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REVIEW (Open Access)

Should we still use azithromycin for gonorrhoea treatment?

Sarah Mensforth A B and Jonathan D. C. Ross A
+ Author Affiliations
- Author Affiliations

A Department of Sexual Health and HIV, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2GW, UK.

B Corresponding author. Email: sarahmensforth@nhs.net

Sexual Health 16(5) 442-448 https://doi.org/10.1071/SH19016
Submitted: 2 February 2019  Accepted: 7 March 2019   Published: 18 June 2019

Journal Compilation © CSIRO 2019 Open Access CC BY-NC-ND

Abstract

This review presents the evidence for azithromycin in the treatment of gonorrhoea, both as monotherapy and as a component of dual therapy. Uncertainties are explored regarding the efficacy of a dual treatment strategy, combining ceftriaxone and azithromycin, in the context of resistance trends and extra-genital infections. The association between microbiological testing and clinical outcome for the individual patient, and the effect of azithromycin use on other sexually transmissible infections, are considered. Finally, in the absence of imminent new antimicrobials, optimising the dose of azithromycin while maintaining tolerability is discussed.

Additional keywords: antimicrobial, Neisseria gonorrhoeae, resistance.


References

[1]  Unemo M. Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge. BMC Infect Dis 2015; 15 364
Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge.Crossref | GoogleScholarGoogle Scholar | 26293005PubMed |

[2]  Public Health England. Gonococcal resistance to antimicrobials surveillance programme report. Data on trends in antimicrobial resistance and decreased susceptibility in gonococcal infection in England and Wales provided by GRASP. London: PHE Publications; 2018. Available online at: https://www.gov.uk/government/publications/gonococcal-resistance-to-antimicrobials-surveillance-programme-grasp-report [verified 19 January 2019].

[3]  European Centre for Disease Prevention and Control. European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP). Sweden: ECDC; 2019. Available online at: https://ecdc.europa.eu/en/about-us/partnerships-and-networks/disease-and-laboratory-networks/euro-gasp [verified 19 January 2019].

[4]  Centers for Disease Control and Prevention. Gonococcal Isolate Surveillance Project (GISP). Atlanta: CDC; 2015. Available online at: https://www.cdc.gov/std/gisp/default.htm [verified 17 December 2018].

[5]  World Health Organization. The Gonococcal Antimicrobial Surveillance Programme (GASP). Geneva: WHO; 2019. Available online at: https://www.who.int/reproductivehealth/topics/rtis/gonococcal_resistance/en [verified 19 January 2019].

[6]  Australian Government Department of Health. Gonorrhoea Surveillance 2018. Canberra: Commonwealth of Australia; 2018. Available online at: http://www.health.gov.au/internet/main/publishing.nsf/Content/ohp-gonorrhoea-surveil.htm [verified 19 January 2019].

[7]  Eyre DW, Sanderson ND, Lord E, Regisford-Reimmer N, Chau K, Barker L, Morgan M, Newnham R, Golparian D, Unemo M. Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae strain with combined ceftriaxone and high-level azithromycin resistance, England, February 2018. Euro Surveill 2018; 23 1800323
Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae strain with combined ceftriaxone and high-level azithromycin resistance, England, February 2018.Crossref | GoogleScholarGoogle Scholar | 29991383PubMed |

[8]  Australian Government Department of Health. Gonorrhoea health alert, multi-drug resistant gonorrhoea. Canberra: Commonwealth of Australia; 2018. Available online at: http://www.health.gov.au/internet/main/publishing.nsf/Content/ohp-gonorrhoea.htm [verified 15 October 2018].

[9]  Electronic Medicines Compendium. Azithromycin 500mg tablets summary of product characteristics [summary of product characteristics]. Surrey: Datapharm Communications Limited; 2018. Available online at: https://www.medicines.org.uk/emc/product/6541/smpc [verified 10 December 2018].

[10]  Vodstrcil LA, Rupasinghe TWT, Kong FYS, Tull D, Worthington K, Chen MY, Huston WM, Timms P, McConville MJ, Fairley CK, Bradshaw CS, Tabrizi SN, Hocking JS. Measurement of tissue azithromycin levels in self-collected vaginal swabs post treatment using liquid chromatography and tandem mass spectrometry (LC-MS/MS). PLoS One 2017; 12 e0177615
Measurement of tissue azithromycin levels in self-collected vaginal swabs post treatment using liquid chromatography and tandem mass spectrometry (LC-MS/MS).Crossref | GoogleScholarGoogle Scholar | 28498845PubMed |

[11]  Kong F, Rupasinghe TW, Simpson JA, Vodstrcil LA, Fairley CK, McConville MJ, Hocking J. Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men. PLoS One 2017; 12 e0174372
Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men.Crossref | GoogleScholarGoogle Scholar | 29240755PubMed |

[12]  Kong FYS, Horner P, Unemo M, Hocking JS. Pharmacokinetic considerations regarding the treatment of bacterial sexually transmitted infections with azithromycin: a review. J Antimicrob Chemother 2019; 74 1157–66.
Pharmacokinetic considerations regarding the treatment of bacterial sexually transmitted infections with azithromycin: a review.Crossref | GoogleScholarGoogle Scholar |

[13]  Lode H, Borner K, Koeppe P, Schaberg T. Azithromycin—review of key chemical, pharmacokinetic and microbiological features. J Antimicrob Chemother 1996; 37 1–8.
Azithromycin—review of key chemical, pharmacokinetic and microbiological features.Crossref | GoogleScholarGoogle Scholar | 8818841PubMed |

[14]  Liu P, Allaudeen H, Chandra R, Phillips K, Jungnik A, Breen JD, Sharma A. Comparative pharmacokinetics of azithromycin in serum and white blood cells of healthy subjects receiving a single-dose extended-release regimen versus a 3-day immediate-release regimen. Antimicrob Agents Chemother 2007; 51 103–9.
Comparative pharmacokinetics of azithromycin in serum and white blood cells of healthy subjects receiving a single-dose extended-release regimen versus a 3-day immediate-release regimen.Crossref | GoogleScholarGoogle Scholar | 17060516PubMed |

[15]  Foulds G, Johnson RB. Selection of dose regimens of azithromycin. J Antimicrob Chemother 1993; 31 39–50.
Selection of dose regimens of azithromycin.Crossref | GoogleScholarGoogle Scholar | 8396095PubMed |

[16]  Crokaert F, Hubloux A, Cauchie P. A phase I determination of azithromycin in plasma during a 6-week period in normal volunteers after a standard dose of 500 mg once daily for 3 days. Clin Drug Investig 1998; 16 161–6.
A phase I determination of azithromycin in plasma during a 6-week period in normal volunteers after a standard dose of 500 mg once daily for 3 days.Crossref | GoogleScholarGoogle Scholar | 18370534PubMed |

[17]  Worm AM, Osterlind A. Azithromycin levels in cervical mucus and plasma after a single 1.0 g oral dose for chlamydial cervicitis. Genitourin Med 1995; 71 244–6.
| 7590717PubMed |

[18]  Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25 73–82.
The pharmacokinetics of azithromycin in human serum and tissues.Crossref | GoogleScholarGoogle Scholar | 2154441PubMed |

[19]  Bignell C, Garley J. Azithromycin in the treatment of infection with Neisseria gonorrhoeae. Sex Transm Infect 2010; 86 422–6.
Azithromycin in the treatment of infection with Neisseria gonorrhoeae.Crossref | GoogleScholarGoogle Scholar | 20940153PubMed |

[20]  Kirkcaldy RD, Weinstock HS, Moore PC, Philip SS, Wiesenfeld HC, Papp JR, Kerndt PR, Johnson S, Ghamen KG, Hook EW, Newman LM, Dowell D, Deal C, Glock J, Venkatasubramanian L, McNiel L, Perlowski C, Lee JY, Lensing S, Trainor N, et al. The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea. Clin Infect Dis 2014; 59 1083–91.
The efficacy and safety of gentamicin plus azithromycin and gemifloxacin plus azithromycin as treatment of uncomplicated gonorrhea.Crossref | GoogleScholarGoogle Scholar | 25031289PubMed |

[21]  Handsfield HH, Dalu Z, Martin DH, Douglas JJ, McCarty JM, Schlossberg D, Azithromycin Gonorrhea Study Group Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Sex Transm Dis 1994; 21 107–11.
Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea.Crossref | GoogleScholarGoogle Scholar | 9071422PubMed |

[22]  Yasuda M, Ito S, Kido A, Hamano K, Uchijima Y, Uwatoko N, Kusuyama H, Watanabe A, Miyamura R, Miyata K. A single 2 g oral dose of extended-release azithromycin for treatment of gonococcal urethritis. J Antimicrob Chemother 2014; 69 3116–8.
A single 2 g oral dose of extended-release azithromycin for treatment of gonococcal urethritis.Crossref | GoogleScholarGoogle Scholar | 24948703PubMed |

[23]  Dean G, Whetham J, Soni S, Kerr L, Greene L, Ross J, Sabin C. O006 Is a short course of azithromycin effective in the treatment of mild to moderate pelvic inflammatory disease (PID)? Sex Trans Infect 2016; 92 A3
O006 Is a short course of azithromycin effective in the treatment of mild to moderate pelvic inflammatory disease (PID)?Crossref | GoogleScholarGoogle Scholar |

[24]  Hook EW, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002; 29 486–90.
A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis.Crossref | GoogleScholarGoogle Scholar | 12172535PubMed |

[25]  Takahashi S, Kiyota H, Ito S, Iwasawa A, Hiyama Y, Uehara T, Ichihara K, Hashimoto J, Masumori N, Sunaoshi K. Clinical efficacy of a single two gram dose of azithromycin extended release for male patients with urethritis. Antibiotics (Basel) 2014; 3 109–20.
Clinical efficacy of a single two gram dose of azithromycin extended release for male patients with urethritis.Crossref | GoogleScholarGoogle Scholar | 27025738PubMed |

[26]  Yin Y-P, Han Y, Dai X-Q, Zheng H-P, Chen S-C, Zhu B-Y, Yong G, Zhong N, Hu L-H, Cao W-L. Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: a retrospective study of national surveillance data from 2013 to 2016. PLoS Med 2018; 15 e1002499
Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: a retrospective study of national surveillance data from 2013 to 2016.Crossref | GoogleScholarGoogle Scholar | 29408881PubMed |

[27]  Martin I, Sawatzky P, Liu G, Allen V, Lefebvre B, Hoang L, Drews S, Horsman G, Wylie L, Haldane D. Decline in decreased cephalosporin susceptibility and increase in azithromycin resistance in Neisseria gonorrhoeae, Canada. Emerg Infect Dis 2016; 22 65–7.
Decline in decreased cephalosporin susceptibility and increase in azithromycin resistance in Neisseria gonorrhoeae, Canada.Crossref | GoogleScholarGoogle Scholar | 26689114PubMed |

[28]  Hottes TS, Lester RT, Hoang LM, McKay R, Imperial M, Gilbert M, Patrick DM, Wong T, Martin I, Ogilvie G. Cephalosporin and azithromycin susceptibility in Neisseria gonorrhoeae isolates by site of infection, British Columbia, 2006 to 2011. Sex Transm Dis 2013; 40 46–51.
Cephalosporin and azithromycin susceptibility in Neisseria gonorrhoeae isolates by site of infection, British Columbia, 2006 to 2011.Crossref | GoogleScholarGoogle Scholar | 23250301PubMed |

[29]  Cole MJ, Spiteri G, Jacobsson S, Woodford N, Tripodo F, Amato-Gauci AJ, Unemo M. Overall low extended-spectrum cephalosporin resistance but high azithromycin resistance in Neisseria gonorrhoeae in 24 European countries, 2015. BMC Infect Dis 2017; 17 617
Overall low extended-spectrum cephalosporin resistance but high azithromycin resistance in Neisseria gonorrhoeae in 24 European countries, 2015.Crossref | GoogleScholarGoogle Scholar | 28893203PubMed |

[30]  Palmer HM, Young H, Winter A, Dave J. Emergence and spread of azithromycin-resistant Neisseria gonorrhoeae in Scotland. J Antimicrob Chemother 2008; 62 490–4.
Emergence and spread of azithromycin-resistant Neisseria gonorrhoeae in Scotland.Crossref | GoogleScholarGoogle Scholar | 18552343PubMed |

[31]  Barbee LA, Soge OO, Katz DA, Dombrowski JC, Holmes KK, Golden MR. Increases in Neisseria gonorrhoeae with reduced susceptibility to azithromycin among men who have sex with men in Seattle, King County, Washington, 2012–2016. Clin Infect Dis 2018; 66 712–8.
Increases in Neisseria gonorrhoeae with reduced susceptibility to azithromycin among men who have sex with men in Seattle, King County, Washington, 2012–2016.Crossref | GoogleScholarGoogle Scholar | 29045604PubMed |

[32]  Fifer H, Cole M, Hughes G, Padfield S, Smolarchuk C, Woodford N, Wensley A, Mustafa N, Schaefer U, Myers R. Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study. Lancet Infect Dis 2018; 18 573–81.
Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study.Crossref | GoogleScholarGoogle Scholar | 29523496PubMed |

[33]  Public Health England. Surveillance of antimicrobial resistance in Neisseria gonorrhoeae in England and Wales. Key findings from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP). London: PHE Publications; 2018. Available online at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/746261/GRASP_2017_report.pdf [verified 17 December 2018].

[34]  Galarza PG, Alcalá B, Salcedo C, Canigia LF, Buscemi L, Pagano I, Oviedo C, Váques JA. Emergence of high level azithromycin-resistant Neisseria gonorrhoeae strain isolated in Argentina. Sex Transm Dis 2009; 36 787–8.
Emergence of high level azithromycin-resistant Neisseria gonorrhoeae strain isolated in Argentina.Crossref | GoogleScholarGoogle Scholar | 19734823PubMed |

[35]  Katz AR, Komeya AY, Soge OO, Kiaha MI, Lee MVC, Wasserman GM, Maningas EV, Whelen AC, Kirkcaldy RD, Shapiro SJ. Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States. Clin Infect Dis 2012; 54 841–3.
Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States.Crossref | GoogleScholarGoogle Scholar | 22184617PubMed |

[36]  Gose SO, Soge OO, Beebe JL, Nguyen D, Stoltey JE, Bauer HM. Failure of azithromycin 2.0 g in the treatment of gonococcal urethritis caused by high-level resistance in California. Sex Transm Dis 2015; 42 279–80.
Failure of azithromycin 2.0 g in the treatment of gonococcal urethritis caused by high-level resistance in California.Crossref | GoogleScholarGoogle Scholar | 25868141PubMed |

[37]  Xue J, Ni C, Zhou H, Zhang C, van der Veen S. Occurrence of high-level azithromycin-resistant Neisseria gonorrhoeae isolates in China. J Antimicrob Chemother 2015; 70 3404–5.
| 26316384PubMed |

[38]  Chisholm SA, Neal TJ, Alawattegama AB, Birley HDL, Howe RA, Ison CA. Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales. J Antimicrob Chemother 2009; 64 353–8.
Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales.Crossref | GoogleScholarGoogle Scholar | 19468025PubMed |

[39]  Lynagh Y, Mac Aogáin M, Walsh A, Rogers TR, Unemo M, Crowley B. Detailed characterization of the first high-level azithromycin-resistant Neisseria gonorrhoeae cases in Ireland. J Antimicrob Chemother 2015; 70 2411–3.
Detailed characterization of the first high-level azithromycin-resistant Neisseria gonorrhoeae cases in Ireland.Crossref | GoogleScholarGoogle Scholar | 25907073PubMed |

[40]  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; 58 624–5.
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?Crossref | GoogleScholarGoogle Scholar | 24189248PubMed |

[41]  Stevens K, Zaia A, Tawil S, Bates J, Hicks V, Whiley D, Liminios A, Lahra MM, Howden BP. Neisseria gonorrhoeae isolates with high-level resistance to azithromycin in Australia. J Antimicrob Chemother 2015; 70 1267–8.
| 25480491PubMed |

[42]  Katz AR, Komeya AY, Kirkcaldy RD, Whelen AC, Soge OO, Papp JR, Kersh EN, Wasserman GM, O’Connor NP, O’Brien PS. Cluster of Neisseria gonorrhoeae isolates with high-level azithromycin resistance and decreased ceftriaxone susceptibility, Hawaii, 2016. Clin Infect Dis 2017; 65 918–23.
Cluster of Neisseria gonorrhoeae isolates with high-level azithromycin resistance and decreased ceftriaxone susceptibility, Hawaii, 2016.Crossref | GoogleScholarGoogle Scholar | 28549097PubMed |

[43]  Chisholm SA, Wilson J, Alexander S, Tripodo F, Al-Shahib A, Schaefer U, Lythgow K, Fifer H. An outbreak of high-level azithromycin resistant Neisseria gonorrhoeae in England. Sex Transm Infect 2016; 92 365–7.
An outbreak of high-level azithromycin resistant Neisseria gonorrhoeae in England.Crossref | GoogleScholarGoogle Scholar | 26601852PubMed |

[44]  Zhang J, van der Veen S. Neisseria gonorrhoeae 23S rRNA A2059G mutation is the only determinant necessary for high-level azithromycin resistance and improves in vivo biological fitness. J Antimicrob Chemother 2019; 74 407–15.
Neisseria gonorrhoeae 23S rRNA A2059G mutation is the only determinant necessary for high-level azithromycin resistance and improves in vivo biological fitness.Crossref | GoogleScholarGoogle Scholar | 30376120PubMed |

[45]  Fifer H, Saunders J, Soni S, Sadiq ST, FitzGerald M. British Association for Sexual Health and HIV national guideline for the management of infection with Neisseria gonorrhoeae (2019) [UK national Guideline]. Macclesfield: BASHH; 2019. Available online at: https://www.bashhguidelines.org/media/1208/gc-2019.pdf [verified 28 January 2019].

[46]  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.
2012 European guideline on the diagnosis and treatment of gonorrhoea in adults.Crossref | GoogleScholarGoogle Scholar | 24400344PubMed |

[47]  Australian STI Management Guidelines. Gonorrhoea. Sydney: ASHA; 2018. Available online at: http://www.sti.guidelines.org.au/sexually-transmissible-infections/gonorrhoea [verified 17 December 2018].

[48]  Centers for Disease Control and Prevention. Gonococcal infections in adolescents and adults. Atlanta: CDC; 2015. Available online at: https://www.cdc.gov/std/tg2015/gonorrhea.htm [verified 17 December 2018].

[49]  World Health Organization. WHO guidelines for the treatment of Neisseria gonorrhoeae. Geneva: WHO; 2016. Available online at: http://apps.who.int/iris/bitstream/handle/10665/246114/9789241549691-eng.pdf;jsessionid=5ED7D8422AEFA59D6A3169875E08671A?sequence=1 [verified 17 December 2018].

[50]  Moran JS, Levine WC. Drugs of choice for the treatment of uncomplicated gonococcal infections. Clinical Infectious Diseases 1995; 20 S47–S65.
Drugs of choice for the treatment of uncomplicated gonococcal infections.Crossref | GoogleScholarGoogle Scholar | 7795109PubMed |

[51]  Ross J, Brittain C, Cole M, Dewsnap C, Harding J, Hepburn T, Jackson L, Keogh M, Lawrence T, Montgomery AA, Roberts TE, Sprange K, Tan W, Thandi S, White J, Wilson J, Duley L, on behalf of the G-ToG Trial Team. Gentamicin compared with Ceftriaxone for the treatment of gonorrhoea: a randomised trial (G-ToG Trial). Lancet 2019; In press.
| 31056291PubMed |

[52]  Khaki P, Bhalla P, Sharma A, Kumar V. Correlation between in vitro susceptibility and treatment outcome with azithromycin in gonorrhoea: a prospective study. Indian J Med Microbiol 2007; 25 354–7.
Correlation between in vitro susceptibility and treatment outcome with azithromycin in gonorrhoea: a prospective study.Crossref | GoogleScholarGoogle Scholar | 18087084PubMed |

[53]  Tapsall JW, Shultz TR, Limnios EA, Donovan B, Lum G, Mulhall BP. Failure of azithromycin therapy in gonorrhea and discorrelation with laboratory test parameters. Sex Transm Dis 1998; 25 505–8.
Failure of azithromycin therapy in gonorrhea and discorrelation with laboratory test parameters.Crossref | GoogleScholarGoogle Scholar | 9858344PubMed |

[54]  Moran JS. Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important? Sex Transm Dis 1995; 22 39–47.
Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important?Crossref | GoogleScholarGoogle Scholar | 7709324PubMed |

[55]  Kidd S, Moore PC, Kirkcaldy RD, Philip SS, Wiesenfeld HC, Papp JR, Kerndt PR, Venkatasubramanian L, Ghanem KG, Hook EW. Comparison of antimicrobial susceptibility of urogenital Neisseria gonorrhoeae isolates obtained from women and men. Sex Transm Dis 2015; 42 434–9.
Comparison of antimicrobial susceptibility of urogenital Neisseria gonorrhoeae isolates obtained from women and men.Crossref | GoogleScholarGoogle Scholar | 26165435PubMed |

[56]  Mouton JW, Muller AE, Canton R, Giske CG, Kahlmeter G, Turnidge J. MIC-based dose adjustment: facts and fables. J Antimicrob Chemother 2018; 73 564–8.
MIC-based dose adjustment: facts and fables.Crossref | GoogleScholarGoogle Scholar | 29216348PubMed |

[57]  Furuya R, Tanaka M, Nakayama H, Kanayama A, Saika T, Iyoda T, Tatewaki M, Matsuzaki K, Kobayashi I. In vitro synergistic effects of double combinations of β-lactams and azithromycin against clinical isolates of Neisseria gonorrhoeae. J Infect Chemother 2006; 12 172–6.
In vitro synergistic effects of double combinations of β-lactams and azithromycin against clinical isolates of Neisseria gonorrhoeae.Crossref | GoogleScholarGoogle Scholar | 16944253PubMed |

[58]  Bignell C, FitzGerald M. UK national guideline for the management of gonorrhoea in adults, 2011. Int J STD AIDS 2011; 22 541–7.
UK national guideline for the management of gonorrhoea in adults, 2011.Crossref | GoogleScholarGoogle Scholar | 21998172PubMed |

[59]  Pereira R, Cole MJ, Ison CA. Combination therapy for gonorrhoea: in vitro synergy testing. J Antimicrob Chemother 2013; 68 640–3.
Combination therapy for gonorrhoea: in vitro synergy testing.Crossref | GoogleScholarGoogle Scholar | 23152483PubMed |

[60]  Wind CM, de Vries HJ, van Dam AP. Determination of in vitro synergy for dual antimicrobial therapy against resistant Neisseria gonorrhoeae using Etest and agar dilution. Int J Antimicrob Agents 2015; 45 305–8.
Determination of in vitro synergy for dual antimicrobial therapy against resistant Neisseria gonorrhoeae using Etest and agar dilution.Crossref | GoogleScholarGoogle Scholar | 25532741PubMed |

[61]  Barbee LA, Soge OO, Holmes KK, Golden MR. In vitro synergy testing of novel antimicrobial combination therapies against Neisseria gonorrhoeae. J Antimicrob Chemother 2014; 69 1572–8.
In vitro synergy testing of novel antimicrobial combination therapies against Neisseria gonorrhoeae.Crossref | GoogleScholarGoogle Scholar | 24468865PubMed |

[62]  Costa-Lourenço APRD, Barros dos Santos KT, Moreira BM, Fracalanzza SEL, Bonelli RR. Antimicrobial resistance in Neisseria gonorrhoeae: history, molecular mechanisms and epidemiological aspects of an emerging global threat. Braz J Microbiol 2017; 48 617–28.
Antimicrobial resistance in Neisseria gonorrhoeae: history, molecular mechanisms and epidemiological aspects of an emerging global threat.Crossref | GoogleScholarGoogle Scholar | 28754299PubMed |

[63]  Golparian D, Shafer WM, Ohnishi M, Unemo M. Importance of multi-drug efflux pumps in the antimicrobial resistance property of clinical multi-drug resistant isolates of Neisseria gonorrhoeae. Antimicrob Agents Chemother 2014; 58 3556–9.
Importance of multi-drug efflux pumps in the antimicrobial resistance property of clinical multi-drug resistant isolates of Neisseria gonorrhoeae.Crossref | GoogleScholarGoogle Scholar | 24733458PubMed |

[64]  Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S, Iwasaku K, Nakayama S, Kitawaki J, Unemo M. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea? Detailed characterization of the first high-level ceftriaxone resistant strain. Antimicrobial agents and chemotherapy 2011; 55 3538–45.
Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea? Detailed characterization of the first high-level ceftriaxone resistant strain.Crossref | GoogleScholarGoogle Scholar | 21576437PubMed |

[65]  Cámara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D, Andreu A, Ardanuy C. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother 2012; 67 1858–60.
Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain.Crossref | GoogleScholarGoogle Scholar | 22566592PubMed |

[66]  Lahra MM, Ryder N, Whiley DM. A new multidrug-resistant strain of Neisseria gonorrhoeae in Australia. N Engl J Med 2014; 371 1850–1.
A new multidrug-resistant strain of Neisseria gonorrhoeae in Australia.Crossref | GoogleScholarGoogle Scholar | 25372111PubMed |

[67]  Lefebvre B, Martin I, Demczuk W, Deshaies L, Michaud S, Labbé A-C, Beaudoin M-C, Longtin J. Ceftriaxone-resistant Neisseria gonorrhoeae, Canada, 2017. Emerg Infect Dis 2018; 24 381–3.
Ceftriaxone-resistant Neisseria gonorrhoeae, Canada, 2017.Crossref | GoogleScholarGoogle Scholar |

[68]  Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012; 56 1273–80.
High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure.Crossref | GoogleScholarGoogle Scholar | 22155830PubMed |

[69]  Poncin T, Fouere S, Braille A, Camelena F, Agsous M, Bebear C, Kumanski S, Lot F, Mercier-Delarue S, Ngangro NN. Multidrug-resistant Neisseria gonorrhoeae failing treatment with ceftriaxone and doxycycline in France, November 2017. Euro Surveill 2018; 23 1800264
Multidrug-resistant Neisseria gonorrhoeae failing treatment with ceftriaxone and doxycycline in France, November 2017.Crossref | GoogleScholarGoogle Scholar | 29845928PubMed |

[70]  Terkelsen D, Tolstrup J, Johnsen CH, Lund O, Larsen HK, Worning P, Unemo M, Westh H. Multidrug-resistant Neisseria gonorrhoeae infection with ceftriaxone resistance and intermediate resistance to azithromycin, Denmark, 2017. Euro Surveill 2017; 22 17-00659
Multidrug-resistant Neisseria gonorrhoeae infection with ceftriaxone resistance and intermediate resistance to azithromycin, Denmark, 2017.Crossref | GoogleScholarGoogle Scholar | 29067905PubMed |

[71]  Young H, Moyes A, McMillan A. Azithromycin and erythromycin resistant Neisseria gonorrhoeae following treatment with azithromycin. Int J STD AIDS 1997; 8 299–302.
Azithromycin and erythromycin resistant Neisseria gonorrhoeae following treatment with azithromycin.Crossref | GoogleScholarGoogle Scholar | 9175650PubMed |

[72]  Soge OO, Harger D, Schafer S, Toevs K, Raisler KA, Venator K, Holmes KK, Kircaldy RD. Emergence of increased azithromycin resistance during unsuccessful treatment of Neisseria gonorrhoeae infection with azithromycin (Portland, OR, 2011). Sex Transm Dis 2012; 39 877–9.
Emergence of increased azithromycin resistance during unsuccessful treatment of Neisseria gonorrhoeae infection with azithromycin (Portland, OR, 2011).Crossref | GoogleScholarGoogle Scholar | 23064537PubMed |

[73]  Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill 2011; 16 19833
| 22027378PubMed |

[74]  Wind CM, de Vries E, Schim van der Loeff MF, van Rooijen MS, van Dam AP, Demczuk WH, Martin I,. Wind CM, de Vries E, Schim van der Loeff MF, van Rooijen MS, van Dam AP, Demczuk WH, Martin I,. Decreased azithromycin susceptibility of Neisseria gonorrhoeae isolates in patients recently treated with azithromycin. Clin Infect Dis 2017; 65 37–45.
Decreased azithromycin susceptibility of Neisseria gonorrhoeae isolates in patients recently treated with azithromycin.Crossref | GoogleScholarGoogle Scholar | 28510723PubMed |

[75]  Clifton S, Town K, Furegato M, Cole M, Mohammed H, Woodhall SC, Dunbar KJ, Fifer H, Hughes G. Is previous azithromycin treatment associated with azithromycin resistance in Neisseria gonorrhoeae? A cross-sectional study using national surveillance data in England. Sex Transm Infect 2018; 94 421–426.
| 29511067PubMed |

[76]  Hicks LA, Taylor TH, Hunkler RJ. US outpatient antibiotic prescribing, 2010. N Engl J Med 2013; 368 1461–2.
US outpatient antibiotic prescribing, 2010.Crossref | GoogleScholarGoogle Scholar | 23574140PubMed |

[77]  Olesen SW, Lipsitch M, Grad YH, Torrone EA, Papp JR, Kirkcaldy RD. Azithromycin susceptibility among Neisseria gonorrhoeae isolates and seasonal macrolide use. J Infect Dis 2019; 219 619–23.
Azithromycin susceptibility among Neisseria gonorrhoeae isolates and seasonal macrolide use.Crossref | GoogleScholarGoogle Scholar | 30239814PubMed |

[78]  Lau A, Bradshaw CS, Lewis D, Fairley CK, Chen MY, Kong FY, Hocking JS. The efficacy of azithromycin for the treatment of genital Mycoplasma genitalium: a systematic review and meta-analysis. Clin Infect Dis 2015; 61 1389–99.
The efficacy of azithromycin for the treatment of genital Mycoplasma genitalium: a systematic review and meta-analysis.Crossref | GoogleScholarGoogle Scholar | 26240201PubMed |

[79]  Couldwell DL, Lewis DA. Mycoplasma genitalium infection: current treatment options, therapeutic failure, and resistance-associated mutations. Infect Drug Resist 2015; 8 147–61.
| 26060411PubMed |

[80]  Gesink DC, Mulvad G, Montgomery-Andersen R, Poppel U, Montgomery-Andersen S, Binzer A, Vernich L, Frosst G, Stenz F, Rink E, Olsen OR, Kock A, Jensen JS. Mycoplasma genitalium presence, resistance and epidemiology in Greenland. Int J Circumpolar Health 2012; 71 18203
Mycoplasma genitalium presence, resistance and epidemiology in Greenland.Crossref | GoogleScholarGoogle Scholar |

[81]  Read TRH, Fairley CK, Murray GL, Jensen JS, Danielewski J, Worthington K, Doyle M, Mokany E, Tan L, Chow EPF, Garland SM, Bradshaw CS. Outcomes of resistance-guided sequential treatment of Mycoplasma genitalium infections: a prospective evaluation. Clin Infect Dis 2019; 68 554–60.
| 29873691PubMed |

[82]  BASHH Clinical Effectiveness Group. Update on the treatment of Chlamydia trachomatis (CT) infection. Macclesfield: BASHH; 2018. Available online at: https://www.bashhguidelines.org/media/1191/update-on-the-treatment-of-chlamydia-trachomatis-infection-final-16-9-18.pdf [verified 17 December 2018].

[83]  Australian STI Management Guidelines. Chlamydia. Sydney: ASHA; 2018. Available online at: http://www.sti.guidelines.org.au/sexually-transmissible-infections/chlamydia [verified 17 December 2018].

[84]  Lu H, Li K, Gong W, Yan L, Gu X, Chai Z, Guan Z, Zhou P. High frequency of the 23S rRNA A2058G mutation of Treponema pallidum in Shanghai is associated with a current strategy for the treatment of syphilis. Emerg Microbes Infect 2015; 4 e10
| 26038763PubMed |

[85]  Grimes M, Sahi SK, Godornes BC, Tantalo LC, Roberts N, Bostick D, Marra CM, Lukehart SA. Two mutations associated with macrolide resistance in Treponema pallidum: increasing prevalence and correlation with molecular strain type in Seattle, Washington. Sex Transm Dis 2012; 39 954–8.
Two mutations associated with macrolide resistance in Treponema pallidum: increasing prevalence and correlation with molecular strain type in Seattle, Washington.Crossref | GoogleScholarGoogle Scholar | 23191949PubMed |