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					            Premier Safety Institute- Safety Share February 2008

                                 Disease Burden; Costs

1. Surg Infect (Larchmt). 2007 Dec;8(6):557-66.

The burden of Clostridium difficile in surgical patients in the United States.
Zerey M, Paton BL, Lincourt AE, Gersin KS, Kercher KW, Heniford BT.

Division of Gastrointestinal and Minimally Invasive Surgery, Carolinas Medical Center,
Charlotte, North Carolina 28203, USA.

Background: Clostridium difficile colitis is the predominant hospital-acquired gastrointestinal
infection in the United States and has emerged as an important nosocomial cause of morbidity
and death. Although several institutional studies have examined the effects of C. difficile on
hospitalized patients, its nationwide impact on surgical patients has yet to be defined.

Methods: To provide a national estimate of the burden of C. difficile, we performed a five-year
retrospective analysis of the Agency for Healthcare Research and Quality's National Inpatient
Sample Database, which represents a stratified 20% sample of hospitals in the United States,
from 1999 to 2003. All surgical inpatient discharge data from 997 hospitals in 37 states were
analyzed to determine the association of C. difficile infections with patient demographics,
hospital characteristics, surgical procedure, length of stay (LOS), total charges, and in-hospital
mortality rate. Univariate analysis was performed to identify any association between the
presence of C. difficile infection and the outcome variables using chi-square contingency table
analysis or the Student t-test following the exclusion of patients with other medical
complications. Multivariate regression analysis was used to determine whether the presence of C.
difficile infection was an independent predictor of increased LOS, total charges, and in-hospital
mortality rate when controlling for surgery type, age, sex, payor, and hospital characteristics.

Results: Clostridium difficile infection was reported as a discharge diagnosis for 8,113 (0.52%)
of all 1,553,597 inpatients who had undergone a general surgical procedure. The incidence
increased significantly in 2002 (34% higher than in 2001; p < 0.0001). The following patient and
hospital characteristics were associated with the highest incidence of C. difficile infection (all p
< 0.0001): Age > 64 years (0.95%); Medicare beneficiary status (0.94%); north-eastern hospital
location (0.73%); and large (0.55%), urban (0.56%), or teaching hospital (0.61%). Patients
undergoing an emergency operation were at higher risk than those having operations performed
electively (0.8% vs. 0.3%; p < 0.0001). Colectomy, small-bowel resection, and gastric resection
were associated with the highest risk of C. difficile infection (incidence after colectomy 1.11%;
odds ratio [OR] 2.77, 95% confidence interval [CI] 2.65, 2.89, p < 0.0001; small-bowel resection
1.17%, OR 2.40, 95% CI 2.26, 2.54, p < 0.0001; gastric resection 1.02%, OR 2.26, 95% CI 2.03,
2.52, p < 0.0001). Patients undergoing cholecystectomy and appendectomy had the lowest risk of
C. difficile infection (cholecystectomy 0.41%, OR 0.37, 95% CI 0.35, 0.39, p < 0.0001;

appendectomy 0.20%, OR 0.45, 95% CI 0.42, 0.49, p < 0.0001). Multivariable analysis
demonstrated that C. difficile was an independent predictor of LOS, which increased by 16.0
days (95% CI 15.6, 16.4 days; p < 0.0001) in the presence of infection. Total charges increased
by $77,483 (95% CI $75,174, $79,793; p < 0.0001), and there was a 3.4-fold increase in the
mortality rate (95% CI 3.02, 3.77; p < 0.0001) compared with patients who did not acquire C.
Conclusions: Epidemiologic data suggest that the incidence of C. difficile infection is increasing
in U.S. surgical patients and that the infection is most prevalent after emergency operations and
among patients having intestinal tract resections. Infection with C. difficile is an independent
predictor of increased LOS, total charges, and mortality rate after surgery and represents a
considerable burden to both patients and hospitals. Preventing C. difficile infection offers a
potentially significant improvement in patient outcomes, as well as a reduction in hospital costs
and resource expenditures.

2. Infect Control Hosp Epidemiol. 2007 Feb;28(2):123-30.

Epub 2007 Jan 26.

Clostridium difficile in the intensive care unit: epidemiology, costs, and
colonization pressure.
Lawrence SJ, Puzniak LA, Shadel BN, Gillespie KN, Kollef MH, Mundy LM.

Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO
63110, USA.

Objective: To evaluate the epidemiology, outcomes, and importance of Clostridium difficile
colonization pressure (CCP) as a risk factor for C. difficile-associated disease (CDAD)
acquisition in intensive care unit (ICU) patients.

Design: Secondary analysis of data from a 30-month retrospective cohort study.

Setting: A 19-bed medical ICU in a midwestern tertiary care referral center.

Patients: Consecutive sample of adult patients with a length of stay of 24 hours or more between
July 1, 1997, and December 31, 1999.

Results: Seventy-six (4%) of 1,872 patients were identified with CDAD; 40 (53%) acquired
CDAD in the ICU, for an incidence of 3.2 cases per 1,000 patient-days. Antimicrobial therapy,
enteral feeding, mechanical ventilation, vancomycin-resistant enterococci (VRE) colonization or
infection, and CCP (5.5 vs 2.0 CDAD case-days of exposure for patients with acquired CDAD vs
no CDAD; P=.001) were associated with CDAD acquisition in the univariate analysis. Only
VRE colonization or infection (45% of patients with acquired CDAD vs 16% of patients without
CDAD; adjusted odds ratio, 2.76 [95% confidence interval, 1.36-5.59]) and a CCP of more than
30 case-days of exposure (20% with acquired CDAD vs 2% with no CDAD; adjusted odds ratio,
3.77 [95% confidence interval, 1.14-12.49]) remained statistically significant in the multivariable

analysis. Lengths of stay (6.1 vs 3.0 days; P<.001 by univariate analysis) and ICU costs ($11,353
vs $6,028; P<.001 by univariate analysis) were higher for patients with any CDAD than for
patients with no CDAD.

Conclusions: In this nonoutbreak setting, the CCP was an independent risk factor for
acquisition of CDAD in the ICU at the upper range of exposure duration. Having CDAD in
the ICU was a marker of excess healthcare use.

 Transmission Risks: Hand Hygiene, Antibiotics, Surveillance, Onset

3. Infect Control Hosp Epidemiol. 2008 Mar;29(3):197-202.

Assessment of Clostridium difficile-Associated Disease Surveillance
Definitions, North Carolina, 2005 *
Kutty PK, Benoit SR, Woods CW, Sena AC, Naggie S, Frederick J, Engemann J, Evans S, Pien
BC, Banerjee SN, Engel J, McDonald LC.

From the Division of Healthcare Quality Promotion, National Center for Preparedness,
Detection, and Control of Infectious Diseases (P.K.K., S.R.B., S.N.B, L.C.M.), and the Epidemic
Intelligence Service, Division of Applied Public Health Training, Office of Workforce and
Career Development (P.K.K.), Centers for Disease Control and Prevention, Department of
Health and Human Services, Atlanta, Georgia; the Department of Veterans Affairs Medical
Center (C.W.W., S.N., J.F.), and the Duke University Medical Center, Division of Infectious
Diseases (C.W.W., S.N., J.E., S.E., B.C.P.), and the Durham County Health Department
(A.C.S.), Durham, and the Division of Infectious Diseases, University of North Carolina, Chapel
Hill (A.C.S.), and the North Carolina Department of Health and Human Services, Raleigh (J.E.),
North Carolina.

Objective. To determine the timing of community-onset Clostridium difficile-associated disease
(CDAD) relative to the patient's last healthcare facility discharge, the association of
postdischarge cases with healthcare facility-onset cases, and the influence of postdischarge cases
on overall rates and interhospital comparison of rates of CDAD.

Design Retrospective cohort study for the period January 1, 2005, through December 31, 2005.

Setting Catchment areas of 6 acute care hospitals in North Carolina.

Methods We reviewed medical and laboratory records to determine the date of symptom onset,
the dates of hospitalization, and stool C. difficile toxin assay results for patients with CDAD who
had diarrhea and positive toxin-assay results. Cases were classified as healthcare facility-onset if
they were diagnosed more than 48 hours after admission. Cases were defined as community-
onset if they were diagnosed in the community or within 48 hours after admission, and were also

classified on the basis of the time since the last discharge: if within 4 weeks, community-onset,
healthcare facility-associated (CO-HCFA); if 4-12 weeks, indeterminate exposure; and if more
than 12 weeks, community-associated. Pearson's correlation coefficient was used to assess the
association between monthly rates of healthcare facility-onset, healthcare facility-associated
(HO-HCFA) cases and CO-HCFA cases. We performed interhospital rate comparisons using
HO-HCFA cases only and using both HO-HCFA and CO-HCFA cases.

Results Of 1046 CDAD cases, 442 (42%) were HO-HCFA cases and 604 (58%) were
community-onset cases. Of the 604 community-onset cases, 94 (15%) were CO-HCFA, 40 (7%)
were of indeterminate exposure, and 208 (34%) community-associated. A modest correlation
was found between monthly rates of HO-HCFA cases and CO-HCFA cases across the 6
hospitals ([Formula: see text], [Formula: see text]). Interhospital rankings changed for 6 of 11
months if CO-HCFA cases were included.

Conclusions A substantial proportion of community-onset cases of CDAD occur less than 4
weeks after discharge from a healthcare facility, and inclusion of CO-HCFA cases
influences interhospital comparisons. Our findings support the use of a proposed definition of
healthcare facility-associated CDAD that includes cases that occur within 4 weeks after

4. Clin Infect Dis. 2008 Jan 15;46 Suppl 1:S19-31.

Antimicrobial-associated risk factors for Clostridium difficile infection.
Owens RC Jr, Donskey CJ, Gaynes RP, Loo VG, Muto CA.

Maine Medical Center, Portland, ME 04102, USA.

Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection
(CDI), presumably through disruption of indigenous intestinal microflora, thereby allowing C.
difficile to grow and produce toxin. Investigations involving animal models and studies
performed in vitro suggest that inhibitory activity against C. difficile and differences in the
propensity to stimulate toxin production may also influence the likelihood that particular drugs
may cause CDI. Although nearly all antimicrobial classes have been associated with CDI,
clindamycin, third-generation cephalosporins, and penicillins have traditionally been considered
to harbor the greatest risk. Recent studies have also implicated fluoroquinolones as high-risk
agents, a finding that is most likely to be related in part to increasing fluoroquinolone resistance
among epidemic strains (i.e., restriction-endonuclease analysis group BI/North American PFGE
type 1 strains) and some nonepidemic strains of C. difficile. Restrictions in the use of
clindamycin and third-generation cephalosporins have been associated with reductions in CDI.
Because use of any antimicrobial has the potential to induce the onset of CDI and disease
caused by other health care-associated pathogens, antimicrobial stewardship programs
that promote judicious use of antimicrobials are encouraged in concert with environmental
and infection control-related efforts.

5. Clin Infect Dis. 2008 Jan 15;46 Suppl 1:S43-9.

Measures to control and prevent Clostridium difficile infection.
Gerding DN, Muto CA, Owens RC Jr.

Hines Veterans Affairs Hospital, Hines, IL 60141, USA.

Control of Clostridium difficile infection (CDI) outbreaks in health care facilities presents
significant challenges to infection control specialists and other health care workers. C. difficile
spores survive routine environmental cleaning with detergents and hand hygiene with alcohol-
based gels. Enhanced cleaning of all potentially contaminated surfaces with 10% sodium
hypochlorite reduces the environmental burden of C. difficile, and use of barrier precautions
reduces C. difficile transmission. Thorough handwashing with chlorhexidine or with soap and
water has been shown to be effective in removing C. difficile spores from hands. Achieving
high-level compliance with these measures is a major challenge for infection control programs.
Good antimicrobial stewardship complements infection control efforts and environmental
interventions to provide a comprehensive strategy to prevent and control outbreaks of CDI.
The efficacy of metronidazole or vancomycin prophylaxis to prevent CDI in patients who
are receiving other antimicrobials is unproven, and treatment with these agents is
ineffective against C. difficile in asymptomatic carriers.

6. Clin Infect Dis. 2007 Nov 1;45(9):1141-51. Epub 2007 Sep 26.

Fluoroquinolone use and risk factors for Clostridium difficile-associated
disease within a Veterans Administration health care system.
McFarland LV, Clarridge JE, Beneda HW, Raugi GJ.

Department of Health Services Research and Development, Veterans Administration Puget
Sound Health Care System, Seattle, WA 98101, USA.

Background: Prompted by the changing profile of Clostridium difficile infection and the impact
of formulary policies in hospitals, we performed this study when an increase in the incidence of
C. difficile-associated disease was noted at our health care center (Veterans Administration
Puget Sound Health Care System, Seattle, Washington).

Methods: A retrospective, matched case-control study of patients presenting to the Veterans
Administration Puget Sound Health Care System, Seattle, Washington during 2004 was
performed. Conditional logistic analysis determined risk factors for case patients, defined as
individuals with diarrhea and test results (i.e., culture or toxin assay results) positive for C.
difficile, and control subjects, defined as individuals with diarrhea and test results negative for C.

Results: C. difficile-associated disease incidence was 29.2 cases per 10,000 inpatient-days. The
increase in the incidence of C. difficile-associated diarrhea that paralleled increased gatifloxacin

use was not attributable to use of the antimicrobial but was a reflection of seasonal variation in
the rate of C. difficile-associated disease. Multivariate analysis controlling for the time at which
the assay was performed, the age of the patient, ward, and source of acquisition (community-
acquired vs. nosocomial disease) found 6 significant risk factors for C. difficile-associated
diarrhea: receipt of clindamycin (adjusted odds ratio [aOR], 29.9; 95% confidence interval [CI],
3.58-249.4), receipt of penicillin (aOR, 4.1; 95% CI, 1.2-13.9), having a lower intestinal
condition (aOR, 2.8; 95% CI, 1.3-6.1), total number of antibiotics received (aOR, 1.4; 95% CI,
1.1-1.7), number of prior hospital admissions (aOR, 1.3; 95% CI, 1.1-1.6), and number of
comorbid conditions (aOR, 1.3; 95% CI, 1.1-1.5).

Conclusions: The increase in the number of cases of C. difficile-associated disease was not
attributable to a formulary change of fluoroquinolones; instead, the incidence was within
expected seasonal variations for C. difficile-associated disease. Recognition of community-
acquired cases and the use of culture may help to identify additional cases of C. difficile-
associated disease. Early diagnosis and treatment of C. difficile cases may shorten the duration of
hospital stays and reduce the number of outbreaks and readmissions, mortality, and other
consequences of C. difficile infection.

7. Infect Control Hosp Epidemiol. 2007 Aug;28(8):926-31.
Epub 2007 Jun 14.

Onset of symptoms and time to diagnosis of Clostridium difficile-associated
disease following discharge from an acute care hospital.

Chang HT, Krezolek D, Johnson S, Parada JP, Evans CT, Gerding DN.

Department of Veterans Affairs, Midwest Center for Health Services and Policy Research and
Research Service, Edward Hines Jr. Veterans Affairs Hospital, Hines, IL 60141, USA.

Objective: To identify patients with a diagnosis of Clostridium difficile-associated disease
(CDAD) in the ambulatory care setting and determine the relationship of symptom onset and
diagnosis to prior hospitalization and exposure to antimicrobials. DESIGN: Single-center,
retrospective study.

Methods: Medical records were reviewed for outpatients and hospitalized patients with a stool
assay positive for C. difficile toxin A from January 1998 through March 2005. Patients with
recurrent CDAD or residing in an extended-care facility were excluded. CDAD in patients who
had been hospitalized in the 100 days prior to diagnosis was considered potentially hospital-

Results: Of the 84 patients who met the inclusion criteria, 75 (89%) received a diagnosis 1-60
days after hospital discharge (median, 12 days), and 71 (85%) received a diagnosis within 30
days after discharge. Of the 69 patients whose records contained information regarding time of
symptom onset, 62 (90%) developed diarrhea within 30 days of a previous hospital discharge,
including 7 patients with symptom onset prior to discharge and 9 with onset on the day of
discharge. The median time from symptom onset to diagnosis was 6 days. Of 84 patients, 77

(92%) had received antimicrobials during a prior hospitalization, but 55 (65%) received
antimicrobials both as inpatients and as outpatients.

Conclusion: If all cases of CDAD diagnosed within 100 days of hospital discharge were
assumed to be hospital-associated, 71 (85%) of 84 patients with CDAD were identified within 30
days, and 75 (89%) of 84 were identified by day 60. Continued outpatient antimicrobial
exposure confounds determination of whether late-onset cases are community- or hospital-

8. Infect Control Hosp Epidemiol. 2007 Apr;28(4):377-81.
Epub 2007 Mar 9.

Predicting Clostridium difficile toxin in hospitalized patients with antibiotic-
associated diarrhea.

Peled N, Pitlik S, Samra Z, Kazakov A, Bloch Y, Bishara J.

Institute of Pulmonology, Rabin Medical Center, Beilinson Hospital, Israel.

Objective: Clostridium difficile infection is implicated in 20%-30% of cases of antibiotic-
associated diarrhea. Studying hospitalized patients who received antibiotic therapy and
developed diarrhea, our objective was to compare the clinical characteristics of patients who
developed C. difficile-associated diarrhea (CDAD) with those of patients with a negative result
of a stool assay for C. difficile toxin.

Methods: A prospective study was done with a cohort of 217 hospitalized patients who had
received antibiotics and developed diarrhea. Patients with CDAD were defined as patients who
had diarrhea and a positive result for C. difficile toxin A/B by an enzyme immunoassay of stool.
The variables that yielded a significant difference on univariate analysis between patients with a
positive assay result and patients with a negative assay result were entered into a logistic
regression model for prediction of C. difficile toxin.Setting. A 900-bed tertiary care medical

Results: Of 217 patients, 52 (24%) had a positive result of assay for C. difficile toxin A/B in
their stool. The logistic regression model included impaired functional capacity, watery diarrhea,
use of a proton pump inhibitor, use of a histamine receptor blocker, leukocytosis, and
hypoalbuminemia. The area under the receiver operating characteristic curve for the model as a
predictor of a positive result for the stool toxin assay was 0.896 (95% confidence interval, 0.661-
1.000; P<.001), with 95% specificity and 68% sensitivity.

Conclusions: Our results may help clinicians to predict the risk of CDAD in hospitalized
patients with antibiotic-associated diarrhea, to guide careful, specific empirical therapy,
and to direct early attention to infection control issues.

9. Ann Thorac Surg. 2007 Apr;83(4):1396-402.

Clostridium difficile in cardiac surgery: risk factors and impact on
postoperative outcome.
Crabtree T, Aitchison D, Meyers BF, Tymkew H, Smith JR, Guthrie TJ, Munfakh N, Moon MR,
Pasque MK, Lawton J, Moazami N, Damiano RJ Jr.

Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis,
Missouri 63110, USA.

Background: Clostridium difficile-associated diarrhea (CDAD) is a potentially preventable and
often troublesome gastrointestinal complication after cardiac surgery.

Methods: A retrospective study was performed of 8,405 cardiac surgery patients at two
institutions between January 1997 and August 2004. Preoperative cardiac risk factors,
perioperative factors including blood product transfusion, antibiotic utilization, and postoperative
morbidity and mortality were recorded. Univariate and multivariate analyses were performed
comparing C. difficile patients with a control group matched by date of surgery and institution.

Results: Sixty-six of the 8,405 patients identified with toxin-positive CDAD produced an overall
incidence of 0.79% (0.70% at institution A and 1.09% at institution B), with a peak overall
incidence of 5.45% in June 2003. Independent prognostic factors for CDAD by multivariate
analysis included advancing age (odds ratio [OR] 1.028, 95% confidence interval [CI]: 1.001 to
1.056; p = 0.034), female sex (OR 2.026, 95% CI: 1.102 to 3.722; p = 0.022), blood product
transfusion (OR 3.277, 95% CI: 1.292 to 8.311; p = 0.006), and increasing cumulative days of
antibiotic administration (OR 1.046, 95% CI: 1.014 to 1.080; p = 0.004). There were no
differences in the proportion of fluoroquinolones, cephalosporins, or penicillin derivatives
administered between groups. The diagnosis of CDAD was associated with a greater median
length of mechanical ventilation (25 hours versus 12 hours, p < 0.001), longer intensive care unit
stay (5 days versus 2 days, p < 0.001), and extended hospital stay (21 days versus 7 days, p <
0.001), with no difference in 30-day mortality (7.6% versus 9.5%, p = 0.80).

Conclusions: Although the overall incidence of CDAD was low, alteration in transfusion
practices and antibiotic utilization may impact the development of CDAD among cardiac
surgical patients.