Animal models and PK/PD PD Examples with selected antibiotics
Examples of animal models Amoxicillin Amoxicillin-clavulanate Macrolides Quinolones
Andes D, Craig WA. AAC 199, :375 Amoxicillin in mouse thigh infection model Serum levels following 7 mg/kg subcutaneous dose in renally impaired mice 500-mg oral dose in normal human volunteers 0% of dosing interval (3. h)
Andes D, Craig WA. AAC 199, :375 Amoxicillin in mouse thigh infection model Serum levels following 7 mg/kg subcutaneous dose in renally impaired mice 500-mg oral dose in normal human volunteers 30% of dosing interval (. h)
Amoxicillin is effective at this dose against strains with MICs of up to mg/l Amox dosed at 7 mg/kg/ h Andes D, Craig WA. AAC 199, :375
Amoxicillin in mouse thigh infection model Serum levels following 7 mg/kg subcutaneous dose in renally impaired mice 500-mg oral dose in normal human volunteers 30% of dosing interval (. h) Andes D, Craig WA. AAC 199, :375 Amoxicillin is effective at this dose against strains with MICs of up to mg/l: 500 mg human dose tid Amox dosed at 7 mg/kg/ h therefore expected to be as effective or more effective Andes D, Craig WA. AAC 199, :375
Maximal bactericidal activity of amoxicillin and cefpodoxime with strains of S. pneumoniae in mouse thigh model 50 Time above MIC (% of dosing interval) 0 30 0 10 Amoxicillin Cefpodoxime 0.016 0.06 0.5 1 16 MIC (mg/l) Craig, W. 001
AMX/CA efficacy against S. pneumoniae Rat S. pneumoniae pneumonia model Log10 decrease in CFU/lung 6 5 3 1 0 AMX/CA MIC g/ml AMX/CA MIC g/ml AMX/CA MIC g/ml 90 mg/kg/d 35-0 mg/kg/d 000/15 mg bid 1000/15 mg tid 75/15 mg tid 75/15 mg bid 500/15 mg tid 15 0 5 30 35 0 5 50 55 60 65 T>MIC (% of dosing interval) Adapted from Berry et al. ICAAC 001, abstract B-9 and Woodnutt & Berry. Antimicrob Agents Chemother 1999;3:35 0
AMX/CA efficacy against S. pneumoniae Rat S. pneumoniae pneumonia model Log10 decrease in CFU/lung 6 5 3 1 0 AMX/CA MIC g/ml AMX/CA MIC g/ml AMX/CA MIC g/ml 90 mg/kg/d 35-0 mg/kg/d 000/15 mg bid 1000/15 mg tid 75/15 mg tid 75/15 mg bid 500/15 mg tid 15 0 5 30 35 0 5 50 55 60 65 T>MIC (% of dosing interval) Adapted from Berry et al. ICAAC 001, abstract B-9 and Woodnutt & Berry. Antimicrob Agents Chemother 1999;3:35 0
AMX/CA efficacy against S. pneumoniae Rat S. pneumoniae pneumonia model Log10 decrease in CFU/lung 6 5 3 1 0 AMX/CA MIC g/ml AMX/CA MIC g/ml AMX/CA MIC g/ml 90 mg/kg/d 35-0 mg/kg/d 000/15 mg bid 1000/15 mg tid 75/15 mg tid 75/15 mg bid 500/15 mg tid 15 0 5 30 35 0 5 50 55 60 65 T>MIC (% of dosing interval) Adapted from Berry et al. ICAAC 001, abstract B-9 and Woodnutt & Berry. Antimicrob Agents Chemother 1999;3:35 0
AMX/CA efficacy against S. pneumoniae Rat S. pneumoniae pneumonia model Log10 decrease in CFU/lung 6 5 3 1 0 AMX/CA MIC g/ml AMX/CA MIC g/ml AMX/CA MIC g/ml 90 mg/kg/d 35-0 mg/kg/d 000/15 mg bid 1000/15 mg tid 75/15 mg tid 75/15 mg bid 500/15 mg tid 15 0 5 30 35 0 5 50 55 60 65 T>MIC (% of dosing interval) Adapted from Berry et al. ICAAC 001, abstract B-9 and Woodnutt & Berry. Antimicrob Agents Chemother 1999;3:35 0
Log 10 decrease in CFU/lung Fluoroquinolone unbound AUC:MIC and bacterial killing Rat S. pneumoniae pneumonia model 6 5 3 1 0 GEM GAT MOX LEV CIP TRO -1 0 10 0 30 >0 -h unbound AUC:MIC ratio Berry et al. ICAAC 1999, abstract15; ICAAC 001 abstract B-990; J Antimicrob Chemother 000;5(Suppl. S1):7 93
S. pneumoniae and H. influenzae pneumonia in rats: ED 50 based on 3 log 10 reduction in cfu/lung 100 AZI SP ED50 (mg/kg/d) 10 CLARI SP AZI HI CLARI HI AZI, CLARI approved human dosing provides PK similar to approx. 5 mg/kg/d in this model 1 0.001 0.00 0.00 0.00 0.015 0.030 0.060 0.10 MIC ( g/ml) 0.50 0.500 1.000.000.000.000 Adapted from Mitten et al. Antimicrob Agents Chemother 001; 5: 55 593
S. pneumoniae and H. influenzae pneumonia in rats: ED 50 based on 3 log 10 reduction in cfu/lung 100 H. influenzae AZI SP Macrolide CLARI SP resistant S. ED50 (mg/kg/d) 10 AZI HI CLARI HI Macrolide susceptible S. pneumoniae pneumoniae (efflux) ED 50 of macrolide resistant (ribosomal methylase) S. pneumoniae: >100 mg/kg/d 1 0.001 0.00 0.00 0.00 0.015 0.030 0.060 0.10 MIC ( g/ml) 0.50 0.500 1.000.000.000.000 Adapted from Mitten et al. Antimicrob Agents Chemother 001; 5: 55 593
S. pneumoniae and H. influenzae pneumonia in rats: ED 50 based on 3 log 10 reduction in cfu/lung 100 AZI SP ED50 (mg/kg/d) 10 CLARI SP AZI HI CLARI HI AZI, CLARI at approved human dosing are effective against macrolide susceptible pneumococci, but are not effective against H. influenzae or macrolide resistant pneumococci 1 0.001 0.00 0.00 0.00 0.015 0.030 0.060 0.10 MIC ( g/ml) 0.50 0.500 1.000.000.000.000 Adapted from Mitten et al. Antimicrob Agents Chemother 001; 5: 55 593
Conclusions In vitro testing provides useful information that can be correlated with results of animal infection models and human infections Animal models can detect small differences in MICs based on correlations with appropriate PK/PD parameters (T>MIC or AUC:MIC ratio)