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Lynch K, Märtson AG. The Importance of Drug Exposure in the Development of Cytomegalovirus Resistance. Int J Antimicrob Agents 2025:107537. [PMID: 40374080 DOI: 10.1016/j.ijantimicag.2025.107537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 04/28/2025] [Accepted: 05/04/2025] [Indexed: 05/17/2025]
Abstract
Human cytomegalovirus (CMV) is a widespread pathogen which remains asymptomatic in healthy individuals. However, CMV disease can be life-threatening in immunocompromised individuals, particularly in transplant patients. This disease is routinely managed by antiviral agents including (val)ganciclovir, foscarnet, cidofovir, letermovir, and maribavir. Subtherapeutic antiviral drug exposure is a common occurrence and can lead to drug-resistant CMV development, a key contributor to disease progression. Breakthrough CMV often results in graft loss, end-organ failure, or death. By optimising intracellular exposure levels of antiviral therapies, it may be possible to improve patient outcomes. Therefore, this review aims to explore the relationship between antiviral exposure and the development of drug-resistant CMV. There are several challenges to achieving optimal concentrations of current and novel CMV therapies. Narrow therapeutic indices and toxicity profiles of current CMV therapeutics contribute to their subtherapeutic exposure and hence suboptimal clinical outcomes. Alternately, novel antivirals such as letermovir and maribavir offer improved pharmacokinetic profiles. However, these agents are associated with rapid resistance development. Overall, a distinct gap exists in understanding the relationship between antiviral exposure and resistance development. As a result, current clinical markers used to predict clinical efficacy lack reliability. In future, resistance development in relation to drug exposure should be included as a clinical trial endpoint to gain understanding of exposure-resistance relationships. With solid knowledge of these relationships, more predictive in vitro and in vivo markers of clinical efficacy can be identified. Additionally, pharmacokinetic-pharmacodynamic models and combination therapies should be further explored in to improve the management of CMV.
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Affiliation(s)
- Katie Lynch
- Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, The Netherlands
| | - Anne-Grete Märtson
- Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, The Netherlands.
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Sun Y, Sen S, Parmar R, Arakawa-Hoyt J, Cappelletti M, Rossetti M, Gjertson DW, Sigdel TK, Sarwal MM, Schaenman JM, Bunnapradist S, Lanier LL, Pickering H, Reed EF. Cytotoxic KLRG1+ IL-7R- effector CD8+ T cells distinguish kidney transplant recipients controlling cytomegalovirus reactivation. Front Immunol 2025; 16:1542531. [PMID: 40028342 PMCID: PMC11868092 DOI: 10.3389/fimmu.2025.1542531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Introduction Cytomegalovirus (CMV) viremia remains a major contributor to clinical complications in solid organ transplant (SOT) patients, including organ injury, morbidity and mortality. Given their critical role in antiviral defense, CD8+ T cells are essential for protective immunity against CMV. Methods Using single-cell RNA sequencing, we investigated the transcriptional signatures and developmental lineages of CD8+ T cells in eight immunosuppressed kidney transplant recipients (KTRs) who received organs from CMV-seropositive donors. Results were validated in a cohort of 62 KTRs using immunophenotyping. Results Our data revealed a significant influence of CMV serostatus on transcriptional variance of CD8+ memory T cells, associating with the first principal component from a global analysis of CD8+ T cells (p =0.0406), forming a continuum with five principal differentiation trajectories driven by CMV primary infection or reactivation. Following CMV primary infection, CD8+ T cells were hallmarked by restrained effector-memory differentiation. CD8+ T cells during CMV reactivation diverged non-linearly into senescent-like cells with signatures of arrested cell cycle, diminished translational activity and downregulated ZNF683 and longitudinally expanding effector cells with robust cytotoxic potential and upregulated ZNF683, acting as a reservoir for long-lived effector cells supporting long-term protection. Notably, CD28lo KLRG1hi IL-7R (CD127)lo HLA-DRhi CD8+ T cells present prior to the detection of viremia in CMV-seropositive patients emerged as a key feature distinguishing patients who did or did not undergo CMV reactivation after prophylaxis discontinuation (p =0.0163). Frequencies of these cells were also positively correlated with CMV-stimulated secretion of IFN-γ (p =0.0494), TNF-α (p =0.0358), MIP-1α (p =0.0262), MIP-1β (p =0.0043). Discussion These results provide insights into the transcriptional regulation that influences the generation of CD8+ T cell immunity to CMV and may inform strategics for monitoring host immune response to CMV to better identify and introduce therapeutic intervention to patients at risk of developing clinically significant CMV viremia.
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Affiliation(s)
- Yumeng Sun
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Subha Sen
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Rajesh Parmar
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Janice Arakawa-Hoyt
- Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, United States
| | - Monica Cappelletti
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - David W. Gjertson
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Tara K. Sigdel
- Department of Surgery, Division of Multi Organ Transplantation, University of California, San Francisco, San Francisco, CA, United States
| | - Minnie M. Sarwal
- Department of Surgery, Division of Multi Organ Transplantation, University of California, San Francisco, San Francisco, CA, United States
| | - Joanna M. Schaenman
- Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Suphamai Bunnapradist
- Division of Nephrology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lewis L. Lanier
- Department of Microbiology and Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, United States
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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Ruiz-Arabi E, Torre-Cisneros J, Aguilera V, Alonso R, Berenguer M, Bestard O, Bodro M, Cantisán S, Carratalà J, Castón JJ, Cordero E, Facundo C, Fariñas MC, Fernández-Alonso M, Fernández-Ruiz M, Fortún J, García-Cosío MD, Herrera S, Iturbe-Fernández D, Len O, López-Medrano F, López-Oliva MO, Los-Arcos I, Marcos MÁ, Martín-Dávila P, Monforte V, Muñoz P, Navarro D, Páez-Vega A, Pérez AB, Redondo N, Álvarez R R, Rodríguez-Benot A, Rodríguez-Goncer I, San-Juan R, Sánchez-Céspedes J, Valerio M, Vaquero JM, Viasus D, Vidal E, Aguado JM. Management of cytomegalovirus in adult solid organ transplant patients: GESITRA-IC-SEIMC, CIBERINFEC, and SET recommendations update. Transplant Rev (Orlando) 2024; 38:100875. [PMID: 39168020 DOI: 10.1016/j.trre.2024.100875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/02/2024] [Accepted: 08/03/2024] [Indexed: 08/23/2024]
Abstract
Cytomegalovirus (CMV) infection remains a significant challenge in solid organ transplantation (SOT). The last international consensus guidelines on the management of CMV in SOT were published in 2018, highlighting the need for revision to incorporate recent advances, notably in cell-mediated immunity monitoring, which could alter the current standard of care. A working group including members from the Group for the Study of Infection in Transplantation and the Immunocompromised Host (GESITRA-IC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Transplantation (SET), developed consensus-based recommendations for managing CMV infection in SOT recipients. Recommendations were classified based on evidence strength and quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The final recommendations were endorsed through a consensus meeting and approved by the expert panel.
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Affiliation(s)
- Elisa Ruiz-Arabi
- Service of Infectious Diseases, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain
| | - Julian Torre-Cisneros
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
| | - Victoria Aguilera
- Hepatology and Liver Transplantation Unit, Hospital Universitario La Fe-IIS La Fe Valencia, CiberEHD and University of Valencia, Spain
| | - Rodrigo Alonso
- Lung Transplant Unit, Pneumology Service, Instituto de Investigación Hospital 12 de Octubre (imas12), University Hospital 12 de Octubre, Madrid, Spain
| | - Marina Berenguer
- Hepatology and Liver Transplantation Unit, Hospital Universitario La Fe-IIS La Fe Valencia, CiberEHD and University of Valencia, Spain
| | - Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d'Hebron University Hospital-VHIR, Barcelona, Spain
| | - Marta Bodro
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Hospital Clinic-IDIBAPS, University of Barcelona, Spain
| | - Sara Cantisán
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Jordi Carratalà
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Bellvitge University Hospital-IDIBELL, University of Barcelona, Spain
| | - Juan José Castón
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Elisa Cordero
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, Microbiology and Parasitology, Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital, Junta de Andalucía, CSIC, Universidad de Sevilla, Sevilla, Spain; Departament of Medicine, Faculty of Medicine, Universidad de Sevilla, Spain
| | - Carme Facundo
- Department of Nephrology, Fundacio Puigvert, Institut de Recerca Sant Pau (IR Sant Pau), RICORS 2024 (Kidney Disease), Barcelona, Spain
| | - María Carmen Fariñas
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain
| | - Mirian Fernández-Alonso
- Microbiology Service, Clínica Universidad de Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Mario Fernández-Ruiz
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Jesús Fortún
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Service of Infectious Diseases, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain
| | - Maria Dolores García-Cosío
- Department of Cardiology, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), CIBERCV, Madrid, Spain
| | - Sabina Herrera
- Department of Infectious Diseases, Hospital Clinic-IDIBAPS, University of Barcelona, Spain
| | - David Iturbe-Fernández
- Department of Pneumology, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Oscar Len
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Vall d'Hebron for Solid Organ Transplantation Research Group, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Francisco López-Medrano
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | | | - Ibai Los-Arcos
- Department of Infectious Diseases, Vall d'Hebron for Solid Organ Transplantation Research Group, Vall d'Hebron University Hospital, Barcelona, Spain
| | - María Ángeles Marcos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Microbiology, Hospital Clinic, University of Barcelona, ISGlobal Barcelona Institute for Global Health, Barcelona, Spain
| | - Pilar Martín-Dávila
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Service of Infectious Diseases, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain
| | - Víctor Monforte
- Lung Transplant Program, Department of Pulmonology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Muñoz
- CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitario Gregorio Marañon, Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - David Navarro
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Microbiology Service, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain. Department of Microbiology School of Medicine, University of Valencia, Spain
| | - Aurora Páez-Vega
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain
| | - Ana Belén Pérez
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Microbiology Unit, Hospital Universitario Reina Sofía-Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain
| | - Natalia Redondo
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | | | | | - Isabel Rodríguez-Goncer
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Rafael San-Juan
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Javier Sánchez-Céspedes
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, Microbiology and Parasitology, Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital, Junta de Andalucía, CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Maricela Valerio
- CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitario Gregorio Marañon, Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - José Manuel Vaquero
- Unit of Pneumology, Thoracic Surgery, and Lung Transplant, Reina Sofía University Hospital, Cordoba, Spain
| | - Diego Viasus
- Division of Health Sciences, Faculty of Medicine, Universidad del Norte, Hospital Universidad del Norte, Barranquilla, Colombia
| | - Elisa Vidal
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - José María Aguado
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.
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Hardinger KL, Brennan DC. Cytomegalovirus Treatment in Solid Organ Transplantation: An Update on Current Approaches. Ann Pharmacother 2024; 58:1122-1133. [PMID: 38501850 DOI: 10.1177/10600280241237534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024] Open
Abstract
OBJECTIVE The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. DATA SOURCES A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation. STUDY SELECTION AND DATA EXTRACTION Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded. DATA SYNTHESIS After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV. CONCLUSIONS Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration.
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Affiliation(s)
- Karen L Hardinger
- Division of Pharmacy Practice and Administration, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Daniel C Brennan
- Johns Hopkins Comprehensive Transplant Center, Baltimore, MD, USA
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Yilmaz ZB, Memisoglu F, Akbulut S. Management of cytomegalovirus infection after liver transplantation. World J Transplant 2024; 14:93209. [PMID: 39295968 PMCID: PMC11317856 DOI: 10.5500/wjt.v14.i3.93209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/05/2024] [Accepted: 05/27/2024] [Indexed: 07/31/2024] Open
Abstract
Cytomegalovirus (CMV) infection is one of the primary causes of morbidity and mortality following liver transplantation (LT). Based on current worldwide guidelines, the most effective strategies for avoiding post-transplant CMV infection are antiviral prophylaxis and pre-emptive treatment. CMV- IgG serology is the established technique for pretransplant screening of both donors and recipients. The clinical presentation of CMV infection and disease exhibits variability, prompting clinicians to consistently consider this possibility, particularly within the first year post-transplantation or subsequent to heightened immunosuppression. At annual symposia to discuss CMV prevention and how treatment outcomes can be improved, evidence on the incorporation of immune functional tests into clinical practice is presented, and the results of studies with new antiviral treatments are evaluated. Although there are ongoing studies on the use of letermovir and maribavir in solid organ transplantation, a consensus reflected in the guidelines has not been formed. Determining the most appropriate strategy at the individual level appears to be the key to enhancing outcomes. Although prevention strategies reduce the risk of CMV disease, the disease can still occur in up to 50% of high-risk patients. A balance between the risk of infection and disease development and the use of immunosuppressants must be considered when talking about the proper management of CMV in solid organ transplant recipients. The objective of this study was to establish a comprehensive framework for the management of CMV in patients who have had LT.
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Affiliation(s)
- Zeynep Burcin Yilmaz
- Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
| | - Funda Memisoglu
- Infectious Diseases and Clinical Microbiology, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
| | - Sami Akbulut
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Türkiye
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Tsui JC, Huang V, Kolomeyer AM, Miller CG, Mishkin A, Maguire AM. EFFICACY OF MARIBAVIR IN VALGANCICLOVIR-RESISTANT CYTOMEGALOVIRUS RETINITIS. Retin Cases Brief Rep 2024; 18:164-167. [PMID: 36730596 DOI: 10.1097/icb.0000000000001372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/18/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis. METHODS Retrospective case report of a lung-transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs. RESULTS A 72-year-old lung-transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the uninjected eye. CONCLUSION This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.
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Affiliation(s)
- Jonathan C Tsui
- Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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Kleiboeker SB. Prevalence of cytomegalovirus antiviral drug resistance in transplant recipients. Antiviral Res 2023; 215:105623. [PMID: 37150409 DOI: 10.1016/j.antiviral.2023.105623] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/30/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023]
Abstract
Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence of resistance is low, the impact of drug resistant CMV infections on patient outcomes is high and genotypic testing is recommended when resistance is suspected. To assess the prevalence of CMV drug resistance mutations among samples submitted for genotypic testing, 2750 patient sample results were analyzed. Testing was performed by sequencing for ganciclovir (GCV), cidofovir (CDV), foscarnet (FOS), maribavir (MBV) and/or letermovir (LMV) resistance conferring mutations. Of the 2750 patient samples, 826 (30.04%) had resistance to one or more anti-CMV drug. Resistance mutations were most common in UL97, with 27.64% and 9.96% of samples having GCV and MBV mutations, respectively. Resistance mutations in UL54 were less common, with 6.11%, 5.98% and 1.76% of samples having GCV, CDV and FOS mutations, respectively. For LMV, resistance mutations in UL56 were present in 7.17% of samples, with mutations at codon 325 representing 80.95% of the observed LMV resistance mutations. Resistance to two drugs was identified in 215 samples and to 3 or more drugs in 35 samples. While a high prevalence of CMV resistance mutations was identified, this must be taken in the context of healthcare providers submitting samples from patients with suspected resistant CMV strains. For these patients, rapid monitoring for resistance allows treatment modifications based on objective results rather than empiric drug selection, which is particularly relevant given the presence of mutations conferring resistance to more than one drug.
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Affiliation(s)
- Steven B Kleiboeker
- Eurofins Viracor Clinical Diagnostics, 18000 West 99th Street, Lenexa, KS, 66219, USA.
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Kotton CN, Kamar N. New Insights on CMV Management in Solid Organ Transplant Patients: Prevention, Treatment, and Management of Resistant/Refractory Disease. Infect Dis Ther 2023; 12:333-342. [PMID: 36583845 PMCID: PMC9925645 DOI: 10.1007/s40121-022-00746-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/08/2022] [Indexed: 12/31/2022] Open
Abstract
Cytomegalovirus (CMV) infection can have both direct and indirect effects after solid-organ transplantation, with a significant impact on transplant outcomes. Prevention strategies decrease the risk of CMV disease, although CMV still occurs in up to 50% of high-risk patients. Ganciclovir (GCV) and valganciclovir (VGCV) are the main drugs currently used for preventing and treating CMV. Emerging data suggest that letermovir is as effective as VGCV with fewer hematological side effects. Refractory and resistant CMV also still occur in solid-organ-transplant patients. Maribavir has been shown to be effective and have less toxicity in the treatment of refractory and resistant CMV. In this review paper, we discuss prevention strategies, refractory and resistant CMV, and drug-related side effects and their impact, as well as optimal use of novel anti-CMV therapies.
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Affiliation(s)
- Camille Nelson Kotton
- grid.32224.350000 0004 0386 9924Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, 55 Fruit Street, Cox 5, Boston, MA 02114 USA
- grid.38142.3c000000041936754XHarvard Medical School, Boston, MA USA
| | - Nassim Kamar
- grid.414295.f0000 0004 0638 3479Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, CHU Toulouse Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France
- grid.7429.80000000121866389INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse, France
- grid.15781.3a0000 0001 0723 035XPaul Sabatier University, Toulouse, France
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9
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Ganciclovir-resistant cytomegalovirus retinitis in a 4-month-old infant. J AAPOS 2022; 26:336-338. [PMID: 36152756 DOI: 10.1016/j.jaapos.2022.08.264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/04/2022] [Accepted: 08/03/2022] [Indexed: 12/15/2022]
Abstract
We present a case of ganciclovir-resistant cytomegalovirus retinitis (CMV) in a 4-month-old boy with congenital CMV infection. This case highlights the potential utility of a combination of intermittent viral load monitoring and retinal examinations in cases of congenital CMV with retinitis.
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10
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Jorgenson MR, Descourouez JL, Leverson GE, Saddler CM, Smith JA, Garg N, Parajuli S, Mandelbrot DA, Odorico JS. A pilot study of an intensified ganciclovir dosing strategy for treatment of cytomegalovirus disease in kidney and/or pancreas transplant recipients. Clin Transplant 2021; 35:e14427. [PMID: 34263938 DOI: 10.1111/ctr.14427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/07/2021] [Accepted: 07/08/2021] [Indexed: 12/15/2022]
Abstract
PROBLEM Mathematical modeling suggests aggressive ganciclovir dosing in the first week of cytomegalovirus disease (CMV) treatment may improve response. This has not been evaluated clinically. METHODS Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19-7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step-down to standard-of-care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16-3/2/19) served as a comparator. PRIMARY OBJECTIVE rate of viral clearance (delta log CMV) at therapy day 7. SECONDARY OBJECTIVE safety/short term efficacy. RESULTS Fifty-four patients met inclusion criteria; 22 high-dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P = .03) and higher presenting viral-load in the high-dose group (log 6.0±.7 vs. log 5.2±1.2, P = .02). High-dose resulted in significantly greater response to therapy at day 7 (log -.92±.51 vs. log -.56±.79, P = .04). Change in WBC at day 7 was not different (-.49±1.92 vs. -.45±5.1, P = .97). Short-term clinical outcomes were similar between groups including mean hospital length-of-stay (P = .52), readmission rates (30 d: P = .38; 90 d: P = .5) and achievement of CMV viral-load less-than-lower-limit-of-quantification by day 90 (73% vs. 84%, P = .06). Rejection after CMV as well as graft/patient survival were similar between groups (P = .56, P > .99, P > .99). CONCLUSION A high-dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes.
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Affiliation(s)
- Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Glen E Leverson
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Christopher M Saddler
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Jeannina A Smith
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Neetika Garg
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Sandesh Parajuli
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Didier A Mandelbrot
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Jon S Odorico
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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11
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Jorgenson MR, Descourouez JL, Garg N, Parajuli S, Mandelbrot DA, Odorico JS, Saddler CM, Smith JA. The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients. Transpl Infect Dis 2021; 23:e13693. [PMID: 34309158 DOI: 10.1111/tid.13693] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 12/26/2022]
Abstract
PURPOSE Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV. METHODS Adult patients receiving a kidney or kidney-pancreas transplant were included if they developed CMV viremia and initiated letermovir 480 mg daily as part of a dual therapy regimen with valganciclovir 900 mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log10 < 3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels. RESULTS Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73-355) IU/ml and did not clear or change significantly after 2, 4 and 12 weeks of adjunctive letermovir (132.5 [range: 34.5-513] IU/ml vs. 68.7 [range: 34.5-574] IU/ml vs. 78.3 [range: 34.5-347] IU/ml, p > 0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir-tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6 ng/ml vs 8.0 ± 4.6 ng/ml). CONCLUSION In kidney and kidney-pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed.
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Affiliation(s)
- Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
| | - Neetika Garg
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Sandesh Parajuli
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Didier A Mandelbrot
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Jon S Odorico
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Christopher M Saddler
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Jeannina A Smith
- Department of Medicine, Division of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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12
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Resistant or refractory cytomegalovirus infections after hematopoietic cell transplantation: diagnosis and management. Curr Opin Infect Dis 2020; 32:565-574. [PMID: 31567572 DOI: 10.1097/qco.0000000000000607] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Refractory or resistant cytomegalovirus (CMV) infections are challenging complications after hematopoietic cell transplantation (HCT). Most refractory or resistant CMV infections are associated with poor outcomes and increased mortality. Prompt recognition of resistant or refractory CMV infections, understanding the resistance pathways, and the treatment options in HCT recipients are imperative. RECENT FINDINGS New definitions for refractory and resistant CMV infections in HCT recipients have been introduced for future clinical trials. Interestingly, refractory CMV infections are more commonly encountered in HCT recipients when compared with resistant CMV infections. CMV terminase complex mutations in UL56, UL89, and UL51 could be associated with letermovir resistance; specific mutations in UL56 are the most commonly encountered in clinical practice. Finally, brincidofovir, maribavir, letermovir, and CMV-specific cytotoxic T-cell therapy expanded our treatment options for refractory or resistant CMV infections. SUMMARY Many advances have been made to optimize future clinical trials for management of refractory or resistant CMV infections, and to better understand new resistance mechanisms to novel drugs. New drugs or strategies with limited toxicities are needed to improve outcomes of difficult to treat CMV infections in HCT recipients.
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13
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Boonsathorn S, Pasomsub E, Techasaensiri C, Apiwattanakul N. Analysis of Ganciclovir-Resistant Cytomegalovirus Infection Caused by the UL97 Gene Mutation in Codons 460 and 520 in Pediatric Patients: A Case Series. Open Forum Infect Dis 2019; 6:ofz480. [PMID: 32528998 PMCID: PMC7275293 DOI: 10.1093/ofid/ofz480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/31/2019] [Indexed: 11/14/2022] Open
Abstract
Background Drug-resistant cytomegalovirus (CMV) infection has been increasingly recognized. However, there are limited data in pediatric patients. In this study, the prevalence and factors associated with CMV infection with UL97 mutations in pediatric patients treated with ganciclovir but not responding to treatment were evaluated. Methods This retrospective study was conducted from January 2013 to December 2017. All patients who were suspected of having ganciclovir-resistant CMV infection and had never had ganciclovir prophylaxis were included. Genotypic assay for UL97 mutations in codons 460 and 520 conferring ganciclovir resistance was performed. Factors associated with the presence of UL97 mutations were analyzed. Results Of 34 patients included, 10 patients (29.4%) had a genotypically confirmed UL97 mutation. The median age (interquartile range [IQR]) was 3 (0.85–8.68) years. Ganciclovir resistance was tested at a median time (IQR) of 22.5 (14.3–31) days after initiation of ganciclovir. All resistant isolates harbored a UL97 mutation in codon 460. Compared with patients infected with CMV without UL97 mutation, those infected with UL97 mutation strains were younger (median age [IQR], 3.02 [0.85–8.68] vs 10.45 [2.7–16.4] years) and had a higher maximum viral load (median [IQR], 5.06 [4.74–6.05] vs 4.42 [4.03–4.87] copies/mL). Six of 10 (60%) patients were successfully treated with high-dose ganciclovir (7.5 mg/kg twice daily). Conclusions UL97 mutation ganciclovir-resistant CMV infection was not uncommon in the pediatric population. Screening for this mutation should be considered in patients experiencing virological worsening while ganciclovir is given, even if patients have not previously received ganciclovir prophylaxis.
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Affiliation(s)
- Sophida Boonsathorn
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ekawat Pasomsub
- Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chonnamet Techasaensiri
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nopporn Apiwattanakul
- Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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14
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Fu L, Santhanakrishnan K, Al-Aloul M, Jones NP, Steeples LR. Management of Ganciclovir Resistant Cytomegalovirus Retinitis in a Solid Organ Transplant Recipient: A Review of Current Evidence and Treatment Approaches. Ocul Immunol Inflamm 2019; 28:1152-1158. [PMID: 31621449 DOI: 10.1080/09273948.2019.1645188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Purpose: Cytomegalovirus retinitis (CMVR) is a serious and potentially sight-threatening infection in immunocompromised individuals. Strategies for the management of drug-resistant CMVR are described. Methods: A case of severe bilateral CMVR in a single lung transplant patient, with UL97 mutation conferring ganciclovir-resistance, is presented. Treatment with standard antiviral agent and adjuvant leflunomide, immunosuppression modifications (calcineurin inhibitors and corticosteroid), intravitreal antiviral therapy and novel use of CMV-immunoglobulin is described. A literature review to support drug-resistant CMVR management is presented. Results: Severe and progressive CMV retinitis was refractory to intravitreal foscarnet and systemic leflunomide. Drug-toxicity restricted systemic antiviral therapy options. The use of combined leflunomide and CMV-immunoglobulins, in the absence of viremia, has not been previously reported. Loss of ganciclovir-resistance was eventually observed permitting successful treatment with systemic and intravitreal ganciclovir. Conclusions: Drug-resistant CMVR is a complex clinical challenge. Multiple systemic and local treatment strategies may be necessary but toxicity, resistance, and co-morbidities may severely restrict available options.
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Affiliation(s)
- L Fu
- Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre , Manchester, UK.,Centre for Ophthalmology and Vision Sciences, Faculty of Medical and Human Sciences, University of Manchester , Manchester, UK
| | - K Santhanakrishnan
- Department of Cardiothoracic Transplant, Wythenshawe Hospital, Manchester University NHS Foundation Trust , Manchester, UK
| | - M Al-Aloul
- Department of Cardiothoracic Transplant, Wythenshawe Hospital, Manchester University NHS Foundation Trust , Manchester, UK
| | - N P Jones
- Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre , Manchester, UK.,Centre for Ophthalmology and Vision Sciences, Faculty of Medical and Human Sciences, University of Manchester , Manchester, UK
| | - L R Steeples
- Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre , Manchester, UK.,Centre for Ophthalmology and Vision Sciences, Faculty of Medical and Human Sciences, University of Manchester , Manchester, UK
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15
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Heliövaara E, Husain S, Martinu T, Singer LG, Cypel M, Humar A, Keshavjee S, Tikkanen J. Drug-resistant cytomegalovirus infection after lung transplantation: Incidence, characteristics, and clinical outcomes. J Heart Lung Transplant 2019; 38:1268-1274. [PMID: 31570289 DOI: 10.1016/j.healun.2019.09.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/28/2019] [Accepted: 09/03/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection and development of CMV drug resistance can cause significant morbidity and mortality in patients with lung transplantation (LTX). We investigated the incidence of CMV drug resistance in adult patients with LTX and characterized this patient group and its outcomes. METHODS We analyzed a single-center retrospective cohort of 735 patients who received LTX between January 2012 and October 2017. We assessed the incidences of CMV UL97 and UL54 genotyping for clinically suspected drug resistance and confirmed drug resistance. Case-matched controls (3 control patients for each resistant patient) were identified by matching for CMV serological status, development of CMV disease or significant viremia (≥3,000 IU/ml), and transplantation date. RESULTS The incidence of drug-resistant CMV was 1.98% (11/556) in donor and/or recipient CMV-positive patients and 4.7% (7/150) in donor-positive/recipient-negative patients. Altogether, 27 patients were tested for drug resistance, and 11 strains were resistant, 8 sensitive, and 8 inconclusive. No differences in immunosuppression, acute rejection, or pre-transplant sensitization were seen between case-matched groups. The peak CMV viral load and mean duration of viremia were significantly higher in the resistant group (324,000 vs. 117,000 mean IU/ml, p = 0.048 and 140 vs. 55 days, p < 0.001, respectively). The resistant group had increased overall mortality after onset of viremia compared with controls (3-year mortality 70% vs. 30%; p = 0.01). CONCLUSIONS Drug-resistant CMV infection is rare, but patients who develop it have decreased overall survival. Peak CMV viral load and duration of CMV viremia were associated with development of resistant CMV infection.
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Affiliation(s)
- Elina Heliövaara
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Shahid Husain
- Division of Infectious Diseases, Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Tereza Martinu
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Lianne G Singer
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Marcelo Cypel
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Atul Humar
- Division of Infectious Diseases, Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Shaf Keshavjee
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Jussi Tikkanen
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada.
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16
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The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2019; 102:900-931. [PMID: 29596116 DOI: 10.1097/tp.0000000000002191] [Citation(s) in RCA: 806] [Impact Index Per Article: 134.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized approach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations.
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17
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Koval CE. Prevention and Treatment of Cytomegalovirus Infections in Solid Organ Transplant Recipients. Infect Dis Clin North Am 2018; 32:581-597. [PMID: 30146024 DOI: 10.1016/j.idc.2018.04.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Despite advances in prevention and treatment, cytomegalovirus (CMV) infection and disease remain an expected problem in solid organ transplant recipients. Because of the effect of immunosuppressing medications, CMV primary, secondary, and reactivated infection requires antiviral medications to prevent serious direct and indirect effects of the virus. Side effects and drug resistance, however, often limit the capacity of traditional antiviral therapies. This article updates the clinician on current and promising approaches to the management and control of CMV in the solid organ transplant recipient.
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Affiliation(s)
- Christine E Koval
- Department of Infectious Diseases, Cleveland Clinic Foundation, 9500 Euclid Avenue, Box G21, Cleveland, OH 44195, USA.
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18
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Cintra-Cabrera M, Suárez-Benjumea A, Bernal-Blanco G, González-Roncero FM, Toapanta-Gaibor NG, Súñer-Poblet M, Pérez-Valdivia MÁ, Fernández-Cuenca F, Gentil-Govantes MÁ, Rocha-Castilla JL. Resistant Cytomegalovirus Infection After Renal Transplantation: Literature Review. Transplant Proc 2018; 50:575-577. [PMID: 29579856 DOI: 10.1016/j.transproceed.2017.09.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 09/21/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Resistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene). METHODS We describe our experience in management of R-CMV after renal transplant at our center (2012-2016). RESULTS We encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks). CONCLUSIONS Resistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.
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Affiliation(s)
- M Cintra-Cabrera
- Department of Nephrology, Hospital Virgen del Rocío, Sevilla, Spain.
| | | | - G Bernal-Blanco
- Department of Nephrology, Hospital Virgen del Rocío, Sevilla, Spain
| | | | | | - M Súñer-Poblet
- Department of Nephrology, Hospital Virgen del Rocío, Sevilla, Spain
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19
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Drug-resistant cytomegalovirus: clinical implications of specific mutations. Curr Opin Organ Transplant 2018; 23:388-394. [DOI: 10.1097/mot.0000000000000541] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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20
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Baradhi KM, Aure RL, El-Amm JM. High-dose Valganciclovir Treatment for Resistant Cytomegalovirus Colitis due to UL97 and UL54 Mutations. Transplant Proc 2018; 50:142-144. [PMID: 29407298 DOI: 10.1016/j.transproceed.2017.11.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/13/2017] [Indexed: 12/26/2022]
Abstract
We report the first case of a ganciclovir-resistant cytomegalovirus (CMV) involving the gastrointestinal tract that was successfully treated with high-dose valganciclovir. A kidney transplant recipient developed drug-resistant CMV colitis which was initially treated with valganciclovir, but his CMV was found to have major resistance to ganciclovir and cidofovir due to UL97 and UL54 mutations. The patient was switched to intravenous foscarnet 40 mg/kg given every twelve hours. However, foscarnet had to be discontinued after 4 days of treatment due to acute kidney injury. Patient was restarted on valganciclovir at a higher target dose of 1800 mg twice a day based on the creatinine clearance. CMV became undetectable 2 weeks after valganciclovir treatment was completed. High-dose valganciclovir along with immune suppression reduction may be a treatment option for CMV colitis with ganciclovir resistance due to dual UL97 and UL54 gene mutations.
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Affiliation(s)
- K M Baradhi
- Division of Nephrology, University of Oklahoma, Tulsa, Oklahoma.
| | - R L Aure
- Division of Nephrology, University of Oklahoma, Tulsa, Oklahoma
| | - J-M El-Amm
- Kidney and Transplant Division, Baptist Integris Nazih Zuhdi Transplant Institute, Oklahoma City, Oklahoma
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21
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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; 37:1258-1271. [PMID: 28699311 DOI: 10.1002/phar.1987] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Ganciclovir-resistant cytomegalovirus (GR-CMV) is emerging as a significant infection in the abdominal transplant population. GR-CMV is difficult to manage, and treatment options are limited. We report a descriptive case series of 15 patients who had documented GR-CMV at our center and review the literature on treatment of GR-CMV. The first case in this series was detected in 2012; the majority of cases occurred after January 1, 2014, with approximately 50% occurring in 2015. UL97 and UL54 viral genome mutations were present in 100% and 40% of CMV-infected patients, respectively. GR-CMV infection occurred ≤ 1 year posttransplantation in 11 patients (73%). All patients experienced dose reduction of valganciclovir (the oral prodrug of ganciclovir) before the development of GR-CMV. Initial treatment for GR-CMV included a variety of regimens, all including reduction in maintenance immunosuppression. Of the 6 patients with detectable GR-CMV by polymerase chain reaction (PCR) who were discharged without GR-CMV treatment and had a length of stay (LOS) less than 14 days, 83% were subsequently readmitted for treatment of GR-CMV within 2 months (60% in < 20 days); none received leflunomide. Of six patients with a LOS ≥ 14 days, 80% had CMV PCR below quantification on hospital discharge, and only one patient was readmitted in less than 20 days; 83% received leflunomide. Following GR-CMV, there was a 50% rejection incidence, 27% graft loss, and 20% mortality. For patients with more than three admissions for GR-CMV treatment, 100% had a major complication: 60% rejection, 20% graft loss, and 40% mortality. Common clinical characteristics of patients with GR-CMV included high-risk serostatus, lymphocyte depletion, and history of valganciclovir dose reduction. Overall, outcomes were poor. It appears that hospital readmission rate was reduced when CMV was treated to negativity with an initial treatment regimen of reduced immunosuppression, foscarnet, intravenous immunoglobulins, and leflunomide.
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Affiliation(s)
| | - Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Didier A Mandelbrot
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Robert R Redfield
- Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin
| | - Jeannina A Smith
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
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22
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Abstract
Cytomegalovirus (CMV), the largest of the herpesviruses, causes a wide range of clinical syndromes, from asymptomatic infection to severe disease in immunocompromised hosts. Laboratory methods for diagnosis include molecular testing, antigenemia, culture, serology, and histopathology. Treatment of CMV infection and disease is indicated in selected immunocompromised hosts, and preventive approaches are indicated in high-risk groups. This chapter reviews the epidemiology, clinical aspects, and the laboratory diagnosis and management of CMV in immunocompromised hosts.
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Abstract
Cytomegalovirus (CMV) is a frequent complication of hematopoietic stem cell transplant in pediatric patients, with significant morbidity and mortality. Antiviral drugs are used as prophylactic, preemptive or therapeutic medicines; however, no uniform guidelines exist for the best strategy to prevent CMV disease. Resistance to standard antiviral therapies can lead to further difficulty in managing CMV disease. Studies for investigational therapies are underway and could provide options for treatment of resistant CMV, while limiting toxicities associated with currently used antiviral therapies.
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Differentiated Levels of Ganciclovir Resistance Conferred by Mutations at Codons 591 to 603 of the Cytomegalovirus UL97 Kinase Gene. J Clin Microbiol 2017; 55:2098-2104. [PMID: 28446569 DOI: 10.1128/jcm.00391-17] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/17/2017] [Indexed: 12/28/2022] Open
Abstract
Diagnostic mutations in the cytomegalovirus UL97 kinase gene are used to assess the level of associated ganciclovir resistance and therapeutic options. The best-known mutations at codons 460, 520, or 591 to 607 individually confer 5- to 10-fold-decreased ganciclovir susceptibility, except that a 3-fold decrease occurs in the case of the amino acid substitution C592G. Less common point and in-frame deletion mutations at codons 591 to 603 remain incompletely characterized. The ganciclovir susceptibilities of 17 mutants in this codon range were evaluated by use of the same recombinant phenotyping system and extensive assay replicates in two types of cell cultures. Amino acid substitutions K599E and T601M conferred no ganciclovir resistance, while A591V conferred 3.8-fold-decreased susceptibility. In-frame deletions of three or more codons conferred at least 8-fold-increased ganciclovir resistance, while the level of resistance conferred by one- or two-codon deletions varied from 4- to 10-fold, depending on their location. Measured levels of ganciclovir resistance were closely comparable when assays were performed in either fibroblasts or modified retinal epithelial cells. The significant revision of a few previously published resistance phenotypes and the new data strengthen the interpretation of genotypic testing for cytomegalovirus drug resistance.
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López-Aladid R, Guiu A, Sanclemente G, López-Medrano F, Cofán F, Mosquera MM, Torre-Cisneros J, Vidal E, Moreno A, Aguado JM, Cordero E, Martin-Gandul C, Pérez-Romero P, Carratalá J, Sabé N, Niubó J, Cervera C, Cervilla A, Bodro M, Muñoz P, Fariñas C, Codina MG, Aranzamendi M, Montejo M, Len O, Marcos MA. Detection of cytomegalovirus drug resistance mutations in solid organ transplant recipients with suspected resistance. J Clin Virol 2017; 90:57-63. [PMID: 28359845 DOI: 10.1016/j.jcv.2017.03.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 01/02/2017] [Accepted: 03/16/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Current guidelines recommend that treatment of resistant cytomegalovirus (CMV) in solid organ transplant (SOT) recipients must be based on genotypic analysis. However, this recommendation is not systematically followed. OBJECTIVES To assess the presence of mutations associated with CMV resistance in SOT recipients with suspected resistance, their associated risk factors and the clinical impact of resistance. STUDY DESIGN Using Sanger sequencing we prospectively assessed the presence of resistance mutations in a nation-wide prospective study between September 2013-August 2015. RESULTS Of 39 patients studied, 9 (23%) showed resistance mutations. All had one mutation in the UL 97 gene and two also had one mutation in the UL54 gene. Resistance mutations were more frequent in lung transplant recipients (44% p=0.0068) and in patients receiving prophylaxis ≥6 months (57% vs. 17%, p=0.0180). The mean time between transplantation and suspicion of resistance was longer in patients with mutations (239 vs. 100days, respectively, p=0.0046) as was the median treatment duration before suspicion (45 vs. 16days, p=0.0081). There were no significant differences according to the treatment strategies or the mean CMV load at the time of suspicion. Of note, resistance-associated mutations appeared in one patient during CMV prophylaxis and also in a seropositive organ recipient. Incomplete suppression of CMV was more frequent in patients with confirmed resistance. CONCLUSIONS Our study confirms the need to assess CMV resistance mutations in any patient with criteria of suspected clinical resistance. Early confirmation of the presence of resistance mutations is essential to optimize the management of these patients.
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Affiliation(s)
- Rubén López-Aladid
- Department of Clinical Microbiology, Hospital Clinic, Universidad de Barcelona, Barcelona Institute for Global Health, Barcelona, (ISGlobal), Spain
| | - Alba Guiu
- Department of Clinical Microbiology, Hospital Clinic, Universidad de Barcelona, Barcelona Institute for Global Health, Barcelona, (ISGlobal), Spain
| | - Gemma Sanclemente
- Department of Infectious Diseases, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
| | - Francisco López-Medrano
- Unit of Infectious Diseases, Instituto de Investigación Hospital 12 Octubre (i + 12) University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain
| | - Frederic Cofán
- Nephrology and Renal Transplant Department, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
| | - M Mar Mosquera
- Department of Clinical Microbiology, Hospital Clinic, Universidad de Barcelona, Barcelona Institute for Global Health, Barcelona, (ISGlobal), Spain
| | - Julián Torre-Cisneros
- Clinical Unit of Infectious Diseases, Hospital Universitario Reina Sofia-IMIBIC-UCO, Córdoba, Spain
| | - Elisa Vidal
- Clinical Unit of Infectious Diseases, Hospital Universitario Reina Sofia-IMIBIC-UCO, Córdoba, Spain
| | - Asunción Moreno
- Department of Infectious Diseases, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
| | - Jose Maria Aguado
- Unit of Infectious Diseases, Instituto de Investigación Hospital 12 Octubre (i + 12) University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain
| | - Elisa Cordero
- Infectious Diseases Department, Hospital Universitario Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBIS), Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, Spain
| | - Cecilia Martin-Gandul
- Infectious Diseases Department, Hospital Universitario Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBIS), Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, Spain
| | - Pilar Pérez-Romero
- Infectious Diseases Department, Hospital Universitario Virgen del Rocío, Sevilla, Instituto de Biomedicina de Sevilla (IBIS), Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, Spain
| | - Jordi Carratalá
- Department of Infectious Diseases, Bellvitge University Hospital, IDIBELL, Barcelona, Spain
| | - Nuria Sabé
- Department of Infectious Diseases, Bellvitge University Hospital, IDIBELL, Barcelona, Spain
| | - Jordi Niubó
- Department of Clinical Microbiology, Bellvitge University Hospital, IDIBELL, Barcelona, Spain
| | - Carlos Cervera
- Department of Medicine, Division of Infectious Diseases, University of Alberto, Edmonton, Canada
| | - Anna Cervilla
- Department of Clinical Microbiology, Hospital Clinic, Universidad de Barcelona, Barcelona Institute for Global Health, Barcelona, (ISGlobal), Spain
| | - Marta Bodro
- Department of Infectious Diseases, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Universidad de Barcelona, Barcelona, Spain
| | - Patricia Muñoz
- Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitario Gregorio Marañón, Madrid, Spain
| | - Carmen Fariñas
- Unidad de Enfermedades Infecciosas, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain
| | - M Gemma Codina
- Microbiology Service, Hospital Vall d'Hebron, Barcelona, Spain
| | | | - Miguel Montejo
- Unidad de Enfermedades Infecciosas, Hospital Universitario de Cruces, Bilbao, Spain
| | - Oscar Len
- Department of Infectious Diseases, Hospital Universitari Vall d'Hebrón, Uniiversitat Autónoma de Barcelona, Barcelona, Spain
| | - M Angeles Marcos
- Department of Clinical Microbiology, Hospital Clinic, Universidad de Barcelona, Barcelona Institute for Global Health, Barcelona, (ISGlobal), Spain.
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How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood 2016; 128:2624-2636. [PMID: 27760756 DOI: 10.1182/blood-2016-06-688432] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 10/17/2016] [Indexed: 12/20/2022] Open
Abstract
Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy. CMV resistance is diagnosed by detecting specific genetic mutations. UL97 mutations confer resistance to ganciclovir and valganciclovir, and a UL54 mutation confers multidrug resistance. Risk factors for resistance include prolonged or previous anti-CMV drug exposure or inadequate dosing, absorption, or bioavailability. Host risk factors include type of HCT and degree of immunosuppression. Depending on the genotyping results, multiple strategies can be adopted to treat resistant CMV infections, albeit no randomized clinical trials exist so far, after reducing immunosuppression (if possible): ganciclovir dose escalation, ganciclovir and foscarnet combination, and adjunct therapy such as CMV-specific cytotoxic T-lymphocyte infusions. Novel therapies such as maribavir, brincidofovir, and letermovir should be further studied for treatment of resistant CMV.
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Avery RK, Arav-Boger R, Marr KA, Kraus E, Shoham S, Lees L, Trollinger B, Shah P, Ambinder R, Neofytos D, Ostrander D, Forman M, Valsamakis A. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation 2016; 100:e74-80. [PMID: 27495775 PMCID: PMC5030152 DOI: 10.1097/tp.0000000000001418] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Antiviral-resistant or refractory cytomegalovirus (CMV) infection is challenging, and salvage therapies, foscarnet, and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments to facilitate clinical trial design for new drugs. METHODS Records of solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity. RESULTS Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11 (28%) of 39 had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13 (33%) of 39 and relapses of viremia occurred in 31%. Mortality was 12 (31%) of 39 and was higher in HCT than SOT (P = 0.001), although ganciclovir resistance was more common in SOT (P = 0.003). Doses of ganciclovir or valganciclovir were low in 10 (26%) of 39 at some time before switching to foscarnet. Renal dysfunction occurred in 20 (51%) of 39 by end of treatment and in 7 (28%) of 25 after 6 months. CONCLUSIONS Outcomes of existing treatment for ganciclovir-resistant or refractory CMV are suboptimal, in terms of virologic clearance, renal dysfunction, and mortality. These data should provide background information for future clinical trials of newer antiviral agents.
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Affiliation(s)
- Robin K. Avery
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Ravit Arav-Boger
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Kieren A. Marr
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Edward Kraus
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Shmuel Shoham
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Laura Lees
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Brandon Trollinger
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Pali Shah
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Rich Ambinder
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Dionysios Neofytos
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Darin Ostrander
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Michael Forman
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
| | - Alexandra Valsamakis
- Division of Infectious Diseases (RKA, KAM, SS, DN, DO), Pediatric Infectious Diseases (R A-B), Nephrology (EK), Pharmacy (LL, BT), Pulmonary and Critical Care (PS), the Sidney Kimmel Cancer Center (RA), and Division of Medical Microbiology, Department of Pathology, Pathology (MF, AV), Johns Hopkins
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El Chaer F, Mori N, Shah D, Oliver N, Wang E, Jan A, Doan V, Tverdek F, Tayar J, Ariza-Heredia E, Chemaly RF. Adjuvant and salvage therapy with leflunomide for recalcitrant cytomegalovirus infections in hematopoietic cell transplantation recipients: A case series. Antiviral Res 2016; 135:91-96. [PMID: 27594527 DOI: 10.1016/j.antiviral.2016.08.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 08/07/2016] [Accepted: 08/08/2016] [Indexed: 10/21/2022]
Abstract
Cytomegalovirus (CMV) reactivation is a clinically significant complication in hematopoietic stem cell transplant (HCT) recipients. Alternative therapy for multidrug-resistant CMV is limited and often fails. Leflunomide has been used to treat resistant CMV infections, however, data on efficacy, safety, and guidance for therapeutic drug level monitoring are lacking. In this report, we describe 3 HCT recipients with multi-drug resistant CMV infections who received leflunomide as adjuvant and salvage therapy. The therapeutic effect of leflunomide as an anti-CMV agent based on virologic responses and therapeutic drug monitoring were evaluated.
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Affiliation(s)
- Firas El Chaer
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Internal Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA
| | - Nobuyoshi Mori
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dimpy Shah
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nora Oliver
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Emily Wang
- Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anna Jan
- Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vi Doan
- Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Frank Tverdek
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean Tayar
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ella Ariza-Heredia
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Roy F Chemaly
- Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Torre-Cisneros J, Aguado J, Caston J, Almenar L, Alonso A, Cantisán S, Carratalá J, Cervera C, Cordero E, Fariñas M, Fernández-Ruiz M, Fortún J, Frauca E, Gavaldá J, Hernández D, Herrero I, Len O, Lopez-Medrano F, Manito N, Marcos M, Martín-Dávila P, Monforte V, Montejo M, Moreno A, Muñoz P, Navarro D, Pérez-Romero P, Rodriguez-Bernot A, Rumbao J, San Juan R, Vaquero J, Vidal E. Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. Transplant Rev (Orlando) 2016; 30:119-43. [DOI: 10.1016/j.trre.2016.04.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 04/02/2016] [Accepted: 04/04/2016] [Indexed: 02/06/2023]
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Potena L, Solidoro P, Patrucco F, Borgese L. Treatment and prevention of cytomegalovirus infection in heart and lung transplantation: an update. Expert Opin Pharmacother 2016; 17:1611-22. [PMID: 27340928 DOI: 10.1080/14656566.2016.1199684] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Heart and lung transplantation are standard therapeutic strategies to improve survival and quality of life in selected patients with end-stage heart or lung diseases. Cytomegalovirus (CMV) is one the most clinically relevant and frequent post-transplant infectious agents, which may cause direct acute syndromes, and chronic indirect graft-related injury. Despite effective antiviral drugs being available to prevent and treat CMV infection, due to the immunosuppression burden and the specific characteristics of thoracic grafts, CMV infection remains a major clinical problem in heart and lung transplant recipients. AREAS COVERED We performed an extensive literature search focused on studies specifically including heart or lung transplantation, when available, or kidney transplant recipients when data on thoracic transplants were not available. We discuss the pros and cons supporting the use of currently available drugs and strategies for CMV prevention and treatment, highlighting current unmet needs. EXPERT OPINION While (Val)Ganciclovir remains the cornerstone of anti-CMV therapy, prolonged universal prophylaxis may expose a large number of patients to an excess of drug toxicity. Additional drugs with lower toxicity may be available in the context of anti-CMV prophylaxis, and effective CMV-risk stratification, by means of novel immune monitoring assays, which may help to customize the therapeutic approach.
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Affiliation(s)
- Luciano Potena
- a Heart and Lung Transplant Program, Academic Hospital S. Orsola-Malpighi , Bologna University , Bologna , Italy
| | - Paolo Solidoro
- b Lung Transplant Center, Cardiovascular Thoracic Department , A.O.U. Città della Salute e della Scienza di Torino , Turin , Italy
| | - Filippo Patrucco
- b Lung Transplant Center, Cardiovascular Thoracic Department , A.O.U. Città della Salute e della Scienza di Torino , Turin , Italy
| | - Laura Borgese
- a Heart and Lung Transplant Program, Academic Hospital S. Orsola-Malpighi , Bologna University , Bologna , Italy
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Maffini E, Giaccone L, Festuccia M, Brunello L, Busca A, Bruno B. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation. Expert Rev Hematol 2016; 9:585-96. [PMID: 27043241 DOI: 10.1080/17474086.2016.1174571] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.
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Affiliation(s)
- Enrico Maffini
- a Department of Oncology, SSCVD Trapianto di Cellule Staminali , A.O.U. Città della Salute e della Scienza di Torino , Torino , Italy.,b Department of Molecular Biotechnology and Health Sciences , University of Torino , Torino , Italy
| | - Luisa Giaccone
- a Department of Oncology, SSCVD Trapianto di Cellule Staminali , A.O.U. Città della Salute e della Scienza di Torino , Torino , Italy.,b Department of Molecular Biotechnology and Health Sciences , University of Torino , Torino , Italy
| | - Moreno Festuccia
- a Department of Oncology, SSCVD Trapianto di Cellule Staminali , A.O.U. Città della Salute e della Scienza di Torino , Torino , Italy.,b Department of Molecular Biotechnology and Health Sciences , University of Torino , Torino , Italy
| | - Lucia Brunello
- a Department of Oncology, SSCVD Trapianto di Cellule Staminali , A.O.U. Città della Salute e della Scienza di Torino , Torino , Italy.,b Department of Molecular Biotechnology and Health Sciences , University of Torino , Torino , Italy
| | - Alessandro Busca
- a Department of Oncology, SSCVD Trapianto di Cellule Staminali , A.O.U. Città della Salute e della Scienza di Torino , Torino , Italy
| | - Benedetto Bruno
- a Department of Oncology, SSCVD Trapianto di Cellule Staminali , A.O.U. Città della Salute e della Scienza di Torino , Torino , Italy.,b Department of Molecular Biotechnology and Health Sciences , University of Torino , Torino , Italy
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Abstract
PURPOSE OF REVIEW The purpose of this study is to provide updated information on diagnosis of cytomegalovirus (CMV) drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds. RECENT FINDINGS For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug-resistant phenotype and may be genotyping artefacts. Next-generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation. SUMMARY Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug-resistant CMV and their genetic barriers to resistance.
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Cherng BPZ, Tan TT, Tan BH. Resistant cytomegalovirus infection in renal transplant recipients. PROCEEDINGS OF SINGAPORE HEALTHCARE 2015. [DOI: 10.1177/2010105815611811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Resistant cytomegalovirus infection is a significant problem in the transplant population including renal transplant recipients. A combination of factors including receipt of potent immunosuppression, high viral loads and suboptimal levels of anti-cytomegalovirus antivirals leads to emergence of resistant strains. Reports of associated poor graft survival and mortality demonstrate the potential pathogenic nature of such strains. Genotypic and phenotypic resistance testing are available for laboratory diagnosis of resistant cytomegalovirus infection and may help guide therapy. Various agents, including novel and newly minted antivirals and treatment approaches have been employed, with variable success. Thus, in spite of major advances in both diagnostics and therapeutics, management of resistant cytomegalovirus infection in renal transplant recipients remains a challenging prospect.
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Affiliation(s)
| | - Thuan Tong Tan
- Department of Infectious Diseases, Singapore General Hospital, Singapore
| | - Ban Hock Tan
- Department of Infectious Diseases, Singapore General Hospital, Singapore
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Keller F, Schröppel B, Ludwig U. Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction. World J Nephrol 2015; 4:330-344. [PMID: 26167456 PMCID: PMC4491923 DOI: 10.5527/wjn.v4.i3.330] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/12/2015] [Accepted: 05/06/2015] [Indexed: 02/06/2023] Open
Abstract
Patients with cancer have a high inherent risk of infectious complications. In addition, the incidence of acute and chronic kidney dysfunction rises in this population. Anti-infective drugs often require dosing modifications based on an estimate of kidney function, usually the glomerular filtration rate (GFR). However, there is still no preferential GFR formula to be used, and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR. In most cases, the anti-infective therapy should start with an immediate and high loading dose. Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment. Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations (e.g., beta lactam antibiotics, penems, vancomycin, antiviral drugs). Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations (e.g., aminoglycosides, daptomycin, colistin, quinolones). Our group created a pharmacokinetic database, called NEPharm, hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy. To avoid the risk of either too low or too infrequent peak concentrations, we prefer the eliminated fraction rule for dose adjustment calculations.
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Chon WJ, Kadambi PV, Xu C, Becker YT, Witkowski P, Pursell K, Kane B, Josephson MA. Use of leflunomide in renal transplant recipients with ganciclovir-resistant/refractory cytomegalovirus infection: a case series from the University of Chicago. Case Rep Nephrol Dial 2015; 5:96-105. [PMID: 26000278 PMCID: PMC4427155 DOI: 10.1159/000381470] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Introduction Although antiviral prophylaxis for cytomegalovirus (CMV) is widely used, CMV infection remains common in renal transplant recipients with adverse consequences. Methods We report 5 cases of renal transplant recipients with resistant CMV infection who were successfully managed with leflunomide at the University of Chicago Medical Center. Results Five renal transplant recipients (2 simultaneous pancreas/kidney transplants, 3 deceased donor kidney transplants) were diagnosed with GCV-resistant CMV infection from 2003 to 2011. Of the 4 patients who had resistance genotype testing, 3 showed a UL97 mutation and 1 patient had a clinically resistant CMV infection. All patients received CMV prophylaxis with valganciclovir for 3 months. The number of days from the date of transplant to viremia ranged from 38 to 458 days (median 219). All 5 patients received other antiviral agents (e.g. ganciclovir, foscarnet), and in 4 patients, viremia was cleared before leflunomide was initiated as consolidation (or maintenance) therapy. Conclusion Leflunomide was well tolerated and successful in preventing recurrence of viremia in renal transplant recipients with resistant CMV infection. The beneficial effect of leflunomide in this setting warrants further investigation.
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Affiliation(s)
- W James Chon
- Section of Nephrology, University of Chicago, Chicago, Ill., USA
| | - Pradeep V Kadambi
- Division of Nephrology and Transplant Medicine, University of Arizona, Tucson, Ariz., USA
| | - Chang Xu
- Section of Nephrology, University of Chicago, Chicago, Ill., USA
| | - Yolanda T Becker
- Section of Transplant Surgery, University of Chicago, Chicago, Ill., USA
| | - Piotr Witkowski
- Section of Transplant Surgery, University of Chicago, Chicago, Ill., USA
| | - Kenneth Pursell
- Section of Infectious Disease, University of Chicago, Chicago, Ill., USA
| | - Brenna Kane
- Department of Pharmacy Services, University of Chicago, Chicago, Ill., USA
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Roman A, Manito N, Campistol JM, Cuervas-Mons V, Almenar L, Arias M, Casafont F, del Castillo D, Crespo-Leiro MG, Delgado JF, Herrero JI, Jara P, Morales JM, Navarro M, Oppenheimer F, Prieto M, Pulpón LA, Rimola A, Serón D, Ussetti P. The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients. Transplant Rev (Orlando) 2014; 28:84-91. [DOI: 10.1016/j.trre.2014.01.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 01/19/2014] [Indexed: 01/10/2023]
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Vaz R, Barros F, Tavares I, Bustorff M, Ferreira I, Pestana M. Ganciclovir-resistant cytomegalovirus infection in renal transplantation. Clin Kidney J 2014; 7:210-3. [PMID: 25852874 PMCID: PMC4377781 DOI: 10.1093/ckj/sfu005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 01/16/2014] [Indexed: 12/13/2022] Open
Affiliation(s)
- Raquel Vaz
- Nephrology and Infectious Diseases Research and Development Group , INEB, University of Porto , Porto , Portugal ; Department of Nephrology , São João Hospital Center , Porto , Portugal
| | - Francisca Barros
- Nephrology and Infectious Diseases Research and Development Group , INEB, University of Porto , Porto , Portugal ; Department of Nephrology , São João Hospital Center , Porto , Portugal
| | - Isabel Tavares
- Nephrology and Infectious Diseases Research and Development Group , INEB, University of Porto , Porto , Portugal ; Department of Nephrology , São João Hospital Center , Porto , Portugal
| | - Manuela Bustorff
- Department of Nephrology , São João Hospital Center , Porto , Portugal
| | - Inês Ferreira
- Nephrology and Infectious Diseases Research and Development Group , INEB, University of Porto , Porto , Portugal ; Department of Nephrology , São João Hospital Center , Porto , Portugal
| | - Manuel Pestana
- Nephrology and Infectious Diseases Research and Development Group , INEB, University of Porto , Porto , Portugal ; Department of Nephrology , São João Hospital Center , Porto , Portugal ; Department of Renal, Urologic and Infectious Diseases, Faculty of Medicine , University of Porto , Porto , Portugal
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Ramsay ID, Lestner JM, O’Sullivan CP, Cruz AL, Li HK, Barker CI. Antiviral Drugs. SIDE EFFECTS OF DRUGS ANNUAL 2014:401-443. [DOI: 10.1016/b978-0-444-63407-8.00029-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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