Intensive Care Med (2015) 41:948–949 DOI 10.1007/s00134-015-3754-9
Quentin Ressaire Christophe Padoin Marc Chaouat Veronique Maurel Alexandre Alanio Axelle Ferry Sabri Soussi Mourad Benyamina Blandine Denis Maurice Mimoun Alexandre Mebazaa Matthieu Legrand
Muscle diffusion of liposomal amphotericin B and posaconazole in critically ill burn patients receiving continuous hemodialysis Accepted: 12 March 2015 Published online: 24 March 2015 Ó Springer-Verlag Berlin Heidelberg and ESICM 2015
Dear Editor, Mucormycoses are opportunistic fungal infections, which occur in patients with impaired host defenses and are associated with very high mortality [1]. Therapeutic management of mucormycosis includes surgical debridement of necrotic lesions and intravenous liposomal amphotericin B (L-AMB), possibly in combination with posaconazole (PSC). Because antifungal drug concentration both in plasma and tissue remains uncertain in burn patients (as
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a result of large positive fluid balance with increase of volume of distribution, renal replacement therapy (RRT), gut dysfunction), we measured plasma and tissue concentration of L-AMB and posaconazole in three critically ill burn patients with proven invasive subcutaneous mucormycosis due to Mucor circinelloides. They had a median age of 45 years (28–54), a mean total burn body surface area of 80 % (min 60–max 96), and simplified acute physiology score II 42 (min 36–max 49). Mucormycosis was diagnosed 16 days (min 12–max19) after burn injury. They all received continuous venovenous hemodialysis with a multifiltrate monitor (dialysate rate of 2000 ml/h and a blood flow rate of 100 ml/min and regional citrate anticoagulation). Patients received L-AMB 10 mg/ kg once daily from diagnosis, in combination with PSC 400 mg oral suspension twice daily for patient 1. Plasma trough concentrations were collected at steady state and muscle biopsies harvested simultaneously, in non-necrotic areas, during a routine debridement surgical procedure. Plasma samples were immediately centrifuged at 4000g for 10 min. Plasma and biopsies were stored at -20 °C until measurements. Weighed tissues were homogenized in water over an ice bath using a Polytron for 2.5 min. Then, plasma and muscle concentrations of L-AMB and PSC were assayed using a validated liquid chromatography method. The limit of quantification
(LOQ) was 0.1 mg/l for both. L-AMB concentrations in muscle were assessed 14 (min 12–max 15) days after initiation of treatment. L-AMB median concentration was 44 lg/g [18–81], exceeding plasma concentration in all patients (Table 1). PSC plasma and tissue concentrations were measured in patient 1 and both were lower than the LOQ. Despite mucormycosis infection being considered under control in patients 2 and 3, all patients died from multiple organ dysfunction. Our study demonstrates good tissue diffusion of L-AMB in skeletal muscles, as previously reported in other tissues (lung, liver, kidney) [2], reaching 10- to 20-fold higher concentrations than in plasma after infusion of high doses of L-AMB. However PSC concentration monitoring revealed a very poor bioavailability resulting in very low plasma and tissue concentrations. Because of highly variable PSC absorption after oral administration of PSC solution, extreme between-patient variability in PSC exposure was observed in a previous study [3]. These results are not expected to result from RRT removal, which has been described to be low [4]. To conclude, our data show good muscular tissue diffusion of L-AMB in critically ill burn patients receiving CVVHD. Tissue diffusion does not appear to be the limiting factor in controlling mucormycosis and efforts should probably be directed towards others factors (i.e., timing of treatment initiation, immune system
Table 1 Plasma and tissue concentrations of liposomal amphotericin B Plasma concentrations (lg/ml)
Patient 1
2.17
Patient 2
2.58
Patient 3
4.76
Muscle concentrations
Sample Sample Sample Sample Sample
1 2 1 2 1
lg/g
lg/ml
41.8 17.8 50.2 30.7 81.3
0.92 0.92 0.72 0.89 4.44
Tissue/plasma ratio
19 8 19 12 17
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5. Dolton MJ, Ray JE, Marriott D, modulation etc.) and reinforce the McLachlan AJ (2012) Posaconazole need for therapeutic drug monitoring exposure-response relationship: of PSC in critically ill burn patients evaluating the utility of therapeutic drug and for an intravenous administration monitoring. Antimicrob Agents Chemother 56:2806–2813 of available antifungal drugs [5].
A. Alanio Laboratoire de Parasitologie-Mycologie, Hoˆpital Saint-Louis, Groupe Hospitalier Laroboisie`re, Saint-Louis, Fernand Widal, Assistance Publique-Hoˆpitaux de Paris (APHP), Paris, France
Acknowledgments The work was supported by a grant from la Fondation des Q. Ressaire V. Maurel A. Ferry S. Soussi M. Benyamina ‘‘Gueules Casse´es’’. A. Mebazaa M. Legrand ()) Conflicts of interest Matthieu Legrand Department of Anesthesiology and Critical received consulting fees from Astellas and Care and Burn Unit, Hoˆpitaux universitaires lecture fees from Gilead. St-Louis-Lariboisie`re, Groupe Hospitalier St-Louis-Lariboisie`re, AP-HP, 75475 Paris, France e-mail:
[email protected] Tel.: ?33 (0)1 42 49 43 48
A. Alanio Institut Pasteur, Unite´ de mycologie mole´culaire, Centre National de Re´fe´rence Mycoses invasives et Antifongiques, Paris, France
References
1. Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP (2012) Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 54(Suppl 1):S23–S34 2. Felton T, Troke PF, Hope WW (2014) Tissue penetration of antifungal agents. Clin Microbiol Rev 27:68–88 3. Ullmann AJ, Cornely OA, Burchardt A, Hachem R, Kontoyiannis DP, To¨pelt K et al (2006) Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother 50:658–666 4. Courtney R, Sansone A, Smith W, Marbury T, Statkevich P, Martinho M et al (2005) Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease. J Clin Pharmacol 45(2):185–192
C. Padoin Laboratoire de Toxicologie, Hoˆpital Avicenne, GHUPSSD, AP-HP, 93000 Bobigny, France M. Chaouat M. Mimoun Service de chirurgie plastique, reconstructrice, esthe´tique et traitement chirurgical des bruˆle´s, Hoˆpital Saint-Louis, Groupe Hospitalier Lariboisie`re, SaintLouis, Assistance Publique-Hoˆpitaux de Paris (AP-HP), Paris, France M. Chaouat A. Alanio M. Mimoun A. Mebazaa M. Legrand Univ Paris Diderot, 75475 Paris, France
A. Alanio CNRS URA3012, Paris, France B. Denis Service de maladies infectieuses et tropicales, Hoˆpital Saint-Louis, Groupe Hospitalier Lariboisie`re, Saint-Louis, Assistance Publique-Hoˆpitaux de Paris (APHP), Paris, France A. Mebazaa M. Legrand Inserm UMR942, Paris, France
