Invasive opportunistic fungal infections (IFI) are important causes of morbidity and mortality in hospitalized pediatric patients. Among immunosuppressed children, the impact of IFI can be devastating, and timely diagnosis with prompt initiation of treatment is imperative for improving outcomes [1▪▪]. Fortunately, there has been an evolution in recent years of both a better understanding of the pharmacology and clinical indications of existing antifungal agents and the development of new antifungals such as broad-spectrum triazoles and a newer class of agents, the echinocandins [2,3].
In this article, we briefly review the recent literature on antifungal treatment in children and adolescents focusing on the pharmacology and pediatric development of antifungal compounds.
Conventional amphotericin B deoxycholate and the three lipid-formulations currently available represent the oldest antifungal agents but are still considered the gold standard for many invasive fungal infections. Successful combination therapy and preserved efficacy in sequential azole–polyene regimens has been recently shown in adults, whereas most pediatric trials involving polyenes over the last years have focused mainly on its safety profile .
Maertens et al.  compared caspofungin versus liposomal amphotericin B (AmB) for empiric antifungal therapy in 82 children with persistent fever and neutropenia. Adverse effects within 14 days of treatment were similar between groups (laboratory toxicity 10.7% versus 19.2% between caspofungin and AmB group and clinical toxicity 48.2% versus 46.2%). Overall success rates were also similar, 46.4% for caspofungin and 32.0% for AmB. These results contrast with results observed in adults in which nephrotoxicity was higher among the AmB group, suggesting the possibility that amphotericin B related nephrotoxicity might not be as clinically apparent in children. Le et al.  also confirmed this in a large retrospective cohort of 92 infants who received at least three doses of amphotericin B deoxycholate. Rise in serum creatinine was seen in 15 neonates and resolved by the end of treatment in all but one patient. Gestational age, birth weight, sex, underlying medical conditions or use of other nephrotoxic medications could not predict amphotericin nephrotoxicity.
Current management guidelines for neonatal candidiasis recommend amphotericin B deoxycholate and suggest fluconazole or amphotericin B lipid products as alternatives [7–9]. A recent Cochrane review on antifungal therapy for newborn infants with IFI concluded that there was insufficient data to support the use of one antifungal versus another (fluconazole versus amphotericin B deoxycholate) in this age group but this was only based on a single trial on 24 neonates . Ascher et al. [11▪] have recently shown among 730 neonates with invasive Candida infections a higher mortality in infants receiving amphotericin B lipid products compared with infants receiving amphotericin B deoxycholate [odds ratio (OR) 1.96, 95% confidence interval (CI): 1.16–3.33, P = 0.01] or fluconazole (OR 2.39, 95% CI: 1.18–4.83, P = 0.02). The authors suggested that inadequate penetration of amphotericin B lipid products into the kidney or inappropriate dosing in premature infants could explain this finding, which should be considered in current clinical care.
The antifungal azoles are heterocyclic synthetic compounds that block ergosterol production. They are divided into two groups: imidazoles and the newer triazoles.
This first-generation triazole still represents an important component of the antifungal armamentarium. Except for premature infants in their first days of life, children have greater normalized plasma clearance, and therefore, relative to weight, require higher dosages (12 mg/kg daily) than adults to achieve comparable exposures.
Selection of less susceptible organisms after fluconazole prophylaxis, specially C. krusei or C. glabrata, and the emergence of non C. albicans species, particularly C. parapsilosis, has been documented in pediatric centers and has accelerated the development of new azoles with an increased spectrum of activity [12,13].
A recent Cochrane review on the treatment of invasive candidiasis in infants and children concluded that the choice of treatment within the azole group should be based on susceptibility profile of the isolate, and potential adverse effects [14▪▪].
Current recommendations from the Infectious Diseases Society of America recommend fluconazole as a reasonable alternative to AmB for the treatment of neonatal candidiasis. The long-term effects of this approach have been evaluated by Kaufman et al. in a prospective, randomized, double-blinded clinical trial in 86 preterm neonates who were followed up to 10 years of life; the fluconazole-treated group had no difference in neurodevelopment and quality of life compared with the placebo group .
This first-generation triazole is only available as an oral formulation that is licensed in the USA for salvage therapy of invasive aspergillosis and for allergic bronchopulmonary aspergillosis . The development of more effective antifungal agents has relegated itraconazole to a second-line therapy for the treatment of invasive fungal infections and as a prophylactic agent, as the drug of choice for secondary prophylaxis of histoplasmosis in HIV-infected children .
This synthetic oral and parenteral second-generation triazole combines the broad spectrum of activity of itraconazole against molds with the increased bioavailability of fluconazole. It is approved for the treatment of invasive aspergillosis, fusariosis and scedosporiosis and for the primary treatment of invasive candidiasis in nonneutropenic patients .
The role of voriconazole as antifungal prophylaxis in children has been studied recently by Mandhaniya et al. , who compared voriconazole with AmB as primary antifungal prophylaxis in 100 children with acute leukemia in a randomized clinical trial. No significant difference in occurrence of invasive fungal infections was noticed between the two groups but drug-related serious events were 6% in the voriconazole arm versus 30% in the AmB arm (P < 0.001) . Molina et al.  have also reported good outcomes associated with voriconazole prophylaxis in 56 children undergoing hematopoietic stem cell transplantation (HSCT); 66.1% completed 6 months of treatment with no empirical or preemptive antifungal treatment, adverse events or IFI.
Voriconazole is increasingly used in pediatric patients for the treatment of IFI. Children are known to hypermetabolize the drug, requiring higher doses than adults to achieve similar concentrations. Children have consistently shown higher rates of intersubject variability and over the last 2 years a pharmacodynamic association between voriconazole more than 1000 ng/ml and survival has been suggested . Soler-Palacin et al.  showed a significant relationship with voriconazole therapeutic plasma levels [therapeutic drug monitoring (TDM)] and early outcome and skin and neurologic toxicity and Doby et al. [23▪] reported similar finding in 10 children under 3 years of age [24▪▪].
The selection of an adequate dosage for voriconazole in children has been a matter of debate over the last few years and still has no definitive answer. The initial dosage recommendations of 5 mg/kg twice daily were based on a small study that revealed a different degree of nonlinearity in voriconazole pharmacokinetics between adults and children. To determine the adequate dosing regimen in children a population pharmacokinetics analysis was subsequently performed and the simulation outcome suggested that exposure levels achieved with 7 mg/kg intravenously (i.v.) or 200 mg orally twice daily for children aged 2–12 years were similar to exposure levels in adults under the approved dosing regimens.
Michael et al.  in 2010 described the pharmacokinetics of voriconazole in immunocompromised children (between 2 and 11 years) receiving the 2005 approved dosage. They compared the exposure (AUC: area under the concentration–time curve) in nine children receiving 7 mg/kg i.v. every 12 h for 10 days versus 12 adults receiving a loading dose of 6 mg/kg every 12 h followed by a maintenance dose of 4 mg/kg twice daily for 10 days. Voriconazole exhibited nonlinear pharmacokinetics in the majority of children with a wide intraindividual and interindividual variability in plasma voriconazole levels. The authors concluded that an i.v. dose of 7 mg/kg every 12 h should be recommended for children aged 2 to less than 12 years.
Walsh et al. reported similar results in a cohort of 50 immunocompromised children (aged 2–12 years) who received 8 mg/kg twice daily i.v. . Driscoll et al. also observed large intersubject variability in 40 immunocompromised children (aged 2–12 years) receiving 7 mg/kg or 200 mg orally twice daily with no clear threshold of voriconazole exposure identified that could predict occurrence of hepatic toxicity . They concluded that higher than 7 mg/kg dosages are needed in children to match adult exposure and weight-based oral dosages may be more appropriate in children than a fixed dose.
Friberg et al. recently reported a population pharmacokinetic analysis on pooled data from 112 immunocompromised children (2–12 years) and 26 adolescents (12–17 years); loading doses of 9 mg/kg i.v. in children achieved comparable exposures to the 6 mg/kg i.v. loading dose in adults, suggesting that even higher dosages of voriconazole than currently recommended might be needed . Taken together, these data raise a question of whether we have a clear understanding of optimal dosage but confirm the role of TDM of voriconazole for children . At this time, the data support the highest dose proposed by Friberg et al. . It is of note that for children less than 2 years no systematic pharmacokinetic data exist, so dosing is empirical. Future strategies like determination of cytochrome P2C19 polymorphisms might aid in the selection of individualized dosage.
This novel second-generation oral triazole is closely related to itraconazole. Unlike voriconazole, posaconazole has potent and broad-spectrum activity against opportunistic endemic fungi (including Zygomycetes including Mucor spp., Rhizopus spp. and Cunninghamella spp.) and dermatophytic fungi. Posoconazole has been approved by the Food and Drug Administration (FDA) for antifungal prophylaxis in patients more than 13 years of age with acute myeloid leukemia, myelodysplastic syndrome, graft versus host diseases or patients undergoing HSCT with prolonged neutropenia .
Thus far, the safety, efficacy and appropriate dosage of posaconazole in children less than 18 years have not been systematically studied. Lehrnbecher et al. conducted a multicenter retrospective survey about posaconazole salvage treatment and identified 15 children with IFI (between 3 and 17 years of age) receiving posaconazole at a median daily dose of 21 mg/kg (range 4.8–33.3) with a favorable safety profile for a median length of 32 days (range 4–262 days) . Data of ongoing pharmacokinetic studies are urgently needed to define a dosage of posaconazole in children, as no specific dose recommendations exist . Welzen et al. recently developed an algorithm of twice daily dosing (rather than the three times daily dosage used in adults) based on allometric scaling (body-weight based) in 12 patients with chronic granulomatous diseases [34▪]. On the basis of clinical experience, posaconazole appears to be a valuable aid in the management of IFI with excellent clinical efficacy and safety and relatively low potential cross-resistance with other azoles and few drug interactions .
Ravuconazole, isavuconazole and albaconazole
These are second-generation extended-spectrum triazoles currently in Phase 3 development. They offer extended half lives, possibly reduced drug interactions and good tolerance. In addition to activity against Candida and Aspergillus spp. they also have a broad spectrum of activity against resistant and emergent fungi compared with fluconazole and itraconazole. Albaconazole, for instance, is the only drug with activity against Scedosporium prolificans, a multiresistant pathogen that nearly always causes fatal infections. Licensure and determination of their place in clinical practice will be only understood after randomized clinical trials, which are or will be underway. Unfortunately no pediatric data are available yet .
Echinocandins exhibit a potent antifungal activity against Candida spp., including azole-resistant pathogens and Aspergillus spp. Reduced susceptibility has been reported in C. parapsilosis due to a natural mutation in the FKS1 gene. All agents have a similar spectrum of antifungal activity, which seems also to extend to Candida-generated biofilms, which has important implications for the treatment of health-care associated infections . Echinocandins have low oral bioavailability and poor distribution to the central nervous system (CNS)/eye and currently remain expensive to use [38,39].
This was the first echinocandin approved by the FDA, in 2001, and since 2008 is the only FDA approved echinocandin for use in persons at least 3 months of age. It is recommended for primary treatment of Candida infections, salvage therapy for invasive aspergillosis infections and empiric antifungal therapy in persistently febrile neutropenic patients. The first large open-label study of caspofungin in 49 children showed similar efficacy outcomes in invasive aspergillosis or candidiasis consistent with previous adult studies without any serious drug-related adverse events .
The recommended dose for children aged 3 months to 17 years is 50 mg/m2 per day with a maximum dose of 70 mg/m2 per day following a loading dose of 70 mg/m2 per day. This is higher in comparison to the adult maximum dose of 50 mg/m2 per day, as clearance of caspofungin is accelerated in childhood compared with adults or neonates. Data based on 12 neonates aged 1–11 weeks showed that reduced doses of 25 mg/m2 per day result in similar exposures as 50 mg/m2 per day in older patients. A recent randomized trial in 32 neonates with invasive candidiasis compared the efficacy of AmB and caspofungin, showing a superior response in the caspofungin arm (86.7% versus 41.7%) with fewer adverse events . Caspofungin is not currently recommended in the United States in patients aged less than 3 months, as insufficient efficacy data are available yet in this population .
This is licensed only in Europe and Japan for the treatment of invasive candidiasis and aspergillosis and for prophylaxis for Candida infections in patients with HSCT and prolonged neutropenia. Micafungin has an excellent in-vitro antifungal activity against Candida spp., has a favorable pharmacokinetics profile allowing once-daily administration and has fewer drug–drug interactions than caspofungin, with rare reports of resistance [43,44]. A recent review conducted by Arrieta et al. on the safety of micafungin among 296 children showed that only 2.4% of patients discontinued the drug due to serious side events [45▪]. No trends by dose or duration of treatment were observed.
Micafungin is the only echinocandin that has been evaluated for fungal prophylaxis in pediatric HSCT recipients. The initial data were derived from a small pediatric population undergoing HSCT that showed that micafungin was effective in preventing Aspergillus spp. and as effective as fluconazole in preventing invasive candidiasis. Since then, subsequent small studies (either open-label or compared with a fluconazole prodrug) have reported low rates of IFI and safe profile when used as prophylaxis. A recent trial conducted in 15 children by Metha et al. has provided data to indicate that alternative day micafungin prophylaxis (3 mg/kg every other day) may be feasible in children 10 years or less .
The largest micafungin pediatric study for IFI was a randomized trial in 98 children comparing micafungin with AmB for at least 14 days that showed success rates in treating invasive aspergillosis and invasive candidiasis that were similar between the two groups (72.9% and 76.5%, respectively). A subsequent open-label multicenter trial in 20 children reported efficacy of 75% when micafungin was used alone or in combination for first-line and second-line candidemia [14▪▪].
Micafungin dosing has not been definitely established for children, and results on effects of dosage in efficacy have not been homogeneous . Initial data suggested linear pharmacokinetics with an inverse correlation between age and clearance. In a multicenter phase I sequential group dose-escalation (0.5–4 mg/kg) study a 1.3-fold to 1.5-fold increase in clearance of micafungin was noted in patients 2–8 years old compared with older children. Doses of 3–4 mg/kg per day for children aged 2–8 years and 2–3 mg/kg per day for those between 9 and 17 years achieved similar exposures of the drug to those observed in adults. Higher mg/kg doses have been proposed for neonates . Yanni et al. have proposed that age-dependent serum protein binding of micafungin rather than intrinsic hepatobiliary clearance is responsible for the higher clearance observed in neonates .
Hope et al. developed a population pharmacokinetic study of micafungin-dosing model for neonates and young infants that reinforced that higher mg/kg dosages are needed for lower weight patients . A spectrum of 0.75–15 mg/kg could be used safely with near maximal rates of decline in fungal burden observed at 10 mg/kg in infants with hematogenous Candida meningoencephalitis, suggesting that higher doses should be considered when treating CNS infections.
The clinical significance of the recent European Medicines Agency warning of micafungin-induced neoplastic events in animals has unclear clinical significance and seems to be a species-dependent class effect .
This agent has a similar spectrum of activity to micafungin with the advantage of showing the lowest ‘paradoxical effect’ in vitro (increased growth at supra-minimum inhibitory concentrations). It has an independent hepatic metabolism or renal excretion resulting in few drug interactions and no need for dose adjustment for renal or hepatic function. No difference in clearance based on age has been reported. A single study of safety and pharmacokinetics in 24 neutropenic children aged 2–17 years reported that doses of 0.75 and 1.5 mg/kg per day achieved similar exposures to adults under maintenance doses of 50 and 100 mg per day, respectively. Its pharmacokinetics have also been studied in neonates; a loading dose of 3 mg/kg, followed by 1.5 mg/kg per day, exhibited AUCs comparable to standard adult regimens . Warn et al. have recently developed a population pharmacokinetic model for anidulafungin treatment of neonatal hematogenous Candida meningoencephalitis in which near maximal antifungal activity was also observed with doses of 10–20 mg/kg per day, suggesting that the current recommendations are suboptimal for this age group if CNS involvement is suspected .
Anidulafungin use is not approved in children yet and no clinical data against Aspergillus exist, although in-vitro and in-vivo activity has been documented.
This has an in-vitro spectrum of activity similar to other echinocandins with an extended half-life that may permit dosing more frequently than once per day. No human efficacy or pediatric data are yet available .
Newer antifungal agents such as the broad-spectrum triazoles and the echinocandins have revolutionized the treatment of invasive fungal diseases among children. Prompt adoption of recent evidence in the management of pediatric fungal diseases will aid physicians in selecting the appropriate therapy.
Conflicts of interest
B.L.: There are no conflicts of interest.
T.E.Z.: Research Funding: Merck.
Consultant: Merck, Pfizer, Cubist, Astellas, Hemocue.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 157).
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