How To Address Onychomycosis In Patients With Diabetes

The complications of diabetes can desensitize patients to the effects of onychomycosis and complicate management of the condition. Given the increased prevalence of onychomycosis in this patient population, these authors discuss common pathogens and assess the available treatment options.

When is a simple case of onychomycosis not so simple? When it affects a patient with diabetes.

   For many people who entrust their care to a podiatric physician, the complaints that bring them into the office start with concerns with appearance and then grow ­— as the nail grows — to complaints of pain. These patients will seek attention before damage occurs to the underlying nail bed but patients with diabetic peripheral neuropathy are immune to that warning signal, sometimes until it is too late.

   The late Paul Brand, MD, stated that “pain is a gift” because it is the body’s early warning system to help it avoid damage.1 While working in India, he worked with patients who had Hansen’s disease, better known as leprosy, and saw the people around him reaching into flames to retrieve pieces of flat bread to turn them over, never sensing the damage this was doing to their fingers.

   It is the same loss of sensation that, in patients with diabetic peripheral neuropathy, prevents them from feeling the pressure from a tight shoe on the toes. When a thickened nail plate is part of the equation, the pressure on the fragile, vascular rich nail bed occurs with frequency. The result is a subungual ulcer.

   Adding to its “thief in the night” approach is the fact that the ulcer lays covered, unseen beneath the nail plate, growing larger and larger until the toe starts to show signs of its presence. The patients and their caregivers are alerted by signs of infection — purulent material oozing from beneath the nail, erythema and/or bleeding. In 2006, Edmonds and Foster noted that the subungual ulcerations more commonly form in patients with ischemia.2 They advised practitioners to examine toenails “for signs of bruising, bleeding, discharge or other abnormalities.”

Pertinent Insights On Debridement

If the patients are fortunate, one will discover the ulcer at the time of the regular debridement of the nail but this happens if and only if the caseous material of an onychomycotic nail receives aggressive debridement. The physician who decides to limit his or her debridement to the length of the nail and the top several layers of onychomycotic nail may miss the presence of an ulceration completely.

   Another clue to the presence of a subungual ulceration in a patient with diabetes is the presence of hallux limitus with a thickened nail. Boffeli and colleagues found this biomechanical abnormality along with the deforming nail to have caused four ulcers.3

   To discover the subungual ulceration, the podiatric physician must not solely depend on an electronic burr to do the job. He or she must enlist the hand instruments to start eliminating the burden of the nail, piercing into the substance of the nail, above the nail bed and working through the soft underlying material until the bed is visible.

   Of course, this takes time and more confident skills than does the fast pass of a burr.

   Even if a podiatric physician decides to utilize oral or topical pharmaceuticals for treatment, one should still debride the nail burden to allow a better outcome with the medication therapy. The onychomycotic nail is a repository of the fungal elements that are creating and spreading the infection.

Is There Trepidation About Utilizing Oral Antifungals?

With what is known now about oral antifungals, they are the best bet for clinical and microbiological cure widely available.4,5 Still, even with more than a decade of positive outcomes for modern oral antifungals, many podiatric physicians still show a reluctance to give them to any patient, much less a patient with diabetes.

   An oft-cited survey in the late 1990s showed that DPMs in very high numbers felt that the most effective way to treat onychomycosis was by oral antifungals.6 When asked how they treated the infection, DPMs said they depended only on debridement, even though they knew it was among the least effective methods to treat the condition.

   There was much speculation at the time about why this discrepancy existed between knowledge and action. Many podiatric physicians and surgeons expressed insecurity about prescribing medications that had potential side effects. The side effects to terbinafine (Lamisil, Novartis), for instance, included primarily hepatic damage, which occurred very rarely, as well as temporary loss of taste, which occurred rarely as well but which some prescribing podiatric physicians reported.

   The disconnect between the actions and knowledge of these highly trained physicians was surprising given the same group’s willingness to perform surgery with its potential complications. A second reason for not utilizing known successful treatments for onychomycosis that threatened amputation in the patient with diabetes was that the infection would eventually return. The answer to that statement by noted podiatric dermatology experts was that sinus infections and strep throat return as well but does that mean that we should not treat these conditions?

   Medical aspects of treatment for podiatric issues have seen more emphasis in the podiatric medical colleges and it will be interesting to see if this population of DPMs trained in the last decade differs from those trained earlier.

   Not only is onychomycosis one of the most common conditions podiatrists treat but the need for timely, effective treatment is particularly important in order to avoid complications that can occur in this population of patients with diabetic peripheral neuropathy and onychomycosis.

What You Should Know About The Complications Of Onychomycosis

Patients with diabetes are at increased risk for developing onychomycosis.7 The thinking is that the presence of angiopathy, retinopathy, neuropathy and increasing age are factors that lead to the development of onychomycosis in these patients.

   Due to some patients’ peripheral vascular disease and poor blood sugar control, onychomycosis can become a considerable public health problem, as noted by Pierard and colleagues.8 They noted that the presence of the mycotic nail may cause injury to the adjacent nail or skin, and may also provide a reservoir of pathogen fungi. This further increases the risk of serious sequelae and spread of infection.

   Furthermore, the study says high-risk patients with diabetes who have compromised lower extremities and severe neuropathy are at increased risk of developing complications from onychomycosis.8 Most notably, they say impaired sensation can make many of those with diabetes less aware of minor abrasions and ulcerations on their feet that may result from trauma, poor nail grooming or by the sharp, brittle shape of infected nails. These lesions may develop into serious paronychia, cellulitis or other bacterial infections, and may contribute to the severity of the diabetic foot. The authors note that osteomyelitis can also arise from a chronically infected nail bed with erosion in patients with diabetes due to the close proximity of the nail bed to the underlying bone.

   Given the need to treat and the potential complications of no treatment, let us take a closer look at the pathogens of onychomycosis and the treatments available.

What About Common Pathogens With Onychomycosis?

When examining the pathogens causing onychomycosis, one will see the typical expected organisms on a regular basis. The pathogens do not differ widely between the diabetic and non-diabetic populations. Some studies noted that Candida was the primary infecting agent by a large percentage but later studies did not have that finding.9

   Dermatophytes, depending on the literature, comprise up to 92 percent of onychomycosis cases.10 Not a lot of research has been dedicated to looking into the other pathogens causing onychomycosis but there are case studies on unusual occurrences of different pathogens.

   Dermatophytes are pathogens of skin due to their ability to attach and extract nutrients from keratin cells. The most common dermatophyte is Trichophyton rubrum, making up nearly 70 percent of all cases. This is followed by Trichophyton mentagrophytes with 20 percent of dermatophytic pathogens.10 Molds and Candida make up most of the remaining cases of onychomycosis.

   Fusarium species, Scopulariopsis brevicaulis and Aspergillus species are the most commonly present molds.11 In patients with diabetes, Candida albicans has an increased prevalence in skin but there is limited evidence to suggest its activity as nail plate pathogen. As C. albicans typically infects fingernails in patients with diabetes, it is important to examine if you suspect Candida as the infectious agent in toenails. It is important to biopsy the nail plate and culture to ensure proper treatment and improved results.

   Not all pathology labs are capable of working with nail biopsy and periodic acid Schiff staining techniques. It is important to use a lab that employs dermatopathologists who will be familiar with what is necessary.

Weighing The Pros And Cons Of Treatment Options

When targeting onychomycosis in patients with diabetes, you must take into account several other factors that wouldn’t affect treatment in the non-diabetic population. As a whole, patients with diabetes are taking multiple medications, may have poor foot hygiene due to multiple issues (inability to reach the feet and neuropathy) and suffer from comorbidities such as ischemia, neuropathy, immune dysfunction and hyperglycemia.

   Without treatment, patients are vulnerable to limb-threatening complications. We encourage prompt treatment. Obtaining a fungal culture and an appropriate history and physical are essential to avoid adverse effects from treatment and improve treatment success.

   Oral antifungals are the mainstay of successful therapy. Terbinafine is the first line agent in both populations with high safety and efficacy. The benefits of terbinafine are the reduced drug interactions due to being metabolized in several P450 isoenzymes of the liver. Terbinafine is most effective against molds and dermatophytes.12 Common drugs that may interact with terbinafine are warfarin (Coumadin, Bristol-Myers Squib), amitriptyline (Elavil), atenolol (Tenormin, AstraZeneca) and cimetidine (Tagamet). These are all medications that a patient with diabetes may be taking and adjustments may be necessary in the medication regimen for a short period.

   One can use itraconazole (Sporanox, Janssen Pharmaceutica) in pulsed doses or continuous use. Pulsed dosing reportedly provides the better efficacy.13 Itraconazole is an effective medication but due to it being metabolized through P450 3A4 enzymes, it carries numerous drug interactions, especially in those with hypoglycemia, and has a black box warning of heart failure. The list of drug interactions is copious.

   Fluconazole (Diflucan, Pfizer) is mostly reserved for treatment of Candida species and has similar side effects as itraconazole. Oral medications may cause problems with liver damage and one should exercise caution in all patients.

   Other options include topical solutions such as ciclopirox (Penlac, Sanofi Aventis). One would apply the lacquer directly to the nail in mild to moderate cases of onychomycosis. There is no valid comparison between the effectiveness of oral antifungals and topicals with studies showing very low success rates with ciclopirox especially.14 The only benefits are that topicals offer reduced drug interaction and minimal side effects. However, if they do little to cure a patient’s condition, they are of no use.

   A recent development in onychomycosis treatment is the advent of laser therapy. Laser therapy works by the creation of free radicals via wavelengths and heat directed at the nail plate. The radical oxygen species will damage and inactivate fungal growth leading to fungal cell death.

   Further research is needed before we can consider laser therapy a viable option in the treatment of onychomycosis but results thus far show promise.15 Clinicians can combine many of the laser therapies with manual debridement and/or with each other for improved results and in cases that do not show initial improvement.

In Conclusion

To effectively treat onychomycosis in the patient with diabetes, the most viable option to date is aggressive manual debridement in combination with oral therapy. Podiatric physicians who choose not to manage their patients on oral therapy themselves can co-manage with a general physician to improve the outcomes for their patients. It is not a matter of being able to treat with oral antifungals and choosing not to.

   In 1998, Gupta and colleagues phrased it well when they said that modern oral antifungals “have a high benefit to risk ratio with shorter treatment times compared with griseofulvin … .”7 Treatment is a matter of giving the patient with diabetes the best opportunity for a successful outcome.

   Mr. Waverly is a third-year podiatric medical student at the College of Podiatric Medicine at the Western University of Health Sciences.

   Dr. Satterfield is an Associate Professor at the College of Podiatric Medicine at the Western University of Health Sciences. She is a Fellow of the American College of Foot and Ankle Orthopedics and Medicine.

References
1. Brand PW. Tenderizing the foot. Foot Ankle Int. 2003;24(6):457-61
2. Edmonds M, Foster AV. ABC of wound healing. Diabetic foot ulcers. Br Med J. 2006; 332(7538):407–10.
3. Boffeli TJ, Bean JK, Natwick JR. Biomechanical abnormalities and ulcers of the great toe in patients with diabetes. J Foot Ankle Surg. 2002;41(6):3359-364.
4. Pollak R, Billstein SA. Safety of oral terbinafine for toenail onychomycosis. J Am Podiatr Med Assoc. 1997;87(12):565-70.
5. Farkas B, Paul C, Dobozy A, et al. Terbinafine (Lamisil) treatment of toenail onychomycosis in patients with insulin-dependent and non-insulin-dependent diabetes mellitus: a multicenter trial. Br J Dermatol. 2002;146(2):254-60.
6. Data on file, Novartis Pharmaceuticals Corporation.
7. Gupta AK, Konnikov N, MacDonald P, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicenter survey. Br J Dermatol. 1998; 139(4):665-71.
8. Pierard GE, Perard-Franchimont C. The nail under fungal siege in patients with type II diabetes mellitus. Mycoses. 2005;48(5):339-342.
9. Cathcart, Cantrell W, Elewski BE. Onychomycosis and diabetes. J Eur Acad Dermatol Venereol. 2009;23(10):1119-1122.
10. Singal A, Khanna D. Onychomycosis: diagnosis and management. Indian J Dermatol Venereol Leperol. 2011;77(6):659-72.
11. Moreno G, Arenas R. Other fungi causing onychomycosis. Clin Dermatol. 2010; 28(2):160-3.
12. Van Duyn Graham L, Elewski BE. Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US. Mycoses. 2011;54(6):679-685.
13. Gupta AK, Tu LQ. Therapies for onychomycosis: A review. Dermatol Clin. 2006; 24(3):275-9.
14. Shemer A, Nathansohn N, Trau H, Amichai B, Grunwald MH. Ciclopirox nail lacquer for the treatment of onychomycosis: an open non-comparative study. J Dermatol. 2010; 37(2):137-9.
15. Landsman AS, Robbins AH, Angelini PF, et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc. 2010;100(3):166-77.

Additional Reference

16. 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(26):1-12.

   For further reading, see “Roundtable Insights On Treating Onychomycosis” in the May 2011 issue of Podiatry Today, “Emerging Concepts In Treating Onychomycosis” in the October 2009 issue or “How To Treat Onychomycosis In Diabetic Patients” in the March 2003 issue.