Checkerboard Analysis To Evaluate Synergistic Combinations of Existing Antifungal Drugs and Propylene Glycol Monocaprylate in Isolates from Recalcitrant Tinea Corporis and Cruris Patients Harboring Squalene Epoxidase Gene Mutation

Abstract

Introduction: Recalcitrant dermatophytic infections of the glabrous skin (tinea corporis/cruris/faciei) pose a huge challenge to healthcare systems. Combinations of oral and topical drugs may potentially improve cure rates but the same has never been objectively assessed for this condition in laboratory or clinical studies.The presentstudy was undertaken with an aim of identifying synergistic combinations of oral and topical antifungals by testing clinical isolates obtained from patients with recalcitrant tinea corporis/cruris. Materials and Methods: Forty two patients with tinea corporis/cruris who had failed oral antifungals or had relapsed within 4 weeks of apparent clinical cure were recruited. Twenty one isolates were identified on sequencing (all T.mentagrophytes/interdigitale species complex ) andwere subjected to antifungal susceptibility testing (AFST) andsqualene epoxidase (SQLE) gene mutation analysis. Finally, five isolates – four with underlying SQLE gene mutations, and one wild type strain, were chosen for checkerboard studies using various combinations of antifungal agents. Results: Most isolates (n=16) showed high MICs to TRB (0.5->16μg/ml), with SQLE gene mutations present in all isolates with MICs ≥0.5μg/ml. Synergistic interactions were seen with combinations of itraconazole with luliconazole, TRB and ketoconazole, PGMC with luliconazole and with the triple combination of Propylene glycol Monocaprylate (PGMC) with luliconazole and ketoconazole. Conclusions: In vitro synergistic interactions provide a sound scientific basis for possible clinical use of antifungal combinations. Hence, these synergistic combinations may be tested for clinical utility in the wake of rising resistance among dermatophytic infections of the glabrous skin.

The emergence and worldwide spread of the species Trichophyton indotineae causing difficult-to-treat dermatophytosis: A new challenge in the management of dermatophytosis

“…Thus, appropriate dosage of TRB in treatment of dermatophytosis could prevent the usage of azole drugs and development of resistance against azole-based antifungal drugs. Recently, in vitro synergistic interactions with varying combinations of ITC, TRB, ketoconazole, and luliconazole (LUZ) have been observed in TRB-resistant Indian strains [ 43 , 44 ]. However, effectiveness of TRB and ITC in combination for treatment of tinea infections in a recent randomised trial showed no added beneficial effect over treatment with ITC alone [ 45 ].…”

Predicting a therapeutic cut‐off serum level of itraconazole in recalcitrant tinea corporis and cruris—A prospective trial

“…However, these guidelines have not taken into consideration the in vitro antifungal susceptibility data and therapeutic serum levels and have led clinicians into empirically prescribing high doses of ITZ for superficial dermatophytosis without conforming to the basic tenets and science of pharmacology that dictate prescription of ITZ 16 . In addition, there is a rising trend of prescribing irrational combinations of antifungals in an attempt to counter the often unsatisfactory clinical responses with ITZ, without regard to in vitro synergy data, thus further subjecting patients to drug toxicity 17,18 …”

“…16 In addition, there is a rising trend of prescribing irrational combinations of antifungals in an attempt to counter the often unsatisfactory clinical responses with ITZ, without regard to in vitro synergy data, thus further subjecting patients to drug toxicity. 17,18 Therapeutic drug monitoring (TDM) has been widely utilised for prophylactic and therapeutic use of ITZ in systemic mycoses.…”

Synthetic Cinnamides and Cinnamates: Antimicrobial Activity, Mechanism of Action, and In Silico Study

“…When tested alone, the compound presented an MIC of 626.62 µM and nystatin presented an MIC of 8.0 µM. When tested in combination, compound 6 presented an MIC of 313.31 µM and nystatin presented an MIC of 3.2 µM, thus demonstrating an additive effect (0.5 < FIC ≤ 1); see Table 5 [ 79 ].…”