Telavancin and vancomycin pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model.
OBJECTIVE
The aim of this study was to compare the pharmacodynamics of telavancin (TLV) and vancomycin (VAN) with Staphylococcus aureus. Their concentrations were simulated between the MIC and the mutant prevention concentration (MPC), and above the MPC.


METHODS
Two strains of S. aureus, glycopeptide-intermediate S. aureus (GISA) Mu-50 and ATCC 43300, were exposed for 5 days to once-daily TLV (half-life 8 h) and twice-daily VAN (half-life 6 h). The simulated ratios of 24 h area under the curve (AUC(24)) to MIC varied from 30-50 to 3400 h. The cumulative antimicrobial effect was expressed by ABBC (area between the level corresponding to the starting inoculum and the time-kill curve calculated from time 0 to 144 h).


RESULTS
With each antibiotic, the ABBC versus log AUC(24)/MIC relationships were bacterial strain-independent. A sigmoid model fits combined data on both organisms exposed to TLV (r(2)=0.78) or VAN (r(2)=0.85). Comparable effects of the proposed therapeutic dose of TLV (10 mg/kg) and a clinical dose of VAN (2x1 g) were predicted for MRSA ATCC 43300 (AUC(24)/MIC 3400 and 500 h, respectively) and a 1.6-fold greater effect of TLV for GISA Mu-50 compared with VAN (AUC(24)/MIC 1700 and 130 h, respectively). Mutants of S. aureus ATCC 43300 resistant to 2x and 4x MIC of VAN but not TLV were enriched in these simulations. No selection of TLV- and VAN-resistant mutants of GISA Mu-50 was observed.


CONCLUSIONS
These in vitro data suggest that the effects of clinically attainable AUC/MIC ratios of TLV are similar to those of VAN on S. aureus 43300 and 2-fold greater on GISA Mu-50.
Lubenko
Irene Yu
IY
Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
Strukova
Elena V
EV
Smirnova
Maria V
MV
Vostrov
Sergey N
SN
Portnoy
Yury A
YA
Zinner
Stephen H
SH
Firsov
Alexander A
AA
D000617:Aminoglycosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D015169:Colony Count, Microbial; D066298:In Vitro Techniques; D000077427:Lipoglycopeptides; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D015233:Models, Statistical; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors; D014640:Vancomycin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; D014640:Vancomycin; C487637:telavancin