title: In vitro studies on the impact of human serum on the antibacterial effect of faropenem.
abstract: The interaction between faropenem and serum in determining antibacterial effect was studied using three target pathogens and two different in vitro methodologies. Strains of Staphylococcus aureus, Streptococcus pneumoniae, capsulate and non capsulate Haemophilus influenzae, all faropenem MIC 0.12 mg/L, were tested in a range of pharmacologically realistic faropenem concentrations with various proportions of serum up to 75%. Using simulated serum bactericidal titres the presence of human serum reduced the activity of faropenem against S. pneumoniae as did heat-treated serum for non-capsulate H. influenzae. Serum on its own was bactericidal against H. influenzae probably due to the presence of complement. The antibacterial effects of combinations of faropenem and serum was assessed in time-kill curves by calculation of the area-under-the bacterial-kill-curve (AUBKC). This was then related to faropenem concentration and the proportion of serum using three-dimensional plots. Serum on its own was mildly inhibitory of the growth of S. aureus, supported improved growth of S. pneumoniae at some proportions and was rapidly bactericidal to H. influenzae, especially the non-capsulate strains. Faropenem had a marked antibacterial effect against all three species in the range 0-2.5 mg/L. Increasing the faropenem concentration from 2.5-10 mg/L produced little or no additional effect. The combination of serum and faropenem had little impact on the antibacterial effect against S. pneumoniae and S. aureus but free drug concentrations were likely to be greater than the MIC in all the combinations used. Against capsulate H. influenzae the effect of serum and faropenem was broadly equivalent while against non-capsulate strains the activity of serum was so great it is difficult to assess the impact of faropenem alone. The interaction between serum and antibiotic in determining antibacterial effect is complex and critically dependent on the proportions of serum and drug concentrations chosen. Three-dimensional plots offer a tool to visualise these complex relationships which may be species specific.
authors.affiliation: Bristol Centre for Antimicrobial Research and Evaluation, University of Bristol and North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK. alasclair.macgowan@north-bristol.swest.nhs.uk
authors.forename: A
authors.initials: A
authors.lastname: MacGowan
authors.forename: K
authors.initials: K
authors.lastname: Bowker
mesh_terms: D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D007769:Lactams / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D044967:Serum; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D047090:beta-Lactams
chemical_list: D007769:Lactams; D047090:beta-Lactams; C107057:fropenem