A Patient With Cutaneous Zygomycosis Due to Saksenaea vasiformis

We report a case of cutaneous zygomycosis caused by Saksenaea vasiformis, an organism rarely implicated in human infection despite its worldwide distribution in soil. Because it fails to sporulate on commonly used mycology media, laboratory diagnosis can be delayed or not made. In contrast to disseminated zygomycosis, cutaneous infection is not uniformly fatal. However, it can be associated with significant morbidity and mortality, particularly if treatment is delayed or inadequate. We present a case that highlights the aggressive nature of this infection and briefly review the literature around this organism. Case Report. A 44-year-old man presented to the General Surgical service at Middlemore Hospital, Auckland, New Zealand with an ulcerating lesion on his right lower shin. Five months earlier he had sustained an oyster shell injury to his leg whilst submerged in mud for several minutes. Initially there was a small, superficial laceration, and over time an enlarging inflammatory lesion developed. Before admission he had completed a course of oral flucloxacillin and amoxycillin-clauvulanate. At presentation he described a 24-hour history of increasing bloody ooze from the wound, pain, and chills. An ulcer measuring 5×5 cm was present on the posterior aspect of the right mid calf. It had a necrotic center with surrounding erythema and edema. Examination was otherwise normal. There was no relevant past medical history. On the day of admission the patient was treated empirically with intravenous flucloxacillin (2.0 g, 6 hourly) and metronidazole (0.5 g 8 hourly), and the macroscopically involved skin, subcutaneous tissue, and muscle were surgically debrided. Staphylococcus aureus was isolated from a wound swab taken at admission. Histological examination of resected dermis, subcutis, and muscle demonstrated marked inflammation, focal necrosis, and hemorrhage. Periodic Acid Schiff (PAS) staining revealed broad, branching, aseptate fungal hyphae suggestive of a zygomycete. The patient was discharged taking itraconazole 400 mg twice daily. Follow-up arrangements failed, and he presented a month later with a nonhealing surgical wound and recurrence of his symptoms. He underwent surgical debridement. Fungal elements were seen in histologic specimens, and a rapidly growing filamentous fungus was cultured from tissue. Hyphae seen in mounts were broad, sparsely septate, and typical of a zygomycete fungus. Despite the rapid growth of the fungus it failed to sporulate initially on Sabouraud’s dextrose agar, potato dextrose agar, tap water, or cornmeal-sucrose-yeast-extract agar. Sporulation was achieved on Czapek Dox after 8 days incubation with the development of typical flask-shaped sporangia consistent with Saksenaea vasiformis. The sporangia are typically long-necked and flask-shaped, arising from dichotomously branched, darkly pigmented rhizoids. They become filled with oblong shaped sporangiospores that are eventually extruded out of the apical opening of the sporangium. Itraconazole was replaced by amphotericin B (0.25 mg/kg daily, increasing to 1.0 mg/kg daily). The patient developed gastrointestinal side effects and acute renal impairment that resolved after stopping amphotericin B and commencing liposomal amphotericin (1mg/kg daily, increasing to 5 mg/kg daily). The patient later developed an acute right posterior tibial neuropathy, indicating involvement of the nerve, either by direct infection or infarction. More extensive debridement was performed and fungal elements persisted in specimens from the edges of debrided tissue. In light of the invasive nature of the infection the patient had an above knee amputation, and 10 more days of liposomal amphotericin. He received 4.6 g of amphotericin before the amputation, and 9.4 g in total. Resection margins were clear. Histologic examination of the posterior tibial neurovascular bundle demonstrated chronic inflammatory infiltrate in the neural and perineural tissue, vasculitis, and occasional fungal elements in a vein and within perineural tissue. At follow up 4 months after amputation there was no evidence of recurrent disease. Discussion. Zygomycosis is an aggressive infection caused by saprophytic fungi of the class Zygomycetes, order Mucorales. They are ubiquitous in the environment, but are an uncommon cause of human infection. There are six recognized clinical forms of zygomycosis: rhinocerebral, pulmonary, cutaneous, gastrointestinal, central nervous system, and disseminated. Risk factors for infection include immunosuppression, diabetic ketoacidosis, trauma, burns, protein-calorie malnutrition, iron overload, and use of desferrioxamine. Increasingly, cutaneous disease is being seen in patients without underlying illness, with a history of trauma to the site of infection [1]. Saksenaea vasiformis is a rare cause of zygomycosis. Ajello et al. described the first report of human infection caused by S. vasiformis in 1976 [2]. A MEDLINE search identified 22 reported cases [2–21] (23 including this case). Almost two-thirds of patients were men, with an age range of 3 months to 72 years (median age 29 years). This is the first case report of this rare fungal infection in New Zealand. There is complete clinical data available for 22 of the 23 patients. Seventeen patients had disease involving the skin and/or soft tissue. In two patients the infection extended beyond soft tissue, with one patient developing contiguous osteomyelitis [3] and the other developing pulmonary lesions [4]. All but 2 [5,6] of these 17 patients with skin/soft tissue infection had a history of injury or nosocomial break in the skin at the site of subsequent infection, providing a route of inoculation for the fungus. Eleven of the 17 patients had no known immune compromise. Of the remaining six patients, one had thalassemia and was asplenic [7], two had diabetes [8,9], one had a malignancy [10], one had a deep burn wound [11], and one had received high dose corticosteroids [12]. The majority of patients (11) were treated with surgical debridement and amphotericin B, and 9 were cured. One patient died of pulmonary S. vasiformis [3], and another died of an unrelated cause [9]. Five patients had surgical debridement alone, curing the infection in three cases. Of the remaining two patients, one died after a cardiac arrest thought to be due to S. vasiformis sepsis [9], and the other of candidemia [12]. Incomplete debridement and amphotericin B cured one patient [13]. In total, 4 of the 17 patients with skin/soft tissue infection died, and in 2 of these the cause of death was attributed to the infection. Disseminated and rhinocerebral disease are not common presentations of S. vasiformis, reported in three and two patients respectively. These patients were more likely to have underlying immunocompromise (one of three with disseminated, one of two with rhinocerebral) and in all of these patients the infection was fatal regardless of treatment [14–18]. We have presented a patient with an unusual cause of zygomycosis. The diagnosis was not made on the first presentation, and appropriate therapy was delayed. A number of issues are highlighted by this case. In contrast to cases of zygomycosis caused by more commonly isolated organisms (Rhizopus species), patients with S. vasiformis are less likely to be immunocompromised. The possibility of zygomycosis with a cutaneous presentation in a nonimmunocompromised patient should not be discounted. We reiterate the importance of aggressive surgical resection with clear wound margins as the mainstay of treatment, and that amphotericin B is the sole drug known to have activity against this organism. Our experience in caring for this patient has also emphasized the value of a multi-disciplinary approach to a difficult clinical problem, and the need for ongoing communication and cooperation between the surgeons, histopathologists, microbiologists, and infectious diseases physicians.