Infectious Diseases in Clinical Practice:
Images in ID-What's the Diagnosis?
A Patient With an Unusual Surgical Site Infection
Avadhani, Amita APN; Louie, Ted MD; Sharma, Alvin MD; Snepar, Richard MD
St Peter's University Hospital, New Brunswick, NJ.
Address correspondence and reprint requests to Ted Louie, MD, 44 Buckingham Dr, Belle Mead, NJ 08502. E-mail: email@example.com.
An 89-year-old man with a medical history of chronic obstructive pulmonary disease, limited-stage prostate cancer, and colon cancer in remission, was incidentally found to have a right lower lobe pulmonary nodule, and was admitted to the hospital for elective video-assisted thorascopic surgery for workup of the nodule. He was in his usual state of health and had no fevers, cough, hemoptysis, or recent weight loss. He subsequently underwent a right lower lobe lobectomy, with placement of chest tubes for drainage. The procedure itself was uneventful. Pathology specimens were sent and were read as pleural fibrosis with granulomas. Routine and acid-fast cultures were sent and proved negative.
On the third postoperative day (POD), he had worsening subcutaneous emphysema and bronchospasm, and was intubated. He subsequently developed hypotension, and intravenous vancomycin and piperacillin/tazobactam were started for pneumonia. He continued to have a complicated postoperative course, with worsening renal function and prolonged respiratory failure leading to tracheostomy. On POD 14, blood cultures grew Candida albicans. He was treated with intravenous fluconazole, and this was changed to caspofungin on POD 21.
On POD 33, it was noted that he had some redness around the right chest tube site. Caspofungin was continued, and vancomycin and aztreonam were added. The area became necrotic, and skin and subcutaneous tissue were debrided at the bedside on POD 37, but within hours, the necrosis had extended down into the abdomen. Cottonlike circular patches developed around the periphery of the lesion (Fig. 1). A repeat debridement was performed on POD 40.
What is your diagnosis?
Pathology specimens revealed fungal forms morphologically consistent with Zygomycetes, invading into the tissue and blood vessels (Fig. 2). Bacterial and fungal cultures were negative.
Zygomycetes fungi are ubiquitous in nature and can be found on decaying vegetation and in the soil. These fungi grow very rapidly and release large numbers of spores that can become airborne. The hyphae of Zygomycetes species are broad (10-20 μm in diameter), irregularly shaped, branch at right angles, are usually not septated, and have been described as "ribbonlike."1
Fungi of the class Zygomycetes and order Mucorales (genera Mucor, Rhizopus, and Absidia) can cause a variety of infections in humans. There is some controversy over the terminology used to refer to infections caused by this class of fungi. The older and more common term mucormycosis is familiar to most clinicians.1 However, in recent literature, zygomycosis is generally used.
The first case of zygomycosis was reported in 1885.2 Between 1940 and 2003, 1049 cases of zygomycosis were reported.3 The spectrum of disease includes rhinocerebral, pulmonary, renal, gastrointestinal, central nervous system, and cutaneous infection.1
Invasive zygomycosis has been well described mostly in immunocompromised hosts, including patients with lymphoma or leukemia, transplant patients, cancer patients receiving chemotherapy, renal failure patients, and patients receiving chronic steroids.3-6 However, zygomycosis is different from other filamentous fungi in that it is also seen in patients who are mildly immunocompromised, such as diabetic patients7 and also in patients receiving concomitant deferoxamine therapy and dialysis,8 intravenous drug users,9 and uncommonly, in patients with no underlying condition but some obvious portal of entry.10,11
In 176 patients with zygomycosis but without underlying conditions, 50% presented with cutaneous disease, although other involvement such as pulmonary or rhinocerebral disease was rare. This is in contrast with 753 patients having zygomycosis with specific underlying conditions, where the incidence of cutaneous involvement was much lower, ranging from 9% in bone marrow transplant patients to 16% with solid-organ transplant patients.
For specific underlying conditions, there seems to be a specific pattern of disease. In Roden et al,3 patients with malignancy, bone marrow transplants, and solid-organ transplants had high incidences of pulmonary disease. Diabetic patients had the most rhinocerebral disease. Intravenous drug users had the most cerebral disease. Patients who had been treated with deferoxamine had the highest incidence of disseminated disease.
Cutaneous disease is uncommon. Of 929 cases of zygomycosis, 176 (19%) were cutaneous.3 Most involve inoculation of the organism by various routes. Cutaneous zygomycosis has been associated with traumatic wounds, burns, surgical wound infections, intramuscular injections, and contaminated dressings.10-12 There have also been outbreaks related to contaminated tongue depressors used as splints for intravenous lines in a pediatric ward,13 and 2 cases of stoma site infections in the area where contaminated colostomy bags were attached.14 Cutaneous lesions can also occasionally occur as a result of hematogenous dissemination.15
The initial skin lesions vary in appearance from indurated areas of cellulitis that eventually develop into ulcerated lesions, to violaceous irregular lesions, to red papules, to ulcerations with surrounding black eschar, as in the present case.10,11 Most cases of cutaneous zygomycosis are localized to the skin. However, these fungi are potentially angioinvasive, and this can lead to significant necrosis.1 Thus, cutaneous infections can occasionally progress rapidly to involve underlying tissue and can be fatal. Of 176 patients with cutaneous zygomycosis, 24% had deep tissue extension. The mortality rate for those with localized cutaneous disease was 10% compared with 26% for those with deep tissue involvement.3
TREATMENT OF ZYGOMYCOSIS/MUCORMYCOSIS
In a review of 929 cases of zygomycosis, the survival rate was 62% for those receiving antifungal therapy alone, 57% for those treated with surgery alone, and 70% for those treated with a combination of antifungal therapy and surgery.3 In patients without underlying disease and limited cutaneous zygomycosis, local debridement may be curative. However, with any evidence of progression of disease beyond the skin into the subcutaneous tissue and muscle, a combination of systemic antifungals and debridement is felt to be necessary. Surgical debridement of primary cutaneous lesions must be performed aggressively, and daily inspection of the wound is mandatory so that necrotic tissue can be removed as soon as possible.1 Repeated operations may be required for satisfactory removal of continuously appearing necrotic tissue. Frozen-section guided debridement has been advocated as an alternative to extensive debridement that has been performed in patients with invasive mucormycosis.16
As with any opportunistic infection, supportive therapy and correction of reversible factors such as hyperglycemia, acidosis, and neutropenia should be aggressively instituted. If possible, doses of immunosuppressive drugs, including steroids, should be decreased. The ultimate outcome of zygomycosis depends, in large part, on the prognosis of the underlying disease and the ability to reverse the predisposing conditions.1
The standard therapy for invasive zygomycosis has been amphotericin B. Recent data have confirmed the in vitro efficacy of amphotericin B against many different agents of zygomycosis.17,18 Because the fungus is relatively refractory to medical treatment, the maximum tolerated dose of amphotericin B deoxycholate is usually recommended, typically 1 to 1.5 mg/kg per day. There are limited data on the use of amphotericin B lipid complex. In 1 study, 17 of 24 patients with invasive zygomycosis responded to amphotericin B lipid complex.19 In a European study, 12 of 20 patients with invasive zygomycosis responded to amphotericin B colloidal dispersion.20 In the review by Roden et al,3 532 patients with zygomycosis were treated with amphotericin B deoxycholate, with a survival rate of 61%, whereas 116 received a lipid formulation of amphotericin B, with a 69% survival rate.
The echinocandins are not active against Zygomycetes, and neither are fluconazole, itraconazole, and notably, voriconazole. This is especially important to remember because some centers are now using voriconazole as antifungal prophylaxis in neutropenic patients21 and patients with severe graft-versus-host disease.22 Thus, the use of azoles for fungal prophylaxis or treatment can select out for Zygomycetes infections.23,24
Posaconazole, in contrast, has been shown to have in vitro activity against zygomycosis17,18,25,26 and also activity in an immunosuppressed murine model.27 There have been case reports of its use in salvage therapy, as well as 2 larger studies.28,29 One case involved a heart-kidney transplant patient who developed infection in the thoracic surgical wound, which subsequently caused pericardial infection and mediastinitis. The patient did not respond to debridement and amphotericin B, but eventually did respond to 6 weeks of posaconazole.30
The clinical efficacy of posaconazole was evaluated in a retrospective study of 91 patients with either proven (n = 69) or probable (n = 22) infection who had zygomycosis and who had failed or could not tolerate standard therapy. Of these patients, most were immunocompromised, with greater than 58% having leukemia or lymphoma. There was cutaneous involvement in 13 patients. Sixty-four of the 91 patients had surgical debridement in addition to antifungals. The success rate was similar in those treated with debridement plus antifungals (61%) and those treated only with antifungals (62%). Posaconazole led to either a complete or partial response in 60% of patients; 21% had stable disease. Thirty-eight percent of patients in the study died. The patients received a median of 182 days of treatment.28 Although there are limitations to this salvage study, this series supports a potential role for posaconazole for the treatment of zygomycosis refractory to standard therapy. A recent study of posaconazole as fungal prophylaxis in more than 300 neutropenic patients likewise showed no cases of zygomycosis.21 Another recent study of posaconazole as fungal prophylaxis in 301 patients with severe graft-versus-host disease showed no cases of zygomycosis.22
Hyperbaric oxygen has been used in some patients with zygomycosis and may be of some benefit.31 Other proposed adjunctive therapies include granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor, which apart from their effects on increasing neutrophil counts, also have immunomodulatory effects.32-35 In 1 study, G-CSF enhanced neutrophil antifungal activity against Aspergillus, Candida, and Rhizopus species, perhaps as a result of an augmented respiratory burst.36 There are case reports and small studies of neutropenic patients with disseminated zygomycosis who were successfully treated with antifungals and G-CSF.32 There is also a small series in which diabetic nonneutropenic patients with rhinocerebral mucormycosis were treated successfully with a combination of amphotericin, surgery, and granulocyte-macrophage colony-stimulating factor.33 Interferon-γ has also been shown in vivo to enhance polymorphonuclear destruction of Zygomycetes.34 It has also been noted that lovastatin seems to have antifungal activity,37 and it has been speculated that diabetic patients taking lovastatin may be at lower risk for developing zygomycosis.38
Our patient had a history of colon cancer that was resected and felt to be in remission, and his prostate cancer was not advanced. Therefore, we consider him to be relatively immunocompetent. Fungal organisms were likely inoculated into his wound site and did progress to involve subcutaneous tissue. This process developed while first on fluconazole and then caspofungin, which is logical, considering the inherent resistance of zygomycosis to these agents. The patient did receive aggressive debridement. Amphotericin B deoxycholate was added to his regimen at this time, but he failed to respond and died soon thereafter. It is unclear if use of hyperbaric oxygen, posaconazole, or G-CSF would have enhanced his chance for survival.
The authors would like to thank Dr. Zaida Olmo-Durham for his invaluable assistance in the preparation of the pathology slides.
1. Sugar AM. Agents of mucormycosis and related species. In: Mandell GL, Bennet JE, Dolin R, et al. Mandell, Douglas, and Bennet's Principles and Practice of Infectious Disease. 6th ed. Philadelphia, PA: Elsevier; 2005:2973-2974.
2. Paultauf A. Mycosis mucorina. Arch Path Anat. 1885;102:543.
3. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634-653.
4. Greenberg RN, Scott LJ, Vaughn HH, et al. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis. 2004;17:517.
5. Henriquez M, Levy R, Raja RM, et al. Mucormycosis in a renal transplant recipient with successful outcome. JAMA. 1979;242:1397-1399.
6. Gonzalez CE, Couriel DR, Walsh TJ. Disseminated zygomycosis in a neutropenic patient: successful treatment with amphotericin B lipid complex and granulocyte colony-stimulating factor. Clin Infect Dis. 1997;24:192.
7. Vasquez JA, Sobel JD. Fungal infections in diabetes. Infect Dis Clin North Am. 1995;9:97-116.
8. Boaelert JR, Fenves AZ, Coburn JW. Deferoxamine therapy and mucormycosis in dialysis patients: report of an international registry. Am J Kidney Dis. 1991;18:660-667.
9. Hopkins RJ, Rothman M, Fiore A, et al. Cerebral mucormycosis associated with intravenous drug use: three case reports and review. Clin Infect Dis. 1994;19:1133-1137.
10. Cocanour CS, Miller-Crotchett P, Reed RL 2nd, et al. Mucormycosis in trauma patients. J Trauma. 1992;32:12.
11. Gartenberg G, Bottone EJ, Keusch GT, et al. Hospital-acquired mucormycosis of skin and subcutaneous tissue. N Engl J Med. 1978;299:1115-1118.
12. Losee JE, Selber J, Vega S, et al. Primary cutaneous mucormycosis: guide to surgical management. Ann Plastic Surg. 2002;49:385-390.
13. A Mitchell SJ, Gray J, Morgan ME, et al. Nosocomial infection with Rhizopus microsporus in preterm infants: association with wooden tongue depressors. Lancet. 1996;348:441-443.
14. LeMaile-Williams M, Burwell LA, Salisbury D, et al. Outbreak of cutaneous Rhizopus arrhizus infection associated with karaya ostomy bags. Clin Infect Dis. 2006;43:e83-e88.
15. Meyer RD, Kaplan MH, Ong M, et al. Cutaneous lesions in disseminated mucormycosis. JAMA. 1973;225:737-738.
16. Langford JD, McCartney DL, Wang RC. Frozen section guided surgical debridement for management of rhino cerebral mucormycosis. Am J Ophthalmol.1997;124:265-267.
17. Torres-Narbonara M, Guiniea J, Martinez-Alarcon J, et al. In vitro activities of amphotericin B, caspofungin, itraconazole, posaconazole, and voriconazole against 45 clinical isolates of zygomycetes: comparison of CLSI M38-A, Sensititre Yeast One, and the E-test. Antimicrob Agents Chemother. 2007;51:1126-1129.
18. Dannaoui E, Meletiadis J, Mouton JW, et al. In vitro susceptibilities of zygomycetes to conventional and new antifungals. J Antimicrob Chemother. 2003;51:45-52.
19. Walsh TJ, Hiemenz JW, Seibel NL, et al. Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 patients. Clin Infect Dis. 1998;26:1383-1396.
20. Herbrecht R, Letcher-Bru V, Bowden RA, et al. Treatment of 21 cases of invasive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis. 2001;20:460-466.
21. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007:356:348-359.
22. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole prophylaxis for severe graft vs host disease. N Engl J Med. 2007;356:335-347.
23. Siwek GT, Dodgson KJ, de Magaes-Silverman M, et al. Invasive zygomycetes in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis. 2004;39:584-587.
24. Trifilio SM, Bennett CL, Yarnold PR, et al. Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem cell transplants or intensive chemotherapy. Bone Marrow Transplant. 2007;39:425-429.
25. Herbrecht R. Posaconazole: a potent, extended spectrum triazole antifungal for the treatment of serious fungal infection. Int J Clin Pract. 2004;58:612-624.
26. Sun QN, Fothergill AW, McCarthy DI, et al. In vitro activity of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of Zygomycetes. Antimicrob Agents Chemother. 2002;46:1581-1582.
27. Sun QN, Najvar LK, Bocanegra R, et al. In vitro activity of posaconazole against Mucor species in an immunosuppressed mouse model. Antimicrob Agents Chemother. 2002;46:2310-2312.
28. Van Burik JA, Hare RS, Solomon HF, et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006;42:e61.
29. Greenberg RN, Mullane K, van Burik JAH, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother. 2006;50:126-133.
30. Tobon AM, Arango M, Fernandez D et al. Mucormycosis in a heart-kidney transplant recipient: recovery after posaconazole therapy. Clin Infect Dis. 2003;36:1488-1491.
31. Bentur Y, Shupak A, Ramon Y. Hyperbaric oxygen therapy for cutaneous, soft tissue zygomycosis complicating diabetes mellitus. Plast Reconstr Surg. 1998;102:822.
32. Gonzalez CE, Couriel DR, Walsh TJ. Disseminated zygomycosis in a neutropenic patient: successful treatment with amphotericin B lipid complex and granulocytic colony stimulating factor. Clin Infect Dis. 1997;24:192-196.
33. Garcia-Diaz JB, Palau L, Pankey GA. Resolution of rhinocerebral zygomycosis associated with adjuvant administration of granulocyte-macrophage colony-stimulating factor. Clin Infect Dis. 2001;32:e166-e170.
34. Gil-Lamaignere C, Simitsopoulo M, Roilides E, et al. Interferon-gamma and granulocyte-macrophage colony stimulating factor augment the activity of polymorphonuclear leukocytes against medically important Zygomycetes. J Infect Dis. 2005;191:1180-1187.
35. Sahin B, Paydas S, Cosar E. Role of granulocyte colony stimulating factor in the treatment of mucormycosis. Eur J Clin Microbiol Infect Dis. 1996;15:866-869.
36. Liles WC, Huang JE, van Burik JA, et al. Granulocyte colony stimulating factor administrated in vivo augments neutrophil-mediated activity against opportunistic fungal pathogens. J Infect Dis. 1997;175(4):1012-1015.
37. Chamilos G, Lewis RE, Kontoyiannis DP. Lovastatin has significant activity against Zygomycetes and interacts synergistically with voriconazole. Antimicrob Agents Chemother. 2006;50:96-103.
38. Kontoyiannis DP. Decrease in the number of reported cases of Zygomycosis among patients with diabetes mellitus: a hypothesis. Clin Infect Dis. 2007;44:1089-1090.
© 2008 Lippincott Williams & Wilkins, Inc.