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FEATURE ARTICLE

Treatment of in Diabetic Patients

Jason A. Winston and Jami L. Miller, MD

n 2005, the estimated number of um because of pressure, just as tight impaired peripheral circulation,4,9 age,4,9 Americans with was 20.8 shoes can cause friction in these family history,4 and intake of immuno- Imillion people, with an additional patients. When combined with peripher- suppressant drugs.4 In addition, duration 1.5 million cases diagnosed that year in al neuropathy, blisters and erosions may of diabetes is correlated with severity of those ≥ 20 years of age.1 Onychomyco- progress to or of onychomycosis when present.4 Male dia- sis is a fungal of the that the underlying bone.3,4,14,15 Extension of betic patients have a three times higher is estimated to cause up to 50% of all the fungal infection to surrounding skin risk of onychomycosis than female dia- nail problems2 and 30% of all cuta- causes tinea pedis, which may lead to betic patients.4 neous fungal .3 Approximate- fissures in the plantar and interdigital The presence of fungal infection in ly one in three people with diabetes are skin. These may also provide a route for the nails increases the risk of other infec- afflicted with onychomycosis.4 Many the entry of bacteria.15 tions of the foot and leg. In one study, studies have been undertaken to assess Patients with diabetes-related comor- diabetic patients with onychomycosis whether diabetic individuals suffer from bidities are at especially increased risk had a 15% rate of secondary infections a higher incidence of onychomycosis for morbidity in onychomycosis. Diabet- compared with a 6% rate of secondary than those without diabetes,4–10 and ic patients suffering from decreased foot infections in diabetic patients without most have concluded that they do. One sensation are more prone to trauma, onychomycosis. Additionally, diabetic study observed an increased risk among which damages the nail and nail matrix, patients with onychomycosis had an all three major groups of organisms that opening portals of entry for the to approximately three times greater risk of can cause onychomycosis: dermato- infect the nail.13,15 Some diabetic patients gangrene or foot compared with phytes, , and nondermatophyte can be obese, which may make the act of diabetic patients without it.10 .5 bending over to examine their feet diffi- The total annual costs for toe, leg, Onychomycosis in people with dia- cult.15 Diabetic patients with cataracts16 and foot amputations in the United betes is more than a cosmetic nuisance; or retinopathy15 may be unable to prop- States in 2003 was almost $2 billion.17 it increases the risk for other foot disor- erly examine their feet regularly. These costs covered 112,551 total ampu- ders and limb amputation.4,10–22 The out- Retinopathy has been found to be an tations, with an average cost of $16,826 come from not treating onychomycosis independent risk factor for onychomyco- for each procedure.17 In 2001, the total in diabetic patients can be worse than in sis in diabetes.9 Other risk factors cost of amputations in diabetic patients those without diabetes. Thus, effective include peripheral neuropathy,3,9,15 was > $1.6 billion.18 The majority of treatment in these patients is of para- lower limb amputations occur in diabetic mount importance.13 Because ony- IN BRIEF patients.19 Because the risk of amputa- chomycosis in diabetic patients can lead Onychomycosis is more common in tion increases with onychomycosis, it is to many complications, most insurance diabetic than nondiabetic patients. It imperative for clinicians to examine dia- companies cover treatment in document- is more than a cosmetic problem, and betic patients’ feet and, when suspicious, ed cases. Thickened, dystrophic nails can diabetic patients have a greater risk of obtain a sample for diagnosis. be very painful and make walking diffi- serious complications from the dis- cult. to adjacent skin from ease, including limb amputations. Causes of Onychomycosis mycotic nails may occur without This article reviews the various diag- Three classes of fungi can cause nail patients’ awareness and can lead to sec- nostic and therapeutic options avail- infections in humans: ondary infections, both fungal and bacte- able for onychomycosis with an (especially species), yeasts rial, including and celluli- emphasis on their roles in diabetic (e.g., albicans), and nonder- 3,4,9,14,15 2,20 tis. Thickened nails can cause patients. matophyte molds. Dermatophytes erosions of the nail bed and hyponychi- constitute the vast majority of infectious

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etiologies.21 In one epidemiological sur- nail except for small fragments is Normal nails can have morphologi- vey, dermatophytes were found in 82% destroyed, leaving a thickened nail bed.23 cal variation, especially as an individual of isolates and in ages. White spots and lines in the nails, ~ 7%.22 punctata, and transverse Only 57% of diabetic patients with striate leukonychia are benign and may Diagnosis of Onychomycosis abnormal-appearing toenails are con- result from minor trauma to the nail firmed to have onychomycosis.4 Many matrix.27 Onycholoysis can be idiopathic Clinical diagnosis common disorders, including , or caused by trauma.28 Dermatophytes Infected nails appear thick, brittle, and , , trauma, can be found in idiopathic discolored, often with a yellow hue. The and idiopathic dystrophic nails are but are considered to be commensal.29 nail plate may separate from the nail bed included in the differential diagnosis. (onycholysis), and there may be inflam- Psoriasis is the most common dis- Laboratory diagnosis mation of the skin near the nail edge order that mimics onychomycosis24 The standard of care in diagnosing ony- (paronychial ).20 and can show subungual hyperkerato- chomycosis is clinical impression with Onychomycosis has four classic sis, onycholysis, and onychodystrophy one confirmatory laboratory finding, clinical presentations in nails. Distal of the entire nail.23 Although psoriasis such as KOH-prepared direct and lateral subungual infection is the usually also has classic manifestations microscopy, fungal culture, or most common type. In this pattern, the on other skin areas, it can be limited to histopathology with periodic acid Schiff infection spreads proximally from the the nails. Pitting and “oil drop” spots (PAS) staining.30–32 It is important to distal or lateral aspects of the nail, even- are far more common in psoriasis than verify clinical suspicion with laboratory tually raising the free edge of the nail in onychomycosis.23,24 Often in psoria- investigations. One study compared the plate and causing onycholysis and nail- sis a “salmon patch,” an irregular yel- costs of empirically treating all patients plate thickening with subungual hyperk- low or pink area under the nail plate, with onychodystrophy with eratosis. The infection spreads proxi- will be present. This does not occur in versus PAS staining all nails and treat- mally, causing yellow-brown onychomycosis.25 ing only those with a positive . discolorations.23 The most common Patients with lichen planus can have The study found that it was cost-effec- organism is , fol- nail manifestations of the disease.24 Clin- tive to first diagnose and then treat lowed by Trichophyton mentagrophytes. icians should carefully examine patients’ empirically.33 Candida species also cause this pattern extremities and mucous membranes for Samples for microscopy, culture, or of infection, as can molds such as the the pathognomic violaceous .26 histopathology can be collected from the Aspergillis and species. When Lichen planus can affect both fingernails nail plate or subungual debris. When col- complicated by infection with pigment- and toenails, causing them to become lecting a sample, care should be taken ed molds or bacteria such as brittle and ridged. Subungual hyperker- with diabetic patients to avoid injuring Pseudomonas aeruginosa, the nails may atosis and distal onycholysis may also the nail bed, which may increase the risk appear dark green to black.23 occur.27 of secondary bacterial infection.15 Proximal subungual infection is rare Onychogryphosis is a severe defor- Histological examination. Most but more common in AIDS and mation of the nail, most often affecting clinicians find it easiest to send nail immunosuppressed patients. In this pat- the great toes. The nail becomes very clippings for histopathological evalua- tern, the organisms invade via the proxi- thick and discolored, resembling a tion with a PAS stain. Clippings are sent mal nail fold and spread to the nail ram’s horn. The nail bed can become to the laboratory in formalin, matrix and then the deep surface of the hypertrophied. Onychogryphosis is are embedded in paraffin, and are nail plate.23 most commonly caused by infrequent stained with haematoxylin, eosin, PAS, White superficial onychomycosis is nail cutting and impaired peripheral cir- and toluidine blue.23 This method, also normally limited to the toenails. It pres- culation but may also be caused by called “PATHPAS,” has been shown to ents with small well-defined superficial trauma.28 be the most sensitive test.30,32,34 One white patches on the nail that can merge Repeated trauma to the nails, which study evaluated 105 patients with sus- to cover the entire nail.16,23 The diseased can increase the risk of onychomycosis,5 pected onychomycosis using KOH nails are brittle and may crumble. The can cause distal onycholysis with subse- preparation, culture, with PAS vast majority of the cases are caused by quent microbial colonization and altered stain, and biopsy with calcoflur white the fungus Trichophyton interdigitale. pigmentation.24 In addition, a subungual stain. Biopsy with calcoflur white stain Total dystrophic onychomycosis is hematoma from trauma may cause dis- was considered the gold standard. The the most severe clinical manifestation of colorations that can be confused with study found that the KOH preparation onychomycosis. In this form, the entire onychomycosis.25 was 80% sensitive and 72% specific,

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biopsy with PAS stain was 92% sensi- even slower and require a longer dura- Topical antifungals alone do have a tive and 72% specific, and culture was tion to treat.15 Several modalities can be place for the reduction of relapses and 59% sensitive and 82% specific.34 used for the treatment of onychomycosis reinfection once the initial infection has Direct examination. Collected in diabetic patients: topical therapy, sys- been fully treated.14 One author recom- pieces are placed on a slide and treated temic therapy, combination therapy, and mends using a miconazole nitrate 2% with 10–30% KOH solution. The slide nail removal.15,23 Patients > 55 years of powder every 3 days to the web spaces may be warmed over a flame to quicken age may have a higher rate of relapse. In to prevent relapses once the initial infec- the clearing of the nail and highlight the addition, patient education is vital to tion has been completely treated.14 fungal features. Some recommend a reduce the risk of recurrence. Many combination of KOH and dimethylsul- studies have compared the mycological Oral therapy foxide for clearer and faster results.23 cure rates, recurrence rates, and cost- Many studies have evaluated systemic Onychomycosis caused by dermato- effectiveness of the various treatment treatments for onychomycosis in the phytes can be diagnosed based on the options. Although it has been shown that general population. However, diabetic appearance of long, regularly-shaped diabetic patients with onychomycosis patients with onychomycosis pose a spe- hyphae. If yeasts are the etiological have a higher rate of complications and cial problem because they frequently agent, the appearance of budding spores infections than diabetic patients without take other medicines and have other can often be seen.21 Although the appear- onychomycosis,10 to our knowledge, no health problems.36 ance of the nail may provide clues to the study has compared treatment options Oral agents (summarized in Table 1) etiological agent, it cannot be used to with outcomes such as diabetic compli- are absorbed via the circulation through diagnose the agent.23 cations or secondary infections. the nail bed and take ~ 7 days to reach Culture. Culture alone without clini- minimal inhibitory concentration (MIC). cal manifestations should not be used to Topical therapy Once administration of the drug is dis- diagnose onychomycosis.21 Cultures There are three classes of topical anti- continued, it can remain active in the nail may be positive without a truly invasive fungal creams: polyenes (e.g., nystatin), for up to 90 days, and the nail does not infection because of contamination with imidazoles (e.g., clotrimazole), and ally- need to be completely clear before the comorbid onychodystrophy.5 For culture, lamines-benzylamines (e.g., ). is stopped.14 samples from the nail plate and subun- All three are active against Candida,but was the standard oral gual keratosis should be placed in only imidazoles and allylamines-benzy- therapy for onychomycosis for > 30 Sabouraud’s agar and incubated at 26º C lamines are active against dermato- years. However, it has a narrow thera- for 7–14 days.20,23 Antibiotics in the agar phytes.20 In general, topical therapy is peutic window and significant adverse prevent the growth of coexisting bacte- not adequate for clearing nail infections, reactions. It also has several interactions ria. If possible, samples should be placed probably because of inadequate penetra- with other drugs and is active only on agar both with and without cyclohex- tion of the medication into the affected against dermatophytes, with a cure rate imide because cycloheximide inhibits tissues and nail bed.23 The exception to of < 40%. For these reasons, it is rarely the growth of most nondermatophytes.23 this is superficial white onychomycosis, used today to treat onychomycosis.23 Unfortunately, culture is less sensitive which is easily treated with a topical The imidazole class of than direct microscopy, especially when agent because the organism grows on is active against most of the organisms a patient has already been given treat- the upper nail plate rather than in the that cause onychomycosis. However, ment. However, culture is the only nail bed. they are not approved for the treatment method available for identification of the nail lacquers are available of onychomycosis in the United States. specific , which may be helpful for treating onychomycosis and pene- is slightly more effica- in the choice of therapy, particularly if trate the nail better than creams and gels. cious than griseofulvin but also has the nails do not respond to therapy with One lacquer contains the active ingredi- many adverse effects and drug interac- oral terbinafine (discussed below).20 ent , which is in a new class tions.20 It is rarely used to treat ony- of antifungals, the morpholines. Another chomycosis today.23 , 300 Treatment of Onychomycosis lacquer contains , which has a mg once a week for 6 months, is more in Diabetes broader spectrum of activity.23 Nail lac- efficacious and has been shown to be The treatment of onychomycosis in dia- quers are applied daily for 48 weeks, and safe.37 betic patients is the same as in patients once-weekly removal with nail polish , a triazole antifungal, without diabetes.13 Toenails grow at one- remover is required. Mycological cure binds more specifically to fungal third to one-half the rate of fingernails rates (negative results on microscopy cytochrome P-450 than other azoles, and thus need to be treated longer.23 and fungal culture) in U.S. studies have reducing the incidence of side effects. It Elderly diabetic patients’ nails may grow been as high as 36%.35 is active against dermatophytes Candida

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FEATURE ARTICLE er y v ed for er function test er function test er function test ing/Other v v v ppr ov A-a bnor mality bnor mality yc homycosis 6–8 w eeks a a er function tests v on Monitor Li Renal function tests Not FD imm une-suppressed patients Pretrea tment li Pretrea tment li Pretrea tment li e pills Complete blood count e ug v pine tes pines in patients with known he patic er s er s ylline Complete blood count in ylline xin ar in ar in ar in eine uride pamil f actions arf arf arf -bloc k Sta tins er a ypo gl ycemics k -Bloc Dig o 2 Caf W W W erf enadine olbutamide Phenytoin heoph heoph V Buspirone ␤ T H a Barbitur T T T om ycin Er ythr Clarithrom ycin Common Dr Benzodiaz e Methylprednisolone Or al h Hydr oc hlorothiazide in patients with known he patic Pr oton pump inhibitor s Or al contr acepti ects Inter f Rash Rash Rash omiting omiting Glipizide Nausea Nausea Cimetidine Nausea Diarrhea Diarrhea Diarrheayb Gl Diarrhea Ur itcaria V V Dizziness Antacids he Headac he Headac Common Fla tulencee Carbamaz disturbance Side Ef aste disturbance Gastr ointestinal Abdominal pain Anticonvulsants T 6 w eekshe Headac 6 w eeks 12 w eeks 12 w eeks Dyspepsia tment s lear c ea oenails: T ing er nails: Length of Tr 6–9 months F 12–18 months Until infection oenails: oenails: ing er nails: ing er nails: T F ge 200 mg ycosis eekl y dail y month w tion hom 1 w eek eac h T 150–300 mg 500–1,000 mg yc or On yte a Administr tions f anisms Dosa some some some twice daily f or g molds, molds, molds, Candida spp. Or T Candida spp. Candida spp. ma tophytes Der ma tophytes, Der ma tophytes,Der Pulse: ma tophytes,Der 250 mg dail y F nonder ma tophyte nonder ma toph nonder ma tophyte NO ood and Dr ug al Medica ole ole Or ine .S .F U le 1. A, iseofulvin ug aconaz erbinaf Dr Gr Fluconaz Itr T FD Tab

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and but not Scytalidium,a shown to be as efficacious as continuous (5.6%), and dyspepsia (4.3%). Liver .23 Because it is lipid-soluble, it therapy.44,45 enzyme abnormalities occurred in remains in the nail plate long after the Terbinafine does not have any signif- 3.3%.53 Common adverse reactions drug is discontinued. It has been detect- icant interactions with oral hypo- occurring while patients took itracona- ed 6 months after discontinuation after a glycemic drugs.46 One study examining zole to treat onychomycosis of the toe- 3-month course. Using 200 mg daily for the safety and efficacy of terbinafine nails included headache (10%), 3 months achieved a mycological cure found that although 9.1% of diabetic (9%), upper respiratory tract infection rate of 79% 6 months after therapy.38 subjects had serious adverse events (8%), and sinusitis (7%). Liver enzyme Because of the high cost of itraconazole, while on terbinafine, no causal relation- elevations caused discontinuation of a pulse regiment has been formulated ship between the drug and the events therapy in 4%.54 With both agents, the and tested. Pulse treatment involves could be found. It was concluded that frequency of adverse events is compara- using 200 mg twice daily for 1 week terbinafine is relatively safe in diabetic ble to placebo.52 The manufacturer of during each of 2 months in fingernails patients and is acceptable for the long- terbinafine recommends obtaining pre- and 3 months in toenails. Pulse therapy term maintenance of healthy nails in dia- treatment liver function tests in all has been reported to be just as effective betic patients.47 patients and monitoring a complete as continuous therapy with fewer Studies comparing continuous blood count in immunosuppressed adverse events and half the cost.39 terbinafine and continuous itraconazole patients receiving terbinafine for > 6 Azole antifungals, including itra- have shown mixed results. One study weeks.53 The manufacturer of itracona- conazole and fluconazole, have been found a 73% mycological cure rate for zole recommends obtaining liver func- shown to elevate levels of oral hypo- continuous terbinafine compared with tion tests only in patients who have pre- glycemic drugs.15 Nevertheless, systemic 45.8% in continuous itraconazole for 12 existing liver function abnormalities or therapy with itraconazole has been found weeks. Both drugs were well tolerated.48 who have had liver abnormalities while to be safe and effective for use in diabet- Another study comparing continuous on other medications.54 ic patients at a dose of 200 mg twice dai- terbinafine and pulse itraconazole in eld- Another consideration in choosing ly.40,41 No statistically significant changes erly patients for 12 weeks plus an addi- medications is cost, especially consider- in hemoglobin A1c levels have been not- tional 4 weeks, if needed, after 6 months ing the long course of treatment for ony- ed in diabetic patients receiving pulse found a mycological cure rate for contin- chomycosis. One study examined the itraconazole for 3 months.40 uous terbinafine of 64% compared with total cost of therapy for continuous Terbinafine, an allylamine antifungal 62.7% for pulse itraconazole.49 A second terbinafine compared with continuous drug, is the first-line agent for treating study of 496 patients with onychomyco- itraconazole. This study included the onychomycosis. Unlike itraconazole’s sis comparing continuous terbinafine costs for the initial physician visit, fol- wide spectrum of activity, terbinafine is with pulse itraconazole found that after low-up visits, mycology, various recom- only active in vivo against dermato- 72 weeks in groups who were treated for mended laboratory investigations while phytes and does not treat Candida or 12 weeks, 75.7% of the terbinafine patients are on the medications, and the mold species.23 Terbinafine, 250 mg group achieved a mycological cure com- costs for treating the various adverse once daily for 3 months, has been shown pared with 38.3% in the itraconazole reactions that could be expected for each to achieve a mycological cure rate of group. In groups who were treated for 16 of the medications. The final cost to treat 82% in toenail onychomycosis and 71% weeks, 80.8% of the terbinafine group onychomycosis with continuous in fingernail onychomycosis.42 In one achieved a mycological cure compared terbinafine was $697.55–$699.11 com- multicenter trial, 89 patients with dia- with 49.1% in the itraconazole group.50 pared with $1,216.40–$1,218.80 for con- betes (both insulin dependent and A third study looked at long-term cure tinuous itraconazole.55 However, the non–insulin dependent) and onychomy- and relapse rates in continuous costs are comparable if pulse itracona- cosis were treated with continuous oral terbinafine compared with pulse itra- zole is compared with continuous terbinafine, 250 mg for 12 weeks, and conazole for 12 and 16 weeks. After 5 terbinafine. were followed for 36 weeks posttreat- years, 47% of the terbinafine group com- ment. After 48 weeks, a mycological pared with 13% of the itraconazole Combination therapy cure rate of 73% was achieved. There group still had negative mycology.51 Combining oral and topical antifungals were no reported episodes of hypo- The newer antifungal agents, includ- is a newly developed treatment option glycemia.36 Another study of 81 diabetic ing terbinafine and itraconazole, rarely that increases the likelihood of a cure. patients with onychomycosis found cause serious adverse reactions.52 Com- One study showed improved efficacy of equal efficacy of terbinafine in individu- mon adverse reactions occurring while terbinafine when combined with topical als with and without diabetes.43 Pulse patients took terbinafine included amorolfine.56 Another showed improved therapy with terbinafine has not been headache (12.9%), diarrhea (5.6%), rash efficacy of continuous itraconazole

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when combined with topical be vigilant in its diagnosis and complete 10Bokyo WL, Doyle JJ, Ryu S, Gause D: 57 Onychomycosis and its impact on secondary amorolfine. Yet another compared in its treatment. infection development in the diabetic population. three groups of patients: those who The most sensitive method for diag- Presentation at the 4th annual meeting of the International Society for Pharmacoeconomics and received terbinafine (4 weeks on, 4 nosis is pathology with PAS staining. Outcomes Research, Arlington, Va., 1999 weeks off) and 48 weeks of topical Culture is also important to guide the 11Levy LA: Epidemiology of onychomycosis ciclopirox; those who received continu- choice of therapy. Currently, the most in special-risk populations. J Am Podiatr Med ous terbinafine for 12 weeks and 48 effective therapy is 250 mg of oral Assoc 87:546–550, 1997 weeks of ciclopirox; and those who terbinafine daily for 12 weeks, possibly 12Scher RK: Onychomycosis: a significant medical disorder. J Am Acad Dermatol 35:S2–S5, received only 12 weeks of continuous with concomitant topical therapy with a 1996 terbinafine without topical antifungal nail lacquer, such as amorolfine or 13Gupta AK, Humke S: The prevalence and medicine. Mycological cure was seen in ciclopirox. Patients should be treated management of onychomycosis in diabetic 66.7, 70.4, and 56.0%, respectively.58 until mycological cure is achieved, and patients. Eur J Dermatol 10:379–384, 2000 Another study found a mycological cure they must be followed closely for recur- 14Rich P: Onychomycosis and tinea pedis in patients with diabetes. J Am Acad Dermatol 43 (5 rate of 88.2 versus 64.7% when continu- rent infection. If the causative organism Suppl.):S130–S134, 2000 ous terbinafine for 16 weeks was com- is a or mold, pulse itraconazole 15Rich P: Special patient populations: ony- bined with topical ciclopirox for 9 should be used instead. After treatment, chomycosis in the diabetic patient. J Am Acad months.59 suppressive topical therapy may be used, Dermatol 35:S10–S12, 1996 such as miconazole nitrate 2% powder 16Martin ES, Elewski BE: Cutaneous fungal infections in the elderly. Clin Geriatr Med Nail removal, avulsion every 3 days. In addition, patient educa- 18:59–75, 2002 Removal of diseased nails can be used tion, including proper foot and toe exam- 17Agency for Healthcare Research and Quali- as an adjunctive therapy but not as the inations, is essential to prevent relapses ty: HCUPnet, Healthcare Cost and Utilization sole therapy for onychomycosis.23 and complications. Project. Rockville, Md., Agency for Healthcare Research and Quality, 2000 Surgical nail avulsion is rarely used to REFERENCES 18Gordois A, Scuffham P, Shearer A, Oglesby treat onychomycosis in diabetic A, Tobian JA: The health care costs of diabetic patients because of their increased risk peripheral neuropathy in the US. Diabetes Care 1National Institute of Diabetes and Digestive 26:1790–1795, 2003 for secondary infections, gangrene, and and Kidney Diseases: National diabetes statistics 19 poor wound healing.60 However, in fact sheet: general information and national esti- Reiber GE, Boyko EJ, Smith DG: Lower mates on diabetes in the United States, 2005. extremity foot ulcers and amputation in diabetes. severe or refractory cases, nail removal Bethesda, Md., U.S. Department of Health and In Diabetes in America. Bethesda, Md., National may be used.20 It may also be used Human Services, National Institutes of Health, Diabetes Data Group, National Institutes of 2005 Health, National Institute of Diabetes and Diges- when oral therapy is contraindicated or tive and Kidney Diseases, 1995 2 3,61 Faergemann J, Baran R: Epidemiology, clini- ineffective. cal presentation and diagnosis of onychomycosis. 20Tom CM, Kane MP: Management of toenail Br J Dermato 149 (Suppl.):1–4, 2003 onychomycosis. Am J Health Syst Pharm 56:865–871, 1999 Education 3Rich P, Hare A: Onychomycosis in a special High-risk diabetic patients, especially patient population: focus on the diabetic. Int J 21Lateur N, Mortaki A, Andre J: Two hundred Dermatol 38 (Suppl. 2):17–19, 1999 ninety-six cases of onychomycosis in children those with peripheral neuropathy or and teenagers: a 10-year laboratory survey. Pedi- 4Gupta AK, Konnikov N, MacDonald P, Rich atr Dermatol 20:385–388, 2003 peripheral vascular disease, need to be P, Rodger NW, Edmonds MW, McManus R, educated about proper foot and leg Summerbell RC: Prevalence and epidemiology of 22Kemna ME, Elewski BE: A U.S. epidemio- 14 toenail onychomycosis in diabetic subjects: a logic survey of superficial fungal diseases. J Am examinations. In patients with a history multicentre survey. Br J Dermatol 139:665–671, Acad Dermatol 35:539–542, 1996 of onychomycosis, it is especially 1998 23Hay RJ, Baran R, Haneke E: Fungal (ony- important to examine the web spaces, 5Pierard GE, Pierard-Franchimont C: The nail chomycosis) and other infections involving the heels, and perionychium for any breaks under fungal siege in patients with type II dia- nail apparatus. In Diseases of the Nails and their betes mellitus. Mycoses 48:339–342, 2005 Management. Baran R, Dawber RPR, de Berker in the skin.14 It is important to stress that DAR, Haneke E, Tosti A, Eds. Malden, Mass. 6Lugo-Somolinos A, Sanchez JL: Prevalence Blackwell Science, 2001 patients cannot rely solely on discomfort of in patients with diabetes. J or pain because of decreased sensation.14 Am Acad Dermatol 26:408–410, 1992 24Elewski BE: Onychomycosis: pathogenesis, diagnosis, and management. Clin Microbiol Rev 7Alteras I, Saryt E: Prevalence of pathogenic 11:415–429, 1998 Conclusion fungi in the toe-webs and toe-nails of diabetic patients. Mycopathologia 67:157–159, 1979 25Mahoney JM, Bennet J, Olsen B: The diag- Onychomycosis is an important cause of nosis of onychomycosis. Dermatol Clin 8Romano C, Massai L, Asta F, Signorini AM: 21:463–467, 2003 morbidity in diabetic patients, increasing Prevalence of dermatophytic skin and nail infec- their risks for limb amputation and local tions in diabetic patients. Mycoses 44:83–86, 26Jaffe R: Onychomycosis: recognition, diag- 2001 nosis, and management. Arch Fam Med and systemic secondary bacterial infec- 7:587–592, 1998 tions. Because onychomycosis is more 9Dogra S, Kumar B, Bhansali A, Chakrabarty A: Epidemiology of onychomycosis in patients 27Mayeaux EJ Jr: Nail disorders. Prim Care common in diabetic patients and can with diabetes mellitus in India. Int J Dermatol 27:333–351, 2000 41:647–651, 2002 complicate the disease, clinicians must 28Singh G, Haneef NS, Uday A: Nail changes

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[Discussion Br J Dermatol 134 superficial fungal infections: focus on onychomy- 37Zisova LG: Fluconazole in the treatment of (Suppl. 46):38, 1996] cosis and dry tinea pedis. J Am Osteopath Assoc onychomycosis. Folia Med 46:47–50, 2004 97:339–346, 1997 49Gupta AK, Konnikov N, Lynde CW: Single- 38Willemsen M, De Doncker P, Willems J, blind, randomized, prospective study on Woestenborghs R, Van de Velde V, Heykants J, terbinafine and itraconazole for treatment of der- Van Cutsem J, Cauwenbergh G, Roseeuw D: matophyte toenail onychomycosis in the elderly. Jason A. Winston is a 4th-year medical Posttreatment itraconazole levels in the nail: new J Am Acad Dermatol 44:479–484, 2001 implications for treatment in onychomycosis. J student at Vanderbilt University School Am Acad Dermatol 26:731–735, 1992 50Evans EG, Sigurgeirsson B: Double blind, of Medicine in Nashville,Tenn. 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166 Volume 24, Number 4, 2006 • CLINICAL DIABETES