Risk Factors For rCDI Research Articles

Incidence and risk factors for recurrent Clostridioides difficile infection in pediatric at-risk groups in selected Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) hospitals.

Incidence and risk factors for recurrent Clostridioides difficile infection (rCDI) are well established in adults, though data are lacking in pediatrics. We aimed to determine incidence of and risk factors for rCDI in pediatrics. This retrospective cohort study of pediatric patients was conducted at 3 tertiary-care hospitals in Canada with laboratory-confirmed CDI between April 1, 2012, and March 31, 2017. rCDI was defined as an episode of CDI occurring 8 weeks or less from diagnostic test date of the primary episode. We used logistic regression to determine and quantify risk factors significantly associated with rCDI. In total, 286 patients were included in this study. The incidence proportion for rCDI was 12.9%. Among hospitalized patients, the incidence rate was estimated at 2.6 cases of rCDI per 1,000 hospital days at risk (95% confidence interval [CI], 1.7-3.9). Immunocompromised patients had higher incidence of rCDI (17.5%; P = .03) and higher odds of developing rCDI independently of antibiotic treatment given for the primary episode (odds ratio [OR], 2.31; 95% CI, 1.12-5.09). Treatment with vancomycin monotherapy did not show statistically significant protection from rCDI, independently of immunocompromised status (OR, 0.33; 95% CI, 0.05-1.15]). The identification of increased risk of rCDI in immunocompromised pediatric patients warrants further research into alternative therapies, prophylaxis, and prevention strategies to prevent recurrent disease burden within these groups. Treatment of the initial episode with vancomycin did not show statistically significant protection from rCDI.

2108. Evaluation of Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection in Patients Living With Cancer at a Large Comprehensive Cancer Center

Abstract Background Bezlotoxumab is a fully human monoclonal antibody that binds and neutralizes Clostridioides difficile toxin B. Administration of bezlotoxumab along with standard of care antibiotic (SoC) treatment of C. difficile infections (CDI) is associated with lower rates of CDI recurrence (rCDI). We aimed to determine the real-world incidence of rCDI in patients with cancer within 12 weeks after receiving bezlotoxumab. Methods This is a retrospective, single-center, descriptive study of patients with cancer that received bezlotoxumab from Jan 2018 through Oct 2021 at a large cancer center. rCDI was defined as a clinical illness associated with a positive stool nucleic acid amplification test with or without a confirmatory toxin assay for which CDI SoC was prescribed. Results A total of 131 patients were included in the study (median age of 63 years, 47% male, 77% Caucasian, 21% ICU admission), with 31% having one or more CDI episodes ≤ 6 months prior to receiving bezlotoxumab. The most common primary cancer type was leukemia (36%) followed by a solid organ tumor (35%), lymphoma (21%), and myeloma (8%). Cytotoxic chemotherapy or immune checkpoint inhibitors were prescribed within 6 months in 78% of cases and 60% of patients were given antibiotics not related to CDI. Fidaxomicin was most frequently administered as SoC (56%), followed by oral vancomycin (44%) with or without intravenous metronidazole. Within 12 weeks following bezlotoxumab treatment, rCDI occurred in 14 (10.7%, 95% Cl 5.4% to 16.0%) patients. Using univariate analysis, patients with rCDI were more likely to have received levofloxacin before and during bezlotoxumab treatment (86% versus 47%; OR 6.76, 95% CI 1.45 - 31.56, p=0.009). Conclusion In this real-world study, the rate of rCDI following use of bezlotoxumab during SoC antibiotics was comparable to that seen in clinical trials. Use of levofloxacin as prophylaxis for prolonged neutropenia in hematologic malignancies was associated with significantly higher rates of rCDI in patients that received bezlotoxumab. Our study suggests that neutropenia and antibiotic induced dysbiosis are risk factors for rCDI despite bezlotoxumab administration. Disclosures Pablo C. Okhuysen, MD, AstraZeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove: Grant/Research Support|Ferring: Advisor/Consultant|Glaxo Smith Kleine: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta: Grant/Research Support|Merck Sharp & Dohme Corp: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|Summit: Advisor/Consultant|Summit: Grant/Research Support.

Risk Factors for Recurrence of Clostridioides difficile in Hospitalized Patients

BackgroundDiarrhea and pseudomembranous colitis associated with Clostridioides difficile – a spore-forming anaerobic Gram-positive bacillus – is a major infection in hospitalized patients with a profound impact on clinical and economic outcomes. Recurrence (rCDI) is common and predisposes to further episodes with poor outcomes. MethodWe aimed to identify a wide range of risk factors for recurrence to guide stewardship initiatives. After ethical approval, we commenced collecting demographic and clinical data of patients older than 18 years with clinically and microbiologically confirmed C. difficile infection. Data were statistically analyzed using R software. ResultsOf 204 patients included in the analysis, 36 (18%) suffered 90-day recurrence, rCDI was higher among females (23%) compared to males (13%), overall age median (IQR) was 66 (51–77), and for rCDI cases 81 (69–86) years. Among 26 variables analyzed to evaluate their association with rCDI, prior clindamycin exposure, concurrent use of aztreonam, patients >76 years, total hospital length of stay, and LOS before diagnosis ≤7 days, WBC ≤ 9.85 × 103 at discharge were more likely to experience rCDI. ConclusionAs identified in this analysis, patients with risk factors for rCDI could be candidates for close monitoring, a high index of suspicion, and risk mitigation interventions to avoid rCDI and improve clinical outcomes.

Prospective Study on Incidence, Risk Factors and Outcome of Recurrent Clostridioides difficile Infections.

Background: Limited and wide-ranging data are available on the recurrent Clostridioides difficile infection (rCDI) incidence rate. Methods: We performed a cohort study with the aim to assess the incidence of and risk factors for rCDI. Adult patients with a first CDI, hospitalized in 15 Italian hospitals, were prospectively included and followed-up for 30 d after the end of antimicrobial treatment for their first CDI. A case–control study was performed to identify risk factors associated with 30-day onset rCDI. Results: Three hundred nine patients with a first CDI were included in the study; 32% of the CDI episodes (99/309) were severe/complicated; complete follow-up was available for 288 patients (19 died during the first CDI episode, and 2 were lost during follow-up). At the end of the study, the crude all-cause mortality rate was 10.7% (33 deaths/309 patients). Two hundred seventy-one patients completed the follow-up; rCDI occurred in 21% of patients (56/271) with an incidence rate of 72/10,000 patient-days. Logistic regression analysis identified exposure to cephalosporin as an independent risk factor associated with rCDI (RR: 1.7; 95% CI: 1.1–2.7, p = 0.03). Conclusion: Our study confirms the relevance of rCDI in terms of morbidity and mortality and provides a reliable estimation of its incidence.

789. Evaluation of Bezlotoxumab for Prevention of Recurrent Clostridioides difficile Infection in Patients at High Risk for Recurrence

BackgroundRecurrent Clostridioides difficile infection (rCDI) within 180 days of the index episode is associated with a 33% increase in mortality and, to-date, few treatment options exist to prevent recurrent infection. Bezlotoxumab (BEZ) is a novel therapeutic option for the prevention of rCDI, yet limited data exist regarding its effectiveness in patients at high-risk for recurrence outside of controlled trials. This study aimed to compare BEZ to a historical standard of care (SoC) cohort for the prevention of rCDI in patients at high risk for recurrence.MethodsA multi-center retrospective cohort study of patients within an academic health-system with one or more risk factors for rCDI. Patients received SoC with oral vancomycin (VAN) or fidaxomicin (FDX) from January 2015 to December 2017 or BEZ, in addition to oral SoC, from September 2017 to September 2019. The primary outcome was rCDI within 90 days of completion of oral VAN or FDX. Secondary outcomes included all-cause readmission, all-cause mortality, and safety events at 90 days.ResultsOne-hundred twenty patients received BEZ in addition to SoC (n=47) or SoC alone (n=73). Mean (SD) age was 55 (16) years, mean (SD) number of lifetime CDI was 3 (2) episodes, and 30.8% of patients had severe CDI. Six (12.8%) patients in the BEZ cohort and thirty-one (42.5%) in the SoC cohort experienced rCDI at 90 days [OR (95% CI) = 0.20 (0.07-0.53), p=< 0.01]. Incidence of all-cause mortality (2.1% vs 5.5%, p=0.67) and all-cause readmission (42.6% vs 56.2%, p=0.20) within 90 days were not statistically different between groups. Patient body weight, timing of BEZ administration, CDI severity, nor prior receipt of fecal microbiota transplantation significantly affected BEZ effectiveness. BEZ was well tolerated with one infusion-related reaction. There were no heart failure exacerbations among BEZ recipients and two exacerbations identified from control group.ConclusionIn patients with at least one risk factor for rCDI, BEZ in addition to SoC was associated with lower rates of recurrent infection than SoC alone and may be a reasonable adjunct therapy in high risk patient populations.Disclosures matthew miller, PharmD, Allergan (Speaker’s Bureau)Tetraphase (Speaker’s Bureau)

Real-World Experience with Bezlotoxumab for Prevention of Recurrence of Clostridioides difficile Infection.

Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of bezlotoxumab in preventing rCDI and to investigate factors related to bezlotoxumab failure in the real world. A retrospective, multicentre cohort study of patients treated with bezlotoxumab in Spain was conducted. We compared the characteristics of cohort patients with those of patients treated with bezlotoxumab in the pivotal MODIFY trials. We assessed recurrence rates 12 weeks after completion of treatment against C. difficile, and we analysed the factors associated with bezlotoxumab failure. Ninety-one patients were included in the study. The cohort presented with more risk factors for rCDI than the patients included in the MODIFY trials. Thirteen (14.2%) developed rCDI at 12 weeks of follow-up, and rCDI rates were numerically higher in patients with two or more previous episodes (25%) than in those who had fewer than two previous episodes of C. difficile infection (CDI) (10.4%); p = 0.09. There were no adverse effects attributable to bezlotoxumab. Despite being used in a more compromised population than that represented in clinical trials, we confirm the effectiveness of bezlotoxumab for the prevention of rCDI.

Efficacy of Bezlotoxumab in Trial Participants Infected With Clostridioides difficile Strain BI Associated With Poor Outcomes.

Bezlotoxumab reduced rates of recurrent Clostridioides difficile infection (rCDI) vs placebo in Monoclonal Antibodies for C. difficile Therapy (MODIFY) I/II trial participants receiving antibacterial drug treatment for CDI. A secondary objective of MODIFY I/II was to assess bezlotoxumab's efficacy against C. difficile strains associated with increased rates of morbidity and mortality. In this post-hoc analysis of pooled MODIFY I/II data, efficacy endpoints were assessed in participants infected with restriction endonuclease analysis BI and non-BI strains of C. difficile at study entry. Treatment outcomes were compared between participants receiving bezlotoxumab (alone or with actoxumab [B, B+A]) and those receiving no bezlotoxumab (placebo or actoxumab [P, A]). From 2559 randomized participants, C. difficile was isolated from 1588 (67.2%) baseline stool samples. Participants with BI strains (n = 328) were older and had more risk factors for rCDI than non-BI strain participants (n = 1260). There were no differences in initial clinical cure rate between BI and non-BI strains in either group. The rCDI rate for BI strains treated with bezlotoxumab was lower than for the no bezlotoxumab group (B, B+A vs P, A: 23.6% vs 43.9%) and was also lower for the non-BI strains (B, B+A vs P, A: 21.4% vs 36.1%). Rates of 30-day CDI-associated rehospitalization were greater with BI vs non-BI strains in both groups. Infection with BI strains of C. difficile predicted poor outcomes in the MODIFY I/II trials. Bezlotoxumab (alone or with actoxumab) treatment was effective both in BI and non-BI subpopulations.

Renal Impairment, C. difficile Recurrence, and the Differential Effect of Bezlotoxumab: A Post Hoc Analysis of Pooled Data From 2 Randomized Clinical Trials.

BackgroundRenal impairment is not a consistently cited risk factor for recurrent Clostridioides difficile infection (rCDI). We examined the association between renal impairment and rCDI and the effect of bezlotoxumab, an anti–toxin B monoclonal antibody, in reducing rCDI in participants with renal impairment.MethodsWe pooled data from 2 randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials conducted in participants receiving bezlotoxumab or placebo infusion during oral antibacterial drug treatment for CDI. We assessed the association between renal impairment and rCDI in placebo-treated participants and evaluated the effect of bezlotoxumab vs placebo in reducing rCDI among participants with renal impairment, defined as an estimated glomerular filtration rate <90 mL/min.ResultsThe proportion of placebo-treated participants experiencing rCDI within 12 weeks was higher in those with renal impairment (n = 919) vs those without renal impairment (n = 612; 36.6% and 27.7%, respectively; difference, 8.9%; 95% CI, 1.3% to 16.3%). Renal impairment was significantly associated with a higher rate of recurrence in placebo-treated participants lacking commonly recognized risk factors for rCDI (renal impairment as only risk factor, 28.8%; vs normal renal function and no risk factors, 12.5%; difference, 16.3%; 95% CI, 3.4% to 28.8%). Among all participants with renal impairment, the rate of rCDI was 19.5% among bezlotoxumab-treated vs 36.6% among placebo-treated participants (difference, –17.1%; 95% CI, –23.4% to –10.6%).ConclusionsThis post hoc analysis adds to the literature suggesting an association of renal impairment as an independent risk factor for rCDI and provides preliminary evidence that patients with renal impairment who suffer with CDI may benefit from adjunctive treatment with bezlotoxumab.

Analysis of C. difficile infection\u2013related outcomes in European participants in the bezlotoxumab MODIFY I and II trials

The MODIFY I/II trials demonstrated that bezlotoxumab, a human monoclonal antibody against Clostridioides difficile toxin B, given during antibiotic treatment for Clostridioides difficile infection (CDI) significantly reduced C. difficile recurrence (rCDI) in adults at high risk for rCDI. Efficacy of CDI-directed intervention may depend on ribotype regional epidemiology, and patient characteristics. This post hoc analysis assessed the efficacy of bezlotoxumab in the subgroup of MODIFY I/II trial participants enrolled in Europe. Data from the bezlotoxumab (10 mg/kg single intravenous infusion) and placebo (0.9% saline) groups from MODIFY I/II were compared to assess initial clinical cure (ICC), rCDI, all-cause, and CDI-associated rehospitalizations within 30 days of discharge, and mortality through 12 weeks post-infusion. Of 1554 worldwide participants, 606 were from Europe (bezlotoxumab n = 313, 51%; placebo n = 292; 48%). Baseline characteristics were generally similar across groups, although there were more immunocompromised participants in the bezlotoxumab group (27.2%) compared with placebo (20.1%). Fifty-five percent of participants were female, and 86% were hospitalized at randomization. The rate of ICC was similar between treatment groups. The rate of rCDI in the bezlotoxumab group was lower compared with placebo among European participants overall, and among those with ≥ 1 risk factor for rCDI. Bezlotoxumab reduced 30-day CDI-associated rehospitalizations compared with placebo. These results are consistent with overall results from the MODIFY trials and demonstrate that bezlotoxumab reduces rCDI and CDI-associated rehospitalizations in European patients with CDI. MODIFY I/II (NCT01241552 and NCT01513239)

Efficacy of Bezlotoxumab in Participants Receiving Metronidazole, Vancomycin, or Fidaxomicin for Treatment of Clostridioides (Clostridium) difficile Infection.

BackgroundIn phase 3 MODIFY I/II trials, bezlotoxumab significantly reduced recurrence of Clostridioides (Clostridium) difficile infection (rCDI) over 12 weeks. Choice of CDI antibacterial treatment may affect CDI-related outcomes; therefore, this prespecified analysis assessed if the magnitude of bezlotoxumab-induced rCDI reduction was influenced by the antibiotic administered.MethodsIn MODIFY I/II (NCT01241552/NCT01513239), participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment. Using pooled data from MODIFY I/II, initial clinical cure (ICC) and rCDI were assessed in metronidazole-, vancomycin-, and fidaxomicin-treated subgroups.ResultsOf 1554 participants in MODIFY I/II, 753 (48.5%) received metronidazole, 745 (47.9%) vancomycin, and 56 (3.6%) fidaxomicin. Fewer participants receiving metronidazole had a prior CDI episode in the previous 6 months (12.9%) or ≥1 risk factor for rCDI (66.0%) vs participants receiving vancomycin (41.2% and 83.6%, respectively) and fidaxomicin (55.4% and 89.3%, respectively). ICC rates were similar in the bezlotoxumab (metronidazole, 81.0%; vancomycin, 78.5%; fidaxomicin, 86.7%) and placebo groups (metronidazole, 81.3%; vancomycin, 79.6%; fidaxomicin, 76.9%). In placebo-treated participants, the rCDI was lower in the metronidazole subgroup vs the vancomycin and fidaxomicin subgroups (metronidazole, 28.0%; vancomycin, 38.4%; fidaxomicin, 35.0%). When analyzed by subsets based on history of CDI, rCDI rates were similar in the metronidazole and vancomycin groups. rCDI rates were lower in all antibiotic subgroups for bezlotoxumab vs placebo (metronidazole: rate difference [RD], –9.7%; 95% confidence interval [CI], –16.4% to –3.1%; vancomycin: RD, –15.4%; 95% CI, –22.7% to –8.0%; fidaxomicin: RD, –11.9%; 95% CI, –38.1% to 14.3%).ConclusionBezlotoxumab reduces rCDI vs placebo in participants receiving metronidazole and vancomycin, with a similar effect size in participants receiving fidaxomicin.

Real-world Experience of Bezlotoxumab for Prevention of Clostridioides difficile Infection: A Retrospective Multicenter Cohort Study.

BackgroundBezlotoxumab is approved for prevention of recurrence of Clostridioides difficile infection (CDI) in adults receiving standard of care (SoC) therapy based on findings from MODIFY clinical trials. However, utilization practices and validation of trial results in the real world are limited.MethodsRecords of patients receiving bezlotoxumab between April 2017 and December 2018 across 34 infusion centers in the United States were retrospectively reviewed. Recurrent CDI (rCDI), defined as diarrhea lasting ≥2 days resulting in treatment, was assessed 90 days postbezlotoxumab.ResultsThe study cohort included 200 patients (median age, 70 years; 66% female; median Charlson comorbidity index, 5), of whom 86% (n = 173) had prior CDI episodes and 79% (n = 158) had ≥2 risk factors for rCDI. SoC antibiotics included vancomycin (n = 137, 68%), fidaxomicin (n = 60, 30%), and metronidazole (n = 3, 2%). Median time from C. difficile stool test to bezlotoxumab and initiation of SoC to bezlotoxumab were 15 days and 11 days, respectively. Within 90 days, 31 of 195 patients (15.9%) experienced rCDI, which corresponds to a success rate of 84.1%. Patients with ≥2 CDI recurrences prebezlotoxumab had a higher risk of subsequent rCDI compared with those with 1 recurrence or primary CDI (hazard ratio, 2.77; 95% confidence interval, 1.14–6.76; P = .025).ConclusionsThis real-world multicenter study demonstrated successful prevention of rCDI with bezlotoxumab comparable to clinical trial results regardless of type of SoC and timing of infusion. Multiple prior CDI recurrences were associated with a higher risk of subsequent rCDI, supporting the use of bezlotoxumab earlier in the disease course.

Characterization and risk factors for recurrence of Clostridioides (Clostridium) difficile infection in Japan: A nationwide real-world analysis using a large hospital-based administrative dataset

ObjectiveRecurrent Clostridioides (Clostridium) difficile infection (rCDI) is common and increases healthcare resource utilization. In this study, we assessed rCDI risk factors using an up-to-date, Japanese national hospital-based database. MethodsC. difficile infection (CDI) episodes, occurring July 2014–June 2017, in patients aged ≥18 years were extracted from the database and a nested case-control analysis was performed. Cases were defined as rCDI episodes which required re-initiation of oral vancomycin or oral/intravenous metronidazole treatment within 8 weeks from the start of initial treatment. Cases were matched to 4 non-rCDI episodes at the timing of rCDI occurrence. Adjusted odds ratios (ORs) were estimated using multivariate conditional logistic regression model. ResultsOf 18,246 initial CDI episodes, 3250 (17.8%) had at least one rCDI. Approximately 90% of episodes occurred in inpatients and 65% were treated with metronidazole. Older age (<75 years vs 75–84 years and vs 85 + years) was associated with higher risk of rCDI (OR = 1.27, 95% confidence interval [1.15, 1.41] and 1.45 [1.30, 1.61], respectively). Use of systemic antibiotics (3.16 [2.90, 3.44]), probiotics (2.53 [2.32, 2.77]), chemotherapy (1.28 [1.08, 1.53]), or proton pump inhibitors (PPIs) (1.17 [1.07, 1.28]), and prior CDI history (1.22 [1.03, 1.43]) were also identified as rCDI risk factors. Vancomycin reduced the risk of rCDI compared with metronidazole treatment (0.83 [0.76, 0.91]). ConclusionThis large, multicenter, nationwide study confirmed that older age, PPIs, antibiotics, probiotics, chemotherapy, and prior CDI history are risk factors for rCDI in Japan. There was a 17% decrease of rCDI risk with vancomycin vs metronidazole treatment.Clinical trial registration number: N/A.

Bezlotoxumab Is Associated With a Reduction in Cumulative Inpatient-Days: Analysis of the Hospitalization Data From the MODIFY I and II Clinical Trials.

BackgroundPatients with recurrent Clostridium difficile infection (rCDI) are more likely to have a hospital readmission and spend increased time in inpatient settings compared with patients with primary CDI. MODIFY I and II demonstrated that bezlotoxumab significantly reduced rCDI vs placebo. A post hoc within-trial analysis assessed whether bezlotoxumab was associated with a reduction in cumulative inpatient-days.MethodsData were pooled from the MODIFY trials to estimate the cumulative hospitalized days summed over the 84-day follow-up period. We adjusted inpatient use data from pooled MODIFY I and II for survival and censoring to estimate 84-day cumulative inpatient-days, overall and for subgroups. Treatment effects were obtained using recycled predictions based on trial protocol and rCDI risk, and 95% confidence intervals were obtained using 1000 bootstrap replicates.ResultsMean cumulative inpatient-days were greater in the placebo arm (14.1 days) vs the bezlotoxumab arm (12.1 days) in the overall population. The mean difference between treatment groups was 2.1 days (95% confidence interval, –0.4 to –3.7). This was consistent in participants with risk factors for rCDI: age ≥65 years, compromised immunity, severe CDI, prior CDI, and ribotype 027/078/244 infection. As the number of risk factors increased, bezlotoxumab resulted in greater reductions in the number of inpatient-days compared with placebo (difference: –1.2 days, –2.3 days, –2.5 days, and –3.0 days for 0, 1, 2, and ≥3 risk factors, respectively).ConclusionsBezlotoxumab was associated with a reduction in cumulative inpatient-days, suggesting that treatment with bezlotoxumab may substantially reduce rCDI-associated health care resource use. Trial registrations. MODIFY I (MK-3415A-001, NCT01241552) and II (MK-3415A-002, NCT01513239)

Bezlotoxumab (BEZ) for Prevention of Clostridium Difficile Infection (CDI) Recurrence (rCDI): Outcomes in Patients with Substantial Renal Impairment (SRI)

BackgroundCDI in patients with SRI is harder to treat and is associated with higher recurrence. MODIFY I/II found that BEZ, a monoclonal antibody against C. difficile toxin B, is superior to placebo (PBO) at preventing rCDI in patients receiving standard of care antibiotics (SoC). This post hoc analysis assessed efficacy of BEZ in patients with SRI in the MODIFY studies.MethodsMODIFY I/II mITT populations were pooled to estimate initial clinical cure (ICC), rCDI, and mortality through 12 weeks. Estimated glomerular filtration rate (eGFR) was calculated with the Modified Diet in Renal Disease (MDRD) method. SRI was defined as eGFR <60 mL/minute/1.73 m2. ICC was defined as SOC ≤16 days and no diarrhea on the 2 days after SoC end. rCDI was defined as diarrhea and toxigenic C. difficile in stool. Mortality within 90 days after randomization was summarized.ResultsOf the included 1554 patients, 1101 had no SRI (≥90: n = 612; 60 to < 90: n = 489); 430 had SRI (30 to <60: n = 290; 15 to <30: n = 71; <15: n = 69); 23 had unknown eGFR. 87% of SRI patients had ≥1 risk factor for rCDI. Relative to patients without SRI, more patients with SRI were ≥65 years (69% vs. 44%), immunocompromised (25 vs. 20%), had ribotype 027 (25% vs. 17%), and used concomitant antibiotics during SoC (41% vs. 31%) or after SoC (36% vs. 28%). SRI patients had more severe CDI (21% vs. 14%), lower CDI cure (78.4% vs. 80.1%), higher rCDI (31.6% vs. 27.8%), and death (11.6% vs. 5.3%) In the SRI cohort, more BEZ vs. PBO patients were inpatients (81% vs. 72%), ≥65 years (72% vs. 65%), immunocompromised (28 vs. 22%), and used systemic antibiotics after SoC ended (40% vs. 32%). The rate of ICC was similar between treatment groups and the rCDI rate was significantly less the BEZ vs. PBO group (Table).ConclusionSRI was associated with worse CDI outcomes. BEZ given with SoC significantly reduced rCDI in patients with SRI and could benefit this hard to treat population.Disclosures Y. Golan, Merck & Co., Inc.: Grant Investigator, Scientific Advisor and Speaker’s Bureau, Research support and Speaker honorarium; Pfizer: Scientific Advisor, Speaker honorarium; Allergab: Grant Investigator and Scientific Advisor, Research grant and Speaker honorarium; The Medicines Company: Scientific Advisor, Speaker honorarium; Seres Pharmaceuticals: Scientific Advisor, Speaker honorarium; H. L. DuPont, BioK International, Salix: Consultant, Consulting fee; University Rebiotix, Seres, Takeda: Grant Investigator, Grant recipient; F. Aldomiro, BMS & ViiV: Scientific Advisor, Consulting fee; MSD, Viiv, Astellas & Pfizer: Participated in Clinical Trials, Research support; E. H. Jensen, Merck & Co., Inc.: Employee, may own stock/hold stock options in Company; M. E. Hanson, Merck & Co. Inc.: Employee, may own stock/hold stock options in the Company; M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company

Genome Wide Analysis Reveals Host Genetic Variants that Associate with Reduction in Clostridium difficile Infection Recurrence (rCDI) in Patients Treated with Bezlotoxumab

BackgroundBezlotoxumab (BEZ) and actoxumab (ACT) are monoclonal antibodies against C. difficile toxins B and A, respectively. Patients receiving a single infusion of BEZ alone or with ACT in the MODIFY I/II trials showed a consistent reduction in the rate of rCDI over a 12-week period compared with a placebo (PBO) infusion. Exploratory genome wide analyses were conducted to determine whether genetic variants across the genome were associated with treatment response (rCDI).MethodsDNA was extracted from blood obtained from patients who consented to genetic analysis (PGx population). Genetic data were generated on a commercial Axiom array platform (Affymetrix). Genotype imputation was performed using the 1000 Genomes Phase 3 reference data and Impute2 software after genetic quality control. Data from BEZ and ACT+BEZ arms were combined to provide increased power. The logistic regression with likelihood ratio test was used to search for single nucleotide polymorphisms (SNPs) that were strongly associated with a treatment effect on rCDI.ResultsAn SNP rs2516513 located in the extended major histocompatibility complex (xMHC), region with a minor allele frequency of 25% in the general population, was associated with rCDI (P = 3.04E-08) (Figure 1). rCDI rates for the PGx population and in subgroups at high/low risk for rCDI stratified by SNP rs2516513 are shown in Table 1. Carriers of the T allele of SNP rs2516513 were associated with a statistically significant reduction in rCDI in BEZ-treated patients but not in PBO-treated patients (DrCDI = -21.5%). The magnitude of the effect of the T allele on rCDI is most prominent in patients who have ≥1 risk factor for rCDI (DrCDI = -24.6%), but is also present in patients without risk factors (DrCDI = -10.6%). In CC homozygous patients, rCDI rates are similar in both treatment groups and in patients at high and low risk of rCDI.ConclusionAn SNP variant rs2516513 is associated with a lower rate of rCDI recurrence in patients treated with BEZ. The location of the associated genetic variant on chromosome 6 within xMHC, suggests that a host driven, immunological mechanism may play a role in rCDI and may predict patients most likely to respond to BEZ. As this is an exploratory finding, the results should be replicated in an independent validation study.Disclosures P. Shaw, Merck & Co., Inc.: Employee, May own stock/hold stock options in Company; J. Shen, Merck & Co., Inc.: Employee, may hold stock/hold stock options in the Company; M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company; J. Li, BGI-Shenzhen: Employee, Salary; R. Mogg, Merck & Co., Inc.: Employee, May hold stock/stock options in the Company; D. V. Mehrotra, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company; R. L. Blanchard, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company

Clinical, epidemiological and microbiological characteristics of relapse and re-infection in Clostridium difficile infection

Recurrent diarrhea is a common complication of Clostridium difficile infection (CDI). Recurrent CDI (r-CDI) may be produced by the persistence of spores (relapse) or by the acquisition of a new strain (reinfection). In this study, we analyze epidemiological, clinical, microbiological and laboratory data from patients with r-CDI, relapse, and reinfection-CDI over 5 years and compared with a control group (non r-CDI). Among 60 patients with r-CDI, 36 patients had stool samples collected from two or more episodes, which were molecularly analyzed. Based on ribotyping, 63.9% of the samples were relapse, and 36.1% reinfection. In a multivariable logistic regression analysis, previous antibiotic exposure was found to be a risk factor for r-CDI (OR: 2.23; 95% CI: 1.0–4.9; p = 0.04). Patients with relapse had previous antibiotic exposure more frequently than did patients with reinfection (p = 0.03), and patients with reinfection suffered more frequently from chronic liver disease (p = 0.02) than did relapse patients. Relapse patients compared with the control group had a higher percentage of previous antibiotic exposure, although the difference was statistically no significant (73.9% vs. 91.3 p = 0.06). No significant differences for the selected variables were observed between the reinfection and control groups, although we observed a higher percentage of patients with chronic liver disease (30.8% vs 13.3%; p = 0.08). All isolates were sensitive to metronidazole and vancomycin. No significant differences in antibiotic susceptibility were found between the different groups. Sporulation and germination frequency of r-CDI were higher than non r-CDI (p = 0.02 and p < 0.01, respectively). Nevertheless, there were statistically not significant differences between the relapse and reinfection groups. Both frequencies were compared between the first and second episode of CDI for the relapse and reinfection groups, but differences were not observed to be statistically significant. In conclusion, our study showed that the recurrence of CDI was associated with antibiotic use and sporulation/germination frequency, regardless of relapse or reinfection. The use of antibiotics would produce a dysbiosis and favor the persistence of the C. difficile spores and relapse. A possible alteration of the intestinal microbiota and the bile salts produced by chronic liver disease could favor reinfection.

Bezlotoxumab Alone and With Actoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients on Standard of Care Antibiotics: Integrated Results of 2 Phase 3 Studies (MODIFY I and MODIFY II)

Background. Actoxumab ((ACT) MK-3415) and bezlotoxumab ((BEZ) MK- 6072) are human monoclonal antibodies against Clostridium difficile toxins A and B, respectively. Methods. Combined data from 2 double-blind, randomized, phase 3 studies in adult patients receiving oral standard of care (SoC) (metronidazole, vancomycin, or fidaxomi- cin) for primary or recurrent Cd ifficile infection (rCDI), including multiple rCDI. In MODIFY I, patients received a single infusion of ACT + BEZ 10 mg/kg each (MK- 3415A), ACT 10 mg/kg alone, BEZ 10 mg/kg alone, or placebo. In MODIFY II, patients received a single infusion of ACT + BEZ, BEZ alone, or placebo. Entry criteria, study visits/ procedures, and efficacy/safety endpoints were the same for both studies. The rCDI (new episode ofdiarrhea andpositive stooltest fortoxigenic Cd ifficile afterclinical cure ofbase- line CDI episode) was the primary endpoint, and global cure (clinical cure of initial epi- sode and no rCDI) was a secondary endpoint; both were evaluated through week 12. Results. A total of 2655 patients (median age 66 years, 57% female) enrolled in 30 countries and 2580 (97%) received the study infusion. Baseline characteristics were ba- lanced across treatment groups. In MODIFY I, the ACT alone group was stopped for ef- ficacy and safety reasons after interim analysis, based on a predefined adaptive plan. In the full analysis set (N = 2327, ACT alone excluded), 53% of patients were ≥65 years of age, 27% had prior CDI, 17% had severe CDI, and 11% were infected with 027 ribotype. The rCDI rates were significantly lower for ACT+BEZ (15.4%) and for BEZ alone (16.5%) versus placebo (26.6%, both 1-sided, P<.0001) and were reduced relative to placebo in subgroups with risk factors for rCDI, including age ≥65 years, history of CDI, infected with 027 ribotype, and severe CDI. Global cure was superior for BEZ alone (63.5%, 1- sided P=.0001) versus placebo and higher for ACT+BEZ (58.1%, 1-sided P=0.0426) versus placebo (53.7%). Safety endpoints were comparable for ACT + BEZ and BEZ alone versus placebo. The most common adverse events were diarrhea (5.9%), nausea (5.9%), and CDI (4.2%) (table).

Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis.

An estimated 20-30% of patients with primary Clostridium difficile infection (CDI) develop recurrent CDI (rCDI) within 2 weeks of completion of therapy. While the actual mechanism of recurrence remains unknown, a variety of risk factors have been suggested and studied. The aim of this systematic review and meta-analysis was to evaluate current evidence on the risk factors for rCDI. We searched MEDLINE and 5 other databases for subject headings and text related to rCDI. All studies investigating risk factors of rCDI in a multivariate model were eligible. Information on study design, patient population, and assessed risk factors were collected. Data were combined using a random-effects model and pooled relative risk ratios (RRs) were calculated. A total of 33 studies (n=18,530) met the inclusion criteria. The most frequent independent risk factors associated with rCDI were age≥65 years (risk ratio [RR], 1.63; 95% confidence interval [CI], 1.24-2.14; P=.0005), additional antibiotics during follow-up (RR, 1.76; 95% CI, 1.52-2.05; P<.00001), use of proton-pump inhibitors (PPIs) (RR, 1.58; 95% CI, 1.13-2.21; P=.008), and renal insufficiency (RR, 1.59; 95% CI, 1.14-2.23; P=.007). The risk was also greater in patients previously on fluoroquinolones (RR, 1.42; 95% CI, 1.28-1.57; P<.00001). Multiple risk factors are associated with the development of rCDI. Identification of modifiable risk factors and judicious use of antibiotics and PPI can play an important role in the prevention of rCDI.

Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients.

Recurrent Clostridium difficile infection (CDI) represents a significant burden on the healthcare system and is associated with poor outcomes in hematopoietic stem cell transplant (HSCT) patients. Data are limited evaluating recurrence rates and risk factors for recurrence in HSCT patients. HSCT patients who developed CDI between January 2010 and December 2012 were divided into 2 groups: non-recurrent CDI (nrCDI) and recurrent CDI (rCDI). Risk factors for rCDI were compared between groups. Rate of recurrence in HSCT patients was compared to that in other hospitalized patients. CDI was diagnosed in 95 of 711 HSCT patients (22 rCDI and 73 nrCDI). Recurrence rates were similar in HSCT patients compared with other hospitalized patients (23.2% vs. 22.9%, P > 0.99). Patients in the rCDI group developed the index case of CDI significantly earlier than the nrCDI group (3.5 days vs. 7.0 days after transplant, P = 0.05). On univariate analysis, patients with rCDI were more likely to have prior history of CDI and neutropenia at the time of the index CDI case. Neutropenia at the time of the index CDI case was the only independent predictor of rCDI (78.8 vs. 34.8%, P = 0.006) on multivariate analysis. The rate of rCDI was similar between HSCT and other hospitalized patients, and the majority of patients developed the index case of CDI within a week of transplantation. Neutropenia at the index CDI case may be associated with increased rates of rCDI.