Treatment of onychomycosis in diabetic patients (2023)

Jason A.Winston;

Jami L. Miller, MD

Three types of fungi can cause nail infections in humans: dermatophytes (especiallyTrichophytonspecies), yeasts (eg.Candida albicans), and non-dermatophytic fungi.^2,20Dermatophytes make up the vast majority of infectious etiologies.²¹In one epidemiological study, dermatophytes were found in 82% of isolates andCandida albicansin ∼ 7%.²²

Infected nails appear thick, brittle and discolored, often with a yellow tinge. The nail plate may separate from the nail bed (onycholysis) and there may be inflammation of the skin near the edge of the nail (paronychial inflammation).²⁰

Onychomycosis has four classic clinical presentations in nails. Distal and lateral subungual infection is the most common type. In this pattern, the infection spreads proximally from the distal or lateral aspects of the nail, eventually elevating the free edge of the nail plate and causing onycholysis and thickening of the nail plate with subungual hyperkeratosis. The infection spreads proximally and causes yellow-brown discolorations.²³The most common organism isTrichophyton rubrum, followed byTrichophyton mentagrophyten. Candidaspecies also cause this pattern of infection, as do fungi such as theAspergillisInFusariumkind. When complicated by infection with pigmented fungi or bacteria such asPseudomonas aeruginosa, the nails may appear dark green to black.²³

Proximal subungual infection is rare, but more common in patients with AIDS and immunosuppression. In this pattern, the organisms invade through the proximal nail fold and spread to the nail matrix and then to the deep surface of the nail plate.²³

White superficial onychomycosis is normally limited to the toenails. It presents with small well-defined superficial white spots on the nail that may coalesce to cover the entire nail.^16,23The diseased nails are brittle and can crumble. The vast majority of cases are caused by the fungusTrichophyton interdigitale.

Total dystrophic onychomycosis is the most serious clinical manifestation of onychomycosis. In this form, the entire nail except for small fragments is destroyed, leaving a thickened nail bed.²³

Only 57% of diabetic patients with abnormal-appearing toenails are confirmed to have onychomycosis.⁴Common conditions including psoriasis, lichen planus, onychogryphosis, trauma and idiopathic dystrophic nails are included in the differential diagnosis.

Psoriasis is the most common condition similar to onychomycosis²⁴and may show subungual hyperkeratosis, onycholysis and onychodystrophy of the entire nail.²³Although psoriasis usually also has classic manifestations on other skin areas, it can be limited to the nails. Pits and "oil drops" are much more common in psoriasis than in onychomycosis.^23,24Often with psoriasis, a "salmon patch" will be present, an irregular yellow or pink area under the nail plate. This does not occur in onychomycosis.²⁵

Patients with lichen planus may have nail manifestations of the disease.²⁴Clinicians should carefully examine the extremities and mucous membranes of the patient for the pathognomic violet-like papules.²⁶Lichen planus can affect both fingernails and toenails, making them brittle and ridged. Subungual hyperkeratosis and distal onycholysis may also occur.²⁷

Onychogryphosis is a severe deformity of the nail, usually affecting the big toes. The nail becomes very thick and discolored, resembling a ram's horn. The nail bed can become hypertrophied. Onychogryphosis is usually caused by occasional nail clipping and impaired peripheral circulation, but can also be caused by trauma.²⁸

Repeated trauma to the nails, which can increase the risk of onychomycosis,⁵can cause distal onycholysis with subsequent microbial colonization and altered pigmentation.²⁴In addition, a subungual hematoma from trauma can cause discolorations that can be confused with onychomycosis.²⁵

Normal nails can show morphological variations, especially as an individual ages. White spots and lines in the nails, leukonychia punctata and striated leukonychia are benign and can result from minor trauma to the nail matrix.²⁷Onycholoysis can be idiopathic or caused by trauma.²⁸Dermatophytes can be found in idiopathic onycholysis but are considered commensal.²⁹

The standard of care in diagnosing onychomycosis is a clinical impression with one confirmatory laboratory finding, such as KOH-prepared direct microscopy, fungal culture, or histopathology with periodic acid-Schiff stain (PAS).^30-32It is important to verify clinical suspicion with laboratory tests. One study compared the cost of empirical treatment of all patients with onychodystrophy with antifungal drugs versus PAS staining of all nails and treatment of only those with positive histology. The study found that it was cost-effective to first diagnose and then treat empirically.³³

Samples for microscopy, culture, or histopathology can be collected from the nail plate or subungual debris. Care should be taken when collecting a sample in diabetic patients to avoid damaging the nail bed, which may increase the risk of a secondary bacterial infection.¹⁵

Histological examination.Most clinicians find it easiest to send nail clippings for histopathological evaluation with a PAS stain. Clippings are sent to the pathology lab in formalin, embedded in paraffin, and stained with hematoxylin, eosin, PAS, and toluidine blue.²³This method, also called "PATHPAS", has proven to be the most sensitive test.^30,32,34One study evaluated 105 patients with suspected onychomycosis using KOH preparation, culture, biopsy with PAS staining, and biopsy with calcoflur white staining. Biopsy with calcoflur white spot was considered the gold standard. The study found that the KOH preparation was 80% sensitive and 72% specific, biopsy with PAS stain was 92% sensitive and 72% specific, and culture was 59% sensitive and 82% specific.³⁴

Instant inquiry.Collected pieces are placed on a slide and treated with 10-30% KOH solution. The slide can be heated over a flame to speed up nail clearing and emphasize fungal features. Some recommend a combination of KOH and dimethyl sulfoxide for clearer and faster results.²³Onychomycosis caused by dermatophytes can be diagnosed based on the appearance of long, regularly shaped hyphae. If yeasts are the etiological agent, the appearance of budding spores can often be seen.²¹Although the appearance of the nail can provide clues to the etiological agent, it cannot be used to diagnose the agent.²³

Culture.Culture alone without clinical manifestations should not be used to diagnose onychomycosis.²¹Cultures may be positive without a truly invasive infection due to contamination with comorbid onychodystrophy.⁵For culture, nail plate and subungual keratosis samples should be placed in Sabouraud's agar and incubated at 26°C for 7-14 days.^20,23Antibiotics in the agar prevent the growth of coexisting bacteria. If possible, samples should be placed on agar both with and without cycloheximide, as cycloheximide inhibits the growth of most non-dermatophytes.²³Unfortunately, culture is less sensitive than direct microscopy, especially when a patient has already been treated. However, culture is the only method available for identification of the specific pathogen, which may be helpful in the choice of therapy, especially if the nails do not respond to oral terbinafine therapy (discussed below).²⁰

The treatment of onychomycosis in diabetic patients is the same as in non-diabetic patients.¹³Toenails grow at one-third to one-half the rate of fingernails and therefore require longer treatment.²³The nails of older diabetic patients may grow even more slowly and require longer treatment times.¹⁵Different modalities can be used for the treatment of onychomycosis in diabetic patients: local therapy, systemic therapy, combination therapy and nail removal.^15,23Patients older than 55 years may have a higher risk of relapse. In addition, patient education is vital to reduce the risk of recurrence. Many studies have compared the mycological cure rates, recurrence rates and cost-effectiveness of the different treatment options. Although diabetic patients with onychomycosis have been shown to have more complications and infections than diabetic patients without onychomycosis,¹⁰to our knowledge, no study has compared treatment options with outcomes such as diabetic complications or secondary infections.

There are three classes of topical antifungal creams: polyenes (eg, nystatin), imidazoles (eg, clotrimazole), and allylamines-benzylamines (eg, terbinafine). All three are actively opposedCandida, but only imidazoles and allylamines-benzylamines are active against dermatophytes.²⁰In general, topical therapy is not sufficient to cure nail infections, probably due to insufficient penetration of the medication into the affected tissues and nail bed.²³The exception to this is superficial white onychomycosis, which is easily treated with a topical agent because the organism grows on the top nail plate rather than in the nail bed.

Antifungal nail polishes are available for the treatment of onychomycosis and penetrate the nail better than creams and gels. One lacquer contains the active ingredient amorolfine, which is part of a new class of antifungal agents, the morpholines. Another varnish contains ciclopirox, which has a broader spectrum of activity.²³Nail polishes are applied daily for 48 weeks and removal with nail polish remover once a week is required. Mycological cure rates (negative results on microscopy and fungal culture) in US studies were as high as 36%.³⁵

Topical antifungals alone have a place in the reduction of recurrences and re-infection once the initial infection has been fully treated.¹⁴One author recommends using a miconazole nitrate 2% powder on the webs every 3 days to prevent relapse once the initial infection has been fully treated.¹⁴

Many studies have evaluated systemic treatments for onychomycosis in the general population. However, diabetic patients with onychomycosis pose a special problem because they often take other medications and have other health problems.³⁶

Oral agents (summarized in Table 1) are absorbed through the circulation through the nail bed and take approximately 7 days to reach minimum inhibitory concentration (MIC). Once the drug is discontinued, it can remain active in the nail for up to 90 days, and the nail does not need to be completely clear before stopping the drug.¹⁴

Griseofulvin was the standard oral therapy for onychomycosis for more than 30 years. However, it has a narrow therapeutic window and significant side effects. It also has several interactions with other drugs and is only active against dermatophytes, with a <40% cure rate. For these reasons, it is rarely used to treat onychomycosis today.²³

The imidazole class of drugs is active against most organisms that cause onychomycosis. However, they are not approved for the treatment of onychomycosis in the United States. Ketoconazole is slightly more effective than griseofulvin, but also has many side effects and drug interactions.²⁰It is rarely used to treat onychomycosis today.²³Fluconazole, 300 mg once a week for 6 months, is more effective and has been shown to be safe.³⁷

Itraconazole, a triazole antifungal agent, binds more specifically to fungal cytochrome P-450 than other azoles, reducing the incidence of side effects. It is active against dermatophytesCandidaInAspergillusbut notScytalidium, a mold.²³Because it is fat soluble, it remains in the nail plate long after the drug is discontinued. It was discovered 6 months after discontinuation after a 3 month course. The use of 200 mg per day for 3 months achieved a mycological cure rate of 79% 6 months after therapy.³⁸Due to the high cost of itraconazole, a pulse regiment has been developed and tested. Pulse treatment involves using 200 mg twice daily for 1 week for each of 2 months in fingernails and 3 months in toenails. Pulse therapy has been reported to be as effective as continuous therapy with fewer side effects and half the cost.³⁹

Azole antifungals, including itraconazole and fluconazole, have been shown to increase levels of oral antidiabetic drugs.¹⁵Nevertheless, systemic therapy with itraconazole has been shown to be safe and effective for use in diabetic patients at a dose of 200 mg twice daily.^40,41No statistically significant changes in hemoglobin A_1clevels have been observed in diabetic patients receiving pulse itraconazole for 3 months.⁴⁰

Terbinafine, an allylamine antifungal medication, is the first-line agent for the treatment of onychomycosis. In contrast to the broad spectrum of action of itraconazole, terbinafine is only active against dermatophytes in vivo and does not treatCandidaof schimmelsoorten.²³Terbinafine 250 mg once daily for 3 months has been shown to achieve a mycological cure rate of 82% in toenail onychomycosis and 71% in fingernail onychomycosis.⁴²In one multicenter study, 89 patients with diabetes (both insulin-dependent and non-insulin-dependent) and onychomycosis were treated with continuous oral terbinafine 250 mg for 12 weeks and followed for 36 weeks post-treatment. After 48 weeks, a mycological cure rate of 73% was achieved. There were no reported episodes of hypoglycaemia.³⁶Another study in 81 diabetic patients with onychomycosis found equal efficacy of terbinafine in subjects with and without diabetes.⁴³Pulse therapy with terbinafine has not been shown to be as effective as continuous therapy.^44,45

Terbinafine has no significant interactions with oral antidiabetic drugs.⁴⁶A study examining the safety and efficacy of terbinafine found that although 9.1% of diabetic patients experienced serious side effects while taking terbinafine, a causal relationship between the drug and the events could not be found. It was concluded that terbinafine is relatively safe in diabetic patients and acceptable for the long-term maintenance of nail health in diabetic patients.⁴⁷

Studies comparing continuous terbinafine and continuous itraconazole have produced mixed results. One study found a mycological cure rate of 73% for continuous terbinafine compared to 45.8% for continuous itraconazole over 12 weeks. Both drugs were well tolerated.⁴⁸Another study comparing continuous terbinafine and pulse itraconazole in elderly patients for 12 weeks plus an additional 4 weeks, if needed, after 6 months found a mycological cure rate for continuous terbinafine of 64% compared to 62.7% for pulse itraconazole.⁴⁹A second study in 496 patients with onychomycosis, comparing continuous terbinafine to pulsed itraconazole, showed that after 72 weeks in groups treated for 12 weeks, 75.7% of the terbinafine group achieved mycological cure compared to 38.3 % in the itraconazole group. In groups treated for 16 weeks, 80.8% of the terbinafine group achieved mycological cure compared to 49.1% in the itraconazole group.⁵⁰A third study looked at long-term cure and relapse rates on continuous terbinafine compared to pulsed itraconazole over 12 and 16 weeks. After 5 years, 47% of the terbinafine group compared to 13% of the itraconazole group still had negative mycology.⁵¹

The newer antifungal drugs, including terbinafine and itraconazole, rarely cause serious side effects.⁵²Common adverse reactions that occurred while patients were taking terbinafine were headache (12.9%), diarrhea (5.6%), rash (5.6%) and dyspepsia (4.3%). Liver enzyme abnormalities occurred in 3.3%.⁵³Common adverse reactions that occurred while patients were taking itraconazole to treat toenail onychomycosis were headache (10%), rhinitis (9%), upper respiratory tract infection (8%), and sinusitis (7%). Liver enzyme elevations caused therapy discontinuation in 4%.⁵⁴With both drugs, the frequency of side effects is comparable to placebo.⁵²The manufacturer of terbinafine recommends pre-treatment liver function tests in all patients and complete blood counts in immunosuppressed patients receiving terbinafine for > 6 weeks.⁵³The manufacturer of itraconazole recommends that liver function tests be performed only in patients with pre-existing liver function abnormalities or who have had liver abnormalities while taking other medications.⁵⁴

Another consideration when choosing medications is cost, especially given the long course of treatment for onychomycosis. One study examined the total cost of therapy for continuous terbinafine compared to continuous itraconazole. This study included the cost of the initial doctor's visit, follow-up visits, mycology, various recommended lab tests while patients are on the drugs, and the cost of treating the various side effects that can be expected for each of the drugs. The final cost for the treatment of onychomycosis with continuous terbinafine was $697.55-$699.11 compared to $1,216.40-$1,218.80 for continuous itraconazole.⁵⁵However, the cost is similar when comparing pulse itraconazole to continuous terbinafine.

Combining oral and topical antifungals is a newly developed treatment option that increases the chances of a cure. One study showed improved efficacy of terbinafine when combined with topical amorolfine.⁵⁶Another showed improved efficacy of continuous itraconazole in combination with topical amorolfine.⁵⁷Yet another compared three groups of patients: those who received terbinafine (4 weeks on, 4 weeks off) and 48 weeks of topical ciclopirox; those who received continuous terbinafine for 12 weeks and 48 weeks of ciclopirox; and those who received terbinafine continuously for only 12 weeks with no topical antifungal agent. Mycological cure was observed in 66.7, 70.4 and 56.0%, respectively.⁵⁸Another study found a mycological cure rate of 88.2 versus 64.7% when continuous terbinafine for 16 weeks was combined with topical ciclopirox for 9 months.⁵⁹

Removal of diseased nails can be used as an additional therapy, but not as the only therapy for onychomycosis.²³Surgical nail avulsion is rarely used to treat onychomycosis in diabetic patients because of their increased risk of secondary infections, gangrene, and poor wound healing.⁶⁰However, in severe or refractory cases, nail removal may be used.²⁰It can also be used when oral therapy is contraindicated or ineffective.^3,61

High-risk diabetic patients, especially those with peripheral neuropathy or peripheral vascular disease, should be educated about appropriate foot and leg exams.¹⁴In patients with a history of onychomycosis, it is especially important to examine the webspaces, heels, and perionychium for any breaks in the skin.¹⁴It is important to emphasize that patients cannot rely solely on discomfort or pain due to decreased sensation.¹⁴

Onychomycosis is a major cause of morbidity in diabetic patients, increasing their risk of limb amputation and local and systemic secondary bacterial infections. Because onychomycosis is more common in diabetic patients and can complicate the disease, clinicians must be vigilant in diagnosis and comprehensive in treatment.

The most sensitive method of diagnosis is pathology with PAS staining. Culture is also important to guide therapy choice. Currently, the most effective therapy is 250 mg oral terbinafine per day for 12 weeks, possibly with concomitant topical therapy with a nail varnish, such as amorolfine or ciclopirox. Patients should be treated until mycological cure is achieved and closely monitored for recurrent infection. If the causative organism is a yeast or fungus, pulse itraconazole should be used instead. After treatment, suppressive topical therapy can be used, such as miconazole nitrate 2% powder every 3 days. In addition, patient education, including proper foot and toe examinations, is essential to prevent relapses and complications.

American Diabetes Association

2006