Coccidioidomycosis

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Coccidioidomycosis

Mahreen Ameen and Wanda Sonia Robles

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

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 southwestern United States, Central and South America. Primary pulmonary disease is usually sub-acute 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 of this. Coccidioidomycosis is an opportunistic infection with advanced 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 haematogenous 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 neighbouring 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 be aware that the combination of atypical skin lesions, pulmonary infiltrates, and a history of travel to endemic areas of the disease may represent disseminated infection with coccidioidomycosis.

Management strategy

Treatment depends on disease extent and predisposing factors. Those with primary pulmonary infection and no risk factors require only periodic assessments for 2 years to ensure that the infection is self-limiting. Some clinicians prefer to treat with oral azoles to prevent any risk of progression, although there are no trial data to support this. Antifungal therapy is indicated for severe or chronic pneumonia, progressive or disseminated infection. Itraconazole (200–600 mg daily) and fluconazole (400–800 mg daily) have replaced amphotericin B as the initial choice of therapy 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 (amphotericin B deoxycholate 0.5–1.5 mg/kg/day or lipid formulations of amphotericin B 2.0–5.0 mg/kg/day) is now recommended for those with severely acute infection with respiratory failure, those with rapidly progressive and disseminated infection, and women during pregnancy. Published reports of its use, however, are still limited to small numbers of patients treated in open-label, non-randomized studies. There have been no clinical trials assessing the efficacy of lipid formulations of amphotericin B. Newly available antifungal agents that 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 as yet evaluating their efficacy against the established 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 in order to prevent recurrence. Recovery from infection confers lifelong immunity and provides the rationale for the ongoing development of a possible vaccine.

First-line therapies

image Fluconazole A
image Itraconazole A

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis.

NIAID Mycoses Study Group. Catanzaro A, Galgiani JN, Levine BE, Sharkey-Mathis PK, Fierer J, Stevens DA, et al. Am J Med 1995; 98: 249–56.

A multicenter, open-label, single-arm study. Of 78 patients enrolled, 22 had soft tissue, 42 had chronic lung, and 14 had skeletal coccidioidomycosis. Forty-nine had at least one concomitant disease, seven of whom had HIV infection. Patients were given fluconazole 200 mg daily. Non-responders were increased to 400 mg daily. Length of treatment was 4 to 8 months. Among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of those with bone, 22 (55%) of those with lung, and 16 (76%) of those with soft tissue disease. There was a 37% relapse rate in patients whose treatment was interrupted (15/47). The study concluded that fluconazole 200–400 mg daily is well-tolerated but demonstrates only moderate efficacy in the treatment of non-meningeal coccidioidomycosis.

Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial.

Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL, Mirels LF, et al. Ann Intern Med 2000; 133: 676–86.

In this randomized, double-blind, placebo-controlled trial, 198 patients with pulmonary and non-meningeal infection were treated with either fluconazole 400 mg daily or itraconazole 200 mg twice daily. Overall efficacy rates at 12 months were similar (itraconazole, 63%; fluconazole 50%; p = 0.8). However, the response rate was higher in patients with bone disease treated with itraconazole (52% vs 26%; p = 0.05). The rates of relapse were comparable (itraconazole, 18%; fluconazole, 28%; p > 0.2). Both drugs were well tolerated.

This is the first prospective, randomized trial comparing two different azole drugs for the treatment of an endemic mycosis. The results demonstrate that both itraconazole and fluconazole are effective therapies for non-meningeal coccidioidomycosis.

Second-line therapies

image Amphotericin B D
image Ketoconazole B

Amphotericin B and coccidioidomycosis.

Johnson RH, Einstein HE. Ann N Y Acad Sci 2007; 1111: 434–41.

This article provides a comprehensive review of the use of amphotericin B in the treatment of coccidioidomycosis. The availability of effective azoles and triazoles means that amphotericins are only used now for widely disseminated infection, in cases of azole intolerance, or when there are contraindications to azoles, such as pregnancy. In meningitis, the intrathecal use of amphotericin B is still used frequently by some clinicians alone or with a triazole. The newer lipid preparations, while more expensive, have significantly reduced toxicity.

Given that all studies to date of amphotericin use for coccidioidomycosis are limited by small numbers, this review article provides a detailed assessment of current indications for its use.

Third-line therapies

image Posaconazole B
image Voriconazole C
image Caspofungin E
image Adjunctive interferon-γ immunotherapy E

Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis.

Catanzaro A, Cloud GA, Stevens DA, Levine BE, Williams PL, Johnson RH, et al. Clin Infect Dis 2007; 45: 562–8.

In this multicenter trial, 20 patients with chronic pulmonary or non-meningeal disseminated coccidioidomycosis were treated with posaconazole 400 mg daily for up to 6 months (median 173 days). Seventeen (85%) patients had a satisfactory response to treatment (≥50% reduction in the Mycoses Study Group score from baseline). No serious adverse effects were reported. Paired baseline and end-of-treatment culture results for Coccidioides species were available for four patients, all of whom converted from being positive to being negative for Coccidioides species. Relapse was experienced by three of nine patients who did not receive antifungal therapy during the follow-up period.

Current guidelines

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Coccidioidomycosis

Mahreen Ameen and Wanda Sonia Robles

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

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 southwestern United States, Central and South America. Primary pulmonary disease is usually sub-acute 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 of this. Coccidioidomycosis is an opportunistic infection with advanced 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 haematogenous 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 neighbouring 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 be aware that the combination of atypical skin lesions, pulmonary infiltrates, and a history of travel to endemic areas of the disease may represent disseminated infection with coccidioidomycosis.

Management strategy

Treatment depends on disease extent and predisposing factors. Those with primary pulmonary infection and no risk factors require only periodic assessments for 2 years to ensure that the infection is self-limiting. Some clinicians prefer to treat with oral azoles to prevent any risk of progression, although there are no trial data to support this. Antifungal therapy is indicated for severe or chronic pneumonia, progressive or disseminated infection. Itraconazole (200–600 mg daily) and fluconazole (400–800 mg daily) have replaced amphotericin B as the initial choice of therapy 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 (amphotericin B deoxycholate 0.5–1.5 mg/kg/day or lipid formulations of amphotericin B 2.0–5.0 mg/kg/day) is now recommended for those with severely acute infection with respiratory failure, those with rapidly progressive and disseminated infection, and women during pregnancy. Published reports of its use, however, are still limited to small numbers of patients treated in open-label, non-randomized studies. There have been no clinical trials assessing the efficacy of lipid formulations of amphotericin B. Newly available antifungal agents that 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 as yet evaluating their efficacy against the established 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 in order to prevent recurrence. Recovery from infection confers lifelong immunity and provides the rationale for the ongoing development of a possible vaccine.

First-line therapies

image Fluconazole A
image Itraconazole A

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis.
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