title: 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.
abstract: OBJECTIVE
  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 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)).
  
  
  RESULTS
  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).
  
  
  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 beta-lactamase-producing strains and those carrying ftsI gene mutations.
authors.affiliation: Microbiology Department, Univ. Complutense, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: González
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Aguilar
authors.forename: Luis
authors.initials: L
authors.lastname: Alou
authors.forename: Maria-Jose
authors.initials: MJ
authors.lastname: Giménez
authors.forename: David
authors.initials: D
authors.lastname: Sevillano
authors.forename: Martha
authors.initials: M
authors.lastname: Torrico
authors.forename: Fabio
authors.initials: F
authors.lastname: Cafini
authors.forename: Pilar
authors.initials: P
authors.lastname: Coronel
authors.forename: Jose
authors.initials: J
authors.lastname: Prieto
mesh_terms: D019980:Amoxicillin-Potassium Clavulanate Combination / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002444:Cefuroxime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D018920:Coculture Techniques; D015169:Colony Count, Microbial; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000254:growth & development*; D006801:Humans; D008826:Microbial Sensitivity Tests; D012641:Selection, Genetic; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D047090:beta-Lactams; D019980:Amoxicillin-Potassium Clavulanate Combination; C073460:cefditoren; D002444:Cefuroxime