RESUMO
BACKGROUND: Pathogenic mutations in the mitochondrial genome are associated with a wide variety of maternally inherited human diseases including sensorineural hearing loss (HL). A specific mutation, m.1555A>G in the mitochondrial 12S rRNA gene, is associated with predisposition to aminoglycoside ototoxicity and HL. Mutation screening in this gene has been recommended before use of aminoglycosides as a preventative strategy to reduce the risk of ototoxicity. OBJECTIVE: To study the incidence of mutations in the 12S rRNA gene in patients being treated with aminoglycosides and its correlation with ototoxicity. METHODS: Patients undergoing treatment with aminoglycosides were prospectively enrolled in this study (n = 27). Total dosage administered and therapeutic levels of the antibiotic were noted. All patients underwent high-frequency pure-tone audiometry pre- and posttherapy and sequencing of the 12S rRNA gene. In addition, 12S rRNA gene was also sequenced in 50 controls to characterize population specific polymorphisms. RESULTS: Five of 27 patients suffered from HL involving the high frequencies: four mild and one moderate. Only one of the five patients with ototoxicity harbored two sequence alterations in 12S rRNA of uncertain pathogenicity. The m.1555A>G and m.961delTInsCn mutations were not detected. CONCLUSIONS: High-frequency pure-tone audiometry is critical for detection of aminoglycoside-induced HL. In the Swiss population, screening for mutations in the 12S rRNA gene, before the initiation of aminoglycoside therapy, is not supported by this limited study. A larger multicenter and multicultural study is warranted to more definitively address this critical clinical issue.
Assuntos
Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Audiometria de Tons Puros , RNA Ribossômico/genética , Adolescente , Adulto , Idoso , Aminoglicosídeos/sangue , Antibacterianos/sangue , Cóclea/efeitos dos fármacos , Predisposição Genética para Doença , Testes Genéticos , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/genética , Humanos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mutação/genética , Mutação Puntual/genética , Polimorfismo Genético/genética , Estudos Prospectivos , RNA Ribossômico/efeitos dos fármacos , Medição de Risco , Análise de Sequência de RNA , Fatores de TempoRESUMO
Specific recommendations from the American Speech-Language Hearing Association (1994) exist for the audiometric surveillance of patients receiving aminoglycoside therapy. However, these recommendations are not based primarily on test-retest repeatability in often seriously ill patients. The probability of ototoxicity is very low during the first three days of aminoglycoside therapy, and significant threshold shifts can be assumed to represent a false-positive result. Baseline thresholds were measured in 28 patients before or not later than 24 h after the beginning of aminoglycoside therapy. These measurements were repeated in 22 patients during the first three days of the drug administration. Three out of 22 patients fulfilled the American Speech-Language-Hearing Association's (1994) criteria for cochleotoxicity making up a false-positive rate of 13%. In actual patients, the false-positive rate of audiometric surveillance during ototoxic drug administration may be substantially higher than in healthy subjects when these criteria are used.
