The in vitro activity of tavaborole, an FDA-approved antifungal drug, was compared to that of four antifungal agents against 170 clinical fungal isolates originating from patients with onychomycosis. Tavaborole had low activity against all isolates compared to itraconazole, terbinafine, and fluconazole, the principal choices for treatment of onychomycosis.
KEYWORDS: tavaborole, antifungal, onychomycosis
ABSTRACT
The in vitro activity of tavaborole, an FDA-approved antifungal drug, was compared to that of four antifungal agents against 170 clinical fungal isolates originating from patients with onychomycosis. Tavaborole had low activity against all isolates compared to itraconazole, terbinafine, and fluconazole, the principal choices for treatment of onychomycosis. Thus, it appears that tavaborole is not a candidate for the treatment of onychomycosis due to Candida species, Aspergillus species, and dermatophytes.
TEXT
Fungal nail infections are common and recurrent problems caused predominantly by different species of dermatophytes, Candida, and filamentous fungi. The distribution pattern has been reported to be variable in different geographic regions (1–3). Whereas most reports indicate that Trichophyton rubrum and Trichophyton interdigitale are the most common agents of onychomycosis, several fungal genera, such as Candida, Aspergillus, Fusarium, Scopulariopsis, Acremonium, Onychocola, and Penicillium, have been isolated from nail samples (4–9). Estimates of the prevalence rate of onychomycosis in the different communities range from 0.5% to 30% (6, 10, 11). It may affect patients with advanced age, distorted nails, hyperhidrosis, diabetes, psoriasis, peripheral vascular disease, genetic predisposition, and immunosuppression (8, 9). Currently, the preferred treatments for onychomycosis include itraconazole, terbinafine, and fluconazole combined with topical nail formulations, such as luliconazole 1% (12, 13), efinaconazole 10% (14), amorolfine 5%, and ciclopirox 8% (15). Despite the introduction of new generations of antimycotics, as well as laser and photodynamic therapy, achievement of complete cure is challenging (16, 17). Tavaborole (5%), a boronic acid quinolone compound, received FDA approval in 2014 for use in the topical treatment of onychomycosis (17). This drug has a unique mechanism of inhibition among antifungals, targeting the leucyl-tRNA synthetase enzyme and thus preventing protein synthesis (18, 19). Tavaborole, due to its small molecular weight, demonstrated appropriate safety with excellent nail penetration through keratin layers (20). Previous limited studies using a few strains showed that tavaborole had in vitro activity against Trichophyton, Candida, Aspergillus, and Fusarium (21, 22), although no antifungal susceptibility data of tavaborole against a large collection of clinical fungi from onychomycosis cases have been published. Therefore, we used a panel of isolates of different species of dermatophytes, molds, and yeasts from patients with onychomycosis to evaluate the in vitro activity of this novel drug and four comparator agents, i.e., voriconazole, itraconazole, fluconazole, and terbinafine.
A total of 170 clinical nail isolates were included in this study. Fifty-one yeasts, consisting of Candida parapsilosis (n = 27), Candida tropicalis (n = 10), Candida albicans (n = 7), Candida krusei (n = 4), Candida orthopsilosis (n = 2), Candida guilliermondii (n = 1), and Candida glabrata (n = 1); as well as 88 molds, including Aspergillus flavus (n = 36), Aspergillus terreus (n = 21), Aspergillus niger (n = 17), Aspergillus tubingensis (n = 8), Fusarium proliferatum (n = 8), Trichophyton interdigitale (n = 8), Trichophyton rubrum (n = 5), Aspergillus oryzae (n = 3), Aspergillus fumigatus (n = 2), Fusarium solani (n = 2), Fusarium verticillioides (n = 2), Fusarium sp. (n = 2), Aspergillus uvarum (n = 1), and Trichophyton tonsurans (n = 1), were recovered from patients suffering from fingernail (n = 70) and toenail (n = 100) infections. Isolates were cultured on Sabouraud dextrose agar (Difco) supplemented with chloramphenicol for 2 to 7 days at 30°C and identified to the species level by PCR restriction fragment length polymorphism and DNA sequencing as previously described (23–25, 33–36). In vitro antifungal susceptibility testing for filamentous fungi and yeast were performed according to Clinical and Laboratory Standards Institute (CLSI) documents M38-A2 and M27-A3, respectively (26, 27). Concentration ranges used were 0.016 to 16 µg/ml for tavaborole (Sigma-Aldrich, Germany), itraconazole (Janssen Research Foundation, Beerse, Belgium), and voriconazole (Pfizer, Central Research, Sandwich, United Kingdom); 0.004 to 4 µg/ml for terbinafine (Novartis Research Institute, Vienna, Austria); and 0.063 to 64 µg/ml for fluconazole (Pfizer). The maximal final concentration of dimethyl sulfoxide in the test wells was <1%. Trays were stored at −80°C until the day of testing. Briefly, conidial suspensions of filamentous fungi were obtained by scraping the mature colonies on potato dextrose agar (Difco) with a moistened swab. The turbidity was measured spectrophotometrically at a wavelength of 530 nm. Transmission was adjusted to 65% to 70% for dermatophytes, 80% to 82% for Aspergillus spp., and 69% to 70% for Fusarium isolates. To obtain the final inoculum, suspensions were diluted 1:50 in RPMI 1640 medium. Microdilution plates were incubated at 35°C for 48 h for Aspergillus and Fusarium, but trays were incubated at 35°C for 96 h for Trichophyton. MIC endpoints were defined as the lowest concentration that caused complete inhibition of growth. In contrast, yeast suspensions were adjusted spectrophotometrically at a wavelength of 530 nm to a transmission in the 75% to 77% range and diluted in RPMI 1640 medium to yield final inocula of 0.5 to 5 × 103 cells/ml. The microdilution trays were incubated at 35°C for 24 h. The MIC values were determined visually and were defined as the lowest concentration of drug that caused ≥50% growth inhibition for all drugs. C. krusei (ATCC 6258) and Paecilomyces variotii (ATCC 3630) were used as quality controls. All tests were performed in duplicate, and differences of the mean values were determined by Student’s t test with the statistical SPSS package (version 7.0). P values of <0.05 were considered statistically significant.
Table 1 summarizes the in vitro susceptibility pattern of 170 clinical nail isolates as the MIC range, MIC mode, MIC50, and, when appropriate, the MIC90 for the five tested antifungal drugs. Tavaborole demonstrated consistently very high MIC values against all filamentous fungi and yeast isolates, compared to those of the other antifungal drugs. Tavaborole showed high MICs for most of the Candida isolates (MIC50 and MIC90, 16 µg/ml), whereas the MIC90s of voriconazole, itraconazole, and terbinafine were lowest for this genus, at 0.25, 4, and 4 µg/ml, respectively (Table 1). Unlike the study by Mao et al. (22), which reported MICs ranging from 0.5 to 1 µg/ml for Candida spp. and 0.125 to 4 µg/ml for the other yeasts, this study showed lower activity, with MIC ranges of 2 to 16 µg/ml. For Aspergillus strains, all antifungal agents except fluconazole demonstrated better activity than tavaborole. As presented in Table 1, MIC50 values of fluconazole and tavaborole were 64 and 2 µg/ml, respectively, whereas all Aspergillus strains showed MIC50 values of ≤1 µg/ml for the remaining drugs. The MICs for tavaborole against all dermatophyte isolates ranged from 4 to 16 µg/ml, compared to 0.016 to >16 µg/ml for voriconazole, 0.016 to >16 µg/ml for itraconazole, 2 to 32 µg/ml for fluconazole, and 0.004 to >4 µg/ml for terbinafine. Overall, MIC50 and MIC90 values of tavaborole (8 and 16 µg/ml) had low activities compared to those of itraconazole (both 0.0625 µg/ml) and terbinafine (0.004 and 0.008 µg/ml) used for treatment of onychomycosis due to dermatophytes. Remarkably, Fusarium sp. demonstrated extremely high MICs to tavaborole (8 to >16 µg/ml); however, the lowest MIC ranges were found with terbinafine (0.032 to >4 µg/ml). Tavaborole MIC50 and MIC90 values of all isolates were 4 and 16 µg/ml, respectively, whereas those of the other agents were, respectively, 0.125 and 1 µg/ml for voriconazole, 0.25 and 2 µg/ml for itraconazole, 4 and 64 µg/ml for fluconazole, and 2 and 4 µg/ml for terbinafine. Furthermore, MIC90 values of tavaborole against all isolates were 2 and 3 log2 dilutions higher than terbinafine and itraconazole, respectively. Tavaborole inhibited only 14.7% (n = 25) of all isolates at a concentration of ≤1 μg/ml, whereas itraconazole and terbinafine inhibited 78.82% (n = 134) and 40% (n = 69) of isolates with this MIC value, respectively. Mao et al. (22) examined tavaborole MIC values (0.5 µg/ml) for only 1 isolate of A. fumigatus. Among 88 Aspergillus strains in the current study, just 5 isolates, including 2 A. flavus, 2 A. niger, and 1 A. uvarum, were inhibited at an MIC of 0.5 µg/ml, and 28.4% (n = 25) of all isolates were inhibited at ≤1 μg/ml of tavaborole (Tables 1 and 2).
TABLE 1.
In vitro susceptibilities of five antifungal drugs against different fungal isolates from patients with onychomycosisa
| Genus | Species (no. of isolates) | MIC parameter | MIC (µg/ml) for: |
||||
|---|---|---|---|---|---|---|---|
| Tavaborole | Voriconazole | Itraconazole | Fluconazole | Terbinafine | |||
| Candida | C. parapsilosis (27) | Range | 2 to >16 | 0.008 to >16 | 0.125 to >16 | 0.0625 to >64 | 4 to >4 |
| MIC50 | 16 | 0.016 | 1 | 0.5 | 4 | ||
| MIC90 | 16 | 0.25 | 2 | 8 | 4 | ||
| GM | 14.49 | 0.06 | 2.46 | 1.71 | 4 | ||
| C. tropicalis (10) | Range | 8 to >16 | 0.0625 to >0.5 | 1 to >8 | 0.25 to >64 | 4 to >4 | |
| MIC50 | 16 | 0.032 | 2 | 2 | 4 | ||
| MIC90 | 16 | 0.25 | 4 | 16 | 4 | ||
| GM | 14.49 | 0.06 | 2.46 | 1.71 | 4 | ||
| C. albicans (7) | Range | 4 to >16 | 0.008 to >0.016 | 0.25 to 16 | 0.125 to >4 | 4 to >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| C. krusei (4) | Range | 8 to 16 | 0.0625 to 0.016 | 0.5 to 1 | 0.5 to 16 | 4 to >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| C. orthopsilosis (2) | Range | 16 | 0.016 | 1 | 0.25 to 1 | 4 to >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| C. guilliermondii (1) | Range | 16 | 0.125 | 4 | 4 | >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| C. glabrata (1) | Range | 16 | 0.125 | 4 | 2 | >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| All Candida strains (52) | Range | 2 to >16 | 0.008 to >16 | 0.125 to >16 | 0.0625 to >16 | 4 to >4 | |
| MIC50 | 16 | 0.032 | 1 | 1 | 4 | ||
| MIC90 | 16 | 0.25 | 4 | 8 | 4 | ||
| GM | 12.58 | 0.03 | 0.77 | 0.74 | 4 | ||
| Aspergillus | A. flavus (36) | Range | 0.5 to 16 | 0.0625 to 0.5 | 0.0625 to 1 | 16 to >64 | 0.032 to 8 |
| MIC50 | 2 | 0.25 | 0.125 | 64 | 0.5 | ||
| MIC90 | 4 | 0.5 | 0.25 | 64 | 4 | ||
| GM | 1.8 | 0.21 | 0.13 | 45.25 | 0.59 | ||
| A. terreus (21) | Range | 1 to 4 | 0.125 to 1 | 0.0625 to 0.25 | 64 | 0.032 to 8 | |
| MIC50 | 2 | 0.25 | 0.016 | 64 | 4 | ||
| MIC90 | 4 | 1 | 0.125 | 64 | 8 | ||
| GM | 2.4 | 0.33 | 0.03 | 64 | 1.8 | ||
| A. niger (17) | Range | 0.5 to 16 | 0.0625 to 2 | 0.0625 to >16 | 32 to >64 | 0.125 to 8 | |
| MIC50 | 1 | 0.25 | 0.032 | 32 | 0.5 | ||
| MIC90 | 16 | 0.5 | 1 | 64 | 4 | ||
| GM | 1.92 | 0.25 | 0.2 | 42.25 | 0.81 | ||
| A. tubingensis (8) | Range | 1 to 8 | 0.125 to 1 | 0.25 to 1 | 64 | 0.25 to 8 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| A. oryzae (3) | Range | 1 to 8 | 0.0625 to 0.125 | 0.032 to 0.125 | 32 to 64 | 0.0625 to 1 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| A. fumigatus (2) | Range | 2 to 16 | 0.0625 to 0.25 | 0.0625 to 0.5 | 64 to >64 | 4 to >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| A. uvarum (1) | Range | 0.5 | 0.125 | 0.016 | >64 | 4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| All Aspergillus strains (88) | Range | 0.5 to 16 | 0.0625 to 2 | 0.016 to >16 | 0.5 to >64 | 0.032 to >4 | |
| MIC50 | 2 | 0.25 | 0.125 | 64 | 1 | ||
| MIC90 | 4 | 0.5 | 0.5 | 64 | 4 | ||
| GM | 2 | 0.24 | 0.1 | 50.79 | 0.92 | ||
| Dermatophytes | T. interdigitale (8) | Range | 4 to 16 | 0.016 to 0.0625 | 0.0625 to 0.125 | 16 to 32 | 0.008 to 4 |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| T. rubrum (5) | Range | 8 to 16 | 0.016 to >16 | 0.016 to >16 | 2 to 16 | 0.008 to >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| T. tonsurans (1) | Range | 8 | 0.032 | 0.032 | 16 | 0.004 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| All dermatophyte strains (14) | Range | 4 to 16 | 0.016 to >16 | 0.016 to >16 | 2 to 32 | 0.004 to >4 | |
| MIC50 | 8 | 0.032 | 0.0625 | 16 | 0.004 | ||
| MIC90 | 16 | 0.032 | 0.0625 | 32 | 0.008 | ||
| GM | 9.28 | 0.02 | 0.03 | 10.24 | 0.007 | ||
| Fusarium | F. proliferatum (8) | Range | 16 to >16 | 1 to 4 | >16 | 64 to >64 | >4 |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| F. verticillioides (2) | Range | 8-16 | 1->16 | 8->16 | >64 | 0.032- >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| F. solani (2) | Range | 16 to >16 | 0.5 to 2 | >16 | >64 | >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| Fusarium sp. (2) | Range | 16 | 2 | >16 | >64 | >4 | |
| MIC50 | ND | ND | ND | ND | ND | ||
| MIC90 | ND | ND | ND | ND | ND | ||
| GM | ND | ND | ND | ND | ND | ||
| All Fusarium strains (14) | Range | 8 to >16 | 0.5 to >16 | 8 to >16 | 64 to >64 | 0.032 to >4 | |
| MIC50 | 16 | 2 | 8 | 64 | 4 | ||
| MIC90 | 16 | 4 | 8 | 64 | 4 | ||
| GM | 14.67 | 2 | 8 | 64 | 4 | ||
aGM, geometric mean; MIC50, concentration at which 50% of the isolates were inhibited; MIC90, concentration at which 90% of the isolates were inhibited; ND, not determined.
TABLE 2.
In vitro susceptibilities of 5 antifungal drugs against 170 fungal isolates from different patients with onychomycosisb
| Antifungal drug | MIC (µg/ml)a |
MIC range | MIC50 | MIC90 | GM | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.004 | 0.008 | 0.016 | 0.031 | 0.063 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >64 | |||||
| Tavaborole | 5 | 20 | 45 | 18 | 19 | 63 | 0.5 to 16 | 4 | 16 | 4.44 | |||||||||
| Voriconazole | 4 | 27 | 14 | 16 | 30 | 30 | 25 | 8 | 9 | 4 | 3 | 0.008 to >16 | 0.125 | 1 | 0.13 | ||||
| Itraconazole | 19 | 10 | 18 | 23 | 20 | 20 | 24 | 7 | 8 | 2 | 19 | 0.016 to >16 | 0.25 | 2 | 0.2 | ||||
| Fluconazole | 1 | 7 | 5 | 11 | 7 | 10 | 5 | 2 | 12 | 8 | 102 | 0.0625 to >64 | 4 | 64 | 3.67 | ||||
| Terbinafine | 10 | 9 | 3 | 1 | 12 | 10 | 13 | 11 | 11 | 89 | 1 | 0.004 to >4 | 2 | 4 | 0.74 | ||||
Numbers in boldface are modal values.
GM, geometric mean; MIC50, concentration at which 50% of the isolates were inhibited; MIC90, concentration at which 90% of the isolates were inhibited.
Tavaborole, in contrast to other recently FDA-approved topical antifungal agents for onychomycosis, including efinaconazole (28) and luliconazole (29), demonstrated lower activity against Aspergillus spp. Luliconazole showed excellent activity against susceptible and resistant A. fumigatus isolates, with MIC ranges of <0.001 to 0.016 µg/ml (30). Also, Siu et al. (14) found that efinaconazole had geometric mean MICs of 0.089 µg/ml for A. fumigatus and 0.11 µg/ml for A. flavus from onychomycosis.
MICs of tavaborole for dermatophyte isolates were similar to those reported by Mao et al. (22) but different from the those in the FDA study. MIC ranges in our study were 4 to 16 µg/ml, Mao et al. (22) reported MICs of 1 to 8 µg/ml, and the FDA evaluation demonstrated MIC ranges of 0.5 to 2 µg/ml. Based on the MIC90 value (16 µg/ml), tavaborole showed low activity, which was not comparable to the MIC90 of terbinafine (0.008 µg/ml) and itraconazole with (0.0625 µg/ml). Almost all dermatophyte isolates (92%) were inhibited at ≥8 μg/ml of tavaborole, except for a single isolate with an MIC of 4 μg/ml (Table 1). Finally, tavaborole MICs of Fusarium isolates in this study (8 to 16 µg/ml) were higher than those found in other reports (<0.5 µg/ml) (22). With the exception of a single isolate of F. verticillioides which had an MIC of 8 µg/ml, all had MICs of 16 µg/ml (Table 1). These results concur with previously published data on azoles versus Fusarium sp., with MICs of ≥8 for itraconazole (31, 32). In conclusion, we found that the in vitro antifungal activity of tavaborole against a panel of different agents of onychomycosis is inferior to those of terbinafine and azoles, except for fluconazole.
ACKNOWLEDGMENTS
The work of M.A. was supported by Mazandaran University of Medical Sciences, Sari, Iran (grant no. 2812), which we gratefully acknowledge. J.F.M. received grants from Astellas, Basilea, and Merck. He has been a consultant to Astellas, Basilea, Scynexis, and Merck and received speaker’s fees from Merck, United Medical, TEVA, and Gilead Sciences.
We have no other conflicts of interest to declare.
We alone are responsible for the content and writing of the paper.
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