Advertisement

A multi-institutional cohort study confirming the risks of Clostridium difficile infection associated with prolonged antibiotic prophylaxis

Open ArchivePublished:September 26, 2017DOI:https://doi.org/10.1016/j.jtcvs.2017.09.089

      Abstract

      Objectives

      The incidence and severity of Clostridium difficile infection (CDI) have increased rapidly over the past 2 decades, particularly in elderly patients with multiple comorbidities. This study sought to characterize the incidence and risks of these infections in cardiac surgery patients.

      Methods

      A total of 5158 patients at 10 Cardiothoracic Surgical Trials Network sites in the US and Canada participated in a prospective study of major infections after cardiac surgery. Patients were followed for infection, readmission, reoperation, or death up to 65 days after surgery. We compared clinical and demographic characteristics, surgical data, management practices, and outcomes for patients with CDI and without CDI.

      Results

      C difficile was the third most common infection observed (0.97%) and was more common in patients with preoperative comorbidities and complex operations. Antibiotic prophylaxis for >2 days, intensive care unit stay >2 days, and postoperative hyperglycemia were associated with increased risk of CDI. The median time to onset was 17 days; 48% of infections occurred after discharge. The additional length of stay due to infection was 12 days. The readmission and mortality rates were 3-fold and 5-fold higher, respectively, in patients with CDI compared with uninfected patients.

      Conclusions

      In this large multicenter prospective study of major infections following cardiac surgery, CDI was encountered in nearly 1% of patients, was frequently diagnosed postdischarge, and was associated with extended length of stay and substantially increased mortality. Patients with comorbidities, longer surgery time, extended antibiotic exposure, and/or hyperglycemic episodes were at increased risk for CDI.

      Key Words

      Abbreviations and Acronyms:

      CDC (Centers for Disease Control and Prevention), CDI (Clostridium difficile infection), CHF (congestive heart failure), CI (confidence interval), COPD (chronic obstructive pulmonary disease), CTSN (Cardiothoracic Surgery Trials Network), HR (hazard ratio), ICU (intensive care unit), IQR (interquartile range), LOS (length of stay), SSI (surgical site infection), VAD (ventricular assist device)
      Figure thumbnail fx1
      Survival by time-varying Clostridium difficile infection status.
      Prolonged antibiotic prophylaxis (>48 hours) was associated with risk of Clostridium difficile infection (CDI), the third most common major infection after cardiac surgery. CDI was associated with a substantial increase in mortality.
      The incidence and severity of Clostridium difficile infection (CDI) has increased recently. Our study found that CDI was associated with longer length of stay, frequent readmissions, and decreased survival. Median time to onset of CDI was >2 weeks postoperatively, with nearly one-half of patients (48%) first diagnosed after discharge. Limiting antibiotic prophylaxis to 2 days and controlling blood glucose levels may reduce the incidence of CDI.
      See Editorial Commentary page 679.
      See Editorial page 659.
      Clostridium difficile, a gram-positive, spore-forming anaerobic bacterium, is the most common source of hospital-acquired gastrointestinal infection.
      • Zerey M.
      • Paton B.L.
      • Lincourt A.E.
      • Gersin K.S.
      • Kercher K.W.
      • Heniford B.T.
      The burden of Clostridium difficile in surgical patients in the United States.
      • Keshavamurthy S.
      • Koch C.G.
      • Fraser T.G.
      • Gordon S.M.
      • Houghtaling P.L.
      • Soltesz E.G.
      • et al.
      Clostridium difficile infection after cardiac surgery: prevalence, morbidity, mortality, and resource utilization.
      • Hall J.F.
      • Berger D.
      Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management.
      • Lemaire A.
      • Dombrovskiy V.
      • Batsides G.
      • Scholz P.
      • Solina A.
      • Brownstone N.
      • et al.
      The effect of Clostridium difficile infection on cardiac surgery outcomes.
      • Kelly C.P.
      • LaMont J.T.
      Clostridium difficile—more difficult than ever.
      • Sailhamer E.A.
      • Carson K.
      • Chang Y.
      • Zacharias N.
      • Spaniolas K.
      • Tabbara M.
      • et al.
      Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality.
      • Kwon J.H.
      • Olsen M.A.
      • Dubberke E.R.
      The morbidity, mortality, and costs associated with Clostridium difficile infection.
      C difficile infection (CDI) can cause a wide spectrum of illness, ranging from mild diarrhea to pseudo-obstruction, pseudomembranous colitis, prolonged ileus, toxic megacolon, large bowel perforation, hemodynamic collapse, multisystem organ failure, shock, and death.
      • Hall J.F.
      • Berger D.
      Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management.
      • Sailhamer E.A.
      • Carson K.
      • Chang Y.
      • Zacharias N.
      • Spaniolas K.
      • Tabbara M.
      • et al.
      Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality.
      • Crabtree T.
      • Aitchison D.
      • Meyers B.F.
      • Tymkew H.
      • Smith J.R.
      • Guthrie T.J.
      • et al.
      Clostridium difficile in cardiac surgery: risk factors and impact on postoperative outcome.
      • Greenstein A.J.
      • Byrn J.C.
      • Zhang L.P.
      • Swedish K.A.
      • Jahn A.E.
      • Divino C.M.
      Risk factors for the development of fulminant Clostridium difficile colitis.
      • Dallal R.M.
      • Harbrecht B.G.
      • Boujoukas A.J.
      • Sirio C.A.
      • Farkas L.M.
      • Lee K.K.
      • et al.
      Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.
      Both the incidence and severity of CDI have been increasing worldwide since the mid- to late-1990s, as evidenced by a variety of single-site, multicenter, and population-based studies.
      • Zerey M.
      • Paton B.L.
      • Lincourt A.E.
      • Gersin K.S.
      • Kercher K.W.
      • Heniford B.T.
      The burden of Clostridium difficile in surgical patients in the United States.
      • Keshavamurthy S.
      • Koch C.G.
      • Fraser T.G.
      • Gordon S.M.
      • Houghtaling P.L.
      • Soltesz E.G.
      • et al.
      Clostridium difficile infection after cardiac surgery: prevalence, morbidity, mortality, and resource utilization.
      • Hall J.F.
      • Berger D.
      Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management.
      • Lemaire A.
      • Dombrovskiy V.
      • Batsides G.
      • Scholz P.
      • Solina A.
      • Brownstone N.
      • et al.
      The effect of Clostridium difficile infection on cardiac surgery outcomes.
      • Kelly C.P.
      • LaMont J.T.
      Clostridium difficile—more difficult than ever.
      • Crabtree T.
      • Aitchison D.
      • Meyers B.F.
      • Tymkew H.
      • Smith J.R.
      • Guthrie T.J.
      • et al.
      Clostridium difficile in cardiac surgery: risk factors and impact on postoperative outcome.
      • Dallal R.M.
      • Harbrecht B.G.
      • Boujoukas A.J.
      • Sirio C.A.
      • Farkas L.M.
      • Lee K.K.
      • et al.
      Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.
      • Khanna S.
      • Pardi D.S.
      The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings.
      • Redelings M.D.
      • Sorvillo F.
      • Mascola L.
      Increase in Clostridium difficile–related mortality rates, United States, 1999-2004.
      • Ricciardi R.
      • Rothenberger D.A.
      • Madoff R.D.
      • Baxter N.N.
      Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States.
      • Salazar M.
      • Baskin L.
      • Garey K.W.
      • DuPont H.L.
      Clostridium difficile–related death rates in Texas, 1999-2005.
      • Warny M.
      • Pepin J.
      • Fang A.
      • Killgore G.
      • Thompson A.
      • Brazier J.
      • et al.
      Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe.
      • Zilberberg M.D.
      • Shorr A.F.
      • Kollef M.H.
      Increase in adult Clostridium difficile–related hospitalizations and case-fatality rate, United States, 2000-2005.
      • Mocanu V.
      • Buth K.J.
      • Johnston L.B.
      • Davis I.
      • Hirsch G.M.
      • Legare J.F.
      The importance of continued quality improvement efforts in monitoring hospital-acquired infection rates: a cardiac surgery experience.
      • Morris A.M.
      • Jobe B.A.
      • Stoney M.
      • Sheppard B.C.
      • Deveney C.W.
      • Deveney K.E.
      Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
      • Stewart D.B.
      • Hollenbeak C.S.
      Clostridium difficile colitis: factors associated with outcome and assessment of mortality at a national level.
      • McDonald L.C.
      • Killgore G.E.
      • Thompson A.
      • Owens Jr., R.C.
      • Kazakova S.V.
      • Sambol S.P.
      • et al.
      An epidemic, toxin gene-variant strain of Clostridium difficile.
      • Elixhauser A.
      • Jhung M.
      Clostridium difficile–Associated Disease in US Hospitals, 1993-2005. Healthcare Cost and Utilization Project Statistical Brief 50.
      • Inkster T.
      Antibiotic prophylaxis for cardiac surgery: a shift away from traditional cephalosporins?.
      • Wysowski D.K.
      Increase in deaths related to enterocolitis due to Clostridium difficile in the United States, 1999-2002.
      • Flagg A.
      • Koch C.G.
      • Schiltz N.
      • Chandran Pillai A.
      • Gordon S.M.
      • Pettersson G.B.
      • et al.
      Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
      • Lessa F.C.
      • Mu Y.
      • Bamberg W.M.
      • Beldavs Z.G.
      • Dumyati G.K.
      • Dunn J.R.
      • et al.
      Burden of Clostridium difficile infection in the United States.
      • Aguayo C.
      • Flores R.
      • Lévesque S.
      • Araya P.
      • Ulloa S.
      • Lagos J.
      • et al.
      Rapid spread of Clostridium difficile NAP1/027/ST1 in Chile confirms the emergence of the epidemic strain in Latin America.
      • Ngamskulrungroj P.
      • Sanmee S.
      • Pusathit P.
      • Piewngam P.
      • Elliott B.
      • Riley T.V.
      • et al.
      Molecular epidemiology of Clostridium difficile infection in a large teaching hospital in Thailand.
      Although some of the increase in observed incidence may be due to the adoption of newer, more sensitive nucleic acid amplification tests, the rates of colectomy and mortality continue to climb.
      • Kelly C.P.
      • LaMont J.T.
      Clostridium difficile—more difficult than ever.
      • Sailhamer E.A.
      • Carson K.
      • Chang Y.
      • Zacharias N.
      • Spaniolas K.
      • Tabbara M.
      • et al.
      Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality.
      • Kwon J.H.
      • Olsen M.A.
      • Dubberke E.R.
      The morbidity, mortality, and costs associated with Clostridium difficile infection.
      • Dallal R.M.
      • Harbrecht B.G.
      • Boujoukas A.J.
      • Sirio C.A.
      • Farkas L.M.
      • Lee K.K.
      • et al.
      Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.
      • Khanna S.
      • Pardi D.S.
      The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings.
      • Redelings M.D.
      • Sorvillo F.
      • Mascola L.
      Increase in Clostridium difficile–related mortality rates, United States, 1999-2004.
      • Ricciardi R.
      • Rothenberger D.A.
      • Madoff R.D.
      • Baxter N.N.
      Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States.
      • Salazar M.
      • Baskin L.
      • Garey K.W.
      • DuPont H.L.
      Clostridium difficile–related death rates in Texas, 1999-2005.
      • Zilberberg M.D.
      • Shorr A.F.
      • Kollef M.H.
      Increase in adult Clostridium difficile–related hospitalizations and case-fatality rate, United States, 2000-2005.
      • Morris A.M.
      • Jobe B.A.
      • Stoney M.
      • Sheppard B.C.
      • Deveney C.W.
      • Deveney K.E.
      Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
      • McDonald L.C.
      • Killgore G.E.
      • Thompson A.
      • Owens Jr., R.C.
      • Kazakova S.V.
      • Sambol S.P.
      • et al.
      An epidemic, toxin gene-variant strain of Clostridium difficile.
      • Wysowski D.K.
      Increase in deaths related to enterocolitis due to Clostridium difficile in the United States, 1999-2002.
      Estimates of hospital cost increases directly due to CDI are as high as $77,000,
      • Zerey M.
      • Paton B.L.
      • Lincourt A.E.
      • Gersin K.S.
      • Kercher K.W.
      • Heniford B.T.
      The burden of Clostridium difficile in surgical patients in the United States.
      • Lemaire A.
      • Dombrovskiy V.
      • Batsides G.
      • Scholz P.
      • Solina A.
      • Brownstone N.
      • et al.
      The effect of Clostridium difficile infection on cardiac surgery outcomes.
      • Stewart D.B.
      • Hollenbeak C.S.
      Clostridium difficile colitis: factors associated with outcome and assessment of mortality at a national level.
      • McDonald L.C.
      • Killgore G.E.
      • Thompson A.
      • Owens Jr., R.C.
      • Kazakova S.V.
      • Sambol S.P.
      • et al.
      An epidemic, toxin gene-variant strain of Clostridium difficile.
      • Nanwa N.
      • Kendzerska T.
      • Krahn M.
      • Kwong J.C.
      • Daneman N.
      • Witteman W.
      • et al.
      The economic impact of Clostridium difficile infection: a systematic review.
      with cumulative annual costs estimated to exceed $200 million for cardiac surgery patients alone
      • Flagg A.
      • Koch C.G.
      • Schiltz N.
      • Chandran Pillai A.
      • Gordon S.M.
      • Pettersson G.B.
      • et al.
      Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
      and nearly $5 billion for CDIs in acute care facilities in the United States.
      • Lessa F.C.
      • Mu Y.
      • Bamberg W.M.
      • Beldavs Z.G.
      • Dumyati G.K.
      • Dunn J.R.
      • et al.
      Burden of Clostridium difficile infection in the United States.
      • Dubberke E.R.
      • Olsen M.A.
      Burden of Clostridium difficile on the healthcare system.
      • Desai K.
      • Gupta S.B.
      • Dubberke E.R.
      • Prabhu V.S.
      • Browne C.
      • Mast T.C.
      Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach.
      The US Centers for Disease Control and Prevention (CDC) has identified CDI as an important cause of infectious disease–related death and has made its prevention a national priority.
      • Lessa F.C.
      • Mu Y.
      • Bamberg W.M.
      • Beldavs Z.G.
      • Dumyati G.K.
      • Dunn J.R.
      • et al.
      Burden of Clostridium difficile infection in the United States.
      Advanced age, blood product transfusions, heart failure, peripheral vascular disease, chronic obstructive pulmonary disease (COPD), liver disease, diabetes, history of stroke, renal failure, mechanical ventilation, urinary catheter use, decubitus ulcers, health care exposure (eg, hospitalization), and antibiotic exposure have been identified as risk factors for CDI.
      • Crabtree T.
      • Aitchison D.
      • Meyers B.F.
      • Tymkew H.
      • Smith J.R.
      • Guthrie T.J.
      • et al.
      Clostridium difficile in cardiac surgery: risk factors and impact on postoperative outcome.
      • Greenstein A.J.
      • Byrn J.C.
      • Zhang L.P.
      • Swedish K.A.
      • Jahn A.E.
      • Divino C.M.
      Risk factors for the development of fulminant Clostridium difficile colitis.
      • Flagg A.
      • Koch C.G.
      • Schiltz N.
      • Chandran Pillai A.
      • Gordon S.M.
      • Pettersson G.B.
      • et al.
      Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
      • Bishara J.
      • Peled N.
      • Pitlik S.
      • Samra Z.
      Mortality of patients with antibiotic-associated diarrhoea: the impact of.
      • Musa S.A.
      • Moran C.
      • Thomson S.J.
      • et al.
      Clostridium difficile–associated disease acquired in the cardiothoracic intensive care unit.
      • Khanafer N.
      • Vanhems P.
      • Barbut F.
      • Luxemburger C.
      Factors associated with Clostridium difficile infection: a nested case-control study in a three year prospective cohort.
      • Huang H.
      • Wu S.
      • Chen R.
      • Xu S.
      • Fang H.
      • Weintraub A.
      • et al.
      Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China.
      Consequently, cardiac surgery would appear to be a particularly vulnerable population; yet the literature has focused primarily on surgical site infections (SSIs) and bloodstream infections in this population.
      • Fowler Jr., V.G.
      • O'Brien S.M.
      • Muhlbaier L.H.
      • Corey G.R.
      • Ferguson T.B.
      • Peterson E.D.
      Clinical predictors of major infections after cardiac surgery.
      • Abboud C.S.
      • Wey S.B.
      • Baltar V.T.
      Risk factors for mediastinitis after cardiac surgery.
      The Cardiothoracic Surgical Trials Network (CTSN), funded by the National Institutes of Health and the Canadian Institutes of Health Research, recently conducted a large multicenter prospective cohort study with the primary objective of identifying management practices associated with infections occurring within 65 days after cardiac surgery.
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      The CTSN study identified CDI as the third most common major infection, following pneumonia and bloodstream infection. To provide a more thorough understanding of CDI and how it affects patients undergoing cardiac surgery, we analyzed this cohort to determine the incidence of CDI and explore its association with adverse outcomes, as well as demographic variables and management practices associated with increased risk of developing CDI.

      Methods

      Population

      The study cohort included all 5158 patients at 10 CTSN sites in the United States and Canada who participated in the prospective Management Practices and the Risk of Infection Following Cardiac Surgery study (ClinicalTrials.gov; NCT01089712) (Figure 1).
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      All patients at the participating sites who had a clinical indication for cardiac surgery, did not have an active systemic infection, were at least 18 years of age, and provided written informed consent were enrolled between February and September 2010. The study received Institutional Review Board approval at each participating clinical center and at the data coordinating center.

      Data

      Demographic data, baseline laboratory values, comorbidities, surgical data, and management practices (eg, antimicrobial prophylaxis, glycemic control) were collected for the prospective cohort study. Comorbidities recorded included hypertension, hypercholesterolemia, diabetes, chronic lung disease, renal insufficiency (ie, history of renal insufficiency/failure and/or serum creatinine >2.0 preoperatively), congestive heart failure (CHF), history of infective endocarditis, cerebrovascular accident, peripheral vascular disease, congenital heart disease, and valvular heart disease. Surgical characteristics captured included procedure status (ie, elective, urgent, or emergent), procedure, type of incision, operative time, use and duration of cardiopulmonary bypass and circulatory arrest, and blood transfusions.
      Participants were followed for up to 65 days to determine the incidences of major and minor infections, all-cause mortality, reoperation, and hospital readmission. The 10 major infections included were deep incisional SSI occurring at the primary chest incision, deep incisional SSI occurring at a secondary incision site (eg, saphenous harvest and groin cannulation sites), mediastinitis, infectious myocarditis or pericarditis, endocarditis, cardiac device infection, pneumonia, empyema, C difficile colitis, and bloodstream infection. CDI was diagnosed according to standard clinical practice at each site. Minor infections were defined as primary and secondary superficial incisional SSIs, symptomatic urinary tract infections, and asymptomatic bacteriuria. Infections were classified based on definitions from the CDC and the National Healthcare Safety Network surveillance,
      • Horan T.C.
      • Andrus M.
      • Dudeck M.A.
      CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.
      and all major infections were adjudicated by an Event Adjudication Committee that included 3 infectious disease experts. Infections other than C difficile in this cohort have been previously described in detail.
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      • Ailawadi G.
      • Chang H.L.
      • O'Gara P.T.
      • O'Sullivan K.
      • Woo Y.J.
      • DeRose Jr., J.J.
      • et al.
      Pneumonia after cardiac surgery: experience of the National Institutes of Health/Canadian Institutes of Health Research Cardiothoracic Surgical Trials Network.
      • Perrault L.P.
      • Kirkwood K.A.
      • Chang H.L.
      • Mullen J.C.
      • Gulack B.C.
      • Argenziano M.
      • et al.
      A prospective multi-institutional cohort study of mediastinal infections after cardiac surgery.
      All data were entered into an electronic data capture system and submitted to the data coordinating center, which was responsible for electronic and local monitoring of the data for quality assurance.

      Statistical Analysis

      Univariable proportional hazards regression models were used to assess differences in patient demographic data, operative characteristics, and postoperative management by a CDI or no CDI during follow-up. We adjusted for patient-level risk factors and management factors but not for site, to avoid obscuring risks related to management practices that may vary by site. Patients missing the 60-day follow-up visit were censored at the time of last contact.
      Variables with a P value ≤.20 were considered when building the multivariable proportional hazards model of time to onset of CDI using a backward stepwise process. This model included death as a competing risk using the method of Fine and Gray.
      • Fine J.P.G.R.
      A proportional hazards model for the subdistribution of a competing risk.
      Assumptions of the Fine–Gray model were checked by testing for an interaction between time and each of the covariates and by plotting the Schoenfeld-type residuals over time.
      • Zhou B.
      • Fine J.
      • Laird G.
      Goodness-of-fit test for proportional subdistribution hazards model.
      An interaction between diabetes and hyperglycemia was explored, given that some previous studies have found a differential risk of hyperglycemia.
      • Furnary A.P.
      • Wu Y.
      Clinical effects of hyperglycemia in the cardiac surgery population: the Portland Diabetic Project.
      • Székely A.
      • Levin J.
      • Miao Y.
      • Tudor I.C.
      • Vuylsteke A.
      • Ofner P.
      • et al.
      Impact of hyperglycemia on perioperative mortality after coronary artery bypass graft surgery.
      • Cardona S.
      • Pasquel F.J.
      • Fayfman M.
      • Peng L.
      • Jacobs S.
      • Vellanki P.
      • et al.
      Hospitalization costs and clinical outcomes in CABG patients treated with intensive insulin therapy.
      • Greco G.
      • Ferket B.S.
      • D'Alessandro D.A.
      • Shi W.
      • Horvath K.A.
      • Rosen A.
      • et al.
      Diabetes and the association of postoperative hyperglycemia with clinical and economic outcomes in cardiac surgery.
      Residuals were plotted to confirm that continuous numerical variables included in the final model could be treated as linear. Akaike information criterion values were considered in final model selection.
      The cumulative incidence function of CDI was plotted, again treating death as a competing risk.
      • Fine J.P.G.R.
      A proportional hazards model for the subdistribution of a competing risk.
      A multivariable extended Cox model was also used to assess the relationship between time to death and a time-varying indicator for CDI, adjusting for factors found to be predictive of mortality in the cohort as a whole
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      and for other non–C difficile infection as a time-varying covariate. Survival estimates for the hypothetical average patient in the cohort (age, 64 years; serum creatinine, 1.165 mg/dL; no diabetes or heart failure; no other infection) were generated from the proportional hazards regression model and plotted by time-varying CDI status.
      A multistate time-inhomogeneous Markov model
      • Allignol A.
      • Schumacher M.
      • Beyersmann J.
      Empirical transition matrix of multi-state models: the etm package.
      was used to determine the excess length of stay (LOS) of the index hospitalization due to CDI. The model assumed a single initial state (index surgical procedure), one intermediate state (CDI), and 2 absorbing states (hospital discharge and death). A bootstrap standard error and 95% confidence interval (CI) for the excess LOS was computed based on 1000 bootstrap samples.
      All variables included in the final models had a P value ≤.05. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC) and R 3.1.1 (R Institute for Statistical Computing, Vienna, Austria).

      Results

      Patient Characteristics

      The study cohort included a total of 5158 patients who enrolled in the study and underwent cardiac surgery between February and September 2010. Patient characteristics of the overall cohort have been reported previously
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      and are summarized in Table 1. In brief, the mean age was 64.4 ± 13.2 years, median body mass index was 28.2 kg/m2 (interquartile range [IQR] 25.1-32.3), and the proportion of women was 33.1%. Common comorbidities included diabetes mellitus (22.7% of patients), heart failure (29.2%), and COPD (14.5%). The most common procedures were isolated valve surgery (36.4%) and isolated coronary artery bypass grafting (32.5%); 90.5% of patients underwent sternotomy, and 18.6% of patients had undergone previous cardiac surgery.
      Table 1Patient and operative characteristics
      CharacteristicC difficile

      (n = 50)
      No C difficile

      (n = 5108)
      Overall

      (n = 5158)
      Hazard ratioP value
      Based on a Cox proportional hazards model in which the outcome is time to C difficile infection and the predictor is patient or operative characteristic.
      Demographics
       Age, y, mean (SD)64.5 (13.4)64.4 (13.2)64.4 (13.2)1.001.9533
       Male sex, n (%)36 (72.0)3414 (66.8)3450 (66.9)1.264.4577
       Race, n (%).0581
      White37 (74.0)4285 (83.9)4322 (83.8)0.420
      Black11 (22.0)529 (10.4)540 (10.5)
      Other2 (4.0)294 (5.8)296 (5.7)0.332
       BMI, median (IQR)28.8 (25.0-34.2)28.2 (25.1-32.2)28.2 (25.1-32.3)1.003.8847
      Baseline laboratory values, median (IQR)
       WBC, × 103/mL7.0 (5.6-8.6)7.0 (5.7-8.4)7.0 (5.7-8.4)0.991.8799
       Creatinine, mg/dL1.2 (1.0-1.6)1.0 (0.8-1.2)1.0 (0.8-1.2)1.186.0027
       Hemoglobin, g/dL13.1 (11.0-14.4)13.4 (12.0-14.5)13.4 (12.0-14.5)0.890.1161
      Cardiac morbidity
       Heart failure, n (%)23 (46.0)1482 (29.0)1505 (29.2)2.093.0092
       Ejection fraction, %, median (IQR)50.0 (35.0-55.0)55.0 (48.0-60.0)55.0 (48.0-60.0)0.962<.0001
       Previous cardiac surgery, n (%)16 (32.0)942 (18.4)958 (18.6)2.071.0163
       Baseline circulatory support, n (%)3 (6.0)132 (2.6)135 (2.6)2.383.1447
       History of infective endocarditis, n (%)0 (0.0)61 (1.2)61 (1.2).9817
      Noncardiac morbidity
       Diabetes, n (%)
      Insulin or oral medications.
      12 (24.0)1157 (22.7)1169 (22.7)1.084.8081
       COPD, n (%).1895
      None38 (76.0)4374 (85.6)4412 (85.5)
      Mild or moderate10 (20.0)634 (12.4)644 (12.5)1.814
      Severe2 (4.0)100 (2.0)102 (2.0)2.303
       Renal failure, n (%).0008
      No36 (72.0)4526 (88.6)4562 (88.4)
      Yes, dialysis-dependent5 (10.0)85 (1.7)90 (1.7)2.309
      Yes, not dialysis-dependent9 (18.0)497 (9.7)506 (9.8)7.428
       History of cerebrovascular accident7 (14.0)513 (10.0)520 (10.1)1.458.3551
      Operative
       Surgery time, h, median (IQR)5.1 (4.2-6.6)4.2 (3.3-5.2)4.2 (3.3-5.2)1.458<.0001
       Bypass time, h, median (IQR)
      91.1% of patients had on-pump surgical procedures.
      2.1 (1.6-3.1)1.8 (1.3-2.3)1.8 (1.3-2.3)1.523.0011
       Sternotomy, n (%)48 (96.0)4621 (90.5)4669 (90.5)2.512.2018
       Surgery type, n (%).4590
      Elective33 (66.0)3773 (73.9)3806 (73.8)
      Urgent15 (30.0)1199 (23.5)1214 (23.5)1.430
      Emergent2 (4.0)136 (2.7)138 (2.7)1.681
       Procedure, n (%)<.0001
      Isolated CABG9 (18.0)1668 (32.7)1677 (32.5)0.407
      Isolated valve12 (24.0)1866 (36.5)1878 (36.4)0.487
      CABG + valve9 (18.0)683 (13.4)692 (13.4)
      Transplant or VAD10 (20.0)112 (2.2)122 (2.4)6.499
      Thoracic aortic6 (12.0)422 (8.3)428 (8.3)1.080
      Other4 (8.0)357 (7.0)361 (7.0)0.847
      Other
       Transferred from outside hospital, n (%)4 (8.0)717 (14.0)721 (14.0)0.535.2302
       Preoperative antibiotic prophylaxis, n (%).0344
      First-generation cephalosporin23 (46.0)1836 (36.0)1859 (36.1)0.922
      Second-generation cephalosporin13 (26.0)2232 (43.7)2245 (43.6)0.431
      Other14 (28.0)1036 (20.3)1050 (20.4)
       Days admitted before surgery, median (IQR)0.0 (0.0-4.0)0.0 (0.0-2.0)0.0 (0.0-2.0)1.008.7761
      SD, Standard deviation; BMI, body mass index; IQR, interquartile range; WBC, white blood cell; COPD, chronic obstructive pulmonary disease; CABG, coronary artery bypass grafting; VAD, ventricular assist device.
      Based on a Cox proportional hazards model in which the outcome is time to C difficile infection and the predictor is patient or operative characteristic.
      Insulin or oral medications.
      91.1% of patients had on-pump surgical procedures.
      CDI was the third most common infection observed (0.97%) after pneumonia (2.38%) and bloodstream infections (1.09%). Compared with patients without CDI, those with CDI were more likely to have a higher serum creatinine level, a lower ejection fraction, previous cardiac surgery, and renal failure (with or without dialysis). Median surgery and bypass times were longer in the patients with CDI, and patients with CDI were more likely to have undergone combined procedures, ventricular assist device (VAD) placement or replacement, or heart transplantation than patients without CDI. Patients with CDI were also more likely to have received more than 48 hours of postoperative antibiotic prophylaxis, were less likely to have received second-generation cephalosporins as postoperative antibiotic prophylaxis, and were more likely to have longer times in the intensive care unit (ICU) and on ventilation (Table 2). Postoperative hyperglycemic episodes and infections other than CDI were also more common in the patients with CDI.
      Table 2Postoperative characteristics
      CharacteristicC difficile

      (n = 50)
      No C difficile

      (n = 5108)
      Overall

      (n = 5158)
      Hazard ratioP value
      Based on a Cox proportional hazards model in which the outcome is time to C difficile infection and the predictor is postoperative characteristic.
      Days of postoperative antibiotic prophylaxis, n (%)<.0001
       2 (24-48 h)13 (26.0)2107 (41.2)2120 (41.1)
       1 (0-24 h)11 (22.0)2585 (50.6)2596 (50.3)0.692
       3 (>48 h)26 (52.0)416 (8.1)442 (8.6)10.033
      Postoperative antibiotic prophylaxis, n (%).0358
       First-generation cephalosporin19 (38.0)1721 (33.7)1740 (33.7)0.721
       Second-generation cephalosporin14 (28.0)2270 (44.4)2284 (44.3)0.404
       Other17 (34.0)1117 (21.9)1134 (22.0)
      ICU LOS, d, median (IQR)5.0 (2.0-8.0)2.0 (1.0-3.0)2.0 (1.0-3.0)1.069<.0001
      Ventilation duration, d, median (IQR)1.0 (0.6-2.1)0.6 (0.4-1.0)0.6 (0.4-1.0)1.087.0001
      Packed RBCs, units, median (IQR)
      48.1% of patients received packed RBC transfusions.
      2.0 (0.0-8.0)0.0 (0.0-3.0)0.0 (0.0-3.0)1.225<.0001
      LOS from surgery (truncated at onset of C difficile), d, median (IQR)10.0 (7.0-17.0)7.0 (6.0-10.0)7.0 (6.0-10.0)1.069<.0001
      Non–C difficile infection, n (%)
      Onset of non–C difficile infection before the onset of C difficile infection.
      14 (28.0)551 (10.8)565 (11.0)3.180.0002
      Hyperglycemia, n (%)
      Hyperglycemia was defined as 1 or more blood sugar measurements above 180 mg/dL during the first 48 h postoperatively.
      37 (74.0)2191 (43.0)2228 (43.3)3.766<.0001
      ICU, Intensive care unit; LOS, length of stay; IQR, interquartile range; RBC, red blood cell.
      Based on a Cox proportional hazards model in which the outcome is time to C difficile infection and the predictor is postoperative characteristic.
      48.1% of patients received packed RBC transfusions.
      Onset of non–C difficile infection before the onset of C difficile infection.
      Hyperglycemia was defined as 1 or more blood sugar measurements above 180 mg/dL during the first 48 h postoperatively.

      Frequency, Severity, and Timing of CDI

      A total of 52 CDIs were identified in 50 patients during the 65-day follow-up period (0.97%). Two of the patients with CDI (4%) required total colectomy. Median time to CDI onset was 17 days after surgery (IQR, 6-28 days; Figure 2). Onset of CDI occurred before hospital discharge in 52% of patients (n = 26) (Table 3), and on the day of discharge in 2 patients. Ten patients had a major infection before the onset of CDI (20.0%), 6 patients had a minor infection before CDI (12.0%), and 2 patients had both a major and a minor infection before CDI.
      Figure thumbnail gr2
      Figure 2Cumulative incidence of C difficile infections.
      Table 3Infection timing for patients with C difficile infection (n = 50)
      TimingValue
      C difficile onset
       Before index hospital discharge, n (%)26 (52.0)
       Time of onset, d, median (IQR)17.0 (8.0-30.0)
      Other infections, n (%)
       Major infection before C difficile10 (20.0)
       Minor infection before C difficile6 (12.0)
       Any infection (major or minor) before C difficile14 (28.0)
      IQR, Interquartile range.

      Risk Factors Associated With CDI

      Renal failure was the sole preoperative patient characteristic associated with a higher risk of CDI in multivariable analysis (P = .004); hazard ratio for dialysis-dependent renal failure compared with no renal failure was 5.08 (95% CI, 1.94-13.28). Approximately one-half of patients were admitted on the day of surgery (median days admitted before surgery, 0.0; IQR, 0.0-2.0); preoperative LOS was not associated with an increased risk of CDI in the multivariable model. Operative and postoperative variables associated with greater CDI risk include hyperglycemia (HR = 2.894, P = .0011; 95% CI, 1.53-5.47; P = .001) and days of postoperative antibiotic prophylaxis (HR = 5.356, P <.0001 for 3 days vs 2 days; 95% CI, 2.61-10.99; P < .001). An ICU LOS >2 days was also associated with increased risk of CDI (HR, 2.451, P = .0079; 95% CI, 1.27-4.75; P = .008) (Figure 3). There was no evidence of a differential effect of hyperglycemia by diabetes status (P = .327).
      Figure thumbnail gr3
      Figure 3Risk factors for C difficile infections. Determined by using a multivariate proportional hazards regression model with death as a competing risk. ICU, Intensive care unit; CDI, Clostridium difficile infection.

      LOS and Readmissions

      For the 26 patients whose onset of CDI occurred during the index hospitalization, the observed mean LOS from hospital admission was 35.3 ± 21.6 days, compared with 17.4 ± 12.0 days for patients diagnosed with CDI after discharge and 11.0 ± 9.1 days for the patients without CDI. A multistate Markov model was used to estimate the incremental LOS of the index hospitalization following surgery; the mean excess LOS of the index hospitalization due to CDI was 12.3 ± 3.2 days (bootstrap 95% CI, 7.39-17.76).
      Thirteen patients who acquired CDI during the follow-up period were readmitted a total of 15 times within the first 30 days after surgery (0.43 readmissions per patient month of follow-up), whereas 602 patients without CDI were readmitted 642 times within the first 30 days after surgery (0.13 readmissions per patient month of follow-up). Over the entire 65-day follow up period, readmission rates were 0.23 per patient month of follow-up for patients with CDI, compared with 0.09 for those without CDI.

      CDI and Mortality

      Mortality during the 65-day follow-up period was higher in the patients with CDI compared with those without CDI (10.0% vs 1.8%; P < .001). In a proportional hazards regression model treating CDI as a time-dependent variable, CDI had a substantial impact on survival (HR, 5.449; 95% CI, 2.14-13.87). The model included non–C difficile infection as a time-varying covariate (HR, 4.063; 95% CI, 2.49-6.62). The model also adjusted for male sex (HR, 0.535; 95% CI, 0.36-0.80), age (HR, 1.036; 95% CI, 1.02-1.05), baseline serum creatinine (HR, 1.20; 95% CI, 1.09-1.31), CHF (HR, 2.011; 95% CI, 1.34-3.02), and diabetes (HR, 1.569; 95% CI, 1.03-2.38), all of which were previously identified as predictors of mortality independent of CDI (Table 4).
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      The effect of CDI on survival for an average patient in the cohort (male, age 64, serum creatinine 1.165 mg/dL, no diabetes or heart failure) is shown in the Central Picture.
      Table 4Impact of C difficile infection on mortality
      VariableHazard ratio95% confidence intervalP value
      C difficile infection status
      C difficile infection status is a time-varying covariate.
      5.449(2.14-13.87).0004
      Male sex0.535(0.36-0.8).0023
      Age1.036(1.02-1.05)<.0001
      Creatinine, per mg/dL1.199(1.09-1.31).0001
      Diabetes (yes/no)1.569(1.03-2.38).0350
      Non–C difficile infection status
      Non-C difficile infection status is a time-varying covariate and refers to infection before the onset of C difficile infection.
      4.063(2.49-6.62)<.0001
      Heart failure (yes/no)2.011(1.34-3.02).0007
      C difficile infection status is a time-varying covariate.
      Non-C difficile infection status is a time-varying covariate and refers to infection before the onset of C difficile infection.

      Discussion

      Most previous studies of major infections in cardiac surgery patients have focused on a subset of infections, predominantly SSIs and bloodstream infections,
      • Fowler Jr., V.G.
      • O'Brien S.M.
      • Muhlbaier L.H.
      • Corey G.R.
      • Ferguson T.B.
      • Peterson E.D.
      Clinical predictors of major infections after cardiac surgery.
      • Abboud C.S.
      • Wey S.B.
      • Baltar V.T.
      Risk factors for mediastinitis after cardiac surgery.
      yet a recent large prospective cohort study identified CDI as the third most common major infection after pneumonia and bloodstream infections.
      • Gelijns A.C.
      • Moskowitz A.J.
      • Acker M.A.
      • et al.
      Management practices and major infections after cardiac surgery.
      Most previous studies have focused on the first 30 days after surgery and/or the index hospitalization period because this is the time frame in which events are collected for national databases, such as the Premier Perspective Comparative database, the Nationwide Inpatient Sample database, and the Society of Thoracic Surgeons database.
      • Flagg A.
      • Koch C.G.
      • Schiltz N.
      • Chandran Pillai A.
      • Gordon S.M.
      • Pettersson G.B.
      • et al.
      Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
      • Fowler Jr., V.G.
      • O'Brien S.M.
      • Muhlbaier L.H.
      • Corey G.R.
      • Ferguson T.B.
      • Peterson E.D.
      Clinical predictors of major infections after cardiac surgery.
      • Bateman B.T.
      • Rassen J.A.
      • Schneeweiss S.
      • Bykov K.
      • Franklin J.M.
      • Gagne J.J.
      • et al.
      Adjuvant vancomycin for antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
      Recent results of an active surveillance study funded by the CDC's Emerging Infections Program showed that whereas the majority of CDI cases reported in the United States were related to health care exposure (ie, an inpatient or outpatient visit within 12 weeks before collection of a C difficile–positive stool sample), only 24% of cases had an in-hospital onset.
      • Lessa F.C.
      • Mu Y.
      • Bamberg W.M.
      • Beldavs Z.G.
      • Dumyati G.K.
      • Dunn J.R.
      • et al.
      Burden of Clostridium difficile infection in the United States.
      Thus, the data from the CTSN infection study provide a unique opportunity to examine the incidence of CDI in the cardiac surgery population and to explore risk factors associated with its occurrence, as well as the relationship between CDI and adverse outcomes.
      As would be expected based on the CDC surveillance results, in the present study, nearly one-half of all CDIs (48%) occurred after index hospital discharge, and 25% of all CDIs occurred after 30 days. This may explain why the frequency of CDI in this study (50 patients; 0.97%) was higher than the 0.21% to 0.75% reported from other national databases of cardiac surgery patients.
      • Flagg A.
      • Koch C.G.
      • Schiltz N.
      • Chandran Pillai A.
      • Gordon S.M.
      • Pettersson G.B.
      • et al.
      Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
      • Bateman B.T.
      • Rassen J.A.
      • Schneeweiss S.
      • Bykov K.
      • Franklin J.M.
      • Gagne J.J.
      • et al.
      Adjuvant vancomycin for antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
      • Poeran J.
      • Mazumdar M.
      • Rasul R.
      • Meyer J.
      • Sacks H.S.
      • Koll B.S.
      • et al.
      Antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
      CDI was more common than expected during study planning and was in fact collected as an “other” serious infection. Thus, the diagnosis was not protocolized, but rather was determined according to standard clinical practice at each site.
      Comorbidities have been frequently associated with the risk of CDI.
      • Zerey M.
      • Paton B.L.
      • Lincourt A.E.
      • Gersin K.S.
      • Kercher K.W.
      • Heniford B.T.
      The burden of Clostridium difficile in surgical patients in the United States.
      • Keshavamurthy S.
      • Koch C.G.
      • Fraser T.G.
      • Gordon S.M.
      • Houghtaling P.L.
      • Soltesz E.G.
      • et al.
      Clostridium difficile infection after cardiac surgery: prevalence, morbidity, mortality, and resource utilization.
      • Crabtree T.
      • Aitchison D.
      • Meyers B.F.
      • Tymkew H.
      • Smith J.R.
      • Guthrie T.J.
      • et al.
      Clostridium difficile in cardiac surgery: risk factors and impact on postoperative outcome.
      • Greenstein A.J.
      • Byrn J.C.
      • Zhang L.P.
      • Swedish K.A.
      • Jahn A.E.
      • Divino C.M.
      Risk factors for the development of fulminant Clostridium difficile colitis.
      • Khanna S.
      • Pardi D.S.
      The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings.
      • Mocanu V.
      • Buth K.J.
      • Johnston L.B.
      • Davis I.
      • Hirsch G.M.
      • Legare J.F.
      The importance of continued quality improvement efforts in monitoring hospital-acquired infection rates: a cardiac surgery experience.
      • Flagg A.
      • Koch C.G.
      • Schiltz N.
      • Chandran Pillai A.
      • Gordon S.M.
      • Pettersson G.B.
      • et al.
      Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
      • Bishara J.
      • Peled N.
      • Pitlik S.
      • Samra Z.
      Mortality of patients with antibiotic-associated diarrhoea: the impact of.
      • Khanafer N.
      • Vanhems P.
      • Barbut F.
      • Luxemburger C.
      Factors associated with Clostridium difficile infection: a nested case-control study in a three year prospective cohort.
      • Huang H.
      • Wu S.
      • Chen R.
      • Xu S.
      • Fang H.
      • Weintraub A.
      • et al.
      Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China.
      • Karanika S.
      • Paudel S.
      • Zervou F.N.
      • Grigoras C.
      • Zacharioudakis I.M.
      • Mylonakis E.
      Prevalence and clinical outcomes of Clostridium difficile infection in the intensive care unit: a systematic review and meta-analysis.
      Not surprisingly, we found that patients who developed CDI were more likely to suffer from renal failure preoperatively and more likely to have longer ICU LOS. Duration of ICU LOS and procedure were related; VAD and transplant recipients spent longer in the ICU than patients undergoing other procedures. Acute hyperglycemia was associated with an increased risk of CDI; however, whether hyperglycemia is indicative of a sicker, more vulnerable patient or if hyperglycemia in and of itself increases the risk of infection is unclear, particularly because diabetes was not associated with the risk of CDI and we did not observe a differential risk of hyperglycemia by diabetes.
      We did not find a significantly higher incidence of CDI associated with older age, diabetes, increased body mass index, or COPD; with urgent or emergent procedure status; in women; or in Caucasian patients as has been observed in other studies.
      • Greenstein A.J.
      • Byrn J.C.
      • Zhang L.P.
      • Swedish K.A.
      • Jahn A.E.
      • Divino C.M.
      Risk factors for the development of fulminant Clostridium difficile colitis.
      • Redelings M.D.
      • Sorvillo F.
      • Mascola L.
      Increase in Clostridium difficile–related mortality rates, United States, 1999-2004.
      • Ricciardi R.
      • Rothenberger D.A.
      • Madoff R.D.
      • Baxter N.N.
      Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States.
      • Mocanu V.
      • Buth K.J.
      • Johnston L.B.
      • Davis I.
      • Hirsch G.M.
      • Legare J.F.
      The importance of continued quality improvement efforts in monitoring hospital-acquired infection rates: a cardiac surgery experience.
      In contrast, African Americans were the racial group that contracted CDI most frequently. Given that only 50 patients in this cohort contracted CDI and the cohort was predominantly male, our analysis may simply have been underpowered to detect a difference. It is also possible that varying diagnostic criteria by site may have obscured any risks associated with demographics. There was not a statistically significant difference in CDI incidence in patients who did not undergo a sternotomy compared to those who did, although it is worth noting that the incidence in both groups was low, so a difference would have to be fairly large to be detectable.
      Moreover, other studies have identified additional risk factors for CDI, including malignancy, chemotherapy, intra-abdominal therapy, malnutrition, and previous CDI.
      • Khanafer N.
      • Vanhems P.
      • Barbut F.
      • Luxemburger C.
      Factors associated with Clostridium difficile infection: a nested case-control study in a three year prospective cohort.
      • Huang H.
      • Wu S.
      • Chen R.
      • Xu S.
      • Fang H.
      • Weintraub A.
      • et al.
      Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China.
      Because the present study was designed to focus on management practices and the risk of infection, many of the variables identified in other studies as risk factors of CDI were not collected in this study.
      Although patients with CDI were readmitted more often during the 65-day follow-up period, this appears to be indicative of the fact that hospital exposure and comorbidities increase the risk of CDI, given that readmissions tended to be for reasons other than CDI; only 7 of the 31 readmissions in this group were due to CDI. In most cases, onset of CDI occurred during the index hospitalization or during a readmission hospitalization. Readmissions for CDI occurred in close proximity to hospital discharge, consistent with the CDC's surveillance study findings.
      As was observed in other reports,
      • Zerey M.
      • Paton B.L.
      • Lincourt A.E.
      • Gersin K.S.
      • Kercher K.W.
      • Heniford B.T.
      The burden of Clostridium difficile in surgical patients in the United States.
      • Keshavamurthy S.
      • Koch C.G.
      • Fraser T.G.
      • Gordon S.M.
      • Houghtaling P.L.
      • Soltesz E.G.
      • et al.
      Clostridium difficile infection after cardiac surgery: prevalence, morbidity, mortality, and resource utilization.
      • Hall J.F.
      • Berger D.
      Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management.
      • Lemaire A.
      • Dombrovskiy V.
      • Batsides G.
      • Scholz P.
      • Solina A.
      • Brownstone N.
      • et al.
      The effect of Clostridium difficile infection on cardiac surgery outcomes.
      • Sailhamer E.A.
      • Carson K.
      • Chang Y.
      • Zacharias N.
      • Spaniolas K.
      • Tabbara M.
      • et al.
      Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality.
      • Crabtree T.
      • Aitchison D.
      • Meyers B.F.
      • Tymkew H.
      • Smith J.R.
      • Guthrie T.J.
      • et al.
      Clostridium difficile in cardiac surgery: risk factors and impact on postoperative outcome.
      • Greenstein A.J.
      • Byrn J.C.
      • Zhang L.P.
      • Swedish K.A.
      • Jahn A.E.
      • Divino C.M.
      Risk factors for the development of fulminant Clostridium difficile colitis.
      • Redelings M.D.
      • Sorvillo F.
      • Mascola L.
      Increase in Clostridium difficile–related mortality rates, United States, 1999-2004.
      • Mocanu V.
      • Buth K.J.
      • Johnston L.B.
      • Davis I.
      • Hirsch G.M.
      • Legare J.F.
      The importance of continued quality improvement efforts in monitoring hospital-acquired infection rates: a cardiac surgery experience.
      • Elixhauser A.
      • Jhung M.
      Clostridium difficile–Associated Disease in US Hospitals, 1993-2005. Healthcare Cost and Utilization Project Statistical Brief 50.
      • Musa S.A.
      • Moran C.
      • Thomson S.J.
      • et al.
      Clostridium difficile–associated disease acquired in the cardiothoracic intensive care unit.
      • Karanika S.
      • Paudel S.
      • Zervou F.N.
      • Grigoras C.
      • Zacharioudakis I.M.
      • Mylonakis E.
      Prevalence and clinical outcomes of Clostridium difficile infection in the intensive care unit: a systematic review and meta-analysis.
      • Mazzeffi M.
      • Gammie J.
      • Taylor B.
      • Cardillo S.
      • Haldane-Lutterodt N.
      • Amoroso A.
      • et al.
      Healthcare-associated infections in cardiac surgery patients with prolonged intensive care unit stay.
      • Bruminhent J.
      • Cawcutt K.A.
      • Thongprayoon C.
      • Petterson T.M.
      • Kremers W.K.
      • Razonable R.R.
      Epidemiology, risk factors, and outcome of Clostridium difficile infection in heart and heart-lung transplant recipients.
      CDI was associated with significantly increased mortality. This finding held after adjusting for age, sex, diabetes, CHF, baseline creatinine, and time-varying non–C difficile infection (HR, 5.449; 95% CI, 2.14-13.87; P < .0004). Mortality observed in patients with CDI in this cohort of cardiac surgery patients (10.0%) was comparable to the death rates from health care–associated CDI in surgical and nonsurgical patients in the United States and Canada over the same time period (6%-35%).
      • Hota S.S.
      • Achonu C.
      • Crowcroft N.S.
      • Harvey B.J.
      • Lauwers A.
      • Gardam M.A.
      Determining mortality rates attributable to Clostridium difficile infection.

      Centers for Disease Control and Prevention. Nearly half a million Americans suffered from Clostridium difficile infections in a single year. CDC Newsroom Release. February 25, 2015. Available at: https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html. Accessed June 25, 2015.

      Despite the fact that patients with CDI tended to generally be at higher risk for adverse outcomes, we did not observe an increase in any major adverse cardiac or cerebrovascular events other than death (ie, myocardial infarction, cerebrovascular accident, or transient ischemic attack) at any point during the 65-day follow-up. A single case of cerebrovascular accident occurring after onset of CDI was the sole nonfatal reported adverse event among the 50 patients ever diagnosed with CDI.
      The risk of CDI increases substantially with prolonged antibiotic exposure, because suppression of the bowel flora allows C difficile to flourish.
      • Gorbach S.L.
      Antibiotics and Clostridium difficile.
      This effect is thought to be particularly pronounced with second-generation cephalosporins.
      • Nelson D.E.
      • Auerbach S.B.
      • Baltch A.L.
      • Desjardin E.
      • Beck-Sague C.
      • Rheal C.
      • et al.
      Epidemic Clostridium difficile–associated diarrhea: role of second- and third-generation cephalosporins.
      Antibiotic prophylaxis lasting ≤48 hours was protective against CDI, but antibiotic prophylaxis lasting ≥3 days was associated with higher risk of CDI regardless of type of antibiotic prophylaxis provided. We had anticipated that a previous postoperative infection would increase the risk of CDI, because the initial postoperative infection would presumably result in antibiotic treatment, yet only 28% of first CDI cases occurred after another infection (major or minor), and other (non–C difficile) infection was not significantly associated with an increased risk of CDI.
      Although the type of antibiotic was significant in univariable analyses, with second-generation cephalosporins associated with a decreased risk of CDI, the finding did not hold in a multivariable model, possibly because the type of antibiotic was correlated with the duration of antibiotic treatment. This also may be related to the limited size of the study (50 patients with CDI). A recent analysis of 154,200 cardiac surgery patients in the Premier database showed an association between antibiotic prophylaxis with cephalosporin and decreased risk of CDI (although it did not distinguish between first- and seond-generation cephalosporins).
      • Poeran J.
      • Mazumdar M.
      • Rasul R.
      • Meyer J.
      • Sacks H.S.
      • Koll B.S.
      • et al.
      Antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
      That study also confirmed an increased risk of CDI with antibiotic prophylaxis that extended past 48 hours.

      Limitations

      In this cohort of more than 5000 patients, the number of patients with CDI was low, limiting this study's statistical power. CDI was potentially underreported, because it was not included in the predefined list of major infections in the protocol; instead, it was captured as a serious “other” infection. Diagnostic criteria were not protocolized, and we do not know how each diagnosis was made (ie, nucleic acid amplification test vs other methods). However, the study was designed to capture all postoperative infections, all events were reviewed and adjudicated by an Event Adjudication Committee of infectious disease experts, and follow-up through the end of the study was 98% complete. Given the thoroughness of data capture and the fact that the reported incidence in this study was higher than that in other studies,
      • Zerey M.
      • Paton B.L.
      • Lincourt A.E.
      • Gersin K.S.
      • Kercher K.W.
      • Heniford B.T.
      The burden of Clostridium difficile in surgical patients in the United States.
      • Keshavamurthy S.
      • Koch C.G.
      • Fraser T.G.
      • Gordon S.M.
      • Houghtaling P.L.
      • Soltesz E.G.
      • et al.
      Clostridium difficile infection after cardiac surgery: prevalence, morbidity, mortality, and resource utilization.
      • Lemaire A.
      • Dombrovskiy V.
      • Batsides G.
      • Scholz P.
      • Solina A.
      • Brownstone N.
      • et al.
      The effect of Clostridium difficile infection on cardiac surgery outcomes.
      • Ricciardi R.
      • Rothenberger D.A.
      • Madoff R.D.
      • Baxter N.N.
      Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States.
      we believe the likelihood of bias due to underreporting is low.
      Medications other than prophylactic antibiotics were not captured in the database, which precluded an analysis of antibiotics administered for other infections occurring before CDI. It also precluded an analysis of medications, such as proton pump inhibitors, that have been previously identified as risk factors for CDI.
      • Bateman B.T.
      • Rassen J.A.
      • Schneeweiss S.
      • Bykov K.
      • Franklin J.M.
      • Gagne J.J.
      • et al.
      Adjuvant vancomycin for antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
      • Aseeri M.
      • Schroeder T.
      • Kramer J.
      • Zackula R.
      Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile–associated diarrhea in hospitalized patients.
      However, other infections, serious or not serious (before the onset of CDI in patients with CDI), were not associated with an increased risk of CDI.
      Discharge disposition also was not captured in the database, precluding an analysis to determine if patients discharged to a rehabilitation or nursing facility were at increased risk of postdischarge CDI compared with patients who were discharged to home.
      Finally, the data on excess LOS due to CDI should be interpreted with caution, because these data do not take into account other potentially informative covariates (eg, index surgical procedure). Because this study was designed to focus on management practices and infection, other complications and adverse events were not collected, and these variables may have affected LOS overall or in the ICU.

      Conclusions

      CDI is a common infection following cardiac surgery and is associated with significant increases in LOS and mortality. Despite intense efforts to reduce the incidence of health care–associated infections, opportunities to improve adherence to quality improvement measures remain, particularly glycemic control and optimal duration of antibiotic prophylaxis (≤48 hours), to reduce the rates of CDI. High-risk patients, such as those with renal failure or those undergoing complex procedures, such as VAD placement or transplant, who will spend an extended length of time in the ICU, are particularly vulnerable to CDI and may warrant additional precautions to reduce the morbidity and mortality associated with CDI. Providers should continue to be vigilant about CDI after discharge, because onset frequently occurs more than 2 weeks after surgery.

      Conflict of Interest Statement

      Authors have nothing to disclose with regard to commercial support.

      Appendix E1. CTSN Investigators

      The following members of the Cardiothoracic Surgical Trials Network (CTSN) were involved in this study:
      National Heart, Lung and Blood Institute: Marissa A. Miller, Wendy C. Taddei-Peters, Dennis Buxton, Ron Caulder, Nancy L. Geller, David Gordon, Neal O. Jeffries, Albert Lee
      National Institute of Neurological Disorders and Stroke: Claudia S. Moy
      Canadian Institutes of Health Research: Ilana Kogan Gombos, Jennifer Ralph
      Network Chairs: Christiana Care Health System, Timothy J. Gardner, (Chair); Brigham and Women's Hospital, Patrick T. O'Gara, (Co-Chair)
      Data Coordinating Center: International Center for Health Outcomes and Innovation Research at Icahn School of Medicine at Mount Sinai, Annetine C. Gelijns, Michael K. Parides, Deborah D. Ascheim, Alan J. Moskowitz, Ellen Moquete, Eric A. Rose, Melissa Chase, Yingchun Chen, Rosemarie Gagliardi, Lopa Gupta, Edlira Kumbarce, Ron Levitan, Karen O'Sullivan, Milerva Santos, Alan Weinberg, Paula Williams, Carrie Wood, Xia Ye
      Core Clinical Site Investigators: Cleveland Clinic Foundation, Eugene H. Blackstone (PI), A. Marc Gillinov, Pamela Lackner, Leoma Berroteran, Diana Dolney, Suzanne Fleming, Roberta Palumbo, Christine Whitman, Kathy Sankovic, Denise Kosty Sweeney; NHLBI Clinical Research Scholars: Gregory Pattakos, Pamela A. Clarke; Columbia University, Michael Argenziano (PI), Mathew Williams, Lyn Goldsmith, Craig R. Smith, Yoshifumi Naka, Allan Stewart, Allan Schwartz; Daniel Bell, Danielle Van Patten; Duke University, Peter K. Smith (PI), Stacey Welsh, John H. Alexander, Carmelo A. Milano, Donald D. Glower, Joseph P. Mathew, J. Kevin Harrison; NHLBI Clinical Research Scholars: Mark F. Berry, Cyrus J. Parsa, Betty C. Tong, Judson B. Williams; East Carolina Heart Institute, T. Bruce Ferguson (PI), Alan P. Kypson, Evelio Rodriguez, Malissa Harris, Brenda Akers, Allison O'Neal; Emory University, John D. Puskas (PI), Vinod H. Thourani, Robert Guyton, Jefferson Baer, Kim Baio, Alexis A. Neill; Montefiore-Einstein Heart Center, New York, NY, Robert E. Michler (PI), David A. D'Alessandro, Joseph J. DeRose, Jr, Daniel J. Goldstein, Ricardo Bello, William Jakobleff, Mario Garcia, Cynthia Taub, Daniel Spevak, Roger Swayze; Montreal Heart Institute, Louis P. Perrault (PI), Arsène-Joseph Basmadjian, Denis Bouchard, Michel Carrier, Raymond Cartier, Michel Pellerin, Jean François Tanguay, Ismael El-Hamamsy, André Denault, Jonathan Lacharité, Sophie Robichaud; NIH Heart Center at Suburban Hospital, Keith A. Horvath (PI), Philip C. Corcoran, Michael P. Siegenthaler, Mandy Murphy, Margaret Iraola, Ann Greenberg; University of Pennsylvania, Michael A. Acker (PI), Y. Joseph Woo, Mary Lou Mayer; University of Virginia, Irving L. Kron (PI), Gorav Ailawadi, Karen Johnston, John M. Dent, John Kern, Jessica Keim Sandra Burks, Kim Gahring
      Protocol Review Committee: David A. Bull (Chair); Patrice Desvigne-Nickens, Executive Secretary; Dennis O. Dixon, Mark Haigney, Richard Holubkov, Alice Jacobs, Frank Miller, John M. Murkin, John Spertus, Andrew S. Wechsler
      Data and Safety Monitoring Board: Frank Sellke (Chair); Cheryl L. McDonald, Executive Secretary; Robert Byington, Neal Dickert, Dennis O. Dixon, John S. Ikonomidis, David O. Williams, Clyde W. Yancy
      Medical Monitors: James C. Fang, Wayne Richenbacher
      Overall Event Adjudication Committee: Vivek Rao (Chair); Karen L. Furie, Rachel Miller, Sean Pinney, William C. Roberts
      Infection Event Adjudication Committee: Rachel Miller (Chair); Shirish Huprikar, Marilyn Levi

      References

        • Zerey M.
        • Paton B.L.
        • Lincourt A.E.
        • Gersin K.S.
        • Kercher K.W.
        • Heniford B.T.
        The burden of Clostridium difficile in surgical patients in the United States.
        Surg Infect. 2007; 8: 557-566
        • Keshavamurthy S.
        • Koch C.G.
        • Fraser T.G.
        • Gordon S.M.
        • Houghtaling P.L.
        • Soltesz E.G.
        • et al.
        Clostridium difficile infection after cardiac surgery: prevalence, morbidity, mortality, and resource utilization.
        J Thorac Cardiovasc Surg. 2014; 148: 3157-3165
        • Hall J.F.
        • Berger D.
        Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management.
        Am J Surg. 2008; 196: 384-388
        • Lemaire A.
        • Dombrovskiy V.
        • Batsides G.
        • Scholz P.
        • Solina A.
        • Brownstone N.
        • et al.
        The effect of Clostridium difficile infection on cardiac surgery outcomes.
        Surg Infect. 2015; 16: 24-28
        • Kelly C.P.
        • LaMont J.T.
        Clostridium difficile—more difficult than ever.
        New Engl J Med. 2008; 359: 1932-1940
        • Sailhamer E.A.
        • Carson K.
        • Chang Y.
        • Zacharias N.
        • Spaniolas K.
        • Tabbara M.
        • et al.
        Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality.
        Arch Surg. 2009; 144: 433-440
        • Kwon J.H.
        • Olsen M.A.
        • Dubberke E.R.
        The morbidity, mortality, and costs associated with Clostridium difficile infection.
        Infect Dis Clin North Am. 2015; 29: 123-134
        • Crabtree T.
        • Aitchison D.
        • Meyers B.F.
        • Tymkew H.
        • Smith J.R.
        • Guthrie T.J.
        • et al.
        Clostridium difficile in cardiac surgery: risk factors and impact on postoperative outcome.
        Ann Thorac Surg. 2007; 83: 1396-1402
        • Greenstein A.J.
        • Byrn J.C.
        • Zhang L.P.
        • Swedish K.A.
        • Jahn A.E.
        • Divino C.M.
        Risk factors for the development of fulminant Clostridium difficile colitis.
        Surgery. 2008; 143: 623-629
        • Dallal R.M.
        • Harbrecht B.G.
        • Boujoukas A.J.
        • Sirio C.A.
        • Farkas L.M.
        • Lee K.K.
        • et al.
        Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.
        Ann Surg. 2002; 235: 363-372
        • Khanna S.
        • Pardi D.S.
        The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings.
        Expert Rev Gastroenterol Hepatol. 2010; 4: 409-416
        • Redelings M.D.
        • Sorvillo F.
        • Mascola L.
        Increase in Clostridium difficile–related mortality rates, United States, 1999-2004.
        Emerg Infect Dis. 2007; 13: 1417-1419
        • Ricciardi R.
        • Rothenberger D.A.
        • Madoff R.D.
        • Baxter N.N.
        Increasing prevalence and severity of Clostridium difficile colitis in hospitalized patients in the United States.
        Arch Surg. 2007; 142: 624-631
        • Salazar M.
        • Baskin L.
        • Garey K.W.
        • DuPont H.L.
        Clostridium difficile–related death rates in Texas, 1999-2005.
        J Infect. 2009; 59: 303-307
        • Warny M.
        • Pepin J.
        • Fang A.
        • Killgore G.
        • Thompson A.
        • Brazier J.
        • et al.
        Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe.
        Lancet. 2005; 366: 1079-1084
        • Zilberberg M.D.
        • Shorr A.F.
        • Kollef M.H.
        Increase in adult Clostridium difficile–related hospitalizations and case-fatality rate, United States, 2000-2005.
        Emerg Infect Dis. 2008; 14: 929-931
        • Mocanu V.
        • Buth K.J.
        • Johnston L.B.
        • Davis I.
        • Hirsch G.M.
        • Legare J.F.
        The importance of continued quality improvement efforts in monitoring hospital-acquired infection rates: a cardiac surgery experience.
        Ann Thorac Surg. 2015; 99: 2061-2069
        • Morris A.M.
        • Jobe B.A.
        • Stoney M.
        • Sheppard B.C.
        • Deveney C.W.
        • Deveney K.E.
        Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
        Arch Surg. 2002; 137: 1096-1100
        • Stewart D.B.
        • Hollenbeak C.S.
        Clostridium difficile colitis: factors associated with outcome and assessment of mortality at a national level.
        J Gastrointest Surg. 2011; 15: 1548-1555
        • McDonald L.C.
        • Killgore G.E.
        • Thompson A.
        • Owens Jr., R.C.
        • Kazakova S.V.
        • Sambol S.P.
        • et al.
        An epidemic, toxin gene-variant strain of Clostridium difficile.
        New Engl J Med. 2005; 353: 2433-2441
        • Elixhauser A.
        • Jhung M.
        Clostridium difficile–Associated Disease in US Hospitals, 1993-2005. Healthcare Cost and Utilization Project Statistical Brief 50.
        Agency for Healthcare Research and Quality, Rockville, Md2006
        • Inkster T.
        Antibiotic prophylaxis for cardiac surgery: a shift away from traditional cephalosporins?.
        J Cardiothorac Vasc Anesth. 2009; 23: 933-935
        • Wysowski D.K.
        Increase in deaths related to enterocolitis due to Clostridium difficile in the United States, 1999-2002.
        Public Health Rep. 2006; 121: 361-362
        • Flagg A.
        • Koch C.G.
        • Schiltz N.
        • Chandran Pillai A.
        • Gordon S.M.
        • Pettersson G.B.
        • et al.
        Analysis of Clostridium difficile infections after cardiac surgery: epidemiologic and economic implications from national data.
        J Thorac Cardiovasc Surg. 2014; 148: 2404-2409
        • Lessa F.C.
        • Mu Y.
        • Bamberg W.M.
        • Beldavs Z.G.
        • Dumyati G.K.
        • Dunn J.R.
        • et al.
        Burden of Clostridium difficile infection in the United States.
        N Engl J Med. 2015; 372: 825-834
        • Aguayo C.
        • Flores R.
        • Lévesque S.
        • Araya P.
        • Ulloa S.
        • Lagos J.
        • et al.
        Rapid spread of Clostridium difficile NAP1/027/ST1 in Chile confirms the emergence of the epidemic strain in Latin America.
        Epidemiol Infect. 2015; 143: 3069-3073
        • Ngamskulrungroj P.
        • Sanmee S.
        • Pusathit P.
        • Piewngam P.
        • Elliott B.
        • Riley T.V.
        • et al.
        Molecular epidemiology of Clostridium difficile infection in a large teaching hospital in Thailand.
        PloS One. 2015; 10: e0127026
        • Nanwa N.
        • Kendzerska T.
        • Krahn M.
        • Kwong J.C.
        • Daneman N.
        • Witteman W.
        • et al.
        The economic impact of Clostridium difficile infection: a systematic review.
        Am J Gastroenterol. 2015; 110: 511-519
        • Dubberke E.R.
        • Olsen M.A.
        Burden of Clostridium difficile on the healthcare system.
        Clin Infect Dis. 2012; 55: S88-92
        • Desai K.
        • Gupta S.B.
        • Dubberke E.R.
        • Prabhu V.S.
        • Browne C.
        • Mast T.C.
        Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach.
        BMC Infect Dis. 2016; 16: 303
        • Bishara J.
        • Peled N.
        • Pitlik S.
        • Samra Z.
        Mortality of patients with antibiotic-associated diarrhoea: the impact of.
        Clostridium difficile. J Hosp Infect. 2008; 68: 308-314
        • Musa S.A.
        • Moran C.
        • Thomson S.J.
        • et al.
        Clostridium difficile–associated disease acquired in the cardiothoracic intensive care unit.
        J Cardiothorac Vasc Anesth. 2011; 25: 263-267
        • Khanafer N.
        • Vanhems P.
        • Barbut F.
        • Luxemburger C.
        Factors associated with Clostridium difficile infection: a nested case-control study in a three year prospective cohort.
        Anaerobe. 2017; 44: 117-123
        • Huang H.
        • Wu S.
        • Chen R.
        • Xu S.
        • Fang H.
        • Weintraub A.
        • et al.
        Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China.
        Anaerobe. 2014; 30: 65-69
        • Fowler Jr., V.G.
        • O'Brien S.M.
        • Muhlbaier L.H.
        • Corey G.R.
        • Ferguson T.B.
        • Peterson E.D.
        Clinical predictors of major infections after cardiac surgery.
        Circulation. 2005; 112: I358-I365
        • Abboud C.S.
        • Wey S.B.
        • Baltar V.T.
        Risk factors for mediastinitis after cardiac surgery.
        Ann Thorac Surg. 2004; 77: 676-683
        • Gelijns A.C.
        • Moskowitz A.J.
        • Acker M.A.
        • et al.
        Management practices and major infections after cardiac surgery.
        J Am Coll Cardiol. 2014; 64: 372-381
        • Horan T.C.
        • Andrus M.
        • Dudeck M.A.
        CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.
        Am J Infect Control. 2008; 36: 309-332
        • Ailawadi G.
        • Chang H.L.
        • O'Gara P.T.
        • O'Sullivan K.
        • Woo Y.J.
        • DeRose Jr., J.J.
        • et al.
        Pneumonia after cardiac surgery: experience of the National Institutes of Health/Canadian Institutes of Health Research Cardiothoracic Surgical Trials Network.
        J Thorac Cardiovasc Surg. 2017; 153: 1384-1391
        • Perrault L.P.
        • Kirkwood K.A.
        • Chang H.L.
        • Mullen J.C.
        • Gulack B.C.
        • Argenziano M.
        • et al.
        A prospective multi-institutional cohort study of mediastinal infections after cardiac surgery.
        Ann Thorac Surg. 2017; ([Epub ahead of print])
        • Fine J.P.G.R.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Zhou B.
        • Fine J.
        • Laird G.
        Goodness-of-fit test for proportional subdistribution hazards model.
        Stat Med. 2013; 32: 3804-3811
        • Furnary A.P.
        • Wu Y.
        Clinical effects of hyperglycemia in the cardiac surgery population: the Portland Diabetic Project.
        Endocr Prac. 2006; 12: 22-26
        • Székely A.
        • Levin J.
        • Miao Y.
        • Tudor I.C.
        • Vuylsteke A.
        • Ofner P.
        • et al.
        Impact of hyperglycemia on perioperative mortality after coronary artery bypass graft surgery.
        J Thorac Cardiovasc Surg. 2011; 142: 430-437
        • Cardona S.
        • Pasquel F.J.
        • Fayfman M.
        • Peng L.
        • Jacobs S.
        • Vellanki P.
        • et al.
        Hospitalization costs and clinical outcomes in CABG patients treated with intensive insulin therapy.
        J Diabetes Complications. 2017; 31: 742-747
        • Greco G.
        • Ferket B.S.
        • D'Alessandro D.A.
        • Shi W.
        • Horvath K.A.
        • Rosen A.
        • et al.
        Diabetes and the association of postoperative hyperglycemia with clinical and economic outcomes in cardiac surgery.
        Diabetes Care. 2016; 39: 408-417
        • Allignol A.
        • Schumacher M.
        • Beyersmann J.
        Empirical transition matrix of multi-state models: the etm package.
        J Stat Softw. 2011; 38: 1-15
        • Bateman B.T.
        • Rassen J.A.
        • Schneeweiss S.
        • Bykov K.
        • Franklin J.M.
        • Gagne J.J.
        • et al.
        Adjuvant vancomycin for antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
        J Thorac Cardiovasc Surg. 2013; 146: 472-478
        • Poeran J.
        • Mazumdar M.
        • Rasul R.
        • Meyer J.
        • Sacks H.S.
        • Koll B.S.
        • et al.
        Antibiotic prophylaxis and risk of Clostridium difficile infection after coronary artery bypass graft surgery.
        J Thorac Cardiovasc Surg. 2016; 151: 589-597
        • Karanika S.
        • Paudel S.
        • Zervou F.N.
        • Grigoras C.
        • Zacharioudakis I.M.
        • Mylonakis E.
        Prevalence and clinical outcomes of Clostridium difficile infection in the intensive care unit: a systematic review and meta-analysis.
        Open Forum Infect Dis. 2016; 3: ofv186
        • Mazzeffi M.
        • Gammie J.
        • Taylor B.
        • Cardillo S.
        • Haldane-Lutterodt N.
        • Amoroso A.
        • et al.
        Healthcare-associated infections in cardiac surgery patients with prolonged intensive care unit stay.
        Ann Thorac Surg. 2017; 103: 1165-1170
        • Bruminhent J.
        • Cawcutt K.A.
        • Thongprayoon C.
        • Petterson T.M.
        • Kremers W.K.
        • Razonable R.R.
        Epidemiology, risk factors, and outcome of Clostridium difficile infection in heart and heart-lung transplant recipients.
        Clin Transplant. 2017; 31 ([Epub ahead of print])
        • Hota S.S.
        • Achonu C.
        • Crowcroft N.S.
        • Harvey B.J.
        • Lauwers A.
        • Gardam M.A.
        Determining mortality rates attributable to Clostridium difficile infection.
        Emerg Infect Dis. 2012; 18: 305-307
      1. Centers for Disease Control and Prevention. Nearly half a million Americans suffered from Clostridium difficile infections in a single year. CDC Newsroom Release. February 25, 2015. Available at: https://www.cdc.gov/media/releases/2015/p0225-clostridium-difficile.html. Accessed June 25, 2015.

        • Gorbach S.L.
        Antibiotics and Clostridium difficile.
        N Engl J Med. 1999; 341: 1690-1691
        • Nelson D.E.
        • Auerbach S.B.
        • Baltch A.L.
        • Desjardin E.
        • Beck-Sague C.
        • Rheal C.
        • et al.
        Epidemic Clostridium difficile–associated diarrhea: role of second- and third-generation cephalosporins.
        Infect Control Hosp Epidemiol. 1994; 15: 88-94
        • Aseeri M.
        • Schroeder T.
        • Kramer J.
        • Zackula R.
        Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile–associated diarrhea in hospitalized patients.
        Am J Gastroenterol. 2008; 103: 2308-2313

      Linked Article

      • Beating Clostridium difficile infection—Insights from the Cardiothoracic Surgery Trials Network
        The Journal of Thoracic and Cardiovascular SurgeryVol. 155Issue 2
        • Preview
          Although Clostridium difficile infection (CDI) after cardiac surgery is uncommon, it is increasingly important.1-4 The report by Kirkwood and colleagues from the Cardiothoracic Surgical Trials Network (CTSN) in this issue of the Journal emphasizes CDI as a serious infection after cardiac surgery.2 This important trial reports a post-hoc analysis from the investigation of management practices and major infections after cardiac surgery already published by the CTSN investigators.5 Recognizing that recommended best practice for antibiotic prophylaxis after cardiac surgery is a 48-hour duration, this trial identified multiple risk factors for major infection, including postoperative antibiotic duration >48 hours and stress hyperglycemia.
        • Full-Text
        • PDF
        Open Archive
      • Carpet-bombing the colon is bad
        The Journal of Thoracic and Cardiovascular SurgeryVol. 155Issue 2
        • Preview
          The important article by Kirkwood and colleagues1 in this issue of the Journal analyzes the “incidence and severity of Clostridium difficile infections” from data found in the Cardiothoracic Surgical Trials Network. The frustrating observation is that the incidence of C difficile is increasing, and the subtext question is this: Is this our fault? We have all had patients with deep sternal wound infections, and we will mount almost any measure to avoid this dread complication. Unlike a hole poked in the undersurface of the transverse arch during a redo, the pain of a deep sternal wound infection can linger and punish for weeks.
        • Full-Text
        • PDF
        Open Archive