Reprinted from www.antimicrobe.org

Hyalohyphomycosis - Antimicrobial Therapy

General 

               The hyalohyphomycosis are difficult to diagnose and often refractory to conventional antifungal therapy, particularly when the host is persistently immunosuppressed.  These infections occur in two settings: in normal hosts in whom surgery and antifungal therapy (local or systemic) is frequently curative; and in immunocompromised hosts where the critical factor for a favorable outcome is recovery from immunosuppression.  

               Various antifungal agents are available that may be effective against some of these infections. Amphotericin B and its lipid formulations have been the mainstay of therapy of invasive fungal infections in severely immunosuppressed patients, although newer triazoles (itraconazole, voriconazole) and caspofungin are now available and may be effective in certain settings (Table 2). Since susceptibility of these pathogens to antifungal agents may be variable and at times difficult to predict, testing the susceptibility of the offending pathogen responsible of a specific infection is recommended.  

               Duration of therapy is determined by the achievement of a complete eradication of the infection and resolution of immunosuppression (see specifics below under endpoints for monitoring therapy). The optimal doses of potentially active antifungal agents are presented in Table 3.  

Specific Infection (Tables 2-4) 

Fusarium Species: Most patients with disseminated fusarial infection and persistent profound immunosuppression succumb to their infection despite intensive antifungal therapy. The immune status of the host remains the single most important factor predicting outcome of disseminated infection (Table 4). By contrast, localized infections, particularly in hosts with normal immunity, respond well to therapy.  

               Since susceptibility of Fusarium spp to antifungal agents is variable, no agent can be considered the drug of choice, and testing individual strains involved in specific infections is recommended. Serious Fusarium infection may be treated with amphotericin B at a dose of at least 1.0 mg/kg/day or with one of the lipid formulations of amphotericin B at higher doses (3-5 mg/kg/day) (Table 3). Anecdotal responses have been observed with voriconazole and itraconazole. Initial therapy consists of either a lipid amphotericin B product at higher dose or an intravenous formulation of itraconazole or voriconazole (Table 3). Caspofungin is not active in vitro against Fusarium species. In vivo studies with this agent are in progress. Given the resistance of fusarial species to antifungal agents, a combination of the above mentioned agents might be considered but it is of unproven value.  Topical natamycin is the drug of choice for fusarial keratitis. This agent is, however, not available for systemic administration.  

Scedosporium Species:  The drugs of choice for infections caused by Pseudallescharia boydii/Scedosporium apiospermum are the newer triazoles itraconazole and voriconazole (Tables 2-4).  Localized infections in an immunologically intact host are best treated with a combination of triazole (itraconazole or voriconazole), local injections of amphotericin B (septic arthritis, endophthalmitis) and surgical debridement.  Multiple brain abscesses in a patient with acute lymphoblastic leukemia was treated successfully with posaconazole despite progression on itraconazole, amphotericin and ketoconazole. 

               In the setting of persistent immunosuppression, maximal tolerated dose of a triazole, in combination with an amphotericin product may be considered but has not been properly evaluated.

               Scedosporium prolificans/inflatum is typically resistant to all antifungal agents both in vitro and in vivo. Severe and disseminated infections are commonly fatal unless rapid improvement in immune status occurs. A combination of antifungal agents may be considered but is of unproven value. Surgical debridement of infected tissue appears to be the only means of halting progression of localized infection with this pathogen.  

Acremonium Species: The agents of choice for these infections are amphotericin B (and its lipid formulations) and the newer triazoles, itraconazole and voriconazole.  Surgical resection of localized lesions is considered a part of successful management (Tables 2-4).  

Table 2.  In Vitro Antifungal Susceptibility of Common Agents of Hyalohyphomycosis and Drug of Choice 

¨Scedosporium ªPaecilomyces

NT: not tested. * Variable: May be species or strain specific. †denotes drug of choice

Topical natamycin application for fusarial keratitis; Natamycin not available as a systemic agent.

Miconazole has activity against S. apiospermum and P. lilacinus, but is associated with significant toxicity. Ketoconazole is moderately active against S. apiospermum and P. lilacinus but has erratic bioavailability. Other triazoles such as Itraconazole and voriconazole are more potent, safer, have oral and intravenous formulations and thus are more appropriate therapeutic agents.

Flucytosine has no activity against Fusarium spp, S. apiospermium and S. inflatum.

Table 3.  Dosing Schedule of Antifungal Agents with Activity Against Hyalohyphomycosis

Agent	Standard daily dose	Maximal daily dose
Polyenes
Amphotericin B	1 mg/kg	1.5 mg/kgÅ
Liposomal Amphotericin B (Ambisome)	3-5 mg/kg	15 mg/Kg
Amphotericin Lipid Complex	3-5 mg/kg
Amphotericin Colloidal Dispersion	3-5 mg/kg
Triazoles
Fluconazole	400 mg	1600 mg
Itraconazle*	400 mg in 2 doses after loading§	800 mg
Voriconazole*	6 mg/kg in 2 doses after loading§
Echinocandins
Caspofungin	70 mg loading then 50 mg

* Use IV formulation in critically ill patients.

§ Loading dose: Itraconazole: 400 mg BID for three days; Voriconazole: 6 mk/kg for two doses.

Å rarely tolerated at this dose

Table 4.  Management of Specific Hyalohyphomycosis