The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Contents lists available at ScienceDirect
The Journal of Foot & Ankle Surgery journal homepage: www.jfas.org
Case Reports and Series
Trichophyton Rubrum Osteomyelitis after Calcaneus External Fixation Pin Stabilization of a Pilon Fracture Gregory R. Waryasz, MD, Jason T. Bariteau, MD Department of Orthopaedic Surgery, Rhode Island Hospital, Brown University Warren Alpert Medical School, Providence, RI
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 4
Fungal organisms are an uncommon cause of osteomyelitis, and no dermatophyte osteomyelitis infections have been reported in published studies. We present the case of Trichophyton rubrum osteomyelitis of the calcaneus. Our patient initially presented with a pilon fracture requiring temporary external fixation while awaiting definitive fixation. From our review of the published data, the present case is the first of this type of fungal osteomyelitis to be reported. The patient was evaluated for a left neck mass during his hospitalization that was later found to be consistent with salivary duct carcinoma of the tail of the parotid gland. A left neck dissection and superficial excision of the parotid gland was performed after fixation of his pilon fracture. Subsequently, he developed an increasing lucency in the calcaneus and symptoms of pain and erythema months after the calcaneus pin had been removed. The osteomyelitis was treated with surgical debridement and 3 months of itraconazole once cultures had definitively grown T. rubrum. Ó 2014 by the American College of Foot and Ankle Surgeons. All rights reserved.
Keywords: bone dermatophytosis fungus infection itraconazole tibia trauma
Fungal osteomyelitis is a rare condition in both immunocompetent and immunocompromised individuals (1,2). The frequency has been increasing owing to the increase in immunocompromised patients. Common pathogens resulting in fungal osteomyelitis have included Candida, Histoplasma, Blastomyces, Coccidioides, Cryptococcus, Mucormycosis, and Sporothrix (1–4). Osteomyelitis can result from direct inoculation, contiguous infection, or hematogenous seeding (5). The typical findings of fungal osteomyelitis have included lytic lesions, with little new bone formation (2,6). The absence of new bone formation or periosteal reaction can make a diagnosis of fungal osteomyelitis more likely (2). Candida osteomyelitis is the most common cause of fungal osteomyelitis. The physical examination in 90% of patients with Candida osteomyelitis will find localizing pain, tenderness, and/or edema (5). The common sites in adults have been the vertebra, ribs, and sternum. The common sites in children have been the femur, humerus, vertebra, and ribs (5). Dermatophytes are a group of keratinophilic fungi that infect tissues with keratin, including the skin and nails (7,8). Dermatophytosis occurs in both immunocompetent and immunocompromised individuals (7). The global burden of dermatomycosis has been reported to be significant (9), with global prevalence estimated at as great as 20% (10).
Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Gregory R. Waryasz, MD, Department of Orthopaedic Surgery, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address: [email protected] (G.R. Waryasz).
The most common dermatophyte is Trichophyton rubrum. The common sources of T. rubrum have included moist walking surfaces, such as swimming pools, showers, locker rooms, and other barefoot walking locations (11). Immunocompromised patients are more likely to develop dermatophytosis. The conditions more commonly associated with deep dermatophytosis include leukemia, lymphoma, diabetes mellitus, Cushing syndrome, malnutrition, cirrhosis of the liver, and immunosuppressive drugs, including corticosteroids and chemotherapeutic agents (12). Chronic corticosteroid use can lead to a form of T. rubrum that can be resistant to antifungal agents until the cortisol levels have returned to normal (13). Case Report Our patient was a 52-year-old male who was a pedestrian struck by a motor vehicle moving at approximately 30 miles/hr. He was found to have a closed right pilon fracture. He was initially treated with an external fixator and calcaneal and proximal tibia pins (Fig. 1). His medical history was significant for hypertension and a previous fungal infection of toe nails refractory to over-the-counter remedies. While awaiting definitive fixation, he was also evaluated for an enlarged left posterior cervical subparotid lymph node and recurrent left-sided Bell’s palsy. He had undergone nondiagnostic fine needle aspiration of this lesion approximately 6 weeks before his trauma. He had a family history of gastric cancer, breast cancer, and prostate cancer. The patient reported a 34-pack year smoking history and only occasional alcohol use. The lymph node was biopsied and
1067-2516/$ - see front matter Ó 2014 by the American College of Foot and Ankle Surgeons. All rights reserved. http://dx.doi.org/10.1053/j.jfas.2014.02.015
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G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Fig. 1. Lateral radiograph on day of injury showing calcaneal pin from external fixator. Fig. 3. Radiograph 8 weeks postoperatively from fixation.
Fig. 2. Initial postoperative lateral ankle radiograph.
demonstrated histologic features consistent with adenocarcinoma. He was evaluated by the oncology service and the gastroenterology service for additional treatment. An upper endoscopy was performed because of concern for primary gastric adenocarcinoma. The gastric mucosal biopsy revealed no evidence of carcinoma; however, the patient had Helicobacter pylori-associated gastritis. Nine days after his initial injury, his soft tissue envelope allowed for definitive fixation of the right pilon fracture with a fibular fixation and reconstruction of the tibial plafond. The external fixation device was removed during the procedure, and the pin tracts were curetted and irrigated. All loose bone was removed from the pin tracts. The patient received perioperative antibiotics. He had no evidence of any active superficial skin infection with dermatophytes at that time at the pin sites. Approximately 1 month after right pilon fixation, he underwent left parotid superficial parotidectomy. The final pathologic findings were consistent with salivary duct carcinoma of the tail of the parotid gland with 9 of 23 lymph nodes positive. The pathologic TNM stage was pT2N2bM0. A left posterior cervical node was also excised, and pathologic examination showed 1 lymph node with metastatic adenocarcinoma. The submandibular gland was normal; however, 5 of 15 lymph nodes were positive for metastatic adenocarcinoma. The oncology service recommended adjuvant radiotherapy. The patient underwent 33 fractions of radiotherapy to a total dose of 66 Gy to the left parotid and lymph nodes. His right ankle did well for 8 weeks postoperatively (Figs. 2 and 3). He was then noted to have increased lucency in the area of the tract of
G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Fig. 4. Radiograph 10 weeks postoperatively from fixation.
the previous external fixation pin site in the calcaneus, which worsened during a 4-week period. He was compliant with casting and non-weightbearing on the injured extremity. Initially, he had no pain, drainage, or redness around this area. He then began to develop pain in his heel and over his anterior ankle dorsally, with mild fluctuance and erythema. The patient declined any additional imaging and wished to proceed with irrigation, debridement, and bone biopsy of the right calcaneal lesion. He was taken to the operating room approximately 12 weeks after the initial external fixation pin had been placed and 11 weeks after it had been removed (Figs. 4 and 5). Intraoperative cultures were performed that were negative for aerobic, anaerobic, and acidfast bacteria. No gross purulence was found. All fungal cultures were initially negative; however, 2 of 3 cultures grew T. rubrum at 13 days of incubation. The erythrocyte sedimentation rate (ESR) was 27 mm/hr and C-reactive protein (CRP) was 9.46 mg/L immediately after surgery. The infectious disease service had been monitoring the patient and began treatment of calcaneal osteomyelitis with itraconazole 200 mg twice daily for 3 months (Fig. 6). Monitoring the inflammatory markers, ESR and CRP, was challenging given his concurrent treatment of his left parotid adenocarcinoma with recent surgery and ongoing radiotherapy. After treatment with irrigation, debridement, and intravenous antibiotics, the patient had complete resolution of the symptoms of the calcaneal osteomyelitis. He had had no recurrence of his symptoms at the 14-month followup visit (Fig. 7).
3
Fig. 5. Radiograph 12 weeks postoperatively from fixation.
Discussion The definition of osteomyelitis in the 2012 study by Gamaletsou et al (5) regarding Candida osteomyelitis was as follows: 1. Compatible with clinical characteristics 2. Consistent radiographic features 3. Isolation of Candida in culture and/or histologic examination from bone or metal hardware Our patient had clinical redness and pain over the calcaneus, a large lytic area visible on radiographic examination, and a positive culture of T. rubrum in 2 cultures. Using these criteria, the patient had a clear diagnosis of osteomyelitis. The ESR and CRP level in fungal osteomyelitis can be normal or elevated and, therefore, will not always a good indicator of osteomyelitis. In our case, the patient had a normal ESR and CRP but had recently undergone left parotid excision and had been undergoing radiotherapy; therefore, these markers were difficult to monitor in our patient. A typical fungal culture can take 2 to 5 weeks to grow (14). Cultures from our operative debridement grew T. rubrum at 13 days. All our bacterial cultures were negative. The micro- and macroscopic pathologic examination did not show any granulomas; however, pathologic examination even with staining will not always show granulomas or the organism (2). We do not routinely stain for
4
G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Fig. 6. Radiograph 3 months postoperatively from debridement.
Fig. 7. Radiograph 14 months postoperatively from debridement.
potassium hydroxide, and our patient had no indications that he would have a fungal osteomyelitis; therefore, specific fungal staining was deferred. T. rubrum has been reported in published studies as the cause of both superficial and deep infections. Superficial manifestations of T. rubrum have included onychomycosis, tinea pedis (athlete’s foot), tinea cruris (jock itch), tinea barbae, and ringworm (12,15). Majocchi granulomas are granulomatous cutaneous lesions in the dermis and subcutaneous tissue due to the disruption of hair follicles and spillage of fungus into the dermis, leading to granulomatous reactions (12). Invasive or deep disease with subcutaneous involvement has usually been limited to immunosuppressed patients and the extremities but have not necessarily been associated with the hair follicles (16). The generalized invasive disseminated dermatophyte infection is rare and can be accompanied by nodules with an appearance similar to that of boils. This condition can lead to dissemination involving the internal organs, including lymph nodes, bone, muscle, liver, spleen, testes, central nervous system, and distant skin areas (16). T. rubrum syndrome is a disorder of lesions in the hands, feet, nails, and at least 1 lesion in another body part other than the groin; positive potassium hydroxide staining from 4 different locations, and a positive culture of T. rubrum from at least 3 of 4 locations (17). The patient we have described had a history of onychomycosis refractory to previous treatments. Eradication of chronic carriers of T. rubrum can require treatment of the foot and all shoe insoles. The successful treatment of insoles with T. rubrum colonization-infected skin scales can be achieved with either terbinafine 1% spray or powder (11). If treatment with
intravenous antifungal agents does not improve the condition, it would be reasonable to consider this type of eradication. Our patient responded well to intravenous itraconazole. Itraconazole inhibits the fungal cytochrome p450 enzyme c14-alphalanosterol demethylase, leading to growth arrest of the fungal cell wall by blocking the ergosterol biosynthesis pathway (9). Itraconazole had been used to treat the deep dermatophytosis in most of the documented case reports (12,18,19); however, we were unable to find any case reports of T. rubrum osteomyelitis. A caveat in the dosage of itraconazole is that it might alter other medication levels owing to its inhibition of fungal cytochrome 3a4 (19). Fluconazole has also been used for deep dermatophyte infections (16). Other active agents and supplemental therapies could include photodynamic treatment (20), hyperbaric oxygen (21), griseofulvin (22), terbinafine (11), miconazole, and calcofluor white (23). Amphotericin-B–infused bone cement has been attempted with adjuvant intravenous medications for Candida osteomyelitis but has not been consistently used (24). Ciclopirox and amorolfine have been used as topical agents for dermatophytes (14). Eugenol has been investigated in the laboratory to inhibit ergosterol biosynthesis in T. rubrum (25). Our case of T. rubrum osteomyelitis after temporary calcaneus external fixation pin placement for temporary stabilization of a pilon fracture is the first reported case of this type of dermatophyte osteomyelitis. Owing to the infrequency of all fungal osteomyelitis infections, standardized treatment regimens have not been developed. The recommendation has been to continue treat as long as the inflammatory markers remain elevated, patients are symptomatic, and the imaging findings have not improved. Our patient was treated
G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
for 3 months with 200 mg of intravenous itraconazole twice daily, with improvement in the imaging findings and no longer had any clinical symptoms. He experienced no negative side effects from the treatment. References 1. D’Antonio D, Piccolomini R, Fioritoni G, Iacone A, Betti S, Fazii P, Mazzoni A. Osteomyelitis and intervertebral discitis caused by blastoschizomyces capitatus in a patient with acute leukemia. J Clin Microbiol 32:224–227, 1994. 2. Kohli R, Hadley S. Fungal arthritis and osteomyelitis. Infect Dis Clin North Am 19:831–851, 2005. 3. De Guzman L, Perlman DC, Hubbard CE. Septic arthritis and osteomyelitis due to the chromoblastomycosis agent fonsecaea pedrosoi. Am J Orthop 41:328–331, 2012. 4. Shaw CJ, Thomason AJ, Spencer JD. Fungal osteomyelitis of the foot: a report of an unusual case. J Bone Joint Surg Br 76:137–139, 1994. 5. Gamaletsou MN, Kontoyiannis DP, Sipsas NV, Moriyama B, Alexander E, Roilides E, Brause B, Walsh TJ. Candida osteomyelitis: analysis of 207 pediatric and adult cases (1970–2011). Clin Infect Dis 55:1338–1351, 2012. 6. Chan YF, Woo KC. Penicillium marneffei osteomyelitis. J Bone Joint Surg Br 72:500–503, 1990. 7. Baltazar L, Soares BM, Silva Carneiro HC, Avila TV, Gouveia LF, Souza DG, Ferreira MVL, Pinotti M, de Assis Santos D, Casalpino PS. Photodynamic inhibition of Trichophyton rubrum: in vitro activity and the role of oxidative and nitrosative bursts in fungal death. J Antimicrob Chemother 68:354–361, 2013. 8. Carrillo-Munoz AJ, Tur-Tur C, Cardenes DC, Estivill D, Giusiano G. Sertaconazole nitrate shows fungicidal and fungistatic activities against Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum, causative agents of tinea pedis. Antimicrob Agents Chemother 55:4420–4421, 2011. 9. Diao Y, Zhao R, Deng X, Leng W, Peng J, Jin Q. Transcriptional profiles of Trichophyton rubrum in response to itraconazole. Med Mycol 47:237–247, 2009. 10. Marques SA, Robles AM, Tortorano AM, Tuculet MA, Negroni R, Mendes RP. Mycoses associated with AIDS in the third world. Med Mycol 31:269–279, 2000. 11. Feuilhade de Chauvin M. A study on the decontamination of insoles colonized by Trichophyton rubrum: effect of terbinafine spray powder 1% and terbinafine spray solution 1%. J Eur Acad Dermatol Venereol 26:875–878, 2012. 12. Gong JQ, Liu XQ, Xu HB, Zeng XS, Chen W, Li XF. Deep dermatophytosis caused by Trichophyton rubrum: report of two cases. Mycoses 50:102–108, 2007.
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13. Peixoto I, Maquine G, Francesconi VA, Francesconi F. Dermatophytosis caused by Trichophyton rubrum as an opportunistic infection in patients with Cushing disease. An Bras Dermatol 85:888–890, 2010. 14. Tchernev G, Penev PK, Nenoff P, Zisova LG, Cardoso JC, Taneva T, GinterHanselmayer G, Ananiev J, Gulubova M, Hristova R, Nocheva D, Guarneri C, Martino G, Kanazawa N. Onychomycosis: modern diagnostic and treatment approaches. Wien Med Wochenschr 163:1–12, 2013. 15. Martinez DA, Oliver BG, Gr€ aser Y, Goldberg JM, Li W, Martinez-Rossi NM, Monod M, Shelest E, Barton RC, Birch E, Brakhage AA, Chen Z, Gurr SJ, Heiman D, Heitman J, Kosti I, Rossi A, Saif S, Samalova M, Saunders CW, Shea T, Summerbell RC, Xu J, Young S, Zeng Q, Birren BW, Cuomo CA, White TC. Comparative genome analysis of Trichophyton rubrum and related dermatophytes reveals candidate genes involved in infection. mBio 3, 2012. e00259-12. € nu € l M, Sarac¸lı MA, Demiriz M, Gu € l U. Deep Trichophyton rubrum infection 16. Go presenting with umbilicated papulonodules in a cardiac transplant recipient. Mycoses 56:361–364, 2013. 17. Pineiro L, Larruskain J, Idigoras P, Perez Trallero E. Trichophyton rubrum syndrome: the tip of the iceberg and a preventable outcome. Mycoses 53:186, 2010. 18. Nir-Paz R, Elinav H, Pierard GE, Walker D, Maly A, Shapiro M, Barton RC, Polacheck I. Deep infection by Trichophyton rubrum in an immunocompromised patient. J Clin Microbiol 41:5298–5301, 2003. 19. Steiner UC, Trueb RM, Schad K, Kamarashev J, Koch S, French LE, Hofbauer GFL. Trichophyton rubrum-induced Majocchi’s granuloma in a heart transplant recipient: a therapeutic challenge. J Dermatol Case Rep 6:70–72, 2012. 20. Smijs TGM, Bouwstra JA, Talebi M, Pavel S. Investigation of conditions involved in the susceptibility of the dermatophyte Trichophyton rubrum to photodynamic treatment. J Antimicrob Chemother 60:750–759, 2007. 21. Hart B. Osteomyelitis (refractory) with literature review supplement. Undersea Hyperb Med 39:753–775, 2012. 22. Rnnest MH, Raab MS, Anderhub S, Boesen S, Kr€ amer A, Larsen TO, Clausen MH. Disparate SAR data of griseofulvin analogues for the dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 cancer cells. J Med Chem 55:652–660, 2012. 23. Kingsbury JM, Heitman J, Pinnell SR. Calcofluor white combination antifungal treatments for Trichophyton rubrum and Candida albicans. PLoS One 7:e39405, 2012. 24. Marra F, Robbins GM, Masri BA, Duncan C, Wasan KM, Kwong EH, Jewesson PJ. Amphotericin B-loaded bone cement to treat osteomyelitis caused by Candida albicans. Can J Surg 44:383–386, 2001. 25. de Oliveira Pereira F, Mendes JM, de Oliveira Lima E. Investigation on mechanism of antifungal activity of eugenol against Trichophyton rubrum. Med Mycol 51:50–513, 2013.
Contents lists available at ScienceDirect
The Journal of Foot & Ankle Surgery journal homepage: www.jfas.org
Case Reports and Series
Trichophyton Rubrum Osteomyelitis after Calcaneus External Fixation Pin Stabilization of a Pilon Fracture Gregory R. Waryasz, MD, Jason T. Bariteau, MD Department of Orthopaedic Surgery, Rhode Island Hospital, Brown University Warren Alpert Medical School, Providence, RI
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 4
Fungal organisms are an uncommon cause of osteomyelitis, and no dermatophyte osteomyelitis infections have been reported in published studies. We present the case of Trichophyton rubrum osteomyelitis of the calcaneus. Our patient initially presented with a pilon fracture requiring temporary external fixation while awaiting definitive fixation. From our review of the published data, the present case is the first of this type of fungal osteomyelitis to be reported. The patient was evaluated for a left neck mass during his hospitalization that was later found to be consistent with salivary duct carcinoma of the tail of the parotid gland. A left neck dissection and superficial excision of the parotid gland was performed after fixation of his pilon fracture. Subsequently, he developed an increasing lucency in the calcaneus and symptoms of pain and erythema months after the calcaneus pin had been removed. The osteomyelitis was treated with surgical debridement and 3 months of itraconazole once cultures had definitively grown T. rubrum. Ó 2014 by the American College of Foot and Ankle Surgeons. All rights reserved.
Keywords: bone dermatophytosis fungus infection itraconazole tibia trauma
Fungal osteomyelitis is a rare condition in both immunocompetent and immunocompromised individuals (1,2). The frequency has been increasing owing to the increase in immunocompromised patients. Common pathogens resulting in fungal osteomyelitis have included Candida, Histoplasma, Blastomyces, Coccidioides, Cryptococcus, Mucormycosis, and Sporothrix (1–4). Osteomyelitis can result from direct inoculation, contiguous infection, or hematogenous seeding (5). The typical findings of fungal osteomyelitis have included lytic lesions, with little new bone formation (2,6). The absence of new bone formation or periosteal reaction can make a diagnosis of fungal osteomyelitis more likely (2). Candida osteomyelitis is the most common cause of fungal osteomyelitis. The physical examination in 90% of patients with Candida osteomyelitis will find localizing pain, tenderness, and/or edema (5). The common sites in adults have been the vertebra, ribs, and sternum. The common sites in children have been the femur, humerus, vertebra, and ribs (5). Dermatophytes are a group of keratinophilic fungi that infect tissues with keratin, including the skin and nails (7,8). Dermatophytosis occurs in both immunocompetent and immunocompromised individuals (7). The global burden of dermatomycosis has been reported to be significant (9), with global prevalence estimated at as great as 20% (10).
Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Gregory R. Waryasz, MD, Department of Orthopaedic Surgery, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail address: [email protected] (G.R. Waryasz).
The most common dermatophyte is Trichophyton rubrum. The common sources of T. rubrum have included moist walking surfaces, such as swimming pools, showers, locker rooms, and other barefoot walking locations (11). Immunocompromised patients are more likely to develop dermatophytosis. The conditions more commonly associated with deep dermatophytosis include leukemia, lymphoma, diabetes mellitus, Cushing syndrome, malnutrition, cirrhosis of the liver, and immunosuppressive drugs, including corticosteroids and chemotherapeutic agents (12). Chronic corticosteroid use can lead to a form of T. rubrum that can be resistant to antifungal agents until the cortisol levels have returned to normal (13). Case Report Our patient was a 52-year-old male who was a pedestrian struck by a motor vehicle moving at approximately 30 miles/hr. He was found to have a closed right pilon fracture. He was initially treated with an external fixator and calcaneal and proximal tibia pins (Fig. 1). His medical history was significant for hypertension and a previous fungal infection of toe nails refractory to over-the-counter remedies. While awaiting definitive fixation, he was also evaluated for an enlarged left posterior cervical subparotid lymph node and recurrent left-sided Bell’s palsy. He had undergone nondiagnostic fine needle aspiration of this lesion approximately 6 weeks before his trauma. He had a family history of gastric cancer, breast cancer, and prostate cancer. The patient reported a 34-pack year smoking history and only occasional alcohol use. The lymph node was biopsied and
1067-2516/$ - see front matter Ó 2014 by the American College of Foot and Ankle Surgeons. All rights reserved. http://dx.doi.org/10.1053/j.jfas.2014.02.015
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G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Fig. 1. Lateral radiograph on day of injury showing calcaneal pin from external fixator. Fig. 3. Radiograph 8 weeks postoperatively from fixation.
Fig. 2. Initial postoperative lateral ankle radiograph.
demonstrated histologic features consistent with adenocarcinoma. He was evaluated by the oncology service and the gastroenterology service for additional treatment. An upper endoscopy was performed because of concern for primary gastric adenocarcinoma. The gastric mucosal biopsy revealed no evidence of carcinoma; however, the patient had Helicobacter pylori-associated gastritis. Nine days after his initial injury, his soft tissue envelope allowed for definitive fixation of the right pilon fracture with a fibular fixation and reconstruction of the tibial plafond. The external fixation device was removed during the procedure, and the pin tracts were curetted and irrigated. All loose bone was removed from the pin tracts. The patient received perioperative antibiotics. He had no evidence of any active superficial skin infection with dermatophytes at that time at the pin sites. Approximately 1 month after right pilon fixation, he underwent left parotid superficial parotidectomy. The final pathologic findings were consistent with salivary duct carcinoma of the tail of the parotid gland with 9 of 23 lymph nodes positive. The pathologic TNM stage was pT2N2bM0. A left posterior cervical node was also excised, and pathologic examination showed 1 lymph node with metastatic adenocarcinoma. The submandibular gland was normal; however, 5 of 15 lymph nodes were positive for metastatic adenocarcinoma. The oncology service recommended adjuvant radiotherapy. The patient underwent 33 fractions of radiotherapy to a total dose of 66 Gy to the left parotid and lymph nodes. His right ankle did well for 8 weeks postoperatively (Figs. 2 and 3). He was then noted to have increased lucency in the area of the tract of
G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Fig. 4. Radiograph 10 weeks postoperatively from fixation.
the previous external fixation pin site in the calcaneus, which worsened during a 4-week period. He was compliant with casting and non-weightbearing on the injured extremity. Initially, he had no pain, drainage, or redness around this area. He then began to develop pain in his heel and over his anterior ankle dorsally, with mild fluctuance and erythema. The patient declined any additional imaging and wished to proceed with irrigation, debridement, and bone biopsy of the right calcaneal lesion. He was taken to the operating room approximately 12 weeks after the initial external fixation pin had been placed and 11 weeks after it had been removed (Figs. 4 and 5). Intraoperative cultures were performed that were negative for aerobic, anaerobic, and acidfast bacteria. No gross purulence was found. All fungal cultures were initially negative; however, 2 of 3 cultures grew T. rubrum at 13 days of incubation. The erythrocyte sedimentation rate (ESR) was 27 mm/hr and C-reactive protein (CRP) was 9.46 mg/L immediately after surgery. The infectious disease service had been monitoring the patient and began treatment of calcaneal osteomyelitis with itraconazole 200 mg twice daily for 3 months (Fig. 6). Monitoring the inflammatory markers, ESR and CRP, was challenging given his concurrent treatment of his left parotid adenocarcinoma with recent surgery and ongoing radiotherapy. After treatment with irrigation, debridement, and intravenous antibiotics, the patient had complete resolution of the symptoms of the calcaneal osteomyelitis. He had had no recurrence of his symptoms at the 14-month followup visit (Fig. 7).
3
Fig. 5. Radiograph 12 weeks postoperatively from fixation.
Discussion The definition of osteomyelitis in the 2012 study by Gamaletsou et al (5) regarding Candida osteomyelitis was as follows: 1. Compatible with clinical characteristics 2. Consistent radiographic features 3. Isolation of Candida in culture and/or histologic examination from bone or metal hardware Our patient had clinical redness and pain over the calcaneus, a large lytic area visible on radiographic examination, and a positive culture of T. rubrum in 2 cultures. Using these criteria, the patient had a clear diagnosis of osteomyelitis. The ESR and CRP level in fungal osteomyelitis can be normal or elevated and, therefore, will not always a good indicator of osteomyelitis. In our case, the patient had a normal ESR and CRP but had recently undergone left parotid excision and had been undergoing radiotherapy; therefore, these markers were difficult to monitor in our patient. A typical fungal culture can take 2 to 5 weeks to grow (14). Cultures from our operative debridement grew T. rubrum at 13 days. All our bacterial cultures were negative. The micro- and macroscopic pathologic examination did not show any granulomas; however, pathologic examination even with staining will not always show granulomas or the organism (2). We do not routinely stain for
4
G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
Fig. 6. Radiograph 3 months postoperatively from debridement.
Fig. 7. Radiograph 14 months postoperatively from debridement.
potassium hydroxide, and our patient had no indications that he would have a fungal osteomyelitis; therefore, specific fungal staining was deferred. T. rubrum has been reported in published studies as the cause of both superficial and deep infections. Superficial manifestations of T. rubrum have included onychomycosis, tinea pedis (athlete’s foot), tinea cruris (jock itch), tinea barbae, and ringworm (12,15). Majocchi granulomas are granulomatous cutaneous lesions in the dermis and subcutaneous tissue due to the disruption of hair follicles and spillage of fungus into the dermis, leading to granulomatous reactions (12). Invasive or deep disease with subcutaneous involvement has usually been limited to immunosuppressed patients and the extremities but have not necessarily been associated with the hair follicles (16). The generalized invasive disseminated dermatophyte infection is rare and can be accompanied by nodules with an appearance similar to that of boils. This condition can lead to dissemination involving the internal organs, including lymph nodes, bone, muscle, liver, spleen, testes, central nervous system, and distant skin areas (16). T. rubrum syndrome is a disorder of lesions in the hands, feet, nails, and at least 1 lesion in another body part other than the groin; positive potassium hydroxide staining from 4 different locations, and a positive culture of T. rubrum from at least 3 of 4 locations (17). The patient we have described had a history of onychomycosis refractory to previous treatments. Eradication of chronic carriers of T. rubrum can require treatment of the foot and all shoe insoles. The successful treatment of insoles with T. rubrum colonization-infected skin scales can be achieved with either terbinafine 1% spray or powder (11). If treatment with
intravenous antifungal agents does not improve the condition, it would be reasonable to consider this type of eradication. Our patient responded well to intravenous itraconazole. Itraconazole inhibits the fungal cytochrome p450 enzyme c14-alphalanosterol demethylase, leading to growth arrest of the fungal cell wall by blocking the ergosterol biosynthesis pathway (9). Itraconazole had been used to treat the deep dermatophytosis in most of the documented case reports (12,18,19); however, we were unable to find any case reports of T. rubrum osteomyelitis. A caveat in the dosage of itraconazole is that it might alter other medication levels owing to its inhibition of fungal cytochrome 3a4 (19). Fluconazole has also been used for deep dermatophyte infections (16). Other active agents and supplemental therapies could include photodynamic treatment (20), hyperbaric oxygen (21), griseofulvin (22), terbinafine (11), miconazole, and calcofluor white (23). Amphotericin-B–infused bone cement has been attempted with adjuvant intravenous medications for Candida osteomyelitis but has not been consistently used (24). Ciclopirox and amorolfine have been used as topical agents for dermatophytes (14). Eugenol has been investigated in the laboratory to inhibit ergosterol biosynthesis in T. rubrum (25). Our case of T. rubrum osteomyelitis after temporary calcaneus external fixation pin placement for temporary stabilization of a pilon fracture is the first reported case of this type of dermatophyte osteomyelitis. Owing to the infrequency of all fungal osteomyelitis infections, standardized treatment regimens have not been developed. The recommendation has been to continue treat as long as the inflammatory markers remain elevated, patients are symptomatic, and the imaging findings have not improved. Our patient was treated
G.R. Waryasz, J.T. Bariteau / The Journal of Foot & Ankle Surgery xxx (2014) 1–5
for 3 months with 200 mg of intravenous itraconazole twice daily, with improvement in the imaging findings and no longer had any clinical symptoms. He experienced no negative side effects from the treatment. References 1. D’Antonio D, Piccolomini R, Fioritoni G, Iacone A, Betti S, Fazii P, Mazzoni A. Osteomyelitis and intervertebral discitis caused by blastoschizomyces capitatus in a patient with acute leukemia. J Clin Microbiol 32:224–227, 1994. 2. Kohli R, Hadley S. Fungal arthritis and osteomyelitis. Infect Dis Clin North Am 19:831–851, 2005. 3. De Guzman L, Perlman DC, Hubbard CE. Septic arthritis and osteomyelitis due to the chromoblastomycosis agent fonsecaea pedrosoi. Am J Orthop 41:328–331, 2012. 4. Shaw CJ, Thomason AJ, Spencer JD. Fungal osteomyelitis of the foot: a report of an unusual case. J Bone Joint Surg Br 76:137–139, 1994. 5. Gamaletsou MN, Kontoyiannis DP, Sipsas NV, Moriyama B, Alexander E, Roilides E, Brause B, Walsh TJ. Candida osteomyelitis: analysis of 207 pediatric and adult cases (1970–2011). Clin Infect Dis 55:1338–1351, 2012. 6. Chan YF, Woo KC. Penicillium marneffei osteomyelitis. J Bone Joint Surg Br 72:500–503, 1990. 7. Baltazar L, Soares BM, Silva Carneiro HC, Avila TV, Gouveia LF, Souza DG, Ferreira MVL, Pinotti M, de Assis Santos D, Casalpino PS. Photodynamic inhibition of Trichophyton rubrum: in vitro activity and the role of oxidative and nitrosative bursts in fungal death. J Antimicrob Chemother 68:354–361, 2013. 8. Carrillo-Munoz AJ, Tur-Tur C, Cardenes DC, Estivill D, Giusiano G. Sertaconazole nitrate shows fungicidal and fungistatic activities against Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum, causative agents of tinea pedis. Antimicrob Agents Chemother 55:4420–4421, 2011. 9. Diao Y, Zhao R, Deng X, Leng W, Peng J, Jin Q. Transcriptional profiles of Trichophyton rubrum in response to itraconazole. Med Mycol 47:237–247, 2009. 10. Marques SA, Robles AM, Tortorano AM, Tuculet MA, Negroni R, Mendes RP. Mycoses associated with AIDS in the third world. Med Mycol 31:269–279, 2000. 11. Feuilhade de Chauvin M. A study on the decontamination of insoles colonized by Trichophyton rubrum: effect of terbinafine spray powder 1% and terbinafine spray solution 1%. J Eur Acad Dermatol Venereol 26:875–878, 2012. 12. Gong JQ, Liu XQ, Xu HB, Zeng XS, Chen W, Li XF. Deep dermatophytosis caused by Trichophyton rubrum: report of two cases. Mycoses 50:102–108, 2007.
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