Cytomegaloviraemia clearance with foscarnet during renal replacement therapy

Cytomegaloviraemia clearance with foscarnet during renal replacement therapy Sir, We report our experience with the use of foscarnet for treatment of refractory, ganciclovir-resistant cytomegalovirus (CMV) disease in a critically ill kidney transplant recipient in his late 60s who was requiring continuous venovenous haemofiltration (CVVH) and haemodialysis. Following kidney transplant from a living donor for renal failure due to diabetes and hypertensive nephrosclerosis, he received basiliximab induction and was maintained on mycophenolate mofetil, prednisone and tacrolimus (later switched to belatacept due to delayed allograft function). Because he was a CMV D+/R− mismatch, he received oral valganciclovir prophylaxis, at renally adjusted dosing (450 mg/day) PP. Five months after transplant, he developed breakthrough CMV viraemia [viral load, 5050 IU/mL (3.70 log IU/mL), COBAS AmpliPrep CMV Monitor, Roche]. He was treated with intravenous ganciclovir and attained an undetectable viral load after 6 weeks of therapy. After treatment discontinuation, he developed recurrent CMV viraemia [2640 IU/mL (2.76 log IU/mL)], which was treated with valganciclovir. This was complicated by severe leucopenia, which was treated with granulocyte colony stimulating factor. CMV viral load increased despite valganciclovir treatment. Genotypic testing (Focus Diagnostics, Inc., San Juan Capistrano, CA, USA) demonstrated UL97 C607C/Y mutation. While this mutation confers ganciclovir resistance, he did not have any symptoms and, thus, treatment was switched from oral valganciclovir to high-dose intravenous ganciclovir and this was complemented by weekly CMV immunoglobulin (human) infusions. Because of the sustained viraemia, he had sequential modulation of his immunosuppressive therapy. Mycophenolate mofetil and belatacept were discontinued while tacrolimus was combined with prednisone. Immunological testing demonstrated that the patient was developing a CMV-specific CD8+ T cell response. However, he continued to have sustained viraemia for the ensuing 4 months, with a peak CMV DNA load of 29400 IU/mL (4.47 log IU/mL) along with profound leucopenia (0.4 × 109 cells/L) and thrombocytopenia (10 × 109 cells/L). Repeated genotype testing revealed UL97 H520Q and UL54 A987G/A and L501L/F mutations that predicted high-level ganciclovir and cidofovir resistance.1 Hence, both tacrolimus and prednisone were discontinued and foscarnet was initiated at 3 g [30 mg/kg adjusted body weight (ABW)] intravenously every 24 h (body weight 122 kg, ABW 95 kg). At this time he was already in renal failure and his creatinine clearance estimated by Cockcroft-Gault was 23 mL/min. At that time, the patient developed acute Legionella pneumophila pneumonia, sepsis and multiorgan failure. He had hypoxaemic respiratory failure necessitating mechanical ventilation, hypotension requiring intravenous vasopressors and acute anuric renal failure requiring CVVH. CVVH was initiated with a prescription consisting of blood flow and haemofiltration rates of 200 mL/min and 3000 mL/h, respectively, with replacement fluid delivered equally pre- and post-filtration. Foscarnet was subsequently adjusted to 3 g (30 mg/kg ABW) every 12 h. After 16 days of therapy, he was able to produce urine and was liberated from CVVH to thrice-weekly intermittent haemodialysis with a prescription consisting of 3 h sessions with blood and dialysate flow rates of 350 and 600 mL/min, respectively, using a high-flux, high-efficiency REVACLEAR dialyser (Baxter International Inc., Deerfield, IL, USA). The foscarnet dosage was adjusted to 6 g (60 mg/kg ABW) administered only after dialysis sessions. After 26 days of total foscarnet therapy, plasma CMV DNA was undetectable (≥95% limit of detection at 91 IU/mL). However, with continued critical illness, ongoing respiratory failure and dependency on vasopressors and mechanical ventilation, the patient and his family decided to withdraw life-prolonging supportive therapy. Foscarnet is the drug of choice for treatment of ganciclovir-resistant CMV disease.2 However, it is not recommended for patients with renal dysfunction. Hence, no data are available for dosing recommendations in patients with acute renal failure or those receiving renal replacement therapies.3 Given its small size (126 Da), low protein binding (<20%), low volume of distribution (0.5 L/kg) and complete urinary excretion, foscarnet is expected to be readily removed by the extracorporeal circuit.3,4 Using this information and foscarnet’s elimination half-life of ∼3–4 h, we extrapolated manufacturer recommendations in the setting of renal dysfunction assuming approximate linearity in dosage reduction arriving at 30 mg/kg every 12 h of ABW given the patient’s morbid obesity during CVVH. Similarly, the haemodialysis dosage of 60 mg/kg administered following dialysis sessions was devised. Due to the lack of assay availability, serum foscarnet concentrations were not evaluated. Despite this, we believe that we had given the patient appropriate dosing since he attained viral clearance. Because the patient was already in acute renal failure prior to the initiation of foscarnet, it is unclear in this case to what degree foscarnet inflicted additional harm to the kidneys. Despite this, foscarnet is a therapeutic option for resistant CMV disease even for those patients in acute renal failure receiving renal replacement therapies. Informed consent A waiver of informed consent was provided. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev  2010; 23: 689– 712. Google Scholar CrossRef Search ADS PubMed  2 Le Page AK, Jager MM, Iwasenko JM et al.   Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients. Clin Infect Dis  2013; 56: 1018– 29. Google Scholar CrossRef Search ADS PubMed  3 Foscarnet (Prescribing Information).  Lake Forest, IL, USA: Hospira, February 2017. 4 Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs  1994; 48: 199– 226. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Cytomegaloviraemia clearance with foscarnet during renal replacement therapy

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Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0305-7453
eISSN
1460-2091
D.O.I.
10.1093/jac/dkx398
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Abstract

Sir, We report our experience with the use of foscarnet for treatment of refractory, ganciclovir-resistant cytomegalovirus (CMV) disease in a critically ill kidney transplant recipient in his late 60s who was requiring continuous venovenous haemofiltration (CVVH) and haemodialysis. Following kidney transplant from a living donor for renal failure due to diabetes and hypertensive nephrosclerosis, he received basiliximab induction and was maintained on mycophenolate mofetil, prednisone and tacrolimus (later switched to belatacept due to delayed allograft function). Because he was a CMV D+/R− mismatch, he received oral valganciclovir prophylaxis, at renally adjusted dosing (450 mg/day) PP. Five months after transplant, he developed breakthrough CMV viraemia [viral load, 5050 IU/mL (3.70 log IU/mL), COBAS AmpliPrep CMV Monitor, Roche]. He was treated with intravenous ganciclovir and attained an undetectable viral load after 6 weeks of therapy. After treatment discontinuation, he developed recurrent CMV viraemia [2640 IU/mL (2.76 log IU/mL)], which was treated with valganciclovir. This was complicated by severe leucopenia, which was treated with granulocyte colony stimulating factor. CMV viral load increased despite valganciclovir treatment. Genotypic testing (Focus Diagnostics, Inc., San Juan Capistrano, CA, USA) demonstrated UL97 C607C/Y mutation. While this mutation confers ganciclovir resistance, he did not have any symptoms and, thus, treatment was switched from oral valganciclovir to high-dose intravenous ganciclovir and this was complemented by weekly CMV immunoglobulin (human) infusions. Because of the sustained viraemia, he had sequential modulation of his immunosuppressive therapy. Mycophenolate mofetil and belatacept were discontinued while tacrolimus was combined with prednisone. Immunological testing demonstrated that the patient was developing a CMV-specific CD8+ T cell response. However, he continued to have sustained viraemia for the ensuing 4 months, with a peak CMV DNA load of 29400 IU/mL (4.47 log IU/mL) along with profound leucopenia (0.4 × 109 cells/L) and thrombocytopenia (10 × 109 cells/L). Repeated genotype testing revealed UL97 H520Q and UL54 A987G/A and L501L/F mutations that predicted high-level ganciclovir and cidofovir resistance.1 Hence, both tacrolimus and prednisone were discontinued and foscarnet was initiated at 3 g [30 mg/kg adjusted body weight (ABW)] intravenously every 24 h (body weight 122 kg, ABW 95 kg). At this time he was already in renal failure and his creatinine clearance estimated by Cockcroft-Gault was 23 mL/min. At that time, the patient developed acute Legionella pneumophila pneumonia, sepsis and multiorgan failure. He had hypoxaemic respiratory failure necessitating mechanical ventilation, hypotension requiring intravenous vasopressors and acute anuric renal failure requiring CVVH. CVVH was initiated with a prescription consisting of blood flow and haemofiltration rates of 200 mL/min and 3000 mL/h, respectively, with replacement fluid delivered equally pre- and post-filtration. Foscarnet was subsequently adjusted to 3 g (30 mg/kg ABW) every 12 h. After 16 days of therapy, he was able to produce urine and was liberated from CVVH to thrice-weekly intermittent haemodialysis with a prescription consisting of 3 h sessions with blood and dialysate flow rates of 350 and 600 mL/min, respectively, using a high-flux, high-efficiency REVACLEAR dialyser (Baxter International Inc., Deerfield, IL, USA). The foscarnet dosage was adjusted to 6 g (60 mg/kg ABW) administered only after dialysis sessions. After 26 days of total foscarnet therapy, plasma CMV DNA was undetectable (≥95% limit of detection at 91 IU/mL). However, with continued critical illness, ongoing respiratory failure and dependency on vasopressors and mechanical ventilation, the patient and his family decided to withdraw life-prolonging supportive therapy. Foscarnet is the drug of choice for treatment of ganciclovir-resistant CMV disease.2 However, it is not recommended for patients with renal dysfunction. Hence, no data are available for dosing recommendations in patients with acute renal failure or those receiving renal replacement therapies.3 Given its small size (126 Da), low protein binding (<20%), low volume of distribution (0.5 L/kg) and complete urinary excretion, foscarnet is expected to be readily removed by the extracorporeal circuit.3,4 Using this information and foscarnet’s elimination half-life of ∼3–4 h, we extrapolated manufacturer recommendations in the setting of renal dysfunction assuming approximate linearity in dosage reduction arriving at 30 mg/kg every 12 h of ABW given the patient’s morbid obesity during CVVH. Similarly, the haemodialysis dosage of 60 mg/kg administered following dialysis sessions was devised. Due to the lack of assay availability, serum foscarnet concentrations were not evaluated. Despite this, we believe that we had given the patient appropriate dosing since he attained viral clearance. Because the patient was already in acute renal failure prior to the initiation of foscarnet, it is unclear in this case to what degree foscarnet inflicted additional harm to the kidneys. Despite this, foscarnet is a therapeutic option for resistant CMV disease even for those patients in acute renal failure receiving renal replacement therapies. Informed consent A waiver of informed consent was provided. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev  2010; 23: 689– 712. Google Scholar CrossRef Search ADS PubMed  2 Le Page AK, Jager MM, Iwasenko JM et al.   Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients. Clin Infect Dis  2013; 56: 1018– 29. Google Scholar CrossRef Search ADS PubMed  3 Foscarnet (Prescribing Information).  Lake Forest, IL, USA: Hospira, February 2017. 4 Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs  1994; 48: 199– 226. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 1, 2018

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