Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin against Staphylococcus aureus

Autor: Françoise Van Bambeke, Paul M. Tulkens, Sandrine Lemaire
Přispěvatelé: UCL - SSS/LDRI - Louvain Drug Research Institute
Rok vydání: 2011
Předmět:
Staphylococcus aureus
Moxifloxacin
Staphylococcal Infections - microbiology
Microbial Sensitivity Tests
medicine.disease_cause
Staphylococcal infections
Models
Biological
Monocytes
Cell Line
Microbiology
Mice
chemistry.chemical_compound
Anti-Infective Agents
Staphylococcus aureus - drug effects
metabolism
Aza Compounds - chemistry
pharmacokinetics
pharmacology
medicine
Extracellular
Animals
Humans
Pharmacology (medical)
Pharmacology
Aza Compounds
Monocytes - metabolism
microbiology
biology
Macrophages
Anti-Infective Agents - chemistry
pharmacokinetics
pharmacology
Quinolines - chemistry
pharmacokinetics
pharmacology
Hydrogen-Ion Concentration
Staphylococcal Infections
biology.organism_classification
medicine.disease
Culture Media
Infectious Diseases
chemistry
Susceptibility
Cell culture
Fluoroquinolones - chemistry
pharmacokinetics
pharmacology
Macrophages - metabolism
Quinolines
Delafloxacin
Culture Media - chemistry
Bacteria
Intracellular
Fluoroquinolones
medicine.drug
Zdroj: Antimicrobial Agents and Chemotherapy, Vol. 55, no. 2, p. 649-658 (2011)
ISSN: 1098-6596
0066-4804
DOI: 10.1128/aac.01201-10
Popis: In contrast to currently marketed fluoroquinolones, which are zwitterionic, delafloxacin is an investigational fluoroquinolone with an anionic character that is highly active against Gram-positive bacteria. We have examined the effect of acidic pH on its accumulation in Staphylococcus aureus and in human THP-1 cells, in parallel with its activity against extracellular and intracellular S. aureus . Moxifloxacin was used as a comparator. Delafloxacin showed MICs 3 to 5 log 2 dilutions lower than those of moxifloxacin for a collection of 35 strains with relevant resistance mechanisms and also proved to be 10-fold more potent against intracellular S. aureus ATCC 25923. In medium at pH 5.5, this difference was further enhanced, with the MIC decreasing by 5 log 2 dilutions. In infected cells incubated in acidic medium, the relative potency was 10-fold higher than that at neutral pH and the maximal relative efficacy reached a bactericidal effect at 24 h. These results can be explained by a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH, making delafloxacin one of the most efficient drugs tested in this model. Opposite effects were seen for moxifloxacin with respect to both activity and accumulation. As reported for zwitterionic fluoroquinolones, delafloxacin was found associated with the soluble fraction in homogenates of eukaryotic cells. Taken together, these properties may confer to delafloxacin an advantage for the eradication of S. aureus in acidic environments, including intracellular infections.
Databáze: OpenAIRE
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