Treating Tinea Pedis In Patients With Diabetes

Patients with diabetes face a higher risk of tinea pedis, which can lead to complications, and research is scarce on the efficacy of medications in diabetic patients with the fungal condition. Accordingly, these authors provide a closer look at treatment and prevention strategies for tinea pedis, which often occurs in concert with onychomycosis.

   Tinea pedis is a contagious fungal infection that affects the feet of approximately 15 to 20 percent of the population, similar to onychomycosis.1-3 In comparison to otherwise healthy individuals, people with diabetes are at an increased risk of developing antifungal infection and are also more likely to face adverse complications including secondary bacterial infections, foot ulcers, paronychias, cellulitis, osteomyelitis, gangrene and lower limb amputation.4-8 Safe and effective treatment of tinea pedis is therefore imperative for people with diabetes.

   Tinea pedis commonly presents as red, itchy scales on the skin in between the toes and/or the soles of the feet. Often, but not always, tinea pedis presents alongside onychomycosis, causing the toenails to become thick, yellow and brittle. Since these conditions are contagious, without proper treatment, the infection may spread to both feet and all toenails.

   While tinea pedis can be uncomfortable and cosmetically displeasing, it is unlikely to cause any serious adverse complications in otherwise healthy individuals. For people with diabetes, however, the presence of this infection can lead to secondary bacterial infections, foot ulceration, paronychia, cellulitis, osteomyelitis, gangrene and possible lower limb amputation.4-8

   Tinea pedis may lead to foot ulceration through the development of skin fissures in the plantar and/or interdigital skin. Onychomycosis, on the other hand, may lead to foot ulceration as a result of a thick, sharp, brittle piece of nail piercing the skin or as a result of vascular compromise arising from increased subungual pressure due to enlarged nails. In both cases, injury creates a portal of entry for pathogens, which promotes the development of further complications.

   Unlike otherwise healthy individuals, people with diabetes are at an increased risk of developing these complications as they often present with some degree of peripheral neuropathy, retinopathy, obesity, elevated blood sugar levels and/or impaired immune function, which prevents them from recognizing, responding and recovering from injuries.9-12

   Accordingly, while people with diabetes are already at an increased risk of foot ulceration, infection and lower limb amputation, the presence of tinea pedis and/or onychomycosis may further increase their risk of developing such complications. Indeed, studies have shown that people with diabetes and onychomycosis have a significantly higher rate of foot ulceration, gangrene and a combination of foot ulcer and gangrene in comparison to people with diabetes but without onychomycosis.12,13

Key Treatment Considerations

In a Cochrane Review, Bell-Syer and colleagues sought to assess the effects and costs of oral treatment interventions for tinea pedis in otherwise healthy individuals.14 They found that terbinafine (Lamisil, Novartis) is more effective than griseofulvin (Grifulvin, Pedinol Pharmacal) therapy. They also noted no significant differences in efficacy between oral itraconazole (Sporanox, Janssen Pharmaceuticals) and oral terbinafine.

   Similarly, Crawford and Hollis reviewed the effects of topical treatment interventions for both tinea pedis and onychomycosis.15 They found that while the available evidence suggests that the most effective topical antifungal agent for treating tinea pedis is terbinafine, limited studies exist for topical antifungal treatment interventions for onychomycosis. Nevertheless, there is some evidence that daily application of ciclopirox olamine (Loprox, Medicis) and butenafine (Mentax, Mylan Bertek Pharmaceuticals) over a period of a year produces effective results.15

   Although studies in otherwise healthy individuals are useful, we cannot necessarily extrapolate the results of these studies to people with diabetes. People with diabetes tend to be more resistant to antifungal treatment regimens as a result of high blood glucose levels and an inability to maintain clean, dry feet (due to obesity and/or retinopathy), which fosters fungal growth.16 People with diabetes also tend to present with polypharmacy and many of these drugs have the potential to interact with antifungal medications.17 Therefore, prescribing requires careful consideration of such interactions.

   We often avoid using itraconazole in people with diabetes, especially in people who are taking oral hypoglycemic medications. Itraconazole belongs to the imidazole family of antifungal agents and metabolizes by the cytochrome P450 3A4 enzyme pathway.18 Since many medications also metabolize via this pathway, itraconazole has the potential for multiple drug interactions. Some oral hypoglycemic medications such as sulfonylurea agents metabolize by this pathway. These medications include tolbutamide (Orinase, Pfizer), glibenclamide and glipizide (Glucotrol, Pfizer). Therefore, if patients take these with itraconazole, plasma levels can rise, resulting in hypoglycemia.19,20

   Other medications that itraconazole may interact with include HMG-CoA reductase inhibitors, calcium channel blockers, warfarin (Coumadin, Bristol-Myers Squibb), cyclosporine, benzodiazepines and certain anti-arrhythmic medications.21 Given the nature of diabetes, it is likely that some patients would also be taking some of these medications. The advantage of itraconazole, however, is that it has broad spectrum antimicrobial activity and research has shown it to be effective against fungal organisms as well as some molds and yeasts.1,22,23

   We often consider terbinafine to be the “safer” and more effective option, despite having reduced efficacy against yeast organisms. Since this drug metabolizes via the cytochrome P450 2D6 enzyme, there is a reduced risk for drug interaction, especially with insulin and/or oral hypoglycemic therapies.20,24 While it is perhaps the safer option for people taking insulin or oral hypoglycemic medications, terbinafine still has the potential to interact with a host of other medications.25 These medications include tricyclic antidepressants, beta blockers, selective serotonin reuptake inhibitors, certain anti-arrhythmic agents and monoamine oxidase inhibitors. Since people with diabetes may be taking some or many of these medications, clinicians need to carefully consider polypharmacy issues when prescribing terbinafine to a person who has diabetes.

   Both itraconazole and terbinafine may cause a number of adverse side effects.1,25,26 Less common but more serious side effects of itraconazole include hepatitis and congestive heart failure. In very rare cases, terbinafine may cause liver disease.

Can Topical Therapies Have An Impact?

Given the potential drug interactions and side effects of oral itraconazole and oral terbinafine, topical therapies are sometimes preferable over these oral antifungal agents, especially for people with diabetes. Since topical ointments act locally, have low systemic absorption and any drug that the body absorbs metabolizes rapidly, there is less potential for adverse side effects and drug interactions.27,28 Furthermore, since many topical treatments (such as ciclopirox 8%) metabolize by glucuronidation, interactions with medications that metabolize via the P-450 system are unlikely.27,29

   Another benefit of topical therapy is that many topical agents have broad spectrum antimicrobial properties and research has shown them to be effective against dermatophytes, yeasts and non-dermatophyte molds.30

Assessing The Shortcomings In The Literature

While there are many antifungal treatment options available, many of which have undergone study in otherwise healthy people, few studies have been conducted to determine the safety and efficacy of these treatment interventions in people with diabetes.

   A recent systematic literature review that aimed to determine the safety and/or efficacy of treatment interventions for tinea pedis and onychomycosis in people with diabetes identified only six different studies.31 From these studies, only three treatment interventions (oral itraconazole, oral terbinafine, topical ciclopirox 8%) underwent scrutiny and all were for the treatment of onychomycosis. Currently, there does not appear to be any evidence for the safety and efficacy of treatment interventions for tinea pedis in people with diabetes.

   Current evidence suggests both oral terbinafine and oral itraconazole therapy are superior (in terms of safety and efficacy) to topical ciclopirox 8% therapy for the treatment of onychomycosis in people with diabetes.31 There is also good (level II) evidence to suggest that oral terbinafine is as safe and effective as oral itraconazole for the treatment of onychomycosis in people with diabetes.20

   However, we cannot generalize the results of these studies to all people with diabetes as studies included in this review were limited by a small sample size and had threats to external validity. Some participants, for example, were not taking any medications known to interact with antifungal agents. Thus, clinical judgment remains critical when prescribing medications.

Pertinent Insights On Combination Therapy

Complete cure of tinea pedis is a lengthy process for people both with and without diabetes. According to studies that examine treatment interventions for people with diabetes, complete cure only occurs for 7 to 50 percent of people after approximately 48 weeks since the beginning of treatment with oral itraconazole or oral terbinafine.31 This is a considerable length of time for a patient who may be at an increased risk of developing a foot ulcer.

   There is also a significant number of patients who are never cured during this period of time but still have the expense of treatment and have also possibly incurred the side effects of the medications.

   Combination therapy is often recommended for people with diabetes as it theoretically reduces the length of treatment time and minimizes the risk of side effects. There is greater antifungal activity and therefore, treatment time is theoretically shorter. This is particularly beneficial for people with diabetes who are likely to have molds and yeasts as well as dermatophytes responsible for their tinea pedis and/or onychomycosis.

   Furthermore, when it comes to combination therapy, the dose required of individual antifungal agents is reduced, thereby minimizing the potential for side effects and drug interactions. Another hypothetical benefit of combination therapy is that the use of a topical antifungal nail lacquer would encourage regular foot inspection, thereby reducing the risk of ulceration.5

Strategies For Tinea Pedis Prevention

Given the risks associated with these infections and the difficulties of treatment, prevention is important for people with diabetes. Since tinea pedis is contagious, thrives in moist, dark environments and spreads by direct contact, people should ensure that their feet are clean and dry, and avoid coming in direct contact with the infectious organisms. Accordingly, clinicians should emphasize the following prevention strategies for patients.

   • Ensure feet are thoroughly dry after having a shower.

   • Wear clean, absorbent socks made of natural fibers, such as cotton, and change them during the day if feet become moist and/or sweaty.

   • Keep shoes dry. There are a number of ways to achieve this. People can remove shoe insoles overnight to allow them to dry and alternate wearing different pairs of shoes to allow them to dry out for a day or two at a time.

   • Avoid direct contact with the fungal organism. Wear sandals in public locker rooms and swimming areas. Do not wear someone else’s shoes, especially if that person has tinea pedis.

   • Elevated blood sugar levels also encourage the development of tinea pedis. Controlling blood sugar levels will therefore assist in the prevention of this infection.

In Conclusion

While the evidence base for treatment interventions for tinea pedis has made great progress over the years, there is still a need for further research that examines treatment interventions in people with diabetes. At present, there are no studies to our knowledge that examine the safety and/or efficacy of medications for tinea pedis in people with diabetes (that fit the criteria of our review).

   Furthermore, while a number of different treatment interventions have been examined for onychomycosis in people with diabetes, these interventions represent a very small proportion of the possible treatment options available. Research that examines the safety and efficacy of other possible treatment modalities (such as combination therapy, mechanical debridement, herbal therapy and light therapy) are needed.

   Perhaps most importantly, efforts are needed to reduce the length of treatment time for people with diabetes. Current evidence suggests that approximately 48 weeks after the commencement of treatment, complete cure rates for tinea pedis vary between 7.7 and 52.9 percent.31 This is a significant length of time to be at an increased risk of complications and a significant number of people are not cured despite enduring treatment and possible side effects.

   Ms. Matricciani is a researcher at the University of South Australia School of Health Sciences.

   Dr. Jones is the Program Director of Podiatry at the University of South Australia School of Health Sciences.

References

1. Thomas J, et al. Tinea pedis and onychomycosis are contagious fungal infections that affect the feet and toenails (respectively) of approximately 15-20% of the population. J Clin Pharm Ther. 2010. 35(5):497-519.
2. Schlefman B. Onychomycosis: a compendium of facts and a clinical experience. J Foot Ankle Surg. 1999; 38(4):290-302.
3. Elewski B, Hay R. Update on the management of onychomycosis: highlights of the Third Annual International Summit on Cutaneous Antifungal Therapy. Clin Infec Dis. 1996; 23(2):305-313.
4. Gupta A, Konnikov N, MacDonald P, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol. 1998; 139(4):665-671.
5. Armstrong D, Holtz K, Wu S. Can the use of a topical antifungal nail lacquer reduce risk for diabetic foot ulceration? Results from a randomised controlled pilot study. International Wound J. 2005; 2(2):166-170.
6. Cox N, Colver G, Paterson W. Management and morbidity of cellulitis of the leg. J Royal Society Medicine. 1998; 91(12):634-637.
7. Pierce R, Daugird A. Recurrent leg cellulitis: pathogenesis, prevention and treatment. J Amer Board Family Med. 1992; 5(1):85-87.
8. Brodell J, Brodell R. Recurrent lymphangitic ellulitis syndrome. Contemporary Orthopaedics. 1992; 25(5):461-468.
9. Rich P. Special patient populations: onychomycosis in the diabetic patient. J Am Acad Dermatol. 1996; 35(3):s10-s12.
10. Pomposelli JJ, Baxter JK 3rd, Babineau TJ, et al. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. J Parenter Enteral Nutr. 1998; 22(2):77-81.
11. Anarella J, Toth C, Debello J. Preventing complications in the diabetic patient with toenail onychomycosis. J Amer Podiatr Med Assoc. 2001; 91(6):325-328.
12. Doyle J, Boyko WL, Ryu S, et al. Onychomycosis among diabetic patients: prevalence and impact of nonfungal foor infection. Presented at American Diabetes Association 60th Scientific Sessions; June 9-13, 2000; San Antonio, TX.
13. Boyko E, Ahroni JH, Cohen V, Nelson KM, Heagerty PJ. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle diabetic foot study. Diabetes Care. 2006; 29(6):1202-1207.
14. Bell-Syer S, Hart R, Crawford F, et al. Oral treatments for fungal infections of the skin of the foot. Cochrane Database of Systematic Reviews 2002(2):CD003584.
15. Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database of Systematic Reviews. 2007; 18(3):CD001434.
16. Tan J, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004; 21(2):101-112.
17. Grant R, Devita NG, Singer DE, Meigs JB. Polypharmacy and medication adherence in patients with type 2 diabetes. Diabetes Care. 2003; 26(5):1408-1412.
18. Venkatakrishnan K, Von Moltke L, Greenblatt D. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clinical Pharmacokinetics. 2000; 38(2):111-180.
19. Verspeelt J, Marynissen J, Gupta AK, De Doncker P. Safety of itraconazole in diabetic patients. Dermatology. 1999; 198(4):382-384.
20. Gupta A, Gover M, Lynde C. Pulse itraconazole vs. continuous terbinafine for the treatment of dermatophyte toenail onychomycosis in patients with diabetes mellitus. J Eur Acad Dermatol Venereol. 2006; 20(10):1188-1193.
21. Gupta A, Katz I, Shear N. Drug interactions with itraconazole, fluconazole, and terbinafine and their management. J Amer Acad Dermatol. 1999; 41(2):237-249.
22. Grant S, Clissold S. Itraconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs. 1989; 37(3):310-344.
23. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy and the severity index for assessing onychomycosis: Part I. J Dermatol Treat. 2008; 19(2):72-81.
24. Vickers A, Sinclair JR, Zollinger M, et al. Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug–drug interactions. Drug Metabolism Dispos. 1999; 27(9):1029-1038.
25. Novartis Pharmaceuticals Australia, Lamisil tablets (terbinafine hydrochloride). https://www.novartis.com.au/PI_PDF/lam.pdf, 2011.
26. Mayser P, Freund V, Budihardja D. Toenail onychomycosis in diabetic patients: issues and management. Am J Clin Dermatol. 2009; 10(4):211-220.
27. Brenner M, Harkless LB, Mendicino RW, Page JC. Ciclopirox 8% nail lacquer topical solution for the treatment of onychomycosis in patients with diabetes: a multicenter, open-label study. J Amer Podiatr Med Assoc. 2007; 97(3):195-202.
28. Gupta A, Einarson TR, Summerbell RC, Shear NH. An overview of topical antifungal therapy in dermatomycoses: a North American perspective. Drugs. 1998; 55(5):645-674.
29. Bohn M, Kraemer K. Dermatopharmacology of ciclopirox nail lacquer topical solution 8% in the treatment of onychomycosis. J Amer Acad Dermatol. 2000; 43(4):S57.
30. Gupta AK. Ciclopirox: an overview. Int J Dermatol. 2001; 40(5):305-310.
31. Matricciani L, Talbot K, Jones S. Safety and efficacy of tinea pedis and onychomycosis treatment in people with diabetes: a systematic review. J Foot Ankle Res. 2011; 4(1):26-38.

   For further reading, see “A Closer Look At Topicals For Tinea Pedis” in the September 2009 issue of Podiatry Today, “Addressing Onychomycosis In Patients With Diabetes” in the March 2012 issue or “How To Detect And Treat Tinea Pedis” in the January 2005 issue.