title: Observation of "seesaw effect" with vancomycin, teicoplanin, daptomycin and ceftaroline in 150 unique MRSA strains.
abstract: BACKGROUND
  Vancomycin (VAN) failures associated with the treatment of complicated methicillin-resistant Staphylococcus aureus (MRSA) infections have been well described. The reported "seesaw effect" demonstrates improved β-lactam activity when VAN and/or daptomycin (DAP) susceptibility decreases. However, there are minimal data comparing ceftaroline (CPT) susceptibility with these agents or teicoplanin (TEI). Therefore, to further explore the seesaw effect, we evaluated the relationship between CPT and VAN, TEI, and DAP susceptibilities.
  
  
  METHODS
  One hundred and fifty clinical MRSA isolates from the Anti-Infective Research Laboratory (Detroit, MI, USA) from 2008 to 2012 were analyzed. VAN, TEI, DAP and CPT minimum inhibitory concentrations (MIC) were determined via Etest methodology. MIC50 and MIC90 were calculated for each antibiotic. Additionally, four isogenic strain pairs were randomly selected for evaluation by time-kill methodology for the potential of enhanced killing by CPT as MICs increased to VAN, TEI, and DAP.
  
  
  RESULTS
  CPT MICs were inversely correlated with VAN, DAP, and TEI MICs with correlation coefficients of -0.535, -0.483, and -0.386, respectively (P ≤ 0.05). Comparison of the MIC relationship for glycopeptides and lipopeptides resulted in a positive correlation for all agent combinations. In time-kill evaluations, CPT demonstrated greater reductions in log10 colony-forming unit (CFU)/mL against mutant strains (3.73 ± 0.67) versus parents (2.79 ± 0.75) despite no change in CPT MIC (P = 0.112).
  
  
  CONCLUSIONS
  This study demonstrated a marked "seesaw effect" whereby CPT displayed increased susceptibility as the VAN, DAP, and TEI MICs increased. Additionally, we observed a positive linear correlation between VAN, DAP, and TEI MICs for all agent combinations. Enhanced activity was noted with CPT in mutant strains versus the parent strains despite no change in MIC. Based upon the enhanced CPT activity observed against strains with decreased susceptibility to VAN, DAP and TEI, CPT may provide an option for infections with reduced susceptibility to glycopeptides or lipopeptides. Further evaluation is warranted to investigate the clinical implications of the seesaw effect.
authors.affiliation: Anti-Infective Research Laboratory, Pharmacy Practice-4148, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI, 48201, USA.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Barber
authors.forename: Cortney E
authors.initials: CE
authors.lastname: Ireland
authors.forename: Natalia
authors.initials: N
authors.lastname: Bukavyn
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak