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Streptogramins and Oxazolidinones 245among these isolates. As expected, in this study quinupristin–dalfopristin wasineffective against E. faecalis strains, with 97.5% of strains determined to benonsusceptible.With its predominantly gram-positive spectrum of activity, quinupristin–dalfopristin is also recommended for the treatment of skin and soft-tissue infectionscaused by S. pyogenes. In the study described by Fluit et al. (Table 1), allS. pyogenes strains tested were susceptible to quinupristin-dalfopristin, with anMIC 90 value 2 mg/mL (22,30).ResistanceResistance to streptogramins is mediated by four distinct mechanisms: modificationof the ribosome target site, efflux, enzymatic inactivation of streptogramin Aor B components, or impermeability of the bacterial envelope. It has beenproposed that acquired resistance to quinupristin–dalfopristin requires at a minimumthe presence of the streptogramin A vat or vga resistance gene (31). Recentstudies (see below) suggest that resistance to the streptogramin combination canalso occur in pneumococci through selective mutations to 23S rRNA or to theribosomal proteins L4 or L22 (32).Resistance to streptogramins A or B can result from modifications to the 23SrRNA or specific ribosomal proteins through one of two mechanisms (i) methylationof A2058 (E. coli numbering) by an Erm dimethylase, resulting in an MLS Bphenotype (resistance to macrolides, lincosamides, and streptogramin B antibiotics)and (ii) mutational changes to the 23S rRNA or 50S ribosomal subunitproteins L4 and L22. As previously discussed (Table 1), methylation of A2058 doesnot confer resistance to streptogramin A type antibiotics, and strains with ermremain susceptible to quinupristin–dalfopristin (33), although bactericidal activityof quinupristin–dalfopristin may be compromised (21). Mutational changes to 23SrRNA or to L4 or L22 ribosomal proteins have resulted in intermediate or resistantphenotypes. In one PROTEKT study of 7746 macrolide-resistant pneumococcalstrains, 6 isolates of 77 with 23S rRNA, L4, or L22 mutations were found to beresistant to quinupristin-dalfopristin, with MIC values of 4 or 8 mg/mL. Fivedistinct combinations of ribosomal mutations correlated with this resistance,including (i) 23S rRNA C2611G (three of four RNA copies), (ii) 23S rRNA A2059G(four of four copies) with G95D in L22, (iii) an L22 tandem duplication 109 RTA-HIT 114 ,(iv) in L4, a K68S with a deletion of the four amino acids 69 GTGR 72 , and(v) in L4, 69 GT 70 changed to 69 VP 70 (32). In another study, quinupristin–dalfopristinresistance in two clinical S. aureus isolates resulted from an L22 deletion of