Efficacy of Ceftaroline in a Rat Model of Endocarditis Against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High Inoculum Effect [PublishAheadOfPrint]

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ), which has been associated with therapeutic failures in high inoculum infections. We assessed the in vitro activity of ceftaroline (CPT), CFZ and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117 that exhibits the CFZ InE and its β-lactamase (βla)-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg and evaluated the activity of CPT (40 mg/kg, Q 8 h), CFZ and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF whereas a marked InE was detected for CFZ (MIC 8 - ≥ 128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log₁₀ CFU/gm in vegetations, respectively, compared to a mean of 5.9 log₁₀ CFU/gm in the CFZ treated group (CPT and NAF vs CFZ, P = 0.001; CPT vs NAF, P = 0.9830). Both CFZ and CPT were efficacious against βla-cured derivative TX0117c compared to T=0 (P= <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be a consideration for high-inoculum infections caused by MSSA exhibiting the CFZ InE.

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