Association of Topical Amphotericin B Lipid Complex Treatment to Standard Therapy for Rhinomaxillary Mucormycosis After Liver Transplantation: A Case Report

Association of Topical Amphotericin B Lipid Complex Treatment to Standard Therapy for Rhinomaxillary Mucormycosis After Liver Transplantation: A Case Report M.V. Trasmonte, J.D. Jiménez, M.Á. Santiago, E. Gálvez, V. Jerez, D. Pérez, M. Robles, V.K. Farje, P. Martínez, P. Nieto, and J.A. Rubio ABSTRACT Solid organ transplantation is becoming increasingly more common in the treatment of end-stage organ failure. The advent of newer immunosuppressive protocols and refined surgical techniques has allowed therapy to become standard care. Infection is a major and frequently life-threatening complication after transplantation and the incidence of opportunistic fungal infections in organ transplant recipients ranges from 2%–50% depending on the type of organ transplanted. We present a case of rhinomaxillary form of mucormycosis infection after liver transplantation. The succession of multiple risk factors in a torpid postoperative period was a key factor in the development of this disease. Multidisciplinary management with an early diagnosis, aggressive surgery, and intravenous and topical antifungal therapy care were definitive for the eradication of infection. The goal of the present report was to show efficacious management including the association of topical treatment with amphotericin B complex lipid to standard therapy and the absence of side effects. OLID organ transplantation is becoming increasingly more common in the treatment of end-stage organ failure. The advent of newer immunosuppressive protocols and refined surgical techniques has allowed therapy to become standard care. Infection is a major and frequently life-threatening complication after transplantation.1 Most infections occur on a relatively consistent timeline, reflecting the interplay of epidemiological risk factors and the “net state of immune suppression.”2–5 Despite being less common than bacterial infections, fungal infections are associated with the highest incidence of infection-related mortality.1,6 Zygomycosis or mucormycosis is the third most invasive fungal infection after candidiasis and aspergillosis.3 Recently, several publications from different institutions have reported an increase in the number of cases of invasive zygomycosis as a result of the new antifungal and immunosuppressive therapies and the emerging immunocompromised population.3,5,7 Mucormycosis is the unifying term used to describe infections caused by fungi belonging to the order Mucorales.4 Most of the species known to cause human disease belong to the family Mucoraceae, which includes the Rhizopus, Mucor, and Absidia genera, and are recognized by their rapid growth rate.3,7 Mucorales typically cause acute,

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aggressive, and frequently angioinvasive infections, especially in immunosuppressed hosts.3,4 Cooperation among pathologists, infectious disease consultants, surgeons, microbiologists, and intensivists is essential in the early stages of infection to avoid treatment delays that increase patient mortality.4,7 The management usually requires a combination of antifungal treatment, surgical intervention, and control of the underlying risk factors.3,4,7,8 Intravenous amphotericin B is the treatment of choice3,7–9 for zygomycosis but topical application has been described in few cases.10 –12 Mucorales can be regarded as intrinsically resistant to azole treatment, and the widespread prophylactic and therapeutic use of some compounds has been related to the selection and induction of resistant strains,3,4 although posaconazole has been successfully used in combination with amphotericin B in salvage therapy or in de-escalation therapy.3,4,7,9 Nevertheless, mortality remains From the Intensive Care Unit, Hospital Infanta Cristina, Badajoz, Spain. Address reprint requests to Victoria Trasmonte, Servicio de Medicina Intensiva, Hospital Infanta Crsitina, Avenida Elvas s/n, 06006, Badajoz, Spain. E-mail: victoriatrasmontemartinez@ hotmail.com

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high even with aggressive therapies.3,4,7,12 The true incidence is not known and probably underestimated because of difficulties in antemortem diagnosis.3,4,12 CASE REPORT The patient was a 58-year-old man with Child-Pugh score A alcoholic liver cirrhosis and hepatocellular carcinoma treated with chemoembolization and radiofrequency ablation. He underwent orthotopic liver transplantation and presented a torpid postoperative course. During this period the patient suffered a hemorrhagic shock in the first 24 hours due to inferior vena cava bleeding, followed by hospital-acquired pneumonia and multifactorial renal failure requiring veno-venous hemofiltration. He also presented an episode of severe cholestasis and acute rejection, suspected from the biopsy report. He was treated with corticosteroids and molecular adsorbent recycling system therapy (MARS). Immunosuppressive treatment was begun as well as antibiotic prophylaxis according to guidelines. Fluconazole was administered for antifungal prophylaxis but was later replaced with anidulafungin. He was discharged from the intensive care unit. Two months after transplantation, the patient gradually developed left frontotemporal pain and severe progressive leukopenia. Immunosuppressive treatment was suspended and treatment with granulocyte colony-stimulating factor was begun. As the symptoms persisted, a sinus computed tomography (CT) was performed, which showed filling of the left maxillary, sphenoidal, and ethmoid sinuses. The results of endoscopic biopsy were compatible with Zygomycosis caused by Lichtheimia ramosa. He was treated with amphotericin B lipid complex (Abelcet, Cephalon Pharma, Herts, UK) at maximum doses. The patient underwent left hemimaxillectomy and complete debridement in addition to packing of the residual cavity. The patient was readmitted to the intensive care unit after surgery. During the postoperative period, daily cleanings with topical amphotericin B lipid complex were performed. Cultivations for fungi were persistently negative and cranium and sinus follow-up CT scans only showed postsurgery changes. Immunosuppressive treatment with cyclosporine was reinitiated on postoperative day 6. The patient had an uneventful course, being discharged 4 months after transplantation. He continued receiving home treatment with oral posaconazole for 2 months. On follow-up 1 year later no evidence of recurrence or fungal infection elsewhere was found, chronic renal disease persisted but without necessity of hemodialysis, and liver graft function remained undisturbed.

DISCUSSION

Despite the high risk of opportunistic infection, the diagnosis of mucormycosis took 1 week to be suspected. The infection was diagnosed 45 days after transplantation, a period characterized by a high state of immunosuppression. The patient gradually developed left frontotemporal pain, edema, facial swelling, and lacrimation initially related with a cluster headache; the pain deteriorated despite hyperbaric oxygen and analgesic treatment, finally leading to intractable pain. As described by others,4,7 the clinical signs and symptoms of mucormycosis are nonspecific and there are no biomarkers to identify this disease. Radiological diagnosis of sinusitis was evident and an invasive approach to identify the causal organism was undertaken; biopsy and culture from sterile sites are critical to distinguish mucormycosis from more common fungi, such as Aspergillus.4,7,9

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Paradoxically, even when fungal hyphae are seen in histopathologic analysis, fungal cultures are only positive in 50% of cases because of the friable nature of nonseptated hyphae, which are frequently damaged during tissue manipulation.4,7 Rhinomaxillary mucormycosis, as occured in our case, is the most common variety, with a high mortality rate. Indicators of poor prognosis include delay in treatment (⬎6 days),7,8 symptomatic intracranial involvement, facial necrosis, or the patient’s underlying disease.4,5 However, some scenarios, underlying risk factors and elements of the clinical and radiographic presentation, should prompt a high index of suspicion for incipient mucormycosis.4,7 Table 1 summarizes factors contributing to a higher risk of mucormycosis in solid organ transplantation. Many risk factors were present in our patient. He suffered posttransplantation multifactorial renal failure and needed continuous veno-venous hemofiltration; he also experienced the reactivation of opportunistic herpes viruses (in this case cytomegalovirus), hospital-acquired pneumonia, acute rejection episode with a slow response to different boluses of solumedrol and monoclonal antibody Basiliximab (Simulect, Novartis Pharma AG, Basel, Switzerland), and severe cholestasis; he also underwent MARS therapy twice. These predisposing settings may have promoted the superimposed mycosis infection. The effects of the various immunosuppressive agents on the immune system are complex.4 It is critical to reverse or

Table 1. Factors Favoring Mucormycosis Suspicion in Solid Organ Transplantation Epidemiological and host clues (risk factors) Solid organ transplantation or retransplantation3,5,7,8 Neutropenia3–5,7–9 Inmunosuppressive agents or inmunocompromised individuals2,3,5,7,12 High-dose corticosteroids3–5,7,9 Acute or chronic rejection episode posttransplantation and its treatment7 Hyperglycemia with or without diabetes mellitus type 1 or 23–5,7,9 Prior azole or echinocandin use3,4,7 Broad-spectrum antimicrobial agents2,7 Iron overload (hypertransfusion)3,4,7,9 Renal failure2,7 Malnutrition4,7 Bacterial infection, reactivation of opportunistic herpes viruses2–4,7 Clinical, radiological, and laboratory clues Community-acquired sinusitis4,7 Oral necrotic lesions in hard palate or nasal turbinates4,9 Maxillary swelling and edema, headache, chest wall cellulitis adjacent to lung infarct4,7,9 Acute vascular event, resulting from the acute hemorrhagic infarct caused by Mucorales4 Multiple (n⬎10) nodules on CT and pleural effusion4,8,9 Reverse halo sign in chest x-ray or CT4,8 Presumed (by CT findings) fungal pneumonia with adequate voriconazole levels4 Presumed (by CT findings) fungal pneumonia with repetitively negative galactomannan and G-glucan serum levels4

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prevent underlying defects in host defense when treating patients with mucormycosis.7,8 Immunosuppressive medications, particularly corticosteroids, should be administered at reduced dosages or stopped if at all possible.8 As shown in our case, profound and protracted lymphopenia associated with neutropenia and its phagocytic defects because of cell number deficiency and functional defects allowed proliferation of the fungus.3,4 The initial corticoid-associated hyperglycemia could have contributed to increasing the risk, but control was excellent with insulin and a decreased corticoid dose.3,4,7 In immunocompetent hosts, it is known that the killing and removal of the Mucorales is mediated by both neutrophils and macrophages. Macrophages kill intracellular spores by oxidative mechanisms, whereas neutrophils can damage fungal hyphae by extracellular mechanism. Phagocytic cell-mediated inhibition of germination of spores is impaired by corticosteroids and diabetes. Therefore, deficiencies of circulating neutrophils (eg, neutropenia) and impaired phagocyte function (as in diabetes mellitus or steroid therapy) also play a role in pathogenesis.9 Intraoperative blood transfusions were low (1200 mL), but hemorrhagic shock due to suture dehiscence needed urgent reintervention and multiple transfusions of blood products, which is associated with iron overload. Iron is required for the growth and virulence of virtually all microbial pathogens7; indeed, the ability to scavenge free iron from the host is clearly an essential component of the pathogenesis of zygomycetes.3,4 The widespread prophylactic and therapeutic uses of azole compounds and echinocandin result in the selection and induction of resistant strains of the infecting organism.4,7 We used fluconazole and anidulafungin prophylactically to avoid the high risk for fungal infections and both of these have no anti- Mucorales activity.3,4 Breakthrough zygomycosis is observed increasingly among patients who are receiving voriconazole or echinocandins, and different trials6,7 reflect either selective pressure or voriconazoleasociated alterations in its virulence. In addition, enhanced angioinvasion, inflammation, and expression of genes involved in stress response and tissue repair have been found in mouse lungs infected with voriconazole-exposed Zygomycetes; itraconazole, caspofungin, and amphotericin B did not affect its virulence. However, there are few data to support such an assumption.6 Given the multiple, interrelated risk factors for invasive fungal infections in most patients with mucormycosis, it is often impossible to describe a single factor that increases the risk and worsens the prognosis of this devastating infection.4 Early recognition and treatment of the infection are, therefore, critical in improving patient survival before angioinvasion and necrosis become too extensive and the infection disseminates to other organs.4,7 Besides surgical management, we administrated intravenous amphotericin B lipid formulations (amphotericin B lipid complex 5 mg/ kg/d) to avoid toxic side effects (greater risk for nephrotoxicity).4,7–9,10 Concomitantly, the compresses used to pack the surgical wound were also soaked in amphotericin B

TRASMONTE, JIMENEZ, SANTIAGO ET AL

solution. Although amphotericin B is a standard treatment, topical instillation is not as common and only a few publications describe its use, such as inhaled amphotericin therapy in lung transplant recipients, on mucous membrane surfaces, or cutaneous mucormycosis with excellent tolerance for the lipid form.10,11 Frankenburg et al10 demonstrated by biodistribution studies that the formulation doses of amphotericin B when dispersed in nonviscous solutions containing 5%–25% ethanol and then applied topically result in much lower levels of the drug in internal organs than those obtained with lower doses administered systematically. When given topically, the site of application is the major tissue of accumulation. Accordingly, higher doses may be used topically with greatly reduced toxic side effects.10 We replaced the soaked compresses every 2 days until 5 weeks after surgery and no side effects were observed. In general, antifungal therapy of mucormycosis should be highly individualized and continued until there is clinical resolution of signs and symptoms of infection. Our patient had resolution of radiographic signs of active disease, and only postinflammatory changes were found. He also had negative follow-up cultures 5 weeks after surgery. A de-escalation strategy with oral posaconazole was continued for 3 months. The availability of posaconazole in an oral formulation that can be administrated safely for prolonged periods makes it an attractive agent for long-term use.3,4,12 Echinocandins have demonstrated modest activity against some Mucorales in vivo, which is enhanced when administered together with lipid amphotericin B formulations.3,4 Increasing the dose of the liposomal amphotericin B or adding an echinocandin or posaconazole are reasonable strategies for patients with progressive infection on lipid amphotericin B therapy alone as salvage therapy.4,8 Although the effects of hyperbaric oxygen therapy for mucormycosis remain controversial,3,4,7 our patient was treated with this because the first suspicion was Horton disease. Specifically, the increase in the partial pressure of oxygen achieved with this method seems to improve neutrophil activity, assist with oxidative killing of amphotericin, inhibit the growth of Mucorales in vitro, and improve the rate of wound healing by increasing the release of tissue growth factors.4 Immune augmentation strategies are also considered, including administration of colony-stimulating factor and cytokines.3,4,7 We used granulocyte colonystimulating factor therapy (Neupogen, Amgen, Thousand Oaks, Calif), with the secondary resolution of the neutropenic state. Polymorphonuclear leukocytes and lipid formulations of amphotericin B act synergistically to damage hyphae of some species. There are limited data to support the routine use of these adjunctive strategies now.4,8 Treating a patient’s underlying medical condition and reducing immunosuppression are essential to therapy. Rapid correction of metabolic abnormalities is mandatory in uncontrolled diabetes. Corticosteroids should be discontinued, if feasible, and other immunosuppressive drugs should be tapered as much as possible.7 We emphasize that

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most evolving management strategies are based on recent preclinical and limited, uncontrolled clinical data and that their validation requires definitive, prospective, controlled clinical trials.8 However, mortality remains high, even with aggressive surgical and antifungal therapy.8,12 Many challenges must be overcome to improve overall outcomes associated with invasive mucormycosis. The immunopathogenesis is poorly understood and the advancement of fungal diagnostics with the implementation of novel fungal biomarkers is a formidable frontier in mucormycosis.4 Finally, improved risk stratification of patients susceptible to mucormycosis based on time-honored host characteristics should lead to an individualized approach to prophylaxis, early diagnostic platforms, and treatment of this uncommon, yet emerging, and frequently devastating opportunistic mycosis.4,7 REFERENCES 1. Hagerty J, Ortiz J, Reich D, et al: Fungal infections in solid organ transplant patients. Surg Infections 4:263, 2003 2. Seton M, Pless M, Fishman J, et al: Case 18-2008: a 68-yearold man with headache and visual changes after liver transplantation. N Engl J Med 358:2619, 2008 3. Torres-Narbona M, Guinea J, Muñoz P, et al: Zygomycetes and zygomycosis in the new area of antifungal therapies. Rev Esp Quimioterap 20:375, 2007

2123 4. Kontoyiannis DP, Lewis RE: How I treat mucormycosis. Blood 118:1216, 2011 5. Castóna JJ, Linares Siciliab MJ, Rivero Romána A, et al: Invasive fungal infections by filamentous fungi. Medicine 9:3702, 2006 6. Lamaris G, Ben-Ami R, Lewis R, et al: Increased virulence of zygomycetes organisms following exposure to voriconazole: a study involving fly and murine models of zygomycosis. J Infect Dis 199:1399, 2009 7. Petrikkos G, Drogari-Apiranthitou M: Zygomicosis in immunocompromised non-haematological patients. Mediterr J Hematol Infect Dis 3:e2011012, 2011 8. Spellberg B, Thomas JW, Dimitrios P, et al: Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 48:1743, 2009 9. Rogers TR: Treatment of zygomycosis: current and new options. J Antimicrob Chemother 61(suppl 1):135, 2008 10. Frankenburg S, Glik D, Klaus S: Efficacious topical treatment for murine cutaneous leishmaniasis with ethanolic formulations of amphotericin B. Antimicrob Agents Chemother 42:3092, 1998 11. Morales P, Galan G, SanMartín E, et al: Intrabronchial instillation of amphotericin B lipid complex: a case report. Transplant Proc 41:2223, 2009 12. Gil-Lamaignere C, Hess R, Salvenmoser S, et al: Effect of media composition and in vitro activity of posaconazole, caspofungin and voriconazole against zygomycetes. J Antimicrob Chemother 55:1016, 2005