the database from 2 randomized controlled phase iii trials comparing vancomycin with fidaxomicin for the treatment of cdi was used to assess the predictive value of fever , leukocyte count , and serum creatinine level [ 9 , 10 ] .
patients were recruited in the united states , canada , and europe ( clinicaltrials.gov registry number nct00314951 , april 2006july 2008 , united states and canada ; and clinicaltrials.gov registry number  nct00468728 , april 2007november 2009 , united states , belgium , canada , france , germany , italy , spain , sweden , and united kingdom ) .
patients with cdi , defined on the basis of diarrhea ( > 3 unformed bowel movements [ ubms ] per day ) and a positive stool toxin test for c. difficile , were randomly assigned to receive 125  mg of vancomycin 4 times daily or 200  mg of fidaxomicin twice daily for 10 days .
the numbers and times of ubms were recorded during treatment and for 2 days after an end - of - therapy visit . for patients with rectal collection devices ,
volume was converted to number of ubms by dividing the volume by 60 ml and rounding up to the nearest whole number . at the end - of - therapy visit ,
clinical failure was defined as the persistence of diarrhea , the need for additional therapy for cdi , or both on the basis of the opinion of the investigator .
recurrence of cdi ( determined by use of the same criteria as for enrollment [ ie , > 3 ubms per 24 hours and a positive stool toxin test result ] ) was assessed during the mean follow - up duration ( sd ) of 28    2 days after completion of therapy . at enrollment , temperature , leukocyte count , and serum creatinine level
were collected . to assess whether the timing of laboratory measurements could influence their prognostic value , we used the database of a prospective cohort study performed at leeds teaching hospital in 2007 . in this database , 104 consecutive adult inpatients with cdi ( defined on the basis of the presence of unformed stool and a positive c. difficile toxin test result )
were included . on days 3 to + 3 relative to day 0 ( the day the diarrheal sample was collected ) ,
data from a minimum of 2 leukocyte counts and creatinine levels on different days were required for patients to be included in the analyses . in both analyses ,
we defined fever as a core body temperature > 38.5c and leukocytosis as a leukocyte count > 15    10 leukocytes / l . because the pre - cdi serum creatinine level was not known for each patient , we substituted the 50% creatinine level increase with a fixed value of the creatinine level > 133  mol / l ( > 1.5  mg / dl ) .
the intention - to - treat population that received at least 1 dose of study medication was used for the analysis .
distributions of the continuous variables of temperature , leukocyte count , and creatinine level were compared for patients with and patients without clinical treatment failure and recurrence .
risk ratios ( rrs ) and 95% confidence intervals ( cis ) were calculated for the associations of fever , leukocytosis , and renal failure with the outcome parameters .
kaplan - meier survival curves were constructed to investigate the association of fever , leukocytosis , and renal failure with the time to resolution of diarrhea ( expressed in hours from the first dose of fidaxomicin or vancomycin ) .
the log - rank test was used to test the difference between the survival curves .
receiver operating characteristic curves were constructed to assess the validity of the cutoffs used to define categorical variables .
variability of leukocyte counts and serum creatinine levels were compared within patients and expressed in absolute differences .
all analyses were carried out in spss for windows software , version 17.0 ( spss , chicago , il ) .
the database from 2 randomized controlled phase iii trials comparing vancomycin with fidaxomicin for the treatment of cdi was used to assess the predictive value of fever , leukocyte count , and serum creatinine level [ 9 , 10 ] .
patients were recruited in the united states , canada , and europe ( clinicaltrials.gov registry number nct00314951 , april 2006july 2008 , united states and canada ; and clinicaltrials.gov registry number  nct00468728 , april 2007november 2009 , united states , belgium , canada , france , germany , italy , spain , sweden , and united kingdom ) .
patients with cdi , defined on the basis of diarrhea ( > 3 unformed bowel movements [ ubms ] per day ) and a positive stool toxin test for c. difficile , were randomly assigned to receive 125  mg of vancomycin 4 times daily or 200  mg of fidaxomicin twice daily for 10 days .
the numbers and times of ubms were recorded during treatment and for 2 days after an end - of - therapy visit . for patients with rectal collection devices ,
volume was converted to number of ubms by dividing the volume by 60 ml and rounding up to the nearest whole number . at the end - of - therapy visit ,
clinical failure was defined as the persistence of diarrhea , the need for additional therapy for cdi , or both on the basis of the opinion of the investigator .
recurrence of cdi ( determined by use of the same criteria as for enrollment [ ie , > 3 ubms per 24 hours and a positive stool toxin test result ] ) was assessed during the mean follow - up duration ( sd ) of 28    2 days after completion of therapy . at enrollment , temperature , leukocyte count , and serum creatinine level
were collected . to assess whether the timing of laboratory measurements could influence their prognostic value , we used the database of a prospective cohort study performed at leeds teaching hospital in 2007 . in this database , 104 consecutive adult inpatients with cdi ( defined on the basis of the presence of unformed stool and a positive c. difficile toxin test result )
were included . on days 3 to + 3 relative to day 0 ( the day the diarrheal sample was collected ) ,
data from a minimum of 2 leukocyte counts and creatinine levels on different days were required for patients to be included in the analyses . in both analyses ,
we defined fever as a core body temperature > 38.5c and leukocytosis as a leukocyte count > 15    10 leukocytes / l . because the pre - cdi serum creatinine level was not known for each patient , we substituted the 50% creatinine level increase with a fixed value of the creatinine level > 133  mol / l ( > 1.5  mg / dl ) .
the intention - to - treat population that received at least 1 dose of study medication was used for the analysis .
distributions of the continuous variables of temperature , leukocyte count , and creatinine level were compared for patients with and patients without clinical treatment failure and recurrence .
risk ratios ( rrs ) and 95% confidence intervals ( cis ) were calculated for the associations of fever , leukocytosis , and renal failure with the outcome parameters .
kaplan - meier survival curves were constructed to investigate the association of fever , leukocytosis , and renal failure with the time to resolution of diarrhea ( expressed in hours from the first dose of fidaxomicin or vancomycin ) .
the log - rank test was used to test the difference between the survival curves .
receiver operating characteristic curves were constructed to assess the validity of the cutoffs used to define categorical variables .
variability of leukocyte counts and serum creatinine levels were compared within patients and expressed in absolute differences .
all analyses were carried out in spss for windows software , version 17.0 ( spss , chicago , il ) .
patients treated with vancomycin ( n  =  566 ) or fidaxomicin ( n  =  539 ) had similar median values for temperature , leukocyte count , and serum creatinine level and were evenly distributed across the groups with respect to dichotomized continuous variables ( data not shown ) .
fever was rare ; only 1.2% of patients ( 13 of 1102 ) had a temperature > 38.5c .
overall , 143 patients ( 13% ) experienced clinical treatment failure at the end of treatment . of the 962 patients who were cured after treatment , 194 ( 20% ) experienced recurrence
the median leukocyte count and creatinine level were significantly higher in patients with clinical treatment failure ; temperature distributions in patients with and those without treatment failure were almost identical .
in addition , dichotomous categories of fever , leukocytosis , and renal failure all showed significant correlation with treatment failure ( table  1 ) .
the median creatinine level was significantly higher in patients with recurrence , and this parameter was the only significant predictor of recurrence ( table  2 ) .
different cutoffs for the continuous variables of temperature , leukocyte count , and creatinine level , assessed by receiver operating characteristics , did not lead to higher relative risks and therefore better performance in the prediction of clinical treatment failure or recurrent cdi . 

table  1.determinants of clinical treatment failure among patients with clostridium difficile infectionvariablemedian valueiqrpcontinuous , outcometemperature ( c )  failure36.836.437.2.180  cure36.736.437.1leukocyte count ( 10
leukocytes / l )  failure10.56.817.4.002  cure8.96.512.1creatinine level ( mol / l )  failure80  62150.005  cure71  6297categorical , cutofffailurerr95% cifever , temperature  >
38.5c4/132.451.075.61  38.5c137/1089leukocytosis , leukocyte level  > 15    10 leukocytes / l38/1532.291.633.21  15    10 leukocytes / l90/829renal failure , creatinine level  133  mol / l41/1602.521.823.50  < 133  mol / l91/896abbreviations : ci , confidence interval ; iqr , interquartile range ; rr , risk ratio .
creatinine conversion : 1  mol / l is equal to 0.0113  mg / dl .
therefore , 133  mol / l is equal to 1.50  mg / dl .
table  2.determinants of clostridium difficile infection recurrencevariablemedian valueiqrpcontinuous , outcometemperature ( c )  no recurrence36.736.437.1.827  recurrence36.736.437.0leukocyte count ( 10
leukocytes / l )  no recurrence8.86.512.1.276  recurrence9.16.612.8creatinine level ( mol / l )  no recurrence716297.008  recurrence8062115categorical , cutoffrecurrencerr95% cifever , temperature  > 38.5c1/90.55.093.51  38.5c192/952leukocytosis , leukocyte level  > 15    10 leukocytes / l22/1151.00.671.50  15    10 leukocytes / l141/739renal failure , creatinine level  133  mol / l32/1191.451.052.02  < 133  mol / l149/805abbreviations : ci , confidence interval ; iqr , interquartile range ; rr , risk ratio . 
creatinine conversion : 1  mol / l is equal to 0.0113  mg / dl .
therefore , 133  mol / l is equal to 1.50  mg / dl .
determinants of clinical treatment failure among patients with clostridium difficile infection abbreviations : ci , confidence interval ; iqr , interquartile range ; rr , risk ratio .  
creatinine conversion : 1  mol / l is equal to 0.0113  mg / dl .
therefore , 133  mol / l is equal to 1.50  mg / dl .  
. determinants of clostridium difficile infection recurrence abbreviations : ci , confidence interval ; iqr , interquartile range ; rr , risk ratio . 
creatinine conversion : 1  mol / l is equal to 0.0113  mg / dl .
therefore , 133  mol / l is equal to 1.50  mg / dl .  
the probability of resolution of diarrhea within 10 days of treatment was slightly lower in patients with renal failure , compared with patients without renal failure ( hr , 0.83 ; 95% ci , .681.02 ; figure  1 ) .
neither fever ( hr , 1.08 ; 95% ci , .611.91 ) nor leukocytosis ( hr , 1.02 ; 95% ci , .841.24 ) was associated with a lower probability of resolution of diarrhea .
although creatinine level distributions were similar between patients treated with fidaxomicin and those treated with vancomycin , we repeated the analysis of renal failure as a predictor of resolution of diarrhea stratified according to treatment group and found similar results ( vancomycin : hr , 0.80 [ 95% ci , .611.05 ] ; fidaxomicin : hr , 0.88 [ 95% ci , .661.19 ] ) . because recurrences occurred less often in patients treated with fidaxomicin
figure  1.kaplan-meier analysis of time to resolution of diarrhea for patients with and without renal failure .
kaplan - meier analysis of time to resolution of diarrhea for patients with and without renal failure .
clinical treatment failure rates were similar in the fidaxomicin and vancomycin treatment groups regardless of clinical status , using the 3 severity factors .
recurrence was significantly more frequent following vancomycin treatment , compared with fidaxomicin treatment . in patients without renal failure , 93 of 402 patients ( 23.1% ) cured by vancomycin therapy
had a recurrence , whereas only 56 of 403 ( 13.9% ) experienced a recurrence after successful fidaxomicin treatment ( p  <  .001 ) . in patients with renal failure at baseline , fidaxomicin therapy
was associated with a 60% reduction in the frequency of recurrences ( 8 of 54 [ 14.8% ] ) relative to vancomycin ( 24 of 65 [ 36.9% ] ; p  =  .007 ) .
likewise , in patients categorized as having leukocytosis or severe cdi , the incidence of recurrence was more than double for patients cured with vancomycin , compared with those treated successfully with fidaxomicin ( p  <  .01 for each comparison ) . because leukocytosis and renal failure at the time of diagnosis were shown to be the strongest predictors , we investigated the stability of these parameters during a 6-day interval around diagnosis . in the population from the database of leeds teaching hospital , the highest mean leukocyte count ( 13.4    10
leukocytes / l ) was found on the day of cdi diagnosis . within the interval from 3 days before to
3 days after the diagnosis of cdi , the mean difference between the highest and lowest leukocyte counts was 6.4    10
> 10    10 leukocytes / l , and 33 ( 38.4% ) patients had a minimum to maximum leukocyte count range that included the cutoff of 15    10
leukocytes / l ; therefore , a difference in timing of a single blood sample around diagnosis could have led to a different severity classification .
the mean serum creatinine concentration was 147  mol / l on the day of diagnosis .
nineteen of 93 patients ( 20.4% ) had a minimum to maximum range in creatinine levels that included the cutoff of 133  mol / l , which could have led to a different classification in the case of different timing .
only renal failure showed a trend toward longer duration of diarrhea during treatment and was correlated significantly with recurrence after successful treatment .
fever was found to be too infrequent in our study to be a useful predictor , but its associated relative risk was significant . in previous studies , leukocytosis and renal failure were also associated with complications and recurrence of cdi [ 3 , 1113 ] .
however , because of the variable nature of these values around the time of cdi diagnosis , a strict definition is needed before incorporating these parameters in a prediction rule .
both fever and leukocytosis are thought to reflect more severe inflammation of the bowel wall . however , fever was too rare in our patient population to be of use as a predictor .
renal failure may reflect loss of effective circulating volume due either to dehydration because of diarrhea or to shock in the context of a systemic inflammatory response .
unfortunately , the predictive value of these parameters may decrease because of underlying illnesses and comorbid conditions .
renal failure was present in 14% of clinical patients and was the only significant predictor of recurrence , and it was the only parameter associated , albeit nonsignificantly , with a longer time to resolution of diarrhea .
thus , creatinine level may be a good predictor , also because of its relatively greater stability around the time of cdi diagnosis in comparison to leukocytosis .
strengths of this study are the large number of patients with cdi in the database with a well - described definition of diarrhea and a consistent measure of ubms .
one limitation is that other potential predictors of severe cdi , such as age , serum albumin level , or use of concomitant antibiotics , were not included in this analysis .
therefore , we were not able to develop a complete risk score . another limitation is the absence of a baseline creatinine level for each patient , precluding us from distinguishing between chronic and acute renal failure .
the results of our study suggest that both leukocytosis and renal failure predict clinical treatment failure , whereas only renal failure is a predictor of recurrence after therapy . however , these predictors are highly dependent on the timing of their determination , hampering their use in clinical practice .
we need better and more closely defined predictors to construct a reliable prediction score for complicated and recurrent cdi that is applicable in clinical practice .
 nonsevere clostridium difficile infection ( cdi ) and severe cdi , which carries a higher risk than nonsevere cdi for treatment failure and cdi recurrence , are difficult to distinguish at the time of diagnosis . to investigate the prognostic value of 3 markers of severe cdi suggested by recent guidelines ( fever , leukocytosis , and renal failure ) , we used the database of 2 randomized controlled trials , which contained information for 1105 patients with cdi . 
 leukocytosis ( risk ratio [ rr ] , 2.29 ; 95% confidence interval [ ci ] , 1.633.21 ) and renal failure ( rr , 2.52 ; 95% ci , 1.823.50 ) were associated with treatment failure . 
 fever , although associated with treatment failure ( rr , 2.45 ; 95% ci , 1.075.61 ) , was rare . 
 renal failure was the only significant predictor of recurrence ( rr , 1.45 ; 95% ci , 1.052.02 ) . 
 different timing of measurements of leukocyte count and serum creatinine level around the cdi diagnosis led to a different severity classification in many cases . in conclusion , both leukocytosis and renal failure are useful predictors , although timing of measurement is important . 
METHODS
Databases
Analyses
RESULTS
DISCUSSION