While research has shown that onychomycosis is more common in patients with diabetes, we need to be cognizant of different etiologies and perhaps reexamine those when an initial treatment course fails to get results.1
A 36-year-old woman presented with a six-month history of a discolored toenail of the right great toe.
She was a moderately overweight Caucasian woman with a 20-year history of juvenile-onset diabetes mellitus. She had poor to moderate control of her disease.
She never suffered serious episodes of diabetic ketoacidosis as a result of her diabetes and had not previously experienced opportunistic infections. Her overall health had been good. She had no occupational or domestic exposure to soil, pigeons, decaying grass or leaf mold. She had no history of travel.
The physical examination confirmed an abnormal, geographic, uniform yellow-tan demarcated area of discoloration in the nail. There was no evidence of thickening, dystrophy, flaking or brittleness. The discoloration of the nail was distinct in comparison to the other toenails. We presumptively diagnosed and treated it as onychomycosis.
The patient underwent treatment with 250 mg of oral terbinafine hydrochloride (Lamisil, Novartis) daily for 12 weeks. On follow-up at six and 18 weeks, there was no effect on the discolored area of the nail although it had grown out sufficiently to permit us to send nail clippings for cultures.
The laboratory prepared and cultured the nail clippings on Sabouraud agar. The fungus was a rapidly growing pathogen with mycelia, pigmented rhizoids and grooved sporangiospores. The fungus assimilated ethanol, glycerol and adonitol but not lactose or nitrate. These findings were consistent with Rhizopus species.
Rhizopus ssp. are opportunistic fungi that sometimes colonize the oropharyngeal cavities and sinuses of healthy individuals.2 In immunosuppressed people or those with chronic diseases such as cancer or diabetes, disease due to Rhizopus may occur.2,3 Percutaneous introduction of Rhizopus spores into wound sites may cause extra-oropharyngeal infection or infection by direct contact with the fungus in the soil may occur.2,4,5
Rhizopus ssp. has worldwide distribution.2 While it is commonly found in soil, it can have other ecological niches including fresh fruits such as strawberries or pigeon droppings.6,7 Rhizopus can be a normal commensal in the sinuses and is rarely pathogenic. Due to its nonpathogenic presence in the sinuses, disease due to Rhizopus is most commonly rhinocerebral, orbital or pulmonary.2,8,9 Researchers have also identified Rhizopus ssp. postoperatively in patients who have undergone sternotomy, those on peritoneal dialysis, patients with leukemia/lymphoma, patients with other cancers, those who have had organ transplant procedures and in those with systemic lupus erythematosus.3,10,11
Rhizopus is rarely pathogenic except in settings of immunosuppression or, as in this patient, in people with diabetes and episodes of hyperglycemia. The significant risk of Rhizopus infection is its angioinvasive tendency, which can lead to thrombosis and necrosis. Sites of infection other than the sinuses and lungs can be due to percutaneous introduction of spores from injuries. When there is systemic involvement, treatment with amphotericin B is indicated.2
Tinea ungium or onychomycosis is typically caused by dermatophytes such as Trichophyton or Microsporum ssp.12,13 Researchers have recognized a wider range of fungal infections of the toenails including common fungi such as Candida or Aspergillus or exotic species such as Scytalidium and Acremonium.12-14 Often the causal agent of onychomycosis is based on geography. Infection of the feet or toenails by Rhizopus has been identified mostly in the developing world or Mideast.4,5
Treatment of onychomycosis is rarely successful with older antifungal regimens although fluconazole (Diflucan, Pfizer), itraconazole (Sporanox, Ortho McNeil) and terbinafine are usually effective with the dermatophytes.12,15 However, the present patient’s case demonstrates that newer medicines may not be effective with an exotic fungus.
The lack of fungal elements on histology was not unusual. It is not uncommon for the fungi not to be visible microscopically. This occurs in approximately 40 percent of culture-proven cases.15 The clinical appearance of the nail did not change in the course of treatment with terbinafine. This antifungal agent interferes with the enzyme squalene epoxidase to inhibit the formation of the fungus-associated lipid ergosterol. Loss of this cell membrane element is believed to cause increased fungal cell wall permeability and death. However, terbinafine is mostly effective in dermatophytes, of which Rhizopus is not a member. 
Based on this experience, we recommend the following protocol for treatment of a patient with an unusual fungal infection of the toenail.
On the first clinical evaluation, collection of the patient’s medical history is useful to anticipate atypical microbiology results. Physical examination of the infected toenail should include documentation of unusual patterns, discoloration or growth of the suspected fungus. Nail clippings for culture are essential. One should initiate treatment with standard therapy but in the event that this fungus grows in culture, consider an alternative treatment.
We have found avulsion of the nail with careful follow-up to be effective. The angioinvasive properties of Rhizopus seen in other settings do not appear to be a risk factor with onychomycosis, possibly because the nail matrix denies the fungus access to a significant blood supply and is an anatomic barrier to dissemination. However, one should report to the primary caregiver the presence of an opportunistic fungus in an at-risk patient in case the presence of one opportunistic fungi connotes a level of disease or immunosuppression that may warrant additional monitoring of the patient.
The patient had an infectious disease consultation to evaluate the risk of angioinvasion or other systemic complication. Considering that the fungus was limited to one nail, the assessment was an anomalous localized fungal infection with mechanical barriers to systemic infection so it did not require systemic treatment. Accordingly, the physician handled her treatment as a podiatric procedure.
After we discussed the treatment options, the patient chose total avulsion of the nail with the anticipation that a new nail might be free of fungus. Accordingly, we anesthetized the right great toe with a digital block of 1% lidocaine, removed the nail and sent the specimen for histologic examination. The patient tolerated the procedure well.
After softening the nail in potassium hydroxide, we sectioned the nail and prepared histologic slides. The slides included routine hematoxylin and eosin as well as a Gomori methenamine silver stain, which characteristically stains fungal elements. Microscopic examination showed lamellar dystrophy but no evidence of fungi.
The patient received a prescription for econazole nitrate 1% applied topically twice daily. At two months, new nail was growing from the matrix. At five months, nail growth was normal without evidence of dystrophy or recurrent fungus.
Dr. Carson is a consultant at Foot and Ankle Specialists of Iowa in Cedar Rapids, Iowa.
Dr. Nassif is in private practice at Foot and Ankle Specialists of Iowa.
Dr. Morse is the President of the American Society of Podiatric Dermatology. He is a Fellow of the American College of Foot and Ankle Surgeons, and the American College of Foot and Ankle Orthopedics and Medicine. Dr. Morse is board certified in foot surgery.
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