Clostridium difficile infection in an endemic setting in the Netherlands European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. A case-control study of community-associated Clostridium difficile infection. Clostridium difficile infection in the "oldest" old: clinical outcomes in patients aged 80 and older. Lack of association of outcomes with treatment duration and microbiologic susceptibility data in Clostridium difficile infections in a non-NAP1/BI/027 setting Hospital-acquired Clostridium difficile infection: determinants for severe disease Lymphopenia as a novel marker of Clostridium difficile infection recurrence. Relapse Versus Reinfection: Recurrent Clostridium difficile Infection Following Treatment With Fidaxomicin or Vancomycin Proton Pump Inhibitor Use and Recurrent Clostridium difficile-associated Disease: A Case-control Analysis Matched by Propensity Score Effect of age on treatment outcomes in Clostridium difficile infection. Successful combat of an outbreak due to Clostridium difficile PCR ribotype 027 and recognition of specific risk factors. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Mortality in patients with Clostridium difficile infection correlates with host pro-inflammatory and humoral immune responses. A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection.
The purpose of this investigation was to study risk factors for  Clostridium difficile infection ( CDI ) in an endemic setting . In a 34-month prospect i ve case – control study , we compared the risk factors and clinical characteristics of all consecutively diagnosed hospitalised CDI patients ( n = 93 ) with those of patients without diarrhoea ( n = 76 ) and patients with non-CDI diarrhoea ( n = 64 ) . The incidence of CDI was 17.5 per 10,000 hospital admissions .  C. difficile polymerase chain reaction ( PCR ) ribotype 014 was the most frequently found type ( 15.9 % ) , followed by types 078 ( 12.7 % ) and 015 ( 7.9 % ) . Independent risk factors for endemic CDI were the use of second-generation cephalosporins , previous hospital admission and previous stay at the intensive care unit ( ICU ) . The use of third-generation cephalosporins was a risk factor for diarrhoea in general . We found no association of CDI with the use of fluoroquinolones or proton pump inhibitors ( PPIs ) . The overall 30-day mortality among CDI patients , patients without diarrhoea and patients with non-CDI diarrhoea was 7.5 % , 0 % and 1.6 % , respectively . In this endemic setting , risk factors for CDI differed from those in outbreak situations . Some risk factors that have been ascribed to CDI earlier were , in this study , not specific for CDI , but for diarrhoea in general . The 30-day mortality among CDI patients was relatively high In 2009 the first European Society of Clinical Microbiology and Infection ( ESCMID ) treatment guidance document for  Clostridium difficile infection ( CDI ) was published . The guideline has been applied widely in clinical practice . In this document an up date and review on the comparative effectiveness of the currently available treatment modalities of CDI is given , thereby providing evidence -based recommendations on this issue . A computerized literature search was carried out to investigate r and omized and non-r and omized trials investigating the effect of an intervention on the clinical outcome of CDI . The Grade s of Recommendation Assessment , Development and Evaluation ( GRADE ) system was used to grade the strength of our recommendations and the quality of the evidence . The ESCMID and an international team of experts from 11 European countries supported the process . To improve clinical guidance in the treatment of CDI , recommendations are specified for various patient groups , e.g. initial non-severe disease , severe CDI , first recurrence or risk for recurrent disease , multiple recurrences and treatment of CDI when oral administration is not possible . Treatment options that are review ed include : antibiotics , toxin-binding resins and polymers , immunotherapy , probiotics , and faecal or bacterial intestinal transplantation . Except for very mild CDI that is clearly induced by antibiotic usage antibiotic treatment is advised . The main antibiotics that are recommended are metronidazole , vancomycin and fidaxomicin . Faecal transplantation is strongly recommended for multiple recurrent CDI . In case of perforation of the colon and /or systemic inflammation and deteriorating clinical condition despite antibiotic therapy , total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended OBJECTIVES The aim of this study was to determine the incidence of and risk factors for  community-associated Clostridium difficile infection ( CDI )  . METHODS Prospect i ve surveillance of community-derived faecal sample s for C. difficile cytotoxin , followed by a question naire-based case-control study in two distinct patient cohorts ( one semi-rural and the other urban ) . RESULTS The proportion of r and omly selected faecal sample s positive for C. difficile cytotoxin was 2.1 % in both patient cohorts ( median ages 73 and 45 years for the urban and semi-rural cohorts , respectively ) .  Exposure to antibiotics  in the previous 4 weeks , particularly multiple agents ( P < 0.001 ) , aminopenicillins ( P < 0.05 ) and oral cephalosporins ( P < 0.05 ) , was significantly more frequent among cases than controls . Hospitalization in the preceding 6 months was significantly associated with CDI ( 45 % versus 23 % ; P = 0.022 ) . However , almost half the cases had not received antibiotic therapy in the month before C. difficile detection , and approximately one-third neither had exposure to antibiotics nor recent hospitalization . Contact with infants aged < or = 2 years was significantly associated with CDI ( 14 % versus 2 % ; P = 0.02 ) . Prior exposure to gastrointestinal-acting drugs ( proton pump inhibitor , H2 antagonist or non-steroidal anti-inflammatory ) was not significantly more common in CDI cases . C. difficile PCR ribotype 001 caused 60 % and 13 % of urban and semi-rural community-associated CDI cases , respectively . CONCLUSIONS Reliance on antibiotic history and age ( > or = 65 years ) will contribute to missed diagnoses of community-associated CDI . Potential risk factors for community-associated CDI should be explored further to explain the large proportion of cases not linked to recent antibiotic therapy or hospitalization OBJECTIVES Clostridium difficile infection ( CDI ) represents a cause of substantial morbidity , particularly for older adults . Although older age is a risk factor for CDI , few studies have specifically focused on clinical outcomes in older adults , particularly the " oldest " old . DESIGN Retrospective review . SETTING University of Michigan Health System . PARTICIPANTS All patients aged 80 and older with a positive cytotoxin assay for C. difficile and a clinical course consistent with CDI during 2006 . MEASUREMENTS Clinical data were recorded , including comorbid conditions and treatment regimens , as well as outcomes , including treatment failure , infection relapse , and 90-day mortality . RESULTS Seventy patients aged 80 and older ( mean 84.0+/-4.1 ) with CDI were identified .  Metronidazole was given as initial therapy in 65 ( 92.8 % ) ; 18 of these 65 ( 27.7 % ) experienced treatment failure , requiring subsequent use of oral vancomycin .  Serious adverse events included three episodes of toxic megacolon , two requiring colectomy . One death was directly attributable to CDI . All-cause mortality was 8.6 % at 30 days and 17.1 % at 90 days . Higher white blood cell ( WBC ) counts were independently associated with treatment failure ( P=.02 ) and coronary artery disease with 90-day mortality ( P=.02 ) . CONCLUSION In older adults with CDI , treatment failure on metronidazole occurred frequently and was associated with higher WBC count . Larger prospect i ve studies are needed to determine risk factors for treatment failure and relapse in order to develop better paradigms for CDI treatment in older adults . Initial therapy with vancomycin may be appropriate for elderly patients , especially those with elevated WBC counts Abstract Background : Concerns regarding the poor response of severe Clostridium difficile infection ( CDI ) treated with metronidazole have arisen over the last 5 y. Methods : We conducted a prospect i ve , non-interventional study of CDI cases at our institution to evaluate the role of drug resistance , co-morbidities , and the emergence of hypervirulent strains on patient outcomes . A total of 118 adult in patients with diarrhea and a positive stool for C. difficile toxin immunoassay had positive stool cultures and were included in the study . All 118 isolates had  vancomycin and metronidazole susceptibility testing via the E-test method ; rep-PCR was performed on 47 isolates . Of the 118 study patients , 107 were treated with either metronidazole or vancomycin .  Results : Initial therapy was metronidazole in 98.1 % ( n = 105 ) and vancomycin in 1.9 % ( n = 2 ) patients . Evaluable clinical response within 5 days of treatment was noted in 52.5 % ( 52/99 ) of cases . The mean duration of treatment was 11.7 ± 7.2 days . The 30-day all-cause mortality rate was 24.6 % ( 29/118 ) . Recurrence occurred in 23.6 % ( 21/89 ) . A recent stay in the intensive care unit was associated with increased 30-day mortality ( odds ratio 3.58 , p = 0.012 ) . There were no isolates resistant to metronidazole or vancomycin . Only 1 isolate was possibly related to the NAP1/BI/027 reference strain . No strain-related differences in deaths or recurrence were noted . Conclusions : Deaths related to CDI in our study appear to be related to multiple factors and did not appear to be independently related to antibiotic susceptibility , strain type , or treatment duration Risk factors of severity ( need for surgical intervention , intensive care or fatal outcome ) were analysed in hospital-acquired Clostridium difficile infection ( CDI ) in a 777-bed community hospital . In a prospect i ve analytical cross-sectional study , age ( ≥65 years ) , sex , CDI characteristics , underlying diseases , severity of comorbidity and PCR ribotypes were tested for associations with severe CDI . In total , 133 cases of hospital-acquired CDI ( mean age 74.4 years ) were identified , result ing in an incidence rate of 5.7/10,000 hospital-days . A recurrent episode of diarrhoea occurred in 25 cases ( 18.8 % ) and complications including toxic megacolon , dehydration and septicaemia in 69 cases ( 51.9 % ) . Four cases ( 3.0 % ) required ICU admission , one case ( 0.8 % ) surgical intervention and 22 cases ( 16.5 % ) died within the 30-day follow-up period . Variables identified to be independently associated with severe CDI were severe diarrhoea ( odds ratio [ OR ] 3.64 , 95 % confidence interval [ CI ] 1.19–11.11 , p = 0.02 ) , chronic pulmonary disease ( OR 3.0 , 95 % CI 1.08–8.40 , p = 0.04 ) , chronic renal disease ( OR 2.9 , 95 % CI 1.07–7.81 , p = 0.04 ) and diabetes mellitus ( OR 4.30 , 95 % CI 1.57–11.76 , p = 0.004 ) . The case fatality of 16.5 % underlines the importance of increased efforts in CDI prevention , in particular for patients with underlying diseases BACKGROUND Treatment of Clostridium difficile infection ( CDI ) is often limited by recurrence in 25 % of cases . The objective of this study was to determine risk factors of CDI recurrence during a provincial endemic . METHODS Data was prospect ively collected for 1 year in a Montréal hospital . Inclusion criteria were : age ≥ 18 years ; admission for ≥ 72 h ; CDI diagnosis during current admission ; no CDI diagnosis in the previous 3 months . RESULTS A total of 121 patients were included , of which 42 % were female . Mean age was 77 years , with a median Charlson comorbidity index of 5 . Forty patients ( 33 % ) had recurrent disease within 2 months of initial CDI treatment . There were 20 deaths ( 17 % ) within the 2-month follow-up period . Higher risk of CDI recurrence was independently associated with older age ( HR=2.26 for each decade ) , female gender ( HR=1.56 ) , and lymphopenia at completion of CDI treatment ( HR=2.18 ) , while a positive C. difficile antitoxin serology was protective ( HR=0.17 ) . CDI recurrence was not associated with either lymphopenia at time of diagnosis , underlying comorbidities , severity or treatment of the initial CDI episode , or re-exposure to antibiotics during the follow-up period . CONCLUSION Lymphopenia at the end of CDI treatment appears to be a strong marker for CDI recurrence . This available and inexpensive test may identify patients who are at higher risk of CDI recurrence Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection ( CDI ) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days . Strains originated from patients who had been entered into two phase 3 r and omized clinical trials of fidaxomicin versus vancomycin .  Isolates of C. difficile from the initial and recurrent episodes within 28 ( ±2 ) days of cure of CDI were compared using restriction endonuclease analysis ( REA ) typing . Paired isolates were available from 90 of 194 ( 46 % ) patients with recurrent CDI . Patients with isolates available were significantly younger ( P = .008 ) and more likely to be from Canadian sites ( P = .0001 ) , compared with patients without isolates . In 75 of 90 subjects ( 83.3 % ) , the identical REA type strain was identified at recurrence and the initial episode ( putative relapse ) . Early recurrences ( 0–14 days after treatment completion ) were relapses in 86.7 % and a new strain ( reinfection ) in 13.3 % . Later recurrences ( 15–31 days after treatment ) were relapses in 76.7 % and reinfections in 23.3 % . Mean time ( ± st and ard deviation ) to recurrence was 12.2 ( ±6.4 ) days for relapses and 14.7 ( ±6.8 ) days for reinfections ( P = .177 ) . The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain ( relapse ) , compared with the other REA groups ( 39 of 42 [ 93 % ] vs 36 of 48 [ 75 % ] , respectively ; P = .023 ) . We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode , a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains , such as groups BI and J , for which relapse rates may be higher than for other REA groups . Caution in generalizing these observations is required , because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates . Clinical Trials Registration . NCT00314951 and NCT00468728 Background and Aim : Clostridium difficile has been increasingly diagnosed in hospitalized patients . An association between proton pump inhibitors ( PPIs ) use and Clostridium difficile-associated disease ( CDAD ) and between recurrent CDAD has been suggested . The aim of this study is to investigate whether PPI use is associated with the development of recurrent CDAD . Methods : This was a retrospective case-control study of patients with CDAD at Yeungnam University Medical Center , seen from January 2004 to December 2008 . C. difficile infection was diagnosed by the presence of C. difficile toxin in the stool . Those with recurrent disease were matched with nonrecurrent controls using multivariate matched sampling methods that incorporated the propensity score . Results : Recurrent CDAD developed in 28 ( 14.1 % ) of the 198 patients with diarrhea and positive C. difficile stool toxin assays . Multivariate analysis of the total population of recurrent versus nonrecurrent CDAD revealed that additional use of non-C. difficile antimicrobial therapy  ( concomitant with the treatment or after or both ) , poor response to therapy with metronidazole  or vancomycin , and recent gastrointestinal surgery were risk factors for recurrent CDAD . We were able to match 21 recurrent CDAD subjects with 21 without recurrent CDAD . Among the matched patients only PPI use was associated with recurrent CDAD ( ie , 47.6 % vs. 4.8 % , P=0.004 for recurrent vs. nonrecurrent CDAD , respectively ) . Conclusions : Among the matched patient groups , only PPI therapy was associated with recurrent CDAD . Prospect i ve studies are needed to clarify whether avoidance of PPIs or specific cotherapies will reduce the incidence of recurrent C. difficile-associated diarrhea OBJECTIVES To determine the effect of advancing age on the clinical outcomes of Clostridium difficile ( CDI ) treatment .  DESIGN Regression modeling of results from two double-blind r and omized multicenter studies on the treatment of primary and first recurrent cases of CDI to examine for effects of age and study drug on outcomes of cure ( resolution of diarrhea ) , recurrence within 4 weeks of completing successful therapy , and cure without recurrence . SETTING Participants were r and omized into studies in the United States , Canada , and Europe . PARTICIPANTS Nine hundred ninety-nine individuals with toxin-positive CDI were r and omized to receive vancomycin ( 125 mg 4 times daily ) or fidaxomicin ( 200 mg twice daily ) for 10 days . MEASUREMENTS The effect of advancing age  in those aged 18 to 40 years and in 10-year increments thereafter was examined . RESULTS The model predicts a 17 % lower clinical cure , 17 % greater recurrence , and 13 % lower sustained clinical response by advancing decade than in those younger than 40 ( P < .01 each ) . Clinical cure was similar in the fidaxomicin and vancomycin treatment groups , although fidaxomicin was associated with a more than 50 % lower relative risk for recurrence than vancomycin ( P < .001 ) . Multivariate regression modeling showed that risk factors accounting for poorer outcomes with advancing age include infection with the BI strain type , inpatient status , renal insufficiency , leukocytosis , hypoalbuminemia , and concomitant medication exposure . CONCLUSION Measurable and progressive deterioration in CDI treatment outcomes occurred with advancing age in those aged 40 and older , highlighting the need for prevention and treatment strategies . Fidaxomicin treatment was associated with a 60 % lower risk of recurrence than vancomycin after adjusting for age , concomitant antibiotics , and C. difficile strain In the period April-September 2005 , an outbreak of  Clostridium difficile infection ( CDI ) due to PCR ribotype 027 occurred among 50 patients in a 341-bed community hospital in Harderwijk , The Netherl and s. A retrospective case-control study was performed to identify risk factors specific for CDI , using a group of patients with CDI ( n = 45 ) , a group of r and omly selected control patients without diarrhoea ( n = 90 ) , and a group of patients with non-infectious diarrhoea ( n = 109 ) . Risk factors for CDI and for non-CDI diarrhoea were identified using multiple logistic regression analysis . Independent risk factors for CDI were : age above 65 years ( OR 2.6 ; 95 % CI 1.0 - 5.7 ) , duration of hospitalization ( OR 1.04 per additional day ; 95 % CI 1.0 - 1.1 ) , and antibiotic use ( OR 12.5 ; 95 % CI 3.2 - 48.1 ) . Of the antibiotics used , cephalosporins and fluoroquinolones were identified as the major risk factors for development of CDI . The risk of developing CDI was particularly high in people receiving a combination of a cephalosporin and a fluoroquinolone ( OR 57.5 ; 95 % CI 6.8 - 483.6 ) . The main factors affecting the risk of non-CDI diarrhoea were proton-pump inhibitors , immunosuppressive drugs , underlying digestive system disease , previous surgery , and gastric tube feeding . The outbreak ended only after implementation of restricted use of cephalosporins and a complete ban on fluoroquinolones , in addition to general hygienic measures , cohorting of patients in a separate ward , education of staff , and intensified environmental cleaning . The results of this study support the importance of appropriate antimicrobial stewardship in the control of hospital outbreaks with C. difficile PCR ribotype 027 OBJECTIVE toxigenic Clostridium difficile is responsible for a spectrum of disease severity ranging from mild diarrhoea to fulminant colitis . This study attempts to determine the proportion of patients in each category of severity and evaluate the risk factors for a more prolonged and complicated course . DESIGN prospect i ve cohort study . SETTING university teaching hospital . SUBJECTS all patients with symptomatic C. difficile infection during 4 months of an outbreak ( January-April 1995 ) ; n=73 ; median age 74 years ( range 17 - 91 ) . MEASUREMENTS incidence of C. difficile-associated disease ( CDAD ) ; severity of disease ; percentage of patients in each category of severity ; risk factors for severe disease/prolonged symptoms ( univariate and multivariable analyses ) . RESULTS the incidence of CDAD was 0.93 % . Of the cases identified , 18 ( 24.7 % ) had mild , self-limiting disease ; 26 ( 35.6 % ) had moderately severe disease ; 23 ( 31.5 % ) had prolonged symptoms and six ( 8.2 % ) had a complicated course . Although CDAD was more common in older patients ( P < 0.001 ) , increasing age was not a risk factor for severity . Significant risk factors for severe CDAD included low Barthel and abbreviated mental test scores ( P < 0.01 , P < 0.001 respectively ) and recent endoscopy ( P=0.03 ) . Logistic regression analysis revealed the following independent predictors of severe CDAD : endoscopy [ odds ratios ( OR ) 4.0 , P=0.03 ] and cognitive impairment ( OR 11.0 , P < 0.01 ) . A trend towards significance was noted for nasogastric tube insertion ( OR 3.1 , P=0.08 ) . Complications of infection included dehydration , malnutrition and faecal incontinence ( which was statistically significantly associated with more severe disease ; P < 0.01 ) . CONCLUSION risk factors for severity of CDAD include functional disability , cognitive impairment , and recent endoscopy . Anticipation of severe CDAD may limit morbidity and mortality IMPORTANCE Clostridium difficile is the most common cause of health care-associated infection in US hospitals . Recurrence occurs in 25 % to 30 % of patients . OBJECTIVE To determine the safety , fecal colonization , recurrence rate , and optimal dosing schedule of nontoxigenic C. difficile strain M3 ( VP20621 ; NTCD-M3 ) for prevention of recurrent C. difficile infection ( CDI ) . DESIGN , SETTING , AND PARTICIPANTS Phase 2 , r and omized , double-blind , placebo-controlled , dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI ( first episode or first recurrence ) and had successfully completed treatment with metronidazole , oral vancomycin , or both at 44 study centers in the United States , Canada , and Europe . INTERVENTIONS Patients were r and omly assigned to receive 1 of 4 treatments : oral liquid formulation of NTCD-M3 , 10(4 ) spores/d for 7 days ( n = 43 ) , 10(7 ) spores/d for 7 days ( n = 44 ) , or 10(7 ) spores/d for 14 days ( n = 42 ) , or placebo for 14 days ( n = 44 ) . MAIN OUTCOMES AND MEASURES The primary outcome was safety and tolerability of NTCD-M3  within 7 days of treatment . Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6 . RESULTS Among 168 patients who started treatment , 157 completed treatment . One or more treatment-emergent adverse events were reported in 78 % of patients receiving NTCD-M3 and 86 % of patients receiving placebo . Diarrhea and abdominal pain were reported in 46 % and 17 % of patients receiving NTCD-M3 and 60 % and 33 % of placebo patients , respectively . Serious treatment-emergent adverse events were reported in 7 % of patients receiving placebo and 3 % of all patients who received NTCD-M3 . Headache was reported in 10 % of patients receiving NTCD-M3 and 2 % of placebo patients . Fecal colonization occurred in 69 % of NTCD-M3 patients : 71 % with 10(7 ) spores/d and 63 % with 10(4 ) spores/d . Recurrence of CDI occurred in 13 ( 30 % ) of 43 placebo patients and 14 ( 11 % ) of 125 NTCD-M3 patients ( odds ratio [ OR ] , 0.28 ; 95 % CI , 0.11 - 0.69 ; P = .006 ) ; the lowest recurrence was in 2 ( 5 % ) of 43 patients receiving 10(7 ) spores/d for 7 days ( OR , 0.1 ; 95 % CI , 0.0 - 0.6 ; P = .01 vs placebo ] ) . Recurrence occurred in 2 ( 2 % ) of 86 patients who were colonized vs 12 ( 31 % ) of 39 patients who received NTCD-M3 and were not colonized ( OR , 0.01 ; 95 % CI , 0.00 - 0.05 ; P < .001 ) . CONCLUSIONS AND RELEVANCE Among patients with CDI who clinical ly recovered following treatment with metronidazole or vancomycin , oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe . Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01259726 OBJECTIVE To describe the epidemiology , diagnosis , risk factors , patient impact , and treatment strategies for recurrent Clostridium difficile-associated disease ( CDAD ) . DESIGN Data were collected as part of a blinded , placebo-controlled clinical trial testing a new combination treatment for recurrent CDAD . Retrospective data regarding prior CDAD episodes were collected from interviews and medical-chart review . Prospect i ve data on the current CDAD episode , risk factors , and recurrence rates were collected during a 2-month follow-up . SETTING S National referral study . PARTICIPANTS Patients with recurrent CDAD . INTERVENTIONS Treatment with a 10-day course of low-dose ( 500 mg/d ) or high-dose ( 2 g/d ) vancomycin or metronidazole ( 1 g/d ) . RESULTS Recurrent CDAD was found to have a lengthy course involving multiple episodes of diarrhea , abdominal cramping , nausea , and fever . CDAD may recur over several years despite frequent treatment with antibiotics . Recurrence rates were similar regardless of the choice or dose of antibiotic . Recurrent CDAD is not a trivial disease : patients may have multiple episodes ( as many as 14 ) , may require hospitalization , and the mean lifetime cost of direct medical care was $ 10,970 per patient . Fortunately , the disease does not become progressively more severe as the number of episodes increase . Two risk factors predictive for recurrent CDAD were found : increasing age and a decreased quality -of-life score at enrollment . CONCLUSIONS Recurrent CDAD is a persistent disease that may result in prolonged hospital stays , additional medical costs , and rare serious complications Recurrent Clostridium difficile diarrhea ( RCDD ) occurs in 20 % of patients after they have received st and ard antibiotic treatment with vancomycin or metronidazole , but the reasons for the recurrences are largely unknown . Patients receiving vancomycin or metronidazole for active C. difficile diarrhea ( CDD ) were referred to our study centers for treatment and a 2-month follow-up as part of a r and omized placebo-controlled trial . Sixty patients had RCDD ( median number of episodes , 3.0 ; range , 2 - 9 episodes ) and 64 were having their first episode of CDD . Patients with RCDD had more-severe abdominal pain and were more likely to have fever but initially responded well to antibiotic therapy . Data on sequential episodes showed no progression in disease severity . Five factors were associated with a higher risk of RCDD : the number of previous CDD episodes , onset of the initial disease in the spring , exposure to additional antibiotics for treatment of other infections , infection with immunoblot type 1 or 2 strains of C. difficile , and female gender . These factors may help to identify patients who are more likely to develop RCDD  and require careful medical supervision Host anti-toxin immune responses play important roles in Clostridium difficile disease and outcome . The relationship between host immune and inflammatory responses during severe C. difficile infection ( CDI ) and the risk of mortality has yet to be defined . We aim ed to investigate the host systemic IgG anti-toxin immune responses , the in vitro cytotoxicity of the infecting C. difficile ribotyped strain , and the host inflammatory markers and their relationship to CDI disease severity and risk of mortality . Inflammatory markers , co-morbidities and CDI outcomes were recorded in a prospect i ve cohort of 150 CDI cases .  Serum anti-cytotoxin A ( TcdA ) and anti-TcdB IgG titres were measured by ELISA and the infecting C. difficile isolate was ribotyped and the in vitro cytotoxin titre assessed . A low median anti-TcdA IgG titre was significantly associated with 30-day all-cause mortality ( P<0.05 ) . Ribotype 027 isolates were significantly more toxinogenic than other ribotypes ( P<0.00001 ) . High cytotoxin titres correlated with increased inflammatory markers but also higher anti-TcdA and -TcdB ( P<0.05 ) IgG responses result ing in a lower risk of mortality . On multivariate analysis , predictors of mortality were peak white cell count > 20 × 10(9 ) l(-1 ) [ odds ratio ( OR ) 11.53 ; 95 % confidence interval ( CI ) 2.38 - 55.92 ] , creatinine concentration > 133 µmol l(-1 ) ( OR 6.54 ; 95 % CI 1.47 - 29.07 ) , Horn 's index > 3 ( OR 4.09 ; 95 % CI 0.76 - 22.18 ) and low anti-TcdA IgG ( OR 0.97 ; 95 % CI 0.95 - 0.99 ) , but not ribotype , cytotoxin titre or anti-TcdB IgG. Thus , host pro-inflammatory and humoral responses correlate with the cytotoxin titre of the infecting strain and effective anti-toxin immune responses reduce the risk of mortality BACKGROUND & AIMS Recent studies of Clostridium difficile infection ( CDI ) have indicated a dramatic increase in metronidazole failure . The aims of this study were to compare current and historical rates of metronidazole failure and to identify risk factors for metronidazole failure . METHODS Eighty-nine patients with CDI in 2004 to 2006 were followed for 60 days and were compared with a historical cohort of 63 CDI patients studied prospect ively in 1998 . Metronidazole failure was defined as persistent diarrhea after 10 days of therapy or a change of therapy to vancomycin . Stool sample s were analyzed for the presence of the North American pulsed-field gel electrophoresis type-1 ( NAP-1 ) strain . RESULTS Metronidazole failure rates were 35 % in both cohorts . There was no difference in the median time to resolution of diarrhea ( 8 vs 5 d ; P = .52 ) or the proportion with > 10 days of diarrhea ( 35 % vs 29 % ; P = .51 ) . Risk factors for metronidazole failure included recent cephalosporin use ( odds ratio [ OR ] , 32 ; 95 % confidence interval [ CI ] , 5 - 219 ) , CDI on admission ( OR , 23 ; 95 % CI , 3 - 156 ) , and transfer from another hospital ( OR , 11 ; 95 % CI , 2 - 72 ) . The frequency of NAP-1 infection in patients with and without metronidazole failure was similar ( 26 % vs 21 % ; P = .67 ) . CONCLUSIONS We found no difference in metronidazole failure rates in 1998 and 2004 to 2006 . Patients with recent cephalosporin use , CDI on admission , and transfer from another hospital were more likely to metronidazole failure . Infection with the epidemic NAP-1 strain was not associated with metronidazole failure in endemic CDI
Older age , use of antibiotics after diagnosis , use of proton pump inhibitors , and strain type were the most frequent risk factors for recurrence .
Older age , leucocytosis , renal failure and co-morbidities were frequent risk factors for complicated CDI .
When considered alone , mortality was associated with age , co-morbidities , hypo-albuminemia , leucocytosis , acute renal failure , and infection with ribotype 027 .
BACKGROUND Clostridium difficile infection ( CDI ) can lead to complications , recurrence , and death .
Numerous studies have assessed risk factors for these unfavourable outcomes , but systematic review s or meta-analyses published so far were limited in scope or in quality .