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Invivo synergism between cefditoren and specific antibodies against a penicillin-resistant serotype 6B Streptococcus pneumoniae in a mice sepsis model

Abstract number: P1565

Cafini F., Gimenez M.J., Yuste J., Sevillano D., Aguilar L., Alou L., Torrico M., Gonzalez N., Prieto J., Coronel P.

Objective: To explore the in vivo effect of the presence of specific antibodies on the efficacy of cefditoren (CDN) treatment of sepsis caused by a serotype 6B S. pneumoniae isolate non-susceptible to b-lactams (penicillin and cefotaxime MIC of 2 mg/l, amoxicillin MIC of 4 mg/l).

Methods: CDN MIC for the infecting strain was 1 mg/l. Eight to 12 week old female BALB/c mice weighing 19–22 g were used. Hyperimmune serum (HS) was obtained from mice weekly inoculated with whole cell heat-inactivated inoculum for 5 weeks. All experiments were performed in groups of 5 animals inoculated with 2×107 cfu by intraperitoneal (i.p.) route. Animals were observed and deaths recorded for 7 days. The highest double dilution (1/2, 1/4, 1/6) of HS producing 0% survival (when single administered 1 h before inoculation of the infecting strain) and the highest CDN dose (6.25, 12.5, 25 and 50 mg/kg; three times daily for 48 h initiating subcutaneous treatment 1 h after inoculation) showing 0% survival of infected animals were determined in separate dose-ranging studies versus placebo. The HS dilution and CDN dose showing 0% survival of infected animals in separate experiments were combined to explore synergism: animals received an i.p. single administration of the HS dilution 1 h prior to inoculation, and CDN treatment (three times daily for 48 h) was initiated 1 h after inoculation.

In addition, for pharmacodynamic purposes, serum concentrations of CDN were measured in non-inoculated mice at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h and 8 h after a single dose administration of the minimal dose obtaining 100% survival in experiments with antibiotic administration alone. Two animals per timepoint were used. The percentage of the dosing interval that concentrations exceeded the MIC (T>MIC) was determined.

Results: The table shows %survival over time.

CDN 50 mg/kg provided a T>MIC of 33.4% of the dosing interval (8 h).

Conclusions: CDN showed 100% efficacy at doses of 50 mg/kg, with T>MIC of 33.4%. In the presence of antibodies, sub-therapeutic doses of CDN produced 100% survival in mice infected by a b-lactam non-susceptible serotype 6B strain, due to the synergistic action of CDN 12.5 mg/kg (0% survival alone) and HS 1/4 dilution (0% survival alone).

Experimental arm% Survival
 24 h48 hDay 7
Control (placebo)4000
HS 1/2 dilution804040
HS 1/4 dilution60200
CDN 50100100100
CDN 25404040
CDN 12.56000
CDN 12.5 + HS 1/4100100100

Session Details

Date: 10/04/2010
Time: 00:00-00:00
Session name: Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Vienna, Austria, 10 - 13 April 2010
Presentation type:
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