Proof of concept: performance testing in models.

Pharmacokinetic (PK) and pharmacodynamic (PD) principles that predict antimicrobial efficacy can be used to set targets for antimicrobial design and optimisation. Although current formulations of amoxicillin and amoxicillin/clavulanate have retained their efficacy against many, but not all, penicillin-nonsusceptible Streptococcus pneumoniae, additional coverage is required to address the growing problem of drug-resistant strains. Accordingly, two new oral formulations of amoxicillin/clavulanate, a paediatric formulation at 90/6.4 mg/kg/day and a pharmacokinetically enhanced formulation at 2000/125 mg twice daily for adults, were designed using PK/PD principles. These principles indicate that for amoxicillin and amoxicillin/clavulanate, a time above MIC of 35-40% of the dosing interval is predictive of high bacterial efficacy. In line with PK/PD predictions, simulation of human pharmacokinetics in in-vitro kinetic models and in a rat model of pneumonia, amoxicillin/clavulanate 2000/125 mg twice daily was highly effective against S. pneumoniae strains with amoxicillin MICs of 4 or 8 mg/L. Against strains with amoxicillin MICs of 4 mg/L, amoxicillin/clavulanate 2000/125 mg twice daily was significantly more effective than the conventional 875/125 mg twice daily formulation, azithromycin and levofloxacin, even though all levofloxacin MICs were < or = 1 mg/L. Following infection with S. pneumoniae strains with amoxicillin MICs of 8 mg/L, the amoxicillin/clavulanate 2000/125 mg twice daily formulation was more effective than the conventional amoxicillin/clavulanate formulations of 875/125 mg twice daily and three times daily and 1000/125 mg three times daily, and had similar or better efficacy than azithromycin and levofloxacin, depending on the strain. These data indicate the potential benefit of therapy with amoxicillin/clavulanate 2000/125 mg twice daily compared with conventional formulations and other marketed antimicrobials in the treatment of respiratory tract infection.