the methods of the original study from which these data were acquired have been previously published ( 10 ) .
briefly , 50 nursing homes with > 100 beds in four provinces ( ontario , manitoba , alberta , saskatchewan ) and four states ( minnesota , michigan , north dakota , montana ) were enrolled in the study . during a 12-month period , residents treated with systemic antimicrobial drugs were identified , and antimicrobial prescriptions were recorded , including name , dose , and duration .
infection control practitioners from each facility recorded the name and antimicrobial - susceptibility patterns of all clinical bacterial cultures obtained from study residents .
susceptibility testing was performed by using methods recommended by the national committee for clinical laboratory standards ( nccls ) .
complete information on all clinical bacterial cultures sent for testing from each home was obtained .
these clinical isolates were obtained for diagnostic purposes among residents in the nursing homes . to minimize biased sampling ,
none of the homes at the time of study collected bacterial specimens from residents for surveillance purposes only .
a survey was performed before the study to ensure that laboratories adhered to nccls methods .
infection control practitioners from each facility recorded the name and antimicrobial - susceptibility patterns of all clinical bacterial cultures obtained from study residents .
data recorded for each nursing home included the following : number of resident beds ; staffing levels ( registered and nonregistered nursing staff hours , healthcare aide hours , infection control practitioner hours , physicians hours , and access to an infectious disease specialist ) ; infrastructure for hygiene facilities ( number of showers and tubs per facility and sinks per 100 resident beds ) ; percentage of residents with intravenous catheters , urinary catheters , and gastrostomy tubes ; percentage of residents that were either wheelchair or bed bound ; and information on recent acute - care stay ( new admissions and returns ) .
the study population was drawn from the fixed cohort of nursing home residents used in the original study . only those residents with clinical isolates of enterobacteriaceae resistant or susceptible to third - generation cephalosporins were eligible to be case - residents and controls in this analysis .
case - residents were defined as nursing home residents in whom a clinical enterobacteriaceae isolate resistant to third - generation cephalosporins was detected . for each case - resident
, we randomly selected three control - residents from those residents in whom clinical isolates of enterobacteriaceae sensitive to third - generation cephalosporins were obtained .
since repeat isolates may not represent independent events , we assessed only the first clinical isolate obtained from each resident ( case - residents and control - residents ) .
data were collected at the individual - resident level regarding prior antimicrobial drug use and antimicrobial drug resistance and susceptibility of bacterial isolates .
total antimicrobial drug use , use of any cephalosporins , use of third - generation cephalosporins , use of fluoroquinolone , and use of trimethoprim - sulfamethoxazole were recorded .
covariates were defined as those variables collected at the level of the nursing home , including staffing and patient and facility characteristics .
we sought to compare antimicrobial drug exposures in nursing home residents from whom enterobacteriaceae resistant to third - generation cephalosporins were isolated to antimicrobial drug exposures in nursing home residents from whom susceptible enterobacteriaceae cultures were obtained .
antimicrobial drug exposure was measured in the 10 weeks before resistant bacteria were detected in residents and was compared to antimicrobial drug exposure during a 10-week interval in residents with susceptible organisms . in the absence of any evidence defining an optimal period for assessment of antimicrobial drug exposures ,
10 weeks was selected by consensus opinion of five infectious disease specialists with research expertise in the field of antimicrobial drug resistance .
this strategy was used because all microbial variables , despite log transformation , were highly skewed .
odds ratios were calculated , representing the risk of nursing home residents having antimicrobial drug  resistant clinical isolates compared to antimicrobial drug  susceptible organisms . to assess for the possible effect of clustering for facility - level variables ,
univariate analyses were also performed with logistic regression with random factors ( logistic - binomial model ) ( egret 2.031 , cytel software corp . , cambridge , ma ) and compared with a logistic regression model in which the factors are fixed ( spss 10.0 , spss inc . , chicago , il ) .
a multivariable model was constructed in which variables with a p value < 0.25 and variables representing the various antimicrobial drugs were selected for inclusion , and the final multivariable model was constructed by using a backwards , stepwise approach . all data entry was performed with sas version 6.0 and 7.0 ( sas institute , cary , nc ) .
the hosmer and lemeshow test was performed to evaluate the overall fit of the model ( 11 ) .
the methods of the original study from which these data were acquired have been previously published ( 10 ) .
briefly , 50 nursing homes with > 100 beds in four provinces ( ontario , manitoba , alberta , saskatchewan ) and four states ( minnesota , michigan , north dakota , montana ) were enrolled in the study . during a 12-month period , residents treated with systemic antimicrobial drugs were identified , and antimicrobial prescriptions were recorded , including name , dose , and duration .
infection control practitioners from each facility recorded the name and antimicrobial - susceptibility patterns of all clinical bacterial cultures obtained from study residents .
susceptibility testing was performed by using methods recommended by the national committee for clinical laboratory standards ( nccls ) .
complete information on all clinical bacterial cultures sent for testing from each home was obtained .
these clinical isolates were obtained for diagnostic purposes among residents in the nursing homes . to minimize biased sampling ,
none of the homes at the time of study collected bacterial specimens from residents for surveillance purposes only .
a survey was performed before the study to ensure that laboratories adhered to nccls methods .
infection control practitioners from each facility recorded the name and antimicrobial - susceptibility patterns of all clinical bacterial cultures obtained from study residents .
data recorded for each nursing home included the following : number of resident beds ; staffing levels ( registered and nonregistered nursing staff hours , healthcare aide hours , infection control practitioner hours , physicians hours , and access to an infectious disease specialist ) ; infrastructure for hygiene facilities ( number of showers and tubs per facility and sinks per 100 resident beds ) ; percentage of residents with intravenous catheters , urinary catheters , and gastrostomy tubes ; percentage of residents that were either wheelchair or bed bound ; and information on recent acute - care stay ( new admissions and returns ) .
the study population was drawn from the fixed cohort of nursing home residents used in the original study . only those residents with clinical isolates of enterobacteriaceae resistant or susceptible to third - generation cephalosporins were eligible to be case - residents and controls in this analysis .
case - residents were defined as nursing home residents in whom a clinical enterobacteriaceae isolate resistant to third - generation cephalosporins was detected . for each case - resident
, we randomly selected three control - residents from those residents in whom clinical isolates of enterobacteriaceae sensitive to third - generation cephalosporins were obtained .
since repeat isolates may not represent independent events , we assessed only the first clinical isolate obtained from each resident ( case - residents and control - residents ) .
data were collected at the individual - resident level regarding prior antimicrobial drug use and antimicrobial drug resistance and susceptibility of bacterial isolates .
total antimicrobial drug use , use of any cephalosporins , use of third - generation cephalosporins , use of fluoroquinolone , and use of trimethoprim - sulfamethoxazole were recorded .
covariates were defined as those variables collected at the level of the nursing home , including staffing and patient and facility characteristics .
we sought to compare antimicrobial drug exposures in nursing home residents from whom enterobacteriaceae resistant to third - generation cephalosporins were isolated to antimicrobial drug exposures in nursing home residents from whom susceptible enterobacteriaceae cultures were obtained .
antimicrobial drug exposure was measured in the 10 weeks before resistant bacteria were detected in residents and was compared to antimicrobial drug exposure during a 10-week interval in residents with susceptible organisms . in the absence of any evidence defining an optimal period for assessment of antimicrobial drug exposures ,
10 weeks was selected by consensus opinion of five infectious disease specialists with research expertise in the field of antimicrobial drug resistance .
this strategy was used because all microbial variables , despite log transformation , were highly skewed .
odds ratios were calculated , representing the risk of nursing home residents having antimicrobial drug  resistant clinical isolates compared to antimicrobial drug  susceptible organisms . to assess for the possible effect of clustering for facility - level variables ,
univariate analyses were also performed with logistic regression with random factors ( logistic - binomial model ) ( egret 2.031 , cytel software corp . , cambridge , ma ) and compared with a logistic regression model in which the factors are fixed ( spss 10.0 , spss inc .
a multivariable model was constructed in which variables with a p value < 0.25 and variables representing the various antimicrobial drugs were selected for inclusion , and the final multivariable model was constructed by using a backwards , stepwise approach . all data entry was performed with sas version 6.0 and 7.0 ( sas institute , cary , nc ) .
the hosmer and lemeshow test was performed to evaluate the overall fit of the model ( 11 ) .
twenty - nine case - residents were identified , and 87 control - residents were initially selected from 26 nursing homes . because of organizational changes in one nursing home during the course of the study , no covariate data could be obtained . since
such group - level data could not be imputed , all participants selected from this particular home were dropped from the analysis .
this included two case - residents and two control - residents . ignoring the missing group - level variables and including these residents in the analysis on the basis of their individual - level variables made no difference in the estimates
the distribution of types of enterobacteriaceae among case - residents and control - residents is shown in table 1
. a greater proportion of citrobacter and enterobacter species were identified in samples from case - residents compared to samples from control - residents ( p = 0.01 for each ) , and a greater proportion of e. coli isolates were identified in samples from control - residents compared to samples from case - residents ( p = 0.01 ) .
most clinical specimens were isolated from urine samples , and a greater proportion of urine isolates were detected in specimens from control - residents as compared to case - residents ( p = 0.05 ) ( table 2 ) .
univariate analyses of individual - level exposures and facility - level exposures are shown in tables 3 and 4 .
the following variables were considered in the multivariable model : prior exposure to any antimicrobial drug , to a cephalosporin , to a third - generation cephalosporin , to a fluoroquinolone , or to trimethoprim - sulfamethoxazole ; the log number of primary care physician hours per 100 resident beds ; whether an infectious disease physician was on staff ; the number of new admissions from acute care hospitals within the last year per 100 resident beds ; and the log percentage of residents in the nursing home with a gastrostomy tube .
10 weeks before date of confirmed enterobacteriaceae infection .  or , odds ratio ; ci , confidence interval . or , odds ratio ; ci , confidence interval ; fte , full - time equivalent ; rn , registered nurse ; na , nursing aide ; icp , infection control practitioner .
the only variables that remained significant after multivariable modeling were prior use of any cephalosporin ( odds ratio [ or ] 4.0 , 95% confidence interval [ ci ] 1.2 to 13.6 , p = 0.029 ) , and log percentage of residents with a gastrostomy tube ( or 3.9 , 95% ci 1.3 to 12.0 , p = 0.016 ) .
the p value obtained for the hosmer and lemeshow test was 0.138 , which suggests that the overall fit of this model is reasonable .
enterobacteriaceae infections resistant to cephalosporins are of concern in long - term care facilities and in the acute - care setting ( 19 ) .
patients with infections resistant to third - generation cephalosporins have been reported to have had longer hospital stays , higher death rates , and greater hospital costs than patients whose infections are susceptible to third - generation cephalosporins ( 4 ) .
a survey of infection control practitioners in ontario showed that no standard approach exists to dealing with esbl - producing e. coli and klebsiella spp . in long - term - care facilities
reservoirs of resistant enterobacteriaceae species will continue to emerge in this setting despite implementation of control measures .
our findings show that recent exposure to any cephalosporin is associated with the isolation of third - generation cephalosporin
few studies have assessed risk factors for enterobacteriaceae resistance to cephalosporins in long - term - care facilities .
weiner et al . described an outbreak of ceftazidime - resistant e. coli infections in chicago nursing homes ( 2 ) .
those researchers conducted a case - control study and found that ciprofloxacin or trimethoprim - sulfamethoxazole exposure was associated with ceftazidime - resistant e. coli in nursing home residents .
cephalosporin treatment may have been given after fluoroquinolone resistance was detected , and this treatment may be linked to cephalosporin resistance found in their study .
muder et al . evaluated modifiable risk factors for antimicrobial drug  resistant enterobacteriaceae infection among patients from a long - term veterans affairs facility in pittsburgh ( 13 ) . in this case - control study ,
patient debility , age , coexisting conditions , and prior antimicrobial therapy were examined as risk factors associated with multidrug - resistant enterobacteriaceae infections .
case - patients were identified as having an enterobacteriaceae infection resistant to two of the following groups of antimicrobial drugs : piperacillin , third - generation cephalosporins , or gentamicin .
only a pressure ulcer [ or 12.2 , 95% ci 3.3 to 44.2 ] and prior ampicillin therapy [ or 13.7 , 95% ci 2.2 to 84.0 ] were associated with resistant enterobacteriaceae infection .
no association was found between prior cephalosporin therapy and a multiple - resistant infection , but whether prior cephalosporin therapy and the acquisition of cephalosporin - resistant infections are linked is unknown . a similar study performed previously by this group identified exposure to ciprofloxacin as a risk factor for the acquisition of ciprofloxacin - resistant gram - negative bacteria ( 14 ) .
our findings confirm that patient debility and prior antimicrobial drug therapy are associated with acquisition of resistant bacteria . in the acute - care setting , similar risk factors for the acquisition of broad - spectrum cephalosporin - resistant enterobacteriaceae have been recognized ( 1519 ) .
the risk of acquiring multidrug - resistant bacterial infection has been reported as increasing in hospitalized patients with prior third - generation cephalosporin therapy ( 6,18,19 ) . a hospital - based case - control study performed in argentina examined risk factors for ceftazidime - resistant k. pneumoniae .
prior antimicrobial drug use was associated with acquisition of this type of resistant infection [ adjusted or 6.21 , 95% ci 1.20 to 32.01 ] .
other risk factors found were prior use of ciprofloxacin , nosocomial infection , and hospitalization stay > 6 days ( 15 ) .
bisson et al . also looked at risk factors for acquisition of esbl - producing klebsiella spp . and
e. coli in which patients with this resistance pattern were compared to patients with no culture exhibiting this resistance pattern ( 16 ) .
prior receipt of antimicrobial therapy was not associated with colonization in these patients , but none were exposed to third - generation cephalosporins . since our study was set in long - term - care facilities and because individual measurements were not done , length of stay was not assessed .
lin et al . performed a case - control study evaluating risk factors for esbl  producing k. pneumoniae among hospital patients in taiwan ( 17 ) .
prior use of ceftazidime was found to be associated with esbl - producing k. pneumoniae infection compared to non - esbl - producing k. pneumoniae infection . a case - control study by bonomo et al . did not find an association between fecal colonization of cefotaxime - resistant gram - negative bacilli and antimicrobial drug use 4 weeks before admission to the hospital ( 20 ) .
comparison of antimicrobial drug - sensitive organisms to antimicrobial drug - resistant organisms can not infer absolute risk for exposure to that antimicrobial drug ( 21,22 ) .
however , lipsitch has discussed several advantages of calculating conditional or ( orc ) versus simple or ( ors ) when interpreting associations between antimicrobial drug use and resistant organisms ( 23 ) .
ors determines a patient s individual risk of acquiring a resistant infection after receiving treatment compared to not getting an infection after receiving treatment .
orc determines the risk of a resistant infection compared to the risk of a nonresistant infection , which allows for insight into whether a suspect infection in a patient is more likely to be resistant to a particular antimicrobial drug compared to someone who has not been treated ( 23 ) .
widespread treatment with antimicrobial drugs promotes the eradication of antimicrobial - susceptible organisms but also confers a selective advantage for developing antimicrobial - resistant organisms .
measuring orc may even be more useful for clinicians than knowing the absolute risk because it gives information about the community - level risk of having a resistant organism compared to a susceptible organism in persons with a particular recent antimicrobial drug history ( 23 ) .
making this comparison is useful for clinicians who are evaluating the odds of a patient s being infected with a resistant organism .
in addition to antimicrobial drug exposure , the percentage of residents with gastrostomy tubes in the home was also found to predict enterobacteriaceae infection resistant to third - generation cephalosporins . in this analysis ,
percentage of gastrostomy tubes among home residents served as a proxy for generalized debility within each nursing home , and our findings suggest that more debilitated patients may be more predisposed to acquiring resistant organisms .
debilitated patients are most likely to harbor resistant organisms ( 24 ) . since we do not know the strain of resistant bacteria applicable to each patient
, we can not infer with certainty that a gastrostomy tube in a nursing home resident is a risk factor for this type of resistant infection . however , weiner et al .
identified gastrostomy tube use at the patient - level as a risk factor for acquiring resistant enterobacteriaceae ( 2 ) .
infections directly associated with gastrostomy tube contamination , resulting in antimicrobial treatment or hospitalization ( 25,26 ) , have also been reported , . however , since gastrostomy tube sites were not systematically tested in this study , this finding can not be inferred .
strengths of this study are that residents were drawn from a large number of nursing homes in both canada and the united states , exposures at both the individual and aggregate levels were examined , and a wide range of variables were considered , including staffing and infrastructure for hand hygiene .
our study has some limitations , including the following : the date of actual acquisition of resistant bacteria is not known ; we only examined clinical isolates , obtained for diagnostic purposes , which may have led to a sampling bias ; and individual level coexisting conditions were not measured .
given the large size of the original study , measuring coexisting conditions was not feasible .
another limitation is that facilities with higher levels of resistant bacteria among residents may obtain more clinical specimens ( or vice versa ) , which may have led to bias in the sample used .
cross - infection within a facility could not be assessed because of lack of molecular typing of isolates .
admissions and readmissions to acute - care facilities within the last year were not identified as risk factors for infection with enterobacteriaceae resistant to third - generation cephalosporins .
the 12-month period may have been too long , but a significant association may have been identified with a 3-month period . in conclusion ,
prior exposure to cephalosporins and an increased use of gastrostomy tubes among nursing home residents predicts for infection with enterobacteriaceae resistance to third - generation cephalosporins .
 limited data identify the risk factors for infection with enterobacteriaceae resistant to third - generation cephalosporins among residents of long - term - care facilities . using a nested case - control study design , nursing home residents with clinical isolates of enterobacteriaceae resistant to third - generation cephalosporins 
 were compared to residents with isolates of enterobacteriaceae susceptible to third - generation cephalosporins . 
 data were collected on antimicrobial drug exposure 10 weeks before detection of the isolates , facility - level demographics , hygiene facilities , and staffing levels . 
 logistic regression models were built to adjust for confounding variables . 
 twenty - seven case - residents were identified and compared to 85 controls . 
 exposure to any cephalosporin ( adjusted odds ratio [ or ] 4.0 , 95% confidence interval [ ci ] 1.2 to13.6 ) and log percentage of residents using gastrostomy tubes within the nursing home ( adjusted or 3.9 , 95% ci 1.3 to 12.0 ) were associated with having a clinical isolate resistant to third - generation cephalosporins . 
Materials and Methods
Study Design
Case Definition
Statistical Analysis
Results
Discussion