Ceftaroline pharmacodynamic activity versus community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus, heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus using an in vitro model

An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5-to 4.0-log 10 -unit reductions in viable counts by 24 h with all strains and a 0.5-to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 g/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT MIC ) of 24.5% ؎ 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ؎ 9.5% was associated with a ؊1-log-unit drop, and one of 32.1% ؎ 8.1% was associated with a ؊2-log-unit drop. The MSSA and MRSA strains had similar fT MIC values. fT MIC values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT MIC . fT MIC s of <50% were associated with growth on 4؋ MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of <2 g/ml. An fT MIC of 25 to 30% would make a suitable pharmacodynamic index target, but fT MIC values of >50% are needed to suppress the emergence of resistance and require clinical evaluation. C eftaroline fosamil (CPT) has been approved by the U.S. FDA for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia: market authorization in the European Union (EU) for complicated skin and soft tissue infections and community-acquired pneumonia is pending.Ceftaroline fosamil (previously PP1-0903, T-91825, and TAK-599) is the prodrug of ceftaroline and is the first ␤-lactam with activity against methicillin-resistant Staphylococcus aureus (MRSA) marketed for clinical use in the United States. International surveillance studies conducted on MRSA strains in North America and the EU indicate that in the United States, the ceftaroline MIC 50 and MIC 90 are 1 and 1 g/ml, respectively, with 5.2% of strains having MICs of Ͼ1 g/ml. In contrast, in Europe the MIC 50 and MIC 90 are 1 and 2 g/ml, respectively, with 17.3% of strains having MICs of Ͼ1 g/ml. The FDA clinical breakpoint for susceptibility among S. aureus isolates is Յ1 g/ml (1, 2). The proposed European (EUCAST) clinical breakpoint has not yet been published, but a breakpoint similar to that used in the United States will present significant problems in laboratory testing of ceftaroline, as it will cut through the MRSA MIC distribution.Ceftar...

Section: Discussionsupporting

confidence: 69%

Pharmacodynamics of Ceftaroline against Staphylococcus aureus Studied in an In Vitro Pharmacokinetic Model of Infection

MacGowan

Noel

Tomaselli

et al. 2013

“…The in vivo efficacy of CPT against S. aureus infections at a high inoculum (10 9 CFU/infection site) has been reported previously in a murine thigh infection model (28), where the use of high inocula did not affect CPT efficacy against three staphylococcal strains tested, namely, MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous vancomycin-intermediate S. aureus (hVISA) strains. Moreover, Zhanel et al (29) evaluated the in vitro pharmacodynamics of a humanized regimen of CPT at 600 mg q12h for 96 h against MRSA, hVISA, and VISA isolates using an inoculum of 10 6 to 10 8 CFU/ml (30) and reported no inoculum effect. In this simulated pharmacodynamic model, which has been described in the literature as simulating the treatment of bacteremic infections over 48 h (31,32), CPT showed a greater reduction in CFU between 24 and 96 h (Ͼ5 log 10 CFU) than the comparators (vancomycin and daptomycin).…”

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

“…Ceftaroline fosamil, the prodrug form of ceftaroline, is approved for the treatment of community-acquired bacterial pneumonia (CABP) caused by methicillin-susceptible S. aureus (MSSA); however, the potential utility in the setting of MRSA pneumonia remains unknown. Several in vitro models of infection have demonstrated reliable bactericidal activity of human-simulated plasma concentrations of ceftaroline against MRSA isolates (7,8,9). Furthermore, ceftaroline therapy reduced the bacterial burden of MRSA in murine and rabbit pneumonia models compared with that in control animals (10,11).…”

mentioning

confidence: 99%

In Vitro Activity of Human-Simulated Epithelial Lining Fluid Exposures of Ceftaroline, Ceftriaxone, and Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus

MacVane

Nicolau

et al. 2014

bStaphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ϳ10 6 CFU/ml. Time-kill curves were constructed, and microbiological response (change in log 10 CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log 10 CFU/ml was largest for ceftaroline q8h (reductions of >3 log 10 CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log 10 CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log 10 CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log 10 CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia.