In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes

Mushtaq, Shazad; Warner, Marina; Ge, Yigong; Kaniga, Koné; Livermore, David M.

doi:10.1093/jac/dkm150

Cited by 127 publications

(106 citation statements)

References 28 publications

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“…No difference was observed for all tigecycline combina- carbapenem, and the next generation of cephalosporins with activity against MRSA, ceftobiprole and ceftaroline. At this point, none of these agents appear to have significant advantages over current antimicrobials for A. baumannii, but in vitro data for doripenem suggest a slight advantage over meropenem (175,275,378,379). Clinical data for doripenem against A. baumannii are still awaited.…”

Section: New Antimicrobialsmentioning

confidence: 99%

Acinetobacter baumannii : Emergence of a Successful Pathogen

2008

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SUMMARY Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

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Section: New Antimicrobialsmentioning

confidence: 99%

Acinetobacter baumannii : Emergence of a Successful Pathogen

2008

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“…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.…”

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confidence: 99%

Activity of Ceftaroline against Enterococcus faecium PBP5

Henry

Verlaine

Amoroso

et al. 2013

Antimicrob Agents Chemother

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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...

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“…In plasma, the prodrug is rapidly converted into active ceftaroline (formerly PPI-0903 M). Ceftaroline has potent activity against MRSA owing to high-affinity binding to penicillin binding protein 2a (10,17) and is also very active against drugresistant Streptococcus pneumoniae and bacteria with multiple resistance phenotypes (9,13,14,15). The in vivo efficacy of ceftaroline has been demonstrated using animal models (1,9,11,12) and in a phase 2 clinical trial of patients with complicated skin or skin structure infections (cSSSI) (16).…”

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confidence: 99%

In Vitro Antimicrobial Activity of a New Cephalosporin, Ceftaroline, and Determination of Quality Control Ranges for MIC Testing

Brown

Traczewski

2009

Antimicrob Agents Chemother

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The spectrum of activity of ceftaroline was evaluated against 1,247 bacterial isolates representing 44 different species or phenotypic groups. For the majority of species, the activity of ceftaroline was comparable or superior to that of ceftriaxone. MIC and/or disk diffusion quality control ranges of ceftaroline were determined for five standard ATCC reference strains.Ceftaroline fosamil (formerly PPI-0903 , an N-phosphono prodrug cephalosporin, is a novel, parenteral, bactericidal, anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin which displays a broad spectrum of activity against important community-and hospital-acquired gram-positive and gram-negative pathogens. In plasma, the prodrug is rapidly converted into active ceftaroline (formerly PPI-0903 M). Ceftaroline has potent activity against MRSA owing to high-affinity binding to penicillin binding protein 2a (10,17) and is also very active against drugresistant Streptococcus pneumoniae and bacteria with multiple resistance phenotypes (9,13,14,15). The in vivo efficacy of ceftaroline has been demonstrated using animal models (1,9,11,12) and in a phase 2 clinical trial of patients with complicated skin or skin structure infections (cSSSI) (16). Phase 3 clinical trials for ceftaroline for treatment of cSSSI were recently completed, and trials are in progress for community-associated pneumonia. Results from the CANVAS-1 trial for cSSSI demonstrated a good safety profile for ceftaroline and noninferiority in clinical cure rates to the combination of vancomycin and aztreonam (6).The present study was designed to compare the in vitro antibacterial activity of ceftaroline with those of ceftriaxone, levofloxacin, and imipenem against a broad range of bacterial pathogens for which ceftaroline might be considered for therapy and to propose MIC and/or disk diffusion quality control ranges for five aerobic quality control strains.A total of 1,247 recent clinical bacterial isolates were tested, which included 203 streptococci, 105 enterococci, 111 S. aureus isolates, 103 coagulase-negative staphylococci, 368 members of the Enterobacteriaceae, 108 nonfermentative gram-negative rods, 105 Haemophilus influenzae isolates, and 144 representatives of miscellaneous species. The majority (i.e., 78.7%) of these strains were recent (Ͻ3 years) clinical isolates from within the United States. The remaining strains were specifically selected in order to provide a challenge set of phenotypic resistance patterns. All organisms were tested by the broth microdilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) (3) using cation-adjusted Mueller-Hinton broth. The medium was supplemented with 3% lysed horse blood for testing of the streptococci or made up as Haemophilus test medium for testing of H. influenzae. All organisms were tested simultaneously by the disk diffusion method outlined by the CLSI (4) using Mueller-Hinton agar plus 5% sheep blood (streptococci), Haemophilus test medium agar (for H. influenzae), or plain Muller-Hinton a...

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In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes

Cited by 127 publications

References 28 publications

Acinetobacter baumannii : Emergence of a Successful Pathogen

Acinetobacter baumannii : Emergence of a Successful Pathogen

Activity of Ceftaroline against Enterococcus faecium PBP5

In Vitro Antimicrobial Activity of a New Cephalosporin, Ceftaroline, and Determination of Quality Control Ranges for MIC Testing

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