Multihospital Outbreak of Clostridium difficile Infection, Cleveland, Ohio, USA

To determine whether a multihospital Clostridium difficile outbreak was associated with epidemic strains and whether use of particular fluoroquinolones was associated with increased infection rates, we cultured feces from C. difficile–infected patients. Use of fluoroquionolones with enhanced antianaerobic activity was not associated with increased infection rates.

To determine whether a multihospital Clostridium diffi cile outbreak was associated with epidemic strains and whether use of particular fl uoroquinolones was associated with increased infection rates, we cultured feces from C. diffi cile-infected patients. Use of fl uoroquionolones with enhanced antianaerobic activity was not associated with increased infection rates.
Beginning in 2002, outbreaks of C. diffi cile infection occurred in several hospitals in the Cleveland, Ohio, USA, area. In response, the Ohio Department of Health (ODH) made C. diffi cile infection a reportable disease in 2006. One objective of the current study was to examine the magnitude of the outbreaks in Cuyahoga County, which comprises Cleveland and the surrounding area, and to determine whether the outbreaks were associated with epidemic BI/ NAP1strains. A second objective was to examine whether use of gatifl oxacin and/or moxifl oxacin was associated with increased rates of C. diffi cile infection in healthcare facilities and to assess whether outbreaks correlated with formulary changes in fl uoroquinolones.

The Study
We used the ODH website (www.odh.state.oh.us) to obtain rates (cases/10,000 patient-days) of initial C. diffi cile infections during January-December 2006 for the 22 hospitals in Cuyahoga County. All healthcare facilities in Ohio were required to submit C. diffi cile infection rates by using a standardized method of reporting. An initial case was defi ned as a fi rst positive laboratory diagnostic test for C. diffi cile, pseudomembranes on endoscopy, or confi rmatory histologic features from surgical or autopsy specimen. An infection that occurred >6 months after a previous infection was classifi ed as an initial infection.
For a subset of 5 hospitals, up to 20 consecutive stool samples from individual patients with C. diffi cile infection were cultured for C. diffi cile (11). C. diffi cile isolates were tested for in vitro cytotoxin production and moxifl oxacin susceptibility and analyzed for binary toxin gene cdtB and partial deletions of the tcdC gene (11)(12)(13). Molecular typing was performed by using PCR ribotyping (11). The 5 hospitals were 1 community hospital, 3 tertiary care facilities, and 1 Veterans Affairs hospital. Three of the hospitals had experienced large outbreaks of C. diffi cile infection in 2002-2003 (i.e., their C. diffi cile incidence doubled and their peak incidence was >20 cases per 1,000 discharges); the other 2 reported an increase in the proportion of cases that were fulminant. The infection control departments of each institution provided information about C. diffi cile infection rates, fl uoroquinolones on formulary, and infection control measures for C. diffi cile during January 2000-December 2006.
Rates of C. diffi cile infection for 2006 were compared among hospitals with moxifl oxacin or gatifl oxacin versus those with levofl oxacin on formulary as primarily fl uoroquinolones used to treat respiratory infections. In addition, for 2 hospitals in the molecular typing analysis that had a formulary change from 1 respiratory fl uoroquinolone to another, we used Poisson analysis to compare rates of C. diffi cile infection during the 12 months before and after the formulary change, with a lag of 1 month after the change. We analyzed data using SPSS statistical software A total of 64 toxigenic C. diffi cile isolates were cultured from feces samples obtained from 5 hospitals. Features of 42 (66%) isolates were consistent with epidemic BI/NAP1 strains (range 55%-83% for each facility), including amplifi cation of the binary toxin gene cdtB and partial deletions in tcdC and resistance to moxifl oxacin (MICs >32 μg/mL). By PCR ribotyping, we observed a characteristic banding pattern for isolates with features of the epidemic strain; 6 isolates with this banding pattern were confi rmed as BI strains in the laboratory of D.G.
Of the 22 facilities, 8 used moxifl oxacin as the primary respiratory fl uoroquinolone, 13 used levofl oxacin, and 1 did not have a respiratory fl uoroquinolone on formulary. The C. diffi cile infection rate did not differ between facilities with levofl oxacin (8.5 cases/10,000 patient-days, 95% confi dence interval [CI] 7.8-9.3) and moxifl oxacin (8.5 cases/10,000 patient-days, 95% CI 7.8-9.2) on formulary (p = 1) (Table). The facility that did not have a respiratory fl uoroquinolone on formulary had a lower rate of C. diffi cile infection than the median rates for facilities that used levofl oxacin or moxifl oxacin. However, 8 facilities had lower C. diffi cile infection rates than did this institution.
Two of the 5 hospitals in the molecular typing analysis changed their formulary fl uoroquinolones during the study period (Figure). Both hospitals made formulary changes from levofl oxacin to gatifl oxacin; however, the increase in C. diffi cile infection rates preceded the formulary change in each hospital. C. diffi cile infection rates did not differ signifi cantly in the 12 months before and after the change from levofl oxacin to gatifl oxacin (relative risk [RR] 1.0, 95% CI 0.97-0.86; p = 0.973). For hospital 2 ( Figure, panel B), a subsequent formulary change from gatifl oxacin to levofl oxacin was associated with a reduction in C. diffi cile infection (RR 0.59, 95% CI 0.51-0.70; p<0.001); an intervention to improve environmental cleaning with a 10% bleach solution occurred at the time of the formulary change.

Conclusions
Our fi ndings provide further evidence that emergence of epidemic NAP1/BI strains in a geographic region may be associated with large multihospital outbreaks of C. diffi cile infection. Before the ODH decision to require mandatory reporting, many area hospitals were either not collecting surveillance data about C. diffi cile infection or were reluctant to share their rates. Therefore, we believe that mandatory public reporting of C. diffi cile infection rates provided a valuable tool to examine the full magnitude of the outbreaks and an incentive for hospitals with high rates to increase efforts to control infection. One area hospital recently reported that the ODH database underestimated the incidence of C. diffi cile infection (14), but this observation does not affect our conclusions because all facilities used the same surveillance defi nitions. Our fi ndings do not support the hypothesis that use of moxifl oxacin or gatifl oxacin is associated with higher rates of C. diffi cile infection than is use of levofl oxacin or ciprofl oxacin.
Our analysis of formulary fl uoroquinolones and C. diffi cile infection has several limitations. First, data on the amount of the fl uoroquinolones used in the hospitals were not available. Second, analysis of hospital formularies does not account for the effects of fl uoroquinolones used in longterm care facilities and among outpatients. Third, we did not assess confounding factors, such as use of other classes