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Abstract
Dermatophytosis has acquired an epidemic-like proportion, fuelling a wide gamut of irrational, unethical and unscientific prescriptions. The menace can be attributed to poorly regulated legislative laws controlling the approval of molecules, unscientific marketing gimmicks by the pharmaceutical industry, over-the-counter availability of drugs and lack of awareness and knowledge among the prescribing physicians. In this review, we have attempted to enlist the irrational and unethical prescription patterns for dermatophytosis.
Keywords: Dermatophytosis, irrational, prescriptions, unethical, unscientific
Introduction 
Superficial dermatophytosis affects 20-25% of the world population and is a common infective dermatosis in clinical practice.[1] According to recent studies, there has been an increase in the incidence of dermatophytosis across the country in the past decade, especially over the past 5–6 years.[2],[3] The major reasons for the epidemic-like situation in the country possibly include the advent of a novel species,[4] increasing urbanisation, working in a hot and humid environment, lower socioeconomic status and topical steroid abuse[5] While a recent paper has highlighted mutations to both azoles and allylamines with clinical failure,[6] this may be possibly due to irrational prescriptions.
Topical therapeutic options for dermatophytosis of the glabrous skin include topical azoles like ketoconazole, clotrimazole, luliconazole, econazole, sulconazole, sertaconazole and eberconazole; topical allylamines like terbinafine, naftifine; ciclopirox olamine etc., while systemic options include fluconazole, ketoconazole, itraconazole, griseofulvin and terbinafine.[7]
Red flags are warning signs indicating a controlled substance prescription is not being obtained for legitimate medical purposes but rather for diversion or abuse. A red flag could be indicative of abuse or misuse, over or under-compliance, drug–drug interactions, or a forged or altered prescription. Red flag prescriptions pose a danger of the development of resistance,[8] bear an unnecessary financial burden on patients and can invite unwanted drug interactions. It is the pharmacist's as well as a clinician's job to evaluate and interpret the seriousness of these warning signs.[9]
The DEA lists the following indicators of improper prescriptions[10]
The prescriber writes significantly more prescriptions (or larger quantities) compared to other practitioners in the area.The patient is returning too frequently for refills.The prescriber writes prescriptions for antagonistic drugs, such as depressants and stimulants, at the same time. Drug abusers often request prescriptions for “uppers and downers.”The patient presents prescriptions written for other people.Multiple patients appear simultaneously or within a short time, all presenting similar prescriptions from the same physician.People who are not regular patrons or residents of the community present prescriptions from the same physician.A compilation of irrational and unscientific therapeutic strategies for dermatophytosis is as under:
Topical amphotericin B
A literature search did not reveal any clinical study on the use of amphotericin B (AMB) in vivo in dermatophytosis. However, a handful of studies have been published documenting the in vitro susceptibility testing of dermatophytes to AMB.[11] The clinical applicability of these data should be judged rationally, as in vitro susceptibility may not always translate into in vivo efficacy. In vitro data should be interpreted with caution as in dermatophytosis, a multitude of factors related to the host (immune response, underlying illness, site of infection), the infecting organism (virulence), and the antifungal agent (dose, pharmacokinetics, pharmacodynamics, drug interactions) may be more important than susceptibility test results in determining clinical outcomes for infected patients. In vitro susceptibility of an organism to an antifungal agent does not consistently predict a successful therapeutic outcome.[12] We therefore believe, that AMB should be restricted for use in invasive systemic mycoses, and unnecessary prescriptions would contribute towards development of resistance, in near future. Amphotericin B-loaded nanoliposomes have been proposed to be a potent antifungal for the topical treatment of onychomycosis, alongside an expectation that there is a minimal probability to induce drug resistance in dermatophyte species.[13] But, this does not support the use of amphotericin gel in dermatophytosis.
Combination of two or more topical antifungals
A combination of drugs always adds to the financial burden of the patients and is also considered unscientific.[14] Certain exceptional circumstances like pregnancy and the presence of comorbidities require the use of a combination of topical antifungals. Apart from this, we suggest that physicians should refrain from resorting to such practices.
Itraconazole 200 mg and 400 mg capsules
The efficacy of capsules of 200 mg and 400 mg strength is not studied and hence unproven. Itraconazole 100 mg pellet-capsule is thought to be the optimal size, allowing easy swallowing. With the same pellet size and technology, the sizes of 200 mg and 400 mg capsules would be expected to be much larger, hence affecting compliance. A change in the pellet size by altering the drug-polymer ratio or removing the PEG20000 layer leads to unstable formulations and adversely influences the bioavailability of itraconazole.[15] Capsules of 200 mg are thought to be unstable, and the molecule has an increased propensity to undergo agglutination and gel formation.[16],[17],[18] Thus, the rampant prescription of 200mg and 400mg capsules is absolutely unscientific and should not be encouraged at all.
It is relevant to point out that the optimal pellet number that can effectively achieve the requisite serum levels has been defined with 100 mg itraconazole,[19] and it is the lack of knowledge of basic concepts of physics that has led the industry to launch 200 and 400 mg capsules which have the same number of pellets as the original 100 mg, with the added issue of variations in size which makes their absorption in the gastric transit time less, thus obviating the perceived logic of a higher strength capsule.[20]
Combination of systemic antifungals
The basic objective behind the treatment of dermatophytosis is to ensure the effectiveness and safety of the drugs, avoid the development of resistance and increase patient's compliance. Optimal use of combination therapy is based on the susceptibility of dermatophytes to the antifungals, concentration of the drugs achieved at the site of infection over a 24-hour dosing interval, mechanism of action of the drugs, dosimetry that is predictive to get a clinical and mycological cure, toxicity of the drugs and the likelihood of the combination to create drug resistance.[21] Combining any two drugs is unacceptable, without considering the rationale and consequences.
Since different species of dermatophytes are predominant in different regions, and antifungal susceptibility is constantly changing over time, it is advisable to perform antifungal sensitivity testing (whenever feasible). The authors propose that efficacy testing should be done by in vitro checkerboard analysis.[22]
Another important factor that needs to be kept in mind is the concentration of drugs achieved at the site of infection over a 24-hour dosing interval. The level should be measured at the site of infection, which is determined by the skin pharmacokinetics of the drugs; that is, the route of delivery of the drugs to the epidermis. Thus, terbinafine and itraconazole are mostly delivered via sebum, not via sweat.[23]
The pharmacodynamics and mechanism of action of the drugs being considered for combining is also important. The concentration of the two drugs in combination competing for albumin binding may be unpredictable. Cytochrome P-450 inhibition or induction may occur, or the two drugs may not be synergistic. Moreover, a combination can aggravate the hepatic toxicity of most antifungal drugs (i.e., azoles and allylamines). Therefore, combining two drugs without a proper rationale is not prudent. A study evaluated the effectiveness of the combination of oral terbinafine and itraconazole in dermatophytosis,[24] but there were quite a few prominent limitations and confounders in it including small (20) sample size in each group, lack of antifungal susceptibility test/checkerboard analysis and, most importantly, a very short treatment duration of 3 weeks only for the treatment of recalcitrant infections.[25]
One open-labelled randomised controlled trial showed itraconazole to be more effective than terbinafine with no benefit in up-dosing or a combination of two drugs.[26],[27] However, certain synergistic combinations between existing antifungals and propylene glycol monocaprylate have been derived by the checkerboard analysis in patients with recalcitrant tinea corporis and cruris, with existing squalene epoxidase gene mutations.[22]
The existent data shows that the combinations of drugs especially oral, should be dictated by multiple steps, including MIC, MFC, animal model studies, and in vitro checkerboard data, followed by an in vivo study. There is no rationale for combining two or more oral antifungals for dermatophytes with low MIC to ITZ in the present epidemic.[28]
Isotretinoin for recalcitrant dermatophytosis
There have been isolated reports of the use of isotretinoin in recalcitrant dermatophytosis.[29],[30] However, since terbinafine and itraconazole are primarily lipophilic and isotretinoin reduces sebum production, the concomitant therapy appears antagonistic. The potential for cumulative liver toxicity is also higher. Hence, this combination should be discouraged.[31]
Salicylic acid peeling in dermatophytosis
Salicylic acid peel was purported to be a cheap and effective option for dermatophytosis in a study comprising 25 patients.[32] However, recurrences were common, thereby contemplating the need for a duration of treatment longer than 4 weeks. Treatment with salicylic acid peel is somewhat analogous to patients' self-medication of tinea with a well-known proprietary formulation of dithranol (salicylic acid 1.15% w/w + dithranol 1.15% w/w + coal tar 5.3% w/w). Salicylic acid 30% is considered to be a superficial chemical peeling agent, which does not penetrate the skin beyond the stratum corneum (or granulosum at the most). Spores of dermatophytes are known to reside within the hair follicles, including the vellus hair, which is responsible for non-response to conventional therapy. Chemical peeling has the potential to further irritate the infected inflamed skin and hence cannot be considered a therapeutic option for tinea corporis.[33]
A basic knowledge of skin PK shows that it is the repository effect of oral antifungal drugs in the stratum corneum that determines the longevity of response.[34] It is counter-intuitive to use a peeling agent to remove the antifungal drug from its site of action, and thus, peels of any sort are a needless adjunct in dermatophytosis.
Antifungal soaps and powders, luliconazole shampoo
Antifungal soaps lack scientific logic and add to the financial burden on the patient. The expected contact time and ultimate concentration of these preparations do not help achieve adequate levels in the stratum corneum; hence, sub-therapeutic levels promote the development of resistance. Plain dusting powders may be helpful in intertriginous infections.[14]
Oral voriconazole for dermatophytosis
Voriconazole is considered to be a rescue drug for invasive fungal functions including mucormycosis. A recent study concluded that the drug can be used to treat recurrent and resistant dermatophytosis with a good efficacy and safety profile and a very low recurrence rate.[35] However, the study had many drawbacks which need to be looked into. Authors did not attempt to acquire AFST data, even though a study from India found that miconazole, luliconazole and amorolfine had a lower minimum inhibitory concentration (MIC) than voriconazole, which in turn was comparable to itraconazole. Notably, the administration of topical agents was not stopped in the study. Moreover, the authors did not provide any definition of 'cure'.[36] The authors used a higher dose of the drug than those prescribed in invasive mycoses. At the 6-week follow-up, 10 of the 40 patients did not have 'clearance', giving a prominently high failure rate of 25%, and notably, 15 of the 40 patients were not seen in the clinic for follow-up.
Conclusion Dermatophytosis has emerged as a public health problem, which is difficult to manage and this is on account of the mirrored misconception of resistance to all oral antifungal drugs, which is a misconceived notion as in vitro data does not show increased MIC to ITZ. The failure of ITZ is possibly due to the erratic quality of ITZ, which is true for the pellet-based capsules, which do not have adequate pellet numbers of the requisite quality.[20] This has led to a spate of self-devised irrational prescriptions. Antifungal stewardship is the need of the hour,[37] with a special focus on antifungal susceptibility testing, followed by validated synergistic antifungal drug combinations preceded by in vitro checkerboard testing, in vivo animal model validation, and clinical trials. This, with appropriate counselling for ensuring adherence to therapy and well-designed randomised controlled trials, would help to re-discover the utility of existent drugs without resorting to illogical prescriptions.[38]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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