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

• Published in: Journal of antimicrobial chemotherapy Vol. 63; no. 6; pp. 1215 - 1222
• Main Authors: González, Natalia, Aguilar, Lorenzo, Alou, Luis, Giménez, Maria-Jose, Sevillano, David, Torrico, Martha, Cafini, Fabio, Coronel, Pilar, Prieto, Jose
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01.06.2009
• Subjects: Amoxicillin-Potassium Clavulanate Combination - pharmacology; Anti-Bacterial Agents - pharmacology; Antibiotics; beta-Lactams - pharmacology; Cefuroxime - pharmacology; Cephalosporins - pharmacology; Coculture Techniques; Colony Count, Microbial; Drug resistance; Haemophilus influenzae - drug effects; Haemophilus influenzae - growth & development; Humans; Influenza; Microbial Sensitivity Tests; Pharmacology; Selection, Genetic
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkp097

The aim was to study the pharmacodynamics of cefditoren, amoxicillin/clavulanic acid and cefuroxime against mixed Haemophilus influenzae strains. Isolates [MICs (mg/L) of cefditoren, cefuroxime and amoxicillin/clavulanic acid] used were: one beta-lactamase-negative (beta(-); 0.015, 1 and 1), one beta-lactamase-positive (beta(+); 0.03, 4 and 8) and two strains exhibiting ftsI gene mutations [one beta(-) ampicillin-resistant (BLNAR; 0.015, 8 and 4) and one beta(+) 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 (AUBC(K)) and in antibiotic simulations determined (ABBC(0-24) = AUBC(K0-24)-AUBC(0-24)). In antibiotic-free medium, total population increased by 1.7 log(10) cfu/mL from 0 to 24 h: final composition approximately 90% beta(-), approximately 6.5% beta(+), approximately 2.5% BLNAR and approximately 1% BLPACR. At the end of antibiotic simulations, the predominant population was BLPACR followed by beta(+) after amoxicillin/clavulanic acid or BLNAR after cefuroxime exposures. ABBC(0-24) was higher (P < 0.01) for cefditoren compared with cefuroxime or amoxicillin/clavulanic acid whether considering total population (70.4 versus approximately 33), beta(+) (77.8 versus approximately 52), BLNAR (66.1 versus 18.6-30.4) or BLPACR (40.8 versus approximately 0). 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 beta-lactamase-producing strains and those carrying ftsI gene mutations.