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Pharmacotherapy with systemic antifungal medications
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In recent years, several new systemic antifungal, antimicrobial agents have been introduced and are available for health care providers to use. These agents comprise several different classes of antifungal medications, with differing mechanisms of action, antifungal spectrum of activity, pharmacokinetics and clinical uses in pediatrics.
In 2009, the Infectious Diseases Society of America published updated guidelines on the management of candidiasis. Antifungal agents are commonly described in four classes: triazoles (eg, fluconazole [Diflucan, Pfizer]), polyenes (eg, amphotericin B), nucleoside analogue flucytosine (Ancobon, Valeant Pharmaceuticals) and echinocandins (eg, caspofungin [Cancidas, Merck]). Griseofulvin, an antifungal agent commonly used in children to treat tinea infection of skin and nails, will be reviewed in a future column.
Other azole antifungal agents include ketoconazole, clotrimazole and miconazole, and they will not be discussed.
This month’s column focuses on the triazole class because these antifungals are perhaps more likely to be used by office-based primary care providers.
Candida and Aspergillus species are the most commonly implicated fungi to result in systemic infection in children. Risk factors for infection and disease from fungal pathogens include recent use of systemic antibiotics, neutropenia and immunosuppression (including immunosuppressive drug therapy), use of central venous catheters and prosthetic devices, and use of parenteral nutrition. Mortality from invasive disease in children from these pathogens can range from 19% to 77%.
Clinical uses of triazoles
The triazole class of antifungal agents includes fluconazole, itraconazole (Sporanox, Ortho-McNeil-Janssen Pharmaceuticals), voriconazole (Vfend, Pfizer) and posaconazole (Noxafil, Schering-Plough). Pediatric labeling for the triazoles includes fluconazole at aged 6 months and older; voriconazole at aged 12 years and older; and posaconazole at aged 13 years and older. Itraconazole is not labeled for use in children aged younger than 18 years, although some efficacy and safety data are available for its use in children.
Notable differences among the triazole agents include antimicrobial spectrum of activity, clinical uses and indications, pharmacokinetic characteristics and dosage-form availability. The triazoles generally provide good activity toward many Candida species. Fluconazole is not active against C. krusei, C. glabrata or Aspergillus species. Voriconazole and posaconazole are described as second-generation triazoles because they provide an extended spectrum of activity toward other fungal species (which may include C. krusei and C. glabrata), including some strains resistant to fluconazole. Itraconazole, voriconazole and posaconazole are active toward Aspergillus and Histoplasma.
Fluconazole can be clinically useful for several infectious diseases caused by Candida species and is recommended for adult and pediatric use in the recently published “Clinical Practice Guidelines” by the IDSA. Recommended pediatric uses in these guidelines include treatment of candidemia and candidiasis (non-neutropenic and select neutropenic patients), urinary tract infection, osteoarticular infection and esophageal candidiasis. Fluconazole may also be used as a single-dose, alternative treatment to topical therapies in the management of uncomplicated vulvovaginal candidiasis and as maintenance therapy (once-weekly dosing) for recurrent infection. Fluconazole can additionally be useful in the therapy of cryptococcal meningitis.
Itraconazole can be used for treatment of mucosal candidiasis and histoplasmosis. Voriconazole may be useful in the treatment of systemic aspergillosis and esophageal candidiasis in neutropenic patients. Few efficacy data currently exist for the use of posaconazole in children.
Pharmacokinetic variables
Important limitations for use of the triazole antifungal agents discussed here include the potential for significant drug-drug interactions. The triazoles inhibit important hepatic drug metabolizing enzymes of the cytochrome P450 family, potentially resulting in clinically important drug-drug interactions. A listing of potentially interacting medications is long for each of the triazoles, and thus, clinicians should consider and evaluate the patient’s concomitant drug therapies before use.
Several potentially significant drug-drug interactions that may be more commonly encountered in pediatrics include benzodiazepines (eg, midazolam), fentanyl or phenytoin. The hepatic metabolism of these medications may be significantly inhibited with concomitant use of a triazole, resulting in increased effects or toxicity. Voriconazole’s hepatic metabolism is interesting in that its metabolism by CYP2C19 may be subject to genetic polymorphism, resulting in interpatient variability and varying extent of metabolism and clinical effect (increased adverse effects or decreased clinical efficacy).
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Differences in oral absorption of the triazoles also exist. Oral absorption of itraconazole is variable and depends in part upon dosage form. Reduction in gastric pH may reduce oral absorption of itraconazole oral capsules. This may occur with concomitant use of proton pump inhibitors (eg, omeprazole or lansoprazole) or H2-antagonists (eg, ranitidine). Administration of itraconazole with an acidic beverage (such as colas) or use of the oral solution (better absorption) may overcome these effects. Effects of food upon oral absorption differ by dosage form: Absorption is enhanced when oral capsules are given with food and when oral solution is taken on an empty stomach. Oral absorption of fluconazole is excellent (oral dose similar to IV dose) and is not affected by food. Oral absorption of voriconazole is also excellent; tablets and oral suspension should be taken on an empty stomach to maximize absorption.
Medication costs
The triazoles can play an important therapeutic role in the treatment of various fungal infectious diseases in children because they have good antimicrobial activity against many common fungal pathogens, and they are available as oral dosage forms, including oral liquids. However, they can be expensive. Fluconazole, itraconazole and voriconazole are all available generically, although only as capsules and tablets for itraconazole and voriconazole, respectively. Fluconazole is available generically as an oral suspension and oral tablets.
For more information:
- Cohen-Wolkowiez M. Curr Opin Infect Dis. 2009;22:553-558.
- Pappas PG. Clin Infect Dis. 2009;48:503-535.
- Steinbach WJ. Pediatr Clin North Am. 2005;52:895-915.
- Steinbach WJ. Adv Exp Med Biol. 2011;697:231-242.
Edward A. Bell, PharmD, BCPS, is Professor of Clinical Sciences at Drake University College of Pharmacy and Blank Children’s Hospital and Clinics in Des Moines, Iowa, and a member of the Infectious Diseases in Children Editorial Board. Disclosure: Bell reports no relevant financial disclosures.
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