Two Pharmacodynamic Models for Assessing the Efficacy of Amoxicillin-Clavulanate against Experimental Respiratory Tract Infections Caused by Strains of Streptococcus pneumoniae

AUTOR(ES)
FONTE

American Society for Microbiology

RESUMO

Two models of respiratory tract infection were used to investigate the pharmacodynamics of amoxicillin-clavulanate against Streptococcus pneumoniae. Eight strains of S. pneumoniae were used in a mouse model in which the animals were infected intranasally and were then treated with a range of doses and dose intervals. The time that the plasma amoxicillin concentration remained above the MIC (T>MIC) correlated well with bacterial killing, such that if T>MIC was below 20% there was no effect on bacterial numbers in the lungs. As T>MIC increased, the response, in terms of decreased bacterial load, improved and at T>MICs of greater than 35 to 40% of the dosing interval, bacteriological cure was maximal. On the basis of equivalent T>MICs, these data would suggest that in humans a dosage of 500 mg three times daily (t.i.d.) should have efficacy equal to that of a dosage of 875 mg twice daily (b.i.d.). This hypothesis was evaluated in a rat model in which amoxicillin-clavulanate was given by computer-controlled intravenous infusion to achieve concentrations that approximate the concentrations achieved in the plasma of humans following oral administration of 500/125 mg t.i.d. or 875/125 mg b.i.d. Infusions continued for 3 days and bacterial numbers in the lungs 2 h after the cessation of the infusion were significantly reduced (P < 0.01) by both treatments in strains of S. pneumoniae for which amoxicillin MICs were below 2 μg/ml. When tested against a strain of S. pneumoniae for which the amoxicillin MIC was 4 μg/ml, the simulated 500/125-mg dose was ineffective but the 875/125-mg dose demonstrated a small but significant (P < 0.01) reduction in bacterial numbers. These data confirm the findings in the mouse and indicate that amoxicillin-clavulanate administered at 875/125 mg b.i.d. would be as effective clinically as amoxicillin-clavulanate administered at 500/125 mg t.i.d.

ACESSO AO ARTIGO

Documentos Relacionados