title: Effect of opsonophagocytosis mediated by specific antibodies on the co-amoxiclav serum bactericidal activity against Streptococcus pneumoniae after administration of a single oral dose of pharmacokinetically enhanced 2000/125 mg co-amoxiclav to healthy volunteers.
abstract: OBJECTIVE
  To measure the effect of opsonophagocytosis mediated by complement activated by specific antibodies on the co-amoxiclav serum bactericidal activity against Streptococcus pneumoniae strains with reduced susceptibility to beta-lactams (amoxicillin MICs of 2, 4, 8 and 16 mg/L).
  
  
  METHODS
  An open Phase I study measuring ex vivo bactericidal activity after anti-pneumococcal vaccination and an oral dose of 2000/125 mg sustained-release co-amoxiclav was carried out. The ex vivo bactericidal activity was investigated through killing curves over 3 h [assuring polymorphonuclear neutrophil (PMN) viability] with serum samples collected 1.5 h and 5 h after dosing. Global killing was measured as the area under the killing curve (AUKC; log cfu x h/mL). The AUKC of the control growth curve of S. pneumoniae in Hanks' balanced salt solution (AUKC(K)) was used as control. The effect of the presence of complement and/or PMN was evaluated by the difference in the AUKC(K) and the different AUKCs obtained in the presence of inactivated serum (AUKC(IS)), active serum (AUKC(S)), inactivated serum plus PMN (AUKC(IS+PMN)) and active serum plus PMN (AUKC(S+PMN)).
  
  
  RESULTS
  Significant differences were found in all cases between the bactericidal activity of active serum+PMN (AUKC(K) - AUKC(S+PMN)) and that of inactivated serum (AUKC(K) - AUKC(IS)) with therapeutic indexes ranging from 0.56 to 3.04. At 1.5 h after dosing, a significantly higher bactericidal activity of co-amoxiclav was obtained when opsonophagocytosis occurred (samples with active serum and PMN) than when not occurring (killing curves with inactivated serum and without PMN), for all amoxicillin non-susceptible strains.
  
  
  CONCLUSIONS
  The results of this ex vivo study suggest that the collaboration of co-amoxiclav and complement-mediated opsonophagocytosis activated by specific antibodies may lay new approaches to overcome in vivo amoxicillin non-susceptibility.
authors.affiliation: Microbiology Department, School of Medicine, Universidad Complutense, Avda. Complutense s/n, 28040 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alou
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Aguilar
authors.forename: David
authors.initials: D
authors.lastname: Sevillano
authors.forename: María-José
authors.initials: MJ
authors.lastname: Giménez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Laguna
authors.forename: Olatz
authors.initials: O
authors.lastname: Echeverría
authors.forename: Antonio
authors.initials: A
authors.lastname: Carcas
authors.forename: Rubin
authors.initials: R
authors.lastname: Lubomirov
authors.forename: Julio
authors.initials: J
authors.lastname: Casal
authors.forename: José
authors.initials: J
authors.lastname: Prieto
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000276:immunology*; D000918:Antibody Specificity; D015169:Colony Count, Microbial; D004359:Drug Therapy, Combination / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000276:immunology; D009895:Opsonin Proteins / Q000276:immunology*; D010403:Penicillin Resistance; D010587:Phagocytosis / Q000276:immunology*; D015610:Serum Bactericidal Test; D022541:Streptococcal Vaccines / Q000008:administration & dosage / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D009895:Opsonin Proteins; D022541:Streptococcal Vaccines; D019980:Amoxicillin-Potassium Clavulanate Combination