In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates
Agnez Jönsson
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Search for more papers by this authorSunniva Foerster
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Institute for Infectious Diseases, University of Bern, Bern, Switzerland
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
Search for more papers by this authorDaniel Golparian
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Search for more papers by this authorRyoichi Hamasuna
Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Search for more papers by this authorSusanne Jacobsson
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Search for more papers by this authorMagnus Lindberg
Department of Dermatovenerology, Örebro University Hospital, Örebro, Sweden
Search for more papers by this authorJörgen Skov Jensen
Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark
Search for more papers by this authorMakoto Ohnishi
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Magnus Unemo
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Magnus Unemo, WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, SE-701 85 Örebro, Sweden. e-mail: [email protected]Search for more papers by this authorAgnez Jönsson
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Search for more papers by this authorSunniva Foerster
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Institute for Infectious Diseases, University of Bern, Bern, Switzerland
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
Search for more papers by this authorDaniel Golparian
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Search for more papers by this authorRyoichi Hamasuna
Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
Search for more papers by this authorSusanne Jacobsson
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Search for more papers by this authorMagnus Lindberg
Department of Dermatovenerology, Örebro University Hospital, Örebro, Sweden
Search for more papers by this authorJörgen Skov Jensen
Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark
Search for more papers by this authorMakoto Ohnishi
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Magnus Unemo
WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
Magnus Unemo, WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, SE-701 85 Örebro, Sweden. e-mail: [email protected]Search for more papers by this authorAbstract
Treatment of gonorrhoea is a challenge worldwide because of emergence of resistance in N. gonorrhoeae to all therapeutic antimicrobials available and novel antimicrobials are imperative. The newer-generation fluoroquinolone sitafloxacin, mostly used for respiratory tract infections in Japan, can have a high in vitro activity against gonococci. However, only a limited number of recent antimicrobial-resistant isolates from Japan have been examined. We investigated the sitafloxacin activity against a global gonococcal panel (250 isolates cultured in 1991–2013), including multidrug-resistant geographically, temporally and genetically diverse isolates, and performed time-kill curve analysis for sitafloxacin. The susceptibility to sitafloxacin (agar dilution) and seven additional therapeutic antimicrobials (Etest) was determined. Sitafloxacin was rapidly bactericidal, and the MIC range, MIC50 and MIC90 was ≤0.001–1, 0.125 and 0.25 mg/L, respectively. There was a high correlation between the MICs of sitafloxacin and ciprofloxacin; however, the MIC50 and MIC90 of sitafloxacin were 6-fold and >6-fold lower, respectively. Sitafloxacin might be an option for particularly dual antimicrobial therapy of gonorrhoea and for cases with ceftriaxone resistance or allergy. However, further in vitro and particularly in vivo evaluations of potential resistance, pharmacokinetics/pharmacodynamics and ideal dosing for gonorrhoea, as well as performance of randomized controlled clinical, trials are crucial.
References
- 1Newman LM, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One 2015; 10: e0143304.
- 2 World Health Organization (WHO). Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. 2012. http://whqlibdoc.who.int/publications/2012/9789241503501_eng.pdf?ua=1
- 3Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 2014; 27: 587–613.
- 4Unemo M, Jensen JS. Antimicrobial-resistant sexually transmitted infections: gonorrhoea and Mycoplasma genitalium. Nat Rev Urol 2017; 14: 139–52.
- 5Unemo M. Current and future antimicrobial treatment of gonorrhoea - the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis 2015; 15: 364.
- 6Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S, Iwasaku K, et al. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother 2011; 55: 3538–45.
- 7Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant N. gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012; 56: 1273–80.
- 8Cámara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D, Andreu A, et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother 2012; 67: 1858–60.
- 9Bignell C, Unemo M, European STI Guidelines Editorial Board. European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS 2012; 2013: 85–92.
- 10 Australasian Sexual Health Alliance (ASHA). Australian STI Management Guidelines for Use in Primary Care. www.sti.guidelines.org.au/sexually-transmissible-infections/gonorrhoea#management (Last updated: 27 June, 2016).
- 11Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64: 1–137.
- 12 Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections. Gonococcal Infections Chapter. 2013. www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/assets/pdf/section-5-6-eng.pdf
- 13 World Health Organization, Department of Reproductive Health and Research. WHO Guidelines for the Treatment of Neisseria gonorrhoeae. 2016. http://www.ncbi.nlm.nih.gov/pubmed/27512795.
- 14Fifer H, Natarajan U, Jones L, Alexander S, Hughes G, Golparian D, et al. Failure of dual antimicrobial therapy in treatment of gonorrhea. N Engl J Med 2016; 374: 2504–6.
- 15Keating GM. Sitafloxacin: in bacterial infections. Drugs 2011; 71: 731–44.
- 16Hamasuna R, Yasuda M, Ishikawa K, Uehara S, Takahashi S, Hayami H, et al. Nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan. J Infect Chemother 2013; 19: 571–8.
- 17Hamasuna R, Yasuda M, Ishikawa K, Uehara S, Hayami H, Takahashi S, et al. The second nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan, 2012–2013. J Infect Chemother 2015; 21: 340–5.
- 18Deguchi T, Yasuda M, Nakano M, Kanematsu E, Ozeki S, Ishihara S, et al. Antimicrobial activity of a new fluoroquinolone, DU-6859a, against quinolone-resistant clinical isolates of Neisseria gonorrhoeae with genetic alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV. J Antimicrob Chemother 1997; 39: 247–9.
- 19Tanaka M, Nakayama H, Haraoka M, Saika T, Kobayashi I, Naito S. Susceptibilities of Neisseria gonorrhoeae isolates containing amino acid substitutions in GyrA, with or without substitutions in ParC, to newer fluoroquinolones and other antibiotics. Antimicrob Agents Chemother 2000; 44: 192–5.
- 20Milatovic D, Schmitz F-J, Brisse S, Verhoef J, Fluit AC. In vitro activities of sitafloxacin (DU-6859a) and six other fluoroquinolones against 8,796 clinical bacterial isolates. Antimicrob Agents Chemother 2000; 44: 1102–7.
- 21Tapsall JW, Ndowa F, Lewis DA, Unemo M. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev Anti Infect Ther 2009; 7: 821–34.
- 22Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J Antimicrob Chemother 2009; 63: 1142–51.
- 23Unemo M, Golparian D, Sánchez-Busó L, Grad Y, Jacobsson S, Ohnishi M, et al. The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization. J Antimicrob Chemother 2016; 71: 3096–108.
- 24Unemo M, Olcén P, Berglund T, Albert J, Fredlund H. Molecular epidemiology of Neisseria gonorrhoeae: sequence analysis of the porB gene confirms presence of two circulating strains. J Clin Microbiol 2002; 40: 3741–9.
- 25 Clinical and Laboratory Standards Institute. 2014 Performance standards for antimicrobial susceptability testing; 25th informational supplement. CLSI document M100-S24. Wayne, PA: Clinical and Laboratory Standards Institute, 2014; Available at: http://clsi.org, Accessed 01/13, 2017.
- 26Foerster S, Unemo M, Hathaway LJ, Low N, Althaus CL. Time-kill curve analysis and pharmacodynamic modelling for in vitro evaluation of antimicrobials against Neisseria gonorrhoeae. BMC Microbiol 2016; 16: 216.
- 27Foerster S, Golparian D, Jacobsson S, Hathaway LJ, Low N, Shafer WM, et al. Genetic resistance determinants, in vitro time-kill curve analysis and pharmacodynamic functions for the novel topoisomerase II inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae. Front Microbiol 2015; 6: 1377.
- 28Wade JJ, Graver MA. A fully defined, clear and protein-free liquid medium permitting dense growth of Neisseria gonorrhoeae from very low inocula. FEMS Microbiol Lett 2007; 273: 35–7.
- 29Chen CY, Nace GW, Irwin PL. A 6 × 6 drop plate method for simultaneous colony counting and MPN enumeration of Campylobacter jejuni, Listeria monocytogenes, and Escherichia coli. J Microbiol Methods 2003; 55: 475–9.
- 30Jacobsson S, Golparian D, Alm RA, Huband M, Mueller J, Jensen JS, et al. High in vitro activity of the novel spiropyrimidinetrione AZD0914, a DNA gyrase inhibitor, against multidrug-resistant Neisseria gonorrhoeae isolates suggests a new effective option for oral treatment of gonorrhea. Antimicrob Agents Chemother 2014; 58: 5585–8.
- 31Onodera S, Hori S. Clinical study of sitafloxacin in the treatment of male gonococcal urethritis. Jpn J Chemother 2008; 56(Suppl. 1): 146–53. In Japanese.
- 32Payne GS, Collins DJ, Loynds P, Mould G, Murphy PS, Dzik-Jurasz ASK, et al. Quantitative assessment of the hepatic pharmacokinetics of the antimicrobial sitafloxacin in humans using in vivo 19F magnetic resonance spectroscopy. Br J Clin Pharmacol 2005; 59: 244–8.
- 33Hori S, Kobayashi H, Saito A. Clinical trials of sitafloxacin (DU-6859a): clinical safety profile [abstract no. L-489 plus poster]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17-20; Chicago (IL).
- 34Nakashima M, Uematsu T, Kosuge K, Umemura K, Hakusui H, Tanaka M. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers. Antimicrob Agents Chemother 1995; 39: 170–1.
- 35O'Grady J, Briggs A, Atarashi S, Kobayashi H, Smith RL, Ward J, et al. Pharmacokinetics and absolute bioavailability of sitafloxacin, a new fluoroquinolone antibiotic, in healthy male and female Caucasian subjects. Xenobiotica Fate Foreign Compd Biol Syst 2001; 31: 811–22.
- 36Sadahira T, Wada K, Ikawa K, Morikawa N, Kurahashi H, Yoshioka T, et al. Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue. J Infect Chemother 2017; 23: 214–7.
- 37Wu G, Wu L, Hu X, Zhou H, Liu J, Zhu M, et al. Pharmacokinetics and safety of sitafloxacin after single oral doses in healthy volunteers. Int J Clin Pharmacol Ther 2014; 52: 1037–44.
- 38Ito S, Yasuda M, Seike K, Sugawara T, Tsuchiya T, Yokoi S, et al. Clinical and microbiological outcomes in treatment of men with non-gonococcal urethritis with a 100-mg twice-daily dose regimen of sitafloxacin. J Infect Chemother 2012; 18: 414–8.
- 39Takahashi S, Hamasuna R, Yasuda M, Ito S, Ito K, Kawai S, et al. Clinical efficacy of sitafloxacin 100 mg twice daily for 7 days for patients with non-gonococcal urethritis. J Infect Chemother 2013; 19: 941–5.
