Are beta-lactam breakpoints adequate to define non-susceptibility for all Haemophilus influenzae resistance phenotypes from a pharmacodynamic point of view?
OBJECTIVE
To investigate the bactericidal activity, against Haemophilus influenzae strains exhibiting different resistance phenotypes, of simulated serum concentrations obtained in humans after administration of 400 mg of cefditoren twice daily, 500 mg of cefuroxime twice daily, 875/125 mg of co-amoxiclav twice daily or 875/125 mg of co-amoxiclav three times daily.


METHODS
An in vitro computerized pharmacodynamic simulation was carried out and colony counts determined over 24 h. Four H. influenzae strains were used, one ampicillin-susceptible strain (Strain 1) and three ampicillin-resistant strains following CLSI and BSAC breakpoints: one beta-lactamase-positive strain with an MIC of co-amoxiclav of 0.5 mg/L (Strain 2), one beta-lactamase-negative ampicillin-resistant strain (BLNAR; ampicillin MIC = 16 mg/L) (Strain 3) and one beta-lactamase-positive strain with an MIC of co-amoxiclav of 4 mg/L (Strain 4). All strains were susceptible to cefuroxime and co-amoxiclav according to current CLSI breakpoints, but Strains 3 and 4 were resistant according to BSAC breakpoints. All strains exhibited cefditoren MIC <or= 0.12 mg/L.


RESULTS
Bacterial counts of Strains 1 and 2 were >or= 6 log(10) reduced with all antibiotics tested at 12 and 24 h. Against Strains 3 and 4, log(10) reductions at 12 and 24 h were significantly higher for cefditoren versus cefuroxime (P < 0.01) (although both exhibited bactericidal activity, i.e. >or= 3 log(10) reduction) and versus the two co-amoxiclav regimens (P < 0.001) (that exhibited negligible initial inocula reductions).


CONCLUSIONS
Cefditoren exhibited the highest bactericidal activity maintained over time against ampicillin-resistant H. influenzae, regardless of beta-lactamase production and/or BLNAR phenotype. From the pharmacodynamic perspective, BSAC breakpoints seem more adequate to define or detect BLNAR strains.
Alou
L
L
Microbiology Department, School of Medicine, Universidad Complutense, Avda.Complutense s/n, 28040 Madrid, Spain.
Giménez
M J
MJ
Sevillano
D
D
Aguilar
L
L
González
N
N
Echeverría
O
O
Torrico
M
M
Coronel
P
P
Prieto
J
J
D019980:Amoxicillin-Potassium Clavulanate Combination / Q000494:pharmacology; D000668:Ampicillin Resistance / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002444:Cefuroxime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D003198:Computer Simulation; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006193:Haemophilus influenzae / Q000187:drug effects*; D006207:Half-Life; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D047090:beta-Lactams; D019980:Amoxicillin-Potassium Clavulanate Combination; C073460:cefditoren; D001618:beta-Lactamases; D002444:Cefuroxime