tetracycline and retapamulin

Retapamulin in vitro activity against 400 Streptococcus pyogenes clinical isolates obtained from skin, pharynx, ear fluid, and blood samples recovered from 2007 to 2009 was studied. The isolates belonged to 26 different emm types, including isolates nonsusceptible to erythromycin (n=187), tetracycline (n=99), ciprofloxacin (n=59), and bacitracin (n=43). Results were compared to the activities of 16 other antibiotics for topical and systemic use. Retapamulin MICs ranged from ≤0.015 to 0.12 μg/ml, showing the highest intrinsic activity among the topical antimicrobial drugs studied.

Topics: Anti-Infective Agents; Bacitracin; Bridged Bicyclo Compounds, Heterocyclic; Ciprofloxacin; Diterpenes; Erythromycin; Microbial Sensitivity Tests; Streptococcus pyogenes; Tetracycline

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Pleuromutilins; Polycyclic Compounds; Sequence Analysis, DNA; Staphylococcus aureus

To assess their effects on susceptibility to retapamulin in Staphylococcus aureus, first-, second-, and third-step mutants with elevated MICs to tiamulin and other investigational pleuromutilin compounds were isolated and characterized through exposure to high drug concentrations. All first- and second-step mutations were in rplC, encoding ribosomal protein L3. Most third-step mutants acquired a third mutation in rplC. While first- and second-step mutations did cause an elevation in tiamulin and retapamulin MICs, a significant decrease in activity was not seen until a third mutation was acquired. All third-step mutants exhibited severe growth defects, and faster-growing variants arose at a high frequency from most isolates. These faster-growing variants were found to be more susceptible to pleuromutilins. In the case of a mutant with three alterations in rplC, the fast-growing variants acquired an additional mutation in rplC. In the case of fast-growing variants of isolates with two mutations in rplC and at least one mutation at an unmapped locus, one of the two rplC mutations reverted to wild type. These data indicate that mutations in rplC that lead to pleuromutilin resistance have a direct, negative effect on fitness. While reduction in activity of retapamulin against S. aureus can be seen through mutations in rplC, it is likely that target-specific resistance to retapamulin will be slow to emerge due to the need for three mutations for a significant effect on activity and the fitness cost of each mutational step.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Pleuromutilins; Polycyclic Compounds; Ribosomal Protein L3; Ribosomal Proteins; Staphylococcus aureus