In Vitro Activities of Nine Antifungal Drugs and Their Combinations against Phialophora verrucosa

Abstract

The in vitro activities of nine antifungal drugs and their combinations against 31 clinical and 15 environmental Phialophora verrucosa strains were tested. The MIC 90 /90% minimum effective concentration (MIC/MEC 90 ) values (g/ml) across all strains were as follows: for terbinafine, 0.25; for posaconazole, 0.5; for voriconazole, 1; for itraconazole, 2; for amphotericin B, 4; for caspofungin and micafungin, 16; and for fluconazole and flucytosine, 64. The highest synergy was shown by the combination of itraconazole plus caspofungin (with synergy against 100% of the 31 clinical strains), followed by amphotericin B plus flucytosine (45.2%) and itraconazole plus terbinafine or micafungin (25.8% or 12.9%, respectively). Phialophora verrucosa is one of the major dematiaceous fungi causing intractable chromoblastomycosis, phaeohyphomycosis, and other infections such as mycetoma and endophthalmitis (1-3). With the chronic repetitious nature of the infections, traditional drugs and physical therapies cannot deal with the relapse, resistance, and incomplete cures of chromoblastomycosis and phaeohyphomycosis (1). Currently, clinical P. verrucosa infection cases and antifungal therapies, including drug combination therapies, have been reported (2, 4-10), but effective therapies are still limited. Previous studies have indicated that terbinafine combined with itraconazole, amphotericin B, or voriconazole showed synergy against dematiaceous molds such as Fonsecaea pedrosoi and Exophiala jeanselmei (11); amphotericin B combined with terbinafine also showed synergy for six P. verrucosa isolates (12). Our group had also explored the susceptibilities of three drugs against only 20 P. verrucosa isolates, including 1 clinical isolate, and no synergy or antagonism was observed when terbinafine was combined with itraconazole or amphotericin B (13). At present, there is limited information available on common antifungals and effective combinations against numerous clinical P. verrucosa isolates. This study aimed to investigate the in vitro susceptibilities of clinical and some environmental strains of P. verrucosa to nine antifungal drugs (fluconazole, flucytosine, amphotericin B, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, and terbinafine) and the potential synergy and antagonism of these drugs when combined in pairs.Forty-six P. verrucosa strains were obtained from the Research Center for Medical Mycology at Peking University, comprising 31 clinical isolates originating from patients with chromoblastomycosis (n ϭ 11), phaeohyphomycosis (n ϭ 19), and subcutaneous cysts (n ϭ 1) and 15 isolates originating from environments in northern China (n ϭ 8), southern China (n ϭ 3), and the garden of a patient's house (n ϭ 4) (see Table S1 in the supplemental material). Antifungals alone or in combination were tested against clinical strains. Environmental strains were used only in the single antifungal susceptibility test. All strains were identified by morphological methods and sequencing of the conserved ribosomal int...

Molecular identification and antifungal susceptibility profiles of clinical strains of Fonsecaea spp. isolated from patients with chromoblastomycosis in Rio de Janeiro, Brazil

“…The synergism found for 100% of the isolates of Phialophora verrucosa by Li et al . [ 18 ] encouraged the use of ITC and CAS combination in our study. A single study [ 65 ] found synergism for isolates of F .…”

“…Other drugs used include posaconazole (POS), voriconazole (VRC), amphotericin B (AMB) and flucytosine (5FC) [ 10 , 16 , 17 ]. In addition, combined therapies of ITC with TRB [ 10 , 18 ], 5FC with AMB [ 17 ], or ITC with 5FC have been used [ 19 ].…”

Intrastromal antifungal injection as a successful modality of treatment for fungal keratitis: a case series

“…18 Recently Li Y et al, concluded that the newer triazoles such as voriconazole had low MICs for Phialophora but that amphotericin B and fluconazole had relatively high MICs/MECs in vitro. 19 Therefore, in case-5 with Phialophora keratitis in post penetrating keratoplasty eye when exhibited resistance to amphotericin B authors attempted intrastromal voriconazole injection. This is mainly because patient opted for non-surgical intervention and refused for another penetrating keratoplasy.…”

Effectiveness of voriconazole and corneal cross-linking on Phialophora verrucosa keratitis: a case report

“…Although an in vitro study reported the efficacy of nine antifungal drugs and their combinations against P. verrucosa [ 14 ], this evidence is still limited in vivo . Wilson et al [ 2 ] showed resistance of P. verrucosa to amphotericin B, while Polack et al .…”