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Safety and Efficacy of Fidaxomicin and Vancomycin
Safety and Efficacy of Fidaxomicin and Vancomycin
Safety and Efficacy of Fidaxomicin and Vancomycin
MAJOR ARTICLE
Clostridioides difficile (formerly Clostridium difficile) infection a hospital-acquired, antibiotic-associated infection, the incidence
(CDI) is caused by an anaerobic, spore-forming, gram-positive of community-acquired CDI is also on the rise [3]. Furthermore,
bacterium [1], and is the leading cause of nosocomial diarrhea in the incidence of pediatric CDI seems to be increasing [4], most
developed countries [2]. Although CDI is classically considered notably among patients with comorbid conditions, such as cancer
[5] or inflammatory bowel disease [6]. The severity of CDI is vari-
able, ranging from asymptomatic colonization or self-limiting di-
arrhea to fulminant colitis [7]. In hospitalized children, CDI has
Received 5 March 2019; editorial decision 11 October 2019; accepted 26 November 2019;
published online November 27, 2019. been associated with increased length of stay and increased risk
Correspondence: J. Wolf, Department of Infectious Diseases, St. Jude Children’s Research
Hospital, 262 Danny Thomas Pl, Mail Stop 320, Memphis, TN 38105-2794 (joshua.wolf@stjude.org). of mortality [8]. However, because asymptomatic colonization
Clinical Infectious Diseases® 2020;71(10):2581–8 with toxigenic C. difficile is common in children aged <2 years [9,
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases 10], the clinical significance of this organism as a cause of diar-
Society of America. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ rhea in young infants is uncertain [11].
by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any The Infectious Disease Society of America and Society
medium, provided the original work is not altered or transformed in any way, and that the
work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
for Healthcare Epidemiology of America guidelines for the
DOI: 10.1093/cid/ciz1149 treatment of CDI in children recommend vancomycin or
Blood samples for the measurement of plasma concentrations outcomes were conducted in subgroups of patients with com-
of fidaxomicin and its main metabolite OP-1118 were taken promised immunity and those ≥2 years of age with CDI diag-
within 30 minutes before and 1–5 hours after the dose, on any nosed by means of direct toxin detection. Further statistical
of days 5–10. Stool samples for the measurement of fidaxomicin methods are detailed in the Supplementary Methods.
and OP-1118 concentrations were taken within 24 hours of any
dose from day 5 to day 10. Pharmacokinetic data were summar- RESULTS
ized for all patients who received ≥1 dose of fidaxomicin and
had ≥1 valid measurement of fidaxomicin or OP-1118 concen- Patient Characteristics
trations in plasma or stool (pharmacokinetic analysis set). Of 159 patients screened, 148 patients were randomized:
100 to fidaxomicin and 48 to vancomycin (Figure 2).
Prior and Concomitant Medication A total of 142 patients received study treatment as allo-
Receipt of any investigational therapy for 28 days before cated and were included in the safety analysis set and the
screening, with the exception of cancer treatments that do not FAS. In the fidaxomicin arm, the median age of patients
affect assessment of diarrhea, was prohibited. Concurrent use was higher (60.0 months) than in the vancomycin arm
of other CDI treatments, antidiarrheal drugs, or fecal trans- (48.0 months), and a greater proportion of patients had
plantation was prohibited during the study period, unless given confirmed CDI in the 3 months before screening (28.6%
for primary treatment failure or suspected CDI recurrence vs 22.7%) (Table 1). In most patients, CDI was diagnosed
after initial clinical response at EOT (Supplementary Table 1). using either polymerase chain reaction or direct toxin test
Pretreatment for CDI before randomization was discouraged. (Table 1). A substantial proportion of patients in both
Drugs that affect peristalsis and potent P-glycoprotein inhibi- treatment groups had ≥1 chronic comorbid condition, in-
tors (eg, cyclosporine) were withheld during the study period cluding infections, gastroesophageal reflux disease, and
if possible. neoplasms (Table 1); the number of patients who received
medications for constipation in the 30 days before the study
Sample Size and Analysis was similar across treatment arms (fidaxomicin, 11 of 98
The target sample size, based on clinical and practical consid- [11.2%]; vancomycin, 5 of 44 [11.4%]). The majority of pa-
erations, was 144 eligible patients, with ≥24 patients in each of tients (122 of 142 [85.9%]) had no protocol deviations during
the following age groups: 0 to <24 months (≥6 to <24 months in the study Supplementary Results. Thirty patients <2 years of
the United States), ≥2 to <6 years, ≥6 to <12 years, and ≥12 to age were enrolled in the study, all of whom had a positive
<18 years. The study was not designed as a superiority trial and toxigenic C. difficile result and a negative rotavirus result
was not powered for this purpose. Post hoc analyses of efficacy before screening (Supplementary Table 2).
population is at particularly high risk of CDI incidence and colonization, and the consequential challenge of CDI diagnosis,
recurrence [28, 29]. The apparently lower treatment effect in in children <2 years old [9, 10]. Consequently, C. difficile testing
this population, compared with the overall FAS, may reflect a in children <2 years old with diarrhea is discouraged in clin-
greater likelihood for these patients to have an alternative [30] ical practice, unless other potential causes have been excluded
or a multifactorial cause for diarrhea [31], and/or to require ad- [12]. Although all patients <2 years old had a positive toxigenic
ditional antibiotics during treatment or follow-up. C. difficile test result and a negative rotavirus result for the pur-
Improved treatment outcomes with fidaxomicin were most poses of this study, it is possible that some children in this age
pronounced in patients aged ≥2 years of age and those whose group had an alternative cause of diarrhea that would not be
CDI was diagnosed by means of direct toxin detection. This expected to respond to the CDI treatments used here. The trend
observation may be related to the high rate of asymptomatic toward improved clinical response with vancomycin in children
aged <2 years may therefore be due to random variation, be- The strengths of the current study include its multicenter,
cause the CIs were particularly wide in this small subpopulation. multicountry design; a relatively even geographic distribution
Similarly, the higher relative efficacy of fidaxomicin in patients of patients between sites; and a relatively even distribution of pa-
whose CDI was diagnosed through direct toxin detection, com- tients enrolled across age groups from ≥6 months to <18 years,
pared with those diagnosis by means of polymerase chain reac- although only 1 patient <6 months old was enrolled. Limitations
tion, is in keeping with finding in a study in adults that found include the single-blinded (rather than double-blinded) design,
greater benefit of adjunctive bezlotoxumab in patients with CDI which was for practical reasons due to differences in formu-
diagnosed by this method [32]. lations and dosing regimens between fidaxomicin and van-
The mean plasma concentrations of fidaxomicin and OP-1118 comycin. Second, CDI was diagnosed based on symptoms of
observed 1–5 hours after the dose were 39.41 and 116.64 watery diarrhea or unformed bowel movements plus a local lab-
ng/mL, respectively. Although higher than the mean concentra- oratory test. However, local diagnostic methods varied between
tions 3–5-hours after the dose in the phase 2 study in children centers, and tests have differing levels of sensitivity and speci-
[27] and the study by Louie et al in adults [23], these results ficity [12]. In addition, colonization with toxigenic C. difficile
indicate that systemic absorption is minimal in children, con- and active toxin production may occur in the absence of di-
sistent with findings in adults. The mean end-of-therapy stool sease, particularly in infants, and no test for CDI reliably distin-
concentration of fidaxomicin of 2.7 mg/g was well in excess of guishes between asymptomatic colonization and true infection
the 90% minimum inhibitory concentration of 0.125 mg/L for [34, 35]. It is therefore possible that some enrolled patients, par-
C. difficile determined in the ClosER surveillance study [33]. ticularly those aged <2 years, were C. difficile carriers. Third,