Current and future antimicrobial treatment of gonorrhoea - the rapidly evolving Neisseria gonorrhoeae continues to challenge

BMC Infectious Diseases

Volumn 15, Issue 1, 2015, Pages

  Unemo, Magnus ^a  

^a ÖREBRO UNIVERSITY   (Sweden)

Author keywords

Antimicrobial resistance; Azithromycin; Ceftriaxone; Gonorrhoea; Neisseria gonorrhoeae; Treatment; Treatment failure

Indexed keywords

ACORAFLOXACIN; ANTIINFECTIVE AGENT; AZITHROMYCIN; CARBAPENEM DERIVATIVE; CEFIXIME; CEFTRIAXONE; CIPROFLOXACIN; DALBAVANCIN; DELAFLOXACIN; DOXYCYCLINE; ERAVACYCLINE; ERTAPENEM; ETX 0914; FOSFOMYCIN; GEMIFLOXACIN; GENTAMICIN; MODITHROMYCIN; PLEUROMUTILIN; PYRIMIDINE DERIVATIVE; QUINOLONE DERIVATIVE; SITAFLOXACIN; SOLITHROMYCIN; SPECTINOMYCIN; UNCLASSIFIED DRUG; BACTERIAL VACCINE;

ANTIBIOTIC RESISTANCE; ANTIMICROBIAL ACTIVITY; BACTERIAL GENE; BACTERIAL STRAIN; BACTERIUM ISOLATE; DRUG EFFICACY; DRUG INDICATION; DRUG RESPONSE; GASTROINTESTINAL DISEASE; GENETIC RESISTANCE; GENOTYPE PHENOTYPE CORRELATION; GONORRHEA; HUMAN; INFECTION CONTROL; MINIMUM INHIBITORY CONCENTRATION; NEISSERIA GONORRHOEAE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT FAILURE; DRUG EFFECTS; ISOLATION AND PURIFICATION; MICROBIOLOGY;

ANTI-INFECTIVE AGENTS; AZITHROMYCIN; BACTERIAL VACCINES; CEFTRIAXONE; DRUG RESISTANCE, BACTERIAL; GONORRHEA; HUMANS; NEISSERIA GONORRHOEAE; TREATMENT FAILURE;

EID: 84939529739     PISSN: None     EISSN: 14712334     Source Type: Journal    
DOI: 10.1186/s12879-015-1029-2     Document Type: Review

References (148)

1. World Health Organization (WHO). Global incidence and prevalence of selected curable sexually transmitted infections - 2008. Geneva: World Health Organization; 2012. p. 2012.
2. World Health Organization (WHO). Department of Reproductive Health and Research. 2012. Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. Geneva: WHO; 2012. p. 1-36.
3. Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st Century: past, evolution, and future. Clin Microbiol Rev. 2014;27:587-613.
4. Buono SA, Watson TD, Borenstein LA, Klausner JD, Pandori MW, Godwin HA. Stemming the tide of drug-resistant Neisseria gonorrhoeae: the need for an individualized approach to treatment. J Antimicrob Chemother. 2015;70:374-81.
5. 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.
6. Goire N, Lahra MM, Chen M, Donovan B, Fairley CK, Guy R, et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nat Rev Microbiol. 2014;12:223-9.
7. Lewis DA. 2010. The gonococcus fights back: is this time a knock out? Sex Transm Infect. 2010;86:415-21.
8. Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol. 2012;7:1401-22.
9. Tapsall JW, Ndowa F, Lewis DA, Unemo M. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Expert Rev Anti Infect Ther. 2009;7:821-34.
10. Bolan GA, Sparling PF, Wasserheit JN. The emerging threat of untreatable gonococcal infection. N Engl J Med. 2012;366:485-7.
11. Ison CA. Antimicrobial resistance in sexually transmitted infections in the developed world: implications for rational treatment. Curr Opin Infect Dis. 2012;25:73-8.
12. Whiley DM, Goire N, Lahra MM, Donovan B, Limnios AE, Nissen MD, et al. The ticking time bomb: escalating antibiotic resistance in Neisseria gonorrhoeae is a public health disaster in waiting. J Antimicrob Chemother. 2012;67:2059-61.
13. Barbee LA. Preparing for an era of untreatable gonorrhea. Curr Opin Infect Dis. 2014;27:282-7.
14. Whiley DM, Lahra MM, Unemo M. Prospects of untreatable gonorrhea and ways forward. Future Microbiol. 2015;10:313-6.
15. Unemo M, Shafer WM. Future treatment of gonorrhoea - novel emerging drugs are essential and in progress? Expert Opin Emerg Drugs. 2015;24:1-4.
16. World Health Organization (WHO). Strategies and laboratory methods for strengthening surveillance of sexually transmitted infections. http://apps.who.int/iris/bitstream/10665/75729/1/9789241504478_eng.pdf (11 June 2015, date last accessed).
17. Centers for Disease Control and Prevention (CDC). Antibiotic-resistant strains of Neisseria gonorrhoeae: policy guidelines for detection, management and control. MMWR. 1987;36(Suppl 5S):13S.
18. Ison CA, Deal C, Unemo M. Current and future treatment options for gonorrhoea. Sex Transm Infect. 2013;89 Suppl 4:iv52-6.
19. Roy K, Wang SA, Meltzer MI. Optimizing treatment of antimicrobial-resistant Neisseria gonorrhoeae. Emerg Infect Dis. 2005;11:1265-73.
20. Unemo M, Shipitsyna E. Domeika M; on behalf of the Eastern European Sexual and Reproductive Health (EE SRH) Network Antimicrobial Resistance Group. Recommended antimicrobial treatment of uncomplicated gonorrhoea in 2009 in 11 East European countries: implementation of a Neisseria gonorrhoeae antimicrobial susceptibility programme in this region is crucial. Sex Transm Infect. 2010;86:442-4.
21. Tapsall JW. Implications of current recommendations for third-generation cephalosporin use in the WHO Western Pacific Region following the emergence of multiresistant gonococci. Sex Transm Infect. 2009;85:256-8.
22. Deguchi T, Yasuda M, Yokoi S, Ishida K, Ito M, Ishihara S, et al. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval. J Infect Chemother. 2003;9:35-9.
23. Unemo M, Golparian D, Syversen G, Vestrheim DF, Moi H. Two cases of verified clinical failures using internationally recommended first-line cefixime for gonorrhoea treatment, Norway, 2010. Euro Surveill. 2010;15(47)
24. Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England. Euro Surveill. 2011;16(14)
25. Unemo M, Golparian D, Stary A, Eigentler A. First Neisseria gonorrhoeae strain with resistance to cefixime causing gonorrhoea treatment failure in Austria, 2011. Euro Surveill. 2011;16(43)
26. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant N. gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012;56:1273-80.
27. Allen VG, Mitterni L, Seah C, Rebbapragada A, Martin IE, Lee C, et al. Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto. Canada JAMA. 2013;309:163-70.
28. Singh AE, Gratrix J, Martin I, Friedman DS, Hoang L, Lester R, et al. Gonorrhea treatment failures with oral and injectable expanded spectrum cephalosporin monotherapy vs dual therapy at 4 Canadian sexually transmitted infection clinics, 2010-2013. Sex Transm Dis. 2015;42:331-6.
29. Lewis DA, Sriruttan C, Müller EE, Golparian D, Gumede L, Fick D, 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 Antimicrobial Chemother. 2013;68:1267-70.
30. Ohnishi M, Golparian D, Shimuta K, Saika T, Hoshina S, Iwasaku K, et al. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea? Detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother. 2011;55:3538-45.
31. Tapsall J, Read P, Carmody C, Bourne C, Ray S, Limnios A, et al. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods. J Med Microbiol. 2009;58:683-7.
32. Chen YM, Stevens K, Tideman R, Zaia A, Tomita T, Fairley CK, et al. Failure of ceftriaxone 500 mg to eradicate pharyngeal gonorrhoea, Australia. J Antimicrob Chemother. 2013;68:1445-7.
33. Read PJ, Limnios EA, McNulty A, Whiley D, Lahra LM. One confirmed and one suspected case of pharyngeal gonorrhoea treatment failure following 500 mg ceftriaxone in Sydney. Australia Sex Health. 2013;10:460-2.
34. Unemo M, Golparian D, Hestner A. Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international recommendations, Sweden, July 2010. Euro Surveill. 2011;16:1-3.
35. Golparian D, Ohlsson A, Janson H, Lidbrink P, Richtner T, Ekelund O, et al. Four treatment failures of pharyngeal gonorrhoea with ceftriaxone (500 mg) or cefotaxime (500 mg), Sweden, 2013 and 2014. Euro Surveill. 2014;19
36. 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;17:1-4.
37. Chisholm SA, Unemo M, Quaye N, Johansson E, Cole MJ, Ison CA, Van de Laar MJ. Molecular epidemiological typing within the European Gonococcal Antimicrobial Resistance Surveillance Programme reveals predominance of a multidrug-resistant clone. Euro Surveill. 2013;18.
38. Cámara J, Serra J, Ayats J, Bastida T, Carnicer-Pont D, Andreu A, et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J Antimicrob Chemother. 2012;67:1858-60.
39. Lahra MM, Ryder N, Whiley DM. A new multidrug-resistant strain of Neisseria gonorrhoeae in Australia. N Engl J Med. 2014;371:1850-1.
40. Tanaka M, Nakayama H, Huruya K, Konomi I, Irie S, Kanayama A, et al. Analysis of mutations within multiple genes associated with resistance in a clinical isolate of Neisseria gonorrhoeae with reduced ceftriaxone susceptibility that shows a multidrug-resistant phenotype. Int J Antimicrob Agents. 2006;27:20-6.
41. 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.
42. Ohnishi M, Watanabe Y, Ono E, Takahashi C, Oya H, Kuroki T, et al. Spreading of a chromosomal cefixime-resistant penA gene among different Neisseria gonorrhoeae lineages. Antimicrob Agents Chemother. 2010;54:1060-7.
43. Shimuta K, Unemo M, Nakayama S, Morita-Ishihara T, Dorin M, Kawahata T, et al. Antimicrobial resistance and molecular typing of Neisseria gonorrhoeae isolates in Kyoto and Osaka, Japan, 2010 to 2012: intensified surveillance after identification of the first strain (H041) with high-level ceftriaxone resistance. Antimicrob Agents Chemother. 2013;57:5225-32.
44. Shimuta K, Watanabe Y, Nakayama S-I, Morita-Ishihara T, Kuroki T, Unemo M, et al. Emergence and evolution of internationally disseminated cephalosporin-resistant Neisseria gonorrhoeae clones from 1995 to 2005 in Japan. BMC Infect Dis. In press.
45. Tomberg J, Unemo M, Ohnishi M, Davies C, Nicholas RA. Identification of the amino acids conferring high-level resistance to expanded-spectrum cephalosporins in the penA gene from the Neisseria gonorrhoeae strain H041. Antimicrob Agents Chemother. 2013;57:3029-36.
46. Grad YH, Kirkcaldy RD, Trees D, Dordel J, Harris SR, Goldstein E, et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet Infect Dis. 2014;14:220-6.
47. Demczuk W, Lynch T, Martin I, Van Domselaar G, Graham M, Bharat A, et al. Whole-genome phylogenomic heterogeneity of Neisseria gonorrhoeae isolates with decreased cephalosporin susceptibility collected in Canada between 1989 and 2013. J Clin Microbiol. 2015;53:191-200.
48. 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.
49. 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 june 17. [Epub ahead of print].
50. Whiley DM, Goire N, Lambert SB, Ray S, Limnios EA, Nissen MD, et al. Reduced susceptibility to ceftriaxone in Neisseria gonorrhoeae is associated with mutations G542S, P551S and P551L in the gonococcal penicillin-binding protein 2. J Antimicrob Chemother. 2010;65:1615-8.
51. Olsen B, Pham TL, Golparian D, Johansson E, Tran HK, Unemo M. Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from Vietnam, 2011. BMC Infect Dis. 2013;13:40.
52. Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM. Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink? J Antimicrob Chemother. 2010;65:2141-8.
53. Moran JS. Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important? Sex Transm Dis. 1995;22:39-47.
54. Moran JS, Levine WC. Drugs of choice for the treatment of uncomplicated gonococcal infections. Clin Infect Dis. 1995;20 Suppl 1:S47-65.
55. Lewis DA. Will targeting oropharyngeal gonorrhoea delay the further emergence of drug-resistant Neisseria gonorrhoeae strains? Sex Transm Infect. 2015;91:234-7.
56. Furuya R, Onoye Y, Kanayama A, Saika T, Iyoda T, Tatewaki M, et al. Antimicrobial resistance in clinical isolates of Neisseria subflava from the oral cavities of a Japanese population. J Infect Chemother. 2007;13:302-4.
57. Saika T, Nishiyama T, Kanayama A, Kobayashi I, Nakayama H, Tanaka M, et al. Comparison of Neisseria gonorrhoeae isolates from the genital tract and pharynx of two gonorrhea patients. J Infect Chemother. 2001;7:175-9.
58. Ndowa F, Lusti-Narasimhan M, Unemo M. The serious threat of multidrug-resistant and untreatable gonorrhoea: the pressing need for global action to control the spread of antimicrobial resistance, and mitigate the impact on sexual and reproductive health. Sex Transm Infect. 2012;88:317-8.
59. European Centre for Disease Prevention and Control (ECDC). Response plan to control and manage the threat of multidrug-resistant gonorrhoea in Europe. Stockholm: ECDC; 2012. p. 1-23. www.ecdc.europa.eu/en/publications/Publications/1206-ECDC-MDR-gonorrhoea-response-plan.pdf (11 June 2015, date last accessed).
60. Centers for Disease Control and Prevention (CDC). Cephalosporin-resistant Neisseria gonorrhoeae public health response plan. 2012. p. 1-43. http://www.cdc.gov/std/gonorrhea/default.htm (11 June 2015, date last accessed).
61. Bignell C, Unemo M. 2012 European guideline on the diagnosis and treatment of gonorrhoea in adults. Int J STD AIDS. 2013;24:85-92.
62. Bignell C, Fitzgerald M. UK national guideline for the management of gonorrhoea in adults, 2011. Int J STD AIDS. 2011;22:541-7.
63. AWMF-Register. Nr. 059/004 - S2k-Leitlinie: Gonorrhoe bei Erwachsenen und Adoleszenten aktueller Stand: 08/2013. 1-31 [In German].
64. Australasian Sexual Health Alliance (ASHA). Australian STI Management Guidelines for Use in Primary Care. www.sti.guidelines.org.au/sexually-transmissible-infections/gonorrhoea#management (11 June 2015, date last accessed).
65. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137.
66. Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections. Gonococcal Infections Chapter. 2013. www.phac-aspc.gc.ca/std-mts/sti-its/cgsti-ldcits/assets/pdf/section-5-6-eng.pdf (11 June 2015, date last accessed).
67. Newman LM, Moran JS, Workowski KA. Update on the management of gonorrhea in adults in the United States. Clin Infect Dis. 2007;44 Suppl 3:S84-S101.
68. Barry PM, Klausner JD. The use of cephalosporins for gonorrhea: the impending problem of resistance. Expert Opin Pharmacother. 2009;10:555-77.
69. Handsfield HH, Dalu ZA, Martin DH, Douglas Jr JM, McCarty JM, Schlossberg D. Multicenter trial of single-dose azithromycin vs ceftriaxone in the treatment of uncomplicated gonorrhoea. Sex Transm Dis. 1994;21:107-11.
70. Handsfield HH, McCormack WM, Hook 3rd EW, Douglas Jr JM, Covino JM, Verdon MS, et al. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. The Gonorrhea Treatment Study Group. N Engl J Med. 1991;325:1337-41.
71. Bai ZG, Bao XJ, Cheng WD, Yang KH, Li YP. Efficacy and safety of ceftriaxone for uncomplicated gonorrhoea: a meta-analysis of randomized controlled trials. Int J STD AIDS. 2012;23:126-32.
72. Portilla I, Lutz B, Montalvo M, Mogabgab WJ. Oral cefixime versus intramuscular ceftriaxone in patients with uncomplicated gonococcal infections. Sex Transm Dis. 1992;19:94-8.
73. Yokoi S, Deguchi T, Ozawa T, Yasuda M, Ito S, Kubota Y, et al. Threat to cefixime treatment for gonorrhea. Emerg Infect Dis. 2007;13:1275-7.
74. Ison CA, Mouton JW, Jones K, Fenton KA, Livermore DM. Which cephalosporin for gonorrhoea? Sex Transm Infect. 2004;80:386-8.
75. Megran DW, Lefebvre K, Willetts V, Bowie WR. Single-dose oral cefixime versus amoxicillin plus probenicid for the treatment of uncomplicated gonorrhea in men. Antimicrob Agents Chemother. 1990;34:355-7.
76. Dunnett DM, Moyer MA. Cefixime in the treatment of uncomplicated gonorrhea. Sex Transm Dis. 1992;19:92-3.
77. Kirkcaldy RD, Weinstock HS, Moore PC, Philip SS, Wiesenfeld HC, Papp JR, 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.
78. Rice LB. Will use of combination cephalosporin/azithromycin therapy forestall resistance to cephalosporins in Neisseria gonorrhoeae? Sex Transm Infect. 2015;91:238-40.
79. Golden MR, Kerani RP, Stenger M, Hughes JP, Aubin M, Malinski C, et al. Uptake and population-level impact of expedited partner therapy (EPT) on Chlamydia trachomatis and Neisseria gonorrhoeae: the Washington State community-level randomized trial of EPT. PLoS Med. 2015;12(1):e1001777.
80. Golden MR, Barbee LA, Kerani R, Dombrowski JC. Potential deleterious effects of promoting the use of ceftriaxone in the treatment of Neisseria gonorrhoeae. Sex Transm Dis. 2014;41:619-25.
81. Low N, Unemo M, Jensen JS, Breuer J, Stephenson JM. Molecular diagnostics for gonorrhoea: implications for antimicrobial resistance and the threat of untreatable gonorrhoea. PLOS Med. 2014;11:e1001598.
82. Sadiq ST, Dave J, Butcher PD. Point-of-care antibiotic susceptibility testing for gonorrhoea: improving therapeutic options and sparing the use of cephalosporins. Sex Transm Infect. 2010;86:445-6.
83. Peterson SW, Martin I, Demczuk W, Bharat A, Hoang L, Wylie J, et al. Molecular assay for the detection of genetic markers associated with decreased susceptibility to cephalosporins in Neisseria gonorrhoeae. J Clin Microbiol. 2015 Apr 15. [Epub ahead of print].
84. 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.
85. Nicol M, Whiley D, Nulsen M, Bromhead C. Direct detection of markers associated with Neisseria gonorrhoeae antimicrobial resistance in New Zealand using residual DNA from the Cobas 4800 CT/NG NAAT assay. Sex Transm Infect. 2015;91:91-3.
86. Speers DJ, Fisk RE, Goire N, Mak DB. Non-culture Neisseria gonorrhoeae molecular penicillinase production surveillance demonstrates the long-term success of empirical dual therapy and informs gonorrhoea management guidelines in a highly endemic setting. J Antimicrob Chemother. 2014;69:1243-7.
87. Buckley C, Trembizki E, Baird RW, Chen M, Donovan B, Freeman K, et al. A multi-target PCR for direct detection of penicillinase-producing Neisseria gonorrhoeae for enhanced surveillance of gonococcal antimicrobial resistance. J Clin Microbiol. 2015 May 20. [Epub ahead of print].
88. Goire N, Ohnishi M, Limnios AE, Lahra MM, Lambert SB, Nimmo GR, et al. Enhanced gonococcal antimicrobial surveillance in the era of ceftriaxone resistance: a real-time PCR assay for direct detection of the Neisseria gonorrhoeae H041 strain. J Antimicrob Chemother. 2012;67:902-5.
89. Goire N, Lahra MM, Ohnishi M, Hogan T, Liminios AE, Nissen MD, et al. Polymerase chain reaction-based screening for the ceftriaxone-resistant Neisseria gonorrhoeae F89 strain. Euro Surveill. 2013;18:20444.
90. Hess D, Wu A, Golparian D, Esmaili S, Pandori W, Sena E, et al. Genome sequencing of a Neisseria gonorrhoeae isolate of a successful international clone with decreased susceptibility and resistance to extended-spectrum cephalosporins. Antimicrob Agents Chemother. 2012;56:5633-41.
91. Ezewudo MN, Joseph SJ, Castillo-Ramirez S, Dean D, Del Rio C, Didelot X, et al. Population structure of Neisseria gonorrhoeae based on whole genome data and its relationship with antibiotic resistance. PeerJ. 2015;3:e806.
92. Ohnishi M, Unemo M. Phylogenomics for drug-resistant Neisseria gonorrhoeae. Lancet Infect Dis. 2014;14:179-80.
93. Morita-Ishihara T, Unemo M, Furubayashi K, Kawahata T, Shimuta K, Nakayama S, 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;69:2086-90.
94. 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.
95. Yasuda M, Ito S, Kido A, Hamano K, Uchijima Y, Uwatoko N, et al. A single 2 g oral dose of extended-release azithromycin for treatment of gonococcal urethritis. J Antimicrob Chemother. 2014;69:3116-8.
96. 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.
97. Chisholm SA, Dave J, Ison CA. High-level azithromycin resistance occurs in Neisseria gonorrhoeae as a result of a single point mutation in the 23S rRNA genes. Antimicrob Agents Chemother. 2010;54:3812-6.
98. 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 Apr 22. [Epub ahead of print].
99. Starnino S, Stefanelli P. Neisseria gonorrhoeae Italian Study Group I. Azithromycin-resistant Neisseria gonorrhoeae strains recently isolated in Italy. J Antimicrob Chemother. 2009;63:1200-4.
100. 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. 2013;58:624-5.
101. Katz AR, Komeya AY, Soge OO, MKiaha MI, Lee MV, Wasserman GM, et al. 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.
102. Galarza PG, Abad R, Canigia LF, Buscemi L, Pagano I, Oviedo C, et al. New mutation in 23S rRNA gene associated with high level of azithromycin resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2010;54:1652-3.
103. Stevens K, Zaia A, Tawil S, Bates J, Hicks V, Whiley D, et al. Neisseria gonorrhoeae isolates with high-level resistance to azithromycin in Australia. J Antimicrob Chemother. 2015;70:1267-8.
104. Bala M, Kakran M, Singh V, Sood S, Ramesh V; Members of WHO GASP SEAR Network. Monitoring antimicrobial resistance in Neisseria gonorrhoeae in selected countries of the WHO South-East Asia Region between 2009 and 2012: a retrospective analysis. Sex Transm Infect. 2013;89 Suppl 4:iv28-35.
105. Dillon JA, Trecker MA, Thakur SD; Gonococcal Antimicrobial Surveillance Program Network in Latin America and the Caribbean 1990-2011. Two decades of the gonococcal antimicrobial surveillance program in South America and the Caribbean: challenges and opportunities. Sex Transm Infect. 2013;89 Suppl 4:iv36-iv41.
106. Kirkcaldy RD, Kidd S, Weinstock HS, Papp JR, Bolan GA. Trends in antimicrobial resistance in Neisseria gonorrhoeae in the USA: the Gonococcal Isolate Surveillance Project (GISP), January 2006-June 2012. Sex Transm Infect. 2013;89 Suppl 4:iv5-10.
107. Lahra MM, Lo YR, Whiley DM. Gonococcal antimicrobial resistance in the Western Pacific Region. Sex Transm Infect. 2013;89 Suppl 4:iv19-23.
108. Spiteri G, Cole M, Unemo M, Hoffmann S, Ison C, van de Laar M. The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP)--a sentinel approach in the European Union (EU)/European Economic Area (EEA). Sex Transm Infect. 2013;89 Suppl 4:iv16-iv18.
109. Lee H, Hong SG, Soe Y, Yong D, Jeong SH, Lee K, et al. Trends in antimicrobial resistance of Neisseria gonorrhoeae isolated from Korean patients from 2000 to 2006. Sex Transm Dis. 2011;38:1082-6.
110. Boslego JW, Tramont EC, Takafuji ET, Diniega BM, Mitchell BS, Small JW, et al. Effect of spectinomycin use on the prevalence of spectinomycin-resistant and penicillinase-producing Neisseria gonorrhoeae. N Engl J Med. 1987;317:272-8.
111. Easmon CS, Forster GE, Walker GD, Ison CA, Harris JR, Munday PE. Spectinomycin as initial treatment for gonorrhoea. Br Med J. 1984;289:1032-4.
112. Ison CA, Littleton K, Shannon KP, Easmon CS, Phillips I. Spectinomycin resistant gonococci. Br Med J (Clin Res Ed). 1983;287:1827-9.
113. Unemo M, Golparian D, Limnios A, Whiley D, Ohnishi M, Lahra MM, et al. In vitro activity of ertapenem vs. ceftriaxone against Neisseria gonorrhoeae isolates with highly diverse ceftriaxone MIC values and effects of ceftriaxone resistance determinants - ertapenem for treatment of gonorrhea? Antimicrob Agents Chemother. 2012;56:3603-9.
114. Quaye N, Cole MJ, Ison CA. Evaluation of the activity of ertapenem against gonococcal isolates exhibiting a range of susceptibilities to cefixime. J Antimicrob Chemother. 2014;69:1568-71.
115. Hauser C, Hirzberger L, Unemo M, Furrer H, Endimiani A. In vitro activity of fosfomycin alone and in combination with ceftriaxone or azithromycin against clinical Neisseria gonorrhoeae isolates. Antimicrob Agents Chemother. 2015;59:1605-11.
116. Brown LB, Krysiak R, Kamanga G, Mapanje C, Kanyamula H, Banda B, et al. Neisseria gonorrhoeae antimicrobial susceptibility in Lilongwe, Malawi, 2007. Sex Transm Dis. 2010;37:169-72.
117. Chisholm SA, Quaye N, Cole MJ, Fredlund H, Hoffmann S, Jensen JS, et al. An evaluation of gentamicin susceptibility of Neisseria gonorrhoeae isolates in Europe. J Antimicrob Chemother. 2011;66:592-5.
118. Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta-analysis. Sex Transm Infect. 2013;89:142-7.
119. Hathorn E, Dhasmana D, Duley L, Ross JD. The effectiveness of gentamicin in the treatment of Neisseria gonorrhoeae: a systematic review. Syst Rev. 2014;3:104.
120. Biedenbach DJ, Turner LL, Jones RN, Farell DJ. Activity of JNJ-Q2, a novel fluoroquinolone, tested against Neisseria gonorrhoeae, including ciprofloxacin-resistant strains. Diagn Microbiol Infect Dis. 2012;74:204-6.
121. Robert MC, Remy JM, Longcor JD, Marra A, Sun E, Duffy EM. In vitro activity of delafloxacin against Neisseria gonorrhoeae clinical isolates. STI & AIDS World Congress 2013. 14-17 July, 2013, Vienna, Austria.
122. Hamasuna R, Yasuda M, Ishikawa K, Uehara S, Hayami H, Takahashi S, et al. The second nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan, 2012-2013. J Infect Chemother. 2015;21:340-5.
123. Kazamori D, Aoi H, Sugimoto K, Ueshima T, Amano H, Itoh K, et al. In vitro activity of WQ-3810, a novel fluoroquinolone, against multidrug-resistant and fluoroquinolone-resistant pathogens. Int J Antimicrob Agents. 2014;44:443-9.
124. Kerstein K, Fyfe C, Sutcliffe JA, Grossman TH. Eravacycline (TP-434) is active against susceptible and multidrug-resistant Neisseria gonorrhoeae. 53rd Annual ICAAC. 10-13 September, 2013, Denver, CO, USA. Poster E-1181.
125. Zhang YY, Zhou L, Zhu DM, Wu PC, Hu FP, Wu WH, et al. In vitro activities of tigecycline against clinical isolates from Shanghai. China Diagn Microbiol Infect Dis. 2004;50:267-81.
126. Alexander BT, Marschall J, Tibbetts RJ, Neuner EA, Dunne Jr WM, Ritchie DJ. Treatment and clinical outcomes of urinary tract infections caused by KPC-producing Enterobacteriaceae in a retrospective cohort. Clin Ther. 2012;34:1314-23.
127. Falagas ME, Karageorgopoulos DE, Dimopoulos G. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of tigecycline. Curr Drug Metab. 2009;10:13-21.
128. Nix DE, Matthias KR. Should tigecycline be considered for urinary tract infections? A pharmacokinetic re-evaluation. J Antimicrob Chemother. 2010;65:1311-2.
129. Fujimoto K, Takemoto K, Hatano K, Nakai T, Terashita S, Matsumoto M, et al. Novel carbapenem antibiotics for parenteral and oral applications: in vitro and in vivo activities of 2-aryl carbapenems and their pharmacokinetics in laboratory animals. Antimicrob Agents Chemother. 2013;57:697-707.
130. Koeth LM, Fisher J. In vitro activity of dalbavancin against Neisseria gonorrhoeae and development of a broth microdilution method. IDWeek 2013. 2-6 October, 2013, San Francisco, Calif, USA. Poster 255.
131. Jacobsson S, Golparian D, Phan LT, Ohnishi M, Fredlund H, Or YS, et al. In vitro activities of the novel bicyclolides modithromycin (EDP-420, EP-013420, S-013420) and EDP-322 against MDR clinical Neisseria gonorrhoeae isolates and international reference strains. J Antimicrob Chemother. 2015;70:173-7.
132. Golparian D, Fernandes P, Ohnishi M, Jensen JS, Unemo M. In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical Neisseria gonorrhoeae isolates and international reference strains including those with various high-level antimicrobial resistance-potential treatment option for gonorrhea? Antimicrob Agents Chemother. 2012;56:2739-42.
133. Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, et al. Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. Antimicrob Agents Chemother. 2010;54:4961-70.
134. Still JG, Schranz J, Degenhardt TP, Scott D, Fernandes P, Gutierrez MJ, et al. Pharmacokinetics of solithromycin (CEM-101) after single or multiple oral doses and effects of food on single-dose bioavailability in healthy adult subjects. Antimicrob Agents Chemother. 2011;55:1997-2003.
135. Hook E III, Oldach D, Jamieson B, Clark K, Fernandes P. 2013. A phase 2 study to evaluate the efficacy and safety of single dose solithromycin (CEM-101) for the treatment of patients with uncomplicated urogenital gonorrhoea. 23rd European Congress of Clinical Microbiology and Infectious Disease. 27-30 April, 2013, Berlin, Germany. Abstract O274.
136. Paukner S, Gruss A, Fritsche TR, Ivezic-Schoenfeld Z, Jones RN. In vitro activity of the novel pleuromutilin BC-3781 tested against bacterial pathogens causing sexually transmitted diseases (STD). 53rd Annual ICAAC. 10-13 September, 2013, Denver, CO, USA. Poster E-1183.
137. Bouchillon SK, Hoban DJ, Hackel MA, Butler DL, Memarsh P, Alley MRK. In vitro activities of AN3365: a novel boron containing protein synthesis inhibitor, and other antimicrobial agents against anaerobes and Neisseria gonorrhoeae. 50th Annual ICAAC. 12-15 September, 2010, Boston, MA, USA. Poster F1-1640.
138. Swanson S, Lee CJ, Liang X, Toone E, Zhou P, Nicholas R. LpxC inhibitors as novel therapeutics for treatment of antibiotic-resistant Neisseria gonorrhoeae. 18th International Pathogenic Neisseria Conference. 9-14 September, 2012, Wurzburg, Germany.
139. Escaich S, Prouvensier L, Saccomani M, Durant L, Oxoby M, Gerusz V, et al. The MUT056399 inhibitor of FabI is a new antistaphylococcal compound. Antimicrob Agents Chemother. 2011;55:4692-7.
140. Jeverica S, Golparian D, Hanzelka B, Fowlie AJ, Matičič M, Unemo M. High in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (VT12-008911) against Neisseria gonorrhoeae isolates with various high-level antimicrobial resistance and multidrug resistance. J Antimicrob Chemother. 2014;69:1866-72.
141. Jacobsson S, Golparian D, Alm RA, Huband M, Mueller J, Jensen JS, et al. High in vitro activity of the novel spiropyrimidinetrione AZD0914, a DNA gyrase inhibitor, against multidrug resistant Neisseria gonorrhoeae isolates suggests a new effective option for oral treatment of gonorrhea. Antimicrob Agents Chemother. 2014;58:5585-8.
142. Huband MD, Bradford PA, Otterson LG, Basarab GS, Kutschke A, Giacobbe R, et al. In vitro antibacterial activity of AZD0914: a new spiropyrimidinetrione DNA Gyrase/Topoisomerase inhibitor with potent activity against Gram-positive, fastidious Gram-negative, and atypical bacteria. Antimicrob Agents Chemother. 2015;59:467-74.
143. Unemo M, Ringlander J, Wiggins C, Fredlund H, Jacobsson S, Cole M, the European Collaborative Group. High in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (also known as AZD0914) among 873 contemporary clinical Neisseria gonorrhoeae isolates in 21 European countries during 2012-2014. Antimicrob Agents Chemother. 2015 june 15. [Epub ahead of print]
144. Palmer T, Walkup G, Basarab G, Fan J, Mills SD, Shapiro A, et al. 2014. AZD0914: A Neisseria gonorrhoeae Topoisomerase II inhibitor with novel mode of inhibition, poster C-1422. Abstr. 54th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC, USA.
145. Alm RA, Lahiri SD, Kutschke A, Otterson LG, McLaughlin RE, Whiteaker JD, et al. Characterization of the novel DNA gyrase inhibitor AZD0914: Low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2015;59:1478-86.
146. Basarab GS, McNulty J, Gales S, Powles-Glover N, Prior H, Lengel D, et al. 2014. Non-clinical safety profile of a novel gyrase inhibitor for treatment of Neisseria gonorrhoeae infections, poster F-268. Abstr. 54th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC, USA.
147. Lawrence K, O'Connor K, Atuah K, Matthews D, Gardner H. 2014. Safety and pharmacokinetics of single escalating oral doses of AZD0914: a novel spiropyrimidinetrione antibacterial agent, poster F-267. Abstr. 54th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC, USA.
148. Jerse AE, Deal CD. Vaccine research for gonococcal infections: where are we? Sex Transm Infect. 2013;89 Suppl 4:iv63-8.