Evidence-based optimal fluconazole dosing regimen for onychomycosis treatment

Although fungi do not cause outbreaks or pandemics, the incidence of severe systemic fungal infections has increased significantly, mainly because of the explosive growth in the number of patients with compromised immune system. Thus, drug resistance in pathogenic fungi, including dermatophytes, is gaining importance. The molecular aspects involved in the resistance of dermatophytes to marketed antifungals and other cytotoxic drugs, such as modifications of target enzymes, over-expression of genes encoding ATP-binding cassette (ABC) transporters and stress-response-related proteins are reviewed. Emphasis is placed on the mechanisms used by dermatophytes to overcome the inhibitory action of terbinafine and survival in the host environment. The relevance of identifying new molecular targets, of expanding the understanding about the molecular mechanisms of resistance and of using this information to design new drugs or to modify those that have become ineffective is also discussed.

These guidelines for management of onychomycosis have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.

The past few years have seen a rapid increase in the introduction of drugs with intermittent dosing schedules (ie, dosed less than once daily). Many of these agents were developed on the assumption that less-frequent dosing would be more convenient for patients and thus contribute to improved adherence, with the potential for improvements in the effectiveness of pharmacotherapy and a reduction in the costs of non-adherence. However, the effect on adherence of intermittent dosing regimens has not been studied. This study investigated the evidence to date concerning the effect on adherence of intermittently dosed agents. Articles from peer-reviewed journals were identified through a search of MEDLINE and International Pharmaceutical Abstracts from 2000 to 2005. The search terms included combinations of intermittent dosing, adherence, compliance, dosing schedule, and dosing regimen. The search focused on articles that reported head-to-head comparisons of older agents having more frequent dosing schedules with newer intermittently dosed agents. Few head-to-head trials were identified that met the inclusion criteria, as most comparative trials of intermittent and daily agents focused on efficacy rather than adherence. Thus, studies of patient preference for the 2 types of agents were included, as preference may have implications for adherence. Eleven trials met the expanded criteria. Overall, adherence was greater with intermittently dosed agents than with more frequently dosed agents for the same conditions; adherence was 8.8% to 12.0% higher for weekly agents than for agents that were dosed once daily. In the single trial of a once-monthly agent, adherence was similar to that with the daily agent over 1 year (87.4% and 86.6%, respectively). In the studies of patient preference, 61% to 96% of patients preferred the intermittently dosed agent. In this preliminary review of the available data, once-weekly dosing was associated with improved patient adherence to therapy compared with once-daily dosing. In the only study of a once-monthly agent, adherence was similar to that with the once-daily agent.