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Antimicrobial Agents and Chemotherapy, July 2004, p . 2727-2729, Vol . 48, No . 7 In Vitro Interactions of Approved and Novel Drugs against Paecilomyces spp.Montserrat Ortoneda,1 Javier Capilla,1 F . Javier Pastor,1 Isabel Pujol,2 Clara Yustes,1 Carolina Serena,1 and Josep Guarro1* Unitat de Microbiologia, Facultat de Medicina,1 Laboratori de Microbiologia, Hospital Universitari de Sant Joan de Reus, Universitat Rovira i Virgili, Reus, Spain2 Received 19 February 2004/ Returned for modification 21 February 2004/ Accepted 27 February 2004
Seven clinical isolates of Paecilomyces spp . (four strains of P . variotii and three strains of P . lilacinus) were tested . The isolates were grown on potato dextrose agar plates and incubated at 30°C for 7 to 10 days . Inocula were prepared by following the NCCLS guidelines (10) and adjusted to a final concentration of 1.1 x 104 to 3.4 x 104 conidia/ml . Antifungal agents were obtained as pure powders . AMB (USP, Rockville, Md.), itraconazole (ITZ) (Janssen Pharmaceutica, Beerse, Belgium), voriconazole (VCZ) (Pfizer Inc., Madrid, Spain), albaconazole (ABZ) (J . Uriach & Cia., Barcelona, Spain), ravuconazole (RVZ) (Bristol-Myers Squibb Company, New Brunswick, N.J.), and terbinafine (TBF) (Novartis, Basel, Switzerland) were dissolved in dimethyl sulfoxide . Micafungin (MFG) was obtained from Fujisawa Pharmaceutical Co . Ltd . (Osaka, Japan) and was dissolved in water .
The MICs of all drugs were defined as the lowest drug concentrations that produced a 100% inhibition of visible fungal growth after 48 to 72 h of incubation at 35°C . Drug interactions were assessed by a checkerboard microdilution method that also included the determination of the MIC of each drug alone in the same plate by using the parameters outlined in NCCLS document M38-A . Antifungal agents were placed in rows or in columns of the trays to test all possible combinations with the highest concentrations being 8 µg/ml for AMB, 32 µg/ml for TBF and MFG, and 16 µg/ml for the azoles . The fractional inhibitory concentration index (FICI) was used to classify drug interaction . FICI is the sum of the FIC of each of the drugs, which in turn is defined as the MIC of each drug when it is used in combination divided by the MIC of the drug when it is used alone . Interaction was synergistic if FICI was
All antifungal agents except TBF showed, in general, some activity against P . variotii when tested alone . For P . lilacinus only the novel azole derivatives, and especially RVZ, were active . These results generally confirmed our earlier studies (1, 3) and those of other authors (7) . The in vitro interactions of the seven antifungal drugs tested in this study are shown in Tables 1 to 3 . Of the 105 combinations evaluated, 23 were synergistic and the rest were indifferent . We detected no antagonistic interactions in any case . TBF combined with the four azoles showed the highest percentage of synergistic interactions (53%) . The combination TBF-VCZ was synergistic against six of the seven strains tested, and it was the only combination that was synergistic against all the strains of P . lilacinus tested . Highly favorable interactions obtained with TBF and azoles against other filamentous fungi have also been found by other authors and are probably due to their combined effects at different stages of the ergosterol biosynthesis pathway (12) . In contrast, the interactions of both AMB and MFG with any of the other antifungal agents and that between AMB and MFG were mainly indifferent; they were synergistic in only 10% of the tests . Concerning the combinations of MFG with azoles, we did not observe the favorable interactions against Candida spp . and Aspergillus spp . that other authors have reported (6) . The lack of synergy of some AMB- or MFG-azole combinations against P . variotii may be related to the low MICs of AMB and MFG for this species . However, these in vitro findings do not exclude a positive interaction in vivo, which merits evaluation in animal models .
Animal models can be important tools in evaluating the significance in vivo of the most promising combinations . We have recently developed a murine model of disseminated infection by the two above-mentioned Paecilomyces species (11), which could be useful for this purpose . However, the peculiar pharmacokinetics of TBF with high clearance from plasma and accumulation in skin and adipose tissues influences the choice of the adequate animal model to be used (8) . In several in vivo studies using different animals, this drug was totally ineffective in spite of showing low in vitro MICs (13) . However, there is some clinical evidence for the good activity of TBF combined with several azoles in clinical practice, including one case of P . lilacinus infection (5) . Further studies are warranted to further elucidate the potential usefulness of these combination therapies .
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0.5, indifferent if FICI was >0.5 and
