title: Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants.
abstract: BACKGROUND
  Concerns have been raised about emergence of ganciclovir resistance as a result of the advent of both routine oral ganciclovir prophylaxis and highly potent immunosuppression. We retrospectively assessed the occurrence of ganciclovir-resistant cytomegalovirus disease among transplant recipients who had received oral ganciclovir prophylaxis and highly potent immunosuppression.
  
  
  METHODS
  We studied 240 recipients of liver, kidney, or pancreas transplants. Antiviral susceptibility testing of blood cytomegaloviral isolates was done when patients failed to respond to intravenous ganciclovir treatment for symptomatic cytomegalovirus infection. Portions of the UL97 gene associated with ganciclovir resistance were sequenced in cytomegalovirus isolates with phenotypic resistance to ganciclovir.
  
  
  RESULTS
  Ganciclovir-resistant cytomegalovirus disease developed in five (7%) of 67 seronegative recipients of cytomegalovirus-seropositive organs (D+/R-) compared with none of 173 seropositive recipients (p=0.002). Among the 25 (10.4%) patients who developed cytomegalovirus disease within 1 year after transplantation, five had ganciclovir-resistant cytomegalovirus disease. Among D+/R-transplant recipients, ganciclovir-resistant cytomegalovirus disease was more common among the group receiving the most potent immunosuppression--ie, recipients of kidney and pancreas or pancreas alone (four of 19) compared with all other transplant recipients (one of 48, p=0.02). Ganciclovir-resistant cytomegalovirus disease was diagnosed at a median of 10 months after transplantation (range 7-12) after lengthened exposure to ganciclovir, was associated with previously described mutations of the UL97 gene, and led to serious clinical complications.
  
  
  CONCLUSIONS
  Ganciclovir-resistant cytomegalovirus is an important cause of late morbidity among D+/R- transplant recipients who have had lengthened exposure to ganciclovir and have received highly potent immunosuppression. Strategies to reduce this complication, especially among D+/R- patients, are warranted.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle 98195-7110, USA. limaye@u.washington.edu
authors.forename: A P
authors.initials: AP
authors.lastname: Limaye
authors.forename: L
authors.initials: L
authors.lastname: Corey
authors.forename: D M
authors.initials: DM
authors.lastname: Koelle
authors.forename: C L
authors.initials: CL
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Boeckh
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000453:epidemiology; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D017245:Foscarnet / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use*; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D020128:Inhibitory Concentration 50; D016030:Kidney Transplantation / Q000009:adverse effects; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D016017:Odds Ratio; D009894:Opportunistic Infections / Q000453:epidemiology / Q000821:virology; D016377:Organ Transplantation / Q000009:adverse effects*; D016035:Pancreas Transplantation / Q000009:adverse effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D000998:Antiviral Agents; D017245:Foscarnet; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D015774:Ganciclovir