Induction of Telithromycin Resistance by Erythromycin in Isolates of Macrolide-Resistant Staphylococcus spp

Abstract

Staphylococcal isolates were examined for possible macrolide-inducible resistance to telithromycin. All macrolide-resistant isolates demonstrated telithromycin D-shaped zones. This result did not discriminate between resistance due to an efflux mechanism (msrA) or a ribosomal target modification (ermA or ermC). Inducible telithromycin resistance in staphylococci does not appear to be analogous to inducible clindamycin resistance.Telithromycin is the first commercially available ketolide. Ketolides are a recently developed class of antimicrobial agents that belong to the macrolide-lincosamide-streptogramin B (MLS B ) family. Ketolides possess significant structural differences from macrolides, including a second site of interaction with the ribosome at domain II on the 23S rRNA of the 50S ribosomal subunit (4). This is in addition to the interaction at domain V, which is where 14-and 15-membered-ring macrolides act (2). These and other modifications improve the stability of ketolides in acidic environments, prevent the induction of MLS B resistance, and maintain activity against organisms that develop inducible resistance to MLS B antimicrobials (2). Mechanisms that confer resistance to MLS B antimicrobials include target site modification and active antimicrobial efflux (1). Target site modification is encoded by constitutive or inducible erm genes (16) that may require exposure to subinhibitory concentrations of erythromycin for optimal expression (18). The active antimicrobial efflux pumps that have been described for Staphylococcus aureus are encoded by the msrA, msrB, and NorA genes (11, 16).We previously reported a practical disk approximation method which identified 97% of S. aureus strains and 100% of coagulase-negative staphylococcus (CoNS) strains with inducible MLS B resistance during routine disk diffusion susceptibility testing (6). A similar method involves placing erythromycin and clindamycin disks in close proximity on standard sheep blood agar plates used for verification of inoculum purity when broth-based susceptibility tests are performed (10). These tests are intended to detect strains with inducible MLS B resistance in order to avoid potential clinical failures with clindamycin therapy (5,7,15,17). The goal of the present study was to determine if inducible telithromycin resistance, like inducible clindamycin resistance, might occur in macrolide-resistant staphylococci.A group of 100 S. aureus clinical isolates and 100 CoNS clinical isolates, some of which have been previously described (6), were selected for study. All isolates were macrolide resistant by standard Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) disk diffusion testing (14). An additional 10 S. aureus isolates that were susceptible to erythromycin were included. Standard CLSI disk diffusion testing (14) was performed on all isolates by use of Mueller-Hinton agar (Becton-Dickinson Microbiology Systems, Cockeysville, MD) with standard 15-g erythromycin disks, 2-g clindamycin disks, and 15-g telithromycin disk...

Distribution, Characterization and Genetic Bases of Erythromycin Resistance in Staphylococci and Enterococci Originating from Livestock

“…A high prevalence of constitutive resistance to TEL could be explained by a high prevalence of isolates with the cMLS B phenotype (Tables 3 and 4), which is usually linked to resistance to ketolides (Schmitz et al., 2002). By contrast, and as similarly observed by Davis et al. (2005), iTEL resistance was frequent in staphylococci resistant (or intermediately resistant) only to ERY (Table 3).…”

CEM-101 Activity against Gram-Positive Organisms

“…All the staphylococcal isolates showing clindamycin-susceptible patterns (10 strains) harbored mrsA, which encodes an efflux resistance mechanism. Telithromycin inducibility was previously observed among Staphylococcus spp., and isolates harboring ermA and ermC were also clindamycin inducible (6).…”

Acquired Inducible Antimicrobial Resistance in Gram-Positive Bacteria

“…msr(A) is inducible by 14- and 15-membered macrolides and confers resistance to 14- and 15-membered macrolides and streptogramins, but not 16-membered macrolides or lincosamides [37]. Msr(A)-mediated resistance to telithromycin is dependent upon prior induction of msr(A) by erythromycin indicating that telithromycin is not an inducer but it is a substrate for msr(A) -mediated efflux (Table 1) [38]. The mechanism of induction of msr(A) has not been confirmed, but analyses of the DNA sequences immediately upstream reveal similarities to MLS B attenuators [Chancey ST, Unpublished Data].…”