Resistance genes of Neisseria gonorrhoeae to cefixime and azithromycin

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Louisa Ivana Utami
Yeva Rosana


Gonorrhea is the second most common sexually transmitted bacterial infection (STI), following Chlamydia. Neisseria gonorrhoeae resistant to antibiotics are increasing globally in the world. In recent years, many studies have reported reduced susceptibility of N.gonorrhoeae to almost all clinically useful antibiotics and also reported cases of multi-resistance. Resistance mechanisms for N. gonorrhoeae can occur through genetic and non-genetic changes. Resistance to cefixime and azithromycin as first-line antibiotics for monotherapy recommended by the World Health Organization (WHO) has been reported from several countries. Genetic changes were reported as the main cause of N.gonorrhoeae resistance to cefixime and azithromycin. Based on the WHO and the United States Centers for Disease Control and Prevention recommendations, countries are increasingly using a combination of cephalosporin and azithromycin for the treatment of gonorrhea. The aim of this review is to analyze genetic variation of N.gonorrhoeae resistance to cefixime and azithromycin. Articles published in English in the last 12 years (from 2010 to 2021) were retrieved from Science Direct, PubMed, Springerlink, Oxford and Nature using relevant searching terms. Mutants of cefixime-resistant N.gonorrhoeae are mediated by mosaic and non-mosaic penA genes encoding penicillin binding protein 2. In addition, mutations in the repressor and promoter genes of mtrR were also found that caused overexpression of the microbial efflux pump. Meanwhile, N. gonorrhoeae resistance to azithromycin reportedly occurs through two strategies, namely overexpression of the efflux pump (mutation of the mtrR codon region) and decreased affinity for antibiotics (single base mutation in the 23S rRNA gene). With the limited choice of antibiotics for the management of N.gonorrhoeae, it is necessary to do regular surveillance for monitoring drug resistance. By understanding the mechanism of resistance, the use of these antibiotics can be rationally optimized.

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How to Cite
Utami, L. I. ., & Rosana, Y. (2023). Resistance genes of Neisseria gonorrhoeae to cefixime and azithromycin. Universa Medicina, 42(1), 108–118.
Review Article


Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 2014;27:587–613. doi: 10.1128/CMR.00010-14

Sethi S, Golparian D, Bala M, et al. Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from India, Pakistan and Bhutan in 2007-2011. BMC Infect Dis 2013;13:35. doi: 10.1186/1471-2334-13-35.

Unemo M, Shafer WM. Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann N Y Acad Sci 2011;1230:E19-28. doi: 10.1111/j.1749-6632.2011.06215.x.

Bailey AL, Potter RF, Wallace MA, Johnson C, Dantas G, Burnham CAD. Genotypic and phenotypic characterization of antimicrobial resistance in Neisseria gonorrhoeae: a cross-sectional study of isolates recovered from routine urine cultures in a high-incidence setting. mSphere 2019;4:e00373-19. doi: 10.1128/mSphere.00373-19.

Berenger BM, Demczuk W, Gratrix J, Pabbaraju K, Smyczek P, Martin I. Genetic characterization and enhanced surveillance of ceftriaxone-resistant Neisseria gonorrhoeae strain, Alberta, Canada, 2018. Emerg Infect Dis 2019;25:1660-7. doi:10.3201/eid2509.190407

Gernert KM, Seby S, Schmerer MW, et al. Azithromycin susceptibility of Neisseria gonorrhoeae in the USA in 2017: a genomic analysis of surveillance data. Lancet Microbe 2020;1:e154-64. doi: 10.1016/S2666-5247(20)30059-8.

World Health Organization. WHO guidelines for the treatment of Neisseria gonorrhoeae. Geneva: World Health Organztion;2016.

Harris SR, Cole MJ, Spiteri G, et al. Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey. Lancet Infect Dis 2018;18:758–68. doi: 10.1016/S1473-3099(18)30225-1.

Ryan L, Golparian D, Fennelly N, et al. Antimicrobial resistance and molecular epidemiology using whole-genome sequencing of Neisseria gonorrhoeae in Ireland, 2014–2016: focus on extended-spectrum cephalosporins and azithromycin. Eur J Clin Microbiol Infect Dis 2018;37:1661–72. doi: 10.1007/s10096-018-3296-5.

Zheng Z, Liu L, Shen X, et al. Antimicrobial resistance and molecular characteristics among Neisseria gonorrhoeae clinical isolates in a Chinese tertiary hospital. Infect Drug Resist 2019; 12:3301-9.

Chen SC, Yin YP, Dai XQ, Unemo M, Chen XS. First nationwide study regarding ceftriaxone resistance and molecular epidemiology of Neisseria gonorrhoeae in China. J Antimicrob Chemother 2016;71:92-9. doi: 10.1093/jac/dkv321.

Demczuk W, Sidhu S, Unemo M, et al. Neisseria gonorrhoeae sequence typing for antimicrobial resistance, a novel antimicrobial resistance multilocus typing scheme for tracking global dissemination of N. gonorrhoeae strains. J Clin Microbiol 2017;55:1454–68. doi: 10.1128/JCM.00100-17.

Peng JP, Yin YP, Chen SC, et al. A whole-genome sequencing analysis of Neisseria gonorrhoeae isolates in China: an observational Study. E Clinical Medicine 2019;7:47-54. doi: 10.1016/j.eclinm.2019.01.010.

Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology 7th ed. Philadelphia: Elsevier;2013.

Lee MH, Byun J, Jung M, et al. Disseminated gonococcal infection presenting as bacteremia and liver abscesses in a healthy adult. Infect Chemother 2015;47:60-3. doi: 10.3947/ic.2015. 47.1.60.

Birrell JM, Gunathilake M, Singleton S, Williams S, Krause V. Characteristics and impact of disseminated gonococcal infection in the “Top End” of Australia. Am J Trop Med Hyg 2019; 101:753-60. doi: 10.4269/ajtmh.19-0288.

Brooks GF, Jawetz E, Melnick JL, et al. Jawetz, Melnick & Adelberg’s medical microbiology. 26th ed. New York: McGraw-Hill Inc; 2013.

Direktorat Jenderal Pengendalian Penyakit dan Penyehatan Lingkungan Kementerian Kesehatan Republik Indonesia. Pedoman Nasional Penanganan Infeksi Menular Seksual. Jakarta: Kementerian Kesehatan Republik Indonesia;2016.

Shaskolskiy B, Dementieva E, Kandinov I, et al. Genetic diversity of Neisseria gonorrhoeae multi-antigen sequence types in Russia and Europe. Int J Infect Dis 2020;93:1–8. doi: 10.1016/j.ijid. 2020.01.020.

Brunner A, Nemes-Nikodem E, Mihalik N, Marschalko M, Karpati S, Ostorhazi S. Incidence and antimicrobial susceptibility of Neisseria gonorrhoeae isolates from patients attending the national Neisseria gonorrhoeae reference laboratory of Hungary. BMC Infect Dis 2014;14:4-11.

Tanaka M, Furuya R, Kobayashi I, Kanesaka I, Ohno A, Kanayama AK. Antimicrobial resistance and molecular characterisation of Neisseria gonorrhoeae isolates in Fukuoka, Japan, 1996–2016. J Glob Antimicrob Resist 2019;17:3–7.

Belkacem A, Jacquier H, Goubard A, et al. Molecular epidemiology and mechanisms of resistance of azithromycin-resistant Neisseria gonorrhoeae isolated in France during 2013-14. J Antimicrob Chemother 2016;71:2471–8. doi: 10.1093/jac/dkw182.

Jacobsson S, Cole MJ, Spiteri G, Day M, Unemo M. Associations between antimicrobial susceptibility/resistance of Neisseria gonorrhoeae isolates in European Union/European Economic Area and patients’ gender, sexual orientation and anatomical site of infection, 2009–2016. BMC Infect Dis 2021;21:273.

Lewis DA, Sriruttan C, Müller EE, et al. Phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure. J Antimicrob Chemother 2013;68:1267–70. doi: 10.1093/jac/dkt034.

Sánchez-Busó L, Yeats CA, Taylor B, et al. A community-driven resource for genomic epidemiology and antimicrobial resistance prediction of Neisseria gonorrhoeae at Pathogenwatch. Genome Med 2021;13:1–22. doi: 10.1186/s13073-021-00858-2.

Kueakulpattana N, Wannigama DL, Luk-in S, et al. Multidrug-resistant Neisseria gonorrhoeae infection in heterosexual men with reduced susceptibility to ceftriaxone, first report in Thailand. Sci Rep 2021;11:1–16. doi: 10.1038/s41598-021-00675-y.

Oree G, Naicker M, Maise H, Abbai NS. Comparison of endocervical swabs to cultured isolates for the detection of antimicrobial resistance determinants in Neisseria gonorrhoeae. J Med Lab Sci Technol South Africa 2022;3:40–6.

Qin X, Zhao Y, Chen W, et al. Changing antimicrobial susceptibility and molecular characterisation of Neisseria gonorrhoeae isolates in Guangdong, China: in a background of rapidly raising epidemic. Int J Antimicrob Agents 2019;54:757–65.

Holderman JL, Thomas JC, Schlanger K, et al. Sustained transmission of Neisseria gonorrhoeae with high-level resistance to azithromycin, in Indianapolis, Indiana, 2017-2018. Clin Infect Dis 2021;73:808–15. doi: 10.1093/cid/ciab132.

Kovari H, de Melo Oliveira MDG, Hauser P, et al. Decreased susceptibility of Neisseria gonorrhoeae isolates from Switzerland to cefixime and ceftriaxone: antimicrobial susceptibility data from 1990 and 2000 to 2012. BMC Infect Dis 2013;13:603.

Karim S, Bouchikhi C, Banani A, et al. Molecular antimicrobial resistance of Neisseria gonorrhoeae in a Moroccan area. Infect Dis Obstet Gynecol 2018;7263849. doi: 10.1155/2018/7263849.

Day MJ, Jacobsson S, Spiteri G. et al. Significant increase in azithromycin “resistance” and susceptibility to ceftriaxone and cefixime in Neisseria gonorrhoeae isolates in 26 European countries, 2019. BMC Infect Dis 2022;22:524.

Liang JY, Cao WL, Li XD, et al. Azithromycin-resistant Neisseria gonorrhoeae isolates in Guangzhou, China (2009-2013): Coevolution with decreased susceptibilities to ceftriaxone and genetic characteristics. BMC Infect Dis 2016;16:152.

Jiang FX, Lan Q, Le WJ, Su XH. Antimicrobial susceptibility of Neisseria gonorrhoeae isolates from Hefei (2014-2015): genetic characteristics of antimicrobial resistance. BMC Infect Dis 2017; 17:366. doi: 10.1186/s12879-017-2472-z.

Lee H, Unemo M, Kim HJ, Seo Y, Lee K, Chong Y. Emergence of decreased susceptibility and resistance to extended spectrum cephalosporins in Neisseria gonorrhoeae in Korea. J Antimicrob Chemother 2015;70:2536–42. doi: 10.1093/jac/dkv146. Calado J, Castro R, Lopes Â, Campos MJ, Rocha M, Pereira F. Antimicrobial resistance and molecular characteristics of Neisseria gonorrhoeae isolates from men who have sex with men. Int J Infect Dis 2019;79:116–22.

Thomas JC, Seby S, Abrams AJ,et al. Evidence of recent genomic evolution in gonococcal strains with decreased susceptibility to cephalosporins or azithromycin in the United States, 2014-2016. J Infect Dis 2019;220:294-305. doi: 10.1093/infdis/jiz079.

Xiu L, Yuan Q, Li Y, Zhang C, Yang L, Peng J. Emergence of ceftriaxone-resistant Neisseria gonorrhoeae strains harbouring a novel mosaic penA gene in China. J Antimicrob Chemother 2020;75:907–10. doi: 10.1093/jac/dkz530.

Pham TL, Golparian D, Ringlander J, Le VH, Nguyen VT, Unemo M. Genomic analysis and antimicrobial resistance of Neisseria gonorrhoeae isolates from Vietnam in 2011 and 2015-16. J Antimicrob Chemother 2021;75:1432–8. doi 10.1093/jac/dkaa040.

Thomas JC, Joseph SJ, Cartee JC, et al. Phylogenomic analysis reveals persistence of gonococcal strains with reduced-susceptibility to extended-spectrum cephalosporins and mosaic penA-34. Nat Commun 2021;12.

Gose S, Nguyen D, Lowenberg D, Samuel M, Bauer H, Pandori M. Neisseria gonorrhoeae and extended-spectrum cephalosporins in California: Surveillance and molecular detection of mosaic penA. BMC Infect Dis 2013;13:570. doi: 10.1186/1471-2334-13-570.

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;14:1–7.doi 10.1186/1471-2334-14-65

Gianecini RA, Golparian D, Zittermann S, et al. Genome-based epidemiology and antimicrobial resistance determinants of Neisseria gonorrhoeae isolates with decreased susceptibility and resistance to extended-spectrum cephalosporins in Argentina in 2011-16. J Antimicrob Chemother 2019;74:1551–9. doi

Jeverica S, Golparian D, Matièiè M, Potoènik M, Mlakar B, Unemo M. Phenotypic and molecular characterization of Neisseria gonorrhoeae isolates from Slovenia, 2006-12: rise and fall of the multidrug-resistant NG-MAST genogroup 1407 clone? J Antimicrob Chemother 2014;69:1517–25. doi: 10.1093/jac/dku026.

Yan J, Xue J, Chen Y, Chen S, et al. Increasing prevalence of Neisseria gonorrhoeae with decreased susceptibility to ceftriaxone and resistance to azithromycin in Hangzhou, China (2015-17). J Antimicrob Chemother 2019;74:29–37. doi: 10.1093/jac/dky412.

Thakur SD, Levett PN, Horsman GB, Dillon JA. Association of Neisseria gonorrhoeae genogroups and specific PBP2/MtrR/PorB mutation patterns with susceptibility to penicillin in a susceptible gonococcal population. J Antimicrob Chemother 2018;73:2682–6. doi: 10.1093/jac/dky233.

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. doi: 10.1186/1471-2334-14-106.

Serra-Pladevall J, Barberá MJ, Rodriguez S, et al. Neisseria gonorrhoeae antimicrobial susceptibility in Barcelona: penA, ponA, mtrR, and porB mutations and NG-MAST sequence types associated with decreased susceptibility to cephalosporins. Eur J Clin Microbiol Infect Dis 2016;35:1549–56.

Zhang C, Wang F, Zhu C, et al. Determining antimicrobial resistance profiles and identifying novel mutations of Neisseria gonorrhoeae genomes obtained by multiplexed MinION sequencing. Sci China Life Sci 2020;63:1063–70. doi: 10.1007/s11427-019-1558-8.

Reimche JL, Chivukula VL, Schmerer MW, et al. Genomic analysis of the predominant strains and antimicrobial resistance determinants within 1479 Neisseria gonorrhoeae isolates from the US Gonococcal Isolate Surveillance Project in 2018. Sex Transm Dis 2021;48:S78–87. doi: 10.1097/OLQ.0000000000001471.

da Costa-Lourenço APR, Abrams AJ, dos Santos KTB, et al. Phylogeny and antimicrobial resistance in Neisseria gonorrhoeae isolates from Rio de Janeiro, Brazil. Infect Genet Evol 2018;58:157–63.

Golparian D, Bazzo ML, Golfetto L, et al. Genomic epidemiology of Neisseria gonorrhoeae elucidating the gonococcal antimicrobial resistance and lineages/sublineages across Brazil, 2015–16. J Antimicrob Chemother 2020;75:3163–72. doi: 10.1093/jac/dkaa318.

Thakur SD, Starnino S, Horsman GB, Levett PN, Dillon JR. Unique combined penA/mtrR/porB mutations and NG-MAST strain types associated with ceftriaxone and cefixime MIC increases in a “susceptible” Neisseria gonorrhoeae population. J Antimicrob Chemother 2014;69:1510–6. doi: 10.1093/jac/dkt543.

Lee SG, Lee H, Jeong SH, Yong D, Chung GT, Lee YS, et al. Various penA mutations together with mtrR, porB and ponA mutations in Neisseria gonorrhoeae isolates with reduced susceptibility to cefixime or ceftriaxone. J Antimicrob Chemother 2010;65:669-75.

Wind CM, De Vries E, Schim Van Der Loeff MF, et al. Decreased azithromycin susceptibility of Neisseria gonorrhoeae isolates in patients recently treated with azithromycin. Clin Infect Dis 2017;65:37–45. doi: 10.1093/cid/cix249.

Pham CD, Nash E, Liu H, et al. Atypical mutation in Neisseria gonorrhoeae 23S rRNA associated with high-level azithromycin resistance. Antimicrob Agents Chemother 2021;65:1–5. doi: 10.1128/AAC.00885-20.

Johnson SR, Grad Y, Abrams AJ, Pettus K, Trees DL. Use of whole-genome sequencing data to analyze 23S rRNA-mediated azithromycin resistance. Int J Antimicrob Agents 2017;49:252-4. doi:10.1016/j.ijantimicag.2016.10.023.

Derbie A, Mekonnen D, Woldeamanuel Y, Abebe T. Azithromycin resistant gonococci: A literature review. Antimicrob Resist Infect Control 2020;9:138. doi: 10.1186/s13756-020-00805-7.

Shigemura K, Osawa K, Miura M, et al. Azithromycin resistance and its mechanism in Neisseria gonorrhoeae strains in Hyogo, Japan. Antimicrob Agents Chemother 2015;59:2695–9. doi: 10.1128/AAC.04320-14.

Handing JW, Ragland SA, Bharathan UV, Criss AK. The MtrCDE efflux pump contributes to survival of Neisseria gonorrhoeae from human neutrophils and their antimicrobial components. Front Microbiol 2018;9:2688. doi:10.3389/fmicb.2018.02688

Chen SC, Yin YP, Dai XQ, Unemo M, Chen XS. Antimicrobial resistance, genetic resistance determinants for ceftriaxone and molecular epidemiology of Neisseria gonorrhoeae isolates in Nanjing, China. J Antimicrob Chemother 2014;69:2959–65. doi: 10.1093/jac/dku245.

Pham CD, Nash E, Liu H, et al. Atypical mutation in Neisseria gonorrhoeae 23S rRNA associated with high-level azithromycin resistance. Antimicrob Agents Chemother 2021 ;65:e00885-20. doi: 10.1128/AAC.00885-20.