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Coccidioidomycosis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Courtesy Julio Salas-Alanís, Instituto Dermatologico de Jalisco, Mexico
Coccidioidomycosis is an endemic systemic mycosis caused by inhalation of dimorphic fungi of the genus Coccidioides ( C. immitis and C. posadasii ). It is endemic in desert regions of the Southwestern United States and Central and South America. Primary pulmonary disease is usually subacute and self-limiting. The immunocompromised are particularly susceptible to chronic pulmonary disease. One percent progress to disseminated disease, and again those with impaired cell-mediated immunity are at greater risk. Coccidioidomycosis is an opportunistic infection with advanced human immunodeficiency virus (HIV) infection and CD4 counts less than 250. Solid-organ transplant recipients, patients with hematologic malignancies, and those on long-term immunosuppressants, including corticosteroids and TNF-α antagonists, are also at risk. Extrapulmonary hematogenous dissemination can affect almost any organ but most frequently involves the skin, lymph nodes, skeletal system, and meninges. Dissemination to the skin can give rise to ulcerative and verrucous lesions with a predilection for the nasolabial area. Subcutaneous abscesses, sinus tracts, and fistulae can develop as a result of coccidioidal infection in neighboring lymph nodes, bones, or joints. Other dermatological manifestations include erythema nodosum and erythema multiforme associated with primary pulmonary infection. Primary infection of the skin is rare.
Dermatologists should consider this diagnosis in patients with atypical skin lesions, pulmonary infiltrates, and a history of travel to endemic areas.
Management Strategy
Treatment depends on disease extent and predisposing factors. Those with primary pulmonary infection and no risk factors require only periodic assessments up to 2 years to ensure that the infection is self-limiting. Some clinicians, however, prefer to treat with oral azoles to prevent any risk of progression, although there are no trial data supporting this. Antifungal therapy is indicated for severe or chronic pneumonia, progressive or disseminated infection . Fluconazole (400–800 mg daily) and itraconazole (200–600 mg daily) are the initial options for most chronic pulmonary and disseminated infections. Ketoconazole (400 mg daily) shows comparable efficacy to the other azoles, but is associated with a higher risk of adverse effects with long-term use. Parenteral amphotericin B (AmB deoxycholate 0.5–1.5 mg/kg/day or lipid formulations of AmB 2.0–5.0 mg/kg/day) is recommended for those with severely acute infection with respiratory failure, those with rapidly progressive and disseminated infection, women during pregnancy, and those who fail azole therapy. Published reports of its use, however, are still limited to small numbers of patients treated in open-label studies. There have been no clinical trials assessing the efficacy of lipid formulations of AmB. Newly available antifungals, which may be used for refractory infection, include the triazoles, posaconazole and voriconazole , in vitro studies having demonstrated their efficacy. However, there have been no comparative studies evaluating their efficacy against azoles used for treating coccidioidomycosis. There are early reports, too, of the successful use of caspofungin , an echinocandin, although results of in vitro susceptibility studies have varied widely.
In addition to drug therapy, surgery is sometimes indicated for the removal of focal infection such as pulmonary cavities, focal osseous infection, or the debridement of soft tissue. Long-term prophylaxis with azoles is indicated for the immunocompromised, and meningeal infection requires lifelong azole therapy to prevent recurrence. Recovery from infection confers lifelong immunity and provides the rationale for ongoing development of a vaccine.
Primary cutaneous coccidioidomycosis: an update
Reyna-Rodríguez IL, Ocampo-Candiani J, Chavez-Alvarez S. Am J Clin Dermatol 2020; 21: 681–96.
The authors state that although a rare entity, primary cutaneous coccidioidomycosis appears to be increasing. They describe 82 cases, the majority of which were treated with first-line azoles. They also note that it has an excellent prognosis even without treatment.
Treatment considerations in pulmonary coccidioidomycosis
Hartmann CA, Aye WT, Blair JE. Expert Rev Respir Med 2016; 10(10): 1079–91.
This review discusses current literature regarding medical treatment options, including the various triazoles and AmB products. In addition, it discusses uncomplicated and complicated pulmonary infections and their sequelae and the approach to managing coccidioidomycosis in certain patient populations, such as pregnant women, transplant recipients, HIV-infected individuals, and recipients of TNF-α inhibitors.
Coccidioidomycosis. Infectious Diseases Society of America Guidelines
Galgiani JN, Ampel NM, Blair JE, et al. Clin Infect Dis 2016.
Management of early coccidioidal infections, which are the commonest clinical presentation; coccidioidal meningitis; management of coccidioidomycosis in specific at-risk groups such as those with HIV; solid-organ transplants; and pregnancy are specifically addressed.
Specific Investigations
The characteristic globular spherules may be seen in potassium hydroxide mounts of infected material: sputum, cerebrospinal fluid, or pus. Culture is the definitive method of establishing the diagnosis. Coccidioides spp. grow rapidly on most media within 5 days. In the mycelial form, the fungus is highly infectious, so cultures should be handled with care. Serological tests are useful and can be used to assess response to therapy.
Tolerability of long-term fluconazole therapy
Davis MR, Nguyen MH, Donnelley MA, et al. J Antimicrob Chemother 2019; 74(3): 768–71.
This was a single-center, retrospective study investigating the tolerability of long-term (> 28 days) fluconazole in 124 adult patients with coccidioidomycosis. They were treated with fluconazole 100–1600 mg daily (the most commonly prescribed dose was 400 mg daily). The median duration of treatment was 147 days (interquartile range [IQR] 59–399 days); 51.6% experienced adverse effects. The most common adverse effects were xerosis (16.9%), alopecia (16.1%), and fatigue (11.3%). Two-thirds experiencing adverse effects required a therapeutic intervention such as dose reduction, discontinuation, or switch to a new antifungal. Patients experiencing adverse effects were prescribed higher total daily fluconazole doses (6.7 vs. 5.7 mg/kg; p <0.01).
The authors report a relatively high rate of adverse effects in a real-world setting as opposed to clinical trials.
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