Antifungal Therapy

Amphotericin B

In severe or refractory coccidioidal disease, an intravenous amphotericin B formulation is considered the drug of choice. Amphotericin B is a polyene antifungal agent that binds to sterols in the fungal cell membrane causing intracellular components to leak resulting in cell death. Its use came into practice in the mid-1950s and recognition of the poor CNS penetration led to the development of administering IT AmB via lumbar, cisternal or ventricular routes in salvage settings (1). IT treatment changed the outcome of CM; however, numerous surgical, mechanical, infectious complications along with headaches, paresthesia, nerve palsies, myelopathy, arachnoiditis, hemorrhage, transverse myelitis and more have led to its use only for those with refractory disease and also with consultation with experienced physicians who have pioneered these techniques.

Data on use of lipid preparations of AmB is scant and is largely derived from animal models. Clemons et al compared the efficacy of intravenous liposomal AmB with those of oral fluconazole and intravenous AmB-d for the treatment of experimental coccidioidal meningitis (CM). All regimens reduced the numbers of colony forming units (CFU) in the brain and spinal cord however liposomal AmB treated animals had 3 to 11 fold lower numbers of CFU than fluconazole and 6 to 35 fold lower numbers of CFU than AmB-d treated rabbits (2). Another animal model that compared intravenous AmB lipid complex (ABLC), AmB-d and oral fluconazole showed that ABLC cleared CFU from CSF faster than AmB-d or fluconazole (3). Though no formal guidelines exist regarding the use of these agents, data above indicate that lipid formulations of AmB may be of benefit as it can be administered at higher doses with less toxicity.

Azoles

The introduction of azoles was a significant breakthrough in the treatment of coccidioidomycosis for both meningeal and non-meningeal disease. These agents act by inhibiting the synthesis of ergosterol in the fungal cell membrane (4). The first trials with azoles included clotrimazole, then miconazole whose use quickly faded due to toxicity, frequency of dosing, ineffectiveness, and lack of oral availability. Ketoconazole was the first oral agent to be used in the treatment of coccidioidomycosis although only 20-30% of patients demonstrated a clinical response to 200-400 mg/day. Dose escalation was attempted to increase drug efficacy however gastrointestinal intolerance, adrenal insufficiency, and gynecomastia ultimately limited the use of this agent (5, 6).

Third generation azoles, the triazoles, were introduced in 1980s and showed promising efficacy with less toxicity, especially with higher dosing and prolonged use. First was itraconazole with excellent in-vitro activity against Coccidioides spp (7). The Mycosis Study Group documented its tolerance and efficacy in which 57% of the 47 patients with nonmeningeal coccidioidomycosis achieved remission (8). In one randomized double blind placebo-controlled trial for nonmeningeal coccidioidomycosis, patients with skeletal infections responded twice as frequently to itraconazole than fluconazole, though the study dose of fluconazole was lower than is currently used (9). Itraconazole CSF penetration is not optimal but it does concentrate in fatty tissues including the brain and has demonstrated efficacy in the treatment of CM(10). Among its different formulations, itraconazole solution has greater bioavailability than capsules and is maximally absorbed in the fasting state (4). For the maximum absorption of the capsular form, an acidic environment with intake of a high-fat meal is preferred. At doses of 800 mg and higher, adverse effects included adrenal insufficiency, hypertension, hypokalemia, and edema. Negative inotropic effects have also been reported (11), but this is uncommon in clinical practice.

Fluconazole was the next to be developed, and it still remains the preferred triazole due to its excellent bioavailability, tolerability, CNS penetration, slow clearance (24-30 hour half-life), little hepatotoxicity, renal clearance, no endocrine side effects, reasonable response rates in prior reports, and generally lower costs. In a multicenter, open-label, single-arm study, among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of the 14 patients with skeletal, 22 (55%) of the 40 patients with chronic pulmonary, and 16 (76%) of the 21 patients with soft-tissue disease (12). Forty-one patients who responded were followed off drug and fifteen (37%) of them experienced reactivation of infection. Tucker et al identified fluconazole to have potential use in coccidioidal meningitis (13, 14). This was followed by landmark study by Galgiani et al that showed fluconazole to achieve the same response rate for coccidioidal meningitis (CM) as its historical counterpart IT AmB (15). Thus, due to its favorable activity and minimal toxicity, current guidelines recommend fluconazole (800-1200 mg) as the preferred agent for meningeal infection. Daily doses up to 2000 mg have been used in some cases. With improving host control of the infection, fluconazole doses may be decreased slowly over time, but a specific effective maintenance dose for meningeal and/or disseminated disease is not well established.

The disadvantage of azole therapy is the inability to eradicate the fungus, which seems to be a class effect, thus treatment is continued indefinitely as a suppressive rather than curative therapy for CM although newer formulations and agents may offer mean fungicidal concentrations achievable in clinical care. Therapeutic drug monitoring of fluconazole can be done in patients with complicated courses of illness or who are not responding clinically. Commonly encountered adverse effects with higher doses (≥400 mg) of fluconazole include dry mouth, dry skin, nausea, reversible alopecia, and abnormal liver function tests.

Newer Triazoles

Voriconazole and posaconazole are newer triazoles and primarily are used in patients whose coccidioidal infection is refractory to first-line azole therapy. They both have excellent activity in-vitro against Coccidioides spp. (Table 2) (16). In vitro concentration studies are frequently based on mycelial phase fungal growth and extrapolation to human disease is the subject of ongoing evaluation. Similar to fluconazole, voriconazole is an attractive choice due to favorable pharmacokinetic/pharmacodynamics in the CSF. Voriconazole is available in parenteral and oral formulations with excellent oral bioavailability. Therapeutic drug monitoring should be considered as voriconazole serum concentrations can vary between individuals (4). Administration of voriconazole may be complicated by drug-drug interactions as a result of its inhibition of CYP2C9, CYP2C19, and CYP3A4 enzymes. Adverse effects may also limit use: besides the visual disturbance, neurotoxicity, hepatotoxicity, photopsia, and QTc prolongation, concerns have been raised with long-term use of voriconazole for the development of periostitis due to hyperfluorosis and of melanoma in situ (17-19). However, a small study of non-transplant patients with chronic coccidioidomycosis on long term fluorinated triazole therapies did not identify significant long-term osseous effects despite elevated plasma fluoride levels (17).

Posaconazole has also been shown to have potent in-vitro and in-vivo activity against Coccidioides spp. It has been tested in murine models and shown to be >200 fold as potent as fluconazole and >50 fold potent as itraconazole along with having fungicidal activity in vivo against C. immitis (20). Posaconazole is available in liquid, capsule, and intravenous formulations. Historically it was available in liquid form only, requiring it be taken with a fatty meal and acidic beverage which limited optimal absorption in severely ill patients. Most reported studies on the use of posaconazole were done prior to the advent of capsule and intravenous formulations. Adverse events include gastrointestinal effects, rash, and elevated transaminases (21). Drug cost remains a significant problem for many patients.

Isavuconazole is a newly available extended-spectrum triazole with in vitro activity against Coccidioides spp (16). Limited clinical data has been presented to date regarding the in vivo efficacy and thus far it has been prescribed only to patients with primary coccidioidal pneumonia. It has been effectively used for other invasive fungal infections including Aspergillus, Mucorales, and other endemic fungi as well and a clinical trial for the treatment of non-meningeal disseminated and chronic coccidioidomycosis is currently underway.

Echinocandins

The echinocandins have little inherent activity against Coccidioides spp. in the mycelial phase, however potential efficacy has been demonstrated in murine models of infection (22). There are case reports of caspofungin being used in combination with azole or amphotericin based therapies. In a series of 9 pediatric patients, Levy et al have reported clinical improvement in 8 cases in which a salvage regimen of caspofungin plus voriconazole was used following treatment failures (23). As publications describing the potential efficacy of these agents are limited, this class should not be used as monotherapy in the treatment of coccidioidomycosis at this time. 

REFERENCES

1. Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect 2001; 16(4): 263-9.
2. Clemons KV, Sobel RA, Williams PL, Pappagianis D, Stevens DA. Efficacy of intravenous liposomal amphotericin B (AmBisome) against coccidioidal meningitis in rabbits. Antimicrob Agents Chemother 2002; 46(8): 2420-6.
3. Capilla J, Clemons KV, Sobel RA, Stevens DA. Efficacy of amphotericin B lipid complex in a rabbit model of coccidioidal meningitis. The Journal of antimicrobial chemotherapy 2007; 60(3): 673-6.
4. Thompson GR, 3rd, Cadena J, Patterson TF. Overview of antifungal agents. Clinics in chest medicine 2009; 30(2): 203-15, v.
5. Pont A, Graybill JR, Craven PC, et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 1984; 144(11): 2150-3.
6. Galgiani JN, Stevens DA, Graybill JR, Dismukes WE, Cloud GA. Ketoconazole therapy of progressive coccidioidomycosis. Comparison of 400- and 800-mg doses and observations at higher doses. The American journal of medicine 1988; 84(3 Pt 2): 603-10.
7. Stevens DA, Clemons KV. Azole therapy of clinical and experimental coccidioidomycosis. Annals of the New York Academy of Sciences 2007; 1111: 442-54.
8. Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA. Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group. The American journal of medicine 1990; 89(3): 282-90.
9. Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Annals of internal medicine 2000; 133(9): 676-86.
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11. Qu Y, Fang M, Gao B, et al. Itraconazole decreases left ventricular contractility in isolated rabbit heart: mechanism of action. Toxicol Appl Pharmacol 2013; 268(2): 113-22.
12. Catanzaro A, Galgiani JN, Levine BE, et al. Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. NIAID Mycoses Study Group. The American journal of medicine 1995; 98(3): 249-56.
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17. Thompson GR, 3rd, Bays D, Cohen SH, Pappagianis D. Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles. Antimicrobial agents and chemotherapy 2012; 56(1): 563-4.
18. Miller DD, Cowen EW, Nguyen JC, McCalmont TH, Fox LP. Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity. Archives of dermatology 2010; 146(3): 300-4.
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20. Lutz JE, Clemons KV, Aristizabal BH, Stevens DA. Activity of the triazole SCH 56592 against disseminated murine coccidioidomycosis. Antimicrob Agents Chemother 1997; 41(7): 1558-61.
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22. Gonzalez GM, Gonzalez G, Najvar LK, Graybill JR. Therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate for coccidioidomycosis in a mouse model. The Journal of antimicrobial chemotherapy 2007; 60(6): 1341-6.
23. Levy ER, McCarty JM, Shane AL, Weintrub PS. Treatment of pediatric refractory coccidioidomycosis with combination voriconazole and caspofungin: a retrospective case series. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2013; 56(11): 1573-8.