The approach to antifungal therapy for invasive fungal infections is determined by the type of fungal infection (yeast vs mold), severity of clinical presentation, patient's underlying immunosuppression, susceptibility data, potential toxicities, and drug interactions. Antifungals are associated with significant drug interactions and toxicities, especially with prolonged treatment courses. A majority of patients are treated empirically for invasive candidiasis before conclusive evidence of infection is available to direct therapy. Empiric therapy for invasive candidiasis should be considered in patients with persistent, unexplained fever and host deficits that predispose patients to candidemia (broad-spectrum antibiotics, presence of central venous catheter, patients with severe organ dysfunction or on dialysis, patients with neutropenia). Response to antifungal therapy for patients with invasive candidiasis is more rapid than for endemic fungal infections. Resolution of fever and sterilization of cultures are indications of response to fungal therapy.
Amphotericin B is a polyene antifungal that binds to fungal cell membrane ergosterol and promotes enhanced permeability leading to fungal cell death.12 Amphotericin B is regarded as the gold standard systemic antifungal because of its fungicidal activity and broad spectrum of antifungal activity (molds and yeasts). Amphotericin B is administered intravenously and available as an injection (eg, 50 mg powder for reconstitution). The conventional formulation of amphotericin B is the desoxycholate (deoxycholate) formulation. This formulation must be prepared in dextrose 5% to facilitate the proper micellular dispersion.13 Lipid-based (liposomal) formulations are also available and include liposomal, lipid-complex, and lipid colloidal dispersion formulations. All formulations of amphotericin B are nephrotoxic and can be associated with infusion-related toxicities (fever, chills, and rigors). Premedication with acetaminophen and diphenhydramine may help lessen infusion-related toxicities.14 Administration of normal saline boluses before (and sometimes after) amphotericin B infusions may help ameliorate the nephrotoxicity.15 The lipid-based agents appear less nephrotoxic than the conventional formulation of amphotericin B.16 Unfortunately liposomal products are considerably more expensive than conventional amphotericin B. The liposomal formulation (AmBisome) has a lower rate of infusion-related reactions than other amphotericin B formulations.17 Despite the improved safety profile; lipid-based amphotericin B formulations have not improved patient survival rates. Lipid-based formulations are dosed at 3 to 6 mg/kg versus the 0.5 to 1.5 mg/kg dose of conventional amphotericin B.12,16 Amphotericin B is the treatment of choice for pregnant patients with fungal infections, because the other classes of antifungal agents have displayed some risk of teratogenicity (categories C and D). Anaphylaxis has been reported with amphotericin B products; therefore the drug should be administered under close clinical observation. Other key drug parameters for amphotericin B products include:
- Avoid use with other nephrotoxic medications
- Drug-induced renal toxicity usually improves with interrupting therapy, decreasing dosage, or increasing dosing interval
- Electrolyte wasting is associated with amphotericin products (hypokalemia, hypomagnesemia)
Flucytosine (5-flucytosine, 5-FC, Ancobon) is a pyrimidine analog that penetrates fungal cells and is converted to 5-fluorouracil which interferes with fungal RNA and protein synthesis. Flucytosine is used as adjunctive treatment of systemic fungal infections (eg, susceptible strains of Candida or Cryptococcus). 5-FC is not used as monotherapy because resistance rapidly develops. The drug is available as an oral capsule and has good absorption and distribution (penetrates well into the CSF).18 5-FC is associated with causing bone marrow suppression (black box warning) leading to blood dyscrasias including neutropenia, thrombocytopenia, and anemia.12 Gastrointestinal adverse effects are also common. Flucytosine is dosed 50 to 150 mg/kg in divided doses every 6 hours in patients with a CrCl greater than 40 mL/min. Use with extreme caution in patients with renal dysfunction and adjust dose as required. Peak serum concentrations should be monitored in all patients (particularly those with a CrCl less than 10 mL/min). Peak levels should not exceed 100 μg/mL.
Azole antifungals interfere with the fungal enzyme 14α-demethylase thereby decreasing ergosterol synthesis and inhibiting cell membrane formation. Azoles are well tolerated, but are associated with cytochrome P-450 drug interactions and occasionally hepatotoxicity.18,19 Most of the drug interactions are due to enzyme inhibition of CYP 3A4 metabolism. Itraconazole and voriconazole are also substrates of some of the P-450 isoenzymes and can have their metabolism affected by other drugs (Table 28-1).
TABLE 28-1 Drug Interactions, Administration, and Dietary Recommendations for Azole Antifungals ||Download (.pdf)
TABLE 28-1 Drug Interactions, Administration, and Dietary Recommendations for Azole Antifungals
|Azole Antifungal||Drug Interactions (CYP 450)||Administration|
|Fluconazole (Diflucan)||I: 1A2 (weak); 2C9 (strong); 2C19 (strong); 3A4 (moderate)||Take with or without regard to meals|
|Itraconazole (Sporanox)||S: 3A4 (major)||Capsule: Absorption enhanced by food and possibly gastric acidity. Cola drinks have been shown to increase the absorption of the capsules in patients with achlorhydria or those taking H-2 receptor antagonists|
|I: 3A4 (strong)||Solution: Take on an empty stomach|
|Capsules and oral solutions are not interchangeable; doses greater than 200 mg are given in two divided doses|
|Voriconazole (Vfend)||S: 2C9 (major); 2C19 (major); 3A4 (minor); I: 2C9 (weak); 2C19 (weak); 3A4 (moderate)|
Oral: Should be taken 1 h before or 1 h after a meal
Dietary: Tablets contain lactose—avoid in lactose intolerance; suspension contains sucrose—use caution in sucrose/fructose malabsorption
|Posaconazole (Noxafil)||I: 3A4 (strong)||Administer with food; food and/or nutritional supplement increases absorption; fasting states do not provide sufficient absorption to ensure adequate plasma concentration.|
Fluconazole (Diflucan) is the most commonly used triazole antifungal and is used for candidiasis, cryptococcal meningitis, and antifungal prophylaxis in allogenic bone marrow transplants. Fluconazole is well tolerated, available in oral (tablet and suspension) and IV formulations, and has a lower rate of drug interactions compared to other triazoles. Fluconazole penetrates into the CSF (thus used for meningitis) and is eliminated renally (dosage adjustments are required for renal dysfunction).18 Fluconazole is effective against Cryptococcus and most Candida species (C. albicans, C. parapsilosis, and C. tropicalis), but is inactive against molds and C. krusei. Fluconazole's susceptibility to C. glabrata is usually defined as "susceptible-dose-dependent" (S-DD), meaning that larger dose may be needed to achieve cure in serious infections.5 The daily dose for fluconazole is the same for oral and IV administration and depends upon the type of fungal infection (400-800 mg daily for candidemia, 150 mg for vaginal candidiasis; 400 mg for cryptococcosis [step-down therapy from amphotericin B + flucytosine]).
Despite having activity against Candida species and some molds including Aspergillus, itraconazole (Sporanox) is not used much because of its lack of predictable pharmacokinetics (eg, bioavailability). The capsule formulation of itraconazole displays wide interpatient oral absorption.20 The bioavailability may be enhanced by administering itraconazole with cola, meals, or nutritional supplements and by avoiding concomitant acid-suppressing agents (eg, proton pump inhibitors, H2 antagonists, antacids). A newer oral solution provides more predictable absorption.21 Due to differences in bioavailability; oral capsules and oral solution cannot be used interchangeably. An IV formulation with a cyclodextrin carrier molecule is available to reach approximate steady-state concentrations more rapidly.22 Itraconazole can display negative inotropic effects and should be used with caution in patients with left ventricular dysfunction or a history of heart failure (black box warning). The daily dose of itraconazole depends upon the type of fungal infection (eg, 200-400 mg daily for aspergillosis; 200 mg daily for endemic fungal infections; 100-200 mg daily for esophageal candidiasis). Trough serum concentrations may be performed to assure therapeutic levels, especially in the face of oral therapy. Itraconazole has largely been relegated to treating the endemic fungi infections.23
Voriconazole (VFEND) is an analog of fluconazole that has a broader spectrum of activity against Candida species. In addition, the drug has good activity against Aspergillus and has become a drug of first choice for invasive aspergillosis.24 Voriconazole is subject to a large number of drug interactions and has been associated with reversible visual disturbances.25 Voriconazole drug interactions are dose dependent, as they exhibit unpredictable nonlinear pharmacokinetics; thus, drug interactions are more difficult to predict and manage. Studies indicate that CYP 2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism; about 3% to 5% of Caucasians and 12% to 23% of Asians are expected to be poor metabolizers of voriconazole. Voriconazole is available in both oral and cyclodextrin IV formulations. There are concerns about the IV cyclodextrin carrier accumulating in and exacerbating renal failure. Visual changes, including blurred vision, changes in visual acuity, color perception, and photophobia, are commonly associated with treatment. Patients should be warned to avoid tasks which depend on vision, including operating machinery or driving. Changes are reversible on discontinuation following brief exposure (less than 28 days). The daily dose of voriconazole depends upon the type of fungal infection (aspergillosis 6 mg/kg every 12 hours on day 1 followed by 4 mg/kg every 12 hours; esophageal candidiasis 200 mg every 12 hours). Patients with mild-moderate hepatic dysfunction (Child Pugh class A and B) should receive a normal loading dose followed by 2 mg/kg every 12 hours. Voriconazole should only be used in severe hepatic dysfunction when the benefits outweigh the risks. In patients with CrCl less than 50 mL/min, accumulation of the IV vehicle cyclodextrin occurs. After the initial IV loading dose, oral voriconazole should be administered to these patients, unless an assessment of the benefit: risk to the patient justifies the use of IV voriconazole.
Posaconazole (Noxafil) is approved for prophylaxis of Candida and Aspergillus infections in high-risk neutropenic patients and in the treatment of oropharyngeal candidasis.26 Posaconazole is available in an oral suspension and has a variable absorption. The absorption can be enhanced by administering with meals or nutritional supplements and by avoiding concomitant acid-suppressing agents.27 The dose of posaconazole depends upon the type of fungal infection. Posaconazole is dosed 200 mg tid for prophylaxis (Aspergillus and Candida) and 400 mg twice daily for treatment of Candida infections.
There are three echinocandin antifungals and they are caspofungin (Cancidas), micafungin (Mycamine), and anidulafungin (Eraxis). Echinocandins inhibit the fungal enzyme (1, 3) β-D-glucan synthase; which inhibits the formation (1, 3) β-D-glucan fibrils, which are essential components for outer cell walls of some fungi.28 These agents are effective against most Candida species and Aspergillus species. Echinocandins are well-tolerated with minimal drug interaction potential. Echinocandins are available as parenteral formulations and do not require dosage adjustments in patients with renal insufficiency.28The dose of caspofungin is 70 mg daily on day 1, followed by 50 mg daily. Patients with a Child-Pugh score of 7 to 9 should be given a maintenance dose of 35 mg/d, instead of 50 mg/d. The dose of micafungin is 50 to 150 mg daily depending upon the indication and the dose of anidulafungin is 50 to 200 mg daily depending upon the indication.
There are studies with all of the antifungal agents in children; amphotericin B, fluconazole, and echinocandins are recommended in neonatal candidiasis.5 Amphotericin B carries a pregnancy category B, whereas most azoles, echinocandins and flucytosine all carry category C status.29 Voriconazole is category D.25,29 Clinicians must weigh the potential benefit/risks of therapy in pregnant patients when using azoles, echinocandins and flucytosine.