Enhanced in vivo activity of cefditoren in pre-immunized mice against penicillin-resistant S. pneumoniae (serotypes 6B, 19F and 23F) in a sepsis model.
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.
Cafini
Fabio
F
Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain.
Yuste
Jose
J
Giménez
Maria-Jose
MJ
Sevillano
David
D
Aguilar
Lorenzo
L
Alou
Luis
L
Ramos-Sevillano
Elisa
E
Torrico
Martha
M
González
Natalia
N
García
Ernesto
E
Coronel
Pilar
P
Prieto
Jose
J
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
D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D002511:Cephalosporins; D015164:Vaccines, Inactivated; C073460:cefditoren