title: Activity of ceftobiprole against Streptococcus pneumoniae isolates exhibiting high-level resistance to ceftriaxone.
abstract: Tracking Resistance in the US Today (TRUST) 2008 surveillance data showed that 6% of Streptococcus pneumoniae were non-susceptible to ceftriaxone [minimum inhibitory concentration (MIC) ≥ 2 μg/mL] and that 8% of the ceftriaxone-non-susceptible isolates exhibited high-level resistance (MIC ≥ 8 μg/mL). Here we describe the activity of ceftobiprole against ceftriaxone-resistant isolates and characterise the genotypic traits associated with resistance. Thirty isolates with ceftriaxone MICs ≥ 8 μg/mL were analysed by sequencing of penicillin-binding protein (PBP) and murM genes. Sequencing of pbp1a, pbp2b and pbp2x showed nine PBP patterns, with the most common (n=17) being: PBP1a T371S (STMK motif), P432T (SRNVP motif); PBP2b T446A (SSNT motif), A619G (KTGTA motif); and PBP2x T338A and M339F (STMK motif), L364F, I371T, R384G, M400T, L546V (LKSGT motif); six isolates had the same pattern without the PBP2b A619G change. For these 23 isolates, MICs were 8 μg/mL for ceftriaxone, 4-8 μg/mL for penicillin and 0.5-2 μg/mL for ceftobiprole. The remaining seven isolates with higher MICs (ceftriaxone 8-32 μg/mL, penicillin 4-32 μg/mL and ceftobiprole 2-4 μg/mL) had fewer PBP active-site motif substitutions. The majority of isolates (17/30) had murM alleles similar to the wild-type, whilst the rest had alleles reflecting a mosaic structure. No murM alleles were associated with higher MICs. Against these 30 isolates, ceftobiprole was 4-16-fold more active than ceftriaxone. Widely described PBP and MurM substitutions probably account for the high ceftriaxone MICs (8 μg/mL) in the majority of isolates. However, seven isolates with ceftriaxone MICs of 8-32 μg/mL had fewer PBP substitutions in active-site motifs, suggesting either that there is another resistance mechanism or that unique PBP mutations may contribute to high-level β-lactam resistance.
authors.affiliation: Janssen Research & Development, 1000 Route 202, Raritan, NJ 08869, USA. tdavies1@its.jnj.com
authors.forename: Todd A
authors.initials: TA
authors.lastname: Davies
authors.forename: Robert K
authors.initials: RK
authors.lastname: Flamm
authors.forename: A Simon
authors.initials: AS
authors.lastname: Lynch
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002443:Ceftriaxone / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D010406:Penicillins / Q000494:pharmacology; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D018440:beta-Lactam Resistance / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D047090:beta-Lactams; C443755:ceftobiprole; D002443:Ceftriaxone; C408066:MurM protein, Streptococcus pneumoniae; D010453:Peptide Synthases