Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid

Transcription

1 AAC Accepts, published online ahead of print on 19 January 2010 Antimicrob. Agents Chemother. doi: /aac Copyright 2010, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. AAC /8/09 Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid Brad Moriyama 1*, Parizad Torabi-Parizi 2,*, Alexandra K. Pratt 2, Stacey A. Henning 1, Gennethel Pennick 3, Yvonne R. Shea 4, Sinchita Roy Chowdhuri 5, Michael G. Rinaldi 3, A. John Barrett 6, and Thomas J. Walsh 5 1 NIH Clinical Center Pharmacy Dept., Bethesda, MD 2 Critical Care Medicine Department, Bethesda, MD 3 University of Texas Health Science Center, San Antonio, TX 4 Department of Laboratory Medicine, Bethesda, MD 5 National Cancer Institute, Bethesda, MD 6 National Heart Lung and Blood Institute, Bethesda, MD * These authors contributed equally to this work. Running title: Pharmacokinetics of Liposomal Amphotericin B in Pleural Fluid Please address correspondence and requests for reprints to Dr. Brad Moriyama, NIH Clinical Center Pharmacy Department, 10 Center Drive Bethesda, MD TEL: (direct) FAX: bmoriyama@cc.nih.gov 1

2 Abstract We report the penetration of liposomal amphotericin B into the pleural fluid of a patient with pulmonary zygomycosis and empyema. The liposomal amphotericin B AUC pleural fluid to AUC serum ratio over 24 hours was 9.4% with pleural fluid concentrations of 2.12 to 4.91 mcg/ml. Given the relatively low intrapleural penetration of liposomal amphotericin B, chest tube drainage may be warranted for successful treatment of zygomycotic empyema. Introduction Invasion of the pleural space is a serious complication of fungal pneumonias (9). There is limited information on the penetration of liposomal amphotericin B (LAmB) into the pleural fluid of humans (20). We report herein a detailed pharmacokinetic sampling and analysis of the penetration of LAmB into the pleural fluid of a patient with pulmonary zygomycosis and empyema. Case Description A 52-year-old female recipient of a myeloablative allogeneic hematopoietic stem cell transplant for mantle cell lymphoma, in November of 2006, was admitted to the Intensive Care Unit with increasing dyspnea. Her course had been complicated by corticosteroid-induced diabetes mellitus, and graft-versus-host disease involving the skin, liver, and GI tract, necessitating high dose corticosteroids, infliximab and daclizumab. Computed tomography showed findings consistent with a cavitary right upper lobe lesion and associated pleural effusion. Surgical wedge resection of the right upper lobe lesion was undertaken, pleural fluid was sampled, and two 32 French drainage chest tubes placed, one inferiorly and one superiorly. 2

3 Wet mount of the pleural fluid showed broad non-septate hyphae morphologically consistent with a Zygomycete. Pathological inspection of the surgical sample similarly showed broad nonseptate hyphae with non-dichotomous branching within the lung tissue, as well as infiltration of the vascular wall and intravascular thrombosis. The patient was diagnosed with pulmonary zygomycosis and empyema. She received LAmB at an initial dose of 5 mg/kg (440 mg) IV every 24 hours for 15 days. Thoracotomy, lung resection, and insertion of chest tubes were performed on day 13 of LAmB therapy. However, in light of worsening renal function (serum creatinine peaked at 2.7 mg/dl), the dosage of LAmB was changed to 7.5 mg/kg (660 mg) IV every 48 hours on day 17 of LAmB therapy. Immunosuppression was reduced by tapering high dose methylprednisolone. Liposomal amphotericin B was administered for a total course of 27 days until the day of the patient s expiration. Liposomal amphotericin B serum and pleural fluid concentrations were measured to assist in the management of the patient s zygomycotic empyema. Serum and pleural fluid concentrations were obtained starting on day 21 and ending on day 22 of LAmB therapy. Serum concentrations were drawn from an arterial line and collected in serum separator tubes, while pleural fluid concentrations were drawn from the patient s inferior chest tube and collected in plain red top tubes. The serum concentration at 24 hours was drawn from a venous catheter due to removal of the patient s arterial line. The samples were protected from light and centrifuged at 3500 x g for 10 minutes. Samples were shipped on ice packs to the Fungus Testing Laboratory at the University of Texas Health Science Center at San Antonio, Texas. Liposomal amphotericin B concentrations were determined by a previously validated HPLC assay (18). 3

4 Serum and pleural fluid concentrations were obtained starting on day 21 of LAmB infusion (Figure 1). Recognizing that samples were obtained for only the first 24 hours, the LAmB area under the concentration versus time curve in serum (AUC serum ) and in pleural fluid (AUC pleural fluid ) were calculated as previously described (17). The AUC serum was 802 mcg h/ml and AUC pleural fluid was 75 mcg h/ml, with an AUC pleural fluid /AUC serum ratio of 9.4% over the 24 hour period. The pleural fluid to serum LAmB concentration ratios for individual time points are presented in Table 1. After 21 days of administration of a cumulative dose of 8,580 mg of LAmB, there was no evidence of intrapleural accumulation. The patient s respiratory status and renal function improved. Following discussion of the duration of chest tube placement, the drainage tubes remained in place, with output decreasing over time. Repeat pleural fluid wet mount and fungal culture remained negative. Unfortunately, on post-operative day 15, the patient died from fulminant Acinetobacter baumannii septic shock and multi-organ failure. Discussion Much has been written about the management of pulmonary zygomycosis, but little is reported about the treatment of zygomycotic empyema (3,4,14). Pleural effusions have been seen more frequently in patients with pulmonary zygomycosis (63%) than in patients with invasive pulmonary aspergillosis (33%) (3). However, only several cases of zygomycotic empyema caused by Absidia spp., Mucor spp., Rhizomucor pusillus, Rhizopus oryzae, Rhizopus spp., Cokeromyces recurvatus, and a non-identified genus have been reported in the English literature (5,7-10,12,13). Pleural zygomycosis can occur as a consequence of pulmonary 4

5 infection that extends into the pleural space, as well as direct inoculation of the fungus into the pleura (8,14). Deoxycholate amphotericin B or lipid formulations of amphotericin B are the primary antifungal agents for the treatment of zygomycosis (15,16). The management of zygomycotic empyema involves parenterally administered amphotericin B with concomitant drainage of the infected pleural effusion. Nephrotoxicity may limit the use of deoxycholate amphotericin B, especially in patients receiving concomitant nephrotoxic drugs and in those with underlying renal insufficiency. Similar to properties of the peritoneum (21), penetration of circulating drugs into the pleural space is limited by an endothelial-mesothelial barrier (19). Current studies suggest that both endothelial cells and mesothelial cells contribute to the relative impermeability of the pleural space to compounds within the endovascular compartment (22). Little is known about the penetration of amphotericin B and its lipid formulations into the pleural space (1,2,11,20). While pleural fluid levels of amphotericin B deoxycholate were 25 to 70% of serum levels in a patient with Blastomyces dermatitidis empyema, the trough concentration was only approximately 0.6 mcg/ml (11). Based upon two time points, Weiler and colleagues reported that the penetration of LAmB into the pleural fluid of a critically ill patient ranged from 3 to 6% (20). We therefore performed a detailed pharmacokinetic sampling and analysis to further characterize penetration of LAmB into pleural fluid. The percentage penetration of LAmB into pleural fluid was low, with an AUC pleural fluid /AUC serum ratio of 9.4% and pleural fluid concentrations of 2.12 to 4.91 mcg/ml. As the sampling in this report was conducted for the first 24 hours post-infusion, the AUC pleural fluid /AUC serum ratio may vary with a 5

6 longer sampling time. However, as the 24 hour sampling period captured the majority of the AUC, the ratio would be similar. Medical therapy alone with liposomal amphotericin B may not be adequate for the management of zygomycotic empyema considering that its achievable pleural fluid concentrations are unlikely to substantially exceed the minimal lethal concentrations of amphotericin B against Zygomycetes (2 to 8 mcg/ml) (6). Given the data presented above, continued pleural fluid drainage is therefore an integral part of the management strategy for patients with zygomycotic empyemas. Similar to the management of bacterial empyemas, the drainage tubes may be placed to water seal and subsequently removed once the drainage is reduced to less than 50 ml per day. In conclusion, the penetration of LAmB into pleural fluid may be relatively low for the treatment of zygomycotic empyema. Chest tube drainage is an important adjunct, with the duration of chest tube placement dictated by the volume of drainage. Downloaded from on July 7, 2018 by guest 6

7 References 1. Bindschadler, D. D., and J. E. Bennett A pharmacologic guide to the clinical use of amphotericin B. J. Infect. Dis. 120: Chabot, G. G., R. Pazdur, F. A. Valeriote, and L. H. Baker Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients. J. Pharm. Sci. 78: Chamilos, G., E. M. Marom, R. E. Lewis, M. S. Lionakis, and D. P. Kontoyiannis Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer. Clin. Infect. Dis. 41: Chamilos, G., M. Luna, R. E. Lewis, G. P. Bodey, R. Chemaly, J. J. Tarrand, A. Safdar, I. I. Raad, and D. P. Kontoyiannis Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period ( ). Haematologica. 91: Cooke, D. T., F. D. Pagani, D. R. Kaul, K. R. Cooke, C. L. Lau, and J. Riddell 4th Successful treatment of pulmonary zygomycosis in two transplant recipients with liposomal amphotericin B and partial surgical resection followed by posaconazole. Mycoses. (Epub ahead of print). 7

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10 18. Wang, L. H., P. C. Smith, K. L. Anderson, and R. M. Fielding High-performance liquid chromatographic analysis of amphotericin B in plasma, blood, urine and tissues for pharmacokinetic and tissue distribution studies. J. Chromatogr. 579: Wang, N. S Anatomy and physiology of the pleural space. Clin. Chest. Med. 6: Weiler, S., R. Bellmann-Weiler, M. Joannidis, and R. Bellmann Penetration of amphotericin B lipid formulations into pleural effusion. Antimicrob. Agents. Chemother. 51: Weiler, S., R. Bellmann-Weiler, S. Dunzendorfer, M. Joannidis, and R. Bellmann Levels of amphotericin B lipid formulations in ascites. J. Antimicrob. Chemother. 62: Zocchi, L Physiology and pathophysiology of pleural fluid turnover. Eur. Respir. J. 20:

11 Acknowledgement The authors thank Dr. Scott Penzak for his thoughtful comments and review of the manuscript. This work was supported in part by the intramural research program of the National Institutes of Health. 11

12 Table 1. Ratios of Pleural Fluid to Serum LAmB Concentrations over 24 hours Time (h) LAmB Concentration LAmB Concentration Pleural Fluid: in Pleural Fluid in Serum Serum (mcg/ml) (mcg/ml) Concentration Ratio Downloaded from on July 7, 2018 by guest 12

13 Figure Legend Figure 1. Serum ( ) and pleural fluid ( ) concentration versus time profile of LAmB 7.5 mg/kg. The curve represents -30 minutes pre-infusion serum and pleural fluid levels with simultaneous levels measured through 24 hours starting on day 21 and ending on day 22 of LAmB therapy. 13

14 Concentration (mcg/ml) Serum levels Pleural fluid levels LAmB infusion Time (h)