Disposition and intracellular levels of moxifloxacin in human THP-1 monocytes in unstimulated and stimulated conditions

Hall, Iris H.; Schwab, Ute; Ward, E. Stacy; Ives, Timothy J.

doi:10.1016/j.ijantimicag.2003.05.004

Cited by 9 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moxifloxacin behaves similarly to the weak bases in this respect, probably due to the presence of a protonatable amino group. The effect of NH 4 Cl on the accumulation of both fluoroquinolones remains unexplained, yet it is consistent with data in the literature about moxifloxacin, which show an increased accumulation of the drug upon short incubation under these conditions (20).…”

Section: Discussionsupporting

confidence: 89%

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

Lemaire

Tulkens

Bambeke

2011

Antimicrob Agents Chemother

169

140

View full text Add to dashboard Cite

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.Fluoroquinolones are one of the first families of fully synthetic antibiotics with large clinical use, and they represent a wide range of molecules, which permits the establishment of in-depth structure-activity relationships (16,17). Over the last 20 years, most fluoroquinolone research efforts have been focused on new molecules with improved activity toward Grampositive cocci because of the increasing spread of multiresistant staphylococci and streptococci. The 8-methoxy fluoroquinolone moxifloxacin is the first example of this new generation to reach the commercial market. It combines many desirable microbiological and pharmacokinetic properties (rapid bactericidal activity, a spectrum covering pertinent pathogens, excellent oral bioavailability, a large tissue distribution, and a propensity to accumulate within eukaryotic cells [see reference 45 for a review]). Moxifloxacin shows extensive activity toward bacteria thriving in the cytosol (Listeria monocytogenes [14]), phagosomes (Legionella pneumophila, Mycobacterium avium, and Mycobacterium tuberculosis [5,9,46]), and phagolysosomes (Staphylococcus aureus [6]), suggesting that it easily diffuses between different subcellular compartments. Yet moxifloxacin activity is partially defeated by the acidic pH prevailing in vacuolar subcellular compartments (6).Delafloxacin [RX-3341; 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] is an investigational fluoro...

show abstract

Section: Discussionsupporting

confidence: 89%

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

Lemaire

Tulkens

Bambeke

2011

Antimicrob Agents Chemother

169

140

View full text Add to dashboard Cite

show abstract

“…Studies with moxifloxacin in THP-1 monocytes show similar differences in IC/EC ratios, of 4.39 by HPLC techniques 28 and more than 50 by the isotope method. 30 Further, the present study demonstrates in THP-1 monocytes that the IC/EC ratio varies with time, pH, stimulation, and drug concentration.…”

Section: Discussionsupporting

confidence: 52%

“…This form of uptake has been observed for both azithromycin and clarithromycin in THP-1 monocytes, 7,8 but not for Table 4. Percentage uptake of grepafloxacin (0.4 µg/ml) by THP-1 monocytes in the presence of energy blockers and transport channel blockers over 6 h (n ϭ 6) 0 30 A mixed transport has also been suggested for macrolides in PMNs 21,22 and in THP-1. 8,29 Previous studies by Hara et al 29 in THP-1 monocytes with grepafloxacin demonstrated similar findings over 60 min at 20 µg/ml.…”

Section: Discussionmentioning

confidence: 95%

“…3 Drug uptake was both temperature-and energydependent, which has also been observed for macrolides and fluoroqinolones in THP-1 monocytes. 8,30 Phagocytic functions of macrophages and monocytes are temperatureand energy-dependent. This process is reduced by NaF and cyanide or azide, which block glucose metabolism and oxidative phosphorylation, respectively.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human THP-1 monocyte uptake and cellular disposition of 14C-grepafloxacin

Hall

Schwab

Ward

et al. 2004

Journal of Infection and Chemotherapy

Self Cite

View full text Add to dashboard Cite

“…Influx probably occurs by simple passive diffusion, although active transport has also been suggested [175,176]. However, neither the mechanism of accumulation nor the subcellular localisation are known with certainty; the bulk of cell‐associated quinolone is found in the soluble fraction of cell homogenates [174,177], but part of the drug could have access to other organelles [178].…”

Section: Tissue Accumulation/distribution and Its Meaningmentioning

confidence: 99%

Quinolones in 2005: an update

Bambeke

Michot

Eldere

et al. 2005

Clinical Microbiology and Infection

333

259

View full text Add to dashboard Cite

Quinolones are one of the largest classes of antimicrobial agents used worldwide. This review considers the quinolones that are available currently and used widely in Europe (norfoxacin, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin) within their historical perspective, while trying to position them in the context of recent and possible future advances based on an understanding of: (1) their chemical structures and how these impact on activity and toxicity; (2) resistance mechanisms (mutations in target genes, efflux pumps); (3) their pharmacodynamic properties (AUC/MIC and Cmax/MIC ratios; mutant prevention concentration and mutant selection window); and (4) epidemiological considerations (risk of emergence of resistance, clonal spread). Their main indications are examined in relation to their advantages and drawbacks. Overall, it is concluded that these important agents should be used in an educated fashion, based on a careful balance between their ease of use and efficacy vs. the risk of emerging resistance and toxicity. However, there is now substantial evidence to support use of the most potent drug at the appropriate dose whenever this is required.

show abstract

Disposition and intracellular levels of moxifloxacin in human THP-1 monocytes in unstimulated and stimulated conditions

Cited by 9 publications

References 17 publications

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

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

Human THP-1 monocyte uptake and cellular disposition of 14C-grepafloxacin

Quinolones in 2005: an update

Contact Info

Product

Resources

About