Total abdominal colectomy versus diverting loop ileostomy with colonic lavage for fulminant clostridium difficile colitis: an updated systematic review and meta-analysis of outcomes.

PURPOSE: Diverting Loop Ileostomy (DLI) with intraoperative colonic lavage has emerged as a potential alternative to Total Abdominal Colectomy (TAC) for treating Fulminant Clostridium Difficile Colitis (FCDC). This study aims to provide an updated review comparing DLI with TAC in managing FCDC. METHODS: A systematic literature search was conducted using PubMed, Scopus, and Embase to identify retrospective and prospective studies comparing DLI with TAC for fulminant CDC treatment. A meta-analysis was performed to evaluate postoperative mortality rates and complications using R Studio version 4.4.1, calculating odds ratios (ORs) with 95% confidence intervals via the Mantel-Haenszel method. Heterogeneity was assessed using the Cochrane Q test and I2 statistics. RESULTS: Our search yielded 228 relevant citations, of which 7 studies with a total of 7,048 patients were included. Of these, 1,728 underwent DLI. The mean age was 63.33 years in the DLI group and 65.74 years in the TAC group. Compared to TAC, DLI had significantly lower postoperative mortality (OR 0.75; 95% CI 0.62-0.90; P = 0.002; I2 = 34%). Trial sequential analysis for postoperative mortality rates showed the benefit of DLI with a sufficiently powered sample. The DLI group also had a significantly higher rate of ostomy reversal (OR 5.68; 95% CI 2.35-13.72; P < 0.001; I2 = 36%). Postoperative complications, such as thromboembolic events, surgical site infections, urinary tract infections, renal failure, and pneumonia, were not significantly different. CONCLUSION: DLI shows a lower postoperative mortality rate and higher ostomy reversal rate than TAC, suggesting it as a potential organ-preserving, minimally invasive alternative. Further high-quality studies and trials are needed to confirm these findings.

Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage.

Pathobionts play a critical role in disease development, but the immune mechanisms against pathobionts remain poorly understood. Here, we report a critical role for interleukin-22 (IL-22) in systemic protection against bacterial pathobionts that translocate into the circulation after infection with the pathogen Clostridium difficile. Infection with C. difficile induced IL-22, and infected Il22(-/-) mice harbored high numbers of pathobionts in extraintestinal organs despite comparable pathogen load and intestinal damage in mutant and wild-type mice. Pathobionts exhibited increased resistant against complement-mediated phagocytosis, and their intravenous administration resulted in high animal mortality. Selective removal of translocated commensals rescued Il22(-/-) mice, and IL-22 administration enhanced the elimination of pathobionts. Mechanistically, IL-22 augmented bacterial phagocytosis by increasing the expression and bacterial binding of complement C3. Our study demonstrates an unexpected role for IL-22 in controlling the elimination of pathobionts that enter the systemic circulation through the regulation of the complement system.

Acid suppression therapy, gastrointestinal bleeding and infection in acute pancreatitis - An international cohort study.

BACKGROUND: Acid suppressing drugs (ASD) are generally used in acute pancreatitis (AP); however, large cohorts are not available to understand their efficiency and safety. Therefore, our aims were to evaluate the association between the administration of ASDs, the outcome of AP, the frequency of gastrointestinal (GI) bleeding and GI infection in patients with AP. METHODS: We initiated an international survey and performed retrospective data analysis on AP patients hospitalized between January 2013 and December 2018. RESULTS: Data of 17,422 adult patients with AP were collected from 59 centers of 23 countries. We found that 23.3% of patients received ASDs before and 86.6% during the course of AP. ASDs were prescribed to 57.6% of patients at discharge. ASD administration was associated with more severe AP and higher mortality. GI bleeding was reported in 4.7% of patients, and it was associated with pancreatitis severity, mortality and ASD therapy. Stool culture test was performed in 6.3% of the patients with 28.4% positive results. Clostridium difficile was the cause of GI infection in 60.5% of cases. Among the patients with GI infections, 28.9% received ASDs, whereas 24.1% were without any acid suppression treatment. GI infection was associated with more severe pancreatitis and higher mortality. CONCLUSIONS: Although ASD therapy is widely used, it is unlikely to have beneficial effects either on the outcome of AP or on the prevention of GI bleeding during AP. Therefore, ASD therapy should be substantially decreased in the therapeutic management of AP.

A systematic review and meta-analysis of diverting loop ileostomy versus total abdominal colectomy for the treatment of Clostridium difficile colitis.

BACKGROUND: Clostridium difficile is an increasingly common source of in-patient morbidity and mortality. We aim to assess the effects of diverting loop ileostomy (DLI) versus total abdominal colectomy (TAC) for Clostridium difficile colitis (CDC), in terms of mortality and morbidity. METHODS: Systematic literature search was performed using PubMed, Embase, Cochrane, and Web of Science databases for randomized and non-randomized studies comparing DLI and TAC for fulminant CDC. Meta-analysis was carried out for mortality and postoperative complications. RESULTS: Five non-randomized studies qualified for inclusion in the quantitative synthesis. In total, 3683 patients were allocated to DLI (n = 733) or TAC (n = 2950). The overall mortality was equivalent (OR 0.73; 95% CI 0.45-1.20; P = 0.22). Regarding secondary outcomes, the pooled analysis revealed the following equivalent rates of postoperative events: thromboembolism (OR 0.45; 95% CI 0.14-1.43; P = 0.18), acute renal failure (OR 1.71; 95% CI 0.91-3.23; P = 0.10), surgical site infection (OR 0.95; 95% CI 0.11-8.59; P = 0.97), pneumonia (OR 0.98; 95% CI 0.36-2.66; P = 0.97), urinary tract infection (OR 0.81; 95% CI 0.26-2.52; P = 0.72), and reoperation (OR 0.95; 95% CI 0.50-1.82; P = 0.78). The ostomy reversal rate was significantly higher in DLI (OR 12.55; 95% CI 3.31-47.55; P = 0.0002). CONCLUSIONS: The overall morbidity and mortality rates between DLI and TAC for the treatment of CDC seemed to be equivalent. Evidence from a randomized controlled trial is needed to clarify the timing and understand the impact of DLI for CDC.

Early Colectomy Saves Lives in Toxic Megacolon Due to Clostridium difficile Infection.

OBJECTIVE: The purpose of the study was to evaluate whether early colectomy in patients who have toxic megacolon due to Clostridium difficile colitis reduces mortality. METHODS: The study was performed using the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2016. All patients 18 to 89 years of age who underwent colectomy for toxic megacolon resulting from C. difficile colitis were included in the study. Other variables included in the study were patient demography, comorbidities, and outcomes. Patients who underwent colectomy before the presentation of septic shock (early group) were compared with patients who underwent colectomy after the onset of septic shock (late group). The main outcome of the study is 30-day all-cause mortality. Because there were some significant differences found in patient baseline characteristics in the univariate analysis, the propensity score of each patient was calculated and pair-matched analysis was performed. All P values are reported as 2-sided, and P < 0.05 was considered statistically significant. RESULTS: One hundred sixty-three patients met the inclusion criteria of the study. Approximately 85% of the patients underwent total abdominal colectomy. The average age of the patients was 65 years old, 51% of the patients were female, and 66% of the patients were white. The overall 30-day mortality was approximately 39%. The mortality rate of patients who underwent colectomy early compared to late was 13 (21%) vs 28 (45%), P = 0.009. The absolute risk difference was 0.24 with 95% CI: 0.07-0.42. CONCLUSIONS: There was a reduction of 24% in 30-day mortality when colectomies were performed before the development of septic shock.

Evaluation of risk factors for a fulminant Clostridium difficile infection after cardiac surgery: a single-center, retrospective cohort study.

BACKGROUND: Clostridium difficile (CD) is the most common pathogen causing nosocomial diarrhea. The clinical presentation ranges from mild diarrhea to severe complications, including pseudomembranous colitis, toxic megacolon, sepsis, and multi-organ failure. When the disease takes a fulminant course, death ensues rapidly in severe and complex cases. Preventive screening or current prophylactic therapies are not useful. Therefore, this study was conducted to detect risk factors for a fulminant CD infection (CDI) in patients undergoing cardiac surgery. METHODS: Between April 1999 and April 2011, a total of 41,466 patients underwent cardiac surgery at our institution. A review of our hospital database revealed 1256 patients (3.0%) with post-operative diarrheal disease who tested positive for CD; these patients comprised the cohort of this observational study. A fulminant CDI occurred in 153 of these patients (12.2%), which was diagnosed on the basis of gastrointestinal complications, e.g. pseudomembranous colitis, and/or the need for post-cardiac surgery laparotomy. Demographic, peri-operative, and survival data were analyzed, and predictors of a fulminant CDI were assessed by binary logistic regression analysis. RESULTS: The 30-day mortality was 6.1% (n = 77) for the entire cohort, with significantly higher mortality among patients with a fulminant CDI (21.6% vs. 4.0%, p <  0.001). Overall mortality (27.7%, n = 348) was also higher for patients with a fulminant course of the disease (63.4% vs. 22.8%, p <  0.001), and a laparotomy was required in 36.6% (n = 56) of the fulminant cases. Independent predictors of a fulminant CDI were: diabetes mellitus type 2 (OR 1.74, CI 1.15-2.63, p = 0.008), pre-operative ventilation (OR 3.52, CI 1.32-9.35, p = 0.012), utilization of more than 8 units of red blood cell concentrates (OR 1.95, CI 1.01-3.76, p = 0.046) or of more than 5 fresh-frozen plasma units (OR 3.38, CI 2.06-5.54, p <  0.001), and a cross-clamp time > 130 min (OR 1.93, CI 1.12-3.33, p = 0.017). CONCLUSIONS: We identified several independent risk factors for the development of a fulminant CDI after cardiac surgery. Close monitoring of high-risk patients is important in order to establish an early onset of therapy and thus to prevent a CDI from developing a fulminant course after cardiac surgery.

How Common-and How Serious- Is Clostridium difficile Colitis After Geriatric Hip Fracture? Findings from the NSQIP Dataset.

BACKGROUND: Patients with geriatric hip fractures may be at increased risk for postoperative Clostridium difficile colitis, which can cause severe morbidity and can influence hospital quality metrics. However, to our knowledge, no large database study has calculated the incidence of, factors associated with, and effect of C. difficile colitis on geriatric patients undergoing hip fracture surgery. QUESTIONS/PURPOSES: To use a large national database with in-hospital and postdischarge data (National Surgical Quality Improvement Program [NSQIP®]) to (1) determine the incidence and timing of C. difficile colitis in geriatric patients who underwent surgery for hip fracture, (2) identify preoperative and postoperative factors associated with the development of C. difficile colitis in these patients, and (3) test for an association between C. difficile colitis and postoperative length of stay, 30-day readmission, and 30-day mortality. PATIENTS AND METHODS: This is a retrospective study. Patients who were 65 years or older who underwent hip fracture surgery were identified in the 2015 NSQIP database. The primary outcome was a diagnosis of C. difficile colitis during the 30-day postoperative period. Preoperative and procedural factors were tested for association with the development of C. difficile colitis through a backward stepwise multivariate model. Perioperative antibiotic type and duration were not included in the model, as this information was not recorded in the NSQIP. The association between C. difficile colitis and postoperative length of stay, 30-day readmission, and 30-day mortality were tested through multivariate regressions, which adjusted for preoperative and procedural characteristics such as age, comorbidities, and surgical procedure. A total of 6928 patients who were 65 years or older and underwent hip fracture surgery were identified. RESULTS: The incidence of postoperative C. difficile colitis was 1.05% (95% CI, 0.81%-1.29%; 73 of 6928 patients). Of patients who had C. difficile colitis develop, 64% (47 of 73 patients) were diagnosed postdischarge and 79% (58 of 73 patients) did not have a preceding infectious diagnosis. Preoperative factors identifiable before surgery that were associated with the development of C. difficile colitis included admission from any type of chronic care facility (versus admitted from home; relative risk [RR] = 1.98; 95% CI, 1.11-3.55; p = 0.027), current smoker within 1 year (RR = 1.95; 95% CI, 1.03-3.69; p = 0.041), and preoperative anemia (RR = 1.76; 95% CI, 1.07-2.92; p = 0.027). Patients who had pneumonia (RR = 2.58; 95% CI, 1.20-5.53; p = 0.015), sepsis (RR = 4.20; 95% CI, 1.27-13.82; p = 0.018), or "any infection" (RR = 2.26; 95% CI, 1.26-4.03; p = 0.006) develop after hip fracture were more likely to have C. difficile colitis develop. Development of C. difficile colitis was associated with greater postoperative length of stay (22 versus 5 days; p < 0.001), 30-day readmission (RR = 3.41; 95% CI, 2.17-5.36; p < 0.001), and 30-day mortality (15% [11 of 73 patients] versus 6% [439 of 6855 patients]; RR = 2.16; 95% CI, 1.22-3.80; p = 0.008). CONCLUSIONS: C. difficile colitis is a serious infection after hip fracture surgery in geriatric patients that is associated with 15% mortality. Patients at high risk, such as those admitted from any type of chronic care facility, those who had preoperative anemia, and current smokers within 1 year, should be targeted with preventative measures. From previous studies, these measures include enforcing strict hand hygiene with soap and water (not alcohol sanitizers) if a provider is caring for patients at high risk and those who are C. difficile-positive. Further, other studies have shown that certain antibiotics, such as fluoroquinolones and cephalosporins, can predispose patients to C. difficile colitis. These medications perhaps should be avoided when prescribing prophylactic antibiotics or managing infections in patients at high risk. Future prospective studies should aim to determine the best prophylactic antibiotic regimens, probiotic formula, and discharge timing that minimize postoperative C. difficile colitis in patients with hip fractures. LEVEL OF EVIDENCE: Level III, therapeutic study.

Protection of Hamsters from Mortality by Reducing Fecal Moxifloxacin Concentration with DAV131A in a Model of Moxifloxacin-Induced Clostridium difficile Colitis.

Lowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effects of an activated charcoal-based adsorbent, DAV131A, on the fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced Clostridium difficile infection. A total of 215 hamsters receiving moxifloxacin subcutaneously (day 1 [D1] to D5) were orally infected at D3 with C. difficile spores. They received various doses (0 to 1,800 mg/kg of body weight/day) and schedules (twice a day [BID] or three times a day [TID]) of DAV131A (D1 to D8). Moxifloxacin concentrations and C. difficile counts were determined at D3, and mortality was determined at D12 We compared mortality rates, moxifloxacin concentrations, and C. difficile counts according to DAV131A regimen and modeled the links between DAV131A regimen, moxifloxacin concentration, and mortality. All hamsters that received no DAV131A died, but none of those that received 1,800 mg/kg/day died. Significant dose-dependent relationships between DAV131A dose and (i) mortality, (ii) moxifloxacin concentration, and (iii) C. difficile count were evidenced. Mathematical modeling suggested that (i) lowering the moxifloxacin concentration at D3, which was 58 µg/g (95% confidence interval [CI] = 50 to 66 µg/g) without DAV131A, to 17 µg/g (14 to 21 µg/g) would reduce mortality by 90%; and (ii) this would be achieved with a daily DAV131A dose of 703 mg/kg (596 to 809 mg/kg). In this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing the fecal free moxifloxacin concentration.

A Surgical Clostridium-Associated Risk of Death Score Predicts Mortality After Colectomy for Clostridium difficile.

BACKGROUND: A Clostridium difficile-associated risk of death score was recently developed and validated by using a national cohort of both nonsurgical and surgical patients admitted with C difficile infection. However, risk scores specifically derived from surgical cohorts and designed for patients with C difficile infection are currently unavailable. OBJECTIVE: The aim of this study was to develop a risk of death score for patients with C difficile infection who are being considered for total abdominal colectomy because of the failure of medical therapy. DESIGN: This is a retrospective cohort study. SETTINGS: This study was conducted with the use of a national database. PATIENTS: All patients undergoing total colectomy for C difficile infection were identified in the National Surgical Quality Improvement Program database from 2005 to 2014. MAIN OUTCOME MEASURES: Variables similar to the original scoring system were used in multivariable analyses to determine the risk of 30-day mortality for patients, and a model was constructed to estimate the predicted probability of mortality after surgery. RESULTS: Of 532 patients who underwent surgery, 32.7% experienced 30-day postoperative mortality. Patient covariates associated with significantly increased mortality included age greater than 80 years (OR 5.5, p = 0.003), need for preoperative mechanical ventilation (OR 3.1, p < 0.001), chronic steroid use (OR 2.9, p < 0.001), underlying cardiopulmonary disease (OR 2.0, p = 0.001), and acute renal failure (OR=1.7, p = 0.03). These and other comorbidities, including hepatic disease, a cancer diagnosis, and both insulin- and noninsulin-dependent diabetes mellitus, were used to construct a model to estimate the predicted probability of mortality, which ranged from 8.0% to 96.1% based on individual comorbidity profiles. These estimates differed substantially when compared with those obtained using the National Surgical Quality Improvement Program risk calculator, which estimated the risk of mortality among surgical patients as being consistently lower. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Our surgical scoring system allows preoperative risk stratification for patients being evaluated for colectomy for C difficile infection, potentially helping to avoid futile surgery. See Video Abstract at http://links.lww.com/DCR/A434.

Diagnosis and outcome of Clostridium difficile infection by toxin enzyme immunoassay and polymerase chain reaction in an island population.

BACKGROUND AND AIM: Clostridium difficile infection (CDI) is a potentially life-threatening cause of diarrhea. Correct laboratory diagnosis is essential to differentiate CDI from other causes of diarrhea. A positive fecal C. difficile toxin (CDT) is the best indicator of CDI, but the significance of a positive fecal nucleic acid amplification test (NAAT) remains unclear. Our aim was to elucidate the significance of CDI diagnostics in patients in Jersey. METHODS: A retrospective, 5-year study was conducted at an island district general hospital of patients who developed CDI. Patients were grouped according to CDT and NAAT status and their association with outcome (indicators of severity and 30-day case-fatality rate) compared. RESULTS: A total of 207 specimens were toxin positive, 92 NAAT positive and toxin negative, and 39 had a stool sample negative by both toxin and NAAT testing. A positive toxin stool sample was associated with both significantly higher white cell count (14.5 × 109 /L vs 11.3 × 109 /L, P = 0.003) and C-reactive protein (114.7 mg/dL vs 82.9 mg/dL, P = 0.001), but NAAT positivity was not (P = 0.269, 0.728). A positive CDT assay was a significant independent predictor of death (odds ratio [OR]: 1.89 [95% CI: 1.04-3.43], P = 0.046), but a positive NAAT in CDT negative samples was not (OR: 1.02 [95% CI: 0.34-3.12], P = 1.0). CONCLUSIONS: The findings of this study, derived from evolving clinical practice, provide greater clarity in the interpretation of CDI diagnostics. In CDT-negative disease, a positive NAAT neither predicts disease severity nor mortality. NAAT-positive and toxin-negative patients require instigation of infection control measures, but the need for specific treatment remains unclear.

Clostridium Difficile Infection Due to Pneumonia Treatment: Mortality Risk Models.

One of the most common gastrointestinal infection after the antibiotic treatment of community or nosocomial pneumonia is caused by the anaerobic spore Clostridium difficile (C. difficile). The aim of this study was to retrospectively assess mortality due to C. difficile infection (CDI) in patients treated for pneumonia. We identified 94 cases of post-pneumonia CDI out of the 217 patients with CDI. The mortality issue was addressed by creating a mortality risk models using logistic regression and multivariate fractional polynomial analysis. The patients' demographics, clinical features, and laboratory results were taken into consideration. To estimate the influence of the preceding respiratory infection, a pneumonia severity scale was included in the analysis. The analysis showed two statistically significant and clinically relevant mortality models. The model with the highest prognostic strength entailed age, leukocyte count, serum creatinine and urea concentration, hematocrit, coexisting neoplasia or chronic obstructive pulmonary disease. In conclusion, we report on two prognostic models, based on clinically relevant factors, which can be of help in predicting mortality risk in C. difficile infection, secondary to the antibiotic treatment of pneumonia. These models could be useful in preventive tailoring of individual therapy.

The role of purified Clostridium difficile glucosylating toxins in disease pathogenesis utilizing a murine cecum injection model.

Most pathogenic Clostridium difficile produce two major exotoxins TcdA and TcdB, in the absence of which the bacterium is non-pathogenic. While it is important to investigate the role of each toxin in the pathogenesis of C. difficile infection (CDI) using isogenic strains, it is impossible to precisely control the expression levels of individual toxins and exclude bacterial factors that may contribute to the toxins' effects during infection. In this study, we utilized an acute intestinal disease model by injecting purified toxins directly into mouse cecum after a midline laparotomy. We evaluated the physical condition of mice by clinical score and survival, and the intestinal tissue damage and inflammation by histology. Depending on the dose of the toxins, mice developed mild to severe colitis, experienced diarrhea or rapidly died. We found that both purified TcdA and TcdB were able to induce clinical disease, intestinal inflammation, and tissue damage that resembled CDI. TcdA was significantly faster in inducing intestinal inflammation and tissue damage, and was approximately five times more potent than TcdB in terms of inducing severe gut disease and death outcomes in mice. Moreover, we found that the two toxins had significant synergistic effects on disease induction. Comparison of the in vivo toxicity of TcdB from clinical strains revealed that TcdB from an epidemic RT 027 strain was more toxic than the others. Our study thus demonstrates that both TcdA and TcdB, independent of other factors from C. difficile bacterium, are able to cause disease that resembles CDI and highlights the importance of targeting both toxins for vaccines and therapeutics against the disease.

[Antimicrobial susceptibilities and molecular characterization of toxin-positive Clostridium difficile isolates: the first report on the presence of hypervirulent strains from Turkey]. / Toksin Pozitif Clostridium difficile Izolatlarinin Antimikrobiyal Duyarliliklari ve Moleküler Karakterizasyonu: Türkiye'den Hipervirülan Suslarin Varligi ile Iliskili Ilk Bildirim.

Clostridium difficile infection is one of the most important hospital-acquired infections. Infections caused by hypervirulent C.difficile strains which produce toxins at high levels, have higher morbidity and mortality rates, more complications and relapses. They are characterized by higher sporulation ratios and resistance rates for fluoroquinolones. In order to prevent serious morbidities, mortalities and remarkable increase in health costs, highly pathogenic C.difficile strains must be identified before causing severe outbreaks. The aim of this study was to determine the antimicrobial susceptibilities and molecular characteristics of 61 C.difficile strains isolated by culture from toxin-positive fecal samples of patients who were admitted to three different laboratories in Ankara, between September 2012 and November 2014. Antimicrobial susceptibilities were determined by using gradient test strips and results were interpreted according to the current CLSI and EUCAST criteria. The presence of toxin genes was investigated by polymerase chain reaction (PCR), and mutations in the tcdC gene were determined by sequence analysis following PCR amplification. Genetic characterization of one hypervirulent strain was performed by Public Health Institution of Turkey using the GenoType CDiff (Hain Lifescience, Germany) test. All strains were susceptible to vancomycin and metronidazole. Three (4.9%) isolates were resistant to moxifloxacin with a minimum inhibitory concentration (MIC) of > 8 µg/ml. The MIC50 and MIC90 values for erythromycin and clindamycin were 1.5-3 µg/ml, and 2-4 µg/ml, respectively. All strains carried the tcdA and tcdB genes, and 1 (1.6%) was positive for the binary-toxin (cdtA and cdtB) genes. The binary-toxin positive strain carried a 54 bp deletion as well as a single nucleotide change in the tcdC gene. Various single nucleotide changes were found in the tcdC gene of 12 strains (19.6%). Our results have shown that, hypervirulent strains exist in our country, but we have no evidence for the presence of ribotype 027 yet. On the other hand, when the increasing incidence of these strains through out the world is taken into consideration, it would be of great importance to perform surveillance studies and characterize the isolated strains.

Fluoroquinolone and Macrolide Exposure Predict Clostridium difficile Infection with the Highly Fluoroquinolone- and Macrolide-Resistant Epidemic C. difficile Strain BI/NAP1/027.

Antibiotics have been shown to influence the risk of infection with specific Clostridium difficile strains as well as the risk of C. difficile infection (CDI). We performed a retrospective case-control study of patients infected with the epidemic BI/NAP1/027 strain in a U.S. hospital following recognition of increased CDI severity and culture of stools positive by C. difficile toxin immunoassay. Between 2005 and 2007, 72% (103/143) of patients with first-episode CDIs were infected with the BI strain by restriction endonuclease analysis (REA) typing. Most patients received multiple antibiotics within 6 weeks of CDI onset (median of 3 antibiotic classes). By multivariate analysis, fluoroquinolone and macrolide exposure was more frequent among BI cases than among non-BI-infected controls (odds ratio [OR] for fluoroquinolones, 3.2; 95% confidence interval [CI], 1.3 to 7.5; (P < 0.001; OR for macrolides, 5.2; 95% CI, 1.1 to 24.0; P = 0.04)). In contrast, clindamycin use was less frequent among the BI cases than among the controls (OR, 0.1; 95% CI, 0.03 to 0.4; P = 0.001). High-level resistance to moxifloxacin and azithromycin was more frequent among BI strains (moxifloxacin, 49/102 [48%] BI versus 0/40 non-BI, P = 0.0001; azithromycin, 100/102 [98%] BI versus 22/40 [55%] non-BI, P = 0.0001). High-level resistance to clindamycin was more frequent among non-BI strains (22/40 [55%] non-BI versus 7/102 [7%] BI, P = 0.0001). Fluoroquinolone use, macrolide use, and C. difficile resistance to these antibiotic classes were associated with infection by the epidemic BI strain of C. difficile in a U.S. hospital during a time when CDI rates were increasing nationally due to the highly fluoroquinolone-resistant BI/NAP1/027 strain.

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria.

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study.

OBJECTIVES: Recurrent Clostridium difficile infection (rCDI) contributes to a significant burden of disease in patients with inflammatory bowel disease (IBD). In this study, we seek to identify risk factors for rCDI in a population of IBD patients at the Mount Sinai Hospital IBD Centre. METHODS: In this retrospective cohort study, IBD patients with rCDI diagnosed between 2010 and 2013 were identified and compared with IBD patients with single-episode CDI. Multivariate regression was used to identify predictors of rCDI in IBD. Outcome analysis was performed for hospitalizations due to CDI, colectomy, and CDI-attributable mortality. RESULTS: A total of 503 patients were included, 110 (22%) of whom had IBD (49% CD, 51% ulcerative colitis). Recurrent CDI occurred in 32% of IBD patients compared with 24% of non-IBD patients (P<0.01). IBD patients with rCDI were more likely than those without rCDI to report recent antibiotic therapy (42.9 vs. 30.7%, P<0.01), 5-aminosalicylic acid (5-ASA) use (51.5 vs. 30.7%, P<0.001), steroid use (51.4 vs. 33.3%, P<0.001), and biologic therapy (48.6 vs. 40.0%, P<0.01). Infliximab (34.3 vs. 17.3%, P<0.01) but not adalimumab was associated with more rCDI events. Using a Cox model of predictors of rCDI in IBD, significant predictors included non-ileal Crohn's disease (hazard ratio (HR) 2.85, 95% confidence interval (CI) 1.30-6.30) and the use of 5-ASA (HR 2.15, 95% CI 1.11-4.18). CONCLUSIONS: Compared with the general population, IBD patients are 33% more likely to experience rCDI. Within the IBD cohort, exposure to certain drug classes (antibiotics, 5-ASA, steroids, certain biologics) and non-ileal Crohn's disease were found to be the predictors of rCDI.

The efficacy of intracolonic vancomycin for severe Clostridium difficile colitis: a case series.

BACKGROUND: Clostridium difficile infection (CDI) unresponsive to the standard treatments of metronidazole and oral vancomycin requires aggressive medical management and possible surgical intervention including colectomy. Intracolonic vancomycin therapy has been reported to be particularly promising in the setting of severe CDI in the presence of ileus. This is a descriptive case series exploring the effect of adjunctive intracolonic vancomycin therapy on the morbidity and mortality in patients with moderate to severe CDI. METHODS: A retrospective chart review was conducted on 696 patients with CDI seen at a single institution. Each patient was assigned a severity score and 127 patients with moderate to severe CDI were identified. We describe the clinical presentation, risk factors and hospital course comparing those that received adjunctive intracolonic vancomycin to those that only received standard therapy. RESULTS: The group that received adjunctive intracolonic vancomycin had higher rates of toxic megacolon, intensive care unit (ICU) admission, and colectomy, and yet maintained a similar mortality rate as the group that received only standard treatment. CONCLUSION: The intracolonic vancomycin group experienced more complications but showed a similar mortality rate to the standard therapy group, suggesting that intracolonic vancomycin may impart a protective effect. This study adds further evidence for the need of a randomized controlled study using intracolonic vancomycin as adjunctive therapy in patients presenting with severe CDI.

Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach.

BACKGROUND: Despite a large increase in Clostridium difficile infection (CDI) severity, morbidity and mortality in the US since the early 2000s, CDI burden estimates have had limited generalizability and comparability due to widely varying clinical settings, populations, or study designs. METHODS: A decision-analytic model incorporating key input parameters important in CDI epidemiology was developed to estimate the annual number of initial and recurrent CDI cases, attributable and all-cause deaths, economic burden in the general population, and specific number of high-risk patients in different healthcare settings and the community in the US. Economic burden was calculated adopting a societal perspective using a bottom-up approach that identified healthcare resources consumed in the management of CDI. RESULTS: Annually, a total of 606,058 (439,237 initial and 166,821 recurrent) episodes of CDI were predicted in 2014: 34.3 % arose from community exposure. Over 44,500 CDI-attributable deaths in 2014 were estimated to occur. High-risk susceptible individuals representing 5 % of the total hospital population accounted for 23 % of hospitalized CDI patients. The economic cost of CDI was $5.4 billion ($4.7 billion (86.7 %) in healthcare settings; $725 million (13.3 %) in the community), mostly due to hospitalization. CONCLUSIONS: A modeling framework provides more comprehensive and detailed national-level estimates of CDI cases, recurrences, deaths and cost in different patient groups than currently available from separate individual studies. As new treatments for CDI are developed, this model can provide reliable estimates to better focus healthcare resources to those specific age-groups, risk-groups, and care settings in the US where they are most needed. (Trial Identifier ClinicaTrials.gov: NCT01241552).

Impact of Evidence-Based Guidelines on Outcomes of Hospitalized Patients With Clostridium difficile Infection.

OBJECTIVES: Clostridium difficile infection (CDI) is the most common healthcare-associated infection in the United States. Clinical practice guidelines for the treatment of CDI were updated in 2010 by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. An institutional guideline for the classification and management of CDI in accordance with the 2010 Society for Healthcare Epidemiology of America/Infectious Diseases Society of America guideline was developed and provided to attending physicians and medical residents in multiple formats. METHODS: We sought to determine the impact of an evidence-based guideline for the treatment of CDI at a community teaching hospital. A retrospective chart review was conducted to identify length of stay (LOS), readmission rates, direct cost, mortality, and physician adherence to guidelines in patients with International Classification of Diseases, Ninth Edition codes and laboratory confirmation of CDI between February 1, 2013 and January 31, 2014. Endpoints included LOS after diagnosis of CDI, 30-day readmission rates, direct cost after diagnosis of CDI, and mortality. RESULTS: A total of 351 patient encounters were included in the study. Although not statistically significant, it was found that guideline-based therapy (n = 131) was associated with a lower median LOS (6 days vs 8 days; P = 0.06). Thirty-day hospital readmission (25.2% vs 29.5%; P = 0.39) and median cost after diagnosis of CDI ($7238.48 vs $8794.81; P = 0.10) also were lower but not statistically significant. Patients with mild-to-moderate infection were found to have a significantly lower median LOS (5 days vs 7 days; P = 0.03) and median cost after diagnosis ($5257.85 vs $7680.56; P = 0.03) when treated with guideline-based therapy. Overall physician adherence to guidelines was low, at 38%. CONCLUSIONS: Treatment with guideline-based therapy for CDI was associated with a trend toward a significantly lower LOS and cost. Barriers to physician adherence to guidelines still exist, despite education and guideline availability. Electronic health record-based order sets or clinical decision tools may improve recognition of and adherence to guidelines.

Induction of antitoxin responses in Clostridium-difficile-infected patients compared to healthy blood donors.

According to the literature Clostridium difficile antitoxins are present in up to 66% of humans. In a survey of ∼400 plasma samples from healthy blood donors we found that less than 6% were positive for anti-TcdA or anti-TcdB antitoxins. Using the same standard immunoassay protocol, we looked for IgG and IgA antitoxins in the blood and stool samples from 25 patients with C. difficile infection (CDI). Some patients with CDI had no antitoxin detected at all, while others had high levels of specific IgG- and IgA-antitoxins against both TcdA and TcdB in blood and IgA-anti-TcdA and -anti-TcdB antibodies in stool. Systemic responses to TcdB and mucosal responses to TcdA predominated. Among patients infected with the NAP1/027/BI strain, systemic IgG-anti-TcdB responses were particularly elevated. In contrast, patients infected with non-027 strains had more elevated mucosal IgA-anti-TcdA responses. Furthermore, high titer sera did not correlate with high neutralizing potential. We hypothesize that paradoxical killing of primed B-cells by antibody-mediated endosomal uptake of the Large Clostridial Toxins, TcdA and TcdB leads to clonal elimination of the fittest B-cells. If this hypothesis is confirmed, immune suppression rather than protective humoral immunity might be the consequence in some patients infected with toxigenic C. difficile.