Diabetes mellitus is a major health problem in the United States, afflicting approximately 17 million people, with 1 million new cases diagnosed each year in people 20 and older.1 Patients with diabetes are at increased risk for toenail onychomycosis, which can cause discomfort, interfere with mobility, impair quality of life and lead to serious secondary infections and subsequent complications.2 Recent large epidemiological studies have shown the prevalence of onychomycosis in the diabetic population to be as high as 35 percent, compared to estimates ranging from 2 to 13 percent in the general population.3-5 Onychomycosis is a fungal infection that does not remit spontaneously. Over time, it can involve the entire nail unit and spread to other nails, as well as subungual and surrounding periungual tissue and adjacent skin. This compromises the integrity of the skin and may result in secondary bacterial infections and nail bed ulceration.6 Several studies have documented the negative effects of onychomycosis on physical and mental health, physical and social functioning, and physical appearance.7-9 What Are The Consequences Of Not Treating Onychomycosis? There is increasing evidence that onychomycosis is an important medical problem, particularly in the diabetic population. Onychomycosis contributes to the severity of the diabetic foot, especially when it is neglected. Diabetes patients who have peripheral sensory neuropathy and impaired circulation are at an increased risk of developing complications associated with onychomycosis. Predisposing factors such as advanced age, male gender, family history of onychomycosis, concurrent intake of immunosuppressive agents and peripheral vascular disease have been described in the literature.4 Thickened, dystrophic and/or brittle mycotic nails develop that may cause pressure erosions of the nail bed and hyponychium. The nails become sharp and cause injury to the surrounding skin, resulting in the formation of fissures that create a portal of entry for bacteria.3, 11, 12, 13 Unfortunately, the diabetic patient who has sensory neuropathy does not readily notice such breaks in the skin. If the natural course of onychomycosis is permitted to evolve in this setting, the patient may develop a progressive disability, paronychia, nail bed ulceration, cellulitis, serious deep space infections and tissue necrosis.4, 6, 11, 12, 14 Given the proximity of the nail bed to the underlying bone, be aware that neglected, infected nail bed erosion can lead to osteomyelitis among patients with diabetes, necessitating lower limb amputation.12,14 More than 60 percent of non-traumatic lower limb amputations in the United States are performed on patients with diabetes and are typically preceded by a diabetic foot ulcer. 1,15 Retrospective studies by Boyko, et. al., and Doyle, et. al., have evaluated onychomycosis and its impact on the development of secondary infections in patients with diabetes.16,17 Patients with onychomycosis or diabetes were identified from the Clinical Care in America Managed Care Database. Patients with diabetes who had been continually enrolled during 1995 and 1996 were identified in order to calculate the rates of secondary infection. The researchers found a 5.9 percent incidence of onychomycosis among patients with diabetes in contrast to the 0.8 percent incidence rate among non-diabetes patients. They also found that the incidence of secondary infections was higher among patients with onychomycosis and diabetes (16 percent) as opposed to diabetes patients without onychomycosis (6 percent). Furthermore, of 335 patients with diabetes, those with onychomycosis had a higher percentage of gangrene and/or foot ulcer compared to those without onychomycosis (12.2 percent vs. 3.8 percent).16,17 Given that onychomycosis poses a significant risk to the patient with diabetes due to the possible sequelae, effective and aggressive treatment strategies are necessary to prevent such complications.5,18 A Guide To Treatment Options When it comes to managing onychomycosis, the options are similar for treating the condition in diabetes patients as well as non-diabetes patients. (However, when you’re considering surgical or medical approaches or a combination approach, pay special attention to the diabetic patients who have a secondary infection superimposed upon a primary pathology as this can create the potential for serious complications.) Traditional means of treating onychomycosis, such as mechanical debridement and most topical antifungal medications, have significant limitations and are not curative. Following appropriate patient screening, you may consider oral antifungal therapy. Adding an oral antifungal to mechanical measures and patient education can provide a curative therapeutic approach in this at-risk patient population. Physical debridement of the fungal nail can effectively relieve the patient’s pain, assist in preventing subungual ulceration, reduce fungal load and improve the appearance of the nail.19 Although debridement is not curative, it plays an important role in managing the infection, providing symptom relief and helping to avoid serious morbidity.20,21 Less commonly, additional surgical measures, such as total or partial avulsion and total or partial matrixectomy, may be indicated for appropriate patients who need more aggressive treatment.14 However, keep in mind that while these modalities may offer comfort to the patient, they do not address the infection. Topical treatments for onychomycosis are also largely palliative and include ciclopirox 8% nail lacquer solution, which exhibits in vitro antifungicidal effects against a variety of fungi and some nondermatophyte molds associated with onychomycosis. Ciclopirox has been found to exhibit modest beneficial effects in clinical trials toward improving the appearance of the nail and is reportedly more effective than older topical agents. However, because long-term treatment for a minimum of 48 weeks is necessary, patient compliance may be suboptimal.22 While it is generally accepted that topical antifungal therapy may be beneficial in mild cases of onychomycosis involving the very distal nail plate, it is not considered effective in curing onychomycosis. That’s because nail plate penetration is insufficient, even when it is combined with palliative debridement or surgical removal of the nail and matrix.14,20 A study by Seebacher, et. al., evaluated the use of ciclopirox 8% nail lacquer solution in 215 patients with diabetes and onychomycosis.22 Patients applied the solution to affected toenails and fingernails once a day for six months. At the final assessment at six months, physicians rated the efficacy of ciclopirox. Results showed that the affected nail area was reduced from a mean of 64.3 percent at baseline to 25.7 percent at six months. Adverse events were mild to moderate with no serious events reported. While this treatment option provided an improvement, there was no record of complete cure rates of the fungal infection in these patients.22 What The Studies Reveal About Itraconazole And Terbinafine In clinical studies, the new generation oral antifungal agents itraconazole and terbinafine have each demonstrated efficacy in the treatment of patients with onychomycosis, although somewhat higher rates of efficacy and lower rates of relapse have been observed with terbinafine.19,23 A randomized, double-blind study of 496 patients with onychomycosis of the toenail compared the efficacy of continuous terbinafine for 12 or 16 weeks with intermittent itraconazole for three or four cycles.24 This study demonstrated that treatment with terbinafine at 250 mg/day over 12 or 16 weeks was associated with better mycologic and clinical cure rates at week 72 than treatment with intermittent itraconazole at 400 mg administered over the same period. Mycologic cure rates reported for the two dosage regimens of terbinafine were 76 percent and 81 percent respectively while clinical cure rates were 54 percent and 60 percent respectively. Mycologic cure rates reported for the two dosage regimens of itraconazole were 38 percent and 49 percent respectively while clinical cure rates were 32 percent and 32 percent respectively.24 In this study, there were no significant differences in adverse events reported between treatment groups, and most of these adverse events were considered by the investigators to be mild or moderate and unrelated to study medications. Albreski, et. al., evaluated the safety of itraconazole in 52 patients with diabetes and onychomycosis who were randomized to receive either itraconazole or standard palliative care.25 Although subjects were receiving a variety of concomitant medications, those requiring drugs metabolized by the cytochrome P450 3A enzyme system or those with baseline liver function tests greater than twice the upper limits of normal were excluded. One subject withdrew from the study because of elevated liver function tests, which returned to normal before the discontinuation of itraconazole. The three other adverse events reported (rash, diarrhea and pedal edema) were considered self-limiting and unrelated to medication. The efficacy and safety of terbinafine have also been evaluated in the diabetic population with onychomycosis.26,27 The following studies demonstrated that terbinafine is effective and well tolerated in this patient population. In a study by Farkas, et. al., 104 patients diagnosed with type 1 or type 2 diabetes and onychomycosis were treated with terbinafine for 12 weeks and followed up for 48 weeks. At week 48, mycologic and clinical cure rates were 71.1 percent and 59.6 percent, respectively, in patients with type 2 diabetes and 75.7 percent and 54.1 percent, respectively, in patients with type 1 diabetes.26 (See “A Closer Look At Terbinafine Treatment Cure Rates” above.) In this study, the researchers didn’t note any clinically relevant changes in the laboratory tests they performed. Adverse events were similar to those reported with terbinafine in the general population and they observed no drug interactions despite the use of multiple concomitant medications among the patient population. They also didn’t observe any hypoglycemic episodes during treatment. In a study by Rich, et. al., of 32 patients diagnosed with diabetes and onychomycosis, three mild to moderate adverse events in two patients were attributed to terbinafine.27 These adverse events included diarrhea, elevated y-glutamyltransferase and decreased taste sensation. No drug interactions were reported. Addressing Concerns Over Oral Agents And Drug Interactions In recent years, concern about adverse reactions associated with oral antifungal agents has generated controversy and discussion among healthcare providers. Attention has focused on the potential risk of drug interactions and hepatic enzyme abnormalities, since these agents are cleared by the hepatic system. Safety is of particular concern in those patients with diabetes who receive hypoglycemic agents among a variety of concomitant medications. Although triazoles such as itraconazole are more specific for fungal cytochrome P450 than for mammalian cytochrome P450, there is still the possibility of interactions with drugs that are metabolized via this pathway. Drugs such as oral midazolam, quinidine, triazolam and HMG CoA-reductase inhibitors, including lovastatin and simvastatin, are contraindicated for use with itraconazole. However, clinical evidence suggests the occurrence of hepatic enzyme abnormalities is no more frequent in patients with diabetes than in the general population and large post-marketing surveillance data are supportive.28 There is also no evidence that oral hypoglycemic drugs are metabolized via the same pathway as itraconazole. In clinical studies, most patients receiving concomitant oral hypoglycemic agents experienced no hypoglycemic episodes.5, 25 The ability of terbinafine to inhibit or induce the cytochrome P450 pathway is negligible and thus carries little potential for interactions with drugs that bind to these enzymes. The largest postmarketing survey of nearly 26,000 patients by Hall, et. al., reported the incidence of adverse events was 10.5 percent.29 These events were mild, transient and reversible, and included primarily gastrointestinal disturbances. Hepatobiliary events appeared no more frequently than in the general population. Most importantly, there were no adverse drug interactions reported among the 880 patients with diabetes who participated in this study.29 Given its different mechanism of action, terbinafine appears to cause few, if any, clinically relevant drug interactions. While the concomitant use of itraconazole with oral hypoglycemic agents is not a contraindication, careful monitoring of blood glucose levels is important. Clearly, this fact reinforces the use of terbinafine in the treatment of onychomycosis with concomitant oral hypoglycemic agents. Why Baseline Screening Is Essential A public health advisory was issued by the U.S. Food and Drug Administration in 2001 concerning the use of itraconazole capsules and terbinafine tablets in the treatment of onychomycosis. The advisory noted a small risk of developing congestive heart failure associated with the use of itraconazole. The FDA also noted that, in rare cases, severe liver failure may be associated with the use of itraconazole or terbinafine.30 Given the possibility of these risks, it is recommended that, after you obtain specimens for confirmation of the diagnosis, you should ensure proper screening of these patients via a baseline blood test to evaluate liver function. To further ensure safety, you may advise patients to have a second liver function test performed at the midpoint of therapy with an oral antifungal agent, although this is not mandatory. In addition, instruct your patients to report any adverse events immediately and to discontinue use of the medication until further notice from their physician. Oral antifungal agents should not be prescribed to those with preexisting liver disease. In Conclusion The current approach to treating onychomycosis in the diabetic population represents a significant shift from palliative maintenance care to more definitive curative treatment, which is best accomplished by the combination of appropriate surgical measures and the prescription of an oral antifungal agent.21 While podiatrists have traditionally treated onychomycosis with periodic debridement, nail avulsion and topical antifungal medication, recent evidence supports the medical efficacy of the newer generation oral antifungal agents. Recent evidence supports the medical efficacy of the newer generation oral antifungal agents in the treatment of onychomycosis in the diabetic patient population. Also be sure to emphasize proper foot care to patients. Encourage daily self-examination with careful inspection of nails, web spaces and heels. Perform periodic debridement and other appropriate surgical measures when indicated. In working with patients’ primary care physicians, you can offer a simple regimen with a high rate of effectiveness and few side effects. Furthermore, when patients with diabetes and onychomycosis are referred to you for more definitive care, they can undergo proper screening for risk factors associated with complications of untreated or inadequately treated onychomycosis and other foot problems. This screening may help reduce the risks of ulceration, gangrene and mutation.1, 2, 10, 12, 15, 16, 26, 31 By providing routine debridement, patient education and effective medical therapy in the form of one of the newer generation oral antifungal agents, we can focus on providing the most effective curative therapy in order to achieve a more successful outcome. Dr. Pollak is in private practice and is President of San Antonio Podiatry Associates, PC. He is a Clinical Assistant Professor in the Department of Orthopedics at the University of Texas Health Science Center. Editor’s Note: For related articles, see “Ten Pearls For Treating Difficult Nails” in the September 2002 issue and “Current Trends In Antifungal Therapy” in the May 2002 issue.
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