Activity of nine oral agents against gram-positive and gram-negative bacteria encountered in community-acquired infections: use of pharmacokinetic/pharmacodynamic breakpoints in the comparative assessment of beta-lactam and macrolide antimicrobial agents.

Abstract Background: The application of pharmacokinetic (PK) and pharmacodynamic (PD) data in conjunction with minimum inhibitory concentrations (MICs) of antibacterial agents has been shown to allow for improved selection and appropriate dosing of antimicrobial agents for specific infections, increasing the likelihood of bacteriologic cure and, through this, reducing the risk for the development of resistant organisms. Objectives: This study was undertaken to provide data on current levels of resistance among common community-acquired bacterial species to 7 betalactam antimicrobial agents (including the combination product amoxicillin/clavulanate), azithromycin, and clarithromycin, determined through application of the PK/PD breakpoints based on time-above-MIC for the beta-lactams and the nonazalide macrolide clarithromycin, and on 24-hour serum area under the curve divided by MIC for the azalide macrolide azithromycin. Methods: The antimicrobial products tested were amoxicillin/clavylanate, cefpodoxime, cefdinir, cefditoren, cefprozil, cefuroxime, cefixime, azithromycin, and clarithromycin. The bacterial species comprised 70 penicillin-susceptible, 68 penicillin-intermediate, and 69 penicillin-resistant strains of Streptococcus pneumoniae ; 46 beta-lactamase-positive and 54 beta-lactamase-negative strains of Haemophilus influenzae ; 49 strains of Moraxella catarrhalis ; and 100 methicillin-sensitive strains of Staphylococcus aureus (MSSA). Strains were isolated from clinical specimens obtained from outpatient-acquired infections in 1 clinical center in the Northeast and 1 in the north-central area of the United States within the past 2 years. National Committee for Clinical Laboratory Standards microdilution MIC methodology was used. PK/PD breakpoints were obtained from previously published studies and were based on blood values. Results: Amoxicillin/clavulanate was the product to which the greatest percentage of susceptible, intermediate, and resistant strains of pneumococci were sensitive at the PK/PD breakpoint, followed by cefditoren, cefpodoxime, cefuroxime, cefdinir, and cefprozil. None of the cephalosporins were active against penicillin-resistant pneumococci. Cefditoren and cefpodozime were the agents to which the greatest percentage of beta-lactamase-positive and beta-lactamase-negative strains of H influenzae were sensitive, followed by amoxicillin/clavulanate, cefdinir, and cefuroxime. Cefprozil was inactive against H influenzae . All of the beta-lactam products were active against M catarrhalis . All but cefpodoxime, cefditoren, and cefixime were active against MSSA. Conclusions: In this study, based on PK/PD breakpoints, amoxicillin/clavulanate had the best overall activity of the 9 antimicrobial products tested. Cefpodoxime and cefditoren were active against ⩾90% of strains of penicillin-susceptible and penicillin-intermediate pneumococci, H influenzae , and M catarrhalis . The macrolides azithromycin and clarithromycin were active against penicillin-susceptible and penicillin-intermediate pneumococci and M catarrhalis ; they were inactive against H influenzae and penicillin-resistant pneumococci.