Binding of Faropenem and Other β-Lactam Agents to Penicillin-Binding Proteins of Pneumococci with Various β-Lactam Susceptibilities

Kosowska-Shick, Klaudia; McGhee, Pamela; Appelbaum, Peter C.

doi:10.1128/aac.01566-08

Cited by 9 publications

(6 citation statements)

References 27 publications

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“…As expected, the penicillin G-susceptible strain 1076 had no changes in the penicillin-binding domains of PBP1A (99% homology to strain R6), -2X (99% homology to strain R6), or -2B (96% homology to strain R6), which are known to be associated with ␤-lactam resistance or effects on PBP binding (2,3,31,34,46,57).…”

Section: Vol 54 2010 Ceftaroline Affinity For Gram-positive Pbps 1671mentioning

confidence: 89%

“…The IC 50 s of ceftaroline for PBP3 ranged from 0.1 to 0.25 g/ml, similar to those of comparators, although S. pneumoniae PBP3 has not been implicated in the killing action of ␤-lactam antibiotics (59). Ceftaroline showed the same or improved affinity for PBP2B relative to those of cefotaxime and ceftriaxone (Table 3), despite the presence of a T446A substitution in all penicillin-resistant strains (34). In penicillin-resistant strain 24, the ceftaroline MIC was 0.25 g/ml, 2-to 4-fold lower than those of cefotaxime and ceftriaxone, with the same affinity for PBP2X (IC 50 ϭ 1 g/ml).…”

Section: Vol 54 2010 Ceftaroline Affinity For Gram-positive Pbps 1671mentioning

confidence: 99%

“…All sequences obtained for pbp1A (nucleotides 870 to 1950), encoding 350 amino acids, pbp2B (nucleotides 655 to 2028), encoding 458 amino acids, pbp2X (nucleotides 301 to 2034), encoding 578 amino acids, and pbp3 (nucleotides 1 to 1242), encoding 413 amino acids, have been described previously (32,34). Their respective GenBank accession numbers are listed in Table 3.…”

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Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Kosowska-Shick

McGhee

Appelbaum

2010

Antimicrob Agents Chemother

160

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We compared the affinities of ceftaroline for all penicillin-binding proteins (PBPs) with those of ceftriaxone and cefotaxime in 6 Staphylococcus aureus and 7 Streptococcus pneumoniae isolates with various resistance phenotypes. Ceftaroline MICs were <1 g/ml against all S. aureus isolates and were <0.25 g/ml for 4 of 7 isolates of S. pneumoniae. Ceftaroline affinities for penicillin-susceptible S. pneumoniae strains were in the order PBP2X and -3 > PBP1A, -1B, and -2A > PBP2B, and ceftaroline had >4-fold higher 50% inhibitory concentrations (IC 50 s) (0.1 to 4 g/ml) for PBP2X, -2A, -2B, and -3 than those for the other cephalosporins tested. Among 3 penicillin-resistant S. pneumoniae strains, ceftaroline had a high affinity for PBP2X (IC 50 , 0.1 to 1 g/ml), a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B (IC 50 , 0.5 to 4 g/ml) and PBP1A (IC 50 , 0.125 to 0.25 g/ml) as well, both of which are also known as major targets for PBP binding activity of cephalosporins. Ceftaroline PBP affinities in methicillin-susceptible S. aureus strains were greater than or equal to those of the 3 other ␤-lactams tested. Ceftaroline bound to PBP2a in methicillinresistant S. aureus (IC 50 , 0.01 to 1 g/ml) with up to 256-fold-higher affinity than those of other agents. Ceftaroline demonstrated very good PBP affinity against all S. aureus and S. pneumoniae strains tested, including resistant isolates.␤-Lactam antibiotics exert their antibacterial effect through covalent interactions with penicillin-binding proteins (PBPs), thus blocking the terminal step in cell wall biosynthesis. ␤-Lactam resistance in Streptococcus pneumoniae is usually caused by amino acid substitutions in the penicillin-binding domains of 1 or more of its 6 PBPs, resulting from point mutations or mosaic genes following recombination (21)(22)(23)35). Altered PBP1A, PBP2X, and PBP2B are the most important PBPs for ␤-lactam resistance among clinical pneumococcal isolates (2,3,31,46,57).In staphylococci, PBPs 1, 2, and 3, which have high affinities for most ␤-lactam antibiotics, are essential for cell growth and survival of methicillin-susceptible strains. Binding of ␤-lactams by these PBPs is lethal (6). Low-molecular-weight PBP4, although it may be important in normal cell wall synthesis and may participate to a limited extent in resistance, is not considered a critical target and may be dispensable (17,41). Methicillin resistance in methicillin-resistant staphylococci (MRSA) is due to expression of a special PBP, PBP2a, which is not present in methicillin-susceptible staphylococci (6,58,59).Ceftaroline fosamil is the developmental intravenous prodrug form of the broad-spectrum cephalosporin ceftaroline (formerly called PPI-0903 M or TAK-91825), which is active against MRSA and has a high affinity for PBP2a (PBP2Ј). It is also active against streptococci, including S. pneumoniae (3,15,16,43,45).In the current study, we determined the affinities of ceftaroline, ceftriaxone, cefotaxime, and penicillin G for PBPs from 6Staphyloco...

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Section: Vol 54 2010 Ceftaroline Affinity For Gram-positive Pbps 1671mentioning

confidence: 89%

Section: Vol 54 2010 Ceftaroline Affinity For Gram-positive Pbps 1671mentioning

confidence: 99%

mentioning

confidence: 99%

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Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Kosowska-Shick

McGhee

Appelbaum

2010

Antimicrob Agents Chemother

160

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“…They have a long history of use, demonstrating both safety and efficacy over a broad range of infections and organisms. However, as frequently occurs with large-scale and long-term use of antimicrobials, there has been a selection for variant strains of bacteria with altered ␤-lactamases and/or altered drug targets (penicillin binding proteins [PBPs]) (5,12,18,19,25,26,28). This selection has limited the utility of this well-known and versatile class of antibiotics (2,4,13,17,22,24).…”

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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

Antimicrob Agents Chemother

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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.

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“…1A ). BLAST searches revealed one Romanian isolate, HMC3243, of unknown serotype ( 28 ) which was partially identical to D219 up to codon 517, whereas the C-terminal part represented R6 sequences ( Fig. 1A and B ).…”

Section: Resultsmentioning

confidence: 99%

Long Persistence of a Streptococcus pneumoniae 23F Clone in a Cystic Fibrosis Patient

Rieger

Mauch

Hakenbeck

2017

mSphere

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Streptococcus pneumoniae is a common resident in the human nasopharynx. However, carriage can result in severe diseases due to a unique repertoire of pathogenicity factors that are rare in closely related commensal streptococci. We investigated a penicillin-resistant S. pneumoniae clone of serotype 23F isolated from a cystic fibrosis patient on multiple occasions over an unusually long period of over 3 years that was present without causing disease. Genome comparisons revealed an apparent nonfunctional pneumococcus-specific gene encoding a hyaluronidase, supporting the view that this enzyme adds to the virulence potential of the bacterium. The 23F clone harbored unique mosaic genes encoding penicillin resistance determinants, the product of horizontal gene transfer involving the commensal S. mitis as donor species. Sequences identical to one such mosaic gene were identified in an S. mitis strain from the same patient, suggesting that in this case S. pneumoniae played the role of donor.

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Binding of Faropenem and Other β-Lactam Agents to Penicillin-Binding Proteins of Pneumococci with Various β-Lactam Susceptibilities

Cited by 9 publications

References 27 publications

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

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

Long Persistence of a Streptococcus pneumoniae 23F Clone in a Cystic Fibrosis Patient

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