Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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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
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.
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.
Direct microscopy
Culture
Serological tests
Imaging studies (chest and bone radiography)
Serology for HIV/AIDS infection (where relevant)
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.
The NIAID Mycoses Study Group. Galgiani JN, Catanzaro A, Cloud GA, Higgs J, Friedman BA, Larsen RA, Graybill JR. Ann Intern Med 1993; 119: 28–35.
Uncontrolled clinical trial which included 50 patients with coccidioidal meningitis. Forty-seven patients were evaluated. Twenty-five had received no previous treatment, and nine were HIV positive. Thirty-seven of 47 patients (79%) responded to treatment. Response rates were similar in patients who had or had not received previous therapy.
Fluconazole demonstrates efficacy in the treatment of coccidioidal meningitis.
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.
NIAID Mycoses Study Group. Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA. Am J Med 1990; 89: 282–90.
A multicenter study which included 51 patients with non-meningeal coccidioidomycosis who suffered with either chronic pulmonary, skin and soft tissue, or osteoarticular disease. Patients were treated with itraconazole 100–400 mg daily for periods up to 39 months. Of 44 patients who completed therapy, 25 (57%) achieved remission, but four (16%) later experienced relapse. Three patients were not able to tolerate treatment which had to be discontinued.
Tucker RM, Denning DW, Dupont B, Stevens DA. Ann Intern Med 1990; 112: 108–12.
This was a prospective, non-randomized, multicenter study. Eight patients with coccidioidal meningitis refractory to standard therapy were treated with itraconazole 300–400 mg daily for a median duration of 10 months. Three patients received intrathecal amphotericin B in addition, and were able to successfully discontinue amphotericin without relapse. Four of five patients on itraconazole monotherapy responded to treatment.
This small but important study demonstrates the efficacy of itraconazole for the treatment of meningeal infection.
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.
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.
Stevens DA, Shatsky SA. Semin Respir Infect 2001; 16: 263–9.
This review advocates the use of intrathecal amphotericin B as a way to avoid the toxicity of intra-cerebrospinal fluid amphotericin treatment.
A good review.
Antony S, Dominguez DC, Sotelo E. J Natl Med Assoc 2003; 95: 982–5.
Report of an immunosuppressed patient on long-term steroid therapy successfully treated with liposomal amphotericin B (AmBisome).
Galgiani JN, Stevens DA, Graybill JR, Dismukes WE, Cloud GA. Am J Med 1988; 84: 603–10.
A randomized clinical trial involving 112 patients with progressive pulmonary, skeletal, or soft tissue infections. Success rate was similar for the two groups (23.2% vs 32.1% for low and high-dose therapy). Side-effects were significantly higher with high-dose therapy (66% vs 38%). Relapse rates were higher with high-dose therapy (52% vs 11%) although it depended also on the organs involved. The study concluded little or no benefit with high-dose ketoconazole for non-meningeal infection.
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.
Stevens DA, Rendon A, Gaona-Flores V, Catanzaro A, Anstead GM, Pedicone L, Graybill JR. Chest 2007; 132: 952–8.
This was an open-label multinational study which included 15 patients with pulmonary (n=7) and disseminated (n=8) disease that was refractory to previous therapy, which included amphotericin B with and without an azole. They were treated with posaconazole 800 mg daily in divided doses for 34–365 days (median 306 days). Seventy-three percent of patients (11/15) responded to treatment, with cure in four patients. Treatment was very well-tolerated.
Kim MM, Vikram HR, Kusne S, Seville MT, Blair JE. Clin Infect Dis 2011; 53: 1060–6.
This was a retrospective study of all cases treated with either voriconazole (n=21) or posaconazole (n= 16) in a single center. There was a 67% and 75% improvement after a median duration of 6 and 17 months of treatment with voriconazole and posaconazole, respectively.
The authors concluded that voriconazole and posaconazole are reasonable but not infallible options for salvage treatment of refractory coccidioidomycosis.
Park DW, Sohn JW, Cheong HJ, Kim WJ, Kim MJ, Kim JH, Shin C. BMC Infect Dis 2006; 6: 26.
A case report of an immunocompetent Korean male with diffuse coccidioidal pneumonia with skin involvement, acquired on a trip to California, USA. He failed initial therapy with amphotericin B deoxycholate 1 mg/kg daily for 40 days. He was switched to intravenous caspofungin (initially 70 mg and then 50 mg daily) and oral fluconazole 400 mg daily. Due to an excellent clinical response, caspofungin was discontinued after 4 months and fluconazole was continued as maintenance therapy.
In another report caspofungin monotherapy failed to treat a case of meningeal infection.
Antony S. Clin Infect Dis 2004; 39: 879–80.
Caspofungin monotherapy was successfully used to treat this case of disseminated infection without meningeal involvement.
Duplessis CA, Tilley D, Bavaro M, Hale B, Holland SM. J Infect 2011; 63: 223–8.
The authors report two cases of refractory coccidioidomycosis which demonstrated improved responses with adjunctive IFN-γ.
IFN γaugments the antifungal activity of effector immune cells against a variety of fungi. Adjunctive immunotherapy given with chemotherapy has the potential to improve host immune responses and facilitate complete eradication of pathogens.
Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Johnson RH, Stevens DA, Williams PL. Clin Infect Dis 2005; 41: 1217–23.
These guidelines replace the guidelines published in 2000, and the most notable difference being that itraconazole and fluconazole have replaced amphotericin B as first-line therapy for most chronic and disseminated forms of infection.
Primary self-limiting infection in an immunocompetent host usually requires no treatment. Recommended dosages of the commonly used azoles are fluconazole 400–800 mg daily, itraconazole 400–600 mg daily, and ketoconazole 400 mg daily. Amphotericin B deoxycholate dosage is 0.5–1.5 mg/kg/day, and the dosage for the lipid formulations is 2.0–5.0 mg/kg/day.
Oral azole for 3 to months with follow-up period to ensure complete resolution.
This may indicate underlying immunosuppression and the patient should be investigated for extrapulmonary infection. Amphotericin B is usually given (especially if there is respiratory distress) and continued for several weeks before switching to an oral azole. One year of total treatment is recommended. In the immunosuppressed, azoles should be continued as secondary prophylaxis.
Oral azoles are given for 1 year. If there is a lack of response, a higher dose or alternative azoles or amphotericin B can be used.
High-dose azoles are recommended. Treatment can be switched to amphotericin B if there is no improvement. Surgical debridement may be required for abscesses or bony sequestrations.
Oral fluconazole (400–1000 mg daily) is favoured. Itraconazole (400–600 mg daily) can also be used. Intrathecal amphotericin B (0.1–1.5 mg per dose) in addition to an azole is an alternative regime. Patients who respond to an azole should continue with this treatment indefinitely.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Fluconazole
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Ketoconazole
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