Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis

Abstract

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in highinoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A ␤-lactamase (␤la)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its ␤la-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), 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 to Ն128 g/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log 10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log 10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P ϭ 0.001; CPT versus NAF, P ϭ 0.9830). Both CFZ and CPT were efficacious against the ␤la-cured derivative, TX0117c, compared to time zero (t 0 ) (P ϭ Ͻ0.0001 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 considered for highinoculum infections caused by MSSA exhibiting the CFZ InE.KEYWORDS ␤-lactamase, Staphylococcus aureus, ceftaroline, endocarditis S taphylococcus aureus continues to be a leading cause of bacterial infections worldwide, including skin and soft tissue infections, bacteremia, pneumonia, endocarditis, septic arthritis, and osteomyelitis (1-3). The prevalence of methicillin-susceptible S. aureus (MSSA) isolates exhibiting the cefazolin (CFZ) inoculum effect (InE) in the United States has been reported to range from 19% to 27% (4, 5). Besides the United States, the overall prevalence of the cefazolin InE was reported to be 36% in South America (Colombia, Ecuador, Peru, and Venezuela), where MSSA ␤-lactamase (␤la) type A and type C were 66% and 31%, respectively (6). In South Korea, the blaZ gene was detected in 92% of 220 MSSA isolates studied, and a pronounced cefazolin InE was observed in 13%, most of which (79%) expressed type A ␤-lactamase (7). More recently, a study

Bistable Bacterial Growth Dynamics in the Presence of Antimicrobial Agents

“…In a therapeutic context, this means that the fate of an initial infection depends on the initial load of bacteria—while small infections are easily cleared even with no antibiotics, large infections are hazardous, even when antibiotics are administered at high doses. This phenomenon, known as the “inoculum effect” (IE), is well established in-vitro [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ], as well as in-vivo in animal models and in human patients [ 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Cefazolin Inoculum Effect and Methicillin-Susceptible Staphylococcus aureus Osteoarticular Infections in Children

“…As early as the 1970s, a subset of MSSA isolates was noted to exhibit striking elevations in 1GC MICs when a greater than standard inoculum was used in susceptibility testing (15,16). This phenomenon, which affects 1GCs (including cefazolin and cephalexin) but not nafcillin/oxacillin, is referred to as the cephalosporin (or cefazolin) inoculum effect (CzIE) (17,18). In a recent study of Argentinian adults with MSSA bacteremia treated with 1GC, it was noted that CzIE was an independent predictor of 30-day all-cause mortality (9).…”

Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis

“…It is assumed that clinical failures occur as a consequence of strains possessing the CzIE at a high bacterial burden at the site of infection. In a previously described experimental model of endocarditis in rats, an MSSA isolate positive for the CzIE was associated with significantly higher bacterial counts in vegetations when treated with cefazolin compared to those with nafcillin, ceftaroline, or daptomycin (12,13). Furthermore, prospective observational data on the use of cefazolin in patients with MSSA bacteremia where the presence of the CzIE was assessed demonstrated that CzIE-positive isolates were associated with a significant increase in therapeutic failure and mortality (14,15).…”