title: Proof of concept: performance testing in models.
abstract: 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.
authors.affiliation: University of Wisconsin and the William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA. wac@medicine.wisc.edu
authors.forename: W A
authors.initials: WA
authors.lastname: Craig
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D051381:Rats; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination