title: Enhanced in vivo activity of cefditoren in pre-immunized mice against penicillin-resistant S. pneumoniae (serotypes 6B, 19F and 23F) in a sepsis model.
abstract: BACKGROUND
  Specific antibodies are likely to be present before S. pneumoniae infection. We explored cefditoren (CDN) total and free values of serum concentrations exceeding the MIC (t>MIC) related to efficacy in a mice sepsis model, and the effect of specific gammaglobulins on in-vitro phagocytosis and in-vivo efficacy.
  
  
  RESULTS
  We used three pneumococcal isolates (serotype, MIC OF CDN): Strain 1 (6B, 1 microg/ml), Strain 2 (19F, 2 microg/ml) and Strain 3 (23F, 4 microg/ml). Hyperimmune serum (HS) was obtained from mice immunized with heat-inactivated strains. In-vitro, phagocytosis by HS diluted 1/10 in presence/absence of sub-inhibitory concentrations was measured by flow cytometry including fluorescent bacteria and a neutrophil cell line. In-vivo dose-ranging experiments with HS (dilutions 1/2-1/16) and CDN (6.25 mg/kg-100 mg/kg tid for 48 h) were performed to determine the minimal protective dilution/dose (highest survival) and the non-protective highest dilution/dose (highest mortality: HS-np dilution and CDN-np dose) over 7 days. Efficacy of CDN-np in animals pre-immunized with HS-np (combined strategy) was explored and blood bacterial clearance determined. The CDN measured protein binding was 86.9%. In-vitro, CDN significantly increased phagocytosis (vs. HS 1/10). In non pre-immunized animals, t>MIC values for CDN of approximately 35% (total) and approximately 19% (free) were associated with 100% survival. Significant differences in survival were found between HS-np alone (< or = 20%) or CDN-np alone (< or = 20%) vs. the combined strategy (90%, 60% and 60% for Stains 1, 2 and 3), with t>MIC (total/free) of 22.8%/14.3%, 26.8%/16.0%, and 22.4%/12.7% for Strains 1, 2 and 3, respectively. Prior to the second dose (8 h), median bacterial counts were significantly lower in animals surviving vs. dead at day 7.
  
  
  CONCLUSIONS
  In mice (CDN protein binding similar to humans) total t>MIC values of approximately 35% (approximately 19% free) were efficacious, with a decrease in the required values in pre-immunized animals. This reinforces that immunoprotection to overcome resistance may provide lifesaving strategies.
authors: Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain.
authors: Fabio
authors: F
authors: Cafini
authors: Jose
authors: J
authors: Yuste
authors: Maria-Jose
authors: MJ
authors: Giménez
authors: David
authors: D
authors: Sevillano
authors: Lorenzo
authors: L
authors: Aguilar
authors: Luis
authors: L
authors: Alou
authors: Elisa
authors: E
authors: Ramos-Sevillano
authors: Martha
authors: M
authors: Torrico
authors: Natalia
authors: N
authors: González
authors: Ernesto
authors: E
authors: García
authors: Pilar
authors: P
authors: Coronel
authors: Jose
authors: J
authors: Prieto
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D000918:Antibody Specificity; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007114:Immunization; D007116:Immunization, Passive; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance / Q000187:drug effects*; D010586:Phagocytes / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D012703:Serotyping; D013296:Streptococcus pneumoniae / Q000145:classification / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D002511:Cephalosporins; D015164:Vaccines, Inactivated; C073460:cefditoren