ORIGINAL STUDY

High Prevalence of Azithromycin-Resistant Neisseria gonorrhoeae Isolates With a Multidrug Resistance Phenotype in Fukuoka, Japan Masatoshi Tanaka, MD, PhD,* Ryusaburo Furuya, MD, PhD,* Shinichiro Irie, MD, PhD,* Akiko Kanayama, PhD,† and Intetsu Kobayashi, PhD† Background: The current guidelines recommend a combination of ceftriaxone and azithromycin as a first-line treatment of gonorrhea in the United States and Europe. Despite not being recommended as a first-line regimen in Japan, an oral 2-g dose of azithromycin did become available for gonococcal infections in 2009. Recently, the emergence of azithromycin-resistant Neisseria gonorrhoeae isolates has been reported in several countries, including Japan. Methods: Antimicrobial susceptibility testing was performed on a total of 677 clinical isolates of N. gonorrhoeae obtained from January 2010 to December 2013 in Fukuoka, Japan. A molecular analysis by N. gonorrhoeae multiantigen sequence typing was conducted on the azithromycin-resistant isolates. Results: The proportion of azithromycin-resistant isolates (minimum inhibitory concentration > 0.5 μg/mL) increased significantly from 1.8% in 2010 to 22.6% in 2013 (P < 0.001). Among 50 azithromycin-resistant isolates, 30 (60%) exhibited a resistant phenotype to multiple drugs including cefixime. The 2 predominant sequence types (STs) identified by N. gonorrhoeae multiantigen sequence typing were ST6798 (por allele 4033 and tbpB allele 110) and ST1407 (por allele 908 and tbpB allele 110) at 40.0% (20/50) and 12.0% (6/50), respectively. There was a statistically significant increase of the proportion of ST6798 from 0% (0/19) in 2010–2012 to 64.5% (20/31) in 2013 (P < 0.001). Conclusions: Over the previous 4 years, an increasing prevalence of azithromycin-resistant N. gonorrhoeae isolates with a multidrug-resistant phenotype was observed. Furthermore, the azithromycin-resistant isolates seemed to belong to 2 predominant STs. As a result, continued surveillance of gonococci resistant to antimicrobial agents, including azithromycin in Fukuoka, Japan, is necessary.

T

he increasing prevalence of Neisseria gonorrhoeae isolates resistant to a variety of antimicrobial agents, such as penicillin, tetracycline, ciprofloxacin, and third-generation cephalosporin, has been a worldwide concern.1 Therefore, the current guidelines routinely recommend a combination of ceftriaxone plus azithromycin as a first-line treatment of gonorrhea in the United States2 and Europe.3 On the other hand, the Japanese guidelines for the treatment of gonorrhea recommend a single-dose regimen of injectable antimicrobial agents of ceftriaxone, cefodizime, or spectinomycin.4 Despite not being recommended as a first-line

From the *Department of Urology, Faculty of Medical, Fukuoka University, Fukuoka, Japan; and †Department of Infection Control and Prevention, Faculty of Medicine, Toho University, Tokyo, Japan. Conflict of interest: None declared. Correspondence: Masatoshi Tanaka, MD, PhD, Department of Urology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: [email protected]. Received for publication February 10, 2015, and accepted March 16, 2015. DOI: 10.1097/OLQ.0000000000000279 Copyright © 2015 American Sexually Transmitted Diseases Association All rights reserved.

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regimen in Japan, an oral 2-g single dose of azithromycin did become available for gonococcal infections in 2009.4 Recently, a new concern about the emergence of azithromycin-resistant N. gonorrhoeae isolates was reported in several countries, including Japan.5–8 We herein investigate the recent 4-year trends in the susceptibility to antimicrobial agents, including azithromycin, among N. gonorrhoeae isolates and determine the sequence type (ST) by the N. gonorrhoeae multiantigen sequence typing (NG-MAST) of azithromycin-resistant isolates in Fukuoka, Japan.

MATERIALS AND METHODS N. gonorrhoeae Strains Antimicrobial susceptibility testing was performed on a total of 677 clinical isolates of N. gonorrhoeae that had been obtained from January 2010 to December 2013. All N. gonorrhoeae isolates were consecutively collected from male and female patients with genital gonorrhea attending sexually transmitted infection clinics in Fukuoka, Japan, and included the total number of isolates in each of these years. None of the isolates were repeat isolates from the same patient. The demographic data were unable to be collected for this investigation. The organisms were identified by Gram staining, oxidase activity, and reaction using the Gonochek II test (EY Laboratories, San Mateo, CA). The isolates were stored at −80°C until they were tested.

Antimicrobial Susceptibility Testing The minimum inhibitory concentrations (MICs) for all isolates were determined using an agar dilution method with a GC agar base containing 1% defined growth supplement and serial 2-fold dilutions of antibiotics as specified in the Clinical Laboratory Standards Institute protocol.9 Briefly, the plates were inoculated with approximately 104 colony-forming units/spot of each isolate with a multipoint inoculator. The World Health Organization reference N. gonorrhoeae strains C, F, G, K, L, and P, and N. gonorrhoeae ATCC49226 strain were included as quality controls. The plates were incubated for 24 hours at 37°C in a 5% CO2 atmosphere. The MICs were defined as the lowest antibiotic concentration observed to inhibit bacterial growth. The antimicrobial agents tested were azithromycin, cefixime, ceftriaxone, ciprofloxacin, penicillin, spectinomycin, and tetracycline. The antimicrobial susceptibility results for ciprofloxacin, penicillin, spectinomycin, and tetracycline were interpreted according to the Clinical Laboratory Standards Institute guidelines.9 The Clinical Laboratory Standards Institute does not define resistance to azithromycin, cefixime, or ceftriaxone. Therefore, the clinical breakpoints set by the European Committee on Antimicrobial Susceptibility Testing (version 3.1) were used for the interpretation of the susceptibility results for these 3 antimicrobial agents.10 The definition of multidrug-resistant N. gonorrhoeae was as follows: resistance to at least 1 of the antimicrobial agents of category I (including cefixime, ceftriaxone, and spectinomycin)

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the statistical significance of binary variables over 4 time points. Other proportions were compared using the χ2 tests. The t test was performed to compare the geometric mean MIC of azithromycin in the isolates between 2010 and 2013. Statistical significance was considered to exit at P < 0.05.

and 2 or more antimicrobial agents belonging to category II (including azithromycin, penicillin, and ciprofloxacin).11

Molecular Typing Gonococcal isolates resistant to azithromycin were analyzed using NG-MAST, as described previously.12 Briefly, the internal regions of the por and tbpB genes were amplified by polymerase chain reaction and both strands of DNA were sequenced by the use of an ABI 3100xl DNA sequencer. The sequence data of por and tbpB were uploaded into the database of the NG-MAST Web site (http://www.ng-mast.net) to obtain the allelic profile and the ST. A genogroup was defined, as reported by the European Centre for Disease Prevention and Control, as all STs that shared 1 allele and showed greater than 99% similarity in the other allele (≤5-base-pair difference for por and ≤4-base-pair difference for tbpB).13 A phylogenetic tree showing the clonal relatedness of NG-MAST was created using the MEGA5 program.14

RESULTS The results of the antimicrobial susceptibility testing of all 677 isolates of N. gonorrhoeae obtained from 2010 to 2013 are shown in Table 1. The overall proportions of resistant isolates to azithromycin, cefixime, ciprofloxacin, penicillin, and tetracycline were 7.4%, 24.5%, 70.9%, 18.0%, and 17.0%, respectively. The overall rate of penicillinase-producing N. gonorrhoeae (PPNG) isolates was only 0.9%. No resistant isolates to ceftriaxone or spectinomycin were identified. The prevalence of azithromycin resistance (MIC > 0.5 mg/L) remarkably increased from 1.8% in 2010 to 22.6% in 2013 (P < 0.001). There were no isolates exhibiting high-level azithromycin resistance (MIC > 16 mg/L), which have been documented in other countries worldwide. The geometric mean MIC of azithromycin also significantly increased from 0.15 mg/L in 2010 to 0.31 mg/L in 2013 (P < 0.001). The azithromycin MICs (MIC50 of 0.25 mg/L, MIC90 of 1 mg/L) for the isolates in 2013 were higher than those

Statistical Analysis In the antimicrobial susceptibility trend analysis from 2010 through 2013, Cochran-Armitage trend tests were used to assess

TABLE 1. Results of the Antimicrobial Susceptibility Testing of 677 N. gonorrhoeae Isolates in Fukuoka, Japan

Year 2010 Azithromycin Resistant, no. (%) MIC50* MIC90* MIC range Cefixime Resistant, no. (%) MIC50 MIC90 MIC range Ceftriaxone Resistant, no. (%) Deceased, no. (%) MIC50 MIC90 MIC range Ciprofloxacin Resistant, no. (%) MIC50 MIC90 MIC range Penicillin Resistant, no. (%) PPNG no. (%) MIC50 MIC90 MIC range Spectinomycin Resistant, no. (%) MIC50 MIC90 MIC range Tetracycline Resistant, no. (%) MIC50 MIC90 MIC range Overall no.

2011

2012

2013

Overall

4 (1.8) 0.12 0.5 0.015–4

5 (2.3) 0.12 0.5 0.015–2

10 (10.2) 0.06 1 0.015–4

31 (22.6) 0.25 1 0.015–2

50 (7.4) — — —

58 (25.8) 0.12 0.25 0.002–0.5

32 (14.8) 0.06 0.25 0.004–0.5

41 (41.8) 0.12 0.25 0.004–0.5

35 (25.6) 0.12 0.25 0.001–0.5

166 (24.5) — — —

0 0 0.015 0.03 0.001–0.06

0 2 (0.9) 0.015 0.03 0.001–0.12

0 2 (2.0) 0.03 0.06 0.001–0.12

0 9 (6.6) 0.015 0.06 0.001–0.12

0 13 (1.9) — — —

156 (69.3) 8 16 0.002–32

155 (71.4) 8 16 0.004–32

70 (71.4) 8 32 0.008–64

99 (72.3) 8 32 0.004–32

480 (70.9) — — —

42 (18.7) 1 (0.4) 0.5 2 0.03–16

35 (16.1) 2 (0.9) 0.5 2 0.003–8

14 (14.3) 0 0.5 2 0.03–4

31 (22.6) 3 (2.2) 0.5 2 0.03–32

122 (18.0) 6 (0.9) — — —

0 16 16 8–32

0 16 16 2–16

0 16 32 4–64

0 — — —

38 (17.5) 0.5 2 0.03–8 217

1 (1) 0.5 1 0.015–8 98

20 (14.6) 0.5 2 0.015–16 137

115 (17.0) — — — 677

0 16 16 4–32 56 (24.9) 0.5 2 0.03–4 225

*MIC (in milligrams per liter) against 50% or 90% of isolates.

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Multidrug Resistance Phenotype in Fukuoka, Japan

FIGURE 1. The number of azithromycin-resistant N. gonorrhoeae isolates of each NG-MAST ST submitted each year. The “Others” were represented by 1 isolate each.

for the isolates in 2010 (MIC50 of 0.12 mg/L, MIC90 of 0.5 mg/L; Table 1). Among 50 azithromycin-resistant isolates during the study periods, 45 (90.0%), 30 (60.0%), 30 (60.0%), and 21 (42.0%) were resistant to ciprofloxacin, penicillin, cefixime, and tetracycline, respectively. Furthermore, 30 (60.0%) were multidrug-resistant gonococci. Three different patterns of multidrug-resistance were observed as follows: 15 isolates (30.0%) were resistant to 5 antibiotics, namely, cefixime, azithromycin, ciprofloxacin, penicillin, and tetracycline: 11 (22.0%) were resistant to 4 antibiotics, namely, cefixime, azithromycin, ciprofloxacin, and penicillin: and the remaining 4 (8.0%) were resistant to 3 antibiotics, namely, cefixime, azithromycin, and ciprofloxacin. The prevalence of cefixime resistance (MIC > 0.12 mg/L) increased from 25.8% in 2010 to 41.8% in 2013, and then fell to 25.6% in 2013. All isolates were susceptible to ceftriaxone (MIC ≤ 0.12 mg/L). Although the percentage of isolates with decreased susceptibility to ceftriaxone (MIC of 0.12 mg/L) increased gradually from 0% in 2010 to 6.6% in 2013 (P < 0.001), the MIC50 and MIC90 of ceftriaxone for the isolates obtained in 2013 were similar and only 2-fold higher, respectively, as compared with those for the isolates obtained in 2010. The percentage of resistant isolates to ciprofloxacin (MIC ≥ 1 mg/L) remained relatively stable at 69.3% in 2010 to 72.3% in 2013 (P = 0.2675), with an MIC50 of 8 mg/L and MIC90 of 32 mg/L in 2013. In addition, the prevalence of penicillin resistance (MIC ≥ 2 mg/L) remained relatively stable (18.7% in 2010 to 22.6% in 2013, P = 0.3273). There were no significant changes in the number of PPNG isolates during this period (0.4% in 2010 to 2.2% in 2013, P = 0.1035). The prevalence of tetracycline-resistant isolates (MIC ≥ 2 mg/L) significantly declined from 24.9% in 2010 to 14.6% in 2013 (P = 0.0001; Table 1). A molecular analysis by NG-MAST was performed on all the azithromycin-resistant isolates (n = 50). Twenty-one different STs were identified, and only 3 isolates (5.0%) had a unique ST. The 2 predominant STs identified were ST6798 (por allele 4033 and tbpB allele 110) and ST1407 (por allele 908 and tbpB allele 110) at 40.0% (20/50) and 12.0% (6/50), respectively. The prevalence of ST6798 statistically increased from 0% (0/19) in 2010–2012 to 64.5% (20/31) in 2013 (P < 0.001; Fig. 1). During the study period, there were no significant differences in the distribution of the other STs, except for an increase in the proportion of ST6798. To investigate the genetic relationship of the 50 azithromycin-resistant isolates, a phylogenetic tree of the sequences of por and tbpB alleles was constructed (Fig. 2). Square Sexually Transmitted Diseases



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A clustered 8 STs with the same tbpB 110 allele, except for ST5893 (tbpB 1209 allele), and included the 2 predominant STs, ST6798 and ST1407. Four STs (ST1906, ST6481, ST6247, and ST10869) were included in a genogroup closely related to ST6798

FIGURE 2. Phylogenetic reconstruction of the concatenated sequences of the por and tbpB alleles for STs of 50 azithromycinresistant isolates from Fukuoka, Japan, between 2010 and 2013. Square A clustered 8 STs with the same tbpB 110 allele, except for ST5893 (tbpB 1209 allele).

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(GST6798), and 2 STs (ST4512 and ST2212) were included in a genogroup closely related to ST1407 (GST1407).

DISCUSSION The prevalence of azithromycin-resistant isolates of N. gonorrhoeae rapidly increased from 1.8% to 22.6% between 2010 and 2013 in Fukuoka, Japan. Moreover, other recent studies have demonstrated that azithromycin-resistant N. gonorrhoeae isolates were also detected in Japanese urban areas, such as Tokyo5 and Osaka.15 A 2-g single dose of azithromycin became available as an oral single-dose regimen for the empirical treatment of gonococcal infections in 2009 in Japan. Azithromycin is not routinely used for gonococcal monoinfections, although it is widely used for chlamydial coinfection in our country. The frequent usage of azithromycin is considered to be the cause of the increase of azithromycin-resistant isolates of N. gonorrhoeae. According to the results of the present study and the other reports,5,15 azithromycin-resistant N. gonorrhoeae isolates will continue to increase in Japan, as the frequent usage of this antibiotic as a convenient oral single-dose regimen is expected. A study recently conducted in Japan revealed that the eradication rate of N.gonorrhoeae isolates with azithromycin MICs of 0.5 mg/L or less was 98.9% (88/89) and that of the isolates with MICs of 1 to 4 mg/L was only 50.0% (7/14) in men with gonococcal urethritis treated with a single 2-g dose of azithromycin.16 In the present study, a high proportion of azithromycin-resistant gonococci (22.6%; MIC > 0.5 mg/L) was observed in 2013. These results indicate that azithromycin should not be empirically administered to patients with gonococcal infections in Japan, and that the usage of azithromycin should be limited to only patients infected with N. gonorrhoeae isolates susceptible to azithromycin (MIC ≤ 0.5 mg/L) by the susceptibility testing. In 2013, the proportions of N. gonorrhoeae isolates resistant to cefixime, ciprofloxacin, penicillin, and tetracycline were 25.6%, 72.3%, 22.6%, and 14.6%, respectively. Therefore, these antibiotics, as well as azithromycin, should not be used empirically for gonorrhea in Japan. Fortunately, no resistant isolates to ceftriaxone or spectinomycin, which are recommended as first-line antibiotics for gonorrhea according to the Japanese guidelines, were detected in the present study. Thus, a single intravenous dose of ceftriaxone 1 g or a single intramuscular dose of spectinomycin 2 g may be recommended hereafter as a first-line regimen for gonococcal infections in Japan. Although there are 2 routes of administration, intravenous and intramuscular, for ceftriaxone in most other countries, only the intravenous injection of ceftriaxone is commercially available for various bacterial infections, including gonococcal infection, in Japan. Many countries currently recommend dual therapy comprising the intramuscular injection of 250 or 500 mg of ceftriaxone combined with 1 or 2 g of oral azithromycin, as a first-line therapy for uncomplicated gonorrhea.2,3 In contrast, the Japanese guidelines recommend a higher dose of 1 g of intravenous ceftriaxone monotherapy. The present findings demonstrated that no isolates resistant to ceftriaxone were identified during the study period, whereas the prevalence of azithromycin-resistant isolates quickly increased up to 22.6% in 2013. These results suggest that a higher dose of 1 g of intravenous ceftriaxone monotherapy should be recommended; however, azithromycin is no longer recommended for dual therapy combined with ceftriaxone in our country. A recent report indicated that dual therapy comprising intramuscular ceftriaxone at a dose of 250 mg plus oral azithromycin at a dose of 1 g is effective against pharyngitis caused by the N. gonorrhoeae strain with a ceftriaxone MIC of 0.125 mg/L, whereas failure is observed with 250 mg of ceftriaxone monotherapy.17 Another

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study demonstrated that a high dose of 1 g of intravenous ceftriaxone monotherapy is effective against pharyngitis caused by the N. gonorrhoeae strain with a ceftriaxone MIC of 0.125 or 0.25 mg/L, whereas failure is noted with intramuscular ceftriaxone monotherapy at a dose of 250 or 500 mg.18 These results suggest that a high dose of 1 g of intravenous ceftriaxone monotherapy may be as effective as dual therapy consisting of 250 mg of ceftriaxone plus 1 g of azithromycin. Recently, the elevated proportion of azithromycin-resistant gonococci was also reported from other countries including Canada,19 Italy,20 Poland,21 Switzerland,22 and Hungary.23 Because the combination of ceftriaxone plus azithromycin is routinely recommended as a first-line treatment of gonorrhea in these countries, continued surveillance of gonococcal susceptibility to azithromycin is necessary. The NG-MAST analysis demonstrated a clonal spread of N. gonorrhoeae isolates, with 20 (64.5%) and 2 (6.5%) of the 31 azithromycin-resistant isolates in 2013 belonging to ST6798 and GST6798 (ST1906 and ST10869), respectively. The predominant clone, ST6798, in azithromycin-resistant isolates in the present study is different from those reported from other countries. The predominant STs of isolates resistant to azithromycin were ST661 (por allele 443 and tbpB allele 10) and ST3158 (por allele 1914 and tbpB allele 110) in Italy6 and Canada,7 respectively. Our previous study demonstrated that ST2958 was the most prevalent ST in Fukuoka24 and Tokyo metropolitan areas (unpublished data) in Japan in 2008 and was very rare in other countries. N. gonorrhoeae isolates belonging to ST2958 showed a tendency of multidrug resistance to ciprofloxacin, penicillin, tetracycline, and cefixime, whereas those belonging to ST6798 showed a tendency of resistance to multiple antibiotics, including azithromycin. ST6798 is closely related to ST2958; ST6798 has single base-pair substitution of cytosine with thymine at nucleotide 290 (C290T) in the por allele 1785 and the same tbpB allele 110 as ST2859. Moreover, there were no azithromycin-resistant isolates belonging to ST2958 during this study period. These data may suggest that the emergence of ST6798 may be due to the evolution from ST2958 with acquired mutations for azithromycin resistance under selective drug pressure. ST1407 was the second prevalent ST found in the present study. ST1407 is well known as a multidrug-resistant clone circulating worldwide.25 Six of the 9 isolates belonging to ST1407 or GST1407 (ST2212 and ST4512) in the present study additionally displayed a multidrug phenotype. One limitation of the present study is the lack of clinical and demographic information for the patients. The combination of antimicrobial resistance and molecular typing results is most powerful when combined with clinical and demographic data, which provides increased information on the clusters identified. Future studies should include clinical and demographic variables, such as age, sex, and the sexual preference of patients. In summary, our data indicated that over the previous 4 years, the prevalence of azithromycin-resistant N. gonorrhoeae isolates with a multidrug-resistant phenotype has increased, which is mostly likely due to the emergence of the 2 predominant STs, T6798 and ST1407. Continued surveillance for the resistance to antimicrobial agents, including azithromycin and ceftriaxone, is necessary as this combination is routinely recommended as a first-line treatment of gonorrhea in the United States and Europe. REFERENCES 1. Lewis DA. Global resistance of Neisseria gonorrhoeae: When theory becomes reality. Curr Opin Infect Dis 2014; 27:62–67. 2. Centers for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treatment guidelines, 2010: Oral cephalosporins no longer a recommended treatment for gonococcal infections. Morb Mortal Wkly Rep 2012; 61:590–594.

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Multidrug Resistance Phenotype in Fukuoka, Japan

3. Bignell C, Unemo M, European STI Guidelines Editorial Board. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS 2013; 24:85–92. 4. Japanese Society of Sexually Transmitted Infections. The guideline of the diagnosis and treatment for gonococcal infections [in Japanese]. Jpn J STI 2011; 22:52–59. 5. Takayama Y, Nakayama S, Shimuta K, et al. Characterization of azithromycin-resistant Neisseria gonorrhoeae isolated in Tokyo in 2005–2011. J Infect Chemother 2014; 20:339–341. 6. Starnino S, Stefanelli P, Neisseria gonorrhoeae Italian Study Group. Azithromycin-resistant Neisseria gonorrhoeae strains recently isolated in Italy. J Antimicrob Chemother 2009; 63:1200–1204. 7. Allen VG, Seah C, Martin I, et al. Azithromycin resistance is coevolving with reduced susceptibility to cephalosporins in Neisseria gonorrhoeae in Ontario, Canada. Antimicrob Agents Chemother 2014; 58:2528–2534. 8. Unemo M, Golparian D, Hellmark B. First three Neisseria gonorrhoeae isolates with high-level resistance to azithromycin in Sweden: A threat to currently available dual-antimicrobial regimens for treatment of gonorrhea? Antimicrob Agents Chemother 2014; 58:624–625. 9. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI Document M100-S22. Wayne, PA: Clinical and Laboratory Standards Institute; 2012. 10. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) Breakpoints tables for interpretation of MICs and zone diameters, Version 4.0, 2014. Available at: http://www.eucast.org/. Accessed February 10, 2015 11. Tapsall JW, Ndowa F, Lewis DA, et al. Meeting the public health challenge of multidrug and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev Anti Infect Ther 2009; 7:821–834. 12. Martin IM, Ison CA, Aanensen DM, et al. Rapid sequence-based identification of gonococcal transmission clusters in a large metropolitan area. J Infect Dis 2004; 189:1497–1505. 13. European Centre for Disease Prevention and Control. Molecular typing of Neisseria gonorrhoeae. Results from a pilot study 2010–2011. 2012. Available at: http://www.ecdc.europa.eu/en/publications/Publications/ 2012 11109-Molecular-typing-gonorrhea.pdf. 14. Tamura K, Peterson D, Peterson N, et al. MEGA5: Molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 2011; 28:2731–2739.

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15. Morita-Ishihara T, Unemo M, Furubayashi K, et al. Treatment failure with 2 g of azithromycin (extended-release formulation) in gonorrhoea in Japan caused by the international multidrug-resistant ST1407 strain of Neisseria gonorrhoeae. J Antimicrob Chemother 2014; 69: 2086–2090. 16. Yasuda M, Ito S, Kido A, et al. A single 2 g oral dose of extendedrelease azithromycin for treatment of gonococcal urethritis. J Antimicrob Chemother 2014; 69:3116–3118. 17. Unemo M, Golparian D, Potočnik M, Jeverica S. Treatment failure of pharyngeal gonorrhoea with internationally recommended first-line ceftriaxone verified in Slovenia, September 2011. Euro Surveill 2012; 17:pii: 20200. 18. Unemo M, Golparian D, Hestner A. Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international recommendations, Sweden, July 2010. Euro Surveill 2011; 16:pii: 19792. 19. Hottes TS, Lester RT, Hoang LM, et al. Cephalosporin and azithromycin susceptibility in Neisseria gonorrhoeae isolates by site of infection, British Columbia, 2006 to 2011. Sex Transm Dis 2013; 40: 46–51. 20. Carannante A, Renna G, Dal Conte I, et al. Changing antimicrobial resistance profiles among Neisseria gonorrhoeae isolates in Italy, 2003 to 2012. Antimicrob Agents Chemother 2014; 58:5871–5876. 21. Mlynarczyk-Bonikowska B, Serwin AB, Golparian D, et al. Antimicrobial susceptibility/resistance and genetic characteristics of Neisseria gonorrhoeae isolates from Poland, 2010–2012. BMC Infect Dis 2014; 14:65. 22. Endimiani A, Guilarte YN, Tinguely R, et al. Characterization of Neisseria gonorrhoeae isolates detected in Switzerland (1998–2012): Emergence of multidrug-resistant clones less susceptible to cephalosporins. BMC Infect Dis 2014; 14:106. 23. Brunner A, Nemes-Nikodem E, Mihalik N, et al. Incidence and antimicrobial susceptibility of Neisseria gonorrhoeae isolates from patients attending the national Neisseria gonorrhoeae reference laboratory of Hungary. BMC Infect Dis 2014; 14:433. 24. Tanaka M, Koga Y, Nakayama H, et al. Antibiotic-resistant phenotypes and genotypes of Neisseria gonorrhoeae isolates in Japan: identification of strain clusters with multidrug-resistant phenotypes. Sex Transm Dis 2011; 38:871–875. 25. Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol 2012; 7: 1401–1422.

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High Prevalence of Azithromycin-Resistant Neisseria gonorrhoeae Isolates With a Multidrug Resistance Phenotype in Fukuoka, Japan.

The current guidelines recommend a combination of ceftriaxone and azithromycin as a first-line treatment of gonorrhea in the United States and Europe...
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