title: Achieving bacterial eradication using pharmacokinetic/pharmacodynamic principles.
abstract: Evidence from studies in otitis media indicates that antimicrobials and dosing regimens that have equivalent bacteriologic efficacy against susceptible pathogens can have significantly different bacteriologic success rates against resistant strains of the same species. Unlike macrolide and fluoroquinolone resistance, penicillin resistance can be overcome in Streptococcus pneumoniae by increasing the dose, and hence increasing the time for which the serum concentrations are above the MIC. The new clinical formulation of extra-strength amoxicillin-clavulanate provides 90 mg/kg per day amoxicillin plus 6.4 mg/kg per day clavulanate (14:1) divided every 12 h, compared with 45/6.4 mg/kg per day b.i.d. with conventional dosing. The pharmacokinetic/pharmacodynamic (PK/PD) profiles of extra-strength amoxicillin-clavulanate predict that the new formulation will be more effective than the conventional formulation against S. pneumoniae with elevated amoxicillin MICs and against Haemophilus influenzae. In an open-label, non-comparative study in children with acute otitis media, the extra-strength formulation had high bacteriologic success rates against the major respiratory pathogens, including penicillin-resistant S. pneumoniae. The development of new antimicrobial agents and formulations should be aimed at meeting PK/PD parameters predictive of bacterial eradication of both susceptible and resistant strains.
authors.affiliation: The Pediatric Infectious Disease Unit, Soroka University Medical Center, Ben-Gurion University, Beer-Sheva, Israel. rdagan@bgumail.bgu.ca.il
authors.forename: Ron
authors.initials: R
authors.lastname: Dagan
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002648:Child; D006192:Haemophilus Infections / Q000188:drug therapy* / Q000382:microbiology; D006193:Haemophilus influenzae / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D010033:Otitis Media / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination