Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection.
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ABSTRACT:
SUBMITTER: Prabhu VS
PROVIDER: S-EPMC5848255 | biostudies-literature | 2017 Oct
REPOSITORIES: biostudies-literature
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Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection.
Prabhu Vimalanand S VS Cornely Oliver A OA Golan Yoav Y Dubberke Erik R ER Heimann Sebastian M SM Hanson Mary E ME Liao Jane J Pedley Alison A Dorr Mary Beth MB Marcella Stephen S
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20171001 7
<h4>Clinical trials registration</h4>NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). ...[more]
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Project description:Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.
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Project description:Clostridium difficile infection (CDI) represents the most prevalent cause of antibiotic-associated gastrointestinal infections in health care facilities in the developed world. Disease symptoms are caused by the two homologous exotoxins, TcdA and TcdB. Standard therapy for CDI involves administration of antibiotics that are associated with a high rate of disease recurrence, highlighting the need for novel treatment paradigms that target the toxins rather than the organism itself. A combination of human monoclonal antibodies, actoxumab and bezlotoxumab, directed against TcdA and TcdB, respectively, has been shown to decrease the rate of recurrence in patients treated with standard-of-care antibiotics. However, the exact mechanism of antibody-mediated protection is poorly understood. In this study, we show that the antitoxin antibodies are protective in multiple murine models of CDI, including systemic and local (gut) toxin challenge models, as well as primary and recurrent models of infection in mice. Systemically administered actoxumab-bezlotoxumab prevents both the damage to the gut wall and the inflammatory response, which are associated with C. difficile in these models, including in mice challenged with a strain of the hypervirulent ribotype 027. Furthermore, mutant antibodies (N297Q) that do not bind to Fcγ receptors provide a level of protection similar to that of wild-type antibodies, demonstrating that the mechanism of protection is through direct neutralization of the toxins and does not involve host effector functions. These data provide a mechanistic basis for the prevention of recurrent disease observed in CDI patients in clinical trials.
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Project description:BackgroundBezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI.MethodsThe analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented.ResultsThe majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI.ConclusionsThe risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit.Clinical trials registrationNCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).
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Project description:Background Thirty-day readmission has become a significant health care metric reflecting the quality of care and on the cost of service delivery. There is little data on the impact of complications following skull base surgery (SBS) on emergency readmission. Identifying modifiable risk factors for readmission may improve care and reduce cost. Design The study was designed as a single-center retrospective cohort study. Methods Records for a consecutive series of 165 patients who underwent open or endoscopic SBS by a single surgeon reviewed. Patients with pituitary adenoma were excluded. The diagnosis, procedure, complications, length of stay (LOS), body mass index (BMI), and smoking status were recorded. Readmission to the neurosurgical department or regional hospitals was either noted prospectively or the patient contacted. Cause and length of readmission was documented. Results Of the 165 cases, 14 (8.5%) were readmitted within 30 days. Causes for readmission included cerebrospinal fluid (CSF) leak in 5/14 or 35.7% (overall rate for readmission for this complication in the series is 3.1%), infection in 4/14 (28.6%), hyponatraemia in 2/14 (14.3%), vascular: sinus thrombosis in 1/14 (7.1%), seizures in 1/14 (7.1%), and epistaxis in 1/14 (7.1%). Initial and readmission LOS was 6 and 14 days, respectively. BMI was higher in those readmitted within 30 days (33.2 kg/m 2 ) versus no readmission (27.1 kg/m 2 ). In addition, of those readmitted within 30 days, 35.7% were smokers compared with 20.8% in those not readmitted. Conclusion In this series, smoking and raised BMI may be indicators for within 30-day readmission and complications in this population, raising the question of risk factor modification prior to elective intervention.
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