Medication Summary
In general, the severity and tempo of coccidioidomycosis dictates the approach to treatment. In patients with suspected or documented uncomplicated primary infection, treatment varies from careful observation to long-term azole therapy.
Although some authors have suggested that empiric treatment may decrease the rate of disseminated infection, evidence has been presented to the contrary. However, groups who are at risk for dissemination (eg, blacks, Filipinos, individuals with HIV or AIDS, individuals with diabetes mellitus, women in the third trimester of pregnancy) warrant more aggressive treatment.
Historically, amphotericin B has been the drug of choice to treat disseminated coccidioidomycosis. Oral azoles have provided a desirable alternative for both initial therapy and completion of courses after amphotericin therapy. The benefits of azoles include oral formulations and fewer adverse effects.
Azole antifungals are not used in pregnant women because these agents are teratogenic. Pregnant women may be treated with amphotericin B.
Patients with more advanced disease require more aggressive treatment. In particular, patients who exhibit signs of meningitis need either intravenous antibiotic therapy with amphotericin unless otherwise contraindicated or high-dose azole therapy with or without intrathecal amphotericin. Steroids may be somewhat beneficial in patients with vasculitis.
Effective antifungal therapy can be given in an outpatient or inpatient setting. The initial use of amphotericin may require an inpatient stay, and long-term amphotericin therapy requires placement of an indwelling intravenous catheter, such as a peripherally inserted central catheter (PICC) line.
Antifungals
Class Summary
Antifungal agents preferentially bind to the primary fungal cell membrane sterol (ergosterol). Amphotericin B increases the permeability of the cell membrane, which in turn causes intracellular components to leak. Azoles interfere with an enzyme in the sterol biosynthesis pathway production of cell membrane ergosterol. Echinocandins block fungal cell wall synthesis by inhibiting 1,3-beta glucan synthase.
Amphotericin B
Amphotericin B is the drug of choice for rapidly progressing coccidioidal infection and disease nonresponsive to oral azole therapy. It is administered IV or intrathecally. Intrathecal amphotericin B has been used for coccidioidal meningitis.
Amphotericin B is a polyene antifungal agent produced by a strain of Streptomyces nodosus. Depending on the concentration attained in body fluids and on fungal susceptibility, this agent can be fungistatic or fungicidal. It binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak, with subsequent cell death. Metabolic clearance is prolonged and not affected by renal or hepatic insufficiency.
Three lipid formulations (Ambisome, Abelcet, Amphotec) promising for reducing toxicity are currently licensed for use when amphotericin B fails or is unacceptably toxic. There is a significant reduction in nephrotoxicity and infusion-related reactions with continuous 24-h infusion vs conventional 2-h to 6-h infusion.
Fluconazole (Diflucan)
Fluconazole is a synthetic triazole antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol. It is used to treat mild-to-moderate infections or severe or life-threatening infections in patients intolerant of amphotericin B. It may be used for maintenance after course of amphotericin B in coccidioidal meningitis. It penetrates CSF well. Metabolic clearance is prolonged in renal dysfunction.
Fluconazole is preferred over ketoconazole because of better response rates and less GI and endocrine adverse effects. It is available as an oral suspension.
Ketoconazole
Ketoconazole is an imidazole broad-spectrum antifungal agent that inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.
This agent has been used in treatment of coccidioidomycosis, although fluconazole and itraconazole are preferred because of low response rates (< 40%) with ketoconazole. In addition, it may have greater GI and endocrine adverse effects at high doses and should be used only if other antifungal therapy is unavailable.
Itraconazole (Sporanox)
A triazole analogue of ketoconazole, itraconazole is preferred to its parent compound because of enhanced safety and efficacy. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. It is used for mild-to-moderate infections that warrant treatment. Despite poor CSF penetration, it is successfully used to treat coccidioidal meningitis.
An IV form is available, but long-term usage is not established. Itraconazole is also available in an oral solution, which provides better, more consistent absorption than the capsule. Take capsules with full meal to improve absorption, but take oral solution on empty stomach, if possible.
Voriconazole (Vfend)
Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Case reports describe efficacy in disseminated disease or meningitis refractory to first-line agents.
Posaconazole (Noxafil)
Posaconazole is a triazole antifungal agent that possesses structural similarities to itraconazole. It blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption.
Posaconazole is available as a delayed-release tablets and as an oral suspension (200 mg/5 mL). It is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Isavuconazole (Cresemba)
Isavuconazole is a triazole antifungal agent formulated as the prodrug isavuconazonium sulfate, and it is available as an IV formulation and an oral formulation (capsules). The oral capsules are well absorbed with an absolute bioavailability of 98 percent that is essentially unaltered by food intake. Isavuconazole is indicated for invasive aspergillosis and mucormycosis.
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Soft tissue abscess due to cocci.
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Pulmonary cocci spherule (Hematoxylin-eosin stain).
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Pulmonary cocci spherule, periodic acid-Schiff stain.
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Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.
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A Coccidioides immitis spherule containing endospores. Courtesy of Thomas Matthew.
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Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.
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A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).
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A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.
