examples with selected antibiotics

Amoxicillin iseffective at thisdose againststrains with MICsof up to 2 mg/LAmox dosed at 7 mg/kg/8 hAndes D, Craig WA. AAC 1998, 42:2375

Amoxicillin in mouse thigh infection modelSerum levels following◦ 7 mg/kg subcutaneousdose in renally impairedmice• 500-mg oral dose in normalhuman volunteers30% ofdosinginterval(2.4 h)Andes D, Craig WA. AAC 1998, 42:2375Amoxicillin is effective atthis dose against strainswith MICs of up to 2 mg/L:500 mg human dose tidAmox dosed at 7 mg/kg/8 htherefore expected to beas effective or moreeffectiveAndes D, Craig WA. AAC 1998, 42:2375

Maximal bactericidal activity of amoxicillin andcefpodoxime with strains of S. pneumoniae inmouse thigh model50Time above MIC(% of dosing interval)40302010AmoxicillinCefpodoxime0.016 0.06 0.25 1 4 16MIC (mg/L)Craig, W. 2001

AMX/CA efficacy against S. pneumoniaeRat S. pneumoniae pneumonia modelLog10 decrease in CFU/lung6543210248AMX/CA MIC 2 g/mlAMX/CA MIC 4 g/mlAMX/CA MIC 8 g/ml22290 mg/kg/d35-40 mg/kg/d22000/125 mg bid1000/125 mg tid875/125 mg tid875/125 mg bid500/125 mg tid15 20 25 30 35 40 45 50 55 60 65T>MIC (% of dosing interval)Adapted from Berry et al. ICAAC 2001, abstract B-988 andWoodnutt & Berry. Antimicrob Agents Chemother 1999;43:35–40

AMX/CA efficacy against S. pneumoniaeRat S. pneumoniae pneumonia modelLog10 decrease in CFU/lung6543210248AMX/CA MIC 2 g/mlAMX/CA MIC 4 g/mlAMX/CA MIC 8 g/ml4444 490 mg/kg/d35-40 mg/kg/d42000/125 mg bid1000/125 mg tid875/125 mg tid875/125 mg bid500/125 mg tid15 20 25 30 35 40 45 50 55 60 65T>MIC (% of dosing interval)Adapted from Berry et al. ICAAC 2001, abstract B-988 andWoodnutt & Berry. Antimicrob Agents Chemother 1999;43:35–40

AMX/CA efficacy against S. pneumoniaeRat S. pneumoniae pneumonia modelLog10 decrease in CFU/lung65432102488AMX/CA MIC 2 g/mlAMX/CA MIC 4 g/mlAMX/CA MIC 8 g/ml88890 mg/kg/d35-40 mg/kg/d2000/125 mg bid1000/125 mg tid875/125 mg tid875/125 mg bid500/125 mg tid15 20 25 30 35 40 45 50 55 60 65T>MIC (% of dosing interval)Adapted from Berry et al. ICAAC 2001, abstract B-988 andWoodnutt & Berry. Antimicrob Agents Chemother 1999;43:35–40

AMX/CA efficacy against S. pneumoniaeRat S. pneumoniae pneumonia modelLog10 decrease in CFU/lung65432102488AMX/CA MIC 2 g/mlAMX/CA MIC 4 g/mlAMX/CA MIC 8 g/ml244 884822 4 490 mg/kg/d35-40 mg/kg/d422000/125 mg bid1000/125 mg tid875/125 mg tid875/125 mg bid500/125 mg tid15 20 25 30 35 40 45 50 55 60 65T>MIC (% of dosing interval)Adapted from Berry et al. ICAAC 2001, abstract B-988 andWoodnutt & Berry. Antimicrob Agents Chemother 1999;43:35–40

Log 10decrease in CFU/lungFluoroquinolone unboundAUC:MIC and bacterial killingRat S. pneumoniae pneumonia model6543210GEMGATMOXLEVCIPTRO-10 10 20 30 >4024-h unbound AUC:MIC ratioBerry et al. ICAAC 1999, abstract1548; ICAAC 2001 abstract B-990;J Antimicrob Chemother 2000;45(Suppl. S1):87–93

S. pneumoniae and H. influenzae pneumonia in rats:ED 50based on 3 log 10reduction in cfu/lung100AZI SPED50 (mg/kg/d)10CLARI SPAZI HICLARI HIAZI, CLARI approved human dosing provides PKsimilar to approx. 25 mg/kg/d in this model10.0010.0020.0040.0080.0150.0300.0600.120MIC (g/ml)0.2500.5001.0002.0004.0008.000Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

S. pneumoniae and H. influenzae pneumonia in rats:ED 50based on 3 log 10reduction in cfu/lung100H. influenzaeAZI SPMacrolideCLARI SPresistant S.ED50 (mg/kg/d)10AZI HICLARI HIMacrolide susceptibleS. pneumoniaepneumoniae(efflux)ED 50 of macrolide resistant(ribosomal methylase) S.pneumoniae: >100 mg/kg/d10.0010.0020.0040.0080.0150.0300.0600.120MIC (g/ml)0.2500.5001.0002.0004.0008.000Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

S. pneumoniae and H. influenzae pneumonia in rats:ED 50based on 3 log 10reduction in cfu/lung100AZI SPED50 (mg/kg/d)10CLARI SPAZI HICLARI HIAZI, CLARI at approved human dosing areeffective against macrolide susceptiblepneumococci, but are not effective against H.influenzae or macrolide resistant pneumococci10.0010.0020.0040.0080.0150.0300.0600.120MIC (g/ml)0.2500.5001.0002.0004.0008.000Adapted from Mitten et al. Antimicrob Agents Chemother 2001; 45: 2585–2593

ConclusionsIn vitro testing provides usefulinformation that can be correlated withresults of animal infection models andhuman infectionsAnimal models can detect smalldifferences in MICs based oncorrelations with appropriate PK/PDparameters (T>MIC or AUC:MIC ratio)