Polyenes
Azoles
Allylamines
Β-Glucan synthase inhibitors (echinocandins)
Pyrimidine analogues
Mitotic inhibitors
Aminoacyl-tRNA synthetase inhibitors
Others
Allylamines, terbinafine and naftifine, appeared in the 1990s and amorolfine years later. Echinocandins, as anidulafungin, caspofungin, and micafungin, were initially used around 1980.
Some have fungistatic, fungicide, or mixed action. Many of them are broad-spectrum drugs that can be used in superficial and/or systemic fungal infections. However, although the list of antimycotics is long and continues to grow, the development of new antifungal agents is rather slow if compared to the development of new antibiotics, despite the growing number of systemic mycosis. The main reason is the similitudes shared by human and fungal cells which are eukaryotes and thus can be more toxic to humans in a parallel manner. They also cause drug interactions and hepatic or renal toxicity more frequently than antibiotics. For this reason, the major developments on new systemic drugs are almost exclusively reserved for systemic life-threatening mycoses [3].
So, even if onychomycosis is the most common nail disease and it’s prevalence increases with age and with the growing immunosuppressed population, the development of novel drugs required for its cure is not focused on being systemic but rather a topical and extremely effective option that, to this moment, we are lacking. Despite adequate treatment, more than 20 % of the onychomycosis that receive oral treatment don’t resolve, even when combined with an adjuvant topical option [4, 5].
Diffusion Treatments
Onychomycosis is cosmopolite and affects around 8 % of the population with its prevalence and causal agents more or less similar worldwide.
Commonly dermatophytes are responsible for the infection, but yeasts and non-dermatophyte molds (NDM) can be isolated. The incidence increases with age and is associated to other diseases such as peripheral vascular insufficiency, diabetes, and any other form of immunosuppression [6].
The prevalence in patients older than 60 years of age is 20 % but dramatically increases to 50 % 10 years later. This can be added to the risk in diabetic patients that is 1.9–2.8 times higher when compared to nondiabetics. In HIV-positive patients, the prevalence ranges from 15 to 40 % [7].
All therapeutic options, systemic or topical, new or old, still pose the disadvantage of prolonged administration. To this moment the standard treatment is oral terbinafine or itraconazole with cure rates of 76 % for the former and 63 % for the latter, and fluconazole has a cure rate of only 48 % [7, 8].
These three antifungals present very similar results among adults and children [9]. However, as the elderly are the most affected age group, drug interactions and liver toxicity frequently discourage systemic administration of antimycotics, so topical agents are preferred. Despite these innovations, there still is the need for a superior option because the cure rate is still very poor [10, 11].
A study analyzed the cases of initially negative KOH results for onychomycosis and concluded that up to 94 % of the tests reported as negative, after more thorough examinations turned out to be positive, so the authors conclude that the systemic antifungal treatment should be indicated on a clinical diagnosis. We personally disagree, because these depend on two important factors which are the experience and skills of the person performing the KOH mount and the clinical ability for onychomycosis diagnosis of the physician [12]. We must also consider what Feuilhade de Chauvin mentions that the fungal species need to be identified for the correct antifungal election, as yeasts and NDM can also cause onychomycosis, despite the fact that dermatophytes are the most common etiological agents [13].
The American Academy of Dermatology reinforced the recommendation for confirmatory testing of onychomycosis before initiating systemic treatment with the intention to reduce unnecessary side effects and economic burden; although they also recognize that overall confirmatory testing is more expensive than treating all suspected cases and that the potentially harmful side effects secondary to oral treatment (usually terbinafine or itraconazole) are extremely infrequent [14].
So, if we are on a clinical setting, we will most commonly seek confirmatory testing, but if our aim is optimization of resources, we most likely won’t solicit them and both options are ethically supported.
Treatment
Systemic
About the first line of oral treatment for onychomycosis, there is no news. Terbinafine and itraconazole are still the ones we must choose from, the former considered the gold standard [15–18].
However, what may be an improvement is the sequential therapy, which is the combination of two oral antifungals that act in different pathways of ergosterol metabolism, with the intention to reduce duration of treatment. For this, patients are given two pulses of itraconazole and, afterward, one or two of terbinafine [19–21].
Fluconazole is a hydro and keratinophilic azole with actions similar to those of itraconazole, dependent on the CYP450 system is used as weekly dosage treatment for onychomycosis during 6–9 months, and is not FDA approved for this purpose [22] but sometimes selected by its covenient posology and broad spectrum.
As Candida sp. and non-dermatophyte molds (NDM) can also cause onychomycosis, these fungi are frequently encountered as unresponsive to the first line of treatment. Voriconazole, an azole usually reserved for severe systemic fungal infections, has been successful in refractory NDM onychomycosis (Scytalidium dimidiatum). One report mentions excellent results in a patient with total onychodystrophy of a fingernail and tinea in both hands and feet. She was treated during 3 months monitoring the drug plasma levels [23–25].
Posaconazole has proven in vitro to have a potent antifungal activity against dermatophytes.
A phase 2 clinical trial of posaconazole in the treatment of onychomycosis receiving 100, 200, or 400 mg once a day during 24 weeks or 400 mg once a day for 12 weeks showed that the diffusion of the drug to the nail plate is similar to other antifungals such as itraconazole or terbinafine, and the levels in the nail plate remain high after treatment is stopped, which suggests that it accumulates in the nail matrix [17, 26].
Posaconazole weekly dosages during a month were indicated to an HIV-positive patient with proximal white onychomycosis caused by Fusarium falciforme and resistant to itraconazole and terbinafine. With this regimen, mycological and clinical cure was obtained and sustained for at least 16 months [27].
Albaconazole is a broad-spectrum antifungal drug with activity against dermatophytes and NDM in vitro and in animal models. It has been studied in phase I and II for superficial dermatophytosis. Phase III is still pending [28].
Pramiconazole is another systemic azole commercialized in the late 2000s. This drug is one of the few developed specifically for superficial mycosis such as tinea versicolor, corporis, pedis, cruris, and onychomycosis. Clinical trials, phases I and II, were successfully reported with similar or superior antifungal activity as ketoconazole and itraconazole. A good absorption and a long half-life, so much that a daily dosage was sufficient, have been reported. It has been proved growth reduction in Candida albicans, Malassezia globosa, Microsporum canis, Trichophyton mentagrophytes, and Trichophyton rubrum. However, after these promising results, the laboratory was sold to another pharmaceutical company and the studies were put on hold [29].
This antimycotic was then used as an oral treatment for seborrheic dermatitis and vulvovaginitis as a phase IIa trial with promising results for yeast infections. However, no further studies with oral therapy have been conducted regarding dermatophyte infections [30, 31]. In vitro studies found that pramiconazole has activity against dermatophytes and yeasts with application of this topical antifungal, comparable with the results obtained with oral administration of itraconazole, miconazole, and terbinafine [32].
Although this is not directly related to antifungal drugs, it has been documented that patients living with HIV and onychomycosis can improve or even cure after the initiation of the combined antiretroviral therapy. These results may be multifactorial and further studies need to be conducted; however, this kind of recovery is not seen in the setting of other diseases that condition immunosuppression under the required specific treatment [33].
Topical
Ciclopirox hydro-lacquer is based on water soluble biopolymer technology which is supposed to be an improvement with previous lacquers, and still studies are being performed with terbinafine nail solution [19].
Naftifine hydrochloride 1 % in gel has proven usefulness in treating fingernail onychomycosis, of the distal subungual variety, with reasonable results and few side effects [34].
Several studies have been recently published about topical efinaconazole in 10 % solution which has been in the market for a couple of years. This azole derivate has been studied for its efficacy, safety, and tolerability as treatment for mild to moderate onychomycosis with results superior to the vehicle which contains alcohol, lipophilic esters, and cyclomethicone. After 52 weeks of treatment 18.5 % of patients showed complete cure, compared to 4.7 % of the control group. Mycologic cure was registered in 56.3 % and complete or partial cure in 2.7 %, and another interesting data obtained is that the mean unaffected new nail growth was higher with efinaconazole when compared to patients that received only the vehicle [35, 36].
Efinaconazole has been tested for toxicity, which is positive during gestation of rats, but not of rabbits. Is not teratogenic either to rats or rabbits [37–39].
In conclusion of all the reports published about 10 % topical efinaconazole, authors agree that it is a safe and effective option, particularly for mild onychomycosis and that, like any other previously tried topical treatment, can work as adjuvant in patients that are receiving systemic therapy. And although by its administration route, no life-threatening adverse reactions are expected, contact dermatitis has been reported [40, 41].
Tavaborole topical solution 5 % is a new treatment option. It is a broad-spectrum antifungal from the benzoxaboroles group that has been tested in phase III trials for efficacy and safety of onychomycosis both in adult and geriatric patients [42, 43]. It has a low molecular weight compared to other topical antifungals, which may enhance nail plate penetration although it showed a low mycological cure rate of 30–36 % [44, 45].
Outlook: Future Developments
The nail unit inherently requires a thick and resistant structure in order to resist environmental and occupational hazards and must be taken into account for the new treatment options.
A downside to topical treatments is the extremely long time the drug needs to be applied (e.g., 12 months for toenails), so an alternative to improve topical medications is to enhance drug penetration through the nail plate. A study on nail plate permeation to topical antifungal drugs found that onychomycosis infection changes nail permeability, opening the nail pores, and, thus, facilitates the passage of hydrophilic molecules, while the hydrophobic molecules did not show any improvement. The authors suggest that the change induced by the nail infection should be used as an advantage, and a small molecular weight hydrophilic antifungal agent with low levels of keratin binding could be of benefit [46, 47].
Other strategies are being developed in order to improve topical drugs penetration. These techniques include iontophoresis, nail abrasion, microporation, laser nail ablation, and laser therapy, among others [19].
The drug ME1111 [2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol is being developed as a new drug against dermatophytes, but still is under study [10].
Ravuconazole is a broad-spectrum azole that so far has been tried only for systemic mycoses and Chagas disease [48].
Luliconazole is a topical azole that has undergone phase I and IIa trials and case studies as topical treatment for onychomycosis as 10 % solution which reached steady plasma levels of the drug. It has also been tested in vitro against Trichophyton rubrum and Trichophyton mentagrophytes. The authors reached the conclusion that this drug has potent fungicidal activity when compared to the other topical azoles and promises good results as a therapeutic option in the near future. It has shown to be more potent than lanoconazole among other antifungals [49–52].
Miltefosine, which is an alkyphospholipid used to treat leishmaniasis and cutaneous breast metastasis, has now been proved to have potent in vitro activity against biofilms of Fusarium oxysporum and Candida albicans. So, probably in the near future, more studies will be performed with this drug that promises good results as topical treatment for non-dermatophyte onychomycosis [53].
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