CHRISTIANSON J, ANDES D, CRAIG W; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. A-1103.
Univ.of Wisconsin and VA Hosp., Madison, WI
BACKGROUND: Doxycycline is recommended in several treatment guidelines for the treatment of respiratory tract infections. We used the neutropenic murine thigh-infection model to characterize which PK/PD parameter was predictive of the in-vivo activity of doxycycline against the respiratory pathogen S. pneumoniae (SP).METHODS: Doxycycline serum kinetics in mice were determined using a microbiologic assay. Mice had 10[6.7-7.2] CFU/thigh of S. pneumoniae ATCC 10813 when treated with saline or doxycycline at 2.4-640 mg/kg fractionated for 6-, 12-, and 24-h dosing. Non-linear regression analysis was used to determine with PK/PD parameter best correlated with efficacy after 24-h of therapy. The total doses required to produce a net bacteriostatic effect at each dosing interval against the various strains were determined using an Emax dose-response model. RESULTS: At a subcutaneous dose of 10 mg/kg doxycycline produced a peak level of 1.35 mg/L, an AUC/dose of 0.89, and had a half-life of 2.59 h. Serum protein binding in mice was 88%. The MIC of doxycycline against the pneumococcal isolate studied was 0.03 mg/L. Saline treated controls died within 24-h, and organism burden in thighs increased 2.25 log[10]. Maximum killing by doxycycline was 4.1 log[10] cfu/thigh over the 24-h treatment period. The 24-h AUC/MIC ratio most highly correlated with efficacy (AUC/MIC R[2]=90%, Peak/MIC R[2]=80%, Free-drug T>MIC R[2]=67%). As shown below, the dosing interval did not have a significant effect (ANOVA p-value=1.00) on the total doses required for a static effect. [table: see text] CONCLUSIONS: The 24-h AUC/MIC is the PK/PD parameter that best predicts the in-vivo activity of doxycycline against S. pneumoniae.
Publication Types:
Keywords:
- Animals
- Area Under Curve
- Humans
- Mice
- Microbial Sensitivity Tests
- Models, Biological
- Muridae
- Neutropenia
- Streptococcus pneumoniae
- pharmacokinetics
- pharmacology
Other ID:
UI: 102270589
From Meeting Abstracts