- Author: Duane R Hospenthal, MD, PhD, FACP, FIDSA, FASTMH; Chief Editor: Mark R Wallace, MD, FACP, FIDSA more...
Antifungal medications are the mainstay of treatment for paracoccidioidomycosis. These include the following:
Itraconazole - The drug of choice [27, 29]
Fluconazole - Not as effective as either itraconazole or ketoconazole; its main advantages are that it is available in oral and intravenous forms and that it penetrates into the CSF well
Amphotericin B - Used in patients with severe disease; it is the only medication in this list in pregnancy category B; all of the other medications are in pregnancy category C or D.
Trimethoprim-sulfamethoxazole (TMP-SMZ) – Continues to be used because of low cost
Sulfadiazine - Also still used because of its low cost
Historically, the sulfonamides have been the most widely used medications for the treatment of paracoccidioidomycosis; their advantage is their low cost. However, relapses are more common with the sulfonamides than with other mediations, and longer courses of therapy may be required.
Reports have documented successful treatment of paracoccidioidomycosis with voriconazole, posaconazole, and terbinafine. The following guidelines may be helpful: Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.
The mechanism of action may involve an alteration of RNA or DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.
Itraconazole, a triazole antifungal agent, is preferred over the previously used agent ketoconazole because of reduced length of therapy and relapse rate. Adverse effects are also less frequent with itraconazole. This is a synthetic fungistatic triazole that inhibits cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
An intravenous formulation is available but no intravenous dose has been established for P brasiliensis treatment.
Imidazole is a broad-spectrum antifungal agent that inhibits the synthesis of ergosterol, a key fungal cell membrane component. This causes cellular components to leak, resulting in fungal cell death.
Amphotericin B, conventional
Amphotericin B is indicated for the treatment of life-threatening fungal infections or when oral antifungal medications cannot be tolerated. The drug is produced from a strain of Streptomyces nodosus. The antifungal activity of amphotericin B results from its ability to insert itself into the fungal cytoplasmic membrane at sites that contain ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium).
At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity. At higher concentrations, however, pores of 40-105 nm in are produced in the cytoplasmic membrane, leading to large losses of ions and other molecules.
A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Indeed, this may be the main fungicidal activity of amphotericin B.
Amphotericin B is not curative by itself; all patients treated with this drug require maintenance treatment with sulfonamide or an azole. Improvement occurs in 65-70% of patients treated with this agent.
Fluconazole has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents the conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. It is not considered the drug of choice in the treatment of paracoccidioidomycosis.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Sulfamethoxazole competes with para-aminobenzoic acid (PABA) and thereby inhibits microbial synthesis of dihydrofolate. Trimethoprim binds to and reversibly inhibits the enzyme dihydrofolate reductase, thereby blocking the production of tetrahydrofolic acid from dihydrofolic acid. Thus, 2 consecutive steps in the synthesis of essential nucleic acids and proteins are blocked. TMP-SMZ is used to treat paracoccidioidomycosis in Central and South America primarily because of its low cost, but it is not the drug of choice.
Therapy with sulfa agents is long term (3-5 y) and is associated with a high relapse rate (20-25%). Paracoccidioidomycosis is the only mycosis amenable to treatment with sulfa drugs.
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