soap (antimicrobial or non-antimicrobial) and water.17 None of the agents (including alcohols, the royal colleges of surgeons of edinburgh and ireland | 325
chlorhexidine, iodophors or triclosan) used in antiseptic hand-wash or antiseptic hand-rub preparations are reliably sporicidal against C. difficile. The physical action of rubbing and rinsing is the only way to remove spores from hands. 2. Stop the precipitating antibiotic The first approach in the treatment of CDI should be to stop the precipitating antibiotic(s), if possible. Studies have shown that CDI will resolve in 15-23% of patients if antibiotics are discontinued.18,19 However, it is often not feasible to discontinue antibiotics for clinical reasons. If antibiotics must be continued for clinical reasons, antibiotic(s) with a lower propensity to induce CDI should be substituted. 3. Supportive therapy Supportive therapy with replacement of fluids and electrolytes is also crucial at the early stage for these patients. Antiperistaltic agents should be avoided because of the theoretical risk of precipitating toxic megacolon by slowing clearance of C. difficile toxin from the intestine.20,21 4. Specic treatment Asymptomatic carriers of C. difficile should not be treated.22 Specific treatment for CDI is indicated where: • it is not possible to discontinue antibiotics because of the underlying condition • if symptoms resolve following cessation of the precipitating antibiotic • the patient has systemic symptoms (particularly if there is evidence of severe colonic inflammation or pseudomembrane formation). Initial treatment of non-severe CDI should be with oral metronidazole. A number of studies comparing oral metronidazole to oral vancomycin indicate that with the exception of severe CDI, metronidazole is as effective as vancomycin and less expensive.20,23 The mean time for diarrhoea resolution has been shown to be three to four days in prospective trials, but most patients will show some improvement of symptoms within one to two days of starting therapy.24 It should not be concluded that treatment has failed before six to seven days of therapy.24 Antibiotic therapy for 10 days is indicated for mild CDI. Therapeutic failure requires confirmation of the diagnosis and the exclusion of ileus or toxic megacolon, as both conditions may prevent the drugs from reaching sufficiently high levels in the colonic lumen. 5. Assessment of severity and management of severe CDI Oral vancomycin is recommended for the treatment of patients with severe CDI.25-27 Patients with ileus may benefit from higher doses of oral vancomycin (500mg every 6 hours).21 Intravenous vancomycin has no role in therapy as it does not achieve adequate faecal levels. This is in contrast to when metronidazole is administered intravenously. Faecal levels are at least as high as when the drug is given orally.28 The presence of complications of colitis, including septicaemia, volume depletion, hypotension, electrolyte imbalance, peritonitis, paralytic ileus and toxic megacolon are usually taken to indicate severe disease.29 A white blood cell count of greater than 20x109/l and elevated serum creatinine are also markers of severe disease.24,30 326 |
Recently, several investigators have developed scoring systems for CDI severity, including one based on variables which correlate with a higher disease severity: fever (38oC), ileus (diagnosed by clinical or radiographic findings), systolic blood pressure < 100mmHg, leucocytosis and specific CT abnormalities (thickened colonic wall, colonic dilatation, ascites).31 In a retrospective study (102 patients) a score of >2 was associated with metronidazole failure. However, validation of this score is required in a prospective study. A similar CDI severity score was developed for use in a randomised double blind, controlled trial of vancomycin versus metronidazole.25 This score combined age (>60years), temperature (>38.3oC), albumin level <2.5mg/dl and peripheral WBC count >15,000cells/mm3, giving one point for each characteristic and giving two points if endoscopic evidence of PMC was present or if the patient required admission to the intensive care unit (ICU). Patients with a score of <2 were considered to have mild CDI and those with >2 were considered to have severe CDI. Among the patients with severe CDI, treatment with metronidazole and vancomycin resulted in clinical cure in 76% and 98% of the patients respectively.25 This superiority of vancomycin in CDI was also shown in a second study.32 Pending the development of a prospectively validated scoring system, others have proposed that severe CDI is defined as occurring in any patient with a peripheral WBC count 15,000cells/mm3 or a creatinine level increased by 50% from baseline. This is meant to have high sensitivity for identifying patients at risk of complications, while accepting a lower specificity.28 In some circumstances, oral therapy cannot be given, especially in severely ill or post-operative patients. Intravenous metronidazole 500mg every six to eight hours may be given in this situation.33 However, some data report therapeutic failure of this regimen in the setting of a dynamic ileus.34 Adjunctive intracolonic vancomycin (ICV) may be an effective therapy in severe CDI.35,36 In a small study, clinical resolution of severe colitis was achieved in eight out of nine patients treated with adjunctive ICV.35 The same authors reviewed the literature and identified successful outcomes in 20 (83.3%) of 24 episodes of C. difficile colitis treated with adjunctive ICV. As ICV has not been evaluated in randomised controlled clinical trials, questions regarding efficacy, optimal dosing and duration of therapy are unanswered. Several cases reports regarding the use of intravenous immunoglobulin to treat refractory or severe CDI have been published but no randomized controlled clinical trials have been performed.37-44 Therefore, there is no published data from which to create evidencebased recommendations for its use. 6. The role of surgery in severe CDI It is generally agreed that severely ill patients should, in addition to their antibiotic therapy, have an early surgical assessment for possible colectomy.24,29,45 However, there are no clear guidelines to date to assist surgeons in making the decision on when to operate. The reported post-emergency colectomy mortality of CDI patients is high (48% to 57%) with a variety of indications for surgery including toxic megacolon, perforation, peritonitis and failure of medical therapy. Because of the poor sensitivity of EIAs, CT findings of pancolitis with an appropriate clinical history may be an indication for surgery.13,46 In the setting of an outbreak of CDI associated with ribotype 027, investigators found that among patients with CDI that required ICU admission, colectomy could be lifesaving in patients aged >65 years and with a leucocytosis of >20x109/l or serum lactate between 2.2
the royal colleges of surgeons of edinburgh and ireland
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and 4.9mmol/l.47 The results of this study also suggest that colectomy should be considered before lactate levels increase to 5mmol/l. The main indications for colectomy in these patients included shock despite vasopressors, megacolon, failed medical management and perforation. Whether these findings can be extrapolated to other non-ICU settings with other ribotypes in an endemic setting remains to be seen. A recent eight year retrospective review of 36 adult patients with severe CDI who underwent colectomy revealed that pre-operative vasopressor requirement and preoperative intubation were risk factors for post-operative mortality.14 In this series, a minority of patients with CDI had surgical management (36/3237), with no standard indication for surgery (common indications were haemodynamic instability, peritonitis and failure to respond to medical management). Interestingly, age, APACHE II score, lactate, immunosuppresion or prior metronidazole therapy had no impact on post-operative mortality in this group. Similarly, a recent 12 year retrospective review of 73 patients undergoing colectomy for CDI revealed that vasopressor requirement, mental state changes and duration of medical management of CDI pre-op were significant predictors of mortality.15 While mental state changes and vasopressor requirements are general indicators of severe infection, the longer duration of pre-operative medical therapy in patients who died supports the conclusion that post-operative mortality can be reduced by prompt surgical intervention once medical management has failed. Again, a minority of patients with CDI required surgical management (73/5718) and age, ASA score, underlying immunosuppresion, pre-existing conditions (diabetes, inflammatory bowel disease, respiratory, renal or coronary artery disease) or antibiotic treatment for C. difficile had no impact on mortality. In addition to a longer trial of medical management, patients that survived had significantly lower lactate levels than the mortality group; however this association was not borne out on multivariate analysis.
Conclusion In summary, the management of severe CDI calls for early surgical consultation and a joint medical and surgical approach. It is generally accepted that in severe infection, timely surgical management may improve survival and a variety of predictors of mortality have been described. However, most of these studies are retrospective; surgery is indicated when medical management has failed. Further prospective studies to investigate predictors of medical failure, including the role of CT, are warranted.
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REFERENCES 1. Musher DM, Aslam S, Logan et al. Relatively poor outcome after treatment of Clostridium difcile colitis with metronidazole. Clin Infect Dis 2005;40: 1586-90 2. Koss K, Clark MA, Sanders DS et al. The outcome of surgery in fulminant Clostridium difcile colitis. Colorectal Dis 2006;8: 149-54 3. Spencer RC. The role of antimicrobial agents in the aetiology of Clostridium difcile-associated disease. J Antimicrob Chemother 1998; 41 Suppl C:21-27 4. Dial S, Alrasadi K, Manoukian C et al. Risk of Clostridium difcile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171: 33-38 5. Nakamura M, Oda M, Akiba Y et al. Autoradiographic demonstration of lansoprazole uptake sites in rat antrum and colon. J Clin Gastroenterol 1995;20 Suppl 2:S8-13 6. Pepin J, Saheb N, Coulombe MA et al. Emergence of uoroquinolones as the predominant risk factor for Clostridium difcile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41: 1254-60 7. Lowe DO, Mamdani MM, Kopp A et al. Proton pump inhibitors and hospitalization for Clostridium difcile-associated disease: a population-based study. Clin Infect Dis 2006;43: 1272-76 8. Pepin J, Valiquette L, Alary ME et al. Clostridium difcile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004; 171:466-72 9. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difcile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005;173: 1037-42 10. Long S, Fenelon L, FitzGerald S et al. First isolation and report of clusters of Clostridium difcile PCR 027 cases in Ireland. Eurosurveillance Weekly 12[4]. 26-4-0007. Ref Type: Electronic Citation 11. Poutanen SM, Simor AE. Clostridium difcile-associated diarrhea in adults. CMAJ 2004;171:51-58 12. Turgeon DK, Novicki TJ, Quick J et al. Six rapid tests for direct detection of Clostridium difcile and its toxins in fecal samples compared with the broblast cytotoxicity assay. J Clin Microbiol 2003;41: 667-70 13. Longo WE, Mazuski JE, Virgo KS et al. Outcome after colectomy for Clostridium difcile colitis. Dis Colon Rectum 2004;47: 1620-26 14. Hall JF, Berger D. Outcome of colectomy for Clostridium difcile colitis: a plea for early surgical management. Am J Surg 2008; 196(3): 884-88 15. Byrn JC, Maun DC, Gingold DS et al. Predictors of mortality after colectomy for fulminant Clostridium difcile colitis. Arch Surg 2008;143: 150-54 16. From the Public Health Service, US Department of Health and Human Services Centers for Disease Control and Prevention Atlanta Georgia. Siegel JD Rhinehart E Jackson M Chiarello L and the Healthcare Infection Control Practices Advisory Committee. Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007. 2007. Ref Type: Internet Communication
the royal colleges of surgeons of edinburgh and ireland | 327
17. SARI Infection Control Sub-committee. Guidelines for Hand Hygiene in Irish Health Care Settings. 2005. Ref Type: Report 18. Olson MM, Shanholtzer CJ, Lee JT et al. Ten years of prospective Clostridium difcile-associated disease surveillance and treatment at the Minneapolis VA Medical Center, 1982-1991. Infect Control Hosp Epidemiol 1994;15: 371-81 19. Teasley DG, Gerding DN, Olson MM et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difcile-associated diarrhoea and colitis. Lancet 1983;2: 1043-46 20. Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difcile-associated disease: old therapies and new strategies. Lancet Infect Dis 2005;5: 549-57 21. Bouza E, Munoz P, Alonso R. Clinical manifestations, treatment and control of infections caused by Clostridium difcile. Clin Microbiol Infect 2005;11 Suppl 4:57-64 22. Johnson S, Homann SR, Bettin KM et al. Treatment of asymptomatic Clostridium difcile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med 1992;117: 297-302 23. Wenisch C, Parschalk B, Hasenhundl M et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difcile-associated diarrhea. Clin Infect Dis 1996;22: 813-18 24. Gerding DN. Metronidazole for Clostridium difcileassociated disease: is it okay for Mom? Clin Infect Dis 2005;40: 1598-600 25. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difcile-associated diarrhea, stratied by disease severity. Clin Infect Dis 2007;45: 302-7 26. Fekety R, Shah AB. Diagnosis and treatment of Clostridium difcile colitis. JAMA 1993;269: 71-75 27. Kuijper EJ, van Dissel JT, Wilcox MH. Clostridium difcile: changing epidemiology and new treatment options. Curr Opin Infect Dis 2007;20: 376-83 28. Pepin J. Vancomycin for the treatment of Clostridium difcile Infection: for whom is this expensive bullet really magic? Clin Infect Dis 2008;46: 1493-98 29. Sunenshine RH, McDonald LC. Clostridium difcileassociated disease: new challenges from an established pathogen. Cleve Clin J Med 2006;73: 187-97 30. Pepin J, Alary ME, Valiquette L et al. Increasing risk of relapse after treatment of Clostridium difcile colitis in Quebec, Canada. Clin Infect Dis 2005;40: 1591-97 31. Belmares J, Gerding DN, Parada JP et al. Outcome of metronidazole therapy for Clostridium difcile disease and correlation with a scoring system. J Infect 2007;55: 495-501 32. Louie T, Gerson M, Grimard D et al. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difcileassociated diarrhea . ICCAC 2007. 2007. Ref Type: Conference Proceeding
328
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the royal colleges of surgeons of edinburgh and ireland
33. Friedenberg F, Fernandez A, Kaul V et al. Intravenous metronidazole for the treatment of Clostridium difcile colitis. Dis Colon Rectum 2001;44: 1176-80 34. Guzman R, Kirkpatrick J, Forward K, Lim F. Failure of parenteral metronidazole in the treatment of pseudomembranous colitis. J Infect Dis 1988;158:1 146-47 35. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difcile colitis: case series and review of the literature. Clin Infect Dis 2002;35: 690-96 36. Apisarnthanarak A, Khoury H, Reinus WR et al. Severe Clostridium difcile colitis: the role of intracolonic vancomycin? Am J Med 2002;112: 328-29 37. Leung DY, Kelly CP, Boguniewicz M et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difcile toxin. J Pediatr 1991;118: 633-37 38. Warny M, Denie C, Delmee M et al. Gamma globulin administration in relapsing Clostridium difcileinduced pseudomembranous colitis with a defective antibody response to toxin A. Acta Clin Belg 1995;50: 36-39 39. Salcedo J, Keates S, Pothoulakis C et al. Intravenous immunoglobulin therapy for severe Clostridium difcile colitis. Gut 1997;41: 366-70 40. Beales IL. Intravenous immunoglobulin for recurrent Clostridium difcile diarrhoea. Gut 2002;51:456 41. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difcile diarrhoea. J Antimicrob Chemother 2004;53: 882-84 42. Murphy C, Vernon M, Cullen M. Intravenous immunoglobulin for resistant Clostridium difcile infection. Age Ageing 2006;35:85-86 43. McPherson S, Rees CJ, Ellis R et al. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difcile diarrhea. Dis Colon Rectum 2006;49: 640-45 44. Juang P, Skledar SJ, Zgheib NK et al. Clinical outcomes of intravenous immune globulin in severe clostridium difcile-associated diarrhea. Am J Infect Control 2007;35: 131-37 45. Synnott K, Mealy K, Merry C et al. Timing of surgery for fulminating pseudomembranous colitis. Br J Surg 1998;85: 229-31 46. Dallal RM, Harbrecht BG, Boujoukas AJ et al. Fulminant Clostridium difcile: an underappreciated and increasing cause of death and complications. Ann Surg 2002;235: 363-72 47. Lamontagne F, Labbe AC, Haeck O et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difcile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007;245: 267-72
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