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Antifungal Agents
Fungal infections in children generally can be divided into superficial infections that affect persons with normal immune systems and invasive infections that occur primarily in children who are immunocompromised. Children can be immunocompromised due to genetic defects, pre-term birth, hematopoietic cell or solid organ transplantation, or following one of the chemotherapeutic regimens used for childhood malignancies. Improved treatments for malignancy and increasing success in the treatment of primary disease can result in patients who survive but are more susceptible to invasive fungal disease during their recovery. Fortunately, there has been a recent surge in the development of antifungal therapies, and several new studies have expanded our knowledge on how to optimize antifungal therapy. Because of the paucity of pediatric data, many recommendations for the use of systemic antifungal agents in children are derived from experience in adults, which is problematic because of the pharmacokinetic differences between children and adults. This chapter provides a brief review of topical antifungal therapy and an overview of the current state of systemic antifungal agents, including recent advances. The preferred treatment for each pathogen is covered in pathogen-specific chapters.
Antifungal Agents for Treatment of Superficial Infections
Among the therapeutic options available for treatment of fungal infections of the hair, skin, and nails, few have been tested in children, and fewer are approved by the US Food and Drug Administration (FDA) for use in children >13. Extrapolating data from adults treated for dermatomycoses to infants and children may not be justified. For example, manifestations of dermatomycoses vary with age, with tinea capitis seen almost exclusively in children.
The use of topical agents should be confined to infections of the epidermis or mucosal surfaces. The choice of treating superficial fungal infections with a topical or a systemic agent depends on the fungal pathogen, the site of infection, and the extent of lesions. Systemic antifungal therapy almost always is used for tinea of the scalp, nails, palms, or soles; creams or solutions are preferred for fissured or intertriginous areas.
Topical Polyenes
Nystatin is a polyene antifungal agent named after New York state. It binds to ergosterol in the fungal cell membrane and causes changes in cell permeability and, eventually, cell lysis. Nystatin is useful for the treatment of mucosal and cutaneous infections caused by Candida species. Nystatin is available as a suspension (100,000 U/mL), powder, cream, or ointment (100,000 U/g); a lozenge (200,000 U) to be dissolved in the mouth; an oral tablet (500,000 U); and a vaginal tablet (100,000 U). Oral forms are administered four or more times daily and are well tolerated since there is no significant systemic absorption, although large oral doses of the suspension can cause nausea. Nystatin is ineffective against the dermatophytes, although some new preparations, including nanocarriers, have shown promising results.
Topical Azoles
The azole class (divided into imidazoles and triazoles based on chemical structure) inhibits ergosterol synthesis in the fungal cell membrane. Clotrimazole is an imidazole with broad-spectrum activity against Candida species and the dermatophytes Trichophyton tonsurans, Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis ( Table 293.1 ). Clotrimazole also is effective against Malassezia furfur, the cause of tinea versicolor. Clotrimazole is one of the few topical antifungal agents studied in children. The 1% cream, lotion, and solution are available over the counter for the treatment of tinea pedis, tinea cruris, and tinea corporis. High concentrations of clotrimazole are achieved topically, but systemic absorption is negligible. Topical application generally is well tolerated but can cause local irritation or urticaria. Clotrimazole is available co-formulated with 0.05% β-methasone, and this combination appears to foster more rapid healing of lesions in adults. However, this combination cream is not recommended for use in children because of the potential for systemic absorption of the corticosteroid.
TABLE 293.1
Categories and Activities of Antifungal Agents Against Dermatomycoses
| Activity Against | ||||||
|---|---|---|---|---|---|---|
| Agent | Category | Trade Name | Candida Species | Trichophyton tonsurans | Other Dermatophytes | Malassezia furfur |
| Nystatin | Topical polyene | Mycostatin | + | − | − | − |
| Clotrimazole | Imidazole | Lotrimin | + | + | + | + |
| Miconazole | Imidazole | Desenex | + | + | + | + |
| Ketoconazole | Imidazole | Nizoral | + | +/− | + | +/− |
| Oxiconazole | Imidazole | Oxistat | + | + | + | + |
| Terbinafine | Allylamine | Lamisil | − | +/− | + | +/− |
| Naftifine | Allylamine | Naftin | − | +/− | + | − |
| Butenafine | Benzylamine | Mentax | − | + | + | +/− |
| Ciclopirox | Hydroxypyridone | Ciclodan | + | + | + | + |
| Griseofulvin | Penicillium derivative | Fulvicin | − | + | + | − |
+, activity; −, no activity; +/−, variable activity.
Miconazole is an imidazole available over the counter as a 2% cream. Its spectrum of activity is identical to that of clotrimazole, and in clinical trials, it has demonstrated equivalent efficacy. Its efficacy in the treatment of superficial Candida infections is better than that of nystatin, and it has the advantage of a once-a-day application. Local side effects, such as those seen with clotrimazole, can occur, and miconazole should be used sparingly in intertriginous areas to avoid maceration of the skin.
Ketoconazole is an imidazole available as a 2% cream. Ketoconazole is effective therapy for dermatomycoses caused by Candida species, T. rubrum, T. mentagrophytes, E. floccosum, and M. furfur. Although it has in vitro activity against T. tonsurans and Microsporum, the clinical relevance of these data to efficacy is not known. Ketoconazole applied topically is not absorbed systemically, but it can cause local irritation. Ketoconazole is also available as an oral tablet formulation, but its use as systemic therapy is associated with life-threatening hepatotoxicity and adrenal insufficiency, and the U.S. FDA recommends against the use of this oral formulation as first-line therapy for any fungal infection.
Econazole is an imidazole nearly identical in structure to miconazole. Its activity and adverse reactions are similar. Published studies demonstrate cure rates for dermatomycoses similar to those of other topical imidazoles, but comparative studies have not been performed, and econazole has no clear advantage over other topical azoles.
Additional topical azoles include oxiconazole, terconazole, sertaconazole, and luliconazole. Oxiconazole is an imidazole that is FDA approved for the treatment of tinea pedis, tinea cruris, tinea corporis, and tinea versicolor. Terconazole is an imidazole formulated only for vaginal use in the treatment of Candida vaginitis. Sertaconazole is an imidazole approved for the treatment of tinea pedis. Depending upon the concentration, Sertaconazole has both fungistatic and fungicidal activity and broad-spectrum activity against dermatophytes, Candida, and Cryptococcus species. The recommended dosage of 2% ointment is applied once or twice a day for 4 weeks in patients ≥12. A randomized trial evaluated the efficacy and tolerability of topical sertaconazole and topical terbinafine, concluding once-daily topical sertaconazole is as effective as terbinafine in localized tinea infections. Luliconazole 1% also has been found to be useful in eradicating dermatophytic infections, with dosage of once daily for 1 week. Luliconazole is approved for tinea pedis, tinea cruris and tinea corporis. A multicenter randomized controlled trial evaluated the efficacy and safety of 5% luliconazole in the treatment of onychomycosis, applied once daily for 48 weeks, and found it well tolerated with no significant adverse effects and a complete cure rate of 14.9% versus 5.1% of the placebo. Eberconazole, lanoconazole, and efinaconazole are FDA-approved topical antifungals with broad-spectrum activity against tinea pedis, tinea corporis, candida, and dermatophytes. The characteristics and efficacy of efinaconazole 10% solution and luliconazole 5% solution were reviewed for the treatment of onychomycosis. Due to low keratin affinity, efinaconazole has high transungual penetration into nails and remains in the nail bed. On the other hand, luliconazole with high keratin affinity permeates from superficial to deep layers of the nails. Pediatric experience with these newer agents is limited.
Griseofulvin
Griseofulvin is FDA approved for tinea capitis (daily for 6–12 weeks), a condition almost uniformly refractory to treatment with topical agents and therefore requiring oral antifungal therapy. Griseofulvin impairs fungal mitosis by interfering with microtubule formation and is deposited in keratin precursor cells, binding to newly formed keratin and thereby preventing fungal invasion. Griseofulvin is fungistatic in vivo against Trichophyton species , E. floccosum, and Microsporum and is not active against Candida or M. furfur. Absorption of griseofulvin from the gastrointestinal tract varies considerably but is increased by decreasing the size of the crystals (microcrystalline and ultracrystalline formulations are available, but the ultracrystalline formulation is not available as a suspension) and administering the drug with a meal high in fat content. Historically, the usual dose of griseofulvin for children was 10–15 mg/kg/day, but many experts now recommend 20–25 mg/kg/day due to increasing resistance.
Griseofulvin has a long-standing history of safety and efficacy in children. Because the liver metabolizes it, an adjustment in dosage is not necessary for patients with renal impairment. Side effects are infrequent but include hypersensitivity rash, urticaria, nausea, vomiting, diarrhea, headache, fatigue, proteinuria, and leukopenia. A study of griseofulvin involving 295 children recorded adverse events in 79 subjects, all of which were mild to moderate and transient. Gastrointestinal complaints were the most common. Others included anemia, rash, abdominal pain, fever, headache, and weight gain. Elevated serum hepatic enzymes can occur, but laboratory monitoring is generally not indicated in healthy children treated for durations of ≥8 weeks. Periodic monitoring of complete blood count and hepatic and renal function is recommended if therapy continues for >8 weeks. Griseofulvin can decrease the effects of oral anticoagulants and contraceptive agents. The concurrent administration of phenobarbital can decrease its antifungal effect.
Squalene Epoxidase Inhibitors
The allylamines terbinafine and naftifine act by inhibiting squalene epoxidase, an enzyme in the pathway leading to the synthesis of ergosterol in the fungal cell membrane. Terbinafine is available as both a topical preparation and an oral tablet. Topical terbinafine is at least as effective as other topical antifungal agents, with the main advantage being favorable clinical responses achievable with short durations of therapy, with high cure rates for tinea pedis observed after even a single application. The oral terbinafine tablet has high absorption (>70%) and a long half-life (approximately 36 hours), penetrates keratinized tissues, and maintains concentrations higher in skin/nails than serum extending for 1 week after the conclusion of treatment. Unlike griseofulvin, no liquid formulation of terbinafine is available. Both griseofulvin and terbinafine are active against the common dermatophytes and have proven efficacy in the treatment of dermatomycoses in adults. Increasing incidence of recalcitrant dermatophytosis has been reported recently, likely due to increasing resistance. A meta-analysis of randomized controlled trials comparing terbinafine with griseofulvin for the treatment of tinea capitis concluded that 2–4 weeks of terbinafine therapy is at least as effective as 6–8 weeks of griseofulvin with no differences in tolerability or adverse effects and overall cost savings with the 4-week therapy. More recent meta-analyses have suggested the superiority of terbinafine for tinea capitis caused by Trichophyton species and griseofulvin for tinea capitis caused by Microsporum species. , Children require higher doses of terbinafine to achieve exposure similar to that of adults. A clinical trial conducted in children with tinea capitis caused by the recalcitrant species M. canis demonstrated higher cure rates in those who received higher doses (7–12.5 mg/kg/day) of terbinafine by tablet.
Butenafine is a benzylamine with a mechanism of action similar to that of the allylamine class of antifungal agents. Butenafine is indicated for the topical treatment of tinea pedis, tinea corporis, and tinea cruris.
Novel Antifungal Agents
Oxaboroles represent a new class of antifungal agents that act by blocking protein synthesis via inhibition of leucylaminoacyl transfer RNA (tRNA) synthetase. This inhibition causes premature termination of protein synthesis leading to growth inhibition and broad-spectrum antifungal activity against dermatophytes, Candida, and non-dermatophyte molds. Tavaborole was the first oxaborole approved by the FDA in 2014 as a topical antifungal for the treatment of onychomycosis. The recommended dosage is tavaborole 5% solution applied once daily for 48 weeks. An in vitro study on cadaveric nails reported superior penetration of 5% tavaborole compared with 8% ciclopirox solution after 14 days of application. , , ,
Morpholines act by inhibiting two enzymes in the ergosterol synthesis pathway (i.e., C-14 sterol reductase and C-8 sterol isomerase). The most commonly used drug of this group is amorolfine, which is primarily used in a lacquer formulation for the management of onychomycosis.
Other Topical Agents
Undecylenic acid is an unsaturated fatty acid antifungal agent available as an ointment, powder, or liquid. Its therapeutic efficacy was first recognized in the 1940s in treating superficial fungal diseases affecting military troops. However, it has little efficacy compared with newer agents. Tolnaftate has similar activity against dermatophytes, with cure rates of 60%–90% for superficial infections. Tinea capitis and tinea unguinum frequently are refractory, most likely because of poor penetration of tolnaftate into involved areas. The advantages of these compounds are that they are safe, inexpensive, and rarely cause local irritation.
Gentian violet is a triphenylmethane dye mixture that is fungicidal against Candida species via an unknown mechanism. It has been used as a traditional remedy for mucocutaneous candidiasis through topical application of a dilute mixture and has gained favor as a treatment for refractory mucocutaneous candidiasis, particularly in resource-poor areas. Disadvantages of gentian violet are the lack of a standard pharmaceutical-grade formulation, mucosal irritation, and surface staining.
Ciclopirox is a hydroxypyrimidine antifungal agent that acts by chelating iron and thereby inhibiting iron-dependent fungal enzymes. Ciclopirox is active against all the clinically relevant dermatophytes, Candida species, and M. furfur and is available in multiple topical formulations to treat infections of the skin and as a nail lacquer to treat onychomycosis. Rilopirox and octopirox are other recently added topical drugs to the hydroxypyrimidine group.
Antifungal Agents for Treatment of Invasive Infections
The armamentarium of antifungal agents for the treatment of invasive fungal infections has increased substantially in recent years ( Tables 293.2 and 293.3 ). Clinicians must consider many factors when selecting therapy, including the disease state, causative organism, antifungal resistance patterns, and host factors such as concurrent medications, hepatic function, and prior exposure to antifungal therapy. Currently licensed systemic antifungal agents include amphotericin B and its lipid derivatives; 5-fluorocytosine (5-FC); the triazoles, including fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole; and the echinocandins, including caspofungin, micafungin, and anidulafungin.
TABLE 293.2
Spectrum of Activity of Selected Systemic Antifungal Agents
| Organism | Antifungal Agent Activity | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| AMB | 5-FC a | FLU | ITRA | VORI | POSA | CAS | MICA | ANID | |
| Yeasts | |||||||||
| Candida species (most) | + | + | + | + | + | + | + | + | + |
| C. lusitaniae | − | + | + | + | + | + | + | + | + |
| C. glabrata | + | + | + /− | + /− | + /− | + /− | + /− | + /− | + /− |
| C. krusei | + | + | − | − | − | − | + | + | + |
| Cryptococcus neoformans | + | + | + | + | + | + | − | − | − |
| Malassezia species | + | + /− | + /− | ||||||
| Trichosporon species | − | − | − | + | + | + | − | − | − |
| Opportunistic Molds | |||||||||
| Aspergillus species (most) | + | − | − | + | + | + | + | + | + |
| A. terreus | − | − | − | + | + | + | + | + | + |
| Agents of mucormycosis | + | − | − | − | − | + | − | − | − |
| Fusarium species | − | − | − | + /− | + | + | − | − | − |
| Scedosporium apiospermum | − | − | − | − | + /− | + /− | − | − | − |
| Dimorphic/Environmental Molds | |||||||||
| Blastomyces dermatiditis | + | − | + | + | + | + | − | − | − |
| Coccidioides immitis | + | − | + | + | + | + | − | − | − |
| Histoplasma capsulatum | + | − | + | + | + | + | − | − | − |
| Paracoccidioides brasiliensis | + | − | + | + | + | + | − | − | − |
| Sporothrix schenckii | + | − | − | + | − | − | − | − | |
| Dematiaceous molds | + /− | + /− | − | + /− | + /− | + /− | − | − | − |
a 5-FC is used only in combination with other agents.
+ , activity; −, no activity; +/−, variable activity; blank, unknown/poorly studied; AMB, amphotericin B; ANID, anidulafungin; CAS, caspofungin; 5-FC, 5-fluorocytosine; FLU, fluconazole; ITRA, itraconazole; MICA, micafungin; POSA, posaconazole; VORI, voriconazole.
TABLE 293.3
Preferred Pediatric Dosing of Approved Systemic Antifungal Agents
| Drug Class | Antifungal Drug | Preferred Adult Dosing | Preferred Pediatric Dosing | Pediatric Dosing Comments |
|---|---|---|---|---|
| Polyene | Amphotericin B deoxycholate (AMB-D; Fungizone) | 1–1.5 mg/kg/day | 1–1.5 mg/kg/day | Children generally tolerate higher doses than do adults |
| Amphotericin B Lipid Complex (ABLC; Abelcet) |
5 mg/kg/day | 5 mg/kg/day | ||
| Liposomal Amphotericin B (L-AmB; AmBisome) | 5 mg/kg/day | 5 mg/kg/day | ||
| Pyrimidine analogue | 5-Fluorocytosine (Ancobon) | 100 mg/kg/day divided q6h | 100 mg/kg/day divided q6h | Use caution with large oral volume for neonates |
| Triazole | Fluconazole (Diflucan) | 200–800 mg/day; 6–12 mg/kg/day |
6–12 mg/kg/day | Dose higher in children due to higher clearance; neonates require further special dosing. Use 12 mg/kg/day dose for invasive candidiasis. |
| Itraconazole (Sporanox) | 200–400 mg/day | 2.5–5 mg/kg/dose bid | Dosing bid preferred in children, and if dose exceeds 200 mg/day | |
| Voriconazole (VFend) | Load: 6 mg/kg/dose bid × 1 day Maintenance: 4 mg/kg/dose bid |
<12 years: Load: 9 mg/kg/dose bid × 1 day Maintenance: 8 mg/kg/dose bid ≥12 years: Same as adult dosing. |
Young children require higher doses due to higher clearance. Oral bioavailability lower in children than in adults. Therapeutic drug monitoring is strongly recommended. | |
| Posaconazole (Noxafil) | Suspension: 200 mg q6h or 400 mg bid Tablet (delayed release): 300 mg bid × 1 day, then 300 mg qd IV: 300 mg bid × 1 day, then 300 mg qd |
<13 years: Suspension: 4 mg/kg/dose 3 times daily ≥13 years: Same as adult dosing. |
Data on pediatric dosing has not been fully studied; the suggested dose for children <13 years is based on a prophylaxis study. Oral absorption of suspension formulation is improved when dose is taken with a fatty meal. | |
| Echinocandin | Caspofungin (Cancidas) | Load: 70 mg qd × 1 day Maintenance: 50 mg qd |
Load: 70 mg/m 2 qd × 1 day Maintenance: 50 mg/m 2 qd |
Dosing for hepatic insufficiency in children is 35 mg/m 2 qd (similar to the adult decrease to 35 mg qd) |
| Micafungin (Mycamine) | 100–150 mg/day | 2–10 mg/kg/day | Highly dependent on age of child; neonates require far higher doses than do older children. | |
| Anidulafungin (Eraxis) | Load: 200 mg qd × 1 day Maintenance: 100 mg qd |
Load: 3 mg/kg/qd × 1 day Maintenance: 1.5 mg/kg/qd |
||
bid, twice daily; q6h, once every 6 hours; qd, once daily;.
ABLC is recommended officially at 5 mg/kg/day, ABCD at 3–5 mg/kg/day, and L-AmB at 3–5 mg/kg/day. Most clinical data have been obtained with the use of these preparations at 5 mg/kg/day, and most clinicians use and prefer this higher dosing.
Polyenes
Amphotericin B Deoxycholate and Lipid Formulations
Mechanism of Action
The oldest antifungal class is the polyene macrolides—amphotericin B and nystatin. Following its initial approval for use in 1958, amphotericin B deoxycholate (AMB-D) remained for years the “gold standard” for the therapy of many invasive fungal infections, as well as the comparator agent for newer antifungal agents. Amphotericin B binds to ergosterol, the principal sterol found in fungal cell membranes, creating transmembrane channels resulting in increased permeability to monovalent cations. Fungicidal activity is believed to be caused by leakage of essential nutrients from the fungal cell. Despite its broad spectrum of activity, there are notable intrinsically resistant organisms, such as Aspergillus terreus .
Pharmacology and Toxicities
Amphotericin B is given as an intravenous (IV) formulation, with once-daily dosing due to its prolonged half-life. Cerebrospinal fluid (CSF) and intraocular concentrations are <5% of serum concentrations. However, amphotericin B and its derivatives have successfully treated invasive fungal infections of the central nervous system (CNS). The primary route of elimination is unknown. Although a small portion of elimination occurs through the kidneys and biliary tract, serum levels are not affected by renal or hepatic impairment. Although not needed to account for differences in drug exposure, dose adjustment may be considered in patients with renal impairment with the goal of reducing further nephrotoxicity, an option being to alternate-day dosing. Amphotericin B is highly protein-bound and poorly dialyzable. It has few direct drug interactions, though additive nephrotoxicity can be seen when used concurrently with other nephrotoxic drugs.
The fungicidal activity of amphotericin B is concentration-dependent, increasing directly with the amount of drug attained at the site of infection but beginning to plateau at concentrations 4–10 times higher than the minimum inhibitory concentration (MIC) of the organism. , Amphotericin B also has a prolonged post-antifungal effect, allowing antifungal activity to persist even after the concentration of the drug falls below the MIC of the organism. Despite in vitro data suggesting a benefit of escalating drug concentrations, there is no conclusive clinical evidence that doses higher than 1 mg/kg/day of amphotericin B deoxycholate are necessary for successful therapy.
The significant dose-limiting toxicity of conventional amphotericin B is nephrotoxicity, which is related to the binding of cholesterol in cell membranes of the distal renal tubules, where the drug concentrates. In addition, amphotericin B stimulates the release of pro-inflammatory cytokines from mononuclear cells, accounting for infusion-related toxicities, including fever, chills, and headache. Several lipid formulations of amphotericin B have been developed to reduce these toxicities. The FDA approved amphotericin B lipid complex (ABLC) in 1995, amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD) in 1996, and liposomal amphotericin B (L-AmB) in 1997.
While the exact mechanism by which lipid amphotericin B formulations reduce toxicity is unknown, several potential mechanisms have been proposed. These include stabilization of the drug in a self-associated state so that it cannot interact with the cholesterol of human cellular membranes; and preferential binding to serum high-density lipoproteins, leading to slower release of amphotericin B to the kidney, compared to conventional amphotericin B that is bound to low-density lipoproteins. In addition, the pharmacokinetics of lipid amphotericin B formulations differ from conventional amphotericin B deoxycholate, with greater distribution to the reticuloendothelial system and lower distribution to the kidney as another potential reason for reduced toxicity. ,
Clinical studies show favorable tolerability of therapy with lipid amphotericin B formulations, both in adults and children. A multicenter study of maximum tolerated dose of L-AmB in adults using doses from 7.5 to 15 mg/kg/day found a nonlinear plasma pharmacokinetic profile with a maximal concentration at 10 mg/kg/day and no demonstrable dose-limiting nephrotoxicity or infusion-related toxicity. A randomized clinical trial comparing L-AmB at a standard dose of 3 mg/kg/day versus a higher dose of 10 mg/kg/day failed to show any improvement in efficacy and yielded more nephrotoxicity with the higher dose. Currently, standard doses of 3–5 mg/kg/day of a lipid formulation of amphotericin B are recommended.
Although amphotericin B-related nephrotoxicity generally is less severe in infants and children than adults, likely due to more rapid clearance of the drug, lower rates of nephrotoxicity have been observed in children and neonates receiving lipid formulations. A pharmacokinetic study of L-AmB conducted in 39 children observed no dose-related trends in adverse events and identified a maximally tolerated dose of 10 mg/kg/day. These results are similar to those observed in adults.
While there are anecdotal reports of using conventional AMB-D in numerous instillation or irrigation methods (including intrathecal, intrapleural, or intra-articular instillation or bladder irrigation), there are no controlled data to support these uses. Often the drug irritates the surrounding tissue, potentially creating more side effects than clinical benefits. Inhaled AMB-D has been used successfully as antifungal prophylaxis in lung transplant recipients but has not been shown to be effective as adjunctive directed therapy in a broader patient population. Intravitreal injection of AMB-D has been used to treat fungal endophthalmitis.
Clinical Experience and Pediatric Data
The optimal duration of amphotericin B therapy is unknown but likely is dependent on the underlying disease, the extent of fungal infection, and the recovery of host immune function. Several pathogen-specific guidelines have been published and include recommendations for the dose and duration of AMB-D-based treatment regimens.
While mortality was slightly lower in patients treated with L-AmB compared with conventional AMB-D in one study with a small number of patients, and a lower rate of breakthrough fungal infections occurred in another study of patients treated empirically for fever and neutropenia, other comparative studies have shown similar clinical outcomes for patients treated with L-AmB and AMB-D. A study of 56 infants with candidiasis, including 52 pre-term infants, showed no differences in mortality or time to resolution of candidemia between neonates receiving AMB-D (n = 34), L-AmB (n = 6), or ABCD (n = 16). The decision to prescribe a lipid formulation of amphotericin B should be based on the potential for reduced nephrotoxicity or infusion-related toxicity rather than the anticipated therapeutic benefit.
Evidence supporting the use of amphotericin B and its lipid formulations in children is primarily derived from extended clinical experience and non-randomized studies demonstrating tolerability and efficacy when used for the treatment of invasive fungal infections. Although newer agents with improved tolerability and efficacy have emerged for conditions such as invasive aspergillosis, AMB-D, and its lipid formulations remain important in the therapy of cryptococcal meningitis, severe manifestations of endemic mycoses, mucormycosis, neonatal candidiasis, and for patients with resistant fungal pathogens or contraindications to other agents.
Pyrimidine Analogues
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