In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

Abstract

In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. We evaluated the activities of terbinafine and itraconazole against 31 isolates of Paracoccidioides brasiliensis. The tests were conducted by using a broth macrodilution procedure. MICs, in micrograms per milliliter, were as follows: terbinafine, 0.015 to 1.0 (geometric mean, 0.1188); itraconazole, 0.007 to 0.5 (geometric mean, 0.03165). The usual therapy for paracoccidioidomycosis is sulfonamides, amphotericin B, and azole derivatives (ketoconazole, itraconazole, and fluconazole). In comparison to amphotericin B, azole derivatives allow shorter treatment courses, can be administered orally, and are equally effective. Itraconazole has as high efficacy as ketoconazole, but with superior tolerance. It is the current drug of choice for treatment of paracoccidioidomycosis. The data obtained in this study indicate that terbinafine is active against P. brasiliensis in vitro and suggest that this allylamine can be considered a new option as drug therapy for paracoccidioidomycosis.Paracoccidioidomycosis, caused by the dimorphic fungus Paracoccidioides brasiliensis, is a systemic human mycosis geographically confined to Latin America (1,25,28). In vitro tests of the susceptibility of P. brasiliensis to antimycotic drugs have been scarce, and the results have not always been consistent; the discrepancies are attributed to the diversity of techniques employed in such studies (7,8,10,11,22,28).Organisms belonging to the kingdom Fungi share eukaryotic characteristics with their human host cells, implying similarities in biochemistry and physiology that limit therapeutics. Therefore, when systemic administration of drugs is required for deep human mycoses, few compounds are sufficiently selective (12). Compounds currently used in the control of infection caused by P. brasiliensis include amphotericin B, trimethoprimsulfamethoxazole, and azole derivatives (26). Unfortunately, amphotericin B has been associated with substantial toxicity, while trimethoprim-sulfamethoxazole has been associated with relapses. Thus, in many clinical situations, the azole derivatives present the best therapeutic option for control of paracoccidioidomycosis (17, 18).Owing to the fact that itraconazole, among the azoles, permits shorter treatment courses and has been shown to be more effective, we decided to compare this drug with the antifungal agent terbinafine, which operates by interfering with the ergosterol biosynthetic pathway and has shown MICs similar to those of itraconazole for filamentous fungi in in vitro studies (10,15). Thus, we aim to determine whether terbinafine might have a role in the management of infections caused by P. brasiliensis. MATERIALS AND METHODSFungal strains and culture conditions. Thirty-one isolates of the P. brasiliensis yeast form, including clinical, environmental, and animal isolates, were examined in this study. Samples consisted of 28 strains isolated from humans, 1 from penguin feces, 1 from dog food, and 1 from an armadillo....

In Vitro Susceptibilities of Isolates of Sporothrix schenckii to Itraconazole and Terbinafine

“…On the other hand terbinafine by virtue of its excellent in vitro and in vivo activity is under comparative evaluation for its therapeutic potential for a wide range of fungal infections (4,6,8,11,21,22).…”

Influence of Different Media, Incubation Times, and Temperatures for Determining the MICs of Seven Antifungal Agents against Paracoccidioides brasiliensis by Microdilution

“…A number of authors have proposed different incubation times ranging from 72 h to 8 days (15)(16)(17)(18)(19) or starting the MIC reading after the growth of the positive control (22) to test P. brasiliensis. There are indications that the exponential growth of P. brasiliensis occurs at between 5 and 7 days of incubation in complete medium (1,2).…”

“…Because large cell aggregates were common, the suspensions were allowed to settle for 3 to 5 min. Subsequently, the supernatants were collected, and their densities were adjusted by spectrophotometry at 530 nm to a transmittance of 70% (17,22). The inoculum sizes ranged from 1 ϫ 10 6 to 5 ϫ 10 6 cells/ml.…”

“…Each isolate was tested with amphotericin B, itraconazole, ketoconazole, fluconazole, sulfamethoxazole, a combination of sulfamethoxazole-trimethoprim, and terbinafine and by following modified versions of the NCCLS susceptibility testing guidelines for yeast fungi (document M27-A2 [8]) and procedures described by Hahn et al (15,17). The following conditions were evaluated: (i) three medium formulations, including RPMI 1640 medium (standard medium), McVeigh and Morton (MVM) medium (30), and modified Mueller-Hinton (MMH) medium (30); (ii) two incubation temperatures, room temperature (25 to 28°C) and 37°C; and (iii) three incubation periods, 7, 10, and 15 days.…”

“…These studies have generally used modified versions of the NCCLS M27-A2 protocols or a Shadomy modified protocol (10). These modifications include differences in inoculum preparation, media used in MIC assays, incubation periods, and experimental temperatures (5,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). However, standardization of the methods used for in vitro susceptibility testing is important to facilitate the establishment of interpretative breakpoints and quality control parameters.…”