Enhanced In Vivo Activity of Cefditoren in Pre-Immunized Mice against Penicillin-Resistant S. pneumoniae

• Published in: PloS one Vol. 5; no. 8; p. e12041
• Main Authors: Cafini, Fabio, Yuste, Jose, Giménez, Maria-Jose, Sevillano, David, Aguilar, Lorenzo, Alou, Luis, Ramos-Sevillano, Elisa, Torrico, Martha, González, Natalia, García, Ernesto, Coronel, Pilar, Prieto, Jose
• Format: Journal Article
• Language: English
• Published: Public Library of Science 10.08.2010
• Subjects: Analysis; Antibodies; Health aspects; Pneumonia; Protein binding
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012041

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. We used three pneumococcal isolates (serotype, MIC of CDN): Strain 1 (6B, 1 [micro]g/ml), Strain 2 (19F, 2 [micro]g/ml) and Strain 3 (23F, 4 [micro]g/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 [almost equal to]35% (total) and [almost equal to]19% (free) were associated with 100% survival. Significant differences in survival were found between HS-np alone ([less than or equal to]20%) or CDN-np alone ([less than or equal to]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. In mice (CDN protein binding similar to humans) total t>MIC values of [almost equal to]35% ([almost equal to]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.