In Vitro Profiling of Ceftaroline against a Collection of Recent Bacterial Clinical Isolates from across the United States

Ge, Yigong; Biek, Donald; Talbot, George H.; Sahm, Daniel F.

doi:10.1128/aac.00149-08

Cited by 125 publications

(109 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It exhibits bacterial killing against our laboratory-derived ampicillin-resistant E. faecium mutant that overproduces the wild-type PBP5. Such a profile differs from those of most E. faecium clinical isolates, which were reported as resistant to all ␤-lactams, including ceftaroline (6). Like other cephalosporins, ceftaroline is not indicated for treatment of enterococcal infections.…”

mentioning

confidence: 57%

“…It is inhibited by ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, which was recently approved by the U.S. Food and Drug Administration (FDA) for use in adult patients with acute bacterial skin and skinstructure infections and community-acquired bacterial pneumonia and more recently approved by the European Medicines Agency (EMA) for similar indications (10, 11). Previous studies have reported that ceftaroline had poor inhibitory activity against ␤-lactam-resistant E. faecium strains, all of which were expected to possess a PBP5 protein (6,12). To better understand these differences, we have characterized the interaction between a wild-type form of PBP5 and ceftaroline.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activity of Ceftaroline against Enterococcus faecium PBP5

Henry

Verlaine

Amoroso

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The opportunistic human pathogen Enterococcus faecium overproduces the low-affinity PBP5. In clinical strains, mutations in PBP5 further reduce its acylation rate by ␤-lactams. Previous studies have reported that ceftaroline had poor inhibitory activity against ␤-lactam-resistant E. faecium strains. In this study, we show that ceftaroline exhibits killing activity against our laboratory-derived ampicillin-resistant E. faecium mutant that overproduces a wild-type PBP5 and that ceftaroline inactivates PBP5 much faster than benzylpenicillin and faster than ceftobiprole. ␤ -Lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) represent the most important group of drugs prescribed to treat bacterial infections. They form stable acyl-enzymes with their targets, the membrane-bound D, D-transpeptidases, which are essential enzymes in peptidoglycan biosynthesis. These proteins are usually referred to as penicillin-binding proteins (PBPs) (1-3). The presence or overproduction of loweraffinity PBPs is responsible for the resistance of Gram-positive cocci against ␤-lactam antibiotics. It is known that the opportunistic human pathogen Enterococcus faecium overproduces the low-affinity PBP5 and that mutations further reduce the acylation rate of PBP5 by altering its amino acid sequence (4, 5). Ceftaroline is a cephalosporin with broad-spectrum activity against Grampositive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and many common Gram-negative bacteria except those producing extended-spectrum ␤-lactamase (ESBL) or AmpC ␤-lactamase (6-8). The Staphylococcus aureus low-affinity PBP2a is closely related to PBP5 (9). It is inhibited by ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, which was recently approved by the U.S. Food and Drug Administration (FDA) for use in adult patients with acute bacterial skin and skinstructure infections and community-acquired bacterial pneumonia and more recently approved by the European Medicines Agency (EMA) for similar indications (10, 11). Previous studies have reported that ceftaroline had poor inhibitory activity against ␤-lactam-resistant E. faecium strains, all of which were expected to possess a PBP5 protein (6,12). To better understand these differences, we have characterized the interaction between a wild-type form of PBP5 and ceftaroline.Ceftaroline MIC values determined by the microdilution method (13) for E. faecium D63r and D63 strains (5) were 2 and 0.25 mg · liter Ϫ1 , respectively. These values contrasted with those reported by others (10-12), who have found that most ampicillinresistant E. faecium clinical isolates were resistant to ceftaroline and concluded that ceftaroline had little activity against most isolates of E. faecium. The killing effects (14) of ceftaroline on E. faecium D63 and D63r strains were studied by exposing exponentially growing cultures of both strains to increasing concentrations of antibiotics corresponding to 1 and 4 times their respective MICs (Fig. 1). Ceftaroline showed k...

show abstract

mentioning

confidence: 57%

mentioning

confidence: 99%

Activity of Ceftaroline against Enterococcus faecium PBP5

Henry

Verlaine

Amoroso

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Ceftaroline fosamil, a prodrug, is rapidly converted via plasma phosphatase enzymes to its bioactive metabolite, ceftaroline (1). Ceftaroline exhibits broad-spectrum bactericidal in vitro activity against Grampositive organisms, including those with contemporary resistant Gram-positive phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae, as well as common Gram-negative pathogens (2,3). Like other ␤-lactam antimicrobials, the activity of ceftaroline is due to inhibition of penicillin-binding proteins, which are involved in the biosynthesis of the bacterial cell wall.…”

mentioning

confidence: 99%

Evaluation of the Effect of a Supratherapeutic Dose of Intravenous Ceftaroline Fosamil on the Corrected QT Interval

Riccobene¹,

Rekeda²,

Rank³

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (⌬⌬QTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ⌬⌬QTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ⌬⌬QTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

show abstract

“…Yine Avrupa ve Amerika'da komplike cilt enfeksiyonu etkeni olarak tanımlanan 246 MRSA suşunun dahil edildiği çalışmalarda ise MİK 50 , MİK 90 ve MİK aralığı sırasıyla 0.5 µg/ml, 0.5 µg/ml ve 0.25-2 µg/ml olarak bildirilmiştir 10,11 . Bu konuda yapılan diğer çalışmalarda seftarolin MİK 90 değerleri 0.5 µg/ml 12 , 1 µg/ml 13,14 ve 2 µg/ml [15][16][17] . Bizim çalışmamızda, cilt enfeksiyonlarından izole edilen MRSA suşları dışında kan ve solunum yolu kültürlerinden izole edilen suşlar da kullanılmıştır.…”

Section: Discussionunclassified