Australasian Society for Infectious Diseases
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Australasian Society for Infectious Diseases |
Guidelines
for use of antifungal agents in treatment of invasive fungal infection (July
2003) TREATMENT
OF SUSPECTED/PROBABLE AND PROVEN FUNGAL INFECTION Voriconazole Herbrecht [38] et. al. conducted an open randomised comparison of voriconazole 6 mg/kg loading dose 12 hourly and then 4 mg/kg 12 hourly or 200 mg orally bd versus amphotericin B 1 mg/kg in 392 patients with invasive aspergillosis. Aspergillosis was defined according to standard definitions [19] as definite or probable. Satisfactory outcome was a complete response of clinical or radiological findings or partial response, which was significant clinical and >=50% radiological improvement. The primary end-point was response at week 12. Patients remained on study if they were changed to other licensed antifungal therapy before week 12. Patients were assessed for outcome at week 12 and at end of study therapy. Most patients had undergone HSCT or were undergoing treatment for haematological malignancy and had pulmonary invasive aspergillosis. At week 12, satisfactory outcome occurred in 53% voriconazole and 32% amphotericin B recipients (95% CI for difference 33% to 10%). Survival of patients receiving voriconazole was 71% versus 58% receiving amphotericin B (Hazard ratio 0.59, 95% CI 0.40 to 0.88). The median duration of study drug was 77 days in voriconazole recipients and 11 days for amphotericin B. This study suggested voriconazole was more effective than amphotericin B followed by other licensed antifungal therapy and may result in improved survival. However, the open label study design creates potential bias and not all confounders can be easily controlled. An open label non-comparative study of efficacy and safety of voriconazole in the treatment of definite or probable invasive aspergillosis in 116 patients was reported by Denning et. al. [39]. Aspergillosis was definite if a histological diagnosis was made or if a positive culture was obtained from a sterile site. The definition of probable invasive aspergillosis and failure of therapy was more lenient than in the above study [38]. Treatment was with intravenous loading followed by 3 mg/kg/day bd for 6-27 days followed by 200 mg bd orally for up to 24 weeks. Overall good responses were seen in 48%, and failure in 31%. Immunosuppression and site of infection influenced the response rate. Better outcome was seen in those with pulmonary disease, with haematological disorders and those receiving initial rather than salvage therapy. Voriconazole 200 mg bd and fluconazole 200 mg daily were compared in 391 immunocompromised patients with biopsy and mycologically proven oesophageal candidiasis [40]. The primary end-point was response as assessed by oesophagoscopy and equivalency was demonstrated. These
studies indicate that voriconazole will be a useful treatment of acute invasive
aspergillosis. It may be more effective than amphotericin B in the treatment of
invasive aspergillosis especially as amphotericin B is commonly used as first
line therapy with a change to another agent on development of toxicity or lack
of improvement. The study of Herbrecht et. al., was designed to test the
initial treatment of aspergillosis in immunocompromised patients only and it should
be remembered that patients on the amphotericin B arm remained on this treatment
for a median of 11 days only before changing to other licensed antifungal therapy. With the availability of antifungal agents acting on different targets in the fungal cell, the possibility of combination therapy exists. In vitro testing suggests combination therapy produces synergy. Its role has been explored in difficult to treat infections such as scedosporiosis and aspergillosis as well as candidiasis and cryptococcosis. However, there is limited clinical experience to confirm these in vitro observations apart from case reports. In vitro testing of Aspergillus species revealed potent synergy with the combination of terbinafine and a triazole [18]. Synergy was most notable with itraconazole and voriconazole, but was also found with fluconazole, an agent that has no activity against Aspergillus species. With Scedosporium prolificans, testing revealed synergy between itraconazole and terbinafine in 95% of isolates [41]. Combinations of caspofungin with fluconazole, flucytosine and amphotericin B have also been tested in vitro. Synergy was noted for these combinations with Cryptococcus neoformans which is not susceptible to caspofungin alone [42]. Synergy was also noted for amphotericin B and caspofungin against Aspergillus spp. and Cryptococcus spp. [43]. A series describing use of combination liposomal amphotericin B and caspofungin in leukaemic patients with proven or suspected aspergillus pneumonia refractory to amphotericin B treatment has recently been published [44]. Although the response was encouraging in 75% of the 30 patients, most of the patients included had possible rather than proven or probable aspergillosis. Currently combination therapy can only be recommended for difficult infections such as with Scedosporium prolificans. Acknowledgments: Thanks to members
of The Mycoses Interest Group and the Australasian Society for Infectious Diseases
for careful review and comments.
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