Evaluation of Ceftaroline Activity against Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate Methicillin-Resistant S. aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model: Exploring the “Seesaw Effect”
Werth, Brian J.
Steed, Molly E.
Kaatz, Glenn W.
Rybak, Michael J.
American Society for Microbiology
Scholarly/refereed, publisher version
MetadataShow full item record
A “seesaw effect” in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to β-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fCmax], 15.2 μg/ml; half-life [t1/2], 2.3 h) and vancomycin at 1 g q12h (targeted fCmax, 18 μg/ml; t1/2, 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ∼107 CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4× higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional β-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted.
Werth et al. "Evaluation of Ceftaroline Activity against Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate Methicillin-Resistant S. aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model: Exploring the “Seesaw Effect” ." Antimicrob. Agents Chemother. June 2013 vol. 57 no. 6 2664-2668 http://dx.doi.org/10.1128/AAC.02308-12
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.