Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity

bThis study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-␤-lactam ␤-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option.

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confidence: 99%

Single- and Multiple-Dose Study To Determine the Safety, Tolerability, and Pharmacokinetics of Ceftaroline Fosamil in Combination with Avibactam in Healthy Subjects

Riccobene¹,

Su²,

Rank³

2013

“…Its bioactive form, ceftaroline, is rapidly released in vivo upon hydrolysis of the phosphonate group (1,3,20,23). The spectrum of activity for ceftaroline includes major pathogens found in acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), including the ESKAPE pathogen S. aureus.…”

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confidence: 99%

“…The spectrum of activity for ceftaroline includes major pathogens found in acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), including the ESKAPE pathogen S. aureus. Ceftaroline has high affinity for PBP2a, the altered PBP responsible for methicillin and thus ␤-lactam resistance in S. aureus (3,16,20).…”

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confidence: 99%

Summary of Ceftaroline Activity against Pathogens in the United States, 2010: Report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Surveillance Program

Flamm

Sader

Farrell

et al. 2012

The Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program is a sentinel resistance monitoring system designed to track the activity of ceftaroline and comparator agents. In the United States, a total of 8,434 isolates were collected during the 2010 surveillance program from 65 medical centers distributed across the nine census regions (5 to 10 medical centers per region). All organisms were isolated from documented infections, including 3,055 (36.2%) bloodstream infections, 2,282 (27.1%) respiratory tract infections, 1,965 (23.3%) acute bacterial skin and skin structure infections, 665 (7.9%) urinary tract infections, and 467 (5.5%) miscellaneous other infection sites. Ceftaroline was the most potent ␤-lactam agent tested against staphylococci. The MIC 90 values were 1 g/ml for methicillin-resistant Staphylococcus aureus (MRSA; 98.4% susceptible) and 0.5 g/ml for methicillin-resistant coagulase-negative staphylococci (CoNS). Ceftaroline was 16-to 32-fold more potent than ceftriaxone against methicillin-susceptible staphylococcal strains. All staphylococcus isolates (S. aureus and CoNS) were inhibited at ceftaroline MIC values of <2 g/ml. Ceftaroline also displayed potent activity against streptococci (MIC 90 , 0.015 g/ml for beta-hemolytic streptococci; MIC 90 , 0.25 g/ml for penicillin-resistant Streptococcus pneumoniae). Potent activity was also shown against Gram-negative pathogens (Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Furthermore, wild-type strains of Enterobacteriaceae (non-extended-spectrum ␤-lactamase [ESBL]-producing strains and non-AmpC-hyperproducing strains) were often susceptible to ceftaroline. Continued monitoring through surveillance networks will allow for the assessment of the evolution of resistance as this new cephalosporin is used more broadly to provide clinicians with up-to-date information to assist in antibiotic stewardship and therapeutic decision making.

“…Ceftaroline has anti-MRSA activity because structural differences allow high binding affinity to the mecA-encoded PBP2a (9,10,16). The U.S. Food and Drug Administration (FDA) granted marketing authorization for Teflaro (ceftaroline fosamil) in October 2010 for the treatment of acute bacterial skin and skin structure infections (including those caused by MRSA and methicillin-susceptible S. aureus [MSSA]) and community-acquired bacterial pneumonia (including those caused by MSSA but not those caused by MRSA) (1). Pharmacokinetic/pharmacodynamic (PK/PD) data predicted organisms with a ceftaroline MIC of Յ2 g/ml could be effectively treated by intravenous infusion of 600 mg every 12 h (23).…”

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confidence: 99%

Activity of Ceftaroline and Epidemiologic Trends in Staphylococcus aureus Isolates Collected from 43 Medical Centers in the United States in 2009

Richter

Heilmann

Dohrn

et al. 2011

A Staphylococcus aureus surveillance program was initiated in the United States to examine the in vitro activity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 from 43 medical centers. All isolates were screened for mecA by PCR and evaluated by pulsed-field gel electrophoresis. Methicillin-resistant S. aureus (MRSA) were analyzed for Panton-Valentine leukocidin (PVL) genes and the staphylococcal cassette chromosome mec (SCCmec) type. All isolates had ceftaroline MICs of <2 g/ml with an MIC 50 of 0.5 and an MIC 90 of 1 g/ml. The overall resistance rates, expressed as the percentages of isolates that were intermediate and resistant (or nonsusceptible), were as follows: ceftaroline, 1.0%; clindamycin, 30.2% (17.4% MIC > 4 g/ml; 12.8% inducible); daptomycin, 0.2%; erythromycin, 65.5%; levofloxacin, 39.9%; linezolid, 0.02%; oxacillin, 53.4%; tetracycline, 4.4%; tigecycline, 0%; trimethoprim-sulfamethoxazole, 1.6%; vancomycin, 0%; and high-level mupirocin, 2.2%. The mecA PCR was positive for 53.4% of the isolates. The ceftaroline MIC 90 s were 0.25 g/ml for methicillin-susceptible S. aureus and 1 g/ml for MRSA. Among the 2,247 MRSA isolates, 51% were USA300 (96.9% PVL positive, 99.7% SCCmec type IV) and 17% were USA100 (93.4% SCCmec type II). The resistance rates for the 1,137 USA300 MRSA isolates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6% (6.2% MIC > 4 g/ml; 1.4% inducible); tetracycline, 3.3%; trimethoprim-sulfamethoxazole, 0.8%; high-level mupirocin, 2.7%; daptomycin, 0.4%; and ceftaroline and linezolid, 0%. USA300 is the dominant clone causing MRSA infections in the United States. Ceftaroline demonstrated potent in vitro activity against recent S. aureus clinical isolates, including MRSA, daptomycinnonsusceptible, and linezolid-resistant strains.