Fidaxomicin for the treatment of Clostridioides difficile in children

Abstract

Fidaxomicin is an oral narrow-spectrum novel 18-membered macrocyclic antibiotic that was initially approved in 2011 by the US FDA for the treatment of Clostridioides difficile infections (CDI) in adults. In February 2020, the FDA approved fidaxomicin for the treatment of CDI in children age >6 months. In adults, fidaxomicin is as efficacious as vancomycin in treating CDI and reduces the risk of recurrent CDI. An investigator-blinded, randomized, multicenter, multinational clinical trial comparing the efficacy and safety of fidaxomicin with vancomycin in children was recently published confirming similar findings as previously reported in adults. Fidaxomicin is the first FDA-approved treatment for CDI in children and offers a promising option for reducing recurrent CDI in this population.

Clostridioides difficile (formerly Clostridium difficile) is a spore-forming, anaerobic, Gram-positive bacteria that is the most common cause of healthcare-associated diarrhea [1–5]. Replacing Staphylococcus aureus as the most common healthcare-associated pathogen, C. difficile infections (CDI) result in nearly 500,000 total infections and 30,000 deaths in the USA alone [1,6]. Despite advances in treatment and detection, the US Center for Disease Control and Prevention (CDC) deemed C. difficile as ‘threat level urgent’ and ‘requires urgent and aggressive action’ starting in 2013 and was reaffirmed as such in 2019 as part of their Antimicrobial Resistance Threats Report [7,8]. In the same 2019 report, the CDC estimated that C. difficile leads to the hospitalizations of 223,900 individuals resulting in 12,800 deaths per year [8]. C. difficile is commonly thought of as a nosocomial infection, but as per the CDC, healthcare-associated CDI cases are decreasing, while community-associated CDI (CA-CDI) cases are increasing [8–13]. Moreover, from 2011 to 2017, recurrent CDI (rCDI) as well as hospitalization related to CA-CDI have increased [14]. There has also been an increase in CDI in special populations that typically lack significant healthcare exposures, such as children [15–17]. Despite a rise in pediatric CDI, treatment recommendations in children have remained relatively stagnant due to a lack of randomized clinical trials of CDI treatments in children [2].

The spectrum of disease caused by C. difficile ranges from asymptomatic colonization to mild diarrhea to life-threatening pseudomembranous colitis [18–21]. C. difficile is transmitted via the fecal–oral route by ingesting C. difficile spores that can transiently contaminate healthcare worker and patient hands [22–25]. C. difficile begins to germinate within the small intestine after it is exposed to primary bile salts such as taurocholate [26,27]. Once the vegetative C. difficile reaches the colon, further germination is halted by exposure to secondary bile salts that are generated by a healthy fecal microbiota [28]. However, if the fecal microbiota is disrupted, overgrowth of the transient C. difficile takes place in the colon, resulting in a release of toxins that cause mucosal disruption and clinical symptoms of diarrhea and colitis [29–31]. The most common cause of disruption to the microbiota is antibiotic exposure, but dysbiosis has also been observed with antineoplastic agents that have antimicrobial properties, inflammatory bowel diseases (IBD) and certain malignancies [2,32–34].

In healthy adults, the frequency of asymptomatic colonization with C. difficile has been documented at 1–3% but has been found to exceed 20% in individuals with healthcare exposures [1,2,35,36]. However, within the pediatric population, the prevalence of C. difficile colonization is more variable. Infants <12 months of age are frequently colonized by C. difficile with some reports exceeding 60% of all children during their first year of life [37]. Infants have been found to be colonized by both toxigenic and nontoxigenic strains, and approximately 50% of newborns are colonized with a toxigenic C. difficile strain [2,38,39]. Yet, despite a high level of colonization, CDI within the first year of life is rare, presumably related to lack of expression of the cellular receptor for C. difficile toxins, although this is unproven in humans [37]. The rate at which infants are colonized with C. difficile progressively decreases after the first year of life. By 3 years of age, both children and adults are colonized by C. difficile at a rate of 1–3% [2,40]. Of note, certain special pediatric populations have higher rates of C. difficile colonization. Two of these populations are children with IBD and children with cancer [41–43]. Nearly 20% of children with IBD are colonized with C. difficile, and more than 30% of children with a malignancy have been found to be colonized by C. difficile [41,42]. The higher rates of colonization also extend to the general pediatric population that has been admitted to the hospital; 25% of hospitalized children have C. difficile colonization [44]. Moreover, this high level of colonization has made the diagnosis of CDI in children difficult. Clinical laboratories typically rely on high sensitivity testing such as nucleic acid amplification test (NAAT) for the diagnosis of CDI [21]. However, NAAT is unable to differentiate between colonization and infection [45]. Because of this, the current guidelines are to limit testing in children <1 year of age [2].

Over the past 2 decades, CDI incidence has nearly doubled within the pediatric population [15,16]. From 1997 to 2006, pediatric CDI hospitalizations increased from 7.2 to 12.8 per 10,000 hospitalizations [15]. From 2012 to 2016, the CDC Emerging Infections Program revealed that the incidence of CDI in children increased from 23.98 to 34.82 per 100,000 patients [46]. These data from the Emerging Infections Program reveal that more than 66% of pediatric CDI is CA-CDI [46]. While these studies are limited by a lack of testing standardization, it reveals a clear trend toward CA-CDI within the pediatric population.

In 2018, the Infectious Diseases Society of America and Society for Healthcare Epidemiologist released an update for the management and treatment of CDI [2]. The previous guidelines were published in 2010. Since that time, fidaxomicin was approved by the US FDA for the treatment of CDI after two large Phase IIb/III clinical studies in adults [29,47,48]. These clinical trials, as well as the robust data showing the superiority of vancomycin over metronidazole for the treatment of CDI in adults, resulted in metronidazole no longer being considered first-line therapy in adults [2,49,50]. However, because of the lack of clinical data in children, metronidazole was still considered a first-line option for mild–moderate CDI (strength of recommendation: weak; low quality of evidence) [2]. While children typically respond well to vancomycin and metronidazole initially, the rate of rCDI has increased in all populations treated with these antibiotics [2,51,52]. Similar to adults, children with primary CDI suffer from rCDI in 20–40% of cases [53–56]. CDI recurrence appears to occur equally in children treated with vancomycin or metronidazole for nonsevere CDI, although symptom resolution may be more rapid in those treated with vancomycin [57]. Recurrence can likely be attributed to the profound affect that metronidazole and vancomycin have on the fecal microbiota [58–61]. By causing continued alterations in the fecal microbiota, after the successful treatment of CDI with vancomycin or metronidazole, the remaining C. difficile spores are able to re-germinate, resulting in rCDI [58]. Since the publication of the 2018 Infectious Diseases Society of America/Society for Healthcare Epidemiologist C. difficile guidelines, a Phase III (SUNSHINE) trial comparing fidaxomicin with vancomycin for the treatment of CDI in the pediatric population has been completed [62,63].

Fidaxomicin clinical pharmacology

Fidaxomicin was approved by the FDA in 2011 for the treatment of CDI in adults after the completion of two large scale, multicenter, multinational Phase IIb/III clinic trials in adults [47,48,64]. In February 2020, the FDA-approved fidaxomicin in patients 6 months of age and older for the treatment of CDI after the completion of a large Phase III clinical trial in children aged 6 months to under 18 years of age [65]. Therefore, it is of interest to review the clinical literature pertaining to fidaxomicin as a treatment option for C. difficile among pediatric patients. The treatment of CDI with fidaxomicin has shown promising evidence of decreased rCDI [63,66]. As the incidence of CDI continues to rise in children, and thus rCDI, the approval of a treatment option that leads to a decrease in rCDI is encouraging.

Chemistry

Fidaxomicin is a novel 18-membered macrocyclic antibiotic derived from the fermentation products of Actinoplanes deccanensis and Dactylosporangium aurantiacum [48,67]. It has a molecular weight of 1058 g/mol and its molecular formula is C₅₂H₇₄C₁₂O₁₈ (Figure 1) [68–70]. Fidaxomicin was discovered in 1970s and was formerly known as lipiarmycin, tiacumicin B, OPT-80, PAR-101 and difimicin [71–73]. Fidaxomicin is hydrolyzed to its active metabolite, OP-1118, in a 2:1 ratio [69]. It is hypothesized that fidaxomicin is hydrolyzed in gastric acid or by enzymatic activity of intestinal microsomes [74]. Antibacterial activity of OP-1118 is 8–16-times lower than fidaxomicin [74].

Figure 1. . Chemical structure of fidaxomicin.

Mechanism of action

Fidaxomicin and its active metabolite, OP-1118, has bactericidal activity against C. difficile by inhibiting transcription of bacterial RNA by RNA polymerases, thus preventing protein synthesis [75]. RNA polymerase is an enzyme that consists of five subunits that comprise its core catalytic enzyme and a separate sigma (σ) subunit responsible for promoter recognition [76]. Fidaxomicin binds to the sigma subunit of RNA polymerases [77]. In vitro studies have reported that binding of fidaxomicin to RNA polymerases inhibits initiation of the separation of DNA strands (precursor step in RNA synthesis). Thus, its mechanism of action differs from other antibiotics that involve inhibition of RNA transcription (e.g., rifamycins) [78]. Fidaxomicin and OP-1118 can inhibit growth of spore production of C. difficile and toxin production [79–81].

Spectrum of activity

Fidaxomicin has narrow spectrum of antimicrobial activity with excellent in vitro activity against C. difficile and C. perfringens and good activity against enterococci and staphylococci but with poor activity against nonanaerobic Gram-negative bacteria [82–84]. Most aerobic and anaerobic Gram-negative bacilli (e.g., Enterobacteriaceae, Pseudomonas, Helicobacter, Fusobacterium, Prevotella and Veillonella) reported fidaxomicin MICs between 32 and 64 μg/ml [85,86]. Moreover, fidaxomicin does not have activity against Candida species (fidaxomicin MIC >64 μg/ml) [86].

Microbiology & mechanism of resistance

In vitro studies have reported C. difficile fidaxomicin MICs to range from ≤0.03^-1 μg/ml with a MIC₉₀ of 0.5 μg/ml with the highest reported MIC for wild-type isolates as 1 μg/ml [85,87–89]. Within the USA, fidaxomicin MICs have not changed within recent years [90]. An in vivo study reported the MIC₅₀ and MIC₉₀ for OP-1118 were 4 and 8 μg/ml, compared with 0.125 and 0.25 μg/ml, respectively, for fidaxomicin [86]. The postantibiotic effect of fidaxomicin ranges from 5.5 to 12.5 h [90]. The postulated mechanism of the postantibiotic effect is due to the mechanism of action of fidaxomicin and/or its nonspecific binding to bacterial cell allowing fidaxomicin to remain inside the cell and exert its antimicrobial activity [91]. Furthermore, fidaxomicin has been shown to bind to the C. difficile exosporium. This creates a ‘persistence of activity’ preventing the outgrowth of the spores at the completion of therapy [92].

A comparative microbiological study reported low mutation rates (<1.4 × 10^-9) at eight-times the MIC of fidaxomicin [91]. C. difficile clones with fidaxomicin MIC of 2 or 4 μg/ml carried mutations in either rpoB (Gln1074Lys or Val1143Phe) or rpoC (Asp237Tyr) genes (genes that encode RNA polymerase, β subunit and β’ subunit) [93]. Another in vitro study reported decreased fidaxomicin susceptibility occurred due to deletion in CD22120 (resulting in a frameshift in homolog of the MarR family of transcriptional regulators) and a mutation in rpoB [94]. A clinical isolate from a patient that developed C. difficile recurrence after receiving fidaxomicin was reported to have a fidaxomicin MIC of 16 μg/ml [89]. The mechanism of resistance for this isolate was considered a single mutation in the β subunit of the RNA polymerase [86]. Another clinical isolate with a V1143D mutation in rpoB was shown to display reduced fidaxomicin susceptibilities with a fidaxomicin MICs of 64 μg/ml and showed a reduced replication rate [95]. There has been no cross-resistance with azithromycin, ampicillin, ciprofloxacin, metronidazole, vancomycin, rifampin and rifaximin [69,96].

Pharmacokinetics/pharmacodynamics

A multicenter, Phase IIa study assessed the pharmacokinetics of fidaxomicin in pediatric patients diagnosed with C. difficile aged 6 months to 18 years [62]. Patients ≥6 years of age received fidaxomicin 200 mg tablet orally every 12 h for 10 days (if unable to swallow tablets, received oral suspension at the same dose and frequency). Patient aged 6 months to <6 years received 32 mg/kg per day (maximum dose: 400 mg/day) divided dose every 12 h in the oral suspension formulation. Plasma and fecal concentrations of fidaxomicin and OP-1118 were measured. Three plasma samples (0–2 h before dosing, 1–2 h after dosing and 3–5 h after dosing) were collected between the 5th and 10th day of treatment. Fecal samples were collected on the tenth or last day of treatment. Thirty-eight patients (11 months to 17 years of age) were treated with fidaxomicin.

Fidaxomicin plasma concentrations at 3–5 h postdose across all age groups ranged from 0.6 to 87.4 ng/ml and OP-1118 concentrations were 2.4–882 ng/ml. The mean postdose fidaxomicin and OP-1118 plasma concentrations were 13.4 and 60 ng/ml, respectively. The peak plasma fidaxomicin and OP-1118 concentrations were not significantly different between age groups, despite younger patients (i.e., less than 2 years of age) receiving higher doses according to weight.

Detectable fecal fidaxomicin and OP-1118 concentrations were found in 30 and 28 fecal samples, respectively. Fecal fidaxomicin concentrations ranged from 268 to 11,500 μg/g of stool (mean: 3227.9 μg/g; standard deviation [SD]: 2668.1 μg/g). Fecal OP-1118 concentrations ranged from below the limit of quantification to 2540 μg/g of stool (mean: 865.5 μg/g; SD: 614.2 μg/g). There was a trend for higher mean OP-1118 stool concentration with high variability among patients less than 2 years of age.

A prospective, multicenter Phase III pediatric study evaluated plasma and fecal concentrations of fidaxomicin [63]. Patients were randomized to receive fidaxomicin 16 mg/kg oral suspension twice daily (maximum: 400 mg/day) for patients aged <6 years of age or 200 mg tablets every 12 h for patients ≥6 years of age but <18 years old for 10 days. Blood samples to determine plasma concentrations of fidaxomicin and OP-1118 were taken within 30 min before and 1–5 h after dose on days 5–10. Stool samples were obtained daily on days 5–10. Eighty-two patients (55 patients received oral suspension and 27 received tablet formulation) had plasma concentrations reported for fidaxomicin and OP-1118. Seventy-four patients (47 received oral suspension and 27 received tablet formulation) had stool concentrations (only 73 patients reported for OP-1118; 46 received oral suspension and 27 received tablet formulation). Postdose mean (SD) plasma concentration increased twofold predose at 39.4 (62.2) ng/ml for fidaxomicin and 116.6 (259.1) ng/ml for OP-1118. Fidaxomicin and OP-1118 plasma concentrations were lower among patient that received oral suspension in comparison with tablet formulation. Mean (SD) of stool concentration for fidaxomicin was 2.7 mg/g (2.5) and for OP-1118 was 0.9 mg/g (0.8). Mean stool concentration of fidaxomicin increased with oral suspension but mean stool concentration of OP-1118 was higher with tablets.

In an adult pharmacokinetic population, after a single dose of fidaxomicin (100, 200, 300, 450 mg), the plasma concentration was low or below the lower limit of quantification (defined as 5 ng/ml) [74]. Plasma concentrations of OP-1118 were slightly higher than fidaxomicin but near the limit of quantification. Fecal recovery of fidaxomicin and OP-1118 for patients after receiving a single dose of 200 or 300 mg ranged from 36.47 to 123.52 mg and 34.73 to 249.07 mg, respectively. The elimination half-life was calculated as 0.94–2.77 h.

A pharmacokinetic study comprised of two Phase II trials among adult patients diagnosed with C. difficile who received fidaxomicin 200 mg every 12 h investigated plasma and fecal concentrations and the impact of renal impairment on plasma concentrations [97]. Plasma concentrations of fidaxomicin and OP-1118 were low on the first and last day of therapy (day 1: fidaxomicin = 0.364–197 ng/ml and OP-1118 = 0.283–363 ng/ml and day 10: fidaxomicin = 0.305–191 ng/ml and OP-1118 = 1.09–871 ng/ml). The plasma concentration of OP-1118 was statistically higher on the last day of therapy in comparison with the first day of therapy (p < 0.001). The mean fecal concentration (±SD) for fidaxomicin and OP-1118 was 1396 ± 1019 and 834 ± 617 μg/g, respectively. There was no significant difference in plasma fidaxomicin concentration 3–5 h after last dose on last day of therapy, regardless of severity of renal impairment. However, OP-1118 concentrations were higher for patients with renal insufficiency (p = 0.01).

Therefore, as in the adult population, the plasma concentrations of fidaxomicin and OP-1118 in pediatric population are relatively low. Fidaxomicin and OP-1118 are primarily excreted in feces following oral administration. The half-life of fidaxomicin and the impact of renal impairment on plasma fidaxomicin concentration in the adult population have been reported. However, dose adjustment for renal and hepatic impairment may not be necessary because of low systemic absorption, and fidaxomicin and its metabolite do not appear to undergo hepatic metabolism.

Fidaxomicin clinical efficacy

Efficacy of fidaxomicin in adult clinical trials

Fidaxomicin was FDA-approved in the USA in 2011 for treatment of CDI in adults. Two large double-blinded, multicenter, multinational, randomized Phase IIb/III were completed in adults comparing vancomycin and fidaxomicin for the treatment of CDI. In 2016, a similar double-blinded Phase III clinical trial comparing the efficacy of fidaxomicin to vancomycin was conducted in Japan as well [98]. All three of these trials demonstrated that fidaxomicin was noninferior to vancomycin in providing an initial clinical cure for CDI, and the incidence of rCDI in subjects treated with fidaxomicin was lower when compared with vancomycin. The pooled data from these trials revealed that both fidaxomicin and vancomycin achieved clinical cure at the end of therapy (EOT) in the modified intention to treat population (87.3 and 86.5%, respectively) [47,64,98]. More notable, however, was that these clinical trials revealed a statistically and clinically significant improvement in CDI global cure (GC) or sustained response, defined as an initial clinical cure and a lack of recurrence within 28 days after the completion of the study drug. The incidence of GC among subjects treated with fidaxomicin was higher than those receiving vancomycin in the modified intention to treat population (74.2 and 64.1%, respectively) [47,64,98].

A fourth clinical trial comparing fidaxomicin to vancomycin was published in 2017 in which a randomized, controlled, open-label, Phase IIIb/IV trial was completed in adults comparing standard course of vancomycin was compared with a novel fidaxomicin regimen (200 mg twice daily for days 1–5 followed by one 200 mg tablet every 48 h for days 7–25) [99]. The study investigators again showed that fidaxomicin, albeit comparing a novel fidaxomicin regimen to standard vancomycin, was superior to vancomycin in achieving a sustained clinical cure. Investigators reported that the extended course of fidaxomicin led to a sustained clinical response at 90 days following treatment in 81% of the patients treated with fidaxomicin and 60% of those treated with vancomycin [99].

Efficacy of fidaxomicin in pediatric clinical trials

O'Gorman et al. conducted an open-label single-arm, multicenter Phase IIa clinical trial in the USA and Canada [62]. The trial consisted of 40 subjects aged 11 months to 17 years of age with CDI. Children age 6 months to <6 years of age received fidaxomicin at a weight base dose of 32 mg/kg per day divided twice daily, and children older than age of 6 years received 200 mg of fidaxomicin every 12 h. Treatment duration was for 10 days, at which time the primary efficacy outcome and clinical response was assessed. In children aged 6–23 months, clinical response was defined as the absence of diarrhea for two consecutive days during treatment with no further CDI therapy within 2 days of completion. In children aged 2–17 years, clinical response was defined as improvement in stool frequency and character for 2 consecutive days during therapy. Improvement was defined as the absence of watery diarrhea for two consecutive days and not requiring further CDI therapy within 2 days of completing the study drug. The study defined CDI recurrence as diarrhea within 28 days after an initial clinical response to fidaxomicin, a positive test for a toxigenic strain of C. difficile, and the study investigator-determined need for retreatment. Of the 38 subjects treated with fidaxomicin, 35 (92.1%) had a clinical response and 25 (65.8%) had a sustained clinical response. Recurrence was documented in 11/35 (31.4%) subjects who initial clinical cure.

Wolf et al. conducted an investigator-blinded, randomized, multicenter, multinational, parallel-group, Phase III trial comparing the safety and efficacy of fidaxomicin and vancomycin for the treatment of CDI in subjects <18 years of age [63]. Subjects were randomized 2:1 for 10 days of treatment with fidaxomicin or vancomycin. Fidaxomicin was dosed as a 16 mg/kg/dose (max 400 mg/day) oral suspension twice a day for patients aged 0–<6 years old (children age <6 months were excluded in the USA), or 200 mg tablets twice a day for patients aged ≥6–<18 years old. The vancomycin was dosed as 10 mg/kg (max 125 mg/dose) oral suspension four-times a day for children aged 0–<6 years old, or 125 mg capsules four-times a day for children aged ≥6–<18 years old. A negative rotavirus test was required in subjects who were younger than 5 years of age. Randomization was stratified by age group. The primary end point was confirmed clinical response (CCR), which was defined as an initial clinical response by the EOT and no further CDI treatment required within 2 days of EOT. The secondary end points were GC (defined as CCR without CDI recurrence within 30 days after the EOT), time to resolution of diarrhea and CDI recurrence. In total, 148 patients were randomized (100 to fidaxomicin and 48 to vancomycin) with 142 patients receiving the study treatment (98 subjects received fidaxomicin and 44 received vancomycin).

The CCR primary end point was achieved in 77.6 and 70.5% of subjects in the fidaxomicin and vancomycin treatment groups, respectively. Symptomatic relief was also similar between the fidaxomicin and vancomycin groups, with diarrhea resolving in 75.5 and 72.7% of subjects, respectively. Similar to the Phase III adult trials there was no clinical or statistically significant difference in initial CCR between the fidaxomicin and vancomycin groups in this pediatric study.

Among those subjects achieving CCR, 11.8% of those treated with fidaxomicin and 29.0% of those treated with vancomycin experienced a CDI recurrence within 30 days of completing therapy (adjusted risk difference -15.8%; 95% CI: -34.5–0.5). GC was significantly more frequent in the fidaxomicin group (68.4 vs 50.0%), and the adjusted risk difference in GC between fidaxomicin and vancomycin groups was 18.8% (95% CI: 1.5–35.3%). Upon subgroup analysis, fidaxomicin was associated with a significantly greater frequency of GC among patients ≥2 years of age, patients ≥2 years of age with a positive C. difficile toxin enzyme immunoassay and nonimmunocompromised children.

It must be noted that the fidaxomicin CCR (78%) and GC (68%) in children in this trial [63,100] were lower when compared with previously reported in adults (87% CCR, 74% GC) [47,64,98]. Comparisons of fidaxomicin efficacy between children and adults are listed in Table 1. The pediatric trial included subjects diagnosed with CDI by NAAT, while the adult trials limited enrollment to subjects whose stool was toxin positive. Thus, it is possible that the pediatric trial included some children with C. difficile colonization and an alternate diarrheal etiology or children with both CDI and a concomitant diarrheal etiology. Nonetheless, the study investigators concluded that fidaxomicin had a similar CCR to that of vancomycin but was associated with a reduced likelihood of rCDI in children. Based on these promising results, in February 2020, the FDA-approved fidaxomicin for the treatment of CDI in pediatric patients.

Table 1. . Comparison of confirmed clinical response, 30 day recurrence, global cure data from children^† and adults^‡ enrolled in separate Phase III trials of fidaxomicin versus vancomycin.

Paramereters	Maturity	Fidaxomicin, n (%)	Vancomycin, n (%)	Relative difference (95% CI)	Absolute difference (95% CI)
CCR	Children	76/98 (77.6%)	31/44 (70.5%)	1.1 (0.88–1.37)	71 more per 1000 (from 87 fewer to 229 more per 1000)
	Adults	561/643 (87.2%)	583/674 (86.5%)	1.01 (0.97–1.05)	7 more per 1000 (from 29 fewer to 44 more per 1000)
30 day CDI recurrence	Children	9/76 (11.8%)	9/31 (29.0%)	0.41 (0.18–0.93)	172 fewer per 1000 (from 347 fewer to 4 more per 1000)
	Adults	84/561 (15.0%)	151/583 (25.9%)	0.58 (0.45–0.74)	109 fewer per 1000 (from 155 fewer to 63 more per 1000)
GC	Children	67/98 (68.4%)	22/44 (50%)	1.37 (0.99–1.89)	184 more per 1000 (from 10 more to 358 more per 1000)
	Adults	477/643 (74.2%)	432/674 (64.1%)	1.16 (1.08–1.24)	101 more per 1000 (from 51 more to 150 more per 1000)

Adult [47,64,98], children [63].

^†Unadjusted full analysis set data.

^‡Modified intention to treat data.

CCR: Confirmed clinical response (initial symptom resolution after 10-day treatment with no further CDI therapy at 2 days after the end of therapy); CDI: Clostridioides difficile infection; GC: Global cure (CCR plus no recurrence at the end of the study).

Fidaxomicin safety

Safety of fidaxomicin in adult clinical trials

Fidaxomicin, similar to vancomycin, is poorly absorbed through the gastrointestinal (GI) tract. This has been demonstrated and reproduced in multiple clinical trials [47,64,74,97]. The plasma concentration of fidaxomicin as well as the primary metabolite, OP-1118, was shown to be negligible during the initial Phase IIa trial in adults [101]. During the initial single-dose Phase I and II trials in adults, there were no cardiac dysrhythmias or hemodynamic instability associated with fidaxomicin [74]. During the Phase IIb and III fidaxomicin trials in adults, there was no significant difference in adverse events (AE) or serious AEs (SAE) when compared with vancomycin [29,47]. Frequency of AEs that were deemed to be drug related by the study investigators during these Phase III trials in adults were similar between fidaxomicin (9.7%) and vancomycin (9.0%) [66].

Safety of fidaxomicin in pediatric clinical trials

Twenty-eight of the 38 children (73.7%) experienced an AE during the Phase IIa fidaxomicin trial in children [62]. The majority were defined as mild (17/28, 60.1%) or moderate (8/38, 29%). Of these 28 children experiencing an AEs, only three (10.7%) experienced a severe AE, namely GI mucositis, septic shock with respiratory failure and adenovirus with dehydration. Around 10.5% of patients experienced vomiting and fever during the trial and 7.9% of patients developed either upper abdominal pain or CDI requiring re-hospitalization after the completion of treatment. SAEs, defined as those that necessitated hospitalization, were life threatening, or were fatal, were documented in nine children; one fatal SAE that occurred in a patient with sepsis and respiratory failure. Of the nine SAEs, none were determined to be related to the study medication. Treatment-related AEs were ascribed to six patients; five were listed as ‘possibly’ related to study treatment by the investigators, and one episode of urticaria was labeled as ‘definitely’ related to study treatment.

Treatment-emergent AEs (TEAEs) and severe TEAEs were similar between fidaxomicin and vancomycin during the Phase III pediatric clinical trial (Table 2) [63]. During the trial, 72/98 (73.5%) subjects who received fidaxomicin and 33/44 (75.0%) patients who received vancomycin experienced TEAEs. The most common TEAE during the trial was fever, which occurred in 13/98 (13.3%) and 10/44 (22.7%), subjects in the fidaxomicin and vancomycin groups, respectively. Drug-related TEAEs were similar between the fidaxomicin and vancomycin groups and were reported in 7/98 (7.1%) and 5/44 (11.4%) subjects in each group, respectively. The fidaxomicin-related TEAEs included constipation (n = 2), as well as diarrhea, fever, oral candidiasis, alanine aminotransferase elevation and irritability (each n = 1). Serious TEAEs were similar between fidaxomicin and vancomycin (24.5 vs 27.3%, respectively), and there were no serious drug-related TEAEs in either group. Furthermore, the investigators found that there was no significant age-related difference in TEAEs between the fidaxomicin and vancomycin groups. Investigators labeled certain TEAEs as those of special interest and included hypersensitivity reactions, hematologic abnormalities (leukopenia, neutropenia and lymphopenia), renal dysfunction, GI hemorrhage, QT prolongation and potential drug-induced liver injury. There was no significant difference detected in these particular TEAEs between groups. Death occurred in three patients who received fidaxomicin and two patients who received vancomycin, but none of these events were caused by the study drug or C. difficile.

Table 2. . Comparison of adverse event data from children and adults enrolled in separate Phase III trials of fidaxomicin versus vancomycin.

Characteristics	Maturity	Fidaxomicin, n (%)	Vancomycin, n (%)	Relative difference (95% CI)	Absolute difference (95% CI)
All TEAE	Children	72/98 (73.5%)	33/44 (75.0%)	0.98 (0.80–1.21)	15 fewer per 1000 (from 170 fewer to 140 more per 1000)
	Adults	458/668 (68.6%)	457/691 (66.1%)	1.04 (0.96–1.12)	24 more per 1000 (from 26 fewer to 74 more per 1000)
Serious TEAE	Children	24/98 (24.5%)	12/44 (27.3%)	0.90 (0.50–1.63)	27 fewer per 1000 (from 185 fewer to 129 more per 1000)
	Adults	161/668 (24.1%)	150/691 (21.7%)	1.11 (0.91–1.35)	24 more per 1000 (from 21 fewer to 69 more per 1000)
Drug-related TEAE	Children	7/98 (7.1%)	5/44 (11.4%)	0.63 (0.21–1.87)	42 fewer per 1000 (from 149 fewer to 65 more per 1000)
	Adults	69/668 (10.3%)	74/691 (10.7%)	0.96 (0.71–1.32)	4 fewer per 1000 (from 36 fewer to 29 more per 1000)

Adult [47,64,98], children [63].

Full analysis set data used for both children and adults.

TEAE: Treatment emergent adverse event.

Conclusion

Metronidazole and vancomycin have long been the primary therapies for CDI in children. Over the past two decades there has been a dramatic rise in pediatric CDI which has been further complicated by frequent rCDI in children [15,46,54]. Previous CDI treatment guidelines have been hampered by a lack of quality clinical data resulting in no significant updates to treatment recommendations for pediatricians [2]. These Phase IIa and III trials are the first major clinical trials for the treatment of CDI in children and introduces fidaxomicin as a safe and efficacious treatment alternative for CDI within the population [62,63]. The data from the Phase III clinical trial show similar CCR with a significantly improved GC compared with that of vancomycin. Thus, as observed in adults, fidaxomicin appears to be superior in reducing the rate of rCDI in children and should be addressed in future CDI treatment guidelines.

Executive summary.

Pediatric Clostridioides difficile background

• C. difficile infections (CDI) are the most common nosocomial infection resulting in nearly 500,000 infections in the USA.

• Pediatric CDI has doubled over the past two decades representing a growing burden in this population.

• Development of pediatric CDI treatment guidelines have been limited by a lack of quality evidence in children.

• In February 2020, the US FDA approved fidaxomicin for the treatment of CDI in children.

Chemistry & mechanism of action

• Fidaxomicin [C₅₂H₇₄C₁₂O₁₈] is a novel 18-membered macrocyclic oral antibiotic derived from the fermentation products of Actinoplanes deccanensis and Dactylosporangium aurantiacum.

• Fidaxomicin is hydrolyzed into it's the active metabolite, OP-1118, in the gastrointestinal (GI) tract at a 2:1 ratio.

• Fidaxomicin and OP-1118 have bactericidal activity against C. difficile by binding to the bacterial RNA polymerase sigma subunit inhibiting the transcription of bacterial RNA, thus preventing protein synthesis.

Microbiological activity

• Fidaxomicin has a narrow spectrum of antimicrobial activity with excellent in vitro activity against C. difficile and C. perfringens but poor antimicrobial activity against nonanerobic Gram-negative bacteria, aerobic gram-negative bacilli and Candida species.

• C. difficile clones with fidaxomicin minimum inhibitory concentrations (MIC) of 2 or 4 μg/ml carried mutations in either rpoB (Gln1074Lys or Val1143Phe) or rpoC (Asp237Tyr) genes, but C. difficile mutation rates are low when exposed to fidaxomicin concentrations at eight-times the MIC.

• There has been no reported cross-resistance with azithromycin, ampicillin, ciprofloxacin, vancomycin, rifampin, rifaximin or metronidazole.

Pharmacokinetic properties

• Fidaxomicin is poorly absorbed through the GI tract in both adults and children.

• In a Phase IIa trial to assess the pharmacokinetics of fidaxomicin in pediatric patients, the mean postdose plasma concentration of fidaxomicin and OP-1118 was 13.4 and 60 ng/ml respectively. The corresponding mean fecal concentrations were 3227.9 and 2540 μg/g for fidaxomicin and OP-1118, respectively.

• Dose adjustment because of renal and hepatic impairment is likely not necessary because of low systemic absorption and fidaxomicin and its metabolite do not appear to undergo hepatic metabolism.

Clinical efficacy

• In an investigator-blinded, randomized, multicenter, multinational, parallel-group, Phase III trial comparing the safety and efficacy of fidaxomicin and vancomycin in a pediatric population, fidaxomicin and vancomycin achieved clinical cure (confirmed clinical response) at similar rates. (77.6 and 70.5%, respectively; Adjusted risk difference: 7.5%; 95% CI adjusted risk difference: -7.4–23.9%).

• Notable secondary outcomes from the Phase III pediatric clinical trial reveal that global cure was achieved more frequently in subjects treated with fidaxomicin over vancomycin (68.4 and 50% respectively; adjusted risk difference: 18.8%; 95% CI-adjusted risk difference: 1.5–35.3%) and recurrence at 30 days was more likely to occur in those treated with vancomycin over fidaxomicin. (29 and 11.8% respectively; adjusted risk difference: -15.8%; 95% CI-adjusted risk difference: -34.5–0.5).

• Fidaxomicin confirmed clinical response and global cure were lower in children when compared with previously reported adult trials.

Safety & tolerability

• Fidaxomicin is typically well-tolerated with no reported serious drug-related treatment emergent adverse events (AE) during the pediatric Phase III trial.

• During the Phase III pediatric clinical trial, subjects treated with fidaxomicin and vancomycin had similar rates of AEs throughout the study (73.5 and 75% respectively).

• Treatment emergent AEs of special interest such as hypersensitivity reactions, hematologic abnormalities, renal dysfunction, GI hemorrhage, QT prolongation and potential drug-induced liver injury were similar in subjects treated with fidaxomicin and vancomycin.

Conclusion

• Fidaxomicin for the treatment of CDI in children is a safe and efficacious treatment option that appears to be superior in reducing the rate of recurrent CDI in children when compared with vancomycin.