Onychomycosis and Diabetes: Patient Case Challenges

Onychomycosis is a common infection that can lead to potentially severe complications in patients who have impaired circulation, peripheral neuropathy, or are immunocompromised. This infection is particularly common in patients with diabetes, many of whom have one or more of these conditions. Onychomycosis treatment reduces risks, but is complicated by the potential for drug-drug interactions between systemic antifungals and the large number of medications often taken by these patients. Several topical therapies are available, including two newer agents that became available in 2014, increasing the potential for individualized treatment selection.

The following case-based activity will test your ability to select appropriate therapies in patients with type 2 diabetes and onychomycosis, while bringing you up to date on risks and management of toenail infections in this vulnerable patient population.

Case :

Albert is a 55-year-old man with type 2 diabetes who presents to your office with thickened, elongated, yellowed toenails (picture shown below). He reports that he first noticed the changes in his toenails about 3 months ago, at which time most of his nails were already involved. Albert was diagnosed with type 2 diabetes 4 years ago, and his blood sugar is currently poorly controlled on metformin alone. He has elevated triglyceride levels for which he is taking a low dose of simvastatin. He is clinically obese, which may have contributed to the fact that he did not notice his toenail infection until it was well entrenched.

On clinical examination, you observe that all of Albert’s toenails are yellow in color and 6 have white lateral streaks. Two nails show involvement extending proximally to the lunula. Several nails, including both great toenails, show subungual hyperkeratosis that is greater than 2 mm thick and two are onycholytic. You estimate that at least 75% of the overall area of Albert’s toenails is infected, with involvement seen in all 10 toenails.

Which of the following clinical characteristics is a risk factor for onychomycosis in patients with diabetes?
A. Female sex
B. Neuropathy
C. Renal dysfunction
D. Younger age

Answer: B. Neuropathy

Discussion: Patients with diabetes can develop peripheral neuropathy, which contributes to the risk of developing onychomycosis, perhaps because this condition impedes proper foot care and allows unrecognized trauma to the nail. 

Men with diabetes are approximately 3 times more likely to develop onychomycosis compared with women with diabetes, and the prevalence of onychomycosis increases with age. Onychomycosis does not seem to be linked to the presence or absence of renal dysfunction in patients with diabetes.

Onychomycosis and Diabetes
Onychomycosis is highly prevalent in patients with diabetes. A North American study of 550 consecutive patients with diabetes found abnormal-appearing toenails in 46% of patients and mycological evidence of onychomycosis in 26% of patients. After adjusting for age, the researchers calculated a 34.9% prevalence in the overall US diabetes population, an estimate that is similar in other studies. Onychomycosis was 2.77 times more likely in patients with diabetes compared with individuals without diabetes. Prevalence in the one-third of patients with type 1 diabetes in this study was lower but still elevated compared with individuals without diabetes, with an odds ratio of 1.69. Onychomycosis was also 3 times more likely in men compared with women with diabetes.


Patients with diabetes have a number of comorbidities that increase their risk of developing onychomycosis, including peripheral neuropathy, compromised immunity, and poor circulation in their extremities. In addition to increasing the risk for developing onychomycosis, these conditions raise the risk that fungal infection will lead to serious complications. Fungal infection causes thickening of the nail, which can in turn lead to subungual ulcerations that go unnoticed in patients with reduced pedal sensibility until bacterial infection sets in or the nail is debrided. These infections can lead to ulceration, gangrene, osteomyelitis, and ultimately to amputation. Onychomycosis is associated with a 2.2-fold increased risk for developing acute bacterial cellulitis even in patients without diabetes, and this risk is exacerbated by cutaneous barrier disruption, being overweight, and a history of venous insufficiency. Additional risk factors for onychomycosis in patients with diabetes include advancing age, male sex, obesity, retinopathy, and a family history of onychomycosis.

Onychomycosis has deleterious effects on quality of life (QoL) in patients with or without diabetes. A telephone survey of 258 patients with confirmed onychomycosis identified nail-trimming problems, embarrassment, pain, nail pressure, and discomfort wearing shoes as common problems. Onychomycosis can have a financial impact on patients in the form of missed workdays and increased medical costs, and may spread to other family members, affecting their QoL as well.

Longer duration of diabetes is associated with increased onychomycosis severity, suggesting a progressive course that might be slowed or halted by early intervention. Given the potential for serious complications as well as its effects on QoL, onychomycosis treatment is an important aspect of care in patients with diabetes.

Which of the following would be the most appropriate treatment recommendation for Albert?
A. Manage within primary care
B. Refer to dermatology
C. Refer to diabetology
D. Refer to podiatry

Answer: D. Refer to podiatry

Discussion: Current foot care guidelines in patients with diabetes recommend overall management by a podiatrist or other specialist with training in the care of the diabetic foot. Podiatrists can perform mechanical debridement or other surgery that may improve response to antifungal therapy.

Care of the Diabetic Foot
The majority of diabetes-related lower extremity amputations occur as a result of a diabetic foot ulcer. Current diabetes management guidelines recommend yearly foot exams that include visual inspection of skin and foot structure, as well as evaluation for poor circulation and loss of protective sensation in the feet, ankles, and lower legs.

Patients with diabetes who are deemed at higher risk for foot infections should be evaluated more frequently. In increasing order of risk, this includes patients with peripheral neuropathy; patients with neuropathy, peripheral arterial disease, and foot deformities; and patients with a history of foot ulcer or amputation. High-risk patients or patients who have developed foot infections will benefit from referral to a podiatrist or other specialist with training in the care of diabetic feet In addition to evaluating and treating onychomycosis, podiatrists can perform mechanical debridement of the nails or other surgical treatment that may improve the response to pharmacologic therapies. Debridement can also reduce pain and improve the appearance of infected nails.

Diagnosis and Evaluation of Onychomycosis
Onychomycosis can develop in a number of clinical patterns, three of which are commonly found in patients with diabetes.

Distal and lateral onychomycosis (DLSO) is the most common presentation caused by dermatophyte infection. In DLSO, the fungus invades from the distal or lateral margins, causing the nail to become thickened and discolored. The nail plate may separate from the nail bed (onycholysis), becoming friable and eventually breaking up in some cases. DLSO is most commonly caused by the fungus Trichophyton rubrum, but it is important to identify the infecting organism because nondermatophyte infection can have a similar presentation.

Superficial white onychomycosis (SWO) occurs when the fungal infection starts in the top surface of the nail plate and spreads down into deeper layers. SWO takes the form of crumbling white lesions that may spread to involve the entire nail. SWO is usually caused by Trichophyton interdigitale (also sometimes referred to as Trichophyton mentagrophytes, particularly in older literature).

In proximal subungual onychomycosis (PSO), the fungal infection starts at the proximal nail fold or beneath the proximal nail plate, and the distal portion of the nail stays normal until late in the disease course. Most cases of PSO involve the toenails and are caused by T rubrum. Traditionally, PSO has been associated with HIV/AIDS infection, although it also occurs as a result of trauma such as when the cuticle is disturbed during a pedicure.

In the North American study of onychomycosis in patients with diabetes, 76% of patients had DLSO alone, 10% had SWO alone, 7% had DLSO plus SWO, and 0.7% had SWO plus PSO. In addition, 5.5% of patients with infections had clinically normal-looking toenails but evidence of onychomycosis on mycological inspection. The infecting organisms in patients with diabetes were predominantly dermatophytes (54% T rubrum and 44% T interdigitale), with 3% of infections caused by Candida species and 9% caused by nondermatophyte molds. This distribution is similar to findings in nondiabetic populations from the same geographical regions.

Diagnosis of Onychomycosis
Accurate diagnosis of onychomycosis is important because of the possibility of nail dystrophies that are not the result of fungal infection.

Noninfectious conditions that can mimic onychomycosis include 

• chronic trauma, 
• psoriasis, 
• onycholysis, 
• onychogryphosis,
•  subungual malignant melanoma, and 
• lichen planus, among others. 

Laboratory confirmation of fungal infection is recommended before starting treatment to rule out dystrophies from other causes, to identify the type of fungus involved, and to detect mixed infections.

The laboratory tests that are most commonly used to diagnose onychomycosis include potassium hydroxide (KOH) dissolution of nail clippings (including subungual debris and superficial scrapings as appropriate) followed by microscopic examination to identify fungal hyphae and spores, periodic acid Schiff (PAS) staining of clippings for histological examination, and fungal culture, in which nail clippings are sent to a diagnostic laboratory where they are cultured to reveal the possible presence of fungi.

KOH testing can be performed in the office, while PAS testing is performed in a diagnostic laboratory, with results returned in a few days.

 Fungal culture is the slowest method, taking 2 to 6 weeks to show results, but is the best method for accurate identification of the fungal species. However, fungi can be difficult to grow, and fungal culture can be negative when other methods indicate the presence of an infection. A 2017 meta-analysis of studies comparing these tests found that PAS staining was the most sensitive, while fungal culture was the most specific. However, the investigators noted that none of the tests has high utility on their own, and argue for the use of all 3 tests to establish a diagnosis, identify the organism involved, and evaluate the extent of nail involvement.

Several molecular methods for identifying infecting organisms in onychomycosis, including polymerase chain reaction (PCR)-based testing, have been developed in recent years. Although PCR is rapid and sensitive, it may also detect dead or non-pathogenic fungi. Further development of these methods is needed before they will be ready for use in routine clinical practice.

Case Continued: Diagnosis
Albert's nails are debrided as much as possible and cleaned with alcohol to remove bacteria and debris. You clip samples from the distal edge of a few of the nails and lift one of the onycholytic nails to take a sample from underneath. Results of PAS testing indicate that the infecting organism is a dermatophyte, most likely T rubrum. You decide to begin treatment based on this finding, which is later confirmed by a positive culture.

Which of the following treatment options would be most appropriate for Albert?
A. Ciclopirox topical solution, 8%, once daily for 48 weeks with removal of unattached nails
B. Itraconazole 200 mg orally once daily for 12 weeks
C. Tavaborole topical solution, 5%, once daily for 48 weeks
D. Terbinafine 250 mg orally once daily for 12 weeks

Answer: D. Terbinafine 250 mg orally once daily for 12 weeks

Discussion: This patient has severe onychomycosis based on the extent of his nail involvement, as well as multiple poor prognostic factors, necessitating treatment with a systemic agent. Terbinafine would be the optimal choice because, unlike itraconazole, it would not be subject to drug-drug interactions with the statin that Albert is also taking.

Severity of Onychomycosis and Prognostic Indicators
The severity of onychomycosis is usually determined by clinical observation, including estimation of the percentage of nail involvement. Although a range of standards have been used, recent clinical trials have considered up to 20% involvement to be mild disease, 20% to 50% or 60% to be moderate disease, and greater than 50% or 60% to be severe disease.
The Onychomycosis Severity Index (OSI) was developed as a standardized tool for assessing disease severity. In addition to guiding initial choice of management, more objective assessment of disease severity could allow for more accurate evaluation of therapeutic efficacy over time. Parameters evaluated in the OSI include percent area of nail involvement, proximity of disease to the matrix, presence of longitudinal streaks or patches, and the height of subungual hyperkeratosis. While primarily a research tool, the OSI identifies disease features that clinicians should consider when evaluating patients. The OSI study team identified a number of patient and disease factors that may also be useful in evaluating a patient's prognosis and considering treatment plans.

                                                  Poor prognostic factors in onychomycosis.

Treating Onychomycosis
Selection of treatment for onychomycosis depends on disease severity, the infecting organism, and the potential for adverse effects of treatment including drug-drug interactions. The last consideration is of particular importance in patients with diabetes, who are likely to be taking multiple additional medications.

Treatment options include 

• oral or topical antifungal medications; 
• device-based therapies such as laser treatment, photodynamic therapy, iontophoresis, or ultrasound; and 
• mechanical or surgical interventions.

Systemic Therapies for Onychomycosis
Oral antifungals that are commonly used to treat onychomycosis are divided into 2 classes: 

1. the azoles, which are represented by itraconazole and fluconazole, and 
2. the allyamine compound terbinafine. 

Itraconazole and terbinafine are US Food and Drug Administration (FDA)-approved for use in onychomycosis; fluconazole is not, but is sometimes used as an alternative treatment. These agents have good efficacy in onychomycosis, but are associated with a slight risk of serious side effects.

All three of these systemic antifungal agents carry a risk for drug-drug interactions. Intraconazole is a substrate and strong inhibitor of cytochrome P450 3A4 (CYP3A4). Its metabolism may be affected by strong inhibitors or inducers of this pathway, and its inhibitory effect may increase the serum concentration of other drugs metabolized by that enzyme. Itraconazole also inhibits P-glycoprotein and can increase serum concentrations of drugs transported by that protein. Fluconazole is a strong inhibitor of CYP2C9 and CYP2C19 and a moderate inhibitor of CYP3A4, and can increase serum concentrations of drugs metabolized by those enzymes. Terbinafine is an inhibitor of CYP2D6 with similar effects on that enzyme's substrates; CYP2D6 inducers such as rifampin may also increase terbinafine clearance.

Itraconazole
Itraconazole is indicated for treating onychomycosis of the toenail or fingernail caused by dermatophytes in non-immunocompromised patients.Three double-blind placebo-controlled studies investigated the effects of 200 mg itraconazole once daily for 12 weeks in patients with onychomycosis of the toenails. Mycological cure (negative KOH findings plus negative culture) occurred in 54% of patients, mycological cure with clear or minimal residual nail involvement occurred in 35% of patients, and 14% of patients experienced a complete cure (mycological cure plus clearance of all clinical signs). Mean time to overall treatment success was approximately 10 months.

Itraconazole can be given continuously for 12 weeks or in a pulsed dose regimen, typically 400 mg itraconazole daily for 1 week followed by 3 weeks of treatment, and repeating this cycle for 3 or 4 months. Higher efficacy rates have been reported for this regimen, including 23% complete cure after 3 cycles and 26% complete cure after 4 cycles.Pulse regimens are not FDA-approved for toenail onychomycosis.

Common adverse events associated with oral itraconazole are gastrointestinal (GI) disturbance and rash. Itraconazole should be taken with meals. Its absorption may be reduced by therapies that reduce stomach acidity, including antacids and gastric acid secretion suppressors.

Itraconazole has a black box warning against its use in patients with ventricular dysfunction or congestive heart failure (CHF) or a history of CHF. There is a potential for life-threatening dysrhythmias in patients taking other CYP3A4-inhibiting drugs. Itraconazole has also been associated with rare cases of severe hepatotoxicity, and liver function monitoring is recommended during its use. Other rare but potentially serious side effects include CHF, peripheral edema, pulmonary edema, and transient or permanent hearing loss.

Terbinafine
Terbinafine is indicated for onychomycosis of the toenails or fingernails caused by dermatophytes. Two placebo-controlled clinical trials investigated the effects of 250 mg terbinafine once daily for 12 weeks in patients with onychomycosis of the toenails. Results were assessed at 48 weeks after treatment initiation. The first trial demonstrated a mycological cure rate of 70%, mycological cure plus no or limited nail involvement in 59% of patients, and complete cure in 38% of patients. Mean time to overall success was about 10 months.

Pulsed dose regimens have been tested for terbinafine, but a meta-analysis of available clinical data found continuous dosing regimens to have superior efficacy.

Terbinafine efficacy was examined in a case-control study of 460 patients with diabetes, 66 of whom were treated for onychomycosis of the toenails. Cure rates were similar to cure rates in patients without diabetes: 71.2% mycological cure (compared with 85% in matched controls) and 62.1% clinical cure (compared with 70% in matched controls).

Common adverse effects of terbinafine include headache, GI symptoms, rash, and pruritus.

Terbinafine is associated with hepatotoxicity and is contraindicated in patients with chronic or active liver disease. Pretreatment transaminase testing is recommended in all patients and periodic liver function testing is suggested. Terbinafine has also been associated with rare occurrences of thrombotic microangiopathy, taste and smell disturbances, depressive symptoms, exacerbations of lupus erythematosus, severe but reversible neutropenia, and severe skin reactions including Stevens-Johnson syndrome.

Fluconazole
Fluconazole is not FDA-approved to treat onychomycosis, but is sometimes used; it has the advantage of being given once weekly rather than daily, which may improve patient adherence. A randomized placebo-controlled dose-ranging study of fluconazole (150 mg, 300 mg, 450 mg) in patients with onychomycosis of the great toenail reported complete cure rates ranging from 28% to 36% at the end of therapy and 37% to 48% at 6-month follow-up. A 2013 meta-analysis of clinical trials that investigated the effects of fluconazole on onychomycosis of the fingernail or toenail found that the optimal regimen was 150 mg weekly for longer than 6 months.

Fluconazole is generally well-tolerated, but headache, GI symptoms, facial edema, rash, and pruritus have been associated with its use.

Fluconazole is contraindicated in combination with other agents that prolong the QT interval and are metabolized by CYP3A4 enzymes, including the antibiotic erythromycin. Fluconazole is associated with rare cases of severe hepatotoxicity and with exfoliative skin disorders. It should be used with caution in patients with liver dysfunction.

Topical Therapies for Onychomycosis

Ciclopirox Lacquer
Ciclopirox lacquer is indicated for treatment of mild to moderate onychomycosis (without lunular involvement) of the fingernails or toenails caused by T rubrum in immunocompetent patients. Ciclopirox is formulated as a nail lacquer to be used as part of a comprehensive management program that includes periodic removal of the unattached portion of infected nails by a healthcare professional with special competence in treating nail disorders.

Efinaconazole
Efinaconazole is approved for the treatment of onychomycosis of the toenails caused by T rubrum or T mentagrophytes. Efinaconazole is formulated as a topical 10% solution to be applied once daily for 48 weeks, using a proprietary integrated brush applicator. Debridement is not required.

Common adverse reactions seen in clinical trials of efinaconazole were ingrown toenails, application site dermatitis, application site vesicles, and application site pain. These were generally mild or moderate and transient, and similar to adverse events seen with vehicle alone.

Efinaconazole has no contraindications and neither inhibits nor induces CYP450 enzymes.[30]

Tavaborole
Tavaborole is indicated for onychomycosis of the toenails caused by T rubrum or T mentagrophytes. Tavaborole is formulated as a 5% topical solution to be applied using the manufacturer supplied dropper once daily for 48 weeks. Debridement is not required.

Common adverse events in clinical trials of tavaborole that occurred more frequently in patients treated with tavaborole compared with vehicle were application site exfoliation, ingrown toenail, application site erythema, and application site dermatitis.

Tavaborole has no contraindications and neither inhibits nor induces CYP450 enzymes.[33]

Case Conclusion
Based on the severity of Albert's onychomycosis, you decide to treat him with a systemic antifungal agent. Pretreatment transaminase testing is negative, making Albert an appropriate candidate for oral terbinafine, which will allow him to continue his statin therapy. You instruct Albert on lifestyle changes and personal hygiene measures that he can take to avoid recurrence. Although Albert experiences mild GI upset at first, these symptoms subside and he takes the full course of medication. At 6-month follow-up, you note that his nails have improved to approximately 40% to 50% involvement. You make sure Albert knows that it may take as long as 18 months for his toenails to fully clear and counsel him on the importance of taking proper care of his feet, with the aid of a professional if necessary.

Note: 

The article has been taken from Medscape.

Go to the link below for complete study of the given case and other similar cases:

http://www.medscape.org/viewarticle/877570_5