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Sir, Macrolide, lincosamide and streptogramin antibiotics are chemically distinct inhibitors of bacterial protein synthesis. Quinupristin/dalfopristin is a combination of streptogramin B and A compounds (SB/SA) with a synergic activity against most Gram-positive bacteria. Expression of MLS resistance in staphylococci may be constitutive or inducible. When expression is constitutive, the strains are resistant to all macrolides, lincosamides and streptogramin B-type antibiotics. Streptogramin A-type antibiotics escape resistance, and synergy with streptogramin B-type antibiotics is retained. Resistance to the B component is mediated by methylation of 23S rRNA, which confers macrolide-lincosamide-streptogramin B (MLSB) resistance when the erm genes are expressed constitutively. Up until now, two kinds of mechanism mediating resistance to the A compound are known: (i) inactivation of the drug by acetylation and (ii) efflux. In staphylococci, three acetyltransferase genes, vat, vatB and vatC and two genes for efflux pumps (ABC porters), vga and vgaB have been described previously. Of 3051 Staphylococcus aureus strains collected by the European SENTRY surveillance study between 1997 and 1999, 35 were non-susceptible to quinupristin/dalfopristin (MIC 2 mg/L). All but one of these non-susceptible isolates were collected in France. This is most probably owing to selective pressure by the use of pristinamycins in France. Twenty-two isolates from a hospital in Lille were of the vatB/vgaB genotype encoding resistance to streptogramin A and possessed in parallel constitutively expressed erm(A) or erm(C) genes encoding MLSB resistance. 2 Of these isolates, 20 strains were resistant to quinupristin/dalfopristin (MIC 8 mg/L) and exhibited an elevated MIC (2–4 mg/L) of vancomycin and teicoplanin. These isolates grew on screening plates for assessing the glycopeptide-intermediate S. aureus (GISA) phenotype. When performing population analysis they were revealed to be hetero-GISA. In addition, these 20 isolates belonged to five different SmaI-restriction patterns when a difference in four or more fragments was used as criterion. For another 12 antimicrobials checked, only MICs of fosfomycin and linezolid were in the susceptible range. The purpose of the present study was to analyse alterations within the translational attenuator of the erm genes harboured by these 20 quinupristin/dalfopristin-resistant S. aureus strains displaying the hetero-GISA phenotype. Twelve of these isolates possessed a constitutively expressed erm(A) gene, the remaining eight strains a constitutively expressed erm(C) gene. To our knowledge this is the first description of alterations within the translational attenuator of MRSA isolates with such a unique resistance phenotype. The type of erm(A) or erm(C) gene expression depends on the structure of the regulatory region, which in both cases is located immediately upstream of the respective erm gene. Based on the close structural relatedness of the regulatory regions of erm(A) and erm(C), similar regulatory processes can be assumed to occur during inducible gene expression via translational attenuation. The presence of erm(A) or erm(C) genes was confirmed by PCR, and combined resistance to 14-, 15and 16-membered macrolides as well as lincosamides was determined by the broth microdilution method. To detect structural alterations in the erm(A) or erm(C) regulatory region, we used a previously described PCR assay. Three slightly different types of structural alteration, i.e. tandem duplications of 25 bp each (Figure, a) were seen among all 12 erm(A)-containing S. aureus isolates (type 1 in 10 isolates, types 2 and 3 in one isolate each). The tandem duplications were located almost at the same position in the regulatory region and comprised the erm(A)associated ribosome-binding site (AGAAGG) as well as Correspondence Journal of Antimicrobial Chemotherapy (2001) 48, 931–942

the journal of antimicrobial chemotherapy/journal of antimicrobial chemotherapy

Characterization of the translational attenuator of 20 methicillin-resistant, quinupristin/dalfopristin-resistant Staphylococcus aureus isolates with reduced susceptibility to glycopeptides