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Case Report of Hepatic Mucormycosis After Liver Transplantation: Successful Treatment With Liposomal Amphotericin B Followed by Posaconazole Sequential Therapy
Case Report of Hepatic Mucormycosis After Liver Transplantation: Successful Treatment With Liposomal Amphotericin B Followed by Posaconazole Sequential Therapy C.S. Abboud, M.D. Bergamasco, C.E.S. Baía, M.P. Lallée, A.S.C. Zan, M.M. Zamorano, O.I. Pereira, and S. Mies ABSTRACT Mucormycosis is a rare but emerging fungal infection complicating solid organ transplantation (SOT), with a cumulative incidence of around 2% during the first year after SOT. The associated mortality rate is high, and surgical debridement is frequently required as part of the treatment along with antifungal therapy based mostly on amphotericin B formulations, We describe here an unusual case of hepatic mucormycosis in a liver transplant recipient that was successfully treated with clinical therapy based on liposomal amphotericin B followed by posaconazole, without surgical resection. UCORMYCOSIS is a rare but emerging fungal infection complicating solid organ transplantation (SOT). Its cumulative incidence is around 2% during the first year after SOT according to recently published data.1 Liver transplantation has been implicated as a risk factor for disseminated disease and earlier occurrence of this infection in comparison with other types of SOT.2 The associated mortality rate is high,3 and surgical debridement is frequently required as part of the treatment.4 Antifungal treatment is usually based on amphotericin B lipidic formulations, while posaconazole is the only commercially available triazole with extended-spectrum activity against zygomycetes.4
M
CASE REPORT A 23-year-old woman underwent orthotopic liver transplantation due to primary biliary cirrhosis. Interestingly, her deceased donor was a kidney transplant recipient, who was under immunosuppressive therapy with tacrolimus (FK), prednisone, and mycophenolate mophetil at the time of his death, caused by hemorrhagic stroke. The recipient received immunosuppressive therapy that consisted of metpylprednisolone, tacrolimus, and sodium mycophenolate. She was also under fluconazole prophylaxis. Forty-seven days after transplantation, she presented with right hypochondrium pain and fever. An abdominal ultrasound was performed and revealed a hepatic abscess in the right lobe sized 53 ⫻ 51 mm. She underwent abscess drainage through ultrasound guided puncture and the culture yielded a multi-drug resistant Pseudomonas aeruginosa. Subsequent ultrasound guided drainages were performed, and the culture was persistently positive for P aeruginosa, despite polymixin B treatment. On day 83 after transplantation, a liver biopsy was performed, due to the persistence of the abscess. Histopathologic
examination showed tissue invasion by nonseptate hyphae compatible with mucormycosis infection but the fungal culture returned negative results. Liposomal amphotericin B (L-AmB) was started at a dose of 5 mg/kg/d. A percutaneous drain was placed in the abscess, and clinical treatment based on L-AmB and polymixin B was continued with clinical improvement and progressive reduction in the abscess dimensions. After 60 days of L-AmB therapy with clinical and radiological improvement, but still with a residual lesion, posaconazole 200 mg orally four times per day was started. At this time, the patient was receiving FK 2 mg twice a day, mycofenolate mofetil (MMF) 180 mg twice a day, and prednisone 10 mg per day. Her FK blood level before posaconazole was 9 g/L. After 6 days on posaconazole therapy, her FK blood level reached 39.5, and she presented with serum creatinine increase (from 1.1 to 1.8 mg/dL) and hyperkalemia. The FK dose was halved, her FK blood level progressively fell to 7.9 g/L, and the patient presented with renal function improvement. Posaconazole was stopped on month 6 after transplantation. At this time, she showed clinical improvement and resolution of the lesion by ultrasound. Eighteen months after the transplantation,
From the Serviço de Controle de Infecção Hospitalar e Seção Médica de Infectologia (C.S.A., M.D.B.), Unidade de Figado– Instituto Dante Pazzanese de Cardiologia (C.E.S.B., M.P.L., A.S.C.Z., O.I.P., S.M.), and Serviço de Anatomia Patológica (M.M.Z.), Institute Dante Pazzanese de Cardiologia, São Paulo, Brazil. Address reprint requests to Cely Saad Abboud, Seção Médica de Infectologia do Instituto Dante Pazzanese de Cardiologia, Av Dr Dante Pazzanese 500, 04012 909, São Paulo, Brazil. E-mail: [email protected]
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.07.042
Transplantation Proceedings, 44, 2501–2502 (2012)
2501
2502 she was doing clinically well, with no signs of relapse of the fungal infection.
DISCUSSION
There are only a few cases of mucormycosis following OLT described in the medical literature, with diverse types of presentation and evolution.3 The first remarkable aspect about the current case is the origin of mucormycosis, whether it occurred as a consequence of the recipient’s immunosuppression or was transmitted by the allograft, as the donor was also an immunocompromised host. This patient had favorable evolution without surgical debridement. Previous reports of mucormycosis in liver transplant recipients have shown mortality rates of 50% to 100%.5 Although surgical treatment is often desirable and one of the mainstreams of mucorales treatment along with prompt effective antifungal therapy, our case shows that clinical success can be achieved with adequate antifungal therapy, as in another recently published case.6 Although there are no systematic data on its use as sequential therapy, it is reasonable to consider it as an option for long-term treatment due to the safety profile and oral route of administration of the therapy. Another issue involving posaconazole therapy is the potential for drug– drug interactions. Posaconazole is a potent inhibitor of CYP enzymes including CYP3A4; this inhibition results in drug interactions with most immunosuppressive agents, such as cyclosporine, tacrolimus, and sirolimus.7 FK area under the curve can be increased by 100% during posaconazole use. Because of this, FK serum level and toxicity monitoring is desirable during posaconazole therapy, and a 50% dose reduction on
ABBOUD, BERGAMASCO, BAÍA ET AL
FK may be warranted. This drug interaction occurred but was successfully managed in our patient. We conclude that posaconazole may be an alternative for long-term sequential or maintenance therapy of mucormycosis in immunosuppressed hosts, although studies are needed to better evaluate this indication for general use as well as its use in the setting of SOT. Drug– drug interactions may occur but can be managed.
REFERENCES 1. Pappas PG, Alexander BD, Andes DR, et al: Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 50:1101, 2010 2. Singh N, Aguado JM, Bonatti H, et al: Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis 200:1002, 2009 3. Davari HR, Malekhossini SA, Salahi HA, et al: Outcome of mucormycosis in liver transplantation: four cases and a review of literature. Exp Clin Transplant 1:147, 2003 4. Almyroudis N, Sutton DA, Linden P, et al: Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature. Am J Transplant 6:2365, 2006 5. Spellberg B, Walsh TJ, Kontoyiannis DP, et al: Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 48:1743, 2009 6. Mezhir JJ, Mullane KM, Zarling J, et al: Successful nonoperative management of gastrointestinal mucormycosis: novel therapy for invasive disease. Surg Infect (Larchmt) 10:447, 2009 7. Brüggemann RJ, Alffenaar JW, Blijlevens NM, et al: Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 48:1441, 2009
M
CASE REPORT A 23-year-old woman underwent orthotopic liver transplantation due to primary biliary cirrhosis. Interestingly, her deceased donor was a kidney transplant recipient, who was under immunosuppressive therapy with tacrolimus (FK), prednisone, and mycophenolate mophetil at the time of his death, caused by hemorrhagic stroke. The recipient received immunosuppressive therapy that consisted of metpylprednisolone, tacrolimus, and sodium mycophenolate. She was also under fluconazole prophylaxis. Forty-seven days after transplantation, she presented with right hypochondrium pain and fever. An abdominal ultrasound was performed and revealed a hepatic abscess in the right lobe sized 53 ⫻ 51 mm. She underwent abscess drainage through ultrasound guided puncture and the culture yielded a multi-drug resistant Pseudomonas aeruginosa. Subsequent ultrasound guided drainages were performed, and the culture was persistently positive for P aeruginosa, despite polymixin B treatment. On day 83 after transplantation, a liver biopsy was performed, due to the persistence of the abscess. Histopathologic
examination showed tissue invasion by nonseptate hyphae compatible with mucormycosis infection but the fungal culture returned negative results. Liposomal amphotericin B (L-AmB) was started at a dose of 5 mg/kg/d. A percutaneous drain was placed in the abscess, and clinical treatment based on L-AmB and polymixin B was continued with clinical improvement and progressive reduction in the abscess dimensions. After 60 days of L-AmB therapy with clinical and radiological improvement, but still with a residual lesion, posaconazole 200 mg orally four times per day was started. At this time, the patient was receiving FK 2 mg twice a day, mycofenolate mofetil (MMF) 180 mg twice a day, and prednisone 10 mg per day. Her FK blood level before posaconazole was 9 g/L. After 6 days on posaconazole therapy, her FK blood level reached 39.5, and she presented with serum creatinine increase (from 1.1 to 1.8 mg/dL) and hyperkalemia. The FK dose was halved, her FK blood level progressively fell to 7.9 g/L, and the patient presented with renal function improvement. Posaconazole was stopped on month 6 after transplantation. At this time, she showed clinical improvement and resolution of the lesion by ultrasound. Eighteen months after the transplantation,
From the Serviço de Controle de Infecção Hospitalar e Seção Médica de Infectologia (C.S.A., M.D.B.), Unidade de Figado– Instituto Dante Pazzanese de Cardiologia (C.E.S.B., M.P.L., A.S.C.Z., O.I.P., S.M.), and Serviço de Anatomia Patológica (M.M.Z.), Institute Dante Pazzanese de Cardiologia, São Paulo, Brazil. Address reprint requests to Cely Saad Abboud, Seção Médica de Infectologia do Instituto Dante Pazzanese de Cardiologia, Av Dr Dante Pazzanese 500, 04012 909, São Paulo, Brazil. E-mail: [email protected]
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.07.042
Transplantation Proceedings, 44, 2501–2502 (2012)
2501
2502 she was doing clinically well, with no signs of relapse of the fungal infection.
DISCUSSION
There are only a few cases of mucormycosis following OLT described in the medical literature, with diverse types of presentation and evolution.3 The first remarkable aspect about the current case is the origin of mucormycosis, whether it occurred as a consequence of the recipient’s immunosuppression or was transmitted by the allograft, as the donor was also an immunocompromised host. This patient had favorable evolution without surgical debridement. Previous reports of mucormycosis in liver transplant recipients have shown mortality rates of 50% to 100%.5 Although surgical treatment is often desirable and one of the mainstreams of mucorales treatment along with prompt effective antifungal therapy, our case shows that clinical success can be achieved with adequate antifungal therapy, as in another recently published case.6 Although there are no systematic data on its use as sequential therapy, it is reasonable to consider it as an option for long-term treatment due to the safety profile and oral route of administration of the therapy. Another issue involving posaconazole therapy is the potential for drug– drug interactions. Posaconazole is a potent inhibitor of CYP enzymes including CYP3A4; this inhibition results in drug interactions with most immunosuppressive agents, such as cyclosporine, tacrolimus, and sirolimus.7 FK area under the curve can be increased by 100% during posaconazole use. Because of this, FK serum level and toxicity monitoring is desirable during posaconazole therapy, and a 50% dose reduction on
ABBOUD, BERGAMASCO, BAÍA ET AL
FK may be warranted. This drug interaction occurred but was successfully managed in our patient. We conclude that posaconazole may be an alternative for long-term sequential or maintenance therapy of mucormycosis in immunosuppressed hosts, although studies are needed to better evaluate this indication for general use as well as its use in the setting of SOT. Drug– drug interactions may occur but can be managed.
REFERENCES 1. Pappas PG, Alexander BD, Andes DR, et al: Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 50:1101, 2010 2. Singh N, Aguado JM, Bonatti H, et al: Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis 200:1002, 2009 3. Davari HR, Malekhossini SA, Salahi HA, et al: Outcome of mucormycosis in liver transplantation: four cases and a review of literature. Exp Clin Transplant 1:147, 2003 4. Almyroudis N, Sutton DA, Linden P, et al: Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature. Am J Transplant 6:2365, 2006 5. Spellberg B, Walsh TJ, Kontoyiannis DP, et al: Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 48:1743, 2009 6. Mezhir JJ, Mullane KM, Zarling J, et al: Successful nonoperative management of gastrointestinal mucormycosis: novel therapy for invasive disease. Surg Infect (Larchmt) 10:447, 2009 7. Brüggemann RJ, Alffenaar JW, Blijlevens NM, et al: Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 48:1441, 2009