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

Abstract

Two models of respiratory tract infection were used to investigate the pharmacodynamics of amoxicillin-clavulanate againstStreptococcus 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.

Development of a twice daily dosing regimen of amoxicillin/clavulanate

“…Clavulanate inhibits beta-lactamases at very low concentrations and has a post-beta-lactamase-inhibitory effect facilitating less frequent dosing [1,2]. Importantly, equivalent bacterial eradication by amoxicillin/clavulanate 875/125 mg BD and amoxicillin/clavulanate 500/125 mg TID was demonstrated in laboratory models simulating human serum pharmacokinetics [3].…”

“…1) hence predicting potential equivalent bacteriological efficacy [5]. Infection models showed equivalent bacterial eradication in vivo for both formulations and similarly, in experimental infection models simulating human serum pharmacokinetics, there were equivalent outcomes [3].…”

Eradication of pathogens from the nasopharynx after therapy of acute maxillary sinusitis with low- or high-dose amoxicillin/clavulanic acid

“…It doubles the concentration of amoxicillin compared with the existing formulation, maintains the same clavulanic acid concentration, and is administered in two divided daily doses. This provides sufficiently high amoxicillin concentrations at the infected site to eradicate penicillin-resistant S. pneumoniae with penicillin and amoxicillin MIC values as high as 4 g/mL [5,[14][15][16]. It provides serum amoxicillin concentrations that exceed 4 g/mL for >40% of the dosing interval based on human and animal pharmacokinetic studies and on pharmacokinetic modelling [5,[14][15][16].…”

“…The new formulation of amoxicillin/clavulanic acid addresses the growing problem of penicillin-resistant S. pneumoniae and is based on pharmacokinetic and pharmacodynamic considerations [4] as well as animal [14,15], laboratory [14] and clinical [16] data. It doubles the concentration of amoxicillin compared with the existing formulation, maintains the same clavulanic acid concentration, and is administered in two divided daily doses.…”

Clinical and bacteriological evaluation of the efficacy of piperacillin in children with pneumonia

“…Regarding penicillin antibiotics, their effi cacy can be expected when TAM exceeds 30%. 7,8 In the present study, the MIC of piperacillin was measured in 11 cases. For H. infl uenzae isolated from them, the maximum MIC of piperacillin was 0.25 µg/ml (TAM, 64.0%).…”