D-106. Emerging Penicillin Resistance in Group B Streptococcus Secondary to PBP2x Mutations

S. Dahesh1, M. E. Hensler1, N. M. Van Sorge1, R. E. Gertz, Jr.2, S. Schrag2, V. Nizet1, B. W. Beall2;
1Univ. of California, La Jolla, CA, 2CDC, Atlanta, GA.

Background: Group B Streptococcus is associated with serious infections in newborn infants, pregnant women and the elderly. GBS resistance to beta-lactam antibiotics (BLA) including penicillin (PCN) has not been reported, and these medications are used first line in GBS therapy and (intrapartum) prophylaxis. Methods: GBS isolates collected by the Active Bacterial Core surveillance (ABCs), a multistate population based invasive disease surveillance system, were studied by PCR amplification and sequence analysis of penicillin-binding protein (PBP) genes vs. published genome sequences. Functional linkage of identified mutations to altered BLA sensitivity was assessed by restoration of the corrected allele episomally on a plasmid or by allelic replacement in the GBS chromosome. Results: Forty GBS from 1999-2005 CDC surveillance (patients <1 to 90 years of age) were identified with elevated MICs (4 to 8-fold greater) to one or more BLA antibiotics. Complete sequencing of the PCN-binding domains of PBP genes pbp1a, pbp2x, and pbp2b associated with BLA resistance in Streptococcus pneumoniae (SPN) was performed. Four isolates, all serotype III and likely clonal, share a single substitution within PBP2X (Q557E); one isolate contained 2 missense mutations affecting a key antibiotic contact motif in the PBP2X PCN binding region (T394I, T555S); another isolate contains a missense mutation within a highly conserved codon in the PBP1A PCN binding domain (T546N). Return of the normal allele of PBP2X (encoding Q557) to a BLA nonsusceptible isolate on a plasmid or by gene replacement within the chromosome restored normal sensitivity profile to BLA antibiotics. Conclusions: GBS strains are emerging with BLA MICs that coincide with intermediate resistance according to present criteria for SPN. Initial analysis suggests these GBS strains bear PBP mutations reminiscent of those associated with SPN BLA resistance. Concern is raised that GBS could be accumulating combinations of mutations required for full resistance to PCN.