How can we predict bacterial eradication?

Abstract

Antimicrobial efficacy is measured in vitro by determination of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of antimicrobials, but these values do not account for fluctuations of drug concentrations within the body or the time course of the drug's in vivo antibacterial activity. However, in vivo bacteriologic efficacy can be predicted by pharmacokinetic/pharmacodynamic (PK/PD) parameters, such as the time for which the serum drug concentration is above the MIC (T>MIC), the ratio of peak serum concentration to the MIC, and the ratio of the area under the 24-h serum concentration-time curve to the MIC (AUC/MIC). Different patterns of antibacterial activity correlate with different PK/PD parameters. For example, a T>MIC of 40-50% of the dosing interval is a good predictor of bacteriologic efficacy for penicillins, cephalosporins, and most macrolides, and an AUC/MIC ratio of at least 25 is required for efficacy with fluoroquinolones and azalides. The PK/PD breakpoint for susceptibility of an organism to a specific dosing regimen of an agent can be determined as the highest MIC met by the relevant PK/PD parameter for bacteriologic efficacy for that agent. These parameters have been validated extensively in animal models, as well as in many human studies where bacteriologic outcome has been determined. The PK/PD breakpoint of an agent is determined primarily by the dosing regimen, and generally applies to all pathogens causing disease at sites where extracellular tissue levels are similar to non-protein-bound serum levels. On this basis, many parenteral beta-lactams are active against almost all strains of Streptococcus pneumoniae, including 'penicillin-non-susceptible' strains, in all body sites except for the central nervous system. Application of PK/PD breakpoints to standard dosing regimens of oral beta-lactams predicts that agents such as cefaclor and cefixime will have efficacy only against penicillin-susceptible strains of S. pneumoniae, while cefuroxime axetil, cefpodoxime and cefdinir will be effective against all penicillin-susceptible as well as many penicillin-intermediate strains. However, the most active oral beta-lactams, amoxicillin and amoxicillin-clavulanate, have predicted efficacy against all penicillin-susceptible and -intermediate pneumococci, as well as against most penicillin-resistant strains, at amoxicillin doses of 45-90 mg/kg per day in children and 1.75-4.0 g/day in adults. These predictions are supported by evidence from animal studies of bacteriologic efficacy. The use of PK/PD parameters to predict bacterial eradication therefore allows an evidence-based approach to the selection of appropriate antimicrobial therapy.