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. 2013 Jun;57(6):2664-8.
doi: 10.1128/AAC.02308-12. Epub 2013 Apr 1.

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"

Brian J Werth  1 , Molly E Steed, Glenn W Kaatz, Michael J Rybak
Affiliations

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"

Brian J Werth et al. Antimicrob Agents Chemother. 2013 Jun.

Abstract

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 [fC(max)], 15.2 μg/ml; half-life [t(1/2)], 2.3 h) and vancomycin at 1 g q12h (targeted fC(max), 18 μg/ml; t(1/2), 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 ~10(7) 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.

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Figures

Fig 1
Fig 1
Activity of simulated drug regimens tested against each isogenic strain pair in the in vitro hollow fiber PK/PD model.
Fig 2
Fig 2
Ceftaroline population analysis profile for various strains tested in this study. Shown are the ceftaroline population analysis profiles for Mu3 (hVISA; VAN MIC, 2 μg/ml; CPT MIC, 2 μg/ml), JH1 (VSSA; VAN MIC, 1 μg/ml; CPT MIC, 0.5 μg/ml), JH9 (VISA; VAN MIC, 8 μg/ml; CPT MIC, 0.5 μg/ml), R6911 (hVISA; VAN MIC, 2 μg/ml; CPT MIC, 0.5 μg/ml), R6913 (VISA; VAN MIC, 4 μg/ml; CPT MIC, 0.5 μg/ml), T51643 (VSSA; VAN MIC, 1 μg/ml; CPT MIC, 1 μg/ml), and H9749-2 (hVISA; VAN MIC, 2 μg/ml; CPT MIC, 1 μg/ml).
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