Importance of -Lactamase Inactivation in Treatment of Experimental Endocarditis Caused by Staphylococcus aureus

The efficacy of cefazolin or cefpirome alone or combined with rifampin was compared with that of vancomycin alone or combined with rifampin in an experimental model of methicillin-resistant, ␤-lactamaseproducing, coagulase-negative staphylococcal endocarditis. Phenotypically, the mecA gene-positive strain used in vivo did not exhibit methicillin resistance by the agar dilution or disk susceptibility method but was resistant in vitro (oxacillin MIC, 64 g/ml) by the microtiter dilution method with 2% NaCl supplementation. Macrodilution broth susceptibilities at standard inocula failed to demonstrate cross-resistance of staphylococci to cefazolin (MIC, 8 g/ml) or cefpirome (MIC, 4 g/ml). In vivo, vancomycin and cefpirome had similar activities, and both regimens were more effective than was cefazolin alone. While the MIC of rifampin was low (0.031 g/ml), monotherapy with rifampin resulted in a bimodal distribution of outcomes due to the expected emergence of resistant mutants. The results in vitro of time-kill synergy studies using rifampin in combination with cefazolin or cefpirome varied with the antimicrobial concentrations tested and did not reliably predict activities in vivo of rifampin-beta-lactam combination therapies. Cefpirome, but not cefazolin or vancomycin, in combination with rifampin was synergistic in vivo. Cefpirome in combination with rifampin was more effective than was cefazolin in combination with rifampin. Both cephalosporin-rifampin regimens were significantly more effective than was cephalosporin or vancomycin monotherapy and were as effective as vancomycin combined with rifampin. These data support further evaluation of rifampin-beta-lactam combinations as possible alternative therapies to vancomycin-containing regimens for selected methicillin-resistant coagulasenegative staphylococcal infections.

Section: Discussionmentioning

confidence: 82%

Effective treatment of cephalosporin-rifampin combinations against cryptic methicillin-resistant beta-lactamase-producing coagulase-negative staphylococcal experimental endocarditis

Brandt

Rouse

Tallan

et al. 1995

“…Studies of antibiotic therapy in animal models of S. aureus endocarditis have differed in showing that cefazolin is equivalent (5, 6) or inferior (11) in efficacy to cephalothin. Whereas the REH values of cefazolin and cephalothin by the type B and C ,-lactamases are comparable, the type A and D P-lactamases hydrolyze cefazolin about 25 times more efficiently than they do cephalothin (Table 4).…”

Section: Resultsmentioning

confidence: 99%

Characterization of four beta-lactamases produced by Staphylococcus aureus

Zygmunt

Stratton

Kernodle

1992

“…In one study, the in vivo effect of the CFZ InE was observed (39) for an MSSA strain, but in a second study using the same strain and animal model, the previous results could not be reproduced (40). High serum CFZ concentrations achieved in the first study and the use of different rabbit strains in the studies were cited as possible causes for these discrepancies (39,40).…”

Section: Discussionmentioning

confidence: 99%

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

Singh

Tran

Nannini

et al. 2017

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