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The development and implementation of stewardship initiatives to optimize the prevention and treatment of cytomegalovirus infection in solid-organ transplant recipients

Published online by Cambridge University Press:  27 May 2020

Margaret R. Jorgenson*
Affiliation:
Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
Jillian L. Descourouez
Affiliation:
Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
Lucas T. Schulz
Affiliation:
Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
Kerry A. Goldrosen
Affiliation:
Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
John P. Rice
Affiliation:
Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
Robert R. Redfield
Affiliation:
Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
Christopher M. Saddler
Affiliation:
Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
Jeannina A. Smith
Affiliation:
Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
Didier A. Mandelbrot
Affiliation:
Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
*
Address for correspondence: Margaret Jorgenson, E-mail: MJorgenson@uwhealth.org

Abstract

Classical stewardship efforts have targeted immunocompetent patients; however, appropriate use of antimicrobials in the immunocompromised host has become a target of interest. Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid-organ transplant (SOT). The treatment of CMV requires a dual approach of antiviral drug therapy and reduction of immunosuppression for optimal outcomes. This dual approach to CMV management increases complexity and requires individualization of therapy to balance antiviral efficacy with the risk of allograft rejection. In this review, we focus on the development and implementation of CMV stewardship initiatives, as a component of antimicrobial stewardship in the immunocompromised host, to optimize the management of prevention and treatment of CMV in SOT recipients. These initiatives have the potential not only to improve judicious use of antivirals and prevent resistance but also to improve patient and graft survival given the interconnection between CMV infection and allograft function.

Type
Review
Copyright
© 2020 by The Society for Healthcare Epidemiology of America. All rights reserved.

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References

Fishman, N.Antimicrobial stewardship. Am J Infect Control 2006;34(5 suppl 1):S55S63.CrossRefGoogle ScholarPubMed
Society for Healthcare Epidemiology of America; Infectious Diseases Society of America; Pediatric Infectious Diseases Society. Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012;33:322327.Google Scholar
Abbo, LM, Ariza-Heredia, EJ.Antimicrobial stewardship in immunocompromised hosts. Infect Dis Clin North Am 2014;28:263279.CrossRefGoogle ScholarPubMed
Robilotti, E, Holubar, M, Seo, SK, Deresinski, S.Feasibility and applicability of antimicrobial stewardship in immunocompromised patients. Curr Opin Infect Dis 2017;30:346353.CrossRefGoogle ScholarPubMed
Asberg, A, Jardine, AG, Bignamini, AA, et al.Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant 2010;10:18811888.CrossRefGoogle ScholarPubMed
Young, PG, Rubin, J, Angarone, M, et al.Ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients: a single-center retrospective cohort study. Transpl Infect Dis 2016;18:390395.CrossRefGoogle ScholarPubMed
Rolling, KE, Jorgenson, MR, Descourouez, JL, Mandelbrot, DA, Redfield, RR, Smith, JA.Ganciclovir-resistant cytomegalovirus infection in abdominal solid organ transplant recipients: case series and review of the literature. Pharmacotherapy 2017;37:12581271.CrossRefGoogle ScholarPubMed
Paya, C, Humar, A, Dominguez, E, et al.Efficacy and safety of valganciclovir versus oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004;4:611620.CrossRefGoogle Scholar
Drew, WL.Ganciclovir resistance: a matter of time and titre. Lancet 2000;356:609610.CrossRefGoogle ScholarPubMed
Avery, RK.Low-dose valganciclovir for cytomegalovirus prophylaxis in organ transplantation: is less really more? Clin Infect Dis 2011;52:322324.CrossRefGoogle ScholarPubMed
Leeaphorn, N, Garg, N, Thamcharoen, N, Khankin, EV, Cardarelli, F, Pavlakis, M.Cytomegalovirus mismatch still negatively affects patient and graft survival in the era of routine prophylactic and preemptive therapy: a paired kidney analysis. Am J Transplant 2019;19:573584.Google ScholarPubMed
Gardiner, BJ, Chow, JK, Brilleman, SL, Peleg, AY, Snydman, DR.The impact of recurrent cytomegalovirus infection on long-term survival in solid organ transplant recipients. Transpl Infect Dis 2019 Oct 3 [Epub ahead of print]. doi: 10.1111/tid.13189.CrossRefGoogle ScholarPubMed
Fishman, JA.Infection in solid-organ transplant recipients. N Engl J Med 2007;357:26012614.CrossRefGoogle ScholarPubMed
Wills, MR, Poole, E, Lau, B, Krishna, B, Sinclair, JH.The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies? Cell Mol Immunol 2015;12:128138.CrossRefGoogle ScholarPubMed
La Rosa, C, Diamond, D.The immune response to human CMV. Future Virol 2012;7:279293.CrossRefGoogle ScholarPubMed
Pescovitz, MD, Rabkin, J, Merion, RM, et al.Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 2000;44:28112815.CrossRefGoogle ScholarPubMed
Patel, T, Imlay, H, Kaul, D, Stuckey, L, Gregg, K.Ganciclovir-resistant CMV (GCV-R CMV) infection leads to poor clinical outcomes and economic burden of ganciclovir-resistant cytomegalovirus infection in lung transplant recipients. Open Forum Infect Dis 2017:4:S730.CrossRefGoogle Scholar
Kotton, CN, Kumar, D, Caliendo, AM, et al.The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900931.CrossRefGoogle ScholarPubMed
Hodson, EM, Ladhani, M, Webster, AC, Strippoli, GF, Craig, JC.Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2013;2:CD003774.Google Scholar
Valcyte prescribning information. Genentech website. https://www.gene.com/download/pdf/valcyte_prescribing.pdf. Updated 2018. Accessed May 11, 2020.Google Scholar
Hwang, SD, Lee, JH, Lee, SW, Kim, JK, Kim, MJ, Song, JH.Effect of low-dose vs standard-dose valganciclovir in the prevention of cytomegalovirus disease in kidney transplantation recipients: a systemic review and meta-analysis. Transplant Proc 2018;50:24732478.CrossRefGoogle ScholarPubMed
Avery, RK.Low-dose valganciclovir for cytomegalovirus prophylaxis in organ transplantation: is less really more? Clin Infect Dis 2011;52:322324.CrossRefGoogle ScholarPubMed
Reischig, T, Kacer, M, Jindra, P, et al.Randomized trial of valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. Clin J Am Soc Nephrol 2015;10:294304.Google ScholarPubMed
Reischig, T, Kacer, M, Hruba, P, et al.Less renal allograft fibrosis with valganciclovir prophylaxis for cytomegalovirus compared to high-dose valacyclovir: a parallel group, open-label, randomized controlled trial. BMC Infect Dis 2018;18:573.Google ScholarPubMed
Siodlak, M, Jorgenson, MR, Descourouez, JL, et al.Impact of high-dose acyclovir cytomegalovirus prophylaxis failure in abdominal solid organ transplant recipients. pharmacotherapy. 2018 May 25 [Epub ahead of print]. doi: 10.1002/phar.2126.CrossRefGoogle ScholarPubMed
Marty, FM, Ljungman, P, Chemaly, RF, et al.Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377:24332444.CrossRefGoogle ScholarPubMed
Letermovir versus valganciclovir to prevent human cytomegalovirus disease in kidney transplant recipients (MK-8228-002). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03443869. Updated May 8, 2020. Accessed May 12, 2020.Google Scholar
Humar, A, Kumar, D, Boivin, G, et al.Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease. J Infect Dis 2002;186:829833.CrossRefGoogle ScholarPubMed
Couzi, L, Helou, S, Bachelet, T, et al.High incidence of anticytomegalovirus drug resistance among D+R− kidney transplant recipients receiving preemptive therapy. Am J Transplant 2012;12:202209.CrossRefGoogle ScholarPubMed
Atabani, SF, Smith, C, Atkinson, C, et al.Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy. Am J Transplant 2012;12:24572464.CrossRefGoogle ScholarPubMed
Kotton, CN.Updates on antiviral drugs for cytomegalovirus prevention and treatment. Curr Opin Organ Transplant 2019;24:469475.CrossRefGoogle ScholarPubMed
Minces, LR, Nguyen, MH, Mitsani, D, et al.Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens. Antimicrob Agents Chemother 2014;58:128135.CrossRefGoogle ScholarPubMed
Bonatti, H, Sifri, CD, Larcher, C, Schneeberger, S, Kotton, C, Geltner, C.Use of cidofovir for cytomegalovirus disease refractory to ganciclovir in solid organ recipients. Surg Infect (Larchmt) 2017;18:128136.CrossRefGoogle ScholarPubMed
Anglicheau, D, Lautrette, A, Scieux, C, Flamant, M, Morinet, F, Legendre, C.Efficacy and safety of lowering immunosuppression to treat CMV infection in renal transplant recipients on valaciclovir prophylaxis: a pilot study. Nephrol Dial Transplant 2003;18:16541656.Google ScholarPubMed
Asberg, A, Jardine, AG, Bignamini, AA, et al.Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant 2010;10:18811888.CrossRefGoogle ScholarPubMed
Myhre, HA, Haug Dorenberg, D, Kristiansen, KI, et al.Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation 2011;92:217223.CrossRefGoogle ScholarPubMed
Erdbrugger, U, Scheffner, I, Mengel, M, et al.Long-term impact of CMV infection on allografts and on patient survival in renal transplant patients with protocol biopsies. Am J Physiol Renal Physiol 2015;309:F925F932.CrossRefGoogle ScholarPubMed
Reischig, T, Jindra, P, Hes, O, et al.Effect of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and tubular atrophy in protocol biopsy at 3 months in renal allograft recipients managed by preemptive therapy or antiviral prophylaxis. Transplantation 2009;87:436444.CrossRefGoogle ScholarPubMed
Sagedal, S, Hartmann, A, Nordal, K, et al.Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004;6:329337.CrossRefGoogle Scholar
Lisboa, LF, Preiksaitis, JK, Humar, A, et al.Clinical utility of molecular surveillance for cytomegalovirus after antiviral prophylaxis in high-risk solid organ transplant recipients. Transplantation 2011;92:10631068.Google ScholarPubMed
Jorgenson, MR, Descourouez, JL, Lyu, B, et al.The risk of cytomegalovirus infection after treatment of acute rejection in renal transplant recipients. Clin Transplant 2019;33(8). doi: 10.1111/tid.13080.CrossRefGoogle ScholarPubMed
Browne, B, Young, JA, Dunn, TB, Matas, AJ.The impact of cytomegalovirus infection ≥ 1 year after primary renal transplantation. Clin Transplant 2010;24:572577.CrossRefGoogle ScholarPubMed
2017 Annual Data Report. Scientific Registry of Transplant Recipients website. http://srtr.transplant.hrsa.gov/annual_reports/Default.aspx. Accessed October 22, 2019.Google Scholar
Core elements of hospital antibiotic stewardship programs. Centers for Disease Control and Prevention website. https://www.cdc.gov/antibiotic-use/core-elements/hospital.html. Accessed May 11, 2020.Google Scholar
Razonable, RR, Humar, A.Cytomegalovirus in solid organ transplant recipients—guidelines of the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant 2019;33(9):e13512. doi: 10.1111/ctr.13512.CrossRefGoogle Scholar
Wang, N, Athans, V, Neuner, E, Bollinger, J, Spinner, M, Brizendine, K.A pharmacist-driven antimicrobial stewardship intervention targeting cytomegalovirus viremia in ambulatory solid organ transplant recipients. Transpl Infect Dis 2018;20(6):e12991. doi: 10.1111/tid.12991.CrossRefGoogle ScholarPubMed
Hensler, D, Richardson, CL, Brown, J, et al.Impact of electronic health record-based, pharmacist-driven valganciclovir dose optimization in solid organ transplant recipients. Transpl Infect Dis 2018;20(2):e12849. doi: 10.1111/tid.12849.CrossRefGoogle ScholarPubMed
Eid, A, Arthurs, S, Deziel, P, Wilhelm, M, Razonable, R.Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes. Clin Transplant 2008;22:162170.CrossRefGoogle ScholarPubMed
Goff, DA, Bauer, KA, Reed, EE, Stevenson, KB, Taylor, JJ, West, JE.Is the “low-hanging fruit” worth picking for antimicrobial stewardship programs? Clin Infect Dis 2012;55:587592.CrossRefGoogle ScholarPubMed
Fryer, JF HA, Anderson, R, Minor, PD, and the collaborative study group. Collaborative study to evaluate the proposed 1st WHO International Standard for human cytomegalovirus (HCMV) for nucleic acid amplification (NAT)-based assays. WHO ECBS Report 2010. World Health Organization website. www.who.int/biologicals/expert_committee/TRS_978_61st_report.pdf?ua=1. Published 2010. Accessed May 12, 2020.Google Scholar
Hayden, RT, Yan, X, Wick, MT, et al.Factors contributing to variability of quantitative viral PCR results in proficiency testing samples: a multivariate analysis. J Clin Microbiol 2012;50:337345.CrossRefGoogle ScholarPubMed
Abate, D, Saldan, A, Fiscon, M, et al.Evaluation of cytomegalovirus (CMV)-specific T cell immune reconstitution revealed that baseline antiviral immunity, prophylaxis, or preemptive therapy but not antithymocyte globulin treatment contribute to CMV-specific T cell reconstitution in kidney transplant recipients. J Infect Dis 2010;202:585594.CrossRefGoogle Scholar
Abate, D, Saldan, A, Mengoli, C, et al.Comparison of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV quantiferon gamma interferon-releasing assays in assessing risk of CMV infection in kidney transplant recipients. J Clin Microbiol 2013;51:25012507.CrossRefGoogle ScholarPubMed
Lee, H, Park, KH, Ryu, JH, et al.Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients. PLoS One 2017;12(12):e0189488. doi: 10.1371/journal.pone.0189488.CrossRefGoogle ScholarPubMed
Kumar, D, Chin-Hong, P, Kayler, L, et al.A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients. Am J Transplant 2019;19:25052516.CrossRefGoogle ScholarPubMed
Banas, B, Steubl, D, Renders, L, et al.Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study. Transpl Int 2018;31:436450.CrossRefGoogle ScholarPubMed
Carbone, J.The immunology of posttransplant CMV infection: potential effect of CMV immunoglobulins on distinct components of the immune response to CMV. Transplantation 2016;100 suppl 3: S11S18.CrossRefGoogle Scholar
Acosta, E, Bowlin, T, Brooks, J, et al.Advances in the development of therapeutics for cytomegalovirus infections. J Infect Dis 2020;221 suppl 1:S32S44.CrossRefGoogle ScholarPubMed
Anderholm, KM, Bierle, CJ, Schleiss, MR. Cytomegalovirus vaccines: current status and future prospects drugs. 2016;76:16251645.Google Scholar
Pei, XY, Zhao, XY, Chang, YJ, et al.Cytomegalovirus-specific T-cell transfer for refractory cytomegalovirus infection after haploidentical stem cell transplantation: the quantitative and qualitative immune recovery for cytomegalovirus. J Infect Dis 2017;216:945956.CrossRefGoogle ScholarPubMed
Smith, C, Beagley, L, Rehan, S, et al.Autologous adoptive T-cell therapy for recurrent or drug-resistant cytomegalovirus complications in solid organ transplant recipients: a single-arm open-label phase I clinical trial. Clin Infect Dis 2019;68:632640.CrossRefGoogle ScholarPubMed