Influence of different resistance traits on the competitive growth of Haemophilus influenzae in antibiotic-free medium and selection of resistant populations by different β-lactams: An in vitro pharmacodynamic approach

Abstract

Objectives: The aim was to study the pharmacodynamics of cefditoren, amoxicillin/clavulanic acid and cefuroxime against mixed Haemophilus influenzae strains. Methods: Isolates [MICs (mg/L) of cefditoren, cefuroxime and amoxicillin/clavulanic acid] used were: one β-lactamase-negative (β-; 0.015, 1 and 1), one β-lactamase-positive (β+; 0.03, 4 and 8) and two strains exhibiting ftsI gene mutations [one β-; ampicillin-resistant (BLNAR; 0.015, 8 and 4) and one β+; amoxicillin/clavulanic acid-resistant (BLPACR; 0.03, 8 and 4)]. A computerized pharmacodynamic model simulating free antibiotic concentrations (calculated considering reported percentages of protein binding) of 400 mg twice-daily cefditoren, 500 mg twice-daily cefuroxime and 875/125 mg three times daily amoxicillin/ clavulanic acid was used to explore antibacterial activity against initial mixed inocula with 25% of each strain. Areas under bacterial curves (AUBCs) from 0 to 24 h (log cfu·h/mL) were calculated and differences between values in antibiotic-free (AUBCK) and in antibiotic simulations determined (ABBC0-24 = AUBCK0-24-AUBC0-24). Results: In antibiotic-free medium, total population increased by 1.7 log10 cfu/mL from 0 to 24 h: final composition ≈90% β-, ≈6.5% β+, ≈2.5%; BLNAR and ≈1% BLPACR. At the end of antibiotic simulations, the predominant population was BLPACR followed by β+ after amoxicillin/ clavulanic acid or BLNAR after cefuroxime exposures. ABBC0-24 was higher (P < 0.01) for cefditoren compared with cefuroxime or amoxicillin/clavulanic acid whether considering total population (70.4 versus ≈33), β+; (77.8 versus ≈52), BLNAR (66.1 versus 18.6-30.4) or BLPACR (40.8 versus ≈0). Conclusions: Cefditoren offered higher antibacterial effect than cefuroxime and amoxicillin/clavulanic acid against a mixed population of H. influenzae strains due to its higher activity against β-lactamase-producing strains and those carrying ftsI gene mutations. The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.