Diagnostic value of fecal calprotein combined with serum C-reactive protein in severe Clostridium difficile infection

Clostridioides difficile Infection in Chronic Kidney Disease/End-Stage Renal Disease.

Tigecycline is a third-line therapy for severe Clostridium difficile infection (CDI) in Australasian guidelines. Differences in strain types make it difficult to extrapolate international tigecycline efficacy data with combination or monotherapy to Australian practice, where experience is limited. To evaluate the efficacy and adverse effects associated with tigecycline combination therapy for severe and severe-complicated CDI in an Australian healthcare setting. This was a retrospective observational study at a metropolitan university-affiliated hospital. All patients between February 2013 and October 2016 treated with adjunctive intravenous tigecycline for >48 h for severe or severe-complicated CDI were included. Tigecycline was given in addition to oral vancomycin ± intravenous metronidazole. The primary outcome was all-cause mortality at 30 days from start of tigecycline combination therapy. Secondary outcomes included clinical cure, colectomy, adverse events and recurrence rates. Thirteen patients with median age of 61 years had severe (n = 9) or severe-complicated (n = 4) CDI at tigecycline commencement. In 92% of patients, tigecycline started within 48 h after in-hospital CDI treatment, for median duration of 9 days. All-cause mortality at 30 days was 8% with no mortality in severe CDI and 25% (1/4) in patients with severe-complicated fulminant CDI, comparing favourably with historical rates of 9-38% and 30-80% in similar respective groups. Clinical cure was achieved in 77% of cases. There were no colectomies and one attributable tigecycline adverse reaction. Tigecycline appears safe and effective as a part of combination therapy in severe CDI, and may be given earlier and for shorter durations than in current guidelines.

The aim of this study was to compare clinical cure rate, recurrence rate and time to resolution of diarrhea in patients with severe and severe-complicated Clostridium difficile infection (CDI) treated with teicoplanin or vancomycin. This two-year prospective observational study included patients with first episode or first recurrence of CDI who had severe or severe-complicated CDI and were treated with teicoplanin or vancomycin. Primary outcomes of interest were clinical cure rate at discharge and recurrence rate after eight weeks follow up, and secondary outcomes were all-cause mortality and time to resolution of diarrhea. Among 287 study patients, 107 were treated with teicoplanin and 180 with vancomycin. The mean age of patients was 73.5 ± 10.6years. One hundred eighty six patients (64.8%) had prior CDI episode. Severe complicated disease was detected in 23/107 (21.5%) and 42/180 (23.3%) patients treated with teicoplanin and vancomycin, respectively. There was no statistically significant difference in time to resolution of diarrhea between two treatment arms (6.0 ± 3.4 vs 6.2 ± 3.1days, p = 0.672). Treatment with teicoplanin resulted in significantly higher clinical cure rate compared to vancomycin [90.7% vs 79.4%, p = 0.013, odds ratio (OR) (95% confidence interval (CI)) 2.51 (1.19-5.28)]. Recurrence rates were significantly lower in patients treated with teicoplanin [9/97 (9.3%) vs 49/143 (34.3%), p < 0.001, OR (95%CI) 0.20 (0.09-0.42)]. There was no statistically significant difference in overall mortality rate. Teicoplanin might be a good treatment option for patients with severe CDI. Patients treated with teicoplanin experienced remarkably lower recurrence rates compared to vancomycin-treated patients.

Introduction: Severe Clostridium difficile infection (CDI) is often complicated by fulminant colitis and multiorgan failure. Urgent subtotal colectomy can be lifesaving, but it is associated with 50% mortality. Fecal microbiota transplantation (FMT) is widely used to treat recurrent CDI; however, only a few case reports describe its use in hospitalized patients who are critically ill. Methods: Patients with severe and severe/complicated CDI (defined as per 2013 ACG guidelines) who were considered for urgent subtotal colectomy between July 2013 and April 2014 were offered the option of FMT at our institution. Patient variables and outcomes were prospectively collected using an IRB study protocol. FMT was performed using a colonoscope and CO2 insufflation with delivery either proximal or distal to the splenic flexure at the discretion of the endoscopist. Fresh stool was obtained from either a patient-selected donor or universal donor for FMT. After initial FMT, oral vancomycin (125 mg q 6 hrs) was started within 24-72 hours and continued until second FMT (range: 5-14 days). If pseudomembranous colitis was present at the time of the second FMT, oral vancomycin was resumed and a third FMT was offered (range: 5-14 days). Results: Seventeen patients (8 with severe and 9 with severe-complicated CDI) with mean age of 68±14.74 years (53% were females; 100% were white; 12% on immunosuppression) underwent FMT. All patients had failed to respond to prior antibiotic therapy (vancomycin or fidaxomicin) and had pseudomembranous colitis on the first FMT. The mean serum albumin level was 2.4±0.42 g/dL and the mean WBC count was 17.4±19.1 k/mm3. Eleven (65%) patients underwent bowel preparation prior to FMT. Stool was delivered proximal to the splenic flexure in 60% and distal to the splenic flexure in the remaining. Ten patients (59%) received a second FMT with median time to repeat FMT of 7.5 days. Three (18%) patients received a third FMT. Fifteen patients (88%) were cured and avoided colectomy within 3 months of initial FMT. Of the 2 patients who died of multiorgan failure, one was under immunosuppression (recent liver transplantation) and the other had septic shock with a pH of 7.09 at the time of initial FMT. No SAEs related to colonoscopy or FMT were observed. Conclusion: Response-guided FMT in combination with vancomycin is a promising treatment alternative to surgery for severe and severe-complicated CDI, a condition that is typically associated with high mortality.

The incidence and severity of Clostridium difficile infection (CDI) is increasing among adults; however, little is known about the epidemiology of CDI among children. We conducted a nested case-control study to identify the risk factors for and a prospective cohort study to determine the outcomes associated with severe CDI at 2 children's hospitals. Severe CDI was defined as CDI and at least 1 complication or ≥2 laboratory or clinical indicators consistent with severe disease. Studied outcomes included relapse, treatment failure, and CDI-related complications. Isolates were tested to determine North American pulsed-field gel electrophoresis type 1 lineage. We analyzed 82 patients with CDI, of whom 48 had severe disease. Median age in years was 5.93 (1.78-12.16) and 1.83 (0.67-8.1) in subjects with severe and nonsevere CDI, respectively (P = 0.012). All patients with malignancy and CDI had severe disease. Nine subjects (11%) had North American pulsed-field gel electrophoresis type 1 isolates. Risk factors for severe disease included age (adjusted odds ratio [95% confidence interval]: 1.12 [1.02, 1.24]) and receipt of 3 antibiotic classes in the 30 days before infection (3.95 [1.19, 13.11]). If infants less than 1 year of age were excluded, only receipt of 3 antibiotic classes remained significantly associated with severe disease. Neither the rate of relapse nor treatment failure differed significantly between patients with severe and nonsevere CDI. There was 1 death. Increasing age and exposure to multiple antibiotic classes were risk factors for severe CDI. Although most patients studied had severe disease, complications were infrequent. Relapse rates were similar to those reported in adults.

Fecal microbiota transplantation (FMT) is a very effective treatment for recurrent Clostridium difficile infection (CDI). Less is known about the application of FMT as a curative treatment of severe or complicated CDI. In this review, we present and discuss evidence supporting the curative use of FMT in severe or complicated CDI. We performed a literature search in PubMed and Embase for studies on the curative use of FMT in severe or complicated CDI. In addition, we describe a patient with severe CDI not responding to initial antibiotic treatment, who was successfully treated with curative FMT. We found 23 reports (12 case reports; 11 case series) about FMT as treatment for severe or complicated CDI. The patients described all had severe or complicated CDI, did not respond to conventional CDI antibiotic treatment and received FMT as last resort treatment. Patients were treated with (sequential) FMT, whether or not followed by additional antibiotic treatment for CDI. FMT, with or without additional antibiotic CDI treatment, appears to be a promising curative treatment option in patients with severe and complicated CDI, or only complicated CDI, who do not respond sufficiently to conventional antibiotic treatment. Treatment with FMT should be considered in these patients before proceeding to emergency bowel surgery.

Colitis-Induced Th17 Cells Increase the Risk for Severe Subsequent Clostridium difficile Infection

Effectiveness and Safety of Fecal Microbiota Transplantation for Clostridioides Difficile Infection: Results From a 5344-Patient Cohort Study

ABSTRACTIntroduction: Up to 15% of hospitalized patients with Clostridioides difficile infection (CDI) develop severe CDI (SCDI) or Fulminant CDI (FCDI). Due to high rates of mortality in medically-refractory CDI cases, 30% of patients with severe infection historically require surgical intervention. However, colectomy itself is an imperfect solution because it is difficult to predict who will fail medical therapy, patients with SCDI are more likely to have underlying medical conditions that make them poor surgical candidates, and post-surgical mortality still approaches 30–50%.Areas covered: This review will serve as a clinically-based review of severe and fulminant CDI management including discussion of models to predict severe infection, emerging treatments, novel targets for therapy, and innovations in surgical management.Expert opinion: Among the most promising studies to emerge in the last decade have involved fecal microbiota transplantation (FMT), which is already recommended by multiple society guidelines for recurrent CDI (RCDI). In the case of SCDI/FCDI, multiple studies have safely and successfully utilized FMT to produce rates of cure in the 70–90% range. Additionally, patients who have FCDI refractory to medical therapy and are poor candidates for colectomy may benefit from FMT as salvage therapy.

Objectives: Fidaxomicin is a macrocyclic antibiotic drug indicated for the treatment of Clostridium difficile infections (CDI). The purpose of this study was to evaluate from a societal perspective the cost-effectiveness and cost-utility of fidaxomicin in the treatment of severe or recurrent CDI compared to the recommended alternative therapy, vancomycin. Methods: The effectiveness estimates of fidaxomicin and vancomycin, provided by two clinical trials in addition to other studies, were extrapolated to 10 days cycles and a time horizon of 1 year using a Markov model. The costs considered in the study included medication, hospitalization, complications and outpatient visits. Estimates of the indirect costs generated by productivity losses due to absenteeism were not included, for lack of relevant evidence for the Portuguese reality and because the population affected by CDI tends to be no longer active in the labor market. Results: Over a one year horizon and compared to vancomycin treatment, in the base case, fidaxomicin treatment in patients with severe ICD is associated with a gain of 0.010 QALY and a cost increase of 138 €. The treatment of patients with recurrent CDI with fidaxomicin is associated with a gain of 0.019 QALYs and a cost reduction of 626 €. Fidaxomicin treatment has an acceptable incremental cost-utility ratio in patients with severe CDI (ICUR: 13,245 €/ QALY) and dominates in patients with recurrent CDI (ICUR: -33,701 €/ QALY). Fidaxomicin treatment in patients with severe and recurrent CDI is also associated with a reduction in the number of recurrences (ICER: 321 €/ recurrence avoided in patients with severe CDI and ICER: -828 €/ recurrence avoided in patients with recurrent CDI). These results are sensitive to the cost of hospitalization, decreasing with a rising cost of hospitalization. In the probabilistic sensitivity analysis the model predicts that the probability of cost-effectiveness of fidaxomicin is 44,9% in the case of severe CDI and 58% for recurrent CDI for a willingness to pay threshold of 30.000 €. Conclusions: In the Portuguese health system context, fidaxomicin presents good cost-effectiveness and cost-utility results, representing a valuable addition to the therapeutic arsenal for the treatment of CDI.

INTRODUCTION: Clostridium difficile infection (CDI) is prevalent in hospitalized patients and accounts for significant morbidity and mortality. Management and outcomes of these patients depend on the severity of CDI. Current classification of severity of CDI includes parameters that depict its inflammatory response. We attempted to study the influence of prior appendectomy on severity and outcomes of CDI. METHODS: We conducted a retrospective chart review of 1248 patients admitted to our institute between 2008 and 2016, whose stool tested positive for Clostridium difficile toxin. Baseline characteristics, comorbidities, and lab values were extracted from the EMR. Information regarding prior appendectomy was obtained from medical documentation and abdominal imaging, whichever was available. Patients were grouped into those with prior appendectomy (group A) and those without (group B). In-hospital Mortality was defined as death during the same hospital admission as CDI. Severity was defined as per the Infectious Diseases Society of America guidelines. The primary outcomes were to 1) assess all-cause in-patient mortality and 2) severity of CDI, attributable to prior appendectomy. RESULTS: There were a total of 1248 patients of which 13.5% (n = 175) had a history of prior appendectomy. The mean age was similar in both groups (57 years), and baseline characteristics were comparable. There was a female preponderance (60.06%) in group A. The dominant patient race was African American (36.6% in group A and 39.8% in group B). All lab parameters were similar in both groups, except WBC counts, which were higher amongst patients with appendectomy (13 vs. 11, ±8) (P 0.013). Group A patients were more likely to have a severe presentation of CDI (40%, n = 68), whereas group B had mostly mild CDI (45.9%, n = 492). Prior appendectomy did affect the severity status, although statistical significance was not achieved (P 0.057). There was no statistical difference in mortality either, with 25 deaths in group A (14.3%) and 169 in group B (15.8%) (P 0.62). Regression analysis performed to ascertain independent predictors of all-cause mortality in CDI did not identify prior appendectomy as a risk factor. CONCLUSION: Prior appendectomy status may affect the severity of CDI and hence the need for colectomy. However, we did not observe a difference in mortality associated with prior appendectomy. Since the prevalence of prior appendectomy was low in our study, larger population studies are needed to establish significant outcomes.

Severe Clostridium difficile infections in intensive care units: Diverse clinical presentations.

Introduction: Fecal microbiota transplantation (FMT) is recommended for recurrent Clostridium difficile infection (CDI). However, surgery still remains the standard of care for severe and severe-complicated CDI refractory to medical therapy despite the resultant high rates of post-surgical mortality at 19-57%. We aimed to measure the impact of a previously described and highly efficacious inpatient sequential FMT protocol on CDI-related mortality and colectomy rates. Methods: CDI associated hospitalizations were identified from electronic medical records before (2009-2012) and after FMT program implementation (2013-2016) at a single tertiary care referral center. Baseline characteristics and outcomes for CDI hospitalizations were retrospectively collected through detailed chart reviews and FMT database analysis. Severe and severe-complicated CDI was classified per ACG guidelines; a subgroup of severe and severe-complicated CDI patients with no response to vancomycin after ≥ 5 days on therapy were defined as refractory. The inpatient FMT program's impact on outcomes such as CDI-related 30-day mortality, CDI-related colectomy, length of stay, and 30-day readmission rates were analyzed using piecewise logistic regression. Results: Between 2009 and 2016, there were 2,826 CDI admissions; 429 met criteria for severe and severecomplicated CDI, among these 110 were refractory. After FMT program initiation, FMT was administered during 128 admissions leading to lower rates of CDI-related mortality and colectomy for patients with severe or severe-complicated CDI (Figure 1) and for those with refractory CDI (Figure 2). Overall, CDI-related mortality decreased from 10.2% to 4.5% (P=0.021) in severe and severe-complicated CDI, and from 43.2% to 12.1% (P<0.001) in refractory CDI admissions. CDI-related colectomy also decreased significantly: from 6.8% to 2.7% (P=0.042) in severe and severe-complicated CDI, and from 31.8% to 7.6% (P=0.001) in refractory CDI. While 30-day readmission rates did not differ after FMT program implementation, the median length of stay for all CDI-related hospitalizations decreased from 9 days (IQR: 5-18) to 8 days (IQR: 4-17) (P=0.01).FigureFigureConclusion: Implementation of an inpatient FMT program was associated with significantly decreased rates of CDI-related mortality and colectomy in severe and severe-complicated CDI as well as therapyrefractory CDI at an institutional level.

Purpose:Clostridium Difficile infection (CDI) can be severe, and associated with complications and mortality. Treatment recommendations are stratified based on severity. However, there are no robust models to predict severe complicated CDI. The objective of this study was to create a clinically useful model to predict severe complicated CDI. Methods: The microbiology laboratory database and patient medical records were queried to identify cases of CDI from June 1, 2007 - May 31, 2010. Severe complicated CDI was defined as need for ICU admission or colectomy, or death within 30 days of CDI diagnosis. Variables including patient demographics, Charlson Co-morbidity index, temperature, peripheral leukocyte count, serum albumin, and change in serum creatinine were obtained. Univariate and multiple variable logistic regression models were used to assess the association of these variables with complications of CDI. Only patients who had data for each variable of interest were included in the multiple variable analyses. Results: The cohort included 1400 patients with CDI (50% female, median age at CDI diagnosis was 63.1 years [range 1.2-100.1]), and 357 (25.5%) were severe complicated CDI cases. The frequency of ICU admission, colectomy, and death within 30 days of diagnosis was 19.3%, 2.3%, and 7.3%, respectively. In univariate analysis, increasing age (OR 1.15, 95% CI 1.08-1.23, p<0.0001), increasing peripheral leukocyte count (OR 1.05, 95% CI 1.03-1.06, p<0.0001), change in serum creatinine >1.5 fold (OR 2.61, 95% CI 2.04-3.34, p<0.0001), serum albumin (OR 0.48, 95% CI 0.35-0.66, p<0.0001), temperature (OR 1.36, 95% CI 1.35-1.59, p=0.0002), and Charlson Co-morbidity index (OR 1.09, 95% CI 1.03-1.15, p=0.001) were associated with severe complicated CDI. Serum albumin and temperature were not included in the multiple variable model due to missing data. In the multiple variable model (adjusting for referral distance), increasing age (OR 1.1, 95% CI 1.03-1.18, p=0.0072), increasing peripheral leukocyte count (OR 1.04, 95% CI 1.03-1.05, p<0.0001) and change in serum creatinine greater than 1.5-fold (OR 2.3, 95% CI 1.75-2.98, p<0.0001) were independent predictors of severe complicated CDI, but Charlson Comorbidity index score was not. Conclusion: Older age, higher peripheral leukocyte count, and rising serum creatinine independently predicted severe complicated CDI. Temperature and low serum albumin were also associated with severe complicated CDI by univariate analysis. An appreciation of these variables could be pivotal in identifying patients at increased risk of CDI complications. It is conceivable that early aggressive monitoring and intervention in these patients could have beneficial effects.

Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.