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.