Topical Antifungal Agents



Topical Antifungal Agents: Introduction




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Topical Antifungal Agents at a Glance





  • Preferred treatment for superficial fungal infection of limited extent.
  • Low cost, low incidence of drug interactions, few side effects and complications, ease of use.
  • Use systemic agent when superficial fungal infection affects large surface area, involves terminal hair or nails, or is resistant to topical management.
  • Topical antifungal classes: imidazoles, allylamines, benzylamines, polyenes.
  • Ciclopirox olamine: unique topical antifungal with broad-spectrum activity, variety of indications.
  • Side effects: irritant dermatitis, allergic contact dermatitis, urticarial reactions.
  • Combination agents (antifungal and steroid): watch for side effects due to glucocorticoids.
  • Combination agents: higher rate of treatment failure, disease relapse.





Superficial fungal infections, including dermatophytoses, candidiasis, and pityriasis versicolor, are most often restricted to the epidermis. In treating these infections, the clinician must select between topical or systemic management. Factors guiding management include, but are not limited to, the:







  • extent and severity of the infection,
  • site of involvement,
  • comorbid conditions or potential drug interactions, if any,
  • anticipated efficacy of treatment,
  • cost and access to medication, and
  • ease of use.






Patients with limited fungal infections confined to glabrous skin are usually best treated with topical agents. Conversely, those with extensive or recalcitrant disease, or with involvement of terminal hair or nails, may be better suited for systemic management. In some cases, either treatment option may be reasonably chosen.






Treatment with topical antifungal therapy enjoys several advantages over systemic management, including:







  • fewer side effects,
  • fewer drug interactions,
  • localization of treatment, and
  • generally lower cost.






Numerous topical antifungal medications are available (Table 219-1). For the most part, specific antifungal agents have replaced nonspecific topical treatments, such as keratolytics (salicylic acid) or antiseptics (gentian violet or Castellani paint), which were once the cornerstones of management.







Table 219-1 Topical Antifungal Agents Commonly Used in Dermatology 






The “ideal” topical antifungal is easily defined (Table 219-2), and is in sum, efficacious, inexpensive, well tolerated, and has low resistance within targeted fungi. Despite widespread availability, few topical antifungal agents have been directly compared with one another in clinical trials. Studies sponsored by the manufacturer often compare just the active agent to the vehicle. Extrapolation between studies is further complicated due to differences in study design, duration of therapy, site of infection, selection methodology, or treatment endpoint.







Table 219-2 Properties of an Ideal Topical Antifungal Agent 






Most topical antifungals belong to one of three classes: (1) imidazoles, (2) allylamines and benzylamines, and (3) polyenes. Agents that do not fit well into this schema are discussed separately.






Imidazoles





Imidazoles represent a broad class of antifungal medications. Certain of these, such as clotrimazole, have been around for decades, while others, such as sertaconazole, have only become available recently.






Mechanism of Action



Imidazoles impede synthesis of a component of the fungal cell wall through inhibition of lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme, which converts lanosterol to ergosterol.1 Depletion of ergosterol results in membrane instability and hyperpermeability; changes incompatible with growth and survival of the fungus. Imidazoles are considered fungistatic in practical application, with the possible exception of sertaconazole when used to treat some Candida species.2 While all imidazoles possess the same mechanism of action, in-vitro studies demonstrate that not all dermatophytes are uniformly susceptible to an imidazole at an equivalent concentration, and this may explain some treatment failures.35



Topical imidazoles possess anti-inflammatory activity via inhibition of neutrophil chemotaxis, calmodulin activity, synthesis of leukotrienes and prostaglandins, and histamine release from mast cells.68 Some agents, such as ketoconazole, yield anti-inflammatory effects equivalent to 1% hydrocortisone.9 Topical imidazoles also demonstrate limited antibacterial properties, particularly with respect to Gram-positive organisms.10,11






Pharmacokinetics



All marketed imidazoles demonstrate excellent penetration of the stratum corneum with strong keratinophilic behavior. Sulconazole may be detected in the stratum corneum up to 96 hours after application.12 Similarly, sertaconazole, the newest of all marketed imidazoles, has a half-life within the stratum corneum of more than 60 hours.13 Because of this high affinity for keratin, systemic absorption of imidazoles is low, with urinary excretion usually in the range of 0.3%–1.0% of the applied dose. Even when applied to inflamed skin, absorption of imidazoles does not usually exceed 4% of the applied dose. Again, sulconazole is unique in that percutaneous absorption in the range of 8%–11% of the applied dose exceeds that of all other imidazoles.12






Indications



Indications for topical imidazole use are detailed in Table 219-3. Because of inherent antibacterial activity, some topical imidazoles have demonstrated modest efficacy in treating erythrasma, impetigo, and ecthyma. Because there are more potent antibacterial agents, this is not a preferred indication for imidazole use.9,14,15




Table 219-3 Indications for the Use of Topical Imidazoles 



Cure rates for superficial fungal infection treated with imidazoles are variable and often depend upon study design. For example, topical miconazole has demonstrated a 63%–100% cure rate, depending upon the study quoted. A thorough review of the literature provides no compelling evidence that significant differences in cure or relapse exist among the various topical imidazoles; however, other considerations may dictate selection of a particular imidazole.



Topical imidazoles are available as a cream or lotion. Although lotions are better suited for use over large areas or upon hair-bearing skin, limited studies suggest a cream may be marginally more effective. In studies performed by the manufacturer, oxiconazole cream yielded a clinical and mycologic cure in 52% of tinea pedis cases while the lotion yielded the same cure in just 41% of cases. Additionally, the potential for irritancy must be considered. In one study of topical clotrimazole for treatment of tinea cruris, erosive reactions developed in 4 of 27 patients while sulconazole did not cause any erosions in the same population.16 Similarly, in a second study, severe irritant reactions were reported with miconazole use but not with sulconazole use.17 Until formal studies of irritancy are performed, we often recommend use of sulconazole in sensitive areas such as the groin. Finally, ease of use may be a factor to consider, as some imidazoles are specifically approved for once-daily dosing (see Section “Dosing Regimen”).






Dosing Regimen



Topical imidazoles are available in a multitude of forms (see Table 219-1). Econazole, ketoconazole, and oxiconazole are approved for once-daily dosing but twice-daily dosing is recommended for the remainder. Nevertheless, although twice-daily dosing is recommended for sulconazole, a study comparing once-daily to twice-daily dosing in tinea corporis and tinea cruris reported an identical rate of cure.16 This might have been predicted based upon the 60-hour half-life within the stratum corneum.13 Application of all topical antifungals, including imidazoles, should include normal skin for a radius of 2 cm beyond the affected area. Duration of treatment with imidazoles has varied. In general, tinea corporis and tinea cruris require treatment for approximately 2 weeks, whereas tinea pedis may require treatment for up to 4 weeks.18 Treatment should be continued for at least 1 week after all symptoms have abated.19






Risks and Precautions



Risks associated with the use of topical imidazoles include those inherent to all topical medications (Table 219-4), and consist chiefly of irritant and allergic reactions. Additionally, clotrimazole is marketed in combination with the topical glucocorticoid, betamethasone dipropionate. It was assumed that the addition of the steroid would more rapidly relieve inflammation, scaling, and pruritus. Early studies demonstrated the combination was indeed more effective than clotrimazole alone in alleviating symptoms.20,21 However, betamethasone dipropionate is a potent topical steroid, and striae and other cutaneous side effects from the steroid component may occur.22 Longer term studies also reported a higher relapse rate (36%) with the combination product.23,24




Table 219-4 Adverse Reactions to Topical Antifungals 



This combination product may comprise 50% or more of antifungal prescriptions by primary care providers, compared to less than 7% among dermatologists.25 It is likely that overuse by nonspecialists occurs because of the mistaken assumption either that the steroid agent is mild, or that the combination will be a “better choice” when the differential diagnosis is unresolved.26 The US Food and Drug Administration has twice revised the product warnings for clotrimazole-betamethasone dipropionate, discouraging use on thin skin, for prolonged periods, or when the diagnosis is in doubt.






Complications



Use of topical imidazoles is associated with few complications. Because of low systemic absorption, drug reactions with topical imidazoles are rare. Nevertheless, in a single study, increased serum tacrolimus levels were observed in renal transplant recipients who used clotrimazole troches for mucocutaneous candidiasis.27 For this reason, use of nystatin may be preferred when treating thrush in transplant patients using tacrolimus.



Concerns of resistance must also be considered. Resistance of Candida albicans to clotrimazole has been described in human immunodeficiency virus-positive patients with mucocutaneous candidiasis.28 Low levels of in-vitro resistance of various Candida species to other topical imidazoles has also been documented.29 Often, this resistance is associated with resistance to oral fluconazole.






Allylamines and Benzylamines





Allylamines and benzylamines are closely related compounds. Currently, two topical allylamines and single topical benzylamine are marketed in the United States (see Table 219-1).






Mechanism of Action



Allylamines and benzylamines share impede synthesis of ergosterol through inhibition of squalene epoxidase, an enzyme that converts squalene to squalene oxide.30 Depletion of ergosterol results in membrane instability and hyperpermeability. Allylamines and benzylamines are considered fungicidal because the accumulation of intracellular squalene leads directly to cell death. The clinical significance of this cidal action is unclear. Unlike imidazoles, the activity of allylamines and benzylamines is independent of the cytochrome P450 enzyme system. When compared to naftifine, terbinafine demonstrates a 10–100-fold increased potency in vitro, although this does not appear to be relevant in clinical use.



Like imidazoles, allylamines, and benzylamines demonstrate anti-inflammatory activity.6,31Naftifine inhibits adhesion of polymorphonuclear cells to endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase proinflammatory pathway.32,33 It is assumed that terbinafine and butenafine yield anti-inflammatory effects through similar mechanisms. Allylamines and benzylamines also demonstrate limited antibacterial properties. A recent study showed lowered minimum inhibitory concentrations for both bacteria and fungi when terbinafine was used in combination with benzoyl peroxide.34






Pharmacokinetics



Allylamines and benzylamines are highly lipid soluble and efficiently penetrate the stratum corneum, where they may persist for extended durations.35Butenafine has been detected within the stratum corneum at minimum inhibitory concentration for at least 72 hours after application,36 and terbinafine may persist at a similar level for up to 7 days after application.37 Systemic absorption of these agents is quite low, with typical urinary excretion in the range of 3%–5% of the applied dose.37






Indications



Indications for the use of topical allylamines and topical benzylamines are detailed in Table 219-5. Despite antibacterial properties, terbinafine has proven inferior to mupirocin for treatment of impetigo,38 and a traditional antibacterial agent should be used. Similarly, although allylamines and benzylamines do demonstrate activity against fungi involved in systemic infection, such as Sporothrix schenckii, Blastomyces dermatitidis, and Histoplasmosis capsulatum, topical therapy is inappropriate.




Table 219-5 Indications for the Use of Topical Allylamines and Benzylamines 



Limited evidence suggests that topical allylamines or benzylamines may be preferred over topical imidazoles for certain dermatophyte infections. Some trials for tinea pedis indicate that 1 week of topical terbinafine is as effective as 4 weeks of topical imidazoles, with cure resulting in 53%–95% of cases.3942 Use of this abbreviated treatment with terbinafine has been confirmed in trials using the active agent versus vehicle alone.43 In some instances, resolution of tinea pedis using terbinafine has occurred with as few as three doses.44



Generic terbinafine 1% cream is more expensive than an equivalent amount of clotrimazole 1%,45 but considering the frequency of application, the amount of medication required, the likelihood of patient compliance and ease of use, and the rapidity of results, some experts recommend topical terbinafine over topical imidazoles for tinea pedis.4648






Dosing Regimen



Topical allylamines and benzylamines are available in a number of forms (see Table 219-1). Each agent has a slightly different dosing regimen based upon the formulation and the location and severity of infection (Table 219-6).


Jun 11, 2016 | Posted by in Dermatology | Comments Off on Topical Antifungal Agents
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