Mary Beth Dorr

Once-Weekly Dalbavancin versus Standard-of-Care Antimicrobial Regimens for Treatment of Skin and Soft-Tissue Infections

Dalbavancin, a novel glycopeptide with a long elimination half-life ( approximately 9-12 days), was compared to standard antimicrobial therapy for skin and soft-tissue infections (SSTIs). In a randomized, controlled, open-label, phase 2 proof-of-concept trial, adults received 1100 mg of dalbavancin (as a single intravenous infusion), 1000 mg of dalbavancin intravenously and then 500 mg intravenously 1 week later, or a prospectively defined standard-of-care regimen. A gram-positive pathogen was isolated from samples obtained from 41 (66%) of 62 patients at baseline; Staphylococcus aureus was the most prevalent species (83% of pathogens). Clinical success rates at a follow-up visit (test of cure) were 94.1% among patients treated with 2 doses of dalbavancin, 61.5% among patients treated with 1 dose of dalbavancin, and 76.2% among patients treated with a standard-of-care regimen. All treatment regimens were well tolerated; drug-related adverse reaction rates were similar across the 3 groups. These findings suggest that a regimen of 2 doses of dalbavancin administered 1 week apart is effective in the treatment of complicated, gram-positive bacterial SSTIs and warrants further study.

Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence

BACKGROUND Although newer studies have evaluated risk factors for recurrent Clostridium difficile infection (CDI), the vast majority did not measure important biomarkers such as endogenous anti-toxin A and anti-toxin B antibody levels. METHODS Data from the placebo group of a phase 2 trial testing monoclonal antibodies to C. difficile toxins A and B for preventing CDI recurrence (rCDI) were analyzed to assess risk factors associated with rCDI. Patients with symptomatic CDI taking metronidazole or vancomycin were enrolled. The primary outcome was rCDI within 84 days of treatment start. Univariate and multivariate logistic regression was used to examine associations between potential risk factors and rCDI. At baseline, demographic and clinical characteristics were recorded; endogenous antibody levels were assessed using 2 enzyme-linked immunosorbent assays. RESULTS A predictor of recurrence was age ≥65 years, and an antibody-mediated immune response to toxin B appears to be protective against rCDI. CONCLUSIONS Our findings demonstrate the importance of clinical as well as immunological risk factors in rCDI and provide more robust evidence for the protective effects of antibody to toxin B in the prevention of rCDI. CLINICAL TRIALS REGISTRATION NCT00350298.

Cost-effectiveness of Bezlotoxumab Compared With Placebo for the Prevention of Recurrent Clostridium difficile Infection

Background Clostridium difficile infection (CDI) is the most commonly recognized cause of recurrent diarrhea. Bezlotoxumab, administered concurrently with antibiotics directed against C. difficile (standard of care [SoC]), has been shown to reduce the recurrence of CDI, compared with SoC alone. This study aimed to assess the cost-effectiveness of bezlotoxumab administered concurrently with SoC, compared with SoC alone, in subgroups of patients at risk of recurrence of CDI. Methods A computer-based Markov health state transition model was designed to track the natural history of patients infected with CDI. A cohort of patients entered the model with either a mild/moderate or severe CDI episode, and were treated with SoC antibiotics together with either bezlotoxumab or placebo. The cohort was followed over a lifetime horizon, and costs and utilities for the various health states were used to estimate incremental cost-effectiveness ratios (ICERs). Both deterministic and probabilistic sensitivity analyses were used to test the robustness of the results. Results The cost-effectiveness model showed that, compared with placebo, bezlotoxumab was associated with 0.12 quality-adjusted life-years (QALYs) gained and was cost-effective in preventing CDI recurrences in the entire trial population, with an ICER of

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence

19824/QALY gained. Compared with placebo, bezlotoxumab was also cost-effective in the subgroups of patients aged ≥65 years (ICER of

Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection

15298/QALY), immunocompromised patients (ICER of

Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection

12597/QALY), and patients with severe CDI (ICER of

Bezlotoxumab for Clostridium difficile Infection Complicating Inflammatory Bowel Disease

21430/QALY). Conclusions Model-based results demonstrated that bezlotoxumab was cost-effective in the prevention of recurrent CDI compared with placebo, among patients receiving SoC antibiotics for treatment of CDI.

Endogenous Serum IgG Antibodies to Clostridium difficile Toxin B Are Associated with Protection against C. difficile Infection Recurrence

Abstract Background Bezlotoxumab 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. Methods The 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. Results The 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. Conclusions The 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 Registration NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

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

Abstract We estimated 30-day all-cause and Clostridium difficile infection (CDI)–associated hospital readmissions in participants at high risk of recurrent CDI enrolled in MODIFY I/II. Bezlotoxumab-treated inpatients experienced fewer CDI-associated readmissions compared with placebo-treated inpatients, notably in participants aged ≥65 years and with severe CDI. Clinical Trials Registration. NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Bezlotoxumab (BEZ) for Prevention of Clostridium difficile Infection (CDI) Recurrence (rCDI): Distinguishing Relapse from Reinfection with Whole Genome Sequencing (WGS)

Background The fully human monoclonal antibody bezlotoxumab binds Clostridioides (Clostridium) difficile toxin B and reduces recurrence rates in patients with C. difficile infection (CDI) receiving antibacterial treatment for a primary or recurrent episode. Objectives To investigate whether the timing of bezlotoxumab administration relative to the onset of antibacterial treatment affected clinical outcome in the Phase 3 trials MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Methods Initial clinical cure and CDI recurrence rates of participants who received bezlotoxumab or placebo were summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI: 0-2, 3-4 and ≥5 days after onset. Results Of 1554 total participants, 649 (41.8%), 469 (30.1%) and 436 (28.1%) received an infusion 0-2, 3-4 and ≥5 days after onset of antibacterial treatment for CDI, respectively. Regardless of timing of administration, there were no differences in initial clinical cure rates between participants receiving bezlotoxumab (range 77.8% to 81.4%) or placebo (77.8% to 81.7%). Bezlotoxumab efficacy was unaffected by timing of administration; rates of CDI recurrence were lower versus placebo in all subgroups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo). Timing of administration also had no effect on time to resolution of diarrhoea, which was achieved by the end of antibacterial treatment in ∼95% of participants in both bezlotoxumab and placebo groups. Conclusions Bezlotoxumab is effective in preventing CDI recurrence and can be administered at any time before ending antibacterial drug treatment.