Activities of Ceftobiprole and Other β-Lactams against
            <i>Streptococcus pneumoniae</i>
            Clinical Isolates from the United States with Defined Substitutions in Penicillin-Binding Proteins PBP 1a, PBP 2b, and PBP 2x

Davies, Todd A.; Shang, Wenchi; Bush, Karen

doi:10.1128/aac.00238-06

Cited by 36 publications

(29 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A distinguishing feature of ceftobiprole is that, in addition to inhibiting the normal complement of PBPs in most species, it also binds with a high affinity to the acquired PBP 2a (PBP 2Ј) of MRSA strains, PBP 2a of Staphylococcus epidermidis, and PBP 2x of penicillin-resistant Streptococcus pneumoniae (14,17,22,26). Ceftobiprole does not bind to PBP 5 of Enterococcus faecium and therefore has high MICs when it is tested with this organism (17).…”

mentioning

confidence: 99%

Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

Queenan

Shang

Kania

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The interactions of ceftobiprole with purified ␤-lactamases from molecular classes A, B, C, and D were determined and compared with those of benzylpenicillin, cephaloridine, cefepime, and ceftazidime. Enzymes were selected from functional groups 1, 2a, 2b, 2be, 2d, 2e, and 3 to represent ␤-lactamases from organisms within the antibacterial spectrum of ceftobiprole. Ceftobiprole was refractory to hydrolysis by the common staphylococcal PC1 ␤-lactamase, the class A TEM-1 ␤-lactamase, and the class C AmpC ␤-lactamase but was labile to hydrolysis by class B, class D, and class A extended-spectrum ␤-lactamases. Cefepime and ceftazidime followed similar patterns. In most cases, the hydrolytic stability of a substrate correlated with the MIC for the producing organism. Ceftobiprole and cefepime generally had lower MICs than ceftazidime for AmpCproducing organisms, particularly AmpC-overexpressing Enterobacter cloacae organisms. However, all three cephalosporins were hydrolyzed very slowly by AmpC cephalosporinases, suggesting that factors other than ␤-lactamase stability contribute to lower ceftobiprole and cefepime MICs against many members of the family Enterobacteriaceae.

show abstract

mentioning

confidence: 99%

Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

Queenan

Shang

Kania

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous studies from this laboratory have shown that ceftobiprole maintained activity against penicillin-and ceftriaxone-resistant S. pneumoniae strains that contained multiple mutations in PBP genes and that ceftobiprole had affinity for the primary cephalosporin targets PBP 1a and PBP 2x in both penicillinsusceptible and -resistant isolates (4,5). Surprisingly, in a penicillin-susceptible isolate, ceftobiprole had measurable PBP 2b affinity (4), which is not a primary target for previously characterized cephalosporins (8).…”

Section: ␤-Lactam Resistance Inmentioning

confidence: 99%

“…Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for ␤-lactam resistance among clinical isolates (5,6,8). Cephalosporins have the highest affinity for PBP 1a and PBP 2x, with no appreciable affinity for PBP 2b, while penicillins have high affinity for all three PBPs in penicillin-susceptible strains (6,8).…”

mentioning

confidence: 99%

Affinity of Ceftobiprole for Penicillin-Binding Protein 2b in Streptococcus pneumoniae Strains with Various Susceptibilities to Penicillin

Davies

Bush

et al. 2010

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Wild-type penicillin-binding protein (PBP) 2b from penicillin-susceptible Streptococcus pneumoniae had high affinity for ceftobiprole and penicillin (50% inhibitory concentrations [IC 50 s] of <0.15 g/ml) but not ceftriaxone (IC 50 of >8 g/ml). In clinical isolates, ceftobiprole and PBP 2b affinities were reduced 15-to 30-fold with a Thr-446-Ala substitution and further still with an additional Ala-619-Gly PBP 2b substitution. Ceftobiprole remained active (MICs of <1 g/ml) against all strains tested and behaved more like penicillin than ceftriaxone with respect to PBP 2b binding. ␤-Lactam resistance inStreptococcus pneumoniae is caused by mutations in the penicillin-binding domains of one or more of its six penicillin-binding proteins (PBPs) resulting from substitution mutations or the acquisition of mosaic genes by recombination (6-8). Altered PBP 1a, PBP 2x, and PBP 2b are the most important PBPs for ␤-lactam resistance among clinical isolates (5,6,8). Cephalosporins have the highest affinity for PBP 1a and PBP 2x, with no appreciable affinity for PBP 2b, while penicillins have high affinity for all three PBPs in penicillin-susceptible strains (6,8).Ceftobiprole is a novel parental cephalosporin with broadspectrum Gram-negative and Gram-positive activities, including activity against methicillin-resistant staphylococci (9). Previous studies from this laboratory have shown that ceftobiprole maintained activity against penicillin-and ceftriaxone-resistant S. pneumoniae strains that contained multiple mutations in PBP genes and that ceftobiprole had affinity for the primary cephalosporin targets PBP 1a and PBP 2x in both penicillinsusceptible and -resistant isolates (4,5). Surprisingly, in a penicillin-susceptible isolate, ceftobiprole had measurable PBP 2b affinity (4), which is not a primary target for previously characterized cephalosporins (8). In this study, we further investigate this finding by determining the affinity of ceftobiprole for PBP 2b from clinical isolates with various susceptibilities to penicillin and by determining the effect of specific pbp2b mutations on ceftobiprole affinity.(This work was presented in part at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America 46th Annual Meeting, Washington, DC, 2008 [4a].) Seven S. pneumoniae isolates were analyzed as described below. The ceftobiprole, ceftriaxone, and penicillin MICs were determined using the broth microdilution method according to CLSI recommendations (1). In this study, CLSI oral penicillin V breakpoints (susceptible, MICs of Յ0.06 g/ml; intermediate, MICs of 0.12 to 1 g/ml; resistant, MICs of Ն2 g/ml) were used because they best differentiate the isolates based on PBP genotypes (i.e., susceptible isolates do not have mutations in pbp2b) (2). PBP gene sequencing and whole-cell competition assays were performed as described previously (4, 5). It should be noted that the penicillin-intermediate and -resistant isolates had multiple mutations in pbp1a and/or pbp...

show abstract

“…It has been described that beta-lactam MIC values correlated closely with increases in the numbers of PBP1a, PBP2x and PBP2b substitutions. 30 Alpha-and beta-hemolytic streptococci have been shown to have low ceftobiprole MICs in several studies. 15,20,21 Penicillin-susceptible, -intermediate and -resistant isolates of S. pneumoniae are highly susceptible to ceftobiprole in vitro.…”

Section: Streptococcus Pneumoniaementioning

confidence: 99%

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

Bustos

Pozo²

2010

IDR

View full text Add to dashboard Cite

Antimicrobial resistance is a global concern. Over the past few years, considerable efforts and resources have been expended to detect, monitor, and understand at the basic level the many different facets of emerging and increasing resistance. Development of new antimicrobial agents has been matched by the development of new mechanisms of resistance by bacteria. Current antibiotics act at a variety of sites within the target bacteria, including the cross-linking enzymes in the cell wall, various ribosomal enzymes, nucleic acid polymerases, and folate synthesis. Ceftobiprole is a novel parenteral cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin-binding protein 2a, rendering it active against methicillin-resistant staphylococci. Its in vitro activity against staphylococci and multiresistant pneumococci, combined with its Gram-negative spectrum comparable to that of other extended-spectrum cephalosporins, its stability against a wide range of beta-lactamases, and its pharmacokinetic and safety profiles make ceftobiprole an attractive and well tolerated new antimicrobial agent. The US Food and Drug Administration granted ceftobiprole medocaril fast-track status in 2003 for the treatment of complicated skin infections and skin structure infections due to methicillin-resistant staphylococci, and subsequently extended this to treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia due to suspected or proven methicillin-resistant Staphylococcus aureus.

show abstract

Activities of Ceftobiprole and Other β-Lactams against Streptococcus pneumoniae Clinical Isolates from the United States with Defined Substitutions in Penicillin-Binding Proteins PBP 1a, PBP 2b, and PBP 2x

Cited by 36 publications

References 22 publications

Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

Affinity of Ceftobiprole for Penicillin-Binding Protein 2b in Streptococcus pneumoniae Strains with Various Susceptibilities to Penicillin

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

Contact Info

Product

Resources

About