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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2009, p. 2136–2138 0066-4804/09/$08.00ϩ0 doi:10.1128/AAC.01506-08Copyright 2009, American Society for Microbiology. All Rights Reserved.
In Vitro Activity of Terbinafine Combined with Caspofungin and Azoles against Pythium insidiosumᰔ Ayrton S. Cavalheiro,1,2 Grazieli Maboni,2 Maria I. de Azevedo,2 Juliana S. Argenta,2 Daniela I. B. Pereira,2 Tatiana B. Spader,2,3 Sydney H. Alves,1,2,3 and Janio M. Santurio1,2* ˜o em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil1; Programa de ˜o em Cieˆncias Farmaceˆuticas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil3; and ´gicas (LAPEMI), Departamento de Microbiologia e Parasitologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil2 Received 11 November 2008/Returned for modification 18 December 2008/Accepted 4 March 2009 In this text we evaluated the in vitro antifungal activities of terbinafine combined with caspofungin,
miconazole, ketoconazole, and fluconazole against 17 Pythium insidiosum strains by using the microdilution
checkerboard method. Synergistic interactions were observed with terbinafine combined with caspofungin
(41.2% of the strains), fluconazole (41.2%), ketoconazole (29.4%), and miconazole (11.8%). No antagonistic
effects were observed. The combination of terbinafine plus caspofungin or terbinafine plus fluconazole may

have significant therapeutic potential for treatment of pythiosis.
Pythiosis is a life-threatening infectious disease in humans to obtain a final concentration range of 2 ϫ 103 to 3 ϫ 103 and animals that is caused by the aquatic oomycete Pythium insidiosum (9). Horses are the most frequently infected ani- The combinations of TRB (Novartis) plus CAS (Merck), mals, and equine pythiosis typically involves ulcerative granu- TRB plus MNZ (Labware), TRB plus ketoconazole (Janssen), lomas (8). In humans, the infection occurs as ophthalmic, sub- and TRB plus FLC (Pfizer) were evaluated using the checker- cutaneous, and systemic forms, which are frequently associated board technique, according to the broth microdilution design with ␣- and ␤-thalassemia (5, 7). Pythiosis therapy, which is (2, 14). In the individual tests, 100 ␮l of each drug concentra- based on amphotericin B or azoles, has been ineffective or tion was plated in microplate wells and an equal volume of the controversial, and the associated prognosis for human and inoculum was added to each well. In the combination tests, the equine pythiosis is poor (5, 7, 8, 9, 12). Therefore, surgical antifungals were plated at a 4ϫ concentrate of 50 ␮l of drug A procedures, including amputation, are often effective, but dis- plus 50 ␮l of drug B and 100 ␮l of the inoculum, resulting in a ease reoccurrence rates are unfortunately high (7).
final 1ϫ drug concentration of each compound. The micro- Combinations of antifungal agents against pythiosis have not plates were incubated at 37°C for 24 h. The MIC was defined been thoroughly studied, and therefore, such in vitro combi- as the lowest drug concentration at which there was 100% natory activities against P. insidiosum require attention (1, 6).
inhibition of fungal growth by visual readings. The tests were The purpose of this study was to investigate the in vitro performed in duplicate, and the assay was repeated when dis- activity of terbinafine (TRB) combined with caspofungin parate values were obtained. The interactions, based on the (CAS), miconazole (MNZ), ketoconazole, and fluconazole respective fractional inhibitory concentration index (FICI), (FLC) against 17 strains of Pythium insidiosum isolated from were interpreted as the following: FICI Յ 0.5, synergism; FICI Ͼ 0.5 to Յ4, indifference; FICI Ͼ 4, antagonism. FICIs were ob- A total of 15 Brazilian P. insidiosum strains isolated from tained using the formula FICI ϭ (MIC of drug A in combination/ equines with pythiosis and two standard strains (ATCC 58637 MIC of drug A alone) ϩ (MIC of drug B in combination/MIC of and CBS 101555) were tested. All strains were maintained in cornmeal agar, and strain identification was confirmed by aPCR-based assay (4).
The susceptibility of the P. insidiosum strains to the antifun- TABLE 1. In vitro activities of TRB, CAS, and azoles against gal agents was tested by microdilution, based on protocol M38-A2 (2). The inoculum consisted of P. insidiosum zoo- spores obtained following zoosporogenesis. Cell numbers of zoospores were counted on a hemocytometer; zoospores were diluted in RPMI 1640 containing L-glutamine and buffered to pH 7.0 with 0.165 M MOPS (morpholinepropanesulfonic acid) * Corresponding author. Mailing address: Campus UFSM, Pre 20, sala 4139, 97105-900 Santa Maria, RS, Brazil. Phone and fax: 55 55 a Range between the lowest and highest MICs for all isolates.
32208906. E-mail: santurio@smail.ufsm.br.
ᰔ Published ahead of print on 16 March 2009.
c MIC of drug capable of inhibiting the growth of 90% of isolates.
IN VITRO ACTIVITY OF DRUGS AGAINST PYTHIUM INSIDIOSUM TABLE 2. In vitro activity of TRB combined with FLC, MNZ, ketoconazole, or CAS against Pythium insidiosumc a LAPEMI, Laborato´rio de Pesquisas Micolo´gicas; ATCC, American Type Culture Collection; CBS, Centraalbureau voor Schimmelcultures.
b interpret., interpretation; S, synergistic; I, indifferent.
c n ϭ 17.
The in vitro activities of individual antifungal agents against either itraconazole or voriconazole was synergistic against 17% P. insidiosum are shown in Table 1. In general, the patterns of of the strains tested and no antagonistic effects were observed.
susceptibility demonstrated that individual drugs had only In this study, we demonstrated significant synergistic effects, as the combinations of TRB plus FLC and TRB plus CAS were The combinations of TRB plus FLC and TRB plus CAS synergistic against 41.2% of P. insidiosum strains. Additionally, both exhibited synergistic effects against seven (41.2%) P. in- synergistic effects were indicated with combinations of TRB sidiosum strains. The combination of TRB plus ketoconazole plus ketoconazole and TRB plus MNZ, albeit to a lower extent was also synergistic against five (29.4%) isolates, while the (against 29.4% and 11.8% of strains, respectively). To our combination of TRB plus MNZ exhibited synergistic effects knowledge, the synergistic effects of these antifungals against against only two (11.8%) isolates (Table 2). Antagonistic ef- P. insidiosum are being reported for the first time in this study, and antagonistic effects of these combination antifungal treat- The use of combination therapy in the treatment of pythiosis could be an alternative to monotherapy (3), but such applica- However, a concern for the use of combination antifungal tion would require further investigation. Herein, we examined therapy in treating P. insidiosum infection is the great variation the in vitro activities of selected antifungal agents singularly or in susceptibility among the different strains, which may be in combination against P. insidiosum.
related to the genetic variability of the strains tested (11).
Our results are difficult to interpret, since only a few previ- However, our in vitro results demonstrate that combination ous studies investigating the susceptibility of P. insidiosum have antifungal therapy may be an alternative in the treatment of P. been reported, and those studies were performed using differ- insidiosum. In vivo studies must be further investigated exper- ent experimental techniques (1, 13). In addition, the break- imentally, since 48.5% of the combined MICs were lower than points for susceptibility tests with antifungal agents against P. the serum concentrations achieved by the respective agents, insidiosum are not defined (2). Therefore, these results suggest which indicates the potential therapeutic utility of our results.
relatively weak antifungal activity of the individual agents,which is in accordance with the well-known therapeutic failures This study was supported by CNPq (the National Council for Sci- in pythiosis treatment. In contrast, the results obtained utiliz- entific and Technological Development of Brazil) and by Laborato ing drug combinations, which are based on FICIs, can be in- ´gicas, Universidade Federal de Santa Maria, Rio terpreted with more confidence for activity.
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