Title: Fidaxomicin use for Clostridioides difficile in pediatrics: Is it all SUNSHINE and roses?   

Reviewing: Wolf J, Kalocsai K, Fortuny C, et al. Safety and efficacy of fidaxomicin and vancomycin in children and adolescents with Clostridioides (Clostridium) difficile infection: a phase 3, multicenter, randomized, single-blind clinical trial (SUNSHINE). Clin Infect Dis. 2019.

Author:                 Shaina Hecht, MD, Fellow, Infectious Diseases, Nationwide Children's Hospital Reviewers:                Sandra Arnold MD, MSc

Amanda Green MD

Background:

There is evidence that the incidence of Clostridioides difficile (CD, formerly Clostridium difficile) infection (CDI) in pediatrics is increasing, and has been associated with increased length of stay and increased risk of mortality in hospitalized children.  Although the majority of initial pediatric CDI cases are successfully treated, up to 40% of cases result in recurrence.  Fidaxomicin, a macrocyclic antibiotic, has been shown to be non-inferior to vancomycin for initial cure of CDI in adults, and significantly reduces the risk of recurrence.  A phase 2a pediatric study, published in 2018, showed a clinical response rate at end of treatment of 92% and a recurrence rate of 31% within 28 days after the end of treatment.  In the current study, the safety and efficacy of fidaxomicin compared to vancomycin was evaluated in pediatrics.

Methods and Results:

This study was a multicenter, investigator-blind, phase 3 trial that prospectively enrolled pediatric patients with non-severe CDI, and randomized patients to treatment with either fidaxomicin or oral vancomycin (2:1).  Diagnosis required diarrhea plus detection of toxin A/B or toxigenic CD in stool using at least one local diagnostic test.  One hundred forty-two patients (of 148 randomized), many of whom had at least one comorbidity, received treatment as allocated, and were followed for safety and efficacy until 30 days after the end of therapy (EOT).

The proportion of patients with confirmed clinical response (defined as clinical response at EOT, with no further requirement for CDI therapy at 2 days after EOT) was similar between patients in the fidaxomicin group and the vancomycin group.  However, there was a significantly higher incidence of recurrence in patients who received vancomycin compared to those who received fidaxomicin (29% versus 12%, respectively) resulting in greater global cure (no relapse within 30 days) with fidaxomicin (68.4%, 67/98) versus vancomycin (50.0%, 22/44) (adjusted treatment difference 18.8%; 95% CI 1.5%, 35.3%).  While not significant, the rate of global cure was higher in immunocompromised patients treated with fidaxomicin.  No serious adverse events were attributed to study treatments.

Critique:

This multicenter, randomized study showed a significantly higher global cure rate in patients treated with fidaxomicin compared to those treated with vancomycin.  Important limitations include enrollment of children < 2 years of age who are more likely to be asymptomatic carriers of toxigenic CD.  Additionally, diagnosis of CDI included PCR and ELISA- based testing, both of which can be positive in asymptomatic carriers.  Despite these concerns, fidaxomicin appears to be a safe and effective treatment option for children with CDI.

Conclusions:

While the study included children who may not have had true CDI, this study supports the safety and efficacy of fidaxomicin use in children and demonstrated a significantly higher cure rate at 30 days in non-severe CDI treated with fidaxomicin.  While the number needed to treat was low (5.3), given the high cost, fidaxomicin will likely be reserved for treatment of patients with a high risk of CDI recurrence, including those with cancer and other serious comorbidities.   Although not statistically significant, the finding of a higher rate of global cure in immunocompromised patients treated with fidaxomicin is promising, suggesting further studies are needed in this patient population. 

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References:

  1. Wolf J, Kalocsai K, Fortuny C, et al. Safety and efficacy of fidaxomicin and vancomycin in children and adolescents with Clostridioides (Clostridium) difficile infection: a phase 3, multicenter, randomized, single-blind clinical trial (SUNSHINE). Clin Infect Dis. 2019.