Evaluation of ceftaroline activity against heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycinintermediate methicillin-resistant S. aureus strains in an in vitro pharmacokinetic/pharmacodynamicmodel: exploring the ‘seesaw effect

A “seesaw effect ” in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to -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 vanco-mycin 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], 15.2g/ml; half-life [t1/2], 2.3 h) and vancomycin at 1 g q12h (targeted fCmax, 18g/ml; t1/2, 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed in-creased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of107 CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of pen-icillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic param-eters were 98 to 119 % of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respec-tively, 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 mu-tant strains. These data support the seesaw hypothesis that ceftaroline, like traditional -lactams, is more active against strain