Activity of ketolide ABT-773 (centhromycin) against erythromycin-resistant Streptococcus pneumoniae: Correlation with extended MLSK phenotypes

Abstract

Objectives: (i) To determine the inhibitory and bactericidal activities of ABT-773, a novel ketolide, against sensitive and erythromycin-resistant pneumococci; (ii) to subdivide erythromycin-resistant pneumococci into resistance phenotypes, more extensive than the conventional M and MLSB groups, by assessing susceptibilities to, and interactions between, erythromycin (14-membered macrolide), clindamycin (lincosamide), rokitamycin (16-membered macrolide), ABT-773 (ketolide), quinupristin (streptogramin B) and dalfopristin (streptogramin A). Methods: MICs and MBCs of ABT-773 were determined for 165 strains of pneumococci (113 resistant to erythromycin). Extended phenotypes for the erythromycin-resistant strains were described in terms of intrinsic susceptibility to, and induction of resistance by, the antibiotics listed above. Results: Erythromycin-resistant strains could be divided into 10 extended phenotypes (designated II-XI), two of which (II and IX) predominated. ABT-773 at 0.12 mg/L inhibited 109 strains (median 0.03 mg/L). MICs for the other four strains (of phenotypes X and XI) were 0.25-1 mg/L. MICs were only slighter higher when measured on agar in CO2 than by the NCCLS method (in broth in air). MBCs were usually ≤2 x MIC, but for 10 strains (eight of phenotype X, one each of types IX and XI) MBCs were >1 mg/L, and three of the latter (all type X) were tolerant. Clones of reduced susceptibility (MICs 1-8 mg/L, increased by up to 32-fold) could be isolated from some strains of phenotypes VII, IX and X, but not from those of type II (efflux mechanism) or from erythromycin-sensitive strains. Conclusions: ABT-773 was active against all 113 erythromycin-resistant pneumococci tested, which belonged to 10 phenotypes. Extended phenotyping of pneumococci revealed interesting and potentially useful subdivisions of the classical phenotypes.