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Zabofloxacin (DW-224a) activity against Neisseria gonorrhoeae including quinolone-resistant strains
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Diagnostic Microbiology and Infectious Disease 62 (2008) 110 – 112 www.elsevier.com/locate/diagmicrobio
Zabofloxacin (DW-224a) activity against Neisseria gonorrhoeae including quinolone-resistant strains Ronald N. Jonesa,b,⁎, Douglas J. Biedenbacha , Paul G. Ambrosec , Matthew A. Wiklerd a JMI Laboratories, North Liberty, IA 52317, USA Tufts University School of Medicine, Boston, MA 02111, USA c Insitute for Clinical Pharmacodynamics at Ordway Research Institute, Albany, NY 12208, USA d Pacific Beach BioSciences, San Diego, CA 92121, USA Received 21 March 2008; accepted 23 May 2008 b
Abstract Zabofloxacin, a new fluoroquinolone compound (DW-224a), was tested by reference agar dilution methods against 35 strains of multiresistant Neisseria gonorrhoeae. The potency of zabofloxacin (MIC50, 0.016 μg/mL) was generally comparable with azithromycin but 8-fold superior to ciprofloxacin. This novel naphthyridine should be explored as an alternative therapy for quinolone-nonsusceptible gonorrhea and Chlamydia trachomatis infections. © 2008 Elsevier Inc. All rights reserved. Keywords: Zabofloxacin; N. gonorrhoeae; DW-224a; Resistance
Zabofloxacin (formerly DW-224a) is a new fluoroquinolone group antimicrobial agent with the following chemical formula: 1-cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazospiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro[1,8] naphthyridine-3-carboxylic acid hydrochloride (Kim et al., 2006; Kwon et al., 2006; Park et al., 2006). Early reports of zabofloxacin in vitro activity showed favorable coverage against respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, β -hemolytic streptococci (Streptococcus pyogenes), and atypical organism species (Kosowska-Shick et al., 2006; Park et al., 2006), associated with very acceptable toxicity (Han et al., 2003) and pharmacokinetic profiles (Kim et al., 2004). In the last decade, the treatment of uncomplicated gonorrhea has been dominated by fluoroquinolones; however, concurrent emergence of quinolone-resistant Neisseria gonorrhoeae (QRNG) strains has been detected (CDC, 2002; Deguchi et al., 1996; Newman et al., 2007; Tanaka
⁎ Corresponding author. JMI Laboratories, North Liberty, IA 52317, USA. Tel.: +1-319-665-3370; fax: +1-319-655-3371. E-mail address: [email protected] (R.N. Jones). 0732-8893/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2008.05.010
et al., 2004; WHO, 2003). Some fluoroquinolones appear to retain some activity against QRNG isolates (Jones et al., 2000), and similar potencies have been noted for zabofloxacin against ciprofloxacin-resistant isolates (Park et al., 2006). Zabofloxacin has an activity comparable with gemifloxacin (MIC90, 1 μg/mL), 4- to 8-fold greater than either moxifloxacin or ciprofloxacin (Jones et al., 2000; Park et al., 2006). In this report, we summarize the comparative activity of zabofloxacin tested against a highly selected challenge collection of gonococci using the reference agar dilution methods of the Clinical and Laboratory Standards Institute (CLSI, 2006). A collection of 35 clinical isolates of N. gonorrhoeae inclusive of 23 (66%) contemporary strains from clinical specimens enriched with 11 (31%) well-characterized resistant phenotypes of N. gonorrhoeae from the JMI Laboratories, North Liberty, IA, collection and the (CLSI, 2006, 2008) quality control (QC) strain were analyzed. The 23 recent clinical strains were obtained from 6 geographically distinct areas where QRNG has been reported to be endemic, which included California (4), Hawaii (4), New York (3), Ohio (4), Oregon (3), and Washington state (5). The 11 well-characterized resistant phenotypes included 5 QRNG (ciprofloxacin-intermediate) isolates.
R.N. Jones et al. / Diagnostic Microbiology and Infectious Disease 62 (2008) 110–112
most comparable in potency with ceftriaxone (MIC50, ≤0.008 μg/mL) against fluoroquinolone-susceptible strains and inhibited all strains at ≤1 μg/mL. Ciprofloxacin MIC values were generally 4- to 8-fold higher than those found for zabofloxacin (MIC90, 0.5 versus 4 μg/mL). These findings confirm the report by Park et al. (2006) who used 27 strains and found an MIC 90 of 1 μg/mL for zabofloxacin (ciprofloxacin MIC90, 8 μg/mL). The zabofloxacin MIC50 for the ciprofloxacin-susceptible, ciprofloxacin-intermediate, and ciprofloxacin-resistant subsets increased from 0.008 to 0.03–0.5 μg/mL, respectively. In contrast, zabofloxacin MIC50 results did not significantly vary as the penicillin MIC values were elevated from susceptible (0.008 μg/mL) to intermediate (0.03 μg/mL) to resistant (0.016 μg/mL, data not shown) levels. This small sample of highly selected N. gonorrhoeae strains with well-characterized and diverse resistances clearly demonstrates that zabofloxacin has the highest activity against QRNG and affirms prior publications and similarities to potencies described for gemifloxacin (Jones et al., 2000; Newman et al., 2007; Park et al., 2006). Because zabofloxacin exhibits acceptable safety at dosing up to 800 mg (data on file, Pacific Beach BioSciences, San Diego, CA), potential single-dose or short-course regimens should be explored to treat uncomplicated gonorrhea caused by QRNG. Such studies are urgently needed to address the contemporary management of the most prevalent sexually transmitted diseases (gonorrhea with or without Chlamydia trachomatis disease).
Table 1 MIC50, MIC90, and MIC range and susceptibility rates for 6 antimicrobials tested against 35 N. gonorrhoeae with elevated resistance rates Antimicrobial
Zabofloxacin Ciprofloxacin Penicillin Ceftriaxone Tetracycline Azithromycin
MIC (μg/mL)
% Susceptible/ resistant
50%
90%
Range
0.016 0.06 0.25 ≤0.008 1 0.25
0.5 4 N4 0.06 N4 0.5
0.002 to 1 ≤0.008 to N4 ≤0.008 to N4 ≤0.008 to 0.12 0.12 to N4 0.06 to 2
111
NA/NA 60/17 29/23 100/– 23/34 NA/NA
NA = breakpoint criteria not available.
MICs of 6 antimicrobial agents were determined by the reference agar dilution method using GC agar base and a defined supplement that is most similar to IsoVitaleX but without 25.9 g of the L-cysteine hydrochloride component (CLSI, 2006, 2008; Jones et al., 1989). The antimicrobial agents tested were zabofloxacin (Dong Wha Pharmaceutical Industry, Seoul, Korea), azithromycin, ceftriaxone, ciprofloxacin, penicillin, and tetracycline, and the results were interpreted according to the CLSI (2008) M100-S18 standard, where available. For azithromycin, breakpoint criteria have not been established, and this compound has not been recommended for treatment of gonorrhea because of documented failures (1-g dose), rapid emergence of resistance (MICs, ≥0.5 μg/mL), and higher costs (Newman et al., 2007). All MIC results were validated using the following QC strains: N. gonorrhoeae ATCC 49226, Staphylococcus aureus ATCC 29213, and Enterococcus faecalis ATCC 29212; all QC values were within published MIC ranges (CLSI, 2008). Using the CLSI (2008) breakpoint criteria, the collection of gonococcal strains showed low susceptible rates of 60%, 29%, and 23% for ciprofloxacin, penicillin G (8 β-lactamase producers), and tetracyclines, respectively (Table 1). Ceftriaxone retained excellent potency (MIC90, 0.06 μg/mL), and azithromycin MIC values ranged to 2 μg/mL with only 80% of strains having an MIC at ≤0.25 μg/mL. Table 2 illustrates the MIC population distributions of the 35 N. gonorrhoeae strains tested against zabofloxacin and 5 comparison agents. Zabofloxacin (MIC50, 0.016 μg/mL) was
References CDC (2002) Centers for Disease Control and Prevention. Increases in fluoroquinolone-resistant Neisseria gonorrhoeae—Hawaii and California, 2001. Morb Mort Wkly Rep 51:1041–1044. Clinical and Laboratory Standards Institute (2006) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—seventh edition, M7-A7. Wayne, PA: CLSI. Clinical and Laboratory Standards Institute (2008) Performance standards for antimicrobial susceptibility testing, 18th informational supplement, M100-S18. Wayne, PA: CLSI. Deguchi T, Yasuda M, Nakano M, Ozeki S, Ezaki T, Saito I, Kawada Y (1996) Quinolone-resistant Neisseria gonorrhoeae: correlation of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of
Table 2 MIC distributions for 35 strains of N. gonorrhoeae tested against zabofloxacin and 5 comparison agents Antimicrobial
Zabofloxacin Ciprofloxacin Penicillin Ceftriaxone Tetracycline Azithromycin
Occurrences at MIC (μg/mL) ≤0.002
0.004
0.008
0.016
0.03
0.06
0.12
0.25
0.5
1
2
≥4
1 – – – – –
1 – – – – –
13 17 1 18 0 0
4 0 7 6 0 0
7 0 0 6 0 0
1 4 2 3 0 1
1 4 1 2 6 14
2 2 7 0 2 13
4 2 8 0 8 5
1 1 1 0 7 1
0 0 2 0 7 1
0 5 6 0 5 0
– = untested concentration.
112
R.N. Jones et al. / Diagnostic Microbiology and Infectious Disease 62 (2008) 110–112
topoisomerase IV with antimicrobial susceptibility profiles. Antimicrob Agents Chemother 40:1020–1023. Han J, Kim JC, Chung MK, Kim B, Choi DR (2003) Subacute toxicity and toxicokinetics of a new antibiotic, DW-224a, after single and 4-week repeated oral administration in dogs. Biol Pharm Bull 26:832–839. Jones RN, Gavan TL, Thornsberry C, Fuchs PC, Gerlach EH, Knapp JS, Murray P, Washington II JA (1989) Standardization of disk diffusion and agar dilution susceptibility tests for Neisseria gonorrhoeae: interpretive criteria and quality control guidelines for ceftriaxone, penicillin, spectinomycin, and tetracycline. J Clin Microbiol 27:2758–2766. Jones RN, Deshpande LM, Erwin ME, Barrett MS, Beach ML (2000) Anti-gonococcal activity of gemifloxacin against fluoroquinoloneresistant strains and a comparison of agar dilution and Etest methods. J Antimicrob Chemother 45(Suppl 1):67–70. Kim EJ, Shin WH, Kim KS, Han SS (2004) Safety pharmacology of DW224a, a novel fluoroquinolone antibiotic agent. Drug Chem Toxicol 27:295–307. Kim HJ, Seol MJ, Park HS, Choi DR, Seong SK, Shin HK, Kwak JH (2006) Antimicrobial activity of DW-224a, a new fluoroquinolone, against Streptococcus pneumoniae. J Antimicrob Chemother 57:1256–1258.
Kosowska-Shick K, Credito K, Pankuch GA, Lin G, Bozdogan B, McGhee P, Dewasse B, Choi DR, Ryu JM, Appelbaum PC (2006) Antipneumococcal activity of DW-224a, a new quinolone, compared to those of eight other agents. Antimicrob Agents Chemother 50:2064–2071. Kwon AR, Min YH, Ryu JM, Choi DR, Shim MJ, Choi EC (2006) In vitro and in vivo activities of DW-224a, a novel fluoroquinolone antibiotic agent. J Antimicrob Chemother 58:684–688. Newman LM, Moran JS, Workowski KA (2007) Update on the management of gonorrhea in adults in the United States. Clin Infect Dis 44(Suppl 3): S84–S101. Park HS, Kim HJ, Seol MJ, Choi DR, Choi EC, Kwak JH (2006) In vitro and in vivo antibacterial activities of DW-224a, a new fluoronaphthyridone. Antimicrob Agents Chemother 50:2261–2264. Tanaka M, Nakayama H, Notomi T, Irie S, Tsunoda Y, Okadome A, Saika T, Kobayashi I (2004) Antimicrobial resistance of Neisseria gonorrhoeae in Japan, 1993–2002: continuous increasing of ciprofloxacin-resistant isolates. Int J Antimicrob Agents 24(Suppl 1):S15–S22. WHO (2003) World Health Organization. Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific Region, 2002. Commun Dis Intell 27:488–491.
Diagnostic Microbiology and Infectious Disease 62 (2008) 110 – 112 www.elsevier.com/locate/diagmicrobio
Zabofloxacin (DW-224a) activity against Neisseria gonorrhoeae including quinolone-resistant strains Ronald N. Jonesa,b,⁎, Douglas J. Biedenbacha , Paul G. Ambrosec , Matthew A. Wiklerd a JMI Laboratories, North Liberty, IA 52317, USA Tufts University School of Medicine, Boston, MA 02111, USA c Insitute for Clinical Pharmacodynamics at Ordway Research Institute, Albany, NY 12208, USA d Pacific Beach BioSciences, San Diego, CA 92121, USA Received 21 March 2008; accepted 23 May 2008 b
Abstract Zabofloxacin, a new fluoroquinolone compound (DW-224a), was tested by reference agar dilution methods against 35 strains of multiresistant Neisseria gonorrhoeae. The potency of zabofloxacin (MIC50, 0.016 μg/mL) was generally comparable with azithromycin but 8-fold superior to ciprofloxacin. This novel naphthyridine should be explored as an alternative therapy for quinolone-nonsusceptible gonorrhea and Chlamydia trachomatis infections. © 2008 Elsevier Inc. All rights reserved. Keywords: Zabofloxacin; N. gonorrhoeae; DW-224a; Resistance
Zabofloxacin (formerly DW-224a) is a new fluoroquinolone group antimicrobial agent with the following chemical formula: 1-cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazospiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro[1,8] naphthyridine-3-carboxylic acid hydrochloride (Kim et al., 2006; Kwon et al., 2006; Park et al., 2006). Early reports of zabofloxacin in vitro activity showed favorable coverage against respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, β -hemolytic streptococci (Streptococcus pyogenes), and atypical organism species (Kosowska-Shick et al., 2006; Park et al., 2006), associated with very acceptable toxicity (Han et al., 2003) and pharmacokinetic profiles (Kim et al., 2004). In the last decade, the treatment of uncomplicated gonorrhea has been dominated by fluoroquinolones; however, concurrent emergence of quinolone-resistant Neisseria gonorrhoeae (QRNG) strains has been detected (CDC, 2002; Deguchi et al., 1996; Newman et al., 2007; Tanaka
⁎ Corresponding author. JMI Laboratories, North Liberty, IA 52317, USA. Tel.: +1-319-665-3370; fax: +1-319-655-3371. E-mail address: [email protected] (R.N. Jones). 0732-8893/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2008.05.010
et al., 2004; WHO, 2003). Some fluoroquinolones appear to retain some activity against QRNG isolates (Jones et al., 2000), and similar potencies have been noted for zabofloxacin against ciprofloxacin-resistant isolates (Park et al., 2006). Zabofloxacin has an activity comparable with gemifloxacin (MIC90, 1 μg/mL), 4- to 8-fold greater than either moxifloxacin or ciprofloxacin (Jones et al., 2000; Park et al., 2006). In this report, we summarize the comparative activity of zabofloxacin tested against a highly selected challenge collection of gonococci using the reference agar dilution methods of the Clinical and Laboratory Standards Institute (CLSI, 2006). A collection of 35 clinical isolates of N. gonorrhoeae inclusive of 23 (66%) contemporary strains from clinical specimens enriched with 11 (31%) well-characterized resistant phenotypes of N. gonorrhoeae from the JMI Laboratories, North Liberty, IA, collection and the (CLSI, 2006, 2008) quality control (QC) strain were analyzed. The 23 recent clinical strains were obtained from 6 geographically distinct areas where QRNG has been reported to be endemic, which included California (4), Hawaii (4), New York (3), Ohio (4), Oregon (3), and Washington state (5). The 11 well-characterized resistant phenotypes included 5 QRNG (ciprofloxacin-intermediate) isolates.
R.N. Jones et al. / Diagnostic Microbiology and Infectious Disease 62 (2008) 110–112
most comparable in potency with ceftriaxone (MIC50, ≤0.008 μg/mL) against fluoroquinolone-susceptible strains and inhibited all strains at ≤1 μg/mL. Ciprofloxacin MIC values were generally 4- to 8-fold higher than those found for zabofloxacin (MIC90, 0.5 versus 4 μg/mL). These findings confirm the report by Park et al. (2006) who used 27 strains and found an MIC 90 of 1 μg/mL for zabofloxacin (ciprofloxacin MIC90, 8 μg/mL). The zabofloxacin MIC50 for the ciprofloxacin-susceptible, ciprofloxacin-intermediate, and ciprofloxacin-resistant subsets increased from 0.008 to 0.03–0.5 μg/mL, respectively. In contrast, zabofloxacin MIC50 results did not significantly vary as the penicillin MIC values were elevated from susceptible (0.008 μg/mL) to intermediate (0.03 μg/mL) to resistant (0.016 μg/mL, data not shown) levels. This small sample of highly selected N. gonorrhoeae strains with well-characterized and diverse resistances clearly demonstrates that zabofloxacin has the highest activity against QRNG and affirms prior publications and similarities to potencies described for gemifloxacin (Jones et al., 2000; Newman et al., 2007; Park et al., 2006). Because zabofloxacin exhibits acceptable safety at dosing up to 800 mg (data on file, Pacific Beach BioSciences, San Diego, CA), potential single-dose or short-course regimens should be explored to treat uncomplicated gonorrhea caused by QRNG. Such studies are urgently needed to address the contemporary management of the most prevalent sexually transmitted diseases (gonorrhea with or without Chlamydia trachomatis disease).
Table 1 MIC50, MIC90, and MIC range and susceptibility rates for 6 antimicrobials tested against 35 N. gonorrhoeae with elevated resistance rates Antimicrobial
Zabofloxacin Ciprofloxacin Penicillin Ceftriaxone Tetracycline Azithromycin
MIC (μg/mL)
% Susceptible/ resistant
50%
90%
Range
0.016 0.06 0.25 ≤0.008 1 0.25
0.5 4 N4 0.06 N4 0.5
0.002 to 1 ≤0.008 to N4 ≤0.008 to N4 ≤0.008 to 0.12 0.12 to N4 0.06 to 2
111
NA/NA 60/17 29/23 100/– 23/34 NA/NA
NA = breakpoint criteria not available.
MICs of 6 antimicrobial agents were determined by the reference agar dilution method using GC agar base and a defined supplement that is most similar to IsoVitaleX but without 25.9 g of the L-cysteine hydrochloride component (CLSI, 2006, 2008; Jones et al., 1989). The antimicrobial agents tested were zabofloxacin (Dong Wha Pharmaceutical Industry, Seoul, Korea), azithromycin, ceftriaxone, ciprofloxacin, penicillin, and tetracycline, and the results were interpreted according to the CLSI (2008) M100-S18 standard, where available. For azithromycin, breakpoint criteria have not been established, and this compound has not been recommended for treatment of gonorrhea because of documented failures (1-g dose), rapid emergence of resistance (MICs, ≥0.5 μg/mL), and higher costs (Newman et al., 2007). All MIC results were validated using the following QC strains: N. gonorrhoeae ATCC 49226, Staphylococcus aureus ATCC 29213, and Enterococcus faecalis ATCC 29212; all QC values were within published MIC ranges (CLSI, 2008). Using the CLSI (2008) breakpoint criteria, the collection of gonococcal strains showed low susceptible rates of 60%, 29%, and 23% for ciprofloxacin, penicillin G (8 β-lactamase producers), and tetracyclines, respectively (Table 1). Ceftriaxone retained excellent potency (MIC90, 0.06 μg/mL), and azithromycin MIC values ranged to 2 μg/mL with only 80% of strains having an MIC at ≤0.25 μg/mL. Table 2 illustrates the MIC population distributions of the 35 N. gonorrhoeae strains tested against zabofloxacin and 5 comparison agents. Zabofloxacin (MIC50, 0.016 μg/mL) was
References CDC (2002) Centers for Disease Control and Prevention. Increases in fluoroquinolone-resistant Neisseria gonorrhoeae—Hawaii and California, 2001. Morb Mort Wkly Rep 51:1041–1044. Clinical and Laboratory Standards Institute (2006) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—seventh edition, M7-A7. Wayne, PA: CLSI. Clinical and Laboratory Standards Institute (2008) Performance standards for antimicrobial susceptibility testing, 18th informational supplement, M100-S18. Wayne, PA: CLSI. Deguchi T, Yasuda M, Nakano M, Ozeki S, Ezaki T, Saito I, Kawada Y (1996) Quinolone-resistant Neisseria gonorrhoeae: correlation of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of
Table 2 MIC distributions for 35 strains of N. gonorrhoeae tested against zabofloxacin and 5 comparison agents Antimicrobial
Zabofloxacin Ciprofloxacin Penicillin Ceftriaxone Tetracycline Azithromycin
Occurrences at MIC (μg/mL) ≤0.002
0.004
0.008
0.016
0.03
0.06
0.12
0.25
0.5
1
2
≥4
1 – – – – –
1 – – – – –
13 17 1 18 0 0
4 0 7 6 0 0
7 0 0 6 0 0
1 4 2 3 0 1
1 4 1 2 6 14
2 2 7 0 2 13
4 2 8 0 8 5
1 1 1 0 7 1
0 0 2 0 7 1
0 5 6 0 5 0
– = untested concentration.
112
R.N. Jones et al. / Diagnostic Microbiology and Infectious Disease 62 (2008) 110–112
topoisomerase IV with antimicrobial susceptibility profiles. Antimicrob Agents Chemother 40:1020–1023. Han J, Kim JC, Chung MK, Kim B, Choi DR (2003) Subacute toxicity and toxicokinetics of a new antibiotic, DW-224a, after single and 4-week repeated oral administration in dogs. Biol Pharm Bull 26:832–839. Jones RN, Gavan TL, Thornsberry C, Fuchs PC, Gerlach EH, Knapp JS, Murray P, Washington II JA (1989) Standardization of disk diffusion and agar dilution susceptibility tests for Neisseria gonorrhoeae: interpretive criteria and quality control guidelines for ceftriaxone, penicillin, spectinomycin, and tetracycline. J Clin Microbiol 27:2758–2766. Jones RN, Deshpande LM, Erwin ME, Barrett MS, Beach ML (2000) Anti-gonococcal activity of gemifloxacin against fluoroquinoloneresistant strains and a comparison of agar dilution and Etest methods. J Antimicrob Chemother 45(Suppl 1):67–70. Kim EJ, Shin WH, Kim KS, Han SS (2004) Safety pharmacology of DW224a, a novel fluoroquinolone antibiotic agent. Drug Chem Toxicol 27:295–307. Kim HJ, Seol MJ, Park HS, Choi DR, Seong SK, Shin HK, Kwak JH (2006) Antimicrobial activity of DW-224a, a new fluoroquinolone, against Streptococcus pneumoniae. J Antimicrob Chemother 57:1256–1258.
Kosowska-Shick K, Credito K, Pankuch GA, Lin G, Bozdogan B, McGhee P, Dewasse B, Choi DR, Ryu JM, Appelbaum PC (2006) Antipneumococcal activity of DW-224a, a new quinolone, compared to those of eight other agents. Antimicrob Agents Chemother 50:2064–2071. Kwon AR, Min YH, Ryu JM, Choi DR, Shim MJ, Choi EC (2006) In vitro and in vivo activities of DW-224a, a novel fluoroquinolone antibiotic agent. J Antimicrob Chemother 58:684–688. Newman LM, Moran JS, Workowski KA (2007) Update on the management of gonorrhea in adults in the United States. Clin Infect Dis 44(Suppl 3): S84–S101. Park HS, Kim HJ, Seol MJ, Choi DR, Choi EC, Kwak JH (2006) In vitro and in vivo antibacterial activities of DW-224a, a new fluoronaphthyridone. Antimicrob Agents Chemother 50:2261–2264. Tanaka M, Nakayama H, Notomi T, Irie S, Tsunoda Y, Okadome A, Saika T, Kobayashi I (2004) Antimicrobial resistance of Neisseria gonorrhoeae in Japan, 1993–2002: continuous increasing of ciprofloxacin-resistant isolates. Int J Antimicrob Agents 24(Suppl 1):S15–S22. WHO (2003) World Health Organization. Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific Region, 2002. Commun Dis Intell 27:488–491.