Antifungal combination therapy in dermatophytosis: a clinical insight

We read with interest the manuscript proposed by Sardana et al, titled “Scientific Rationale of Antifungal Drug Combination, including oral itraconazole and terbinafine, in Recalcitrant Dermatophytoses. ” It would be a pleasure to respond to the comments and concerns put forth by the author of the above manuscript. The author states that there seems to be false portrayal of low cure rates with the two frontline drugs, itraconazole and terbinafine in our study. However, it is to be noted that the studies cited in the proposed manuscript reporting significant clearance of dermatophytosis with one to two weeks therapy belong to a decade ago (1,2). There has been an undisputable and dramatic shift in the epidemiological, clinical as well as therapeutic behavior of dermatophytic fungi over the past few years (3,4). The upsurge in frequent clinical failures with the conventional antifungal dosage and duration (one to two weeks of treatment) has bewildered the dermatologists all across the country (3,5). This is in accordance with our study, documenting high clinical failures at three weeks of monotherapy with either drugs (6). The recent study by Majid et al has also observed the decreasing efficacy of terbinafine as well as higher relapse with standard (two weeks) terbinafine therapy in dermatophytosis (7). Similarly, monotherapy of itraconazole in its conventional dosage and duration seems to be failing in the management of these infections (8). The study represents a pilot study evaluating the efficacy and safety profile of monotherapy as well as the combination therapy; hence small sample size was recruited considering the potential additive hepatotoxicity of the drugs. However, undoubtedly, there is dire need of further studies with larger sample size to aid and corroborate these results. As stated in the methodology, same brand of drugs were given to all the patients in each group to rule out inter-brand variability, hence eliminating the concern of bias in final clinical outcome as questioned by the author (6). The antifungal susceptibility testing was not done in our study therefore the time kill studies and pharmacodynamics of drugs could not be evaluated which has been quoted as one of the limitations of the study. However, it is to be noted the conclusion drawn from our study is primarily clinical and antifungal resistance was not the primary focus of the study. Neither has antifungal resistance been implicated as the reason for high failure rates noted in case of monotherapy in our study. Besides, a poor correlation has been observed widely between the MIC values and the clinical response to antifungal drugs, further questioning its clinical implications, especially in resource limited settings (9). In the face of emergence of recalcitrant dermatophytosis, individualized and experience based treatment approach is more in vogue. In an attempt to confront this, many guidelines and treatment approaches have been suggested by various authors; combination of oral antifungals has been proposed as one of the therapeutic strategies, especially in recalcitrant cases of dermatophytosis (10). In vitro synergistic effect of terbinafine and itraconazole has been demonstrated against various nondermatophytic fungi which may be attributed to inhibition of two different sequential enzymes by terbinafine and itraconazole in the pathway of ergosterol biosynthesis (11,12). The superior efficacy of combination therapy noted in our study could be because of similar effect against dermatophytosis, although further in vitro checkerboard studies against dermatophytosis are indeed needed to confirm this hypothesis. The multi-drug therapy including the drugs of different formulations has been an archaic and accepted trend in various infectious diseases e.g. anti-tubercular therapy (ATT) or WHOMDT wherein various drugs of different formulations i.e. capsule and tablet forms are taken together under respective national control programs. Hence, the clinical practicality of tablet terbinafine affecting the absorption of capsule itraconazole is still ambiguous. Further, author states in the manuscript that itraconazole in the dose of 100mg BD/OD for 4–6weeks gives an adequate clinical respond in such infections. The similar clinical response was observed in our study where almost half of the partial responders at 3weeks of itraconazole therapy showed complete resolution with continued treatment for 6weeks. However, it should be emphasized that prolonged monotherapy up to 6weeks or in some cases even more is required to achieve complete resolution of such infections in the current scenario. It is noteworthy that better clinical cure rate was obtained with 3weeks of itraconazole and terbinafine combination therapy in our study suggesting the superiority of this combination over monotherapy which may limit the duration of therapy without significant adverse effects. However, it is to be noted that the use of combination therapy has not been promoted or suggested as a first line therapy for dermatophytosis, but may be considered, especially in cases of recalcitrant dermatophytosis.