Dataset Information

Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae.

ABSTRACT: 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 PBP1A, -1B, and -2A > PBP2B, and ceftaroline had >or=4-fold higher 50% inhibitory concentrations (IC(50)s) (0.1 to 4 microg/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 microg/ml), a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B (IC(50), 0.5 to 4 microg/ml) and PBP1A (IC(50), 0.125 to 0.25 microg/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 beta-lactams tested. Ceftaroline bound to PBP2a in methicillin-resistant S. aureus (IC(50), 0.01 to 1 microg/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.

SUBMITTER: Kosowska-Shick K

PROVIDER: S-EPMC2863635 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae.

Kosowska-Shick K K McGhee P L PL Appelbaum P C PC

Antimicrobial agents and chemotherapy 20100301 5

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 <or=1 microg/ml against all S. aureus isolates and were <or=0.25 microg/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, an ...[more]

PMID: 20194704

Similar Datasets

Project description:To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Project description:Streptococcus suis is a zoonotic pathogen causing disease in both animals and humans, and the emergence of increasingly resistant bacteria to antimicrobial agents has become a significant challenge globally. The objective of this study was to investigate the genetic basis for declining susceptibility to penicillin and other β-lactams among S. suis. Antimicrobial susceptibility testing and penicillin-binding proteins (PBP1a, PBP2a, PBP2b, and PBP2x) sequence analysis were performed on 225 S. suis isolated from diseased pigs. This study found that a growing trend of isolates displayed reduced susceptibility to β-lactams including penicillin, ampicillin, amoxicillin/clavulanic acid, and cephalosporins. A total of 342 substitutions within the transpeptidase domain of four PBPs were identified, of which 18 substitutions were most statistically associated with reduced β-lactams susceptibility. Almost all the S. suis isolates which exhibited penicillin-non-susceptible phenotype (71.9%) had single nucleotide polymorphisms, leading to alterations of PBP1a (P409T) and PBP2a (T584A and H588Y). The isolates may manifest a higher level of penicillin resistance by additional mutation of M341I in the 339STMK active site motif of PBP2x. The ampicillin-non-susceptible isolates shared the mutations in PBP1a (P409T) and PBP2a (T584A and H588Y) with additional alterations of PBP2b (T625R) and PBP2x (T467S). The substitutions, including PBP1a (M587S/T), PBP2a (M433T), PBP2b (I428L), and PBP2x (Q405E/K/L), appeared to play significant roles in mediating the reduction in amoxicillin/clavulanic acid susceptibility. Among the cephalosporins, specific mutations strongly associated with the decrease in cephalosporins susceptibility were observed for ceftiofur: PBP1a (S477D/G), PBP2a (E549Q and A568S), PBP2b (T625R), and PBP2x (Q453H). It is concluded that there was genetically widespread presence of PBPs substitutions associated with reduced susceptibility to β-lactam antibiotics.

Dataset Information

Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae.

Publications

Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets