Twenty-Five Years of New Horizons in Treating Fungal Lower Extremity Conditions

For more than two decades, podiatrists have witnessed dramatic shifts in how fungal nail and skin infections are managed. Treatment strategies have steadily advanced and continue to evolve. This retrospective looks back at the breakthroughs in treating fungal lower extremity conditions as part of our year-long celebration of this milestone anniversary of Podiatry Today with HMP Global.

Q: In or around the year 2000, what options existed for treating conditions like onychomycosis and tinea pedis? 

William P. Scherer, DPM, MS, recalls the 1995 approval of itraconazole (Sporanox) by the Food and Drug Administration (FDA) as an “exciting time for podiatry.” As he notes, itraconazole was the first new oral antifungal medication to be approved since griseofulvin’s release in the 1950s, calling itraconazole “significantly more effective.” 

“Podiatrists could finally offer a safe and effective solution to improve, or even cure toenail fungus, though many were concerned about potential liver toxicity and the high cost of the medication,” says Dr. Scherer.

In addition to Sporanox and ciclopirox (Penlac), Tracey Vlahovic, DPM, FFPM RCPS (Glasg), also recalls the emergence of terbinafine (Lamisil) around the same time. She recalls Novartis’s “Digger the Dermatophyte” commercials being “incredibly effective” as a marketing campaign for terbinafine. As Dr. Vlahovic remembers, “Patients would come in and say, ‘I don’t want that ugly guy from the commercials under my toe!’”

After the 1996 FDA approval of terbinafine, Dr. Scherer notes podiatrists had 2 evidence-based oral medications. He recalls that seemingly every week at that time Janssen Pharmaceutica or Novartis hosted educational meetings or sponsored seminars to inform podiatrists about the new oral antifungal medications. 

Q: Where are we today with treatment options for these conditions, and what patient impact have you seen as a result?

As Dr. Scherer says, terbinafine ultimately won the battle against itraconazole for market share in treating onychomycosis, becoming the standard oral therapy due to its superior efficacy, safety profile, and cost-effectiveness.¹ He notes that while itraconazole remained a valuable option—particularly for cases involving broader fungal coverage such as saprophytic molds or Candida infections, or for patients who could not tolerate terbinafine—it gradually became a second-line therapy. The cost of a full 12-week course of terbinafine was $547 in 1999 and had dropped to $10 by 2015, which he notes made terbinafine significantly more affordable than itraconazole.² 

“This dramatic price reduction made oral antifungal therapy accessible to a broader range of patients,” says Dr. Scherer. “Many who had previously been unable to afford expensive brand-name treatments were thrilled to finally have the opportunity to try an effective oral medication for their fungal nail infections.”

Dr. Scherer says the 2014 FDA approvals of efinaconazole 10% solution (Jublia, Ortho Dermatologics) and tavaborole 5% solution (Kerydin) for onychomycosis were “another exciting advancement in podiatric care.” He notes those new topicals were a “significant improvement” over older topicals, citing better nail penetration and proven clinical results. 

Dr. Vlahovic, a Professor at Samuel Merritt University College of Podiatric Medicine, notes the newer topical medications “eliminated the messiness of the lacquer, and have much improved penetration into the nail plate.” In addition, Dr. Vlahovic, Senior Vice President of Podiatric Education for Sagis Diagnostics, cites the penetration of tavaborole and efinaconazole through nail polish and their approval for use in children 6 and above. Tavaborole and efinaconazole solutions were designed with patient convenience and cosmetic acceptability in mind, she says. “Both are alcohol-based solutions that penetrate the nail plate effectively and dry quickly, leaving no visible residue which is an advantage over earlier topical agents. This allows patients to maintain normal cosmetic practices, including the use of nail polish, without significantly impairing drug delivery, a feature that can improve adherence and quality of life during long treatment courses.” 

A recent study showed efinaconazole penetration with the use of gel nail cosmetics,³ shared Dr. Vlahovic. “Patients with polypharmacy concerns welcome the use of a topical agent. However, compared to systemic agents, these topicals require daily application for up to 48 weeks, and therapeutic outcomes can still be influenced by the extent of nail involvement, degree of onycholysis, and patient adherence. While their safety profile and compatibility with cosmetic practices make them attractive options, clinicians must balance these benefits with realistic counseling about the time commitment. No matter which agent is used, oral or topical, the nail takes 52 weeks to grow out from proximal to distal, so patients need a “tincture of patience” when it comes to any of these nail innovations.”  

Although the cure rates of efinaconazole and tavaborole were lower than oral medications⁴ Dr. Scherer add that patients welcomed the topicals as they wanted to avoid potential systemic side effects or liver toxicity. This was especially true, in his experience, for older patients and those with diabetes, who he observed were often hesitant to take oral antifungals, but were frustrated with the limited efficacy of prior topicals. 

Patient hesitancy to undertake treatment with oral antifungals may have also resulted from misinformation leading to bias from patients. Dr. Vlahovic points out that although the literature shows that hepatotoxicity is rare, it also supports the vital importance of evidence-based and accurate patient education efforts on the topic.^5-7

Q: What do you think the future holds in this subject matter?

Antifungal resistance and antifungal stewardship will increasingly shape the treatment of onychomycosis, according to Dr. Scherer, a Senior Podiatric Medical Advisor to Bako Diagnostics who practices in Florida.

Historically, he notes although terbinafine has demonstrated high cure rates and low resistance, since the mid-2010s, he has observed increased reports of terbinafine-resistant dermatophytes—particularly in India, where the widespread misuse of the antifungal–steroid combination creams has driven resistance rates as high as 30–40% of the population.^8,9 As Dr. Scherer explains, terbinafine resistance occurs when there are mutations in the SQLE gene, which encodes the squalene epoxidase enzyme in dermatophytes. The mutations alter the enzyme’s structure, which reduces terbinafine binding and rendering the topical ineffective, and he notes as a result, the nail fungus can survive despite appropriate oral treatment. 

Dr. Scherer says that polymerase chain reaction (PCR) molecular testing is available to detect SQLE mutations in toenail samples, noting this can help podiatrists make more informed treatment decisions. Dr. Scherer is concerned “about a possible future in which a significant percentage of the U.S. population may harbor terbinafine-resistant infections and require the development of newer and more effective antifungal medications.”

Dr. Scherer emphasizes that antifungal stewardship prioritizes accurate disease diagnosis through laboratory analysis, appropriate selection of antifungal agents, and appropriate dosing and treatment duration. In conditions such as onychomycosis or tinea pedis, he notes antifungal stewardship includes confirming fungal infection with laboratory diagnostic testing before initiating therapy, which he says can help avoid empiric or prolonged treatment without clear indications. Tests include the periodic acid-Schiff stain (PAS), Grocott’s methenamine silver stain (GMS), fluorescent microscopy (FM), and PCR (including testing for terbinafine resistance). He adds that antifungal stewardship also involves educating patients about adherence and discouraging the misuse of over-the-counter antifungal-steroid combinations. 

“By adopting antifungal stewardship, podiatrists can help preserve the long-term effectiveness of available treatments and reduce the growing threat of antifungal resistance,” says Dr. Scherer. 

Dr. Vlahovic points to several products and therapies in the pipeline for onychomycosis. If approved by the FDA, these products will “expand options and potentially be an exciting addendum to the therapies we currently have,” she notes. n

1. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004 Mar;150(3):537-44. doi: 10.1046/j.1365-2133.2003.05728.x. PMID: 15030339.

2. Mikailov A, Cohen J, Joyce C, Mostaghimi A. Cost-effectiveness of confirmatory testing before treatment of onychomycosis. JAMA Dermatol. 2016;152(3):276–281. doi:10.1001/jamadermatol.2015.4190 

3. Pandit B, Elewski B, Vlahovic TC. Concealing meets healing in the treatment of toenail onychomycosis: A review of concurrent nail polish use with topical efinaconazole 10% solution. J Clin Aesthet Dermatol. 2024;17(9):38-42. 

4. Frazier WT, Santiago-Delgado ZM, Stupka KC 2nd. Onychomycosis: rapid evidence review. Am Fam Physician. 2021;104(4):359-367. 

5. Sun CW, Hsu S. Terbinafine: Safety profile and monitoring in treatment of dermatophyte infections. Dermatol Ther. 2019;32:e13111.

6. Kramer ON, Albrecht J. Clinical presentation of terbinafine-induced severe liver injury and the value of laboratory monitoring: a critically appraised topic. Br J Dermatol. 2017;177:1279-1284.

7. Ishack S, Miller RC, Lipner SR. Insights into the “fear factor” regarding terbinafine-associated hepatotoxicity in an assessment of online information. J Am Acad Dermatol. 2022;86(6):E269-E271.

8. Cañete-Gibas CF, Mele J, Patterson HP, et al. Terbinafine-resistant dermatophytes and the presence of Trichophyton indotineae in North America. J Clin Microbiol. 2023;61(8):e0056223. doi:10.1128/jcm.00562-23

9. Ebert A, Monod M, Salamin K, et al. Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study. Mycoses. 2020;63(7):717-728. doi:10.1111/myc.13091