Journal of Antimicrobial Chemotherapy (1999) 43, 149-151
© 1999 The British Society for Antimicrobial Chemotherapy
Brief reports |
Comparative in-vitro activity of voriconazole (UK-109,496) and six other antifungal agents against clinical isolates of Scedosporium prolificans and Scedosporium apiospermum
Unidad de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda (Madrid), Spain.
Abstract
We report the in-vitro susceptibility of 27 clinical isolates of Scedosporium apiospermum and 43 of Scedosporium prolificans. S. apiospermum was resistant to fluconazole and flucytosine, with variable susceptibility to amphotericin B, itraconazole, ketoconazole and susceptible to miconazole. Voriconazole was much more active than fluconazole and flucytosine, more active than amphotericin B, itraconazole and ketoconazole and was as active as miconazole against S. apiospermum isolates. Voriconazole and the other six antifungal agents showed low activity against S. prolificans isolates.
Introduction
Scedosporium apiospermum (Pseudallescheria boydii) and Scedosporium prolificans are members of the dematia ceous hyphomycetous genus Scedosporium. 1 These moulds are pathogenic in humans, causing asymptomatic colonization, localized infections following penetrating trauma or intravenous drug abuse, and disseminated infections particularly in immunosuppressed patients. 1 They are widespread in nature as soil saprophytes. 2
Optimal treatment of these fungal infections is unknown. Debridement or excision of necrotic tissue and antifungal chemotherapy should be the treatment of choice, 3 but indications for surgery are limited, and dose and duration of chemotherapy have not been established. Results of treatment have been variable. Prognosis depends mainly on the patient's immune status and feasi bility of surgical debridement. 3 In neutropenic patients with disseminated infection, death is the usual outcome despite antifungal treatment. 1 ,3
Little is known about the susceptibility of Scedosporium spp. to antifungal agent. 3 ,4 Isolates of S. apiospermum are considered to be susceptible to miconazole and resistant to fluconazole and flucytosine; they appear to have variable susceptibility to itraconazole, ketoconazole and amphotericin B. 4 S. prolificans is multi-resistant: recent studies show that antifungal drugs have low activity against this organism in vitro. 3
Voriconazole (UK-109,496) is a new, broad-spectrum triazole with activity against Candida spp., Cryptococcus neoformans and some moulds. 4 Animal studies and recently published clinical data suggest that it is effective in the treatment of invasive mycoses. 5 In the present study we describe the results of in-vitro determinations of susceptibility to voriconazole and other antifungal agents carried out on 27 clinical isolates of S. apiospermum and 43 of S. prolificans.
Materials and methods
All mould isolates tested were obtained from clinical specimens, from more than 20 different Spanish hospitals between 1992 and March 1998. Their sites of isolation are listed in Table I. Susceptibility testing was performing according to the NCCLS reference micromethod, with minor modifications. 6 The medium used for susceptibility testing was RPMI 1640 with L-glutamine (Sigma–Aldrich Química, Madrid, Spain) buffered with morpholine propanesulphonic acid (MOPS) (Sigma–Aldrich Química) to a final molarity of 0.165 M, adjusted to pH 7.0 by using 10 M NaOH, and supplemented with 18 g/L of glucose (RPMI–2% glucose). 7 The antifungal drugs used in the susceptibility testing procedure were amphotericin B (Squibb, Madrid, Spain), flucytosine (Roche, Madrid, Spain), ketoconazole, miconazole and itraconazole (Jans sen Pharmaceutica, Madrid, Spain), and fluconazole and voriconazole (UK-109,496; Pfizer Ltd, Sandwich, UK). All seven initial solutions of antifungal agents were diluted with RPMI–2% glucose. The concentration of vori conazole ranged from 64 to 0.125 mg/L. The concentrations of the other six antifungal agents ranged from 16 to 0.03 mg/L. The microtitre plates contained two-fold serial dilutions of the antifungal drugs and two drug-free medium wells for sterility and growth controls.
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Inoculum suspensions were standardized to get a spec trophotometric reading of 68–71% transmission at 530 nm. Thus, final suspensions containing 1–5 x 106 cfu/mL were obtained. Each well contained 10 µL of inoculum sus pension (c. 105 cfu/mL). The microtitre plates were incubated at 35°C in humid atmosphere for 48 h and read macroscopically with a mirror. The MIC was defined as the lowest concentration of the antifungal agent that completely inhibited fungal growth.
Paecilomyces variotii (ATCC 22319), Aspergillus fumigatus (ATCC 9197) and Candida parapsilosis (ATCC 22019) were used as reference strains to control the quality and to monitor the reproducibility of susceptibility tests. The MIC values of 30 consecutive determinations varied by no more than two two-fold dilutions. The MICs of voriconazole were 0.06–0.25 mg/L for P. variotti,0.5–1 mg/L for A. fumigatus and 0.007–0.03 mg/L forC. parapsilosis.
Results
The in-vitro susceptibility results are summarized in Table II. S.
apiospermum had
variable susceptibility to the seven antifungal drugs tested. Six isolates were inhibited by
2 mg/L of amphotericin B, and seven by 4 mg/L. For all S. apiospermum isolates the flucytosine
and fluconazole MICs were very high. However, four isolates of S. apiospermum were
inhibited by itraconazole concen trations 
2 mg/L, and six by 4 mg/L. Thirteen (50%)
of the S. apiospermum isolates were inhibited by ketoconazole concentrations of 2
mg/L. The in-vitro activity of miconazole against S. apiospermum seemed better than
that of the other antifungal drugs tested; 17 isolates were inhibited by miconazole concentrations
of 1 mg/L. Voriconazole MICs were 1 mg/L for 22/27 isolates. In all cases
voriconazole was more potent than flucytosine, amphotericin B, fluconazole, itraconazole and
ketoconazole. In contrast to S. apiospermum, the in-vitro activity of all antifungal drugs
tested was very low against S. prolificans (Table II)).
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Discussion
In order to ascertain the susceptibility of Scedosporium spp. we studied the in-vitro activity of seven antifungal agents against 27 clinical isolates of S. apiospermum and 43 of S. prolificans.
Miconazole appears to be the antifungal agent of choice to treat S. apiospermum infections, but it is associated with several adverse effects. 3 Itraconazole is a good alternative in some cases, but is poorly absorbed after oral administration, although a new oral formulation is absorbed much more reliably.8 ,9 S. apiospermum infections are difficult to treat: fluconazole and flucytosine lack activity against this organism. 3 ,4
New therapeutic approaches are clearly needed for treatment of these mycoses. In our
study, S. apiospermum isolates seem to be susceptible to voriconazole (most MICs were
1 mg/L). Voriconazole was much more active than fluconazole and flucytosine, more active
than ampho tericin B, itraconazole and ketoconazole and showed good activity (comparable to
that of miconazole) against S. apiospermum isolates. In patients receiving voriconazole
200 mg po bd for the treatment of acute and chronic invasive aspergillosis, the concentration of
this antifungal agent in serum was 3.27 mg/L; this bioavailability warrants clinical studies.
10
Our in-vitro susceptibility results show that S. prolificans is multi-resistant. Voriconazole, like itraconazole, had low activity against S. prolificans, this activity was slightly higher than that of the other antifungal drugs studied.
Few data correlating susceptibilities to in-vitro azole agents with response to therapy in vivo are available, especially from patients with mould infection. However, the low MICs and high bioavailability of voriconazole are promising and indicate that this new triazole should be a suitable agent, even in the immunocompromised host, for the treatment of S. apiospermum infections. The in-vitro susceptibility results of voriconazole suggest that the drug may be ineffective against S. prolificans.
Acknowledgments
This work was supported in part by grant 96/0598 from the Fondo de Investigaciones Sanitarias and by grant European TMR ERBFMRXCT 970145. B. Ruiz-Díez and M. Cuenca-Estrella are Fellows of the Institute de Salud Carlos III (grant 96/4027) and the Fondo de Investigaciones Sanitarias (grant 97/5551) respectively. We thank Pfizer, Productos Roche, Janssen Farmaceútica and Squibb Industria Farmaceútica for supplying the anti-fungal powders
Notes
* Corresponding author. Unidad de Micología, Centro
Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda (Madrid),
Spain. Tel:
+34-91-5097961; Fax: +34-91-5097966; E-mail:
juan1.rodriguez-tudela{at}isciii.es 
References
1 . Rippon, J. W. (1988). Pseudallescheriasis. In Medical Mycology: the Pathogenic Fungi and the Pathogenic Actinomycetes, 3rd edn (Rippon, J. W., Ed.), pp. 651–80. W. B. Saunders, Philadelphia, PA.
2 . de Hoog, G. S., Marvin-Sikkema, F. D., Lahpoor, G. A., Gottschall, J. C., Prins, R. A. & Gueho, E. (1994). Ecology and physiology of the emerging opportunistic fungi Pseudoallescheria boydii and Scedosporium prolificans. Mycoses 37,71 –5.[Medline]
3 . Berenguer, J., Rodríguez-Tudela, J. L., Richard, C., Alvarez, M., Sanz, M. A., Guztelurrutia, L. et al. and the Scedosporium prolificans Spanish Study Group. (1997). Deep infections caused by Scedosporium prolificans. A report on 16 cases in Spain and a review of the literature. Medicine 76, 256–65.[Medline]
4 . Radford, S. A., Johnson, E. M. & Warnock, D. W. (1997). In vitro studies of activity of voriconazole (UK-109,496), a new triazole antifungal agent, against emerging and less-common mold pathogens. Antimicrobial Agents and Chemotherapy 41,841 –3.[Abstract]
5 . Schwartz, S., Milatovic, D. & Thiel, E. (1997). Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia. British Journal of Haematology 97, 663–5.[Web of Science][Medline]
6 . National Committee for Clinical Laboratory Standards. (1997). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard Document M27-A. NCCLS, Villanova, PA.
7
.
Rodríguez-Tudela, J. L. &
Martínez-Suárez, J. V. (1994).
Improved medium for fluconazole susceptibility testing of Candida albicans. Antimicrobial Agents and Chemotherapy 38, 45–8.
8 . Nomdedéu, J., Brunet, S., Martino, R., Altés, A., Ausina, V. & Domingo-Albós, A. (1993). Successful treatment of pneumonia due to Scedosporium apiospermum with itraconazole: case report. Clinical Infectious Diseases 16, 731–3.[Web of Science][Medline]
9 . De Beule, K. (1996). Itraconazole: pharmacology, clinical experience and future development. International Journal of Antimicrobial Agents 6, 175–81.
10 . Martin, M. V., Yates, J. & Hitchcock, C. A. (1997). Comparison of voriconazole (UK-109,496) and itraconazole in prevention and treatment of Aspergillus fumigatus endocarditis in guinea pigs. Antimicrobial Agents and Chemotherapy 41,13 –6.[Abstract]
Received 29 May 1998; returned 17 July 1998; revised 3 August 1998; accepted 12 August 1998
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