MiscellaneousMonday, May 09, 2011, 12:30 - 13:30
Ribosomal mutations associated with ketolide resistance in Haemophilus influenzae found in the SENTRY Antimicrobial Surveillance ProgramD. Farrell*, L. Deshpande, R. Mendes, R. Jones (North Liberty, US)
Objectives: To determine the mechanisms of ketolide resistance in H. influenzae. Ketolide resistance is very rare in H. influenzae and is usually associated with a variety of ribosomal mutations. We report on the ribosomal mutations detected in 9 telithromycin (TELI) -resistant H. influenzae found in the SENTRY Program (2009) and assess the activity of solithromycin (SOLI, formerly CEM-101), a new fluoroketolide in clinical development.
Methods: 1,198 H. influenzae isolates obtained from patients with community-acquired bacterial pneumonia in 24 countries were tested for susceptibility to TELI by CLSI methods (M07-A8 and M100-S20-U) as part of the SENTRY Program during 2009. Only nine (0.8%) isolates were found to be TELI-resistant (MIC, >=16 mg/L). Extended MICs were performed by Etest and strains were screened for mutations in the 23S rRNA, L22 and L4 proteins by PCR and DNA sequencing.
Results: Seven different mutation patterns were observed in 8 of the 9 strains. No mutations were detected in the genes sequenced for one strain (Isolate 3042). The highest TELI MIC values (>256 mg/L) were found in two geographically diverse (Sweden and USA) strains with a 23S rRNA A2059G mutation. H. influenzae with L4 and L22 riboprotein mutations showed TELI MIC values from 32 to 256 mg/L. TELI was 1.5- to at least 4- fold more active than azithromycin (AZI); and SOLI was 2- to at least 4-fold more active than TELI. Against all 1,198 H. influenzae isolates, the MIC50/90 for TELI and SOLI were 1/4 and 1/2 mg/L, respectively.
Conclusions: Ketolide resistance in H. influenzae continues to be rare (<1%) globally. Resistance was found to be associated with a variety of ribosomal mutations and was widely distributed geographically thus suggesting a lack of both local and global spread. Although solithromycin MIC results were 2- to at least 4-fold lower than telithromycin against these strains, cross-resistance to solithromycin was confirmed. The mechanism of ketolide resistance in one UK strain is under further investigation.