RESUMO
In a human immunodeficiency virus-infected subject, cytomegalovirus (CMV) isolated 9 months after the patient began oral ganciclovir prophylaxis was resistant to ganciclovir and cidofovir and contained mutations in both UL97 and Pol coding regions. At 1 year, retinitis developed, which progressed despite intravenous ganciclovir followed by foscarnet and then cidofovir. A subsequent buffy coat virus isolate was resistant to all three drugs and contained new mutations in UL97 and Pol. By individually transferring the observed mutations to laboratory strain AD169, it was shown that a mutation at codon 603 of UL97 conferred resistance to ganciclovir, a mutation at codon 412 of Pol conferred resistance to both ganciclovir and cidofovir, and a mutation at codon 802 of Pol conferred resistance to ganciclovir and foscarnet. This case illustrates the development of multidrug resistance during prolonged exposure to antiviral therapy for CMV and cross-resistance arising from point mutations in the CMV Pol gene.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/virologia , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , Organofosfonatos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , DNA Polimerase Dirigida por RNA/genética , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Adulto , Fármacos Anti-HIV/uso terapêutico , Antivirais/administração & dosagem , Cidofovir , Citomegalovirus/genética , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Citosina/análogos & derivados , Citosina/uso terapêutico , Resistência Microbiana a Medicamentos/genética , Resistência a Múltiplos Medicamentos/genética , Quimioterapia Combinada , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Humanos , Masculino , Mutação , Compostos Organofosforados/uso terapêutico , Recombinação Genética , Análise de Sequência de DNARESUMO
Cytomegalovirus (CMV) isolates from subjects who received ganciclovir therapy were tested for susceptibility to ganciclovir by a plaque reduction assay. Results were correlated with restriction enzyme and sequence analysis of the CMV UL97 phosphotransferase gene. Of the 30 isolates, 20 had one or more mutations in UL97 affecting amino acid encoding at codons 460, 520, or 591-596. All 20 were resistant to ganciclovir, with an IC50 of > 6.0 microM (range, 6.7-50.0). The remaining 10 isolates had no mutations at these loci; 8 were susceptible to ganciclovir while the other 2 were borderline resistant (IC50s, 6.6 and 7.2 microM). None of 40 control CMV isolates from untreated subjects contained any amino acid changes at these loci. The three most common mutations at codons 460, 594, and 595 were detected by restriction digest analysis in 16 (80%) of 20 isolates and in 16 (73%) of 22 isolates with ganciclovir IC50s > 6.0 microM. These results indicate that the majority of ganciclovir-resistant clinical isolates contain diagnostically useful mutations in UL97.
Assuntos
Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Resistência Microbiana a Medicamentos , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Genes Virais , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Mutação Puntual , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Códon/genética , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/virologia , Primers do DNA , DNA Viral/análise , Fibroblastos , Humanos , Masculino , Dados de Sequência Molecular , Fosfotransferases/genética , Reação em Cadeia da Polimerase , Mapeamento por Restrição , PeleRESUMO
Prosthetic valve thrombosis is a life-threatening situation requiring prompt diagnosis and treatment. Treatment has usually been surgical and has been associated with a high mortality. Thrombolytic therapy is a therapeutic alternative to surgery and has been successful in a number of cases. This report concerns the technique used to diagnose the condition, treatment strategy, and documentation of the results of therapy.
