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Current Concepts In Treating Onychomycosis In Patients With Diabetes

Given the increased prevalence of onychomycosis in patients with diabetes and the potential risk for related complications, this author reviews confirmatory diagnostic tests and offers insights on management of the condition in this patient population.

For most of us, our patients are both older and have some degree of diabetes mellitus. This special patient population often has abnormal toenails as well as the trifecta of arterial insufficiency, neuropathy and immune compromise. This perfect storm puts many of our patients at increased risk for pressure ulceration, secondary bacterial infection and subsequent toe or limb loss.1,2

Medicare has reviewed medical claims history and found a concurrence of onychomycosis and diabetes diagnosis codes that tripled the risk of subsequent ulceration, infection and gangrene.3 Gupta and colleagues studied the prevalence of onychomycosis in both the normal population and the diabetic population.4,5 They found both diabetes and male gender each nearly tripled the risk of having onychomycosis. They also found that about one-third of patients with diabetes have onychomycosis.

The World Health Organization reports that 347 million people worldwide have diabetes.6 Although the team approach to diabetic limb care has resulted in a substantial reduction in limb loss nationally, it remains a daily challenge for us to treat onychomycosis and help reduce the societal impact of diabetic limb loss.

Patients are predisposed to their infection chiefly by their genetic susceptibility. In addition, advanced age, peripheral vascular disease, immune compromise, obesity and smoking have been associated with onychomycosis.5,7-13 UpToDate® advises treatment of onychomycosis with a Grade 2C recommendation.14 This means published medical evidence supports individualized treatment. UpToDate® suggests clinicians give special consideration to the treatment of onychomycosis in patients with a history of cellulitis, venous insufficiency or edema as well as patients with diabetes.

Management of most medical problems improves when a classification system guides treatment. This is also true of onychomycosis in patients with diabetes. A newer, expanded classification of onychomycosis clinical subtypes helps to direct treatment choices, prognosis and outcomes (see the table “A Guide To The Clinical Subtypes Of Onychomycosis” at right).15 This updated version adds mixed type onychomycosis to the traditional classification.

Diagnosing onychomycosis has traditionally been based on clinical findings of nail plate thickening and discoloration, and subungual hyperkeratosis. These diagnostic criteria had been sufficient until effective oral agents became available. Due to the small but significant potential risk of oral antifungal adverse events, definitive diagnosis has become more important. Also remember that most studies have found that nearly half of abnormal nails may not be fungal at all. These nail dystrophies are often clinically indistinguishable from psoriasis, following micro- and macrotraumatic scarring, ischemia, lichen planus or even iron deficiency.14

The use of handheld dermoscopy can significantly improve clinical diagnosis. Specifically, the so-called aurora borealis pattern of linear longitudinal dermatophytic spikes found with a dermatoscope highly correlates with positive mycological testing.  

Diagnostic Tests And Onychomycosis: What You Should Know  
Although 75 percent of podiatrists and dermatologists report feeling very confident at diagnosing onychomycosis clinically, only two-thirds order a confirmatory diagnostic test.16 In a 2007 survey by Koshnick and colleagues, podiatrists, dermatologists and family doctors preferred using the KOH as a diagnostic test.15 Light microscope examination of nail bed debris treated with KOH and chlorazol black E fungal stain is the most economical test and boasts over 94 percent sensitivity.17

The KOH wet mount is a Clinical Laboratories Improvement Act-waived test that one can perform in the clinic with a light microscope.18 The use of KOH examinations statistically correlates with the confidence of the examiner in interpreting the microscopic findings. Podiatrists tend to be less confident than dermatologists in interpreting potassium hydroxide exams.16

Many clinicians rely on anatomic pathology and mycologic methods. Each test has a specific indication. Short of molecular methods, the microscopic periodic acid Schiff stain (PAS) has the highest sensitivity and can detect live organisms within the nail plate tissue itself.18 The Gomori methenamine silver stain can improve sensitivity even further. If it is necessary to determine specificity (the first and last name of the organism), then one can order fungal cultures. Unfortunately, fungal cultures have the lowest sensitivity. Not all specimens actually germinate so one can’t identify them mycologically. In cases in which the nail appears discolored brown or black, one can add a Fontana–Masson stain to detect melanin.

In a 2007 survey, 21 percent of podiatrists did not obtain a confirmatory diagnostic test prior to the treatment of onychomycosis while 63 percent of dermatologists did.16 This may be due to podiatric patients tending to prefer management with topical antifungals and debridement while dermatology patients are more likely to accept oral antifungal therapy.

How To Measure The Severity Of Onychomycosis
In addition to making an accurate diagnosis, it is important to measure the severity of the infection at the beginning of therapy to document clinical progress accurately over time. There are several ways to measure severity. Relying on the subjective impressions of the patient for a condition that normally takes many months to heal is often inaccurate and not encouraging. Taking clinical photographs is helpful only to the extent that the images are readily available in the chart. Measuring the proximal clear zone can be useful but this tool does not measure the overall reduction in the area of the nail unit infection and can be significantly skewed by a single spike, masking progress in the remainder of the nail unit. The proximal clear zone measured in millimeters, however, is a quick indication of how much healthy nail is present in the target nail.

A more complete clinical severity measurement tool is the Onychomycosis Severity Index.19 Not only does it measure more relevant clinical characteristics than the proximal clear zone but trained observers have validated the index. The Onychomycosis Severity Index assesses the percentage area of the infection on a 5-point scale and multiplies that by the proximal extent of the infection (also on a 5-point scale). Severity of the infection is not only a function of area and how proximal the infection has extended but also the overall thickness of the diseased nail. Since it is obvious that thickened nail plates and dermatophytic spikes are significantly more difficult to clear than thin nail plates, the Onychomycosis Severity Index method adds 10 points of severity if the thickness of mycotic nail exceeds 2 mm or there is subungual crumbling or proximal pointing spikes.19

Not only does the Onychomycosis Severity Index facilitate severity documentation over time but it is a valid tool for clinical staging and directing therapy for improved outcomes. Mild onychomycosis corresponds to a score of 1-5, moderate onychomycosis can range between 6 to 15 points and severe onychomycosis would have a score between 16 to 35 points. For mild to moderate cases, clinicians can treat the condition with efficacious topical antifungals and/or laser therapy while moderate to severe cases are best to manage with an appropriate oral antifungal therapy.  

Where Professional Debridement And Shoe Fit Can Help Mitigate Risks
Professional debridement not only improves cure rates but I have found it improves initial patient satisfaction. In patients with diabetes, debridement can immediately reduce the thickness and decrease the pressure on the fragile nail bed, thereby reducing the risk of secondary bacterial infection. An important component of a diabetic foot examination and evaluation of risk is simple shoe modification.

Foot measurements with a Brannock device help determine the appropriateness of the foot gear for patients with diabetes. Feet of both men and women can become longer and wider with age. One should evaluate the heel-to-toe and heel-to-ball Brannock measurements, and accommodate the patient with correctly sized shoes. The increased rigidity of hammered digits, severity of hallux valgus deformities, progressive diabetic peripheral neuropathy and severity of onychomycosis are all factors that are important components of a therapeutic shoe prescription for patients with diabetes. It is more important that the patients’ foot gear fit their feet rather than their head (i.e. the patient’s idea of shoe preference).

Key Considerations With Oral Antifungals In Patients With Diabetes
Oral antifungals are indicated for moderate to severe onychomycosis. One should evaluate patients in general and especially those with diabetes for oral antifungal therapy. Patients with diabetes face a greater risk of their onychomycosis triggering secondary ulceration, infection and gangrene.3

Oral antifungal agents are not contraindicated in patients with diabetes. For example, there are no significant interactions between hypoglycemic drugs and terbinafine (Lamisil, Novartis). Most patients with diabetes are reducing cardiovascular risk with statin therapy. Concurrent terbinafine therapy is not contraindicated by statins but monitoring of liver function tests is recommended. A prudent plan is reviewing baseline creatinine, liver function tests and complete blood cell count before continuous oral antifungal therapy begins and reviewing again in four to six weeks.

Therapeutic guidelines advise the course of oral antifungal therapy in patients with diabetes to extend from the usual three months to four months.3 This is because patients with diabetes are generally immunocompromised to some degree and they often have slower nail growth rates due to accompanying peripheral arterial disease.

Too many of our patients with diabetes develop end-stage renal disease and require hemodialysis. Irimie and colleagues isolated the dermatophytes in 87 patients on hemodialysis and found them to be most susceptible to terbinafine.20 Prescribing oral terbinafine to a hemodialysis patient requires nephrology consultation for dosage adjustment and monitoring for potential adverse effects. The package information for terbinafine does not provide a dosage adjustment for renal impairment. However, creatinine clearance of terbinafine decreases by 50 percent in patients with CrCl =50 mL/minute and one should avoid this. Fungal peritonitis is a serious complication in patients on peritoneal dialysis. Chang and coworkers reported one case caused by Paecilomyces lilacinus that they were able to treat with a combination of oral voriconazole (Vfend, Pfizer) and terbinafine.21

Can Topical Treatments And Laser Therapy Have An Impact For Diabetic Onychomycosis?
The newer topical antifungals like efinaconazole (Jublia, Valeant Pharmaceuticals) and tavaborole (Kerydin, Anacor Pharmaceuticals) may be three times more effective than ciclopirox (Loprox, Medicis).22 In fact, their efficacy rates in controlled studies now rival oral itraconazole (Sporanox, Janssen Pharmaceuticals).22 It is important to remember, however, that efinaconazole and tavaborole are primarily indicated for cases of mild to moderate distal and lateral subungual onychomycosis. Clinicians and patients could be disappointed when they use even these more effective topicals alone to treat severe or total dystrophic onychomycosis. Since the newer topical antifungal therapies can be expensive, mycological testing and severity monitoring are important.

White superficial onychomycosis in patients with diabetes quickly clears and one can readily treat it with a combination of rotary debridement and a topical antifungal. Cases of superficial white onychomycosis typically occur in plates that are occluded by the skin of adjacent overlapping digits.23 Males in nursing home populations are especially affected by this Trichophyton mentagrophytes superficial nail plate infection.

The Food and Drug Administration has found various non-ablative laser therapies to be safe and effective for temporary clearing of mild to moderate onychomycosis.12 My colleagues and I recently conducted a study of the clinical effectiveness of the 1064 Nd:YAG laser in 32 patients with 57 fungal infected hallux nails and moderate to severe onychomycosis.24 The study included patients with and without diabetes. We achieved significant improvement in the onychomycosis severity indices, proximal clear zones and overall patient satisfaction.

When it comes to treating onychomycosis in patients with diabetes, the use of laser therapy without careful control of target tissue temperatures can lead to serious complications. Moutran and colleagues recently reported a case of onychomycosis that recurred after oral terbinafine therapy.25 A 64-year-old female with type 2 diabetes mellitus and diabetic neuropathy received Nd:YAG 1064 short pulse laser therapy. Soon after laser treatment, the patient developed severe thermal burns and subsequent osteomyelitis, which required bilateral hallux amputations. Using equipment with continuous temperature monitoring improves safety. The efficacy of laser therapy for onychomycosis seems less dependent on temperature than we previously thought.26  

Emphasizing The Importance Of Debridement
Professional debridement is important to both patients with diabetes as well as other patients with neuropathy and impaired vision. Neuropathic patients attempting to trim toenails can end up with tissue loss and secondary infection. Serious damage can occur when patients with impaired sensation and/or reduced vision attempt to perform self care of toenails. Good debridement technique with less risk of repetitive injury to the operator can best occur with a curved 6-inch nail nipper taking small rather than larger bites. Instead of increasing squeezing forces of the intrinsic muscles of the hand to trim thick, hard nail plates, first taking small bites, and then flexing and rolling the wrist accomplishes the task with less force and fatigue. Generally, bone-cutting double action forceps are not necessary. Small, straight nail nippers require more work than 6-inch nail nippers and are more suitable for slant back trimming of nail edges.

In addition to debridement with larger nail nippers, a rotary drill with a cooling water spray allows thorough reduction in thickness of the nail plate without a potentially harmful temperature rise that a patient with impaired temperature sensation may not feel as is often the case in patients with diabetic peripheral neuropathy.

Gupta and colleagues found that 3 percent of their studied population of patients with diabetes with clinically normal appearing nails had mycological evidence of onychomycosis.3 Accordingly, earlier detection and treatment at a time when onychomycosis is easier to treat is especially important in the diabetic population.

Thorough, effective treatment of onychomycosis in both patients with and without diabetes often centers on a combination of oral and topical antifungal therapies along with periodic professional debridement. Initial professional debridement and testing improves patient satisfaction. Adding pulsed oral terbinafine daily for one week every nine weeks until clear is a therapy one can combine with topical efinaconazole or tavaborole to improve treatment outcomes and patient satisfaction. It is important to emphasize that the genetic nature of the disease often predisposes the patient to recurrence. Long-term prophylactic topical antifungal use to suppress any tinea pedis is essential.

In Summary
Understanding the increased risk of secondary complications of onychomycosis in patients with diabetes should lead to more aggressive employment of effective treatment strategies. Recognizing the clinical subtype that the patient exhibits, taking the time to measure treatment progress accurately, fine tuning therapies and implementing a prevention program are all essential steps in the care of the patient with diabetes and onychomycosis.

Dr. Bodman is an Associate Professor at the Kent State University College of Podiatric Medicine. He is a Diplomate of the American Board of Podiatric Medicine. Dr. Bodman is in private practice in Ohio.

References

  1.     Bristow IR, Spruce MC Fungal foot infection, cellulitis and diabetes: a review. Diabet Med. 2009;26(5):548.
  2.     Roujeau JC, Sigurgeirsson B, Korting HC, Kerl H, Paul C. Chronic dermatomycoses of the foot as risk factors for acute bacterial cellulitis of the leg: a case-control study. Dermatology. 2004; 209(4):301-7.
  3.     Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients. Clin Diabetes. 2006; 24(4):160-66.
  4.     Gupta AK, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW, McManus R, Summerbell RC. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol. 1998;139(4):665-71.
  5.     Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatology. 2000; 10(5):379-384.
  6.     World Health Organization. www.who.int/mediacentre/factsheets/fs312/en/ . Published October 2013. Accessed October 15, 2014.
  7.     Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA, Summerbell RC. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000;43(2 Pt 1):244-8.
  8.     Baran R. The nail in the elderly. Clin Dermatol. 2011; 29(1):54-60.
  9.     Gupta AK, Gupta MA, Summerbell RC, Cooper EA, Konnikov N, Albreski D, MacDonald P, Harris KA. The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol. 2000; 14(6):466-469.
  10.     Abdelaziz AM, Mahmound KM, Elsawy EM, Bakr MA. Nail changes in kidney transplant recipients. Nephrol Dial Transplant. 2010; 25(1):274-277.
  11.     Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol. 2000; 39(10):746-753.
  12.     Doner N, Yasar S, Ekmekci TR. Evaluation of obesity associated dermatoses in obesity and overweight individual. Turk Derm. 2000; 45:146-151.
  13.     Gupta AK, Simpson FC. Medical devices for the treatment of onychomycosis. Dermatl Ther. 2012; 25(6):574-581.
  14.     Goldstein AO, Dellavalle RP, Levy ML, Rosen T, Ofori AO. UpToDate: Onychomycosis. Available at www.uptodate.com/contents/onychomycosis . Topic 4034, Version 18.0. Accessed 11/1/2014.
  15.     Hay RJ, Baran R. Onychomycosis: a proposed revision of the clinical classification. J Am Acad Dermatol. 2011;65(6):1219.
  16.     Koshnick RL, Lilly KK, St Clair K, Finnegan MT, Warshaw EM. Use of diagnostic tests by dermatologists, podiatrists and family practitioners in the United States: pilot data from a cross-sectional survey. Mycoses. 2007;50(6):463-9.
  17.     Dermatologic Lab & Supply, Inc. 608 13th Ave. Council Bluffs, IA USA 51501-6401
  18.     Lilly KK, Koshnick RL, Grill JP, Khalil ZM, Nelson DB, Warshaw EM. Cost-effectiveness of diagnostic tests for toenail onychomycosis: A repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests. J Am Acad Dermatol. 2006;55(4):620-6.  
  19.     Carney C, Tosti A, Daniel R, Scher R, Rich P, DeCoster J, Elewski B. A new classification system for grading the severity of onychomycosis: Onychomycosis Severity Index. Arch Dermatol. 2011; 147(11):1277-82.
  20.     Irimie M, Tataru A, Oanta A, Moga M. In vitro susceptibility of dermatophytes isolated from patients with end-stage renal disease: a case-control study. Mycoses. 2014;57(3):129-34.
  21.     Chang BP, Sun PL, Huang FY, Tsai TC, Lin CC, Lee MD, Chen YC, Sheu JC, Tsai JD. Paecilomyces lilacinus peritonitis complicating peritoneal dialysis cured by oral voriconazole and terbinafine combination therapy. J Med Microbiol. 2008;57(Pt 12):1581-4.
  22.     Del Rosso JQ. The role of topical antifungal therapy for onychomycosis and the emergence of newer agents. J Clin Aesthet Dermatol. 2014;7(7):10-8.
  23.     Bodman, MA, Brlan, MR. Superficial white onychomycosis. J Am Podiatr Med Assoc. 1995; 85(4):205-8.
  24.     Blazer M, Bodman M, Caldwell B, Johnson R. Clinical effectiveness of Nd:YAG Laser followed by topical therapy for moderate and severe onychomycosis. Manuscript is in preparation for J Am Podiatr Med Assoc.
  25.     Moutran R, Maatouk I, Hélou J. Diabetic neuropathy and Nd-YAG (1064 nm) laser for onychomycosis: be careful. Letter to the Editor. J Eur Acad Dermatol Venereol. 2014; epub Mar 24.
  26.     Carney C, Cantrell W, Warner J, Elewski B. Treatment of onychomycosis using a sub millisecond 1064-nm neodymium: yttrium-aluminum-garnet laser. Am Acad Dermatol. 2013;69(4):578-82.
  27.     Relative Sensitivities of Onychomycosis Tests. Quest Diagnostics. Downloaded 12/10/14. Available at www.questdiagnostics.com/testcenter/testguide.action?dc=TG_Onychomycosis .

For further reading, see “Keys To Managing Severe Onychomycosis” in the May 2013 issue of Podiatry Today, “How To Address Onychomycosis In Patients With Diabetes” in the March 2012 issue or “Roundtable Insights On Treating Onychomycosis” in the May 2011 issue.

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Myron Bodman, DPM
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