Difficile Infection Recurrence Research Articles

Retrospective subgroup analysis of fecal microbiota, live-jslm (REBYOTA®) administered by colonoscopy under enforcement discretion for the prevention of recurrent Clostridioides difficile infection.

Fecal microbiota, live-jslm (RBL; REBYOTA®), is the first Food and Drug Administration (FDA)-approved, single-dose, rectally administered, microbiota-based live biotherapeutic product for preventing Clostridioides difficile infection (CDI) recurrence. Alternative routes of administration are of clinical interest. Evaluate the safety and efficacy of RBL administration via colonoscopy. Retrospective analysis of electronic medical records of participants administered RBL via colonoscopy under FDA enforcement discretion. The number of participants with treatment and/or procedure-emergent adverse events (TEAEs) was evaluated. Treatment success and sustained clinical response, defined as the absence of CDI recurrence within 8 weeks and 6 months, respectively, were evaluated. TEAEs were experienced by 75% (6/8) of participants; most were mild to moderate in severity, and none due to RBL or its administration. Most participants had treatment success (80%; 8/10); 75% (6/8) had sustained clinical response. Real-world safety and efficacy of RBL administered via colonoscopy were consistent with clinical trials of rectally administered RBL.

658. Oral Vancomycin Taper for First Occurrence of Clostridioides difficile Compared to Standard of Care: An Observational Retrospective Matched Cohort Study

Abstract Background Clostridioides difficile infection (CDI) recurrence rates may be reduced with fidaxomicin, but financial barriers can limit access. Tapered and/or pulsed oral vancomycin is recommended in patients with recurrent CDI, however there is currently limited data for use in treating initial CDI. Methods Multicenter retrospective propensity-matched cohort study in patients ≥ 18 years old hospitalized with a first occurrence of CDI from 6/18/2018 – 12/21/2021 conducted at Norton Healthcare in Louisville, Kentucky. Standard of care (SOC) was receipt of oral vancomycin for 10-14 days compared to a standardized oral vancomycin taper (Figure 1). Subjects were matched based on age < or ≥ 65 and receipt of non-CDI antibiotics during index hospitalization or within 6 months post-discharge. Selected baseline characteristics and receipt of CDI and non-CDI antibiotics were collected. Non-CDI antibiotics were stratified by high, medium or low risk for CDI. The primary outcome was CDI recurrence within 6 months of hospital discharge. Secondary outcomes included time to recurrence, recurrence rates stratified by age group < or ≥ 65 years, CDI severity of illness per IDSA guidelines and all-cause mortality within 6 months of hospital discharge. Categorical variables were analyzed using Chi-squared and Fisher’s exact tests as appropriate. Standardized Oral Vancomycin Taper Results Recurrence rates at 6 months were 5.3% (4/75) in the taper arm and 28% (21/75) in the SOC arm (p=0.002). All-cause mortality was 20% (15/75) in the taper arm and 5.3% in the SOC arm (p=.026). Severe/fulminant CDI occurred in 49.3% of the taper arm and 58.7% of the SOC arm (p=0.53). Both groups received antibiotics at the same rate based on matching, and rates of antibiotics considered high risk for CDI were similar at 65% in the taper and SOC groups (65% vs. 61.3%, p=0.809). More patients in the taper arm were immunocompromised (25.3% vs 9.3%, p=0.029). Conclusion A significantly lower rate of CDI recurrence was observed at 6 months with tapered oral vancomycin coupled with higher all-cause mortality in patients being treated for first CDI. Additional information is needed to elucidate the clinical utility of this approach. Disclosures Ashley M. Wilde, PharmD, BCIDP, Pfizer: Grant/Research Support

Derivation of clinical predictive factors (CHIEF) for first recurrent Clostridioides difficile infection

Current models for predicting Clostridioides difficile infection (CDI) recurrence rates have a limited capacity to account for important risk factors. This study developed a clinical prediction rule for CDI recurrence. This retrospective cohort study evaluated 209 patients with CDI at a university hospital in Japan. Logistic regression and receiver operating characteristic curve analyses were performed to identify potential predictors (age, sex, underlying diseases, antibiotic use, acid suppressants, immunosuppressants, CDI history) of CDI recurrence. Forty-five patients developed recurrent CDI. Univariate analyses identified several significant recurrence predictors (enteral feeding, inflammatory bowel diseases [IBD], community-onset CDI, severe CDI). Enteral feeding (odds ratio: 3.87, 95% confidence interval: 1.75-8.56) and IBD (odds ratio: 7.08, 95% confidence interval: 1.28-39.06) were significant factors in the multivariate analysis. The CHIEF predictive scoring system was developed using 5 relevant variables (carbapenem use, hematologic malignancy, IBD, enteral feeding, fluoroquinolone use); the area under the receiver operating characteristic curve for the CHIEF score was 0.70. The CHIEF score incorporates useful, clinically available factors and could help identify patients at risk of recurrent CDI. These findings contribute to the understanding of risk factors associated with CDI recurrence and provide support for the development of prevention strategies.

S1709 Rate of Utilization of Bezlotoxumab for Prevention of Clostridioides difficile Infection Recurrence in a Community Hospital

S1709 Rate of Utilization of Bezlotoxumab for Prevention of Clostridioides difficile Infection Recurrence in a Community Hospital

Efficacy of Bezlotoxumab Against Clostridioides difficile Infection: A Case-Series Study at a University Hospital in Japan and Literature Review.

Background Clostridioides difficile infection (CDI) recurrence is a public health concern as well as a health economic burden. Bezlotoxumab treatment is one way to prevent recurrence; however, its clinical results have not been reported in Japan. Therefore, we investigated the efficacy and safety of bezlotoxumab in patients with CDI at a university hospital in Japan and compared them with previously reported findings. Methodology We retrospectively examined all patients with some risk factors for recurrent CDI who received bezlotoxumab at the discretion of physicians at the Aichi Medical University Hospital, Aichi, Japan, between July 2018 and July 2022. The primary outcome was the three-month CDI recurrence rate. The secondary outcomes were an initial clinical cure and the six-month CDI recurrence rate. The safety of the administration was also assessed. Results A total of nine patients who received bezlotoxumab were included during the study period. The rate of CDI recurrence within three months was 28.5% (2/9). Two patients died due to other causes before their diarrhea improved. None of the patients experienced CDI recurrence between three and six months after the initial clinical cure of the baseline episode. Patients showed good tolerability to bezlotoxumab with no adverse effects. Two patients with a single episode of CDI recurrence before bezlotoxumab administration showed no recurrence. Conclusions In this Japanese case-series study, the efficacy of bezlotoxumab in preventing CDI recurrence in elderly patients with CDI and multiple underlying diseases was inferior to that reported in previous studies that analyzed real-world data. It is possible that bezlotoxumab may not be fully effective in elderly patients with CDI.

Characteristics of Hospitalized Adults 55 and Older With Clostridioides difficile Infection.

Clostridioides difficile infection in older adults can result in severe infection, difficulty in treating, and complicated disease process, yet few studies have examined the characteristics of hospitalized older adults and recurrent Clostridioides difficile infection. A retrospective cohort study was conducted to explore the characteristics of hospitalized adults 55 years and older with initial Clostridioides difficile infection and recurrences by extracting routinely documented data in the electronic health record. A sample of 1,199 admissions on 871 patients was included, with a recurrence rate of 23.9% (n = 208). During the first admission, there were 79 deaths (9.1%). Clostridioides difficile infection recurrence was more prevalent in patients between 55 and 64 years old, and if discharged to a skilled nursing facility or with home health services. Chronic diseases significantly more prevalent in recurrent Clostridioides difficile infection included hypertension, heart failure, and chronic kidney disease. On initial admission, no laboratory abnormalities were significantly associated with recurrent Clostridioides difficile infection. This study indicates the need for utilizing routinely captured electronic health record data during acute hospitalizations to aid in targeting care to reduce morbidity, mortality, and recurrence.

Real-World Budget Impact of Fidaxomicin versus Vancomycin or Metronidazole for In-Hospital Treatment of Clostridioides difficile Infection

Fidaxomicin, a macrocyclic antibiotic, selectively kills Clostridioides difficile and reduces C. difficile infection (CDI) recurrence compared with vancomycin, but some studies and guidelines report fidaxomicin as being less cost-effective. The aim of this study was to compare the cost-effectiveness and budget impact of fidaxomicin versus vancomycin or metronidazole for treating CDI in a real-world UK setting. Data were retrospectively collected from medical records of 86 patients with CDI treated with vancomycin or metronidazole at a single UK hospital between April 2011 and March 2012, and prospectively from 62 patients with CDI treated with fidaxomicin between August 2012 and July 2013. CDI cases were matched by age, financial year, and healthcare resource use to control cases. CDI recurrence rates were lower with fidaxomicin (6.5%) than vancomycin/metronidazole (19.8%). An estimated 12 additional recurrent CDIs were prevented with fidaxomicin treatment. Patients with CDI had significantly higher healthcare costs than those without CDI, with a mean excess spend of GBP 10,748 and GBP 17,451 per patient in the fidaxomicin (p = 0.015) and vancomycin/metronidazole cohorts (p < 0.001), respectively. A second CDI was associated with mean excess costs of GBP 8373 and GBP 20,249 per patient in the fidaxomicin and vancomycin/metronidazole cohorts, respectively. Despite higher fidaxomicin drug costs, overall cost savings were estimated at GBP 140,292 (GBP 2125 per CDI). In this real-world study, first-line CDI treatment with fidaxomicin reduced healthcare costs versus vancomycin/metronidazole, consistent with previous studies.

Comparative biofilm-forming ability between Clostridioides difficile strains isolated in Latin America and the epidemic NAP1/027 strain.

One of the challenges in treating Clostridioides difficile infection (CDI) is that the bacterium forms biofilms, a critical virulence mechanism known to promote antibiotic resistance and, as a result, consequently, a higher recurrence of the disease. The goal of this study was to compare the ability of three MLST Clade 2 strains to form a biofilm in vitro: ICC-45 (ribotype SLO231/UK[CE]821), a ST41 toxinotype IXb isolated in Brazil; and two epidemic NAP1/027/ST01 strains: NAP1/027/ST01 (LIBA5756), isolated during a 2010 outbreak in Costa Rica and the reference epidemic strain NAP1/027/ST01 (R20291); and ATCC700057, a non-toxigenic strain. The ability of strains to form biofilm was evaluated using crystal violet staining. In addition, samples were stained with the Film Tracer biofilm matrix (Invitrogen®) and the biofilm matrix thickness was measured using confocal microscopy. The matrix architecture was determined using Scanning electron microscop. Confocal microscopy was used to detect the presence of toxin A (tcdA) using an anti-Clostridioides difficile TcdA antibody. The expression of virulence genes (tcdA, tcdB, tcdC, cdtB, spo0A, slpA, cwp66 and cwp84) was examined, as well as the effect of antibiotics metronidazole (MTZ) and vancomycin (VAN) on biofilm growth. All of the strains tested formed a moderate biofilm with 1.1 <DO570nm>3.5. After 72h, biofilm biomass of the NAP1/027/ST01 epidemic strains (LIBA5756 and R20291) was significantly higher than ICC-45 and ATCC 700057 biofilms, as confirmed by electron and confocal microscopy. At 120h, the LIBA5756 biofilm biomass decreased compared to other strains. The toxigenic strains R20291 or LIBA 5756 had higher expression of genes tcdA, tcdB, tcdC, cdtA, slpA and spo0A than ICC-45, but there were no significant differences in the expression levels of cdtB, cwp66 and cwp84. In epidemic strains, VAN and MTZ inhibited biofilm formation; however, in the ICC-45 strain, MIC concentrations of VAN and MIC and 4MIC of MTZ did not inhibit biofilm formation. The three MLST Clade 2 isolated from different rybotipes, two of which were isolated from Latin America, are competent biofilm-forming bacteria, indicating their ability to induce C. difficile infection recurrence, making treatment difficult.

Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial

BackgroundEffective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660—a standardized microbiota-based investigational live biotherapeutic—and a closely-matched historical control cohort.MethodsThis prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered with doses 7 days apart. Treatment success was defined as the absence of CDI diarrhea without the need for retreatment for 8 weeks after completing study treatment. A historical control group with matched inclusion and exclusion criteria was identified from a retrospective chart review of participants treated with standard-of-care antibiotics for recurrent CDI who matched key criteria for the study. The primary objective was to compare treatment success of RBX2660 to the historical control group. A key secondary outcome was the safety profile of RBX2660, including adverse events and CDI occurrence through 24 months after treatment. In addition, fecal samples from RBX2660-treated participants were sequenced to evaluate microbiome composition and functional changes from before to after treatment.ResultsIn this Phase 2 open-label clinical trial, RBX2660 demonstrated a 78.9% (112/142) treatment success rate compared to a 30.7% (23/75) for the historical control group (p < 0.0001; Chi-square test). Post-hoc analysis indicated that 91% (88/97) of evaluable RBX2660 responders remained CDI occurrence-free to 24 months after treatment demonstrating durability. RBX2660 was well-tolerated with mostly mild to moderate adverse events. The composition and diversity of RBX2660 responders’ fecal microbiome significantly changed from before to after treatment to become more similar to RBX2660, and these changes were durable to 24 months after treatment.ConclusionsIn this Phase 2 trial, RBX2660 was safe and effective for reducing rCDI recurrence as compared to a historical control group. Microbiome changes are consistent with restorative changes implicated in resisting C. difficile recurrence.Clinical Trials Registration NCT02589847 (10/28/2015)

SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection

BackgroundCurrent therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection.MethodsWe conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed.ResultsAmong the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination.ConclusionsIn patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.)

AAV-mediated delivery of actoxumab and bezlotoxumab results in serum and mucosal antibody concentrations that provide protection from C. difficile toxin challenge.

Clostridium difficile is the leading cause of antibiotic-associated nosocomial diarrhea in the developed world. When the host-associated colon microbiome is disrupted by the ingestion of antibiotics, C. difficile spores can germinate, resulting in infection. C. difficile secretes enterotoxin A (TcdA) and cytotoxin B (TcdB) that are responsible for disease pathology. Treatment options are limited as the bacterium demonstrates resistance to many antibiotics, and even with antibacterial therapies, recurrences of C. difficile are common. Actotoxumab and bezlotoxumab are human monoclonal antibodies that bind and neutralize TcdA and TcdB, respectively. In 2016, the US food and drug administration (FDA) approved bezlotoxumab for use in the prevention of C. difficile infection recurrence. To ensure the long-term expression of antibodies, gene therapy can be used. Here, adeno-associated virus (AAV)6.2FF, a novel triple mutant of AAV6, was engineered to express either actotoxumab or bezlotoxumab in mice and hamsters. Both antibodies expressed at greater than 90 μg/mL in the serum and were detected at mucosal surfaces in both models. Hundred percent of mice given AAV6.2FF-actoxumab survived a lethal dose of TcdA. This proof of concept study demonstrates that AAV-mediated expression of C. difficile toxin antibodies is a viable approach for the prevention of recurrent C. difficile infections.

Real-life experience with fidaxomicin in Clostridioides difficile infection: a multicentre cohort study on 244 episodes

The high cost of fidaxomicin has restricted its use despite the benefit of a lower Clostridioides difficile infection (CDI) recurrence rate at 4weeks of follow-up. This short follow-up represents the main limitation of pivotal clinical trials of fidaxomicin, and some recent studies question its benefits over vancomycin. Moreover, the main risk factors of recurrence after treatment with fidaxomicin remain unknown. We designed a multicentre retrospective cohort study among four Spanish hospitals to assess the efficacy of fidaxomicin in real life and to investigate risk factors of fidaxomicin failure at weeks 8 and 12. Two-hundred forty-four patients were included. Fidaxomicin was used in 96 patients (39.3%) for a first episode of CDI, in 95 patients (38.9%) for a second episode, and in 53 patients (21.7%) for a third or subsequent episode. Patients treated with fidaxomicin in a first episode were younger (59.9years vs 73.5years), but they had more severe episodes (52.1% vs. 32.4%). The recurrence rates for patients treated in the first episode were 6.5% and 9.7% at weeks 8 and 12, respectively. Recurrence rates increased for patients treated at second or ulterior episodes (16.3% and 26.4% at week 8, respectively). Age greater than or equal to 85years and having had a previous episode of CDI were identified as recurrence risk factors at weeks 8 and 12. We conclude that the outcomes with fidaxomicin in real life are at least as good as those observed in clinical trials despite a more demanding evaluation. Be it 85years of age or older, and the use after a first episode appears to be independent factors of CDI recurrence after treatment with fidaxomicin.

Clinical complications in patients with primary and recurrent Clostridioides difficile infection: A real-world data analysis.

Objective:Clostridioides difficile infection and recurrent C. difficile infection result in substantial economic burden and healthcare resource use. Sepsis and bowel surgery are known to be serious complications of C. difficile infection. This study evaluated clinical complications in patients with C. difficile infection and recurrent C. difficile infection during a 12-month period following the primary C. difficile infection.Methods:A retrospective analysis of commercial claims data from the IQVIA PharMetrics Plus™ database was conducted for patients aged 18–64 years with an index C. difficile infection episode requiring inpatient stay or an outpatient visit for C. difficile infection followed by a C. difficile infection treatment. Each C. difficile infection episode ended after a 14-day C. difficile infection-claim-free period was observed. Recurrent C. difficile infection was defined as a further C. difficile infection episode within an 8-week window following the claim-free period. Clinical complications were documented over 12 months of follow-up and stratified by the number of recurrent C. difficile infection episodes (0 rCDI, 1 rCDI, 2 rCDI, and 3+ rCDI).Results:In total, 46,571 patients with index C. difficile infection episode were included. During the 6-month pre-index, the mean (standard deviation) baseline Charlson comorbidity index score, by increasing the recurrent C. difficile infection group, was 1.2 (1.9), 1.5 (2.2), 1.8 (2.3), and 2.3 (2.5). During the 12-month follow-up, sepsis occurred in 16.5%, 27.3%, 33.1%, and 43.3% of patients, and subtotal colectomy or diverting loop ileostomy was performed in 4.6%, 7.3%, 8.9%, and 10.5% of patients, respectively, by increasing the recurrent C. difficile infection group.Conclusions:Reduction in recurrent C. difficile infection is an important step to reduce the burden of serious clinical complications, and new treatments are needed to reduce C. difficile infection recurrence.

The Impact of Appendectomy in Clostridium difficile Infection and Length of Hospital Stay

IntroductionWe aim to investigate Clostridium difficile infection (CDI) recurrence, severity, complications, and length of hospital stay in patients with and without prior history of appendectomy who were admitted to the hospital with CDI.MethodWe analyzed retrospective data for 862 patients, 18 years and older, with C. difficile inpatients diagnosed between January 1, 2017 and December 31, 2018 and sorted into two groups, with or without prior appendicectomy, to look for outcomes such as recurrence, hospital stay, complications, and related death in each group and use statistical analysis for comparison.ResultThere were 862 patients admitted with CDI, of which 122 (14.2%) had a prior history of appendectomy and 740 (85.8%) did not. Patients with an appendectomy prior were older (median age of 75 vs. 69, p = 0.0033) and had a higher proportion of females (68.9% vs. 53.6%, p = 0.0017).C. difficile recurrence in prior appendicectomy group vs. no appendectomy group was 12.3% and 9.3%, respectively, but no statistical difference was noted (p = 0.28). Also, there was no statistical difference in complications like ileus, colectomy, and mortality related to CDI in both groups. However, patients with appendectomies had significantly shorter hospital stays during C. difficile admission compared to patients without appendectomies (median of six days vs. seven days, p = 0.0014).ConclusionOur study shows that there is no statistical difference in the recurrence, severity, and complications of CDI in the presence or absence of the appendix but remarkably noted that people with prior appendicectomy had a shorter hospital stay.

Clostridioides difficile Spore Formation and Germination: New Insights and Opportunities for Intervention.

Spore formation and germination are essential for the bacterial pathogen Clostridioides difficile to transmit infection. Despite the importance of these developmental processes to the infection cycle of C. difficile, the molecular mechanisms underlying how this obligate anaerobe forms infectious spores and how these spores germinate to initiate infection were largely unknown until recently. Work in the last decade has revealed that C. difficile uses a distinct mechanism for sensing and transducing germinant signals relative to previously characterized spore formers. The C. difficile spore assembly pathway also exhibits notable differences relative to Bacillus spp., where spore formation has been more extensively studied. For both these processes, factors that are conserved only in C. difficile or the related Peptostreptococcaceae family are employed, and even highly conserved spore proteins can have differential functions or requirements in C. difficile compared to other spore formers. This review summarizes our current understanding of the mechanisms controlling C. difficile spore formation and germination and describes strategies for inhibiting these processes to prevent C. difficile infection and disease recurrence.

Analysis of predisposing factors for the development of Clostridioides difficile infection recurrence.

AbstractThe purpose of this study is to evaluate the influence of several risk factors and, among them, the role of different types of antibiotics, in the development of the first recurrent episode of Clostridioides difficile (CD) infection. We performed a case control study from 2006 to 2016. We included patients admitted to the hospital with CD infection that received any antibiotic treatment during the year before the onset of the infection. First, we described the characteristics of CD infection in a Spanish third level hospital and then we compared first cases of CD infection that presented recurrence with those that did not. We included 110 cases, corresponding to 94 individuals. There were 14 first CD infection episodes that later presented recurrence (12.7%). Receiving more than 3 types of antibiotics during the year before the onset of symptoms was associated with higher risk of presenting a recurrent episode (OR = 4.69, 95% CI 1.01-21.78), as well as the past history of neoplasia (OR = 4.58, 95% CI 1.00-20.98). The number of previous hospital admissions was associated with the development of recurrences in the univariate study (p < 0.05). No differences were observed related to the type of antibiotic used immediately before the CD episode neither with the treatment received. The number of types of antibiotics used during the year before the first episode of CD infection or having a personal history of neoplasia was associated with 4 times higher risk of recurrent episodes. Type of antibiotic used did not show to influence recurrences.

Composite Kernel Association Test (CKAT) for SNP-set joint assessment of genotype and genotype-by-treatment interaction in Pharmacogenetics studies.

It is of substantial interest to discover novel genetic markers that influence drug response in order to develop personalized treatment strategies that maximize therapeutic efficacy and safety. To help enable such discoveries, we focus on testing the association between the cumulative effect of multiple single nucleotide polymorphisms (SNPs) in a particular genomic region and a drug response of interest. However, the currently existing methods are either computational inefficient or not able to control type I error and provide decent power for whole exome or genome analysis in Pharmacogenetics (PGx) studies with small sample sizes. In this article, we propose the Composite Kernel Association Test (CKAT), a flexible and robust kernel machine-based approach to jointly test the genetic main effect and SNP-treatment interaction effect for SNP-sets in Pharmacogenetics (PGx) assessments embedded within randomized clinical trials. An analytic procedure is developed to accurately calculate the P-value so that computationally extensive procedures (e.g. permutation or perturbation) can be avoided. We evaluate CKAT through extensive simulation studies and application to the gene-level association test of the reduction in Clostridium difficile infection recurrence in patients treated with bezlotoxumab. The results demonstrate that the proposed CKAT controls type I error well for PGx studies, is efficient for whole exome/genome association analysis and provides better power performance than existing methods across multiple scenarios. The R package CKAT is publicly available on CRAN https://cran.r-project.org/web/packages/CKAT/. Supplementary data are available at Bioinformatics online.

Analysis of the impact of secondary prophylaxis on Clostridioides difficile recurrence in critically ill adults.

Introduction:Clostridioides (formerly Clostridium) difficile infection recurrence in patients re-exposed to antibiotics for treatment of a non-Clostridioides difficile infection is high at approximately 33%. Low-dose per os vancomycin (e.g. 125 mg q12 h) or metronidazole (e.g. 500 mg intravenous/per osq8 h) may help prevent recurrences, but study of secondary prophylaxis in critically ill patients is needed.Objectives:To determine whether critically ill adults receiving low-dose per os vancomycin for secondary Clostridioides difficile infection prophylaxis have fewer recurrences of Clostridioides difficile infection in 90 days compared with patients receiving metronidazole for secondary Clostridioides difficile infection prophylaxis or control (no secondary prophylaxis).Methods:This was a retrospective, two-center, observational study in a large academic medical center and affiliated community hospital. Included patients had a history of Clostridioides difficile infection within 1 year of receiving antibiotics for clinical care. We compared patients receiving secondary prophylaxis with vancomycin or metronidazole and control patients; in addition, an unplanned fourth group (vancomycin/metronidazole combination) was identified and analyzed. The primary outcome was Clostridioides difficile infection recurrence within 90 days of a course of broad-spectrum antibiotic therapy. Fisher’s exact, analysis of variance, and Kruskal–Wallis tests were used to compare Clostridioides difficile infection recurrence with prophylaxis group and additional contributing factors.Results:Eighty-two patients were included: 38 control (46.3%), 20 metronidazole (24.4%), 17 vancomycin (20.7%), and 7 combination (8.5%). Ten of 82 patients (12.2%) had at least one Clostridioides difficile infection recurrence; 8/38 patients in the control group (21.1%), 1/7 patients in the combination group (14.3%), 1/17 patients in the per os vancomycin group (5.9%), and 0/20 in the metronidazole group (0%; p = 0.073). As a post hoc secondary analysis, the three prophylaxis groups were coalesced into one group and compared with control (4.5% vs 21%; p = 0.039). Additional factors (e.g. age, obesity, immunosuppression, acid suppression) were not significantly associated with Clostridioides difficile infection recurrence or with prophylaxis group.Conclusion:There was no difference in Clostridioides difficile infection recurrence between prophylaxis groups, however, given the low recurrence rate, prospective evaluation with a larger sample of critically ill patients is necessary.

Bezlotoxumab for prevention of Clostridium difficile infection recurrence: Distinguishing relapse from reinfection with whole genome sequencing

BackgroundBezlotoxumab has been shown to prevent Clostridium difficile infection recurrence (rCDI) in high-risk patients. MethodsWe used whole genome sequencing to estimate the impact of bezlotoxumab on same-strain relapse or new-strain reinfection in MODIFY I/II trials. Reinfection with a new strain and relapse with the same strain were differentiated by the comparison of ribotype (RT) and pair-wise single-nucleotide whole genome sequencing (WGS) variations (PWSNV). Relapse was assigned if the baseline RT and the RT isolated during rCDI were the same, and if PWSNVs were ≤ 2. Reinfection was assigned if the baseline RT and the RT isolated during rCDI were different, or if the RT was the same but PWSNVs were > 10. Unknown status was assigned if the RT was the same but PWSNVs were 3–10. Results259 rCDI events were evaluable (50 [19.3%] reinfection; 198 [76.4%] relapse). The proportion of relapses was higher for ribotype 027 (84.5%) compared with other ribotypes (74.1%). Cumulative incidence of relapse was significantly lower for bezlotoxumab versus no bezlotoxumab (p < 0.0001), with a non-significant trend towards reduction for reinfection (p = 0.14). ConclusionBezlotoxumab treatment significantly reduced the rate of CDI relapse versus a regimen without bezlotoxumab. (NCT01241552/NCT01513239).

Influence of prior appendectomy and cholecystectomy on Clostridioides difficile infection recurrence and mortality

BackgroundRemote appendectomy was linked to increased incidence of Clostridioides difficile infection (CDI). We evaluated the effect of absence of vermiform appendix and/or gallbladder on recurrence rate and severity of CDI. MethodsWe assessed a systemwide patient cohort diagnosed with initial CDI in 2014 (n = 250). The primary outcome was recurrence. ResultsAppendix and gallbladder were absent among 47 and 64 patients, respectively. CDI recurrence rate was similar among patients without and with appendix (24/47, 51.1% versus 90/203 patients, 44.3%; p = 0.404) and similar among patients without and with gallbladder (29/64 patients, 45.3% versus 85/186 patients, 45.7%; p = 0.957). Mortality was similar between appendectomy versus appendix in situ patients (3/47, 6.4% versus 9/203, 4.4%; p = 0.573), but higher mortality rate was seen among those without gallbladder (7/64 patients with prior cholecystectomy, 10.9% versus 5/186 patients with intact gallbladder, 2.7%; p = 0.008). ConclusionClostridioides difficile recurrence rate is not affected by remote appendectomy or cholecystectomy. Patients with prior cholecystectomy experience higher mortality rates associated with their CDI.