Stratégies thérapeutiques des infections à C. difficile en réanimation Paris, SRLF Janvier 2009 Stratégies thérapeutiques des infections à C. difficile en réanimation Jean-François TIMSIT Réanimation médicale CHU Albert Michallon INSERM/UJF U823 Grenoble

Que se passe t-il? incidence  formes graves mortalité attribuable  virulence  résistance aux antibiotiques (FQ, EM)  récidives après metronidazole

Antiobio, antineoplasiques

TRT Cl difficile Réhydratation et arrêt ATB Pas de modificateurs du transit ou d’anti-secrétoires Metronidazole per os ou vancomycine? Autres traitements? Timing de la chirurgie pour les formes les plus graves? Prévention : Saccharomyces boulardii Mesure hygiène,manuportage

Gravité clinique et poursuite des ATB Modena S et al. J Clin Gastroenterol 2006; 40: 49-54

Impact de l’acidité gastrique sur Clostridium difficile? Oui: CMAJ 2004 Dial S Risk of clostridium difficile diarrhea among hospital inpatients prescribed proton pup inhibitors: cohort and case control studies Non: ICAAC 2006 - D’après J. Pépin, communication orale 539 7 6 5 4 Log10 cfu/ml 3 2 Il existe plusieurs études cas-témoins contradictoires en ce qui concerne le rôle des inhibiteurs de pompes à protons comme facteur favorisant la survenue des colites à Clostridium difficile. Toutes ces études posent le problème de possibles facteurs confondants, ou d’un manque de puissance. Pourtant, il ne s’agit pas d’une question accessoire, car les IPP sont parmi les médicaments les plus prescrits dans le monde : au Québec, 50 % des patients hospitalisés en reçoivent au moins une fois, dans 50 % des cas sans raison valable. Jacques Pépin a présenté une étude fondamentale qui plaide fortement contre une association entre IPP et C. difficile : l’acidité gastrique ne semble avoir aucun impact sur C. difficile. Il n’y a donc pas de raison pour qu’un antiacide, même puissant, représente un surrisque… 1 Temps 0 Après 1 h d’incubation dans du liquide gastrique Après 3 h d’incubation Klebsiella Candida Spores de Clostridium difficile

Vancomycine ou metronidazole CMI90:1.0-2.0 mg/l La plus haute jamais rapportée: 16 mg/L Metronidazole CMI  2 mg/L Pelaez 2005: 415 souches CMI90 4mg/L CMI > 32:6% cas Mais pas de corrélation bio-clinique Wang et al – Diagn Microbiol Infect Dis 1999; 34:1; Aspevall et al – AAC 2006; 50:1890; Pelaez et al – AAC 2005; 49:1147

PK metronidazole Oral Metronidazole IV Metronidazole Absorption rapide: pic 1-2 h  paroi colique Concentration fécale Diarrhée liquide: 9.3 µg/g (range 0.8-24) Selles moulées:1.2 µg/g (range 0-10.2) Porteurs asymptomatiques  0 IV Metronidazole 3 patients  6.3 µg/g à 24 µg/g Données cliniques publiées anecdotiques Bolton RP et al – Gut 1986; 27:1169; Dion YM et al – Ann Surg 1980; 192:221; Johnson S et al – Ann Intern Med 1992; 117:297

PK Vancomycine Oral Vancomycine IV Vancomycine Pos :125 mg X 4  > 3000 µg/g dans les selles Atteint la valve ileo-caecale en moins de 6 heures En cas d’ileus???? Pic retardé??? Posologies plus élevées IV Vancomycine Pepin J - Clin Infect Dis 2008; 46:1493; Johnson et al – Ann Intern Med 1992; 117:297; Tedesco F – Lancet 1978- 2:226

Vancomycine ou metronidazole: ERV? Durée séjour C3G, FQ  ERV  C dif + +/- VAN IV VAN Per Os MET + +/-

Vancomycine ou metronidazole: ERV? Quebec, épidemie de C dif O27  vancomycine per os conseillée 2002 2003 2004 ERV 106 275 554 Jette et al- Rapport 2004 Institut national de santé publique du Québec

Both Oral Metronidazole and Oral Vancomycin Promote Persistent Overgrowth of Vancomycin-Resistant Enterococci during Treatment of Clostridium difficile-Associated Disease Legend of the figure: FIG. 1. Concentration of VRE in stools of patients with preexisting VRE colonization who were treated with oral metronidazole versus oral vancomycin for C. difficile-associated disease. Day 0, before treatment on day of CDAD diagnosis. For the metronidazole group (n 37), the number of subjects monitored to 1 to 5 days, 6 to 10 days, 11 to 15 days, 16 to 20 days, and 21 to 25 days were 37, 28 (76%), 22 (59%), 19 (51%), and 16 (43%), respectively. For the vancomycin group (n 19), the number of subjects monitored to 1 to 5 days, 6 to 10 days, 11 to 15 days, 16 to 20 days, and 21 to 25 days were 19, 14 (74%), 11 (58%), 11 (58%), and 8 (42%), respectively. The durations of treatment (mean the SD) with metronidazole and vancomycin were 11.2 1.9 and 12.1 2.0, respectively. Error bars indicate the standard error. For treatment of mild to moderate Clostridium difficile-associated disease (CDAD), oral metronidazole has been recommended as the preferred agent, in part due to concern that vancomycin may be more likely to promote colonization by vancomycin-resistant enterococci (VRE). We performed a prospective observational study to examine the effects of oral metronidazole or vancomycin treatment of CDAD on acquisition and concentration of VRE stool colonization. Before, during, and after 90 courses of CDAD therapy, stool samples were cultured for VRE, and the concentrations were quantified. Eighty-seven subjects (97%) had received antibiotics within the past month. For 56 treatment courses in which preexisting VRE colonization was present, metronidazole (n 37 courses) and vancomycin (n 19 courses), each promoted persistent VRE overgrowth during therapy, and the concentration decreased significantly in both groups by 2 weeks after completion of treatment (P <0.049). For 34 treatment courses in which baseline cultures were negative for VRE, new detection of VRE stool colonization occurred during 3 (14%) of the 22 courses of metronidazole and 1 (8%) of the 12 courses of vancomycin (P 1.0). These results demonstrate that both oral metronidazole and oral vancomycin promote the overgrowth of VRE during treatment of CDAD. New CDAD treatments are needed that are less likely to disrupt the intestinal microflora and promote overgrowth of healthcare-associated pathogens. Al-Nassir WN – AAC 2008; 2403

Vancomycine ou metronidazole: coûts? Vanco suspension orale $300-600 Mais Vanco IV $45 Metronidazole PO 10j  $20 VANCOMYCINE 1G PDR LYO INJ : 3.21 VANCOMYCINE 125MG PDR LYO INJ : 1,79 VANCOMYCINE voie orale n’est plus commercialisée FLAGYL 4% SUSP BUV : 3.33 METRONIDAZOLE BBM 0,5% INJ FL 100ML : 0,39 Coûts CHU Grenoble VANCOMYCINE 1G PDR LYO INJ : 3.21€ VANCOMYCINE 125MG PDR LYO INJ : 1,79€ VANCOMYCINE voie orale n’est plus commercialisée FLAGYL 4% SUSP BUV : 3.33€ METRONIDAZOLE BBM 0,5% INJ FL 100ML : 0,39€ …

Traitement de la diarrhée à CD (avant 2003) Standard: Metronidazole per os pendant 7 à 10 jours 400 mg x 3/jour Option: Vancomycine per os, 7 à 10 jours 125 mg x 4/jour Doses plus élevées pour les épisodes sévères Standard (?) pour les patients avec albumine <25 g/l En USI La résistance clinique de CD au metronidazole et à la vancomycine n’est pas rapportée … mais le changement d’antibiotiques est recommandé par certains en cas de persistance des symptômes au delà d’une semaine

Increasing Risk of Relapse after Treatment of Clostridium difficile Colitis in Quebec, Canada Probabilities of recurrence among patients with Clostridium difficile associated diarrhea treated with only metronidazole, comparing 1991-2002 to 2003-2004 (top). Treatment with only vancomycin during 1991 2002 to 2003-2004 (bottom) Clinical Infectious Diseases    2005;40:1591-1597

Traitement des diarrhées à CD : échecs et rechutes/récidives Aslam S et al. Lancet Infect Dis 2005; 5: 549-57

Peut-être partiellement liée au clone O27 Clinical Infectious Diseases 2005; 40:1598–1600 - Augmentation du taux de récidive sous metronidazole des études récentes par rapport aux études randomisées anciennes Peut-être partiellement liée à une population plus âgée et plus immunodéprimée Peut-être partiellement liée au clone O27 - Bien que l’efficacité de la vancomycine dans les études récentes semble inchangée  Molécule sous surveillance

A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile –Associated Diarrhea, Stratified by Disease Severity Zar – CID 2007 Monocentrique 8 ans 172 inclusions  150 analysables pour le CJP (87%)

172 inclusions  150 analysables pour le CJP (87%) A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile –Associated Diarrhea, Stratified by Disease Severity Monocentrique 8 ans 172 inclusions  150 analysables pour le CJP (87%) * Background.  The incidence and severity of Clostridium difficile–associated diarrhea (CDAD) has been increasing, and there have been recent reports of metronidazole treatment failure. Metronidazole is still commonly used as first-line treatment for CDAD but has never been compared with vancomycin in a prospective, randomized, double-blind, placebo-controlled trial. We conducted such a trial, stratifying patients according to disease severity, to investigate whether one agent was superior for treating either mild or severe disease. Methods.  From October 1994 through June 2002, patients with CDAD were stratified according to whether they had mild or severe disease based on clinical criteria and were randomly assigned to receive oral metronidazole (250 mg 4 times per day) or oral vancomycin (125 mg 4 times per day) for 10 days. Both groups received an oral placebo in addition to the study drug. Patients were followed up for 21 days to assess cure, treatment failure, relapse, or intolerance. Results.  One hundred seventy-two patients were enrolled, and 150 of these patients successfully completed the trial. Among the patients with mild CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 90% and 98% of the patients, respectively ( ). Among the patients with severe CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 76% and 97% of the patients, respectively ( ). Clinical symptoms recurred in 15% of the patients treated with metronidazole and 14% of those treated with vancomycin. Conclusions.  Our findings suggest that metronidazole and vancomycin are equally effective for the treatment of mild CDAD, but vancomycin is superior for treating patients with severe CDAD. Assessment of efficacy. The primary outcomes assessed were cure, treatment failure, and relapse. Cure was defined as resolution of diarrhea by day 6 of treatment and a negative result of a C. difficile toxin A assay at days 6 and 10 of treatment. Treatment failure was defined as persistence of diarrhea and/ or a positive result of a C. difficile toxin A assay after 6 days of treatment, the need for colectomy, or death after 5 days of therapy. Relapse was defined as recurrence of C. difficile toxin A–positive diarrhea by day 21 after initial cure. Intolerance was defined as the inability or refusal to continue the medication because of adverse reactions. Noncompliance was defined as missing 13 doses of the study medication during the 10 days of therapy for reasons other than intolerance. Lettres: la difference persiste si on tient compte des 13 exclus avant J6… Pas de recherche de O27 Pas de difference sur l’arret des antibiotiques .005 *:Resolution of diarrhea by day 6 of treatment and a negative result of a C. d toxin A assay at days 6 and 10 of treatment Relapse 9/66(14) 5/69 (7) 14/13 (10) .27 Zar FA et al - CID 2007:45

Vanco or metronidazole? Bishara et al- CID 2007:45 (15 December)

Metronidazole 1360 vs vancomycin 219, both 37 Quebec, 1991-2006, n=1616 Metronidazole 1360 vs vancomycin 219, both 37 Definition: Severe/complicated CDAD death d30, (b) septic shock, (c) megacolon, (d) perforation, or (e) emergency colectomy RF of S-CDAD: age>or=65 yr, male sex, immunosuppression, hospital acquisition, tube feeding, short duration of diarrhea, fever, elevated leukocytosis, or creatinine. Decrease in S-CDAD:2005-2006 (NAP1/O27) Adjusted risk of S-CDAD 1991-2002 Vanco:AOR 0.21, 95% CI 0.05-0.99, P=0.048 2003-2006 Vanco: AOR 0.90, 95% CI 0.53-1.55, P=0.71 Am J Gastroenterol. 2007 Dec;102(12):2781-8. Epub 2007 Sep 26. Comment in: Am J Gastroenterol. 2007 Dec;102(12):2789-92. Am J Gastroenterol. 2008 Aug;103(8):2147; author reply 2147. Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027. Pépin J, Valiquette L, Gagnon S, Routhier S, Brazeau I. Department of Microbiology and Infectious Diseases, University of Sherbrooke, Sherbrooke, Quebec, Canada. OBJECTIVE: To reassess the comparative efficacy of vancomycin versus metronidazole in the treatment of Clostridium difficile-associated disease (CDAD) after the emergence in 2003 of the hypervirulent NAP1/027 strain. METHODS: A retrospective cohort study was conducted in a tertiary-care Canadian hospital among 1,616 patients treated initially with metronidazole (N=1,360), vancomycin (N=219), or both (N=37), between 1991 and 2006, and followed for 60 days after diagnosis. Primary outcome was severe/complicated CDAD (SC-CDAD) defined as any of: (a) death within 30 days, (b) septic shock, (c) megacolon, (d) perforation, or (e) emergency colectomy. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated, stratifying into pre-epidemic (1991-2002) and epidemic (2003-2006) periods. Secondary outcome was recurrence within 60 days. RESULTS: Risk factors for SC-CDAD were the same in both periods: age>or=65 yr, male sex, immunosuppression, hospital acquisition, tube feeding, short duration of diarrhea, fever, elevated leukocytosis, or creatinine. Adjusting for confounders and using metronidazole therapy as baseline, vancomycin therapy was associated with a lower probability of developing SC-CDAD in 1991-2002 (AOR 0.21, 95% CI 0.05-0.99, P=0.048) but not during 2003-2006 (AOR 0.90, 95% CI 0.53-1.55, P=0.71). For both metronidazole and vancomycin, risk of recurrence increased in 2003-2004 but decreased in 2005-2006. CONCLUSIONS: Loss of superiority of vancomycin over metronidazole coincided with the emergence of NAP1/027. Toxin hyperproduction by NAP1/027 might be such that the disease follows its natural course. Novel therapeutic approaches are needed. The higher risk of recurrence in 2003-2004 probably reflected reinfections rather than relapses. Pepin J et al - Am J Gastroenterol. 2007 Dec;102(12):2781-8

Gerdings et al – Clin Infect Dis 2008; 46:S32 Age > 60 – 1 T > 38°3C – 1 Alb < 25g/l – 1 WBC > 15000/mm3 – 1 Pseudomembranes– 2 ICU - 2 *: Total  2 Gerdings et al – Clin Infect Dis 2008; 46:S32

Metronidazole vs Metro + Rifampicine Lagrotteria D et al CID 2006; 43: 547-52

Metronidazole vs Metro + Rifampicine Lagrotteria D et al CID 2006; 43: 547-52

Nitazoxanide et diarrhée à CD Nitrothiazolide CMI90 0.06-0.5 mg/l Excrétion de 2/3 dose dans les fèces activité comparable au metronidazole Musher DM et al. CID 2006; 43: 421-7 Après un echec Metronidazole (pas d’amélioration clinique à 14 j): 26/35 réponse au traitement 19/35 guérison Musher DM et al – JAC 2007; 705-710 Anti helminthique et anti protozoaire

Nitazoxanide vs Vancomycine N=49 (27 V;22 N) Response 20/27(74%) V and 17/22(77%) N Day 31 disease free 20/23 (86%) V 17/18 (95%) N Relapse 2 V, vs 1 N Sustained response rates 18/27(67%) V vs. 16 of 22 (73%) N Musher D et al – 48th ICAAC 2008 – K524b

Vancomycine vs Tolevamer Polymère anionique soluble capable de fixer les toxines A et B Arret de la diarrhée à 48 h: Vanco 500: 73/80 91% Tolevamer 6g: 58/70 83% Tolevamer 3g: 48/72 67% Louie TJ et al. CID 2006; 43: 411-20

Tolevamer vs Vanco : effets 2aires Louie TJ et al. CID 2006; 43: 411-20

Tolevamer (étude phase III) Phase III : 1100 pts, 300 sites, double aveugle Tolevamer (9g forme liquide) vs Metronidazole (1.5g) et Vancomycine (500mg) (2:1:1) Critère ppal : résolution des diarrhées à CD à J10 528 pat (268T, 125 V, 135 M) Formes sévères: 25%, récurrentes 17% Succès clinique: T 42% (112/268), V 81% (101/125), M 73% (99/135) Récurrence: T 6%, V 18%, M 19%  Infériorité vs les 2 antibiotiques de référence Bouza E et al – 18th ECCMID Avr 2008

McFarland et al., JAMA; 271, 1913-1918, (1994). OBJECTIVE--To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile-associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole). DESIGN--A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. SETTING--National referral study of ambulatory or hospitalized patients from three main study coordinating centers. PATIENTS--A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. INTERVENTION--Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. MAIN OUTCOME MEASURE--Recurrence of active CDD. RESULTS--A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P = .04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P = .86). There were no serious adverse reactions associated with S boulardii. CONCLUSIONS--The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD.

S. Boulardii vs placebo : Cessation of diarrhea S. Boulardii vs placebo : Recurrence of diarrhea Pilai & Nelson - Cochrane Database of Systematic Reviews, Issue 4, 2008

Probiotiques et traitement ICD McFarland LV Am J Gastroenterol 2006; 101: 812-22

Gerdings et al – Clin Infect Dis 2008; 46:S32 Age > 60 – 1 T > 38°3C – 1 Alb < 25g/l – 1 WBC > 15000/mm3 – 1 Pseudomembranes– 2 ICU - 2 *: Total  2 Gerdings et al – Clin Infect Dis 2008; 46:S32

Colites pseudo-membraneuses fulminantes à Clostridium difficile Étude rétrospective, 2003-2005 CHU Sherbrooke et hôpital Maisonneuve-Rosemont (Québec) 165 patients admis en réanimation pour une colite pseudo-membraneuse Mortalité à 30 jours 87/165 (53 %) 38 des 87 décès (44 %) dans les 48 heures suivant l’admission en réanimation Intérêt de la colectomie ? La mortalité des colites à Clostridium difficile ribotype 027 est élevée (27 % au 1er septembre 2006 en France). Une partie de ces décès est directement attribuable au C. difficile, avec des tableaux de choc septique ou de colite fulminante. Le traitement de ces tableaux est mal codifié, notamment en ce qui concerne le traitement chirurgical « de sauvetage » (colectomie). Jacques Pépin a étudié 165 patients consécutifs admis en réanimation pour une colite fulminante à C. difficile. La mortalité de ces formes est très élevée (53 %) et précoce : 44 % des décès surviennent dans les 48 premières heures de réanimation. ICAAC 2006 - D’après J. Pépin, communication orale 539

Colectomie et CPM age  75 years AOR, 6.5; 95% CI, 1.7–24.3 immunosuppression AOR, 7.9; 95% CI, 2.3–27.2 shock requiring vasopressors AOR, 3.4; 95% CI,1.3– 8.7 leukocytosis  50 X 109/L AOR, 18.6; 95% CI, 3.7–94.7 lactate  5 mmol/L AOR, 12.4; 95% CI, 2.4–63.7 Objectives: To determine whether emergency colectomy reduces mortality in patients with fulminant Clostridium difficile-associated disease (CDAD), and to identify subgroups of patients more likely to benefit from the procedure. Summary Background Data: Many hospitals in Quebec, Canada, have noted since 2003 a dramatic increase in CDAD incidence and in the proportion of cases severe enough to require intensive care unit (ICU) admission. The decision to perform an emergency colectomy remains largely empirical. Methods: Retrospective observational cohort study of 165 cases of CDAD that required ICU admission or prolongation of ICU stay between January 2003 and June 2005 in 2 tertiary care hospitals of Quebec. Multivariate analysis was performed through logistic regression; adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated. The primary outcome was mortality within 30 days of ICU admission. Results: Eighty-seven (53%) cases resulted in death within 30 days of ICU admission, almost half (38 of 87, 44%) within 48 hours of ICU admission. The independent predictors of 30-day mortality were: leukocytosis 50 109/L (AOR, 18.6; 95% CI, 3.7–94.7), lactate 5 mmol/L (AOR, 12.4; 95% CI, 2.4–63.7), age 75 years (AOR, 6.5; 95% CI, 1.7–24.3), immunosuppression (AOR, 7.9; 95% CI, 2.3–27.2) and shock requiring vasopressors (AOR, 3.4; 95% CI, 1.3– 8.7). After adjustment for these confounders, patients who had an emergency colectomy were less likely to die (AOR, 0.22; 95% CI, 0.07– 0.67, P 0.008) than those treated medically. Colectomy seemed more beneficial in patients aged 65 years or more, in those immunocompetent, those with a leukocytosis 20 109/L or lactate between 2.2 and 4.9 mmol/L. Conclusion: Emergency colectomy reduces mortality in some patients with fulminant CDAD. (Ann Surg 2007;245: 267–272) Emergency colectomy were less likely to die AOR, 0.22; 95%CI, 0.07– 0.67, P =0.008 Lamontagne F et al. Ann Surg 2007; 245: 267-72

Réponse immunitaire anti-toxine A et Evolution clinique de l’ICD Maroo P et al. Gastroenterology 2006; 130: 1311-6

Mab anti-toxine A vs placebo Données animales encourageantes (Babcock AAC 2006; 6339) Ac monoclonal anti Cdta 10 mg/kg 1 fois J0 Phase II – Patients traités pour CDAD 29 Mab vs 17 Pb Recurence: 17 vs 18%; NS Anti-toxin B significantly lower in case of recurrence  phase II combination anti-toxin A and B ongoing B-1925 Serum Anti-Toxin B Antibody Correlates with Protection from Recurrent Clostridium difficile Associated Diarrhea (CDAD) B. LEAV1, B. BLAIR 1, C. REILLY 1, I. LOWY 2, D. AMBROSINO 1; 1Massachusetts Biologic Lab., Boston, MA, 2Medarex, Inc., Bloomsbury, NJ. Background: Previous studies have demonstrated a correlation between C. difficile anti-toxin A serum antibodies and protection against symptomatic disease and recurrence. Methods:A neutralizing monoclonal antibody (MAb) to C. difficile toxin A (CDA1) developed by MBL and Medarex, Inc. was studied in a phase II, randomized, double blind, placebo-controlled trial in patients receiving standard of care treatment for CDAD. Subjects received a single intravenous infusion of 10mg/kg CDA1 or placebo on day 0 of the study and were evaluated for recurrence of CDAD during the 56 day study period. Serum samples were obtained prior to and after infusion to measure anti-toxin A and B antibody concentrations and specific neutralizing activity. Results: 29 patients received CDA1 and 17 received placebo. Recurrence occurred in 17% in the CDA1 group and 18% in the placebo group with a trend toward delay in time to recurrence in the group treated with CDA1. Geometric mean concentrations by ELISA (0.3 vs. 1.2 µg/ml, P= 0.02) and neutralizing titers (6 vs. 107, P=0.003) of anti-toxin B antibody at day 28 were significantly lower for subjects with recurrence compared to those who did not recur. In a multiple logistic regression analysis both anti-toxin A (trend) and anti-toxin B (P=0.02) correlated with protection from recurrence. Conclusion: In this prospective study, recurrence of CDAD was associated with significantly lower concentrations and neutralizing activity of anti-toxin B antibody. These results are consistent with our data from animal studies that demonstrate that antibodies to both toxins optimally protect against recurrence. A phase II clinical trial with a combination of anti-toxin A and B human MAbs is currently underway in patients with CDAD as adjunctive treatment and for prevention of recurrence. Leav B et al – 48th ICAAC 2008– B-1925

Tt des Complications (2) : rechute Repeat treatment with metronidazole or vancomycin using standard regimens Oral vancomycin in tapering or pulse dosing (125 mg every other day for 4–6 wk) Biotherapy: Oral lactobacilli, such as Lactinex (1 g 4 times daily), or Lactobacillus GG (1 tablet or 1010 CFU twice daily for 4–6 wk), or S. boulardii (two 250-mg capsules twice daily for 4–6 wk) Anion exchange resin: oral cholestyramine Fecal transplant (30–50 g fresh stool from healthy donor in normal saline delivered by enema or nasogastric tube) IVIG (400 mg/kg repeat in 3 wk) Combinations of above Bartlett JG – Ann Intern Med 2006; 145:758