Azithromycin iv pharmacodynamic parameters predicting Streptococcus pneumoniae killing in epithelial lining fluid versus serum: an in vitro pharmacodynamic simulation.
OBJECTIVE
To investigate the azithromycin pharmacodynamic parameters predicting bacterial killing in epithelial lining fluid (ELF) versus serum against macrolide-susceptible and -resistant Streptococcus pneumoniae isolates (with different resistance genotypes), through the simulation of concentrations achieved after a 500 mg intravenous (iv) once a day regimen.


METHODS
An in vitro computer-controlled pharmacodynamic simulation of human azithromycin concentrations in serum and ELF was carried out, and colony counts were determined over 24 h. Four strains with MIC values (mg/L) of 0.5 [mef(A) and erm(B) negative], 2 [mef(A) positive and erm(B) negative], 8 [mef(A) positive and erm(B) negative] and 256 [mef(A) negative and erm(B) positive] were used.


RESULTS
Significant (P < 0.05) azithromycin antibacterial activity versus antibiotic-free controls was found in serum and ELF against the susceptible and mef(A) positive strains, but not against the erm(B) positive strain. AUC(0-24)/MIC values around or higher than 25 were needed to achieve (time to 99.9% reduction of initial inocula of around 6 h) and maintain (24 h inocula reduction > or =3 log(10)cfu/mL) bactericidal activity without regrowth. This was achieved only with the susceptible strain in serum, but also with the mef(A) positive strain exhibiting an MIC of 2 mg/L in ELF.


CONCLUSIONS
The results of this study support that the suggested breakpoint for susceptibility (< or =2 mg/L) may be adequate to predict S. pneumoniae eradication with ELF but not with serum concentrations obtained after a 500 mg iv once a day regimen.
Sevillano
David
D
Microbiological Department, School of Medicine, Universidad Complutense, Avda Complutense s/n, 28040 Madrid, Spain.
Alou
Luis
L
Aguilar
Lorenzo
L
Echevarría
Olatz
O
Giménez
María-José
MJ
Prieto
José
J
D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D017963:Azithromycin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D001826:Body Fluids / Q000378:metabolism*; D015169:Colony Count, Microbial; D003198:Computer Simulation; D024881:Drug Resistance, Bacterial; D004848:Epithelium; D007275:Injections, Intravenous; D008565:Membrane Proteins / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013296:Streptococcus pneumoniae / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C117866:MefA protein, Streptococcus; D008565:Membrane Proteins; D017963:Azithromycin; C111078:ErmTR protein, bacteria; D008780:Methyltransferases