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Pregnancy risk categories: Table 1 in Antimicrobial Agents.
AzolesTop
Mechanism of action: Azoles act on the cell membrane of fungi. They inhibit cytochrome P450-dependent 14-alpha-demethylase, which is the enzyme responsible for converting lanosterol to ergosterol.
1) Spectrum of activity: The most important activity is against yeast, including most Candida spp (with the exception of decreased activity against Candida glabrata and full resistance in Candida krusei), Cryptococcus spp, and endemic fungi (Histoplasma, Blastomyces, Coccidioides, and Paracoccidioides spp). It is not active against molds (eg, Aspergillus spp). Fluconazole can also be used for the treatment of cutaneous leishmaniasis.
2) Adverse reactions: All azoles are associated with hepatic toxicity; the effects may range from mild elevations in transaminases to severe hepatic reactions. QT prolongation, especially in patients with underlying risk factors. Alopecia noted in patients receiving long-term therapy (>3 months).
3) Pregnancy risk: C.
1) Spectrum of activity: Activity is similar to that of fluconazole with respect to Candida species; however, it offers a broader spectrum of activity against endemic fungi where it is the preferred drug over fluconazole for first-line treatment. In addition, itraconazole has added activity against Sporothrix schenckii and certain molds, such as Aspergillus species.
2) Adverse reactions: Hepatotoxicity risk similar to that of fluconazole. Contraindicated in patients with underlying ventricular dysfunction, as itraconazole has been associated with hypertension, hypokalemia, and peripheral edema leading to congestive heart failure. Central nervous system (CNS) effects, such as delirium and peripheral neuropathy, have been noted.
3) Pregnancy risk: C.
1) Spectrum of activity: The spectrum of antifungal activity is broadest among all azoles and includes fluconazole-resistant C krusei. Voriconazole is most often used as first-line therapy for mold infections including Aspergillus spp, Scedosporium spp, and most Fusarium spp. Voriconazole is also active against amphotericin-resistant strains of Aspergillus terreus. Voriconazole has no activity against Mucorales species. It has very good vitreous, retinal, and CNS concentrations. One of the major limitations of voriconazole is the significant intraindividual and interindividual pharmacokinetic variability that can lead to clinical failures. Therapeutic drug monitoring (if available) should be carried out to ensure adequate blood levels are achieved.
2) Adverse reactions: Hepatotoxicity and QT prolongation similar to fluconazole. Ocular effects, such as visual changes, blurred vision, bright spots, and photophobia, have been noted but tend to subside after the first week of treatment. Dermatologic reactions including rash, photosensitivity, and other exfoliative reactions (Stevens-Johnson syndrome). Long-term use has been associated with painful periostitis and rare cases of malignancy (melanoma, squamous cell carcinoma) have been reported in patients with underlying risk factors. IV formulation contains cyclodextrin, which has a relative contraindication of creatinine clearance <50 mL/min.
3) Pregnancy risk: D.
4. Posaconazole (oral [delayed release, suspension; tablet], IV):
1) Spectrum of activity: Posaconazole has a spectrum of antifungal activity comparable with that of voriconazole. Additionally, it shows in vitro activity against Mucorales species. For most mold infections, posaconazole is usually reserved for treatment of refractory infections. It is, however, first-line treatment for invasive fungal infection prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome undergoing chemotherapy and those with grade 2 and higher graft-versus-host disease receiving immunosuppressive medications.
2) Adverse reactions: Risk of hepatotoxicity low compared with other azoles. Use with caution in patients at high risk of QT prolongation. The IV formulation contains cyclodextrin, which has a relative contraindication of creatinine clearance <50 mL/min.
3) Pregnancy risk: C.
1) Spectrum of activity: The spectrum is similar to voriconazole with added activity against Mucorales species. A unique benefit of isavuconazole is that the IV formulation is free of cyclodextrin and as such can be used in patients with creatinine clearance <50 mL/min.
2) Adverse reactions: Hypersensitivity reactions including anaphylaxis and severe skin reactions (Stevens-Johnson syndrome). Hepatotoxicity.
3) Pregnancy risk: C.
6. Ketoconazole (oral, topical):
1) Spectrum of activity: The antifungal spectrum of ketoconazole is limited to dermatophytes causing skin and nail infections. Ketoconazole is also active against Candida spp, but compared with fluconazole it has lower clinical efficacy and more adverse effects.
2) Adverse reactions: With ketoconazole applied topically, severe irritation and pruritus may occur. Systemic adverse effects include severe hepatotoxicity and adrenal suppression.
3) Pregnancy risk: C.
1) Spectrum of activity: Active against Candida species, including fluconazole-susceptible and resistant isolates. Currently approved for the prevention of recurrent vulvovaginitis in women who are not of reproductive potential.
2) Adverse reactions: Most common reactions include headache and nausea. Not recommended in patients with moderate or severe hepatic impairment or in patients with estimated glomerular filtration rate (eGFR) 15 to 29 mL/min or end-stage renal disease (ESRD).
3) Pregnancy risk: X.
PolyenesTop
Amphotericin B (standard and lipid formulations: amphotericin B lipid complex, amphotericin B colloidal dispersion, liposomal amphotericin B; IV, inhaled):
1) Mechanism of action: Amphotericin B acts on the fungal cell membrane. It binds to ergosterol and causes leakage of intracellular contents, leading to cell death. The lipid composition of all 3 of the lipid formulations is different and contributes to their different pharmacokinetic parameters.
2) Spectrum of activity: This agent has a broad spectrum of activity that includes the yeast Candida spp, Cryptococcus neoformans, endemic fungi (Histoplasma, Blastomyces, Coccidioides, Paracoccidioides spp), and S schenckii. Mold activity includes Aspergillus and Mucorales species. Amphotericin is not active against Candida lusitaniae, Candida guilliermondii, and Aspergillus terreus. Aspergillus ustus complex has variable susceptibility. Amphotericin can be used for the treatment of both cutaneous and visceral leishmaniasis.
The use of aerosolized or nebulized amphotericin is limited to patients with cystic fibrosis and prophylaxis in certain high-risk populations, such as lung transplant recipients.
3) Adverse reactions: Infusion-related complications (nausea, vomiting, fever, chills) are common with the administration of amphotericin B deoxycholate and liposomal formulations. Fewer infusion-related adverse effects are observed with lipid formulations of amphotericin. The most important adverse effect is nephrotoxicity. Use with caution in patients with underlying renal insufficiency or in patients receiving concomitant renal-toxic medications. Amphotericin B deoxycholate is more nephrotoxic than the lipid-based formulations. Electrolyte abnormalities, including hypokalemia, hypomagnesemia, and hypocalcemia, have been noted and warrant frequent electrolyte monitoring throughout the duration of therapy.
4) Pregnancy risk: B (all formulations).
EchinocandinsTop
Discussed agents include caspofungin (IV), anidulafungin (IV), micafungin (IV), and rezafungin (IV).
1. Mechanism of action: These agents act on fungal cell wall and inhibit synthesis of (1,3)-beta-D-glucan, which results in loss of cell integrity and cell lysis.
2. Spectrum of activity: Echinocandins have limited yeast and mold activity compared with azoles and polyenes. They are predominantly used for the treatment of Candida infections and have the added advantage over azoles in that they are active against C krusei and C glabrata, although increasing resistance has been noted in C glabrata. Echinocandins, however, have higher minimum inhibitory concentrations with Candida parapsilosis and C guilliermondii. Most Candida auris isolates are susceptible to echinocandins. All of the echinocandins have in vitro activity against Aspergillus species and are reserved for use as an alternative therapy. They are not active against dimorphic fungi (Histoplasma, Blastomyces, Coccidioides, Paracoccidioides spp) or C neoformans. While in vitro activity against Mucorales species has been noted, this has not been supported by clinical data. These agents exhibit a high degree of plasma protein binding, which limits distribution to the cerebrospinal fluid, urine, and the eye. All echinocandins can be used in ESRD. Anidulafungin and rezafungin do not require any dose adjustment in the setting of moderate to severe liver impairment.
3. Adverse reactions: Echinocandins are well tolerated and all 4 have a similar adverse effect profile. Hepatotoxicity with increases in transaminases and alkaline phosphatase with rare clinically significant hepatitis and hepatic failure may develop. Infusion-related symptoms (rash, pruritus, fever).
4. Pregnancy risk: C.
Glucan Synthesis InhibitorsTop
1. Mechanism of action: A triterpenoid antifungal that inhibits (1,3)-beta-D-glucan synthetase, leading to disruption of cell wall formation.
2. Spectrum of activity: Similar to that of echinocandins; however, ibrexafungerp has a different binding site and may retain activity against some echinocandin-resistant strains of Candida spp. It is currently approved for the treatment of vulvovaginal candidiasis and prevention of recurrent vulvovaginitis.
3. Adverse reactions: Most common reactions include gastrointestinal (GI) manifestations (diarrhea, vomiting, abdominal pain) and headache (>10%). Hepatotoxicity, rash/hypersensitivity, dysmenorrhea, vaginal bleeding, and back pain (<2%).
4. Pregnancy risk: X.
Nucleoside AnaloguesTop
1) Spectrum of activity: This drug is primarily used in combination therapy with amphotericin in the treatment of C neoformans and Candida meningitis. Flucytosine has no activity against Aspergillus species or Mucorales species.
2) Adverse reactions: Hematologic effects (leukopenia, thrombocytopenia). Hepatotoxicity (elevation in transaminases). Use with extreme caution in patients with renal dysfunction; dosage adjustment required.
3) Pregnancy risk: C.
2. Terbinafine (oral, topical):
1) Spectrum of activity: Topical and oral preparations are indicated for use in the treatment of onychomycosis. The use of oral terbinafine has been also emerging for combination therapy in the treatment of multidrug-resistant molds, such as Scedosporium prolificans and A ustus complex.
2) Adverse effects: Hypersensitivity reactions. GI effects, such as taste disturbance. Hematologic effects (lymphopenia and neutropenia). Hepatic effects (acute failure, cholestatic injury).
3) Pregnancy risk: B.
