Prevention of healthcare-associated Clostridium difficile infection: What works?

Prevention of Clostridium difficile infection (CDI) has become extremely important because of increases in CDI incidence and severity. Unfortunately CDI prevention efforts are hampered by lack of data to support optimal prevention methods, especially for endemic CDI. Studies are needed to define optimal prevention practices and to investigate novel prevention methods

A randomized, double-blind, phase 3 safety and efficacy study of ridinilazole versus vancomycin for treatment of Clostridioides difficile infection: Clinical outcomes with microbiome and metabolome correlates of response

BACKGROUND: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI. METHODS: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs. RESULTS: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome. CONCLUSIONS: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566

A randomized, placebo-controlled trial of fidaxomicin for prophylaxis of Clostridium difficile-associated diarrhea in adults undergoing hematopoietic stem cell transplantation

Background: Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. Methods: In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as prophylaxis failure to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Results: Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. Conclusions: While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients. Clinical Trials Registration: NCT01691248

Frequent hospital readmissions for Clostridium difficile infection and the impact on estimates of hospital-associated C. difficile burden

ObjectiveClostridium difficile infection (CDI) is associated with hospitalization and may cause readmission following admission for any reason. We aimed to measure the incidence of readmissions due to CDI.DesignRetrospective cohort study.PatientsAdult inpatients in Orange County, California, who presented with new-onset CDI within 12 weeks of discharge.MethodsWe assessed mandatory 2000-2007 hospital discharge data for trends in hospital-associated CDI (HA-CDI) incidence, with and without inclusion of postdischarge CDI (PD-CDI) events resulting in rehospitalization within 12 weeks of discharge. We measured the effect of including PD-CDI events on hospital-specific CDI incidence, a mandatory reporting measure in California, and on relative hospital ranks by CDI incidence.ResultsFrom 2000 to 2007, countywide hospital-onset CDI (HO-CDI) incidence increased from 15 per 10,000 to 22 per 10,000 admissions. When including PD-CDI events, HA-CDI incidence doubled (29 per 10,000 in 2000 and 52 per 10,000 in 2007). Overall, including PD-CDI events resulted in significantly higher hospital-specific CDI incidence, although hospitals had disproportionate amounts of HA-CDI occurring postdischarge. This resulted in substantial shifts in some hospitals' rankings by CDI incidence. In multivariate models, both HO and PD-CDI were associated with increasing age, higher length of stay, and select comorbidities. Race and Hispanic ethnicity were predictive of PD-CDI but not HO-CDI.ConclusionsPD-CDI events associated with rehospitalization are increasingly common. The majority of HA-CDI cases may be occurring postdischarge, raising important questions about both accurate reporting and effective prevention strategies. Some risk factors for PD-CDI may be different than those for HO-CDI, allowing additional identification of high-risk groups before discharge