Mutant prevention concentration of ozenoxacin for quinolone-susceptible or -resistant Staphylococcus aureus and Staphylococcus epidermidis

Autoři: Y. López aff001;  M. Tato aff002;  D. Gargallo-Viola aff003;  R. Cantón aff002;  J. Vila aff001;  I. Zsolt aff005
Působiště autorů: Institute of Global Health of Barcelona, Barcelona, Spain aff001;  Department of Clinical Microbiology, Hospital Universitario Ramón y Cajal & Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain aff002;  ABAC Therapeutics, Barcelona, Spain aff003;  Department of Clinical Microbiology, Hospital Clinic, School of Medicine, University of Barcelona, Spain aff004;  Medical Department, Ferrer Internacional, Barcelona, Spain aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223326


Ozenoxacin (OZN) belongs to a new generation of non-fluorinated quinolones for the topical treatment of skin infections which has shown to be effective in the treatment of susceptible and resistant Gram-positive cocci. The mutant prevention concentration (MPC) of ozenoxacin, levofloxacin and ciprofloxacin was determined in quinolone-susceptible and -resistant strains including methicillin-susceptible S. aureus, methicillin-resistant S. aureus, methicillin-susceptible S. epidermidis and methicillin-resistant S. epidermidis with different profile of mutation in the quinolone resistance determining regions (QRDR). The MPC value of OZN for the methicillin-susceptible S. aureus strain susceptible to quinolones, without mutations in QRDR, was 0.05 mg/L, being 280-fold lower than that observed with ciprofloxacin and levofloxacin. In methicillin-susceptible and–resistant S. aureus strains with mutations in the gyrA or/and grlA genes the MPC of OZN went from 0.1 to 6 mg/L, whereas the MPC of levofloxacin and ciprofloxacin was > 50 mg/L for the same strains. For methicillin-susceptible and–resistant S. epidermidis the results were similar to those abovementioned for S. aureus. According to our results, the MPC of OZN was far below the quantity of ozenoxacin achieved in the epidermal layer, suggesting that the in vivo selection of mutants, if it occurs, will take place at low frequency. Ozenoxacin is an excellent candidate for the treatment of bacterial infections caused by susceptible and quinolone-resistant staphylococci isolated usually from skin infections.

Klíčová slova:

Antimicrobial resistance – Methicillin-resistant Staphylococcus aureus – Mutant strains – Skin infections – Staphylococcus – Staphylococcus aureus – Staphylococcus epidermidis – Staphylococcal infection


1. Marsilio F, Di Francesco CE, Di Martino B. Coagulase-Positive and Coagulase-Negative Staphylococci Animal Diseases. Pet-To-Man Travel Staphylococci 2018; 43–50.

2. Gad Gamal Fadl M., El-Ghafar Abd El-Ghafar F. Abd, El-Domany Ramadan A. A., Hashem Zeinab Shawky. Epidemiology and antimicrobial resistance of staphylococci isolated from different infectious diseases. Braz. J. Microbiol. 2010 June 28; 41 (2): 333–344 doi: 10.1590/S1517-838220100002000012 24031501

3. Maina EK, Kiiyukia C, Wamae CN, Waiyaki PG and Kariuki S. Characterization of methicillin-resistant Staphylococcus aureus from skin and soft tissue infections in patients in Nairobi, Kenya. Int J Infect Dis 2013; 17: e115–9 doi: 10.1016/j.ijid.2012.09.006 23092752

4. Sladden MJ, Johnston GA. Common skin infections in children. Aust Fam Physician 2004; 329: 95–99.

5. Otto M. Staphylococcus epidermidis—the ‘accidental’ pathogen. Nat Publ Gr 2009; 7: 555–567.

6. Pereira LB. Impetigo—Review. An Bras Dermatol. 2014 Mar-Apr; 89(2): 293–299. doi: 10.1590/abd1806-4841.20142283 24770507

7. Koning S, van der Sande R, Verhagen AP, van Suijlekom-Smit LW, Morris AD, Butler CC., et al. Interventions for impetigo. Cochrane Database of Systematic Reviews; 2012. Jan 18;1:CD003261.

8. Vila J, Hebert AA, López Y, García-Castillo M, Cantón R, Torrelo A, et al. Ozenoxacin: a review of preclinical and clinical efficacy. Expert Rev Anti Infect Ther 2019; 17: 159–168. doi: 10.1080/14787210.2019.1573671 30686133

9. Copin R, Sause WE, Fulmer Y, Balasubramanian D, Dyzenhaus S, Ahmed JMet al. Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci. 2019; 116(5): 1745–1754. doi: 10.1073/pnas.1814265116 30635416

10. Hebert AA, Albareda N, Rosen T, Torrelo A, Grimalt R, Rosenberg N, Zsolt I MX. Topical Antibacterial Agent for Treatment of Adult and Pediatric Patients With Impetigo: Pooled Analysis of Phase 3 Clinical Trials. Drugs Dermatol 2018; 17: 1046–1052.

11. Yamakawa T, Mitsuyama J, Hayashi K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J Antimicrob Chemother 2002; 49: 455–465. doi: 10.1093/jac/49.3.455 11864945

12. López Y, Tato M, Espinal P, Garcia-Alonso F, Gargallo-Viola D, Cantón R, et al. In vitro activity of Ozenoxacin against Gram-positive bacteria susceptible and resistant to other quinolones. Antimicrob Agents Chemother 2013 Dec; 57 (12): 6389–92. doi: 10.1128/AAC.01509-13 24080666

13. López Y, Tato M, Espinal P, Garcia-Alonso F, Gargallo-Viola D, Canton R, et al. In vitro selection of mutants resistant to ozenoxacin compared with levofloxacin and ciprofloxacin in Gram-positive cocci. J. Antimicrob. Chemother 2014 Jan; 70 (1):57–61. doi: 10.1093/jac/dku375 25261416

14. Canton R, Morrissey I, Vila J, Tato M, García-Castillo M, López Y, et al. Comparative in vitro antibacterial activity of ozenoxacin against Gram-positive clinical isolates. Future Microbiol 2018; 13: 3–19. doi: 10.2217/fmb-2017-0289 29745242

15. Kanayama S, Ikeda F, Okamoto K, Nakajima A, Matsumoto T, Ishii R, et al. In vitro antimicrobial activity of ozenoxacin against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus and Streptococcus pyogenes isolated from clinical cutaneous specimens in Japan. J Infect Chemother 2016; 22: 720–723. doi: 10.1016/j.jiac.2016.03.006 27091753

16. Fàbrega A, Madurga S, Giralt E, et al. Mechanism of action of and resistance to quinolones. Microb Biotechnol 2009; 2: 40–61. doi: 10.1111/j.1751-7915.2008.00063.x 21261881

17. Dwyer DJ, Kohanski MA, Hayete B, Collins JJ. Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol Syst Biol. 2007; 3:91 doi: 10.1038/msb4100135 17353933

18. Zhao X, Hong Y, Drlica K. Moving forward with reactive oxygen species involvement in antimicrobial lethality. J Antimicrob Chemother 2015; 70: 639–642. doi: 10.1093/jac/dku463 25422287

19. Hong Y, Zeng J, Wang X, Drlica K and Zhao X. Post-stress bacterial cell death mediated by reactive oxygen species. Proc Natl Acad Sci 2019; 116 (20): 10064–10071. doi: 10.1073/pnas.1901730116 30948634

20. Hooper DC, Jacoby GA. Mechanisms of drug resistance: quinolone resistance. Ann N Y Acad Sci 2015; 1354: 12–31. doi: 10.1111/nyas.12830 26190223

21. Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 2003; 52: 11–17. doi: 10.1093/jac/dkg269 12805267

22. Drlica K, Zhao X. Mutant Selection Window Hypothesis Updated. Clin Infect Dis 2007; 44: 681–688. doi: 10.1086/511642 17278059

23. Gebru E, Choi MJ, Lee SJ, Damte D and Park SC. Mutant-prevention concentration and mechanism of resistance in clinical isolates and Enrofloxacin/ marbofloxacin-selected mutants of Escherichia coli of canine origin. J Med Microbiol 2011; 60: 1512–1522. doi: 10.1099/jmm.0.028654-0 21596912

24. Metzler K, Hansen GM, Hedlin P, Harding E, Drlica K, and Blondeau JM. Comparison of minimal inhibitory and mutant prevention drug concentrations of 4 fluoroquinolones against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus. Int J Antimicrob Agents 2004; 24: 161–167. doi: 10.1016/j.ijantimicag.2004.02.021 15288315

25. Liu L, Zhu Y, Hu L, Cheng J, Ye Y, and Li J. Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis. J Antibiot (Tokyo) 2013; 66: 709–12.

26. Remy JM, Tow-Keogh CA, McConnell TS, Dalton JM, and Devito JA. Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization. J Antimicrob Chemother 2012; 67: 2814–20. doi: 10.1093/jac/dks307 22875850

27. Gropper S, Albareda N, Santos B, Febbraro S. Skin tissue exposure of once- versus twice-daily topical ozenoxacin 2% cream: a Phase I study in healthy volunteers. Future Microbiol. 2014;9(8 Suppl):S17–22. doi: 10.2217/fmb.14.83 25209520

28. Y. López, Tato M, Cantón R and Vila J. The effect of Ozenoxacin and other quinolones on topoisomerases type II from Staphylococcus aureus and Escherichia coli. Present 53 rd Intersci Conf Antimicrob Agents Chemother (ICAAC), 2013 sep 10–13, Denver, USA Abstr C1-522c.

29. López Y, García-Castillo M, Garcia-Fernandez S, Gargallo-Viola D, Zsolt I, Cantón et al. Acumulación de Ozenoxacino y otras quinolonas en bacterias Gram Positivas. [Abstract Spanish] Abst 0280 Enferm Infecc Microbiol Clin 2018;36 (Espec Cong 1)146.

Článek vyšel v časopise


2019 Číslo 10