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Abstract

Levonadifloxacin is a broad-spectrum anti-staphylococcal drug that is under development. We investigated the activity of levonadifloxacin against methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains phagocytized in THP-1 monocytes to evaluate its scope for treatment of intracellular staphylococcal infections.

The microdilution minimum inhibitory concentrations (MICs) of levonadifloxacin, moxifloxacin, levofloxacin and ciprofloxacin against MSSA ATCC 25923 and MRSA ATCC 43300 strains at pH 7.4±0.1 (original medium pH) and 5.5±0.1 (phagosome pH environment) were determined by following Clinical and Laboratory Standards Institute (CLSI) guidelines. The activity of antibiotics was investigated by extracellular and intracellular time–kill studies at 1–16× MIC concentrations. A suspension of ~5× logc.f.u. ml test organism in supplemented RPMI 1640 medium was employed to determine the extracellular activity, while test organism phagocytized at a 4 : 1 ratio of bacteria to THP-1 monocytes was employed to investigate the intracellular activity. At intervals of 0, 2, 6 and 24 h, colony-forming unit (c.f.u.) counts were performed in triplicate on inoculated brain heart infusion (BHI) agar plates for both methods.

At pH 7.4, the MIC of levonadifloxacin against both tested strains was 2, 8 and 16 times lower than those of moxifloxacin, levofloxacin and ciprofloxacin, respectively. At pH 5.5, the MIC of levonadifloxacin was reduced by ≥8× against both tested strains compared to its MIC at pH 7.4. In contrast, comparator quinolones showed a fourfold elevation in MIC at pH 5.5. In the study assessing the extracellular bactericidal effect, levonadifloxacin at 1× MIC manifested ≥4.5 logc.f.u. ml killing for both strains. Moxifloxacin and levofloxacin also showed bactericidal activity, while ciprofloxacin showed no killing. In intracellular conditions, levonadifloxacin manifested 1.0 log and 2.0 log killing for intracellular ATCC 25923 and ATCC 43300, respectively. These killing effects were better overall than those of comparator quinolones.

Within a clinically achievable concentration range, levonadifloxacin achieved a 90–99 % intracellular reduction of MSSA and MRSA strains phagocytized in THP-1 monocytes. Therefore, levonadifloxacin has the potential to be a therapeutic option for the management of intracellular methicillin- and quinolone-resistant staphylococcal infections.

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2019-11-05
2024-10-12
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References

  1. Fraunholz M, Sinha B. Intracellular Staphylococcus aureus: live-in and let die. Front Cell Infect Microbiol 2012; 2:43 [View Article]
    [Google Scholar]
  2. Sendi P, Proctor RA. Staphylococcus aureus as an intracellular pathogen: the role of small colony variants. Trends Microbiol 2009; 17:54–58 [View Article]
    [Google Scholar]
  3. Dusane DH, Kyrouac D, Petersen I, Bushrow L, Calhoun JH et al. Targeting intracellular Staphylococcus aureus to lower recurrence of orthopaedic infection. J Orthop Res 2018; 36:1086–1092 [View Article]
    [Google Scholar]
  4. Rollin G, Tan X, Tros F, Dupuis M, Nassif X et al. Intracellular survival of Staphylococcus aureus in endothelial cells: a matter of growth or persistence. Front Microbiol 2017; 8:1354 [View Article]
    [Google Scholar]
  5. Strobel M, Pförtner H, Tuchscherr L, Völker U, Schmidt F et al. Post-invasion events after infection with Staphylococcus aureus are strongly dependent on both the host cell type and the infecting S. aureus strain. Clin Microbiol Infect 2016; 22:799–809 [View Article]
    [Google Scholar]
  6. Thwaites GE, Gant V. Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus?. Nat Rev Microbiol 2011; 9:215–222 [View Article]
    [Google Scholar]
  7. Ellington JK, Harris M, Hudson MC, Vishin S, Webb LX et al. Intracellular Staphylococcus aureus and antibiotic resistance: implications for treatment of staphylococcal osteomyelitis. J Orthop Res 2006; 24:87–93 [View Article]
    [Google Scholar]
  8. Tuchscherr L, Kreis CA, Hoerr V, Flint L, Hachmeister M et al. Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis. J Antimicrob Chemother 2016; 71:438–448 [View Article]
    [Google Scholar]
  9. Barcia-Macay M, Seral C, Mingeot-Leclercq M-P, Tulkens PM, Van Bambeke F. Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. Antimicrob Agents Chemother 2006; 50:841–851 [View Article]
    [Google Scholar]
  10. Gade ND, Qazi MS. Fluoroquinolone Therapy in Staphylococcus aureus Infections: Where Do We Stand?. J Lab Physicians 2013; 5:109–112 [View Article]
    [Google Scholar]
  11. Lemaire S, Tulkens PM, Van Bambeke F. Contrasting effects of acidic pH on the extracellular and intracellular activities of the anti-gram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus . Antimicrob Agents Chemother 2011; 55:649–658 [View Article]
    [Google Scholar]
  12. Nguyen HA, Grellet J, Paillard D, Dubois V, Quentin C et al. Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model. J Antimicrob Chemother 2006; 57:883–890 [View Article]
    [Google Scholar]
  13. Redgrave LS, Sutton SB, Webber MA, Piddock LJV. Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol 2014; 22:438–445 [View Article]
    [Google Scholar]
  14. Shi G, Chen X, Wang H, Wang S, Guo X et al. Activity of sitafloxacin against extracellular and intracellular Staphylococcus aureus in vitro and in vivo: comparison with levofloxacin and moxifloxacin. J Antibiot 2012; 65:229–236 [View Article]
    [Google Scholar]
  15. Bhagwat SS, McGhee P, Kosowska-Shick K, Patel MV, Appelbaum PC. In vitro activity of the quinolone WCK 771 against recent U.S. hospital and community-acquired Staphylococcus aureus pathogens with various resistance types. Antimicrob Agents Chemother 2009; 53:811–813 [View Article]
    [Google Scholar]
  16. Bhagwat SS, Mundkur LA, Gupte SV, Patel MV, Khorakiwala HF. The anti-methicillin-resistant Staphylococcus aureus quinolone WCK 771 has potent activity against sequentially selected mutants, has a narrow mutant selection window against quinolone-resistant Staphylococcus aureus, and preferentially targets DNA gyrase. Antimicrob Agents Chemother 2006; 50:3568–3579 [View Article]
    [Google Scholar]
  17. Upadhyay DJ PM, Gupte SV, Agarwal SK, Shreenivas K, Jafri MA. WCK 771A - An Investigational Fluorquinolone (Fq) with Unusual Property of Retaining Potency in Acidic Medium, Human Urine and Efficacy in Mouse Pyelonephritis Model ICAAC: Chicago2001; 2001
    [Google Scholar]
  18. CLSI Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, Approved standard-11th ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2018
    [Google Scholar]
  19. CLSI Performance Standards for Antimicrobial Susceptibility Testing, 29th edition, CLSI supplement M100-S29. Wayne, PA: Clinical and Laboratory Standards Institute; 2019
    [Google Scholar]
  20. CLSI Methods for Determining Bactericidal Activity of Antimicrobial Agent, Approved Guideline-M26-A. Wayne, PA: Clinical and Laboratory Standards Institute; 1999
    [Google Scholar]
  21. Lemaire S, Van Bambeke F, Mingeot-Leclercq M-P, Tulkens PM. Activity of three β-lactams (ertapenem, meropenem and ampicillin) against intraphagocytic Listeria monocytogenes and Staphylococcus aureus . J Antimicrob Chemother 2005; 55:897–904 [View Article]
    [Google Scholar]
  22. Seral C, Barcia-Macay M, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F. Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages. J Antimicrob Chemother 2005; 55:511–517 [View Article]
    [Google Scholar]
  23. Vallet CM, Marquez B, Ngabirano E, Lemaire S, Mingeot-Leclercq M-P et al. Cellular accumulation of fluoroquinolones is not predictive of their intracellular activity: studies with gemifloxacin, moxifloxacin and ciprofloxacin in a pharmacokinetic/pharmacodynamic model of uninfected and infected macrophages. Int J Antimicrob Agents 2011; 38:249–256 [View Article]
    [Google Scholar]
  24. Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunol Rev 2015; 264:182–203 [View Article]
    [Google Scholar]
  25. Rodvold KA, Gotfried MH, Chugh R, Gupta M, Yeole R et al. Intrapulmonary pharmacokinetics of Levonadifloxacin following oral administration of Alalevonadifloxacin to healthy adult subjects. Antimicrobial agents and chemotherapy 2018; 62:
    [Google Scholar]
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