In Vitro Activities of the Novel Ketolide Telithromycin (HMR 3647) against Erythromycin-Resistant Streptococcus Species

Abstract

The in vitro susceptibilities of 184 erythromycin-resistant streptococci to a novel ketolide, telithromycin (HMR 3647), were tested. These clinical isolates included 111 Streptococcus pyogenes, 18 group C streptococcus, 18 group G streptococcus, and 37 Streptococcus pneumoniae strains. The MICs for all but eight S. pyogenes strains were <0.5 g/ml, indicating that telithromycin is active in vitro against erythromycin-resistant Streptococcus strains. All strains for which MICs were >1 g/ml had an erm(B) resistance gene and six strains for which MICs were >4 g/ml had a constitutive erm(B) gene (MIC range, 4 to 64 g/ml). Interestingly, for S. pneumoniae strains with a constitutive erm(B) gene, MICs were <0.25 g/ml (MIC range, <0.008 to 0.25 g/ ml). Our in vitro data show that for S. pyogenes strains which constitutively express the erm(B) methylase gene, MICs are so high that the strains might be clinically resistant to telithromycin.Ketolides represent a new generation of macrolides, in which a 3-keto group replaces L-cladinose in the lactone ring. Ketolides have shown to be more active in vitro than other macrolides against various gram-positive bacteria such as Enterococcus species (6, 24), Staphylococcus aureus (6, 13), and Streptococcus species, including erythromycin-resistant Streptococcus pneumoniae and Streptococcus pyogenes strains (6,16,18). On the other hand, methicillin-resistant and some erythromycin-resistant S. aureus strains, as well as some Staphylococcus epidermidis strains (1, 18), seem to be resistant to ketolides (1, 6, 13).In streptococci, there are two well-characterized macrolide resistance mechanisms: target site modification and active drug efflux. Target site modification is mediated by methylases encoded by the erm (erythromycin ribosome methylation) genes (21, 26). Methylation of A2058 of the peptidyl transferase loop of 23S rRNA causes resistance to macrolides as well as to lincosamides and streptogramin B antibiotics (the MLS B resistance phenotype) (26). The expression of the erm genes can be either constitutive or inducible (27). In streptococci, erm genes are carried on both the chromosome and plasmids (2, 21) and are associated with conjugative transposons (25). The activeefflux mechanism, encoded by the mef (macrolide efflux) genes, is more specific and causes resistance only to 14-and 15-member-ring macrolides (the M resistance phenotype) (3,22). Expression of mef genes is constitutive (C. Arpin, M. H. Canron, P. Noury, and C. Quentin, Letter, J. Antimicrob. Chemother. 44:133-134, 1999). The mef genes are chromosomal (11,17) and, at least in the case of S. pyogenes, can be transferred by conjugation (11).The present work was carried out to study the activity of a novel ketolide, telithromycin (HMR 3647), against Streptococcus species with known macrolide resistance determinants. In addition, its activity against nine S. pneumoniae strains with an unknown macrolide resistance mechanism was tested. MATERIALS AND METHODSBacterial strains. Altogether 184 erythromycin-resistant strep...

In Vitro Activity of Telithromycin against Macrolide-Susceptible and Macrolide-Resistant Pharyngeal Isolates of Group A Streptococci in the United States

“…Previous studies have demonstrated that telithromycin resistance in GAS is found exclusively in macrolide-resistant isolates expressing erm(B) (8,10,19). Consistent with this, we demonstrated the presence of erm(B) in two strains of GAS expressing the MLS i phenotype that were resistant to telithromycin.…”

Ketolide Antimicrobial Activity Persists after Disruption of Interactions with Domain II of 23S rRNA

“…Similarly, methylation of the tylosin contact site at G748 confers specific resistance to a subgroup of macrolides that are structurally related to tylosin (30). Telithromycin is the first ketolide to be approved for clinical use, and it has been demonstrated to be an effective antimicrobial agent (11,(24)(25)(26)(27). It is yet too soon to evaluate fully the extent to which resistance to telithromycin might develop in clinical isolates and whether this will involve mutation in domain II of the rRNA.…”

Estudio de la actividad comparativa in vitro de telitromicina en patógenos respiratorios adquiridos en la comunidad en 13 centros clínicos chilenos

“…Balfour et al, Bryskier y otros investigadores, han publicado que telitromicina es 2 a 5 veces más activa que claritromicina contra cocáceas gram positivas sensibles a eritromicina, tanto en Staphylococcus, S pneumoniae y S pyogenes 4,6 . Un hecho relevante es que telitromicina en S pneumoniae es activa independiente de su susceptibilidad a penicilina y eritromicina [21][22][23] . Nuestros resultados avalan esta observación, reflejada en una CIM 90 baja, independiente del resistotipo.…”

“…La CIM 90 de las cepas de SPNS y SPNI fue de 0,03 µg/ml y las cepas de SPNR presentaron una CIM 90 de 0,06 µg/ml. Todas las cepas de S pyogenes siguen siendo sensibles a penicilina, no así a macrólidos, en que hay cepas resistentes que se han asociado con el consumo del antibiótico [10][11][12]22,23 . Las cepas de S pyogenes estudiadas en esta serie, 100% fueron sensibles a telitromicina con CIM 50 de 0,015 µg/ml y CIM 90 de 0,5 µg/ml, a diferencia de la sensibilidad a eritromicina que fue de 89,5%, con rangos de CIM 50 y CIM 90 de 0,03 y 0,06 µg/ ml, respectivamente (Tabla 3).…”