Explaining the poor bacteriologic eradication rate of single-dose ceftriaxone in group a streptococcal tonsillopharyngitis: a reverse engineering solution using pharmacodynamic modeling.

OBJECTIVE: To explore pharmacokinetic factors underlying the poor bacteriologic eradication rate with a single 500-mg dose of ceftriaxone for streptococcal tonsillopharyngitis and to identify the minimum ceftriaxone dose required for effective treatment. METHODS: Population modeling techniques were applied to pharmacokinetic data derived from paired plasma and tonsil samples from 153 children to assess the contribution of pharmacokinetic variability to patients' responses to ceftriaxone. In addition, a Monte Carlo simulation was performed to determine (1) the amount of time that free ceftriaxone concentrations must exceed the minimum inhibitory concentration (MIC) of group A Streptococcus to achieve bacteriologic eradication and (2) the ceftriaxone dose required to maintain free drug concentrations above the target MIC for the requisite amount of time. Ceftriaxone MICs for group A Streptococcus were obtained from a previous trial, in which all MICs (n = 115) were < or = 0.064 mg/L; 33.9% were susceptible at < or = 0.016 mg/L, 66.4% were susceptible at 0.032 mg/L, and 1.7% were susceptible at 0.064 mg/L. RESULTS: Mean population pharmacokinetic parameters and their variances reflected substantial variability of clearance and half-life in the target population. Tonsillar ceftriaxone protein binding was 89.1%. The proportions of 1000 simulated patients with free ceftriaxone concentrations that exceeded MICs of 0.016 mg/L, 0.032 mg/L, and 0.064 mg/L at 24 hours were 71.7%, 65.4%, and 57.2%, respectively, and at 48 hours were 41.8%, 35.8%, and 28.6%, respectively. The amount of time that free ceftriaxone concentrations need to exceed MIC to achieve bacteriologic success was estimated to be 36 hours. Using this time criterion, two 500-mg doses of ceftriaxone separated by 18 hours should achieve a bacteriologic cure rate of approximately 95%. CONCLUSIONS: Pharmacokinetic variability and high ceftriaxone tonsillar protein binding explain the high microbiologic failure rate for a single 500-mg dose of ceftriaxone in group A streptococcal tonsillopharyngitis. Monte Carlo simulation suggests that a second dose administered 18 hours after the first will be required to achieve an acceptable bacteriologic cure rate.

Avaliaçäo comparativa da eficácia e tolerabilidade do nimesulide, diclofenaco e dipirona sódica aplicados aos processos inflamatórios do trato respiratório superior em populaçäo pediátrica / Comparative assessment on the efficacy and tolerability of nimesulide, diclofenac potassium and dipyrone applyed to inflammatory processes of the superior respiratory tract in the pediatric population

Em um estudo randomizado, comparativo e prospectivo se analizou a eficácia e a tolerabilidade de dois antiinflamatórios (nimesulide e diclofenaco potássico) e uma droga analgésica/antitérmica (dipirona) diante de processos inflamatórios do trato respiratório superior (faringites e/ou amigdalites) em uma populaçäo pediátrica. Os sinais e sintomas próprios a essas patologias foram analisados e a febre monitorizada durante um período de 24 horas. Observou-se uma melhora significativa e homogênea dos sinais e sintomas em todos os grupos de tratamento. A febre apresentou queda pronunciada após a administraçäo de nimesulide e diclofenaco e também após a administraçäo da dipirona, sendo que ocorreu uma reversäo do efeito da dipirona após algumas horas. Dois pacientes apresentaram efeitos adversos que, no caso do diclofenaco devido a intensidade, forçaram a retirada do medicamento. Os dados obtidos ressaltam a eficácia antipirética do nimesulide tal qual a da dipirona com as vantagens em tolerabilidade que näo säo encontradas com o uso de diclofenaco potássico. Assim concluímos que o nimesulide, além de uma poderosa açäo antitérmica, apresenta vantagens no combate ao processo inflamatório, principalmente com relaçäo a sua segurança.