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Itraconazole therapy for cryptococcal meningitis and cryptococcosis
D W Denning1, R M Tucker, L H Hanson
1Department of Medicine, Santa Clara Valley Medical Center, San Jose, Calif.
Abstract:
We studied the efficacy of itraconazole, a new oral triazole, in 33 patients (32 were immunocompromised) with cryptococcosis. Diagnoses included cryptococcal meningitis (24 patients), cryptococcemia (19 patients), cryptococcuria (4 patients), osteomyelitis (1 patient), pulmonary cryptococcosis (1 patient), and soft-tissue cryptococcosis (2 patients). Twenty-six patients had the acquired immunodeficiency syndrome, and 4 were transplant recipients. Therapy (200 mg two times per day) was monitored by clinical response, culture, and cryptococcal antigen testing. Cryptococcemia was abolished in 10 (100%) of 10 assessable patients; clinical abnormalities also cleared. Thirteen (65%) of 20 assessable patients with cryptococcal meningitis had complete responses (clinical resolution and negative cultures), 5 (25%) had partial responses, and therapy failed in 2 (10%). Ten (71%) of 14 patients with the acquired immunodeficiency syndrome who had meningitis and were treated with itraconazole as their sole therapy had complete responses, 3 (21%) had partial responses, and therapy failed in 1 (7%). Partial responses or failures were all associated with the failure of previous therapy, severe disease, low serum itraconazole concentrations, or a resistant organism. Noncompliance was associated with relapse (4 patients). Meningitis recrudesced in 3 (20%) of 15 patients who responded to therapy. All 4 patients with pulmonary cryptococcosis, soft-tissue cryptococcosis, or osteomyelitis responded to therapy (100%). Cryptococcuria was abolished in 3 (60%) of 5 assessable patients. The median survival of the 20 patients with the acquired immunodeficiency syndrome who had meningitis exceeded 10.5 months at this writing. Overall results compare favorably with amphotericin B therapy with or without flucytosine. Forty of 44 isolates of Cryptococcus neoformans were susceptible in vitro to itraconazole (minimum inhibitory concentration less than or equal to 3.13 mg/L), 3 were borderline (minimum inhibitory concentration, 6.25 mg/L), and 1 was resistant (minimum inhibitory concentration, 12.5 mg/L). As itraconazole does not penetrate cerebrospinal fluid, the meningitis results are noteworthy and suggest that meningeal and parenchymal penetration is critical. Itraconazole is promising for the treatment of cryptococcosis in patients with and without the acquired immunodeficiency syndrome.
Insights
Itraconazole effectively treats cryptococcosis, including meningitis, in immunocompromised patients. This new oral triazole shows promising results comparable to existing therapies.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Cryptococcosis is a serious fungal infection, particularly in immunocompromised individuals.
- Standard treatments like amphotericin B have limitations and potential toxicities.
Purpose of the Study:
- To evaluate the efficacy and safety of itraconazole for treating various forms of cryptococcosis.
- To compare itraconazole's effectiveness against established antifungal therapies.
Main Methods:
- A study involving 33 patients (32 immunocompromised) with diverse cryptococcal infections.
- Therapy involved oral itraconazole (200 mg twice daily), with monitoring via clinical response, cultures, and antigen testing.
- In vitro susceptibility testing of Cryptococcus neoformans isolates to itraconazole was performed.
Main Results:
- Excellent outcomes were observed for cryptococcemia (100% abolition) and localized infections (pulmonary, osteomyelitis, soft-tissue; 100% response).
- For cryptococcal meningitis, 65% of assessable patients achieved complete response, with notable success (71% complete response) in AIDS patients receiving itraconazole monotherapy.
- Relapses occurred in 20% of meningitis patients, often linked to noncompliance, prior treatment failure, or severe disease. In vitro, 91% of isolates were susceptible to itraconazole.
Conclusions:
- Itraconazole demonstrates significant efficacy in treating cryptococcosis, including challenging cases of cryptococcal meningitis, even in severely immunocompromised patients.
- Despite limited cerebrospinal fluid penetration, itraconazole's effectiveness in meningitis suggests critical tissue penetration.
- Itraconazole presents a promising oral therapeutic option for cryptococcosis, potentially offering an alternative to intravenous amphotericin B.