New Antifungal Agents in Pediatric Practice
Fariba shirvani , Associate Professor of Pediatric infectious diseases,Shaheed Beheshti University of Medical Sciences and Health Services
Invasive fungal infections (IFI) may occur in immunocompromised children ,hematological malignancies, hematopoetic stem cell transplant (HSCT), neonatesespecially the very low birth weight infants (VLBW) and extremely low birth weight (ELBW). These infections areassociated with significant mortality, morbidity, and high health care costs.different types of antifungals are polyenes(Amphotricin), Triazols(Psoconazol,Ravoconazole,Voriconazole,Isavoconazole,Albaconazole),Echinocandins(Caspofungin,Anidulafungin,Micafungin and Nucleosids(Flucytosin).
Polyenes act on cell membrane. Azoles exert their antifungal activity by binding to the ergosterol biosynthetic enzyme, lanosterol 14-α demethylase and inhibiting ergosterol synthesis,Echinocandines act on cell wall. These agents are glucan synthesis inhibitors that specifically inhibit beta (1-3)-D-glucan synthesis, thereby compromising the integrity of the fungal cell wall. Beta (1-3)-D-glucan synthesis does not occur in human cells.Nucleosides act on Nucleic acid synthesis. In this brief review we describe different antifungal drugs and their indication of prescription in children and neonates. Amphotericin B is a broad-spectrum
antifungal agent. products are available as parenteral agents. Newer and more costly (lipid-based) formulations of amphotericin B are increasingly being used in clinical practice.
The major toxicities associated with amphotericin B are nephrotoxicity and infusion-related events (fevers, chills and rigors). The lipid-based products are less nephrotoxic, with comparable efficacy relative to conventional amphotericin B(amphotericin B deoxycholate). Amphotericin B acts onCandida albicans, Candida tropicalis Candida parapsilosis Cryptococcus neoformans Dimorphic fungi.The variable agents (amphotericin B products) have comparable efficacy, although in some clinical settings, the lipid products might be advantageous because higher doses per unit body weight can be used while preserving renal function. The lipid-based products are usually recommended in patients who are refractory to or intolerant of amphotericin B deoxycholate . The lipid-based agents that are most readily available for clinical use are amphotericin B lipid complex and liposomal amphotericin B. A third lipid-based product, amphotericin B colloidal dispersion, is associated with more fever and chills compared with
conventional amphotericin .New generation triazoles have an expanded spectrum of action with cidal activity against a broad spectrum of molds and enhanced activity against Candida spp. and other yeast.Voriconazole has been developed from fluconazole by adding a α-methyl group and substituting a fluoropyrimidine ring for one of the azole groups. It has fungicidal activity against Aspergillus and other molds but not against Zygomycetes. (FDA) approved it for the treatment of primary acute invasive aspergillosis and serious infections caused by Scedosporium spp. and Fusarium spp in 2002. It can be used as both oral and intravenous formulations. It may also be used to treat systemic Candida infections, although in clinical practice, fluconazole would be considered first. Voriconazole has not yet been formally tested in neonates. Ravuconazole
is available as oral and intravenous formulations. Structurally similar to fluconazole and voriconazole, it has a half-life of approximately 100 h which would make it ideal for step-down therapy and treatment in ambulatory care settings. It has activity against Candida species, Aspergillus species, Cryptococcus neoformans, Histoplasma capsulatum and Coccidioides immitis. Posaconazole is similar in structure to itraconazole and has a broad-spectrum of activity in vitro against a wide array of yeasts, moulds, and especially the Zygomycetes, It is active in vivo in several experimental models of pulmonary, cerebral, and disseminated aspergillosis. There is no data available on the safety and efficacy of posaconazole in neonates. . this agent is being used as salvage therapy in situations in which first-line antifungal agents have failed or are contraindicated due to toxicity.
Caspofungin is used in adults for empiric therapy of presumed fungal infections. caspofungin has received FDA approval for pediatric use July 2008,it is used in febrile neutropenic patients, treatment of candidemia, esophageal candidiadis , and treatment of refractor invasive pulmonary aspergillosis. In some centres, it is widely used as empirical treatment in febrile neutropenic patients with impaired renal function. Flucytosine is available as an oral agent. It is invariably used in combination with amphotericin B in the treatment of Candida or cryptococcal infections, notably involving the central nervous system. When combined with amphotericin B, the renal impairment caused by amphotericin B may increase the flucytosine levels in the body and, thus, potentiate its toxicity.
Combinations of antifungal agents
There is no convincing evidence that combination anti-fungal therapy offers advantages over monotherapy with the exception of therapy for cryptococcal meningitis. However, many
experts advise combination therapy for some conditions including central nervous system fungal infections; disease with incomplete response to initial therapy, notably where optimal
dosing is compromised by toxicity; empirical therapy of severe disease presumed to be due to organisms that are knownto have distinct fungal susceptibility profiles (ie, a different drug is needed for each likely pathogen); and initial therapy of selected cases of invasive pulmonary aspergillosis, particularly for diseases in close proximity to major mediastinal blood vessels.