Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea

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References

• 1  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.7,821–834 (2009).▪ Comprehensive review describing initiatives by the WHO to enhance global antimicrobial resistance surveillance and meet the public health challenges posed by international spread of multidrug-resistant and extensively drug-resistant Neisseria gonorrhoeae.
  MedlineGoogle Scholar
• 2  Cohen MS, Hoffman IF, Royce RA et al. Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. Lancet349,1868–1873 (1997).
  Medline CASGoogle Scholar
• 3  Barry PM, Klausner JD. The use of cephalosporins for gonorrhea: the impending problem of resistance. Expert Opin. Pharmacother.10,555–577 (2009).
  Medline CASGoogle Scholar
• 4  Bolan GA, Sparling PF, Wasserheit JN. The emerging threat of untreatable gonococcal infection. N. Engl. J. Med.366,485–487 (2012).
  MedlineGoogle Scholar
• 5  Centers for Disease Control and Prevention (CDC). Cephalosporin susceptibility among Neisseria gonorrhoeae isolates – United States, 2000–2010. MMWR Morb. Mortal. Wkly Rep.60,873–877 (2011).
  MedlineGoogle Scholar
• 6  Chisholm SA, Alexander S, Desouza-Thomas L et al. Emergence of a Neisseria gonorrhoeae clone showing decreased susceptibility to cefixime in England and Wales. J. Antimicrob. Chemother.66,2509–2512 (2011).
  Medline CASGoogle Scholar
• 7  Cole MJ, Unemo M, Hoffmann S, Chisholm SA, Ison CA, van de Laar MJ. The European gonococcal antimicrobial surveillance programme, 2009. Euro. Surveill.16(42),19995 (2011).
  MedlineGoogle Scholar
• 8  Golparian D, Hellmark B, Fredlund H, Unemo M. Emergence, spread and characteristics of Neisseria gonorrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden. Sex. Transm. Infect.86,454–460 (2010).
  MedlineGoogle Scholar
• 9  Kirkcaldy RD, Ballard RC, Dowell D. Gonococcal resistance: are cephalosporins next? Curr. Infect. Dis. Rep.13,196–204 (2011).
  MedlineGoogle Scholar
• 10  Kubanova A, Frigo N, Kubanov A et al. The Russian gonococcal antimicrobial susceptibility programme (RU-GASP) – national resistance prevalence in 2007 and 2008, and trends during 2005–2008. Euro. Surveill.15(14),19533 (2010).
  MedlineGoogle Scholar
• 11  Lewis DA. The gonococcus fights back: is this time a knock out? Sex. Transm. Infect.86,415–421 (2010).
  MedlineGoogle Scholar
• 12  Lewis DA, Lukehart SA. Antimicrobial resistance in Neisseria gonorrhoeae and Treponema pallidum: evolution, therapeutic challenges and the need to strengthen global surveillance. Sex. Transm. Infect.87(Suppl. 2),ii39–ii43 (2011).
  MedlineGoogle Scholar
• 13  Martin I, Jayaraman G, Wong T, Liu G, Gilmour M. Canadian Public Health Laboratory Network. Trends in antimicrobial resistance in Neisseria gonorrhoeae isolated in Canada: 2000–2009. Sex. Transm. Dis.38,892–898 (2011).
  Medline CASGoogle Scholar
• 14  Newman LM, Moran JS, Workowski KA. Update on the management of gonorrhea in adults in the United States. Clin. Infect. Dis.44(Suppl.3),S84–S101 (2007).
  Medline CASGoogle Scholar
• 15  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.38,871–875 (2011).
  Medline CASGoogle Scholar
• 16  Tanaka M, Shimojima M, Saika T et al. Nationwide antimicrobial susceptibility survey of Neisseria gonorrhoeae isolates in Japan. Kansenshogaku Zasshi.85,360–365 (2011).
  MedlineGoogle Scholar
• 17  Unemo M, Shafer WM. Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann. NY Acad. Sci.1230,E19–E28 (2011).
  MedlineGoogle Scholar
• 18  WHO Western Pacific and South East Asian Gonococcal Antimicrobial Surveillance Programmes; Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific and South East Asian Regions, 2010. Commun. Dis. Intell.36,95–100 (2012).
  MedlineGoogle Scholar
• 19  Workowski KA, Berman S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm. Rep.59(RR-12),1–110 (2010).
  MedlineGoogle Scholar
• 20  Stoltey JE, Barry PM. The use of cephalosporins for gonorrhea: an update on the rising problem of resistance. Expert Opin. Pharmacother.13,1411–1420 (2012).▪ Comprehensive updated review emphasizing many important actions needed to meet the challenge of multidrug-resistant gonorrhea.
  Medline CASGoogle Scholar
• 21  Deguchi T, Yasuda M, Yokoi S et al. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval. J. Infect. Chemother.9,35–39 (2003).
  Medline CASGoogle Scholar
• 22  Ison CA, Hussey J, Sankar KN, Evans J, Alexander S. Gonorrhoea treatment failures to cefixime and azithromycin in England, 2010. Euro. Surveill.16(14),19833 (2011).
  MedlineGoogle Scholar
• 23  Ohnishi M, Golparian D, Shimuta 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.55,3538–3545 (2011).▪▪ Detailed phenotypic and genetic characterization of the first N. gonorrhoeae strain with high-level ceftriaxone resistance (identified in Japan).
  Medline CASGoogle Scholar
• 24  Unemo M, Golparian D, Hestner A. Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international recommendations, Sweden, July 2010. Euro. Surveill.16(6),19792 (2011).
  MedlineGoogle Scholar
• 25  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.56,1273–1280 (2012).▪ Detailed phenotypic and genetic characterization of the second N. gonorrhoeae strain with high-level ceftriaxone resistance (identified in France).
  Medline CASGoogle Scholar
• 26  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.16(43),19998 (2011).
  MedlineGoogle Scholar
• 27  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.15(47),19721 (2010).
  MedlineGoogle Scholar
• 28  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.17(25),20200 (2012).
  MedlineGoogle Scholar
• 29  Tapsall J, Read P, Carmody C et al. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods. J. Med. Microbiol.58(Pt 5),683–687 (2009).
  Medline CASGoogle Scholar
• 30  Yokoi S, Deguchi T, Ozawa T et al. Threat to cefixime treatment of gonorrhea. Emerg. Infect. Dis.13,1275–1277 (2007).
  MedlineGoogle Scholar
• 31  Cámara J, Serra J, Ayats J et al. Molecular characterization of two high-level ceftriaxone-resistant Neisseria gonorrhoeae isolates detected in Catalonia, Spain. J. Antimicrob. Chemother.67,1858–1860 (2012).
  Medline CASGoogle Scholar
• 32  Whiley DM, Goire N, Lahra MM et al. The ticking time bomb: escalating antibiotic resistance in Neisseria gonorrhoeae is a public health disaster in waiting. J. Antimicrob. Chemother.67,2059–2061 (2012).
  Medline CASGoogle Scholar
• 33  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.88,317–318 (2012).
  MedlineGoogle Scholar
• 34  Furuya R, Onoye Y, Kanayama A et al. Antimicrobial resistance in clinical isolates of Neisseria subflava from the oral cavities of a Japanese population. J. Infect. Chemother.13,302–304 (2007).
  Medline CASGoogle Scholar
• 35  Saika T, Nishiyama T, Kanayama A et al. Comparison of Neisseria gonorrhoeae isolates from the genital tract and pharynx of two gonorrhea patients. J. Infect. Chemother.7,175–179 (2001).
  Medline CASGoogle Scholar
• 36  Tanaka M, Nakayama H, Huruya K 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. Agents27,20–26 (2006).
  Medline CASGoogle Scholar
• 37  Ohnishi M, Watanabe Y, Ono E et al. Spreading of a chromosomal cefixime-resistant penA gene among different Neisseria gonorrhoeae lineages. Antimicrob. Agents Chemother.54,1060–1067 (2010).
  Medline CASGoogle Scholar
• 38  Dillon JA, Parti RP. Fluoroquinolone resistance in Neisseria gonorrhoeae: fitness cost or benefit? J. Infect. Dis.205,1775–1777 (2012).
  Medline CASGoogle Scholar
• 39  Jerse AE, Sharma ND, Simms AN, Crow ET, Snyder L, Shafer WM. A gonococcal efflux pump system enhances bacterial survival in a female mouse model of genital tract infection. Infect. Immun.71,5576–5582 (2003).
  Medline CASGoogle Scholar
• 40  Warner DM, Folster JP, Shafer WM, Jerse AE. Regulation of the MtrC-MtrD-MtrE efflux-pump system modulates the in vivo fitness of Neisseria gonorrhoeae. J. Infect. Dis.196,1804–1812 (2007).
  Medline CASGoogle Scholar
• 41  Warner DM, Shafer WM, Jerse AE. Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC-MtrD-MtrE Efflux pump system confer different levels of antimicrobial resistance and in vivo fitness. Mol. Microbiol.70,462–478 (2008).
  Medline CASGoogle Scholar
• 42  Johnson PJ, Stringer VA, Shafer WM. Off-target gene regulation mediated by transcriptional repressors of antimicrobial efflux pump genes in Neisseria gonorrhoeae. Antimicrob. Agents Chemother.55,2559–2565 (2011).
  Medline CASGoogle Scholar
• 43  Kunz AN, Begum AA, Wu H. Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations. J. Infect. Dis.205,1821–1829 (2012).
  Medline CASGoogle Scholar
• 44  Tapsall J, Whiley D, Sloots T. Applications of molecular testing in clinical laboratories for the diagnosis and control of gonorrhea. Future Microbiol.1,317–324 (2006).
  CASGoogle Scholar
• 45  Tapsall JW, Limnios EA, Murphy DM; Australian Gonococcal Surveillance Programme. Analysis of trends in antimicrobial resistance in Neisseria gonorrhoeae isolated in Australia 1997–2006. J. Antimicrob. Chemother.61,150–155 (2008).
  Medline CASGoogle Scholar
• 46  Morris SR, Knapp JS, Moore DF et al. Using strain typing to characterise a fluoroquinolone-resistant Neisseria gonorrhoeae transmission network in southern California. Sex. Transm. Infect.84,290–291 (2008).
  Medline CASGoogle Scholar
• 47  Tapsall J. Antibiotic resistance in Neisseria gonorrhoeae is diminishing available treatment for gonorrhea: some possible remedies. Exp. Rev. Anti Infect. Ther.4,619–628 (2006).
  Medline CASGoogle Scholar
• 48  Akasaka S, Muratani T, Yamada Y, Inatomi H, Takahashi K, Matsumoto T. Emergence of cephem- and aztreonam-high-resistant Neisseria gonorrhoeae that does not produce beta-lactamase. J. Infect. Chemother.7,49–50 (2001).
  Medline CASGoogle Scholar
• 49  Tanaka M, Nakayama H, Tunoe H et al. A remarkable reduction in the susceptibility of Neisseria gonorrhoeae isolates to cephems and the selection of antibiotic regimens for the single-dose treatment of gonococcal infection in Japan. J. Infect. Chemother.8,81–86 (2002).
  Medline CASGoogle Scholar
• 50  Ito M, Yasuda M, Yokoi S et al. Remarkable increase in central Japan in 2001–2002 of Neisseria gonorrhoeae isolates with decreased susceptibility to penicillin, tetracycline, oral cephalosporins, and fluoroquinolones. Antimicrob. Agents Chemother.48,3185–3187 (2004).
  Medline CASGoogle Scholar
• 51  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.65,2141–2148 (2010).
  Medline CASGoogle Scholar
• 52  Takahashi S, Kurimura Y, Hashimoto J et al. Antimicrobial susceptibility and penicillin-binding protein 1 and 2 mutations in Neisseria gonorrhoeae isolated from male urethritis in Sapporo, Japan. J. Infect. Chemother. doi:10.1007/s10156-012-0450-3 (2012) (Epub ahead of print).
  Google Scholar
• 53  Lo JY, Ho KM, Leung AO et al. Ceftibuten resistance and treatment failure of Neisseria gonorrhoeae infection. Antimicrob. Agents Chemother.52,3564–3567 (2008).
  Medline CASGoogle Scholar
• 54  Martin I, Sawatzky P, Allen V et al. Emergence and characterization of Neisseria gonorrhoeae isolates with decreased susceptibilities to ceftriaxone and cefixime in Canada: 2001–2010. Sex. Transm. Dis.39,316–323 (2012).
  MedlineGoogle Scholar
• 55  Li SY. Global transmission of multiple-drug resistant Neisseria gonorrhoeae strains refractive to cephalosporin treatment. J. Formos. Med. Assoc.111,463–464 (2012).
  MedlineGoogle Scholar
• 56  Starnino S, Galarza P, Carvallo ME et al. Retrospective analysis of antimicrobial susceptibility trends (2000–2009) in Neisseria gonorrhoeae isolates from countries in Latin America and the Caribbean shows evolving resistance to ciprofloxacin, azithromycin and decreased susceptibility to ceftriaxone. Sex. Transm. Dis.39,813–821 (2012).
  Medline CASGoogle Scholar
• 57  Su X, Jiang F, Qimuge, Dai X, Sun H, Ye S. Surveillance of antimicrobial susceptibilities in Neisseria gonorrhoeae in Nanjing, China, 1999–2006. Sex. Transm. Dis.34,995–999 (2007).
  Medline CASGoogle Scholar
• 58  Liao M, Gu WM, Yang Y, Dillon JA. Analysis of mutations in multiple loci of Neisseria gonorrhoeae isolates reveals effects of PIB, PBP2 and MtrR on reduced susceptibility to ceftriaxone. J. Antimicrob. Chemother.66,1016–1023 (2011).
  Medline CASGoogle Scholar
• 59  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.86,442–444 (2010).
  Medline CASGoogle Scholar
• 60  Unemo M, Shipitsyna E, Domeika M; the Eastern European Sexual and Reproductive Health (EE SRH) Network Antimicrobial Resistance Group. Gonorrhoea surveillance, laboratory diagnosis and antimicrobial susceptibility testing of Neisseria gonorrhoeae in 11 countries of the eastern part of the WHO European region. APMIS119,643–649 (2011).
  MedlineGoogle Scholar
• 61  Dillon JA. Sustainable antimicrobial surveillance programs essential for controlling Neisseria gonorrhoeae superbug. Sex. Transm. Dis.38,899–901 (2011).
  MedlineGoogle Scholar
• 62  Moran JS, Levine WC. Drugs of choice in the treatment of uncomplicated gonococcal infection. Clin. Infect. Dis.20(Suppl. 1),S47–S65 (1995).
  MedlineGoogle Scholar
• 63  Moran JS. Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important? Sex. Transm. Dis.22,39–47 (1995).
  Medline CASGoogle Scholar
• 64  Bignell C, Fitzgerald M; Guideline Development Group. UK national guideline for the management of gonorrhoea in adults, 2011. Int. J. STD AIDS22,541–547 (2011).▪▪ Updated guidelines for the management of gonorrhea in adults in the UK.
  Medline CASGoogle Scholar
• 65  Ohnishi M, Saika T, Hoshina S et al. Ceftriaxone-resistant Neisseria gonorrhoeae, Japan. Emerg. Infect. Dis.17(1),148–149 (2010).
  Google Scholar
• 66  Chisholm S, Unemo M, Quaye N-N et al. Molecular epidemiological typing within the European gonococcal antimicrobial resistance surveillance programme (EURO-GASP) reveals predominance of a multi-drug resistant clone. Presented at: 18th International Pathogenic Neisseria Conference. Wurzburg, Germany, 9–14 September 2012.
  Google Scholar
• 67  Buono S, Wu A, Hess DC et al. Using the Neisseria gonorrhoeae multiantigen sequence-typing method to assess strain diversity and antibiotic resistance in San Francisco, California. Microb. Drug Resist.18,510–517 (2012).
  Medline CASGoogle Scholar
• 68  Heymans R, Bruisten SM, Golparian D, Unemo M, de Vries HJ, van Dam AP. Clonally related Neisseria gonorrhoeae isolates with decreased susceptibility to the extended-spectrum cephalosporin cefotaxime in Amsterdam, The Netherlands. Antimicrob. Agents Chemother.56,1516–1522 (2012).
  Medline CASGoogle Scholar
• 69  Huang CT, Yen MY, Wong WW et al. Characteristics and dissemination of mosaic penicillin-binding protein 2-harboring multidrug-resistant Neisseria gonorrhoeae isolates with reduced cephalosporin susceptibility in northern Taiwan. Antimicrob. Agents Chemother.54,4893–4895 (2010).
  Medline CASGoogle Scholar
• 70  Mavroidi A, Tzelepi E, Siatravani E, Godoy D, Miriagou V, Spratt BG. Analysis of emergence of quinolone-resistant gonococci in Greece by combined use of Neisseria gonorrhoeae multiantigen sequence typing and multilocus sequence typing. J. Clin. Microbiol.49,1196–1201 (2011).
  Medline CASGoogle Scholar
• 71  Pandori M, Barry PM, Wu A et al. Mosaic penicillin-binding protein 2 in Neisseria gonorrhoeae isolates collected in 2008 in San Francisco, California. Antimicrob. Agents Chemother.53,4032–4034 (2009).
  Medline CASGoogle Scholar
• 72  Tapsall JW, Ray S, Limnios A. Characteristics and population dynamics of mosaic penA allele-containing Neisseria gonorrhoeae isolates collected in Sydney, Australia, in 2007–2008. Antimicrob. Agents Chemother.54,554–556 (2010).
  Medline CASGoogle Scholar
• 73  Hess D, Wu A, Golparian D et al. Genome sequencing of a Neisseria gonorrhoeae isolate of a successful international clone with decreased susceptibility/resistance to extended-spectrum cephalosporins. Antimicrob. Agents Chemother.56(11),5633–5641 (2012).
  Medline CASGoogle Scholar
• 74  Allen VG, Farrell DJ, Rebbapragada A et al. Molecular analysis of antimicrobial resistance mechanisms in Neisseria gonorrhoeae isolates from Ontario, Canada. Antimicrob. Agents Chemother.55,703–712 (2011).
  Medline CASGoogle Scholar
• 75  Ameyama S, Onodera S, Takahata M et al. Mosaic-like structure of penicillin-binding protein 2 gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob. Agents Chemother.46,3744–3749 (2002).
  Medline CASGoogle Scholar
• 76  Ito M, Deguchi T, Mizutani KS et al. Emergence and spread of Neisseria gonorrhoeae clinical isolates harboring mosaic-like structure of penicillin-binding protein 2 in central Japan. Antimicrob. Agents Chemother.49,137–143 (2005).
  Medline CASGoogle Scholar
• 77  Lee SG, Lee SG, Lee H 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.65,669–675 (2010).
  Medline CASGoogle Scholar
• 78  Lindberg R, Fredlund H, Nicholas R, Unemo M. Neisseria gonorrhoeae isolates with reduced susceptibility to cefixime and ceftriaxone: association with genetic polymorphisms in penA, mtrR, porB1b, and ponA. Antimicrob. Agents Chemother.51,2117–2122 (2007).
  Medline CASGoogle Scholar
• 79  Osaka K, Takakura T, Narukawa K et al. Analysis of amino acid sequences of penicillin-binding protein 2 in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime and ceftriaxone. J. Infect. Chemother.14,195–203 (2008).
  Medline CASGoogle Scholar
• 80  Takahata S, Senju N, Osaki Y, Yoshida T, Ida T. Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae. Antimicrob. Agents Chemother.50,3638–3645 (2006).
  Medline CASGoogle Scholar
• 81  Tomberg J, Unemo M, Davies C, Nicholas RA. Molecular and structural analysis of mosaic variants of penicillin-binding protein 2 conferring decreased susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae: role of epistatic mutations. Biochemistry49,8062–8070 (2010).▪▪ Detailed analysis and verification of amino acid alterations in PBP2 that are important for decreased susceptibility to expanded-spectrum cephalosporins in N. gonorrhoeae.
  Medline CASGoogle Scholar
• 82  Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall JW. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J. Antimicrob. Chemother.63,1142–1151 (2009).
  Medline CASGoogle Scholar
• 83  Whiley DM, Limnios A, Ray S, Sloots TP, Tapsall JW. Diversity of penA alterations and subtypes in Neisseria gonorrhoeae strains from Sydney, Australia, that are less susceptible to ceftriaxone. Antimicrob. Agents Chemother.51,3111–3116 (2007).
  Medline CASGoogle Scholar
• 84  Whiley DM, Goire N, Lambert SB 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.65,1615–1618 (2010).
  Medline CASGoogle Scholar
• 85  Whiley DM, Goire N, Lambert SB, Nissen MD, Sloots TP, Tapsall JW. Reduced susceptibility to ceftriaxone in Neisseria gonorrhoeae is spread internationally by genetically distinct gonococcal populations. J. Antimicrob.Chemother.66,1186–1187 (2011).
  Medline CASGoogle Scholar
• 86  Zhao S, Duncan M, Tomberg J, Davies C, Unemo M, Nicholas RA. Genetics of chromosomally mediated intermediate resistance to ceftriaxone and cefixime in Neisseria gonorrhoeae. Antimicrob. Agents Chemother.53,3744–3751 (2009).▪ Detailed analysis of the effects of penA mosaic allele, and synergy with mtrR and penB, on the susceptibility to extended-spectrum cephalosporins in N. gonorrhoeae.
  Medline CASGoogle Scholar
• 87  Ochiai S, Sekiguchi S, Hayashi A et al. Decreased affinity of mosaic-structure recombinant penicillin-binding 2 for oral cephalosporins in Neisseria gonorrhoeae. J. Antimicrob. Chemother.60,54–60 (2007).
  Medline CASGoogle Scholar
• 88  Hagman KE, Pan W, Spratt BG, Balthazar JT, Judd RC, Shafer WM. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology141,611–622 (1995).
  Medline CASGoogle Scholar
• 89  Shafer WM, Folster JP. Towards an understanding of chromosomally mediated penicillin resistance in Neisseria gonorrhoeae: evidence for a porin-efflux pump collaboration. J. Bacteriol.188,2297–2299 (2006).
  Medline CASGoogle Scholar
• 90  Veal WL, Nicholas RA, Shafer WM. Overexpression of the MtrC-MtrD-MtrE efflux pump due to an mtrR mutation is required for chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. J. Bacteriol.184,5619–5624 (2002).
  Medline CASGoogle Scholar
• 91  Zarantonelli L, Borthagaray G, Lee EH, Shafer WM. Decreased azithromycin susceptibility of Neisseria gonorrhoeae due to mtrR mutations. Antimicrob. Agents Chemother.43,2468–2472 (1999).
  Medline CASGoogle Scholar
• 92  Johnson SR, Sandul AL, Parekh M et al. Mutations causing in vitro resistance to azithromycin in Neisseria gonorrhoeae. Int. J. Antimicrob. Agents21,414–419 (2003).
  Medline CASGoogle Scholar
• 93  Ohneck EA, Zalucki YM, Johnson PJ et al. A novel mechanism of high-level, broad-spectrum antibiotic resistance caused by a single base pair change in Neisseria gonorrhoeae. MBio20, 2(5) e00187–e00111 (2011).
  Google Scholar
• 94  Olesky M, Hobbs M, Nicholas RA. Identification and analysis of amino acid mutations in porin IB that mediate intermediate-level resistance to penicillin and tetracycline in Neisseria gonorrhoeae. Antimicrob. Agents Chemother.46,2811–2820 (2002).
  Medline CASGoogle Scholar
• 95  Olesky M, Zhao S, Rosenberg RL, Nicholas RA. Porin-mediated antibiotic resistance in Neisseria gonorrhoeae: ion, solute, and antibiotic permeation through PIB proteins with penB mutations. J. Bacteriol.188,2300–2308 (2006).
  Medline CASGoogle Scholar
• 96  Ropp PA, Hu M, Olesky M, Nicholas RA. Mutations in ponA, the gene encoding penicillin-binding protein 1, and a novel locus, penC, are required for high-level chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. Antimicrob. Agents Chemother.46,769–777 (2002).
  Medline CASGoogle Scholar
• 97  Whiley DM, Jacobsson S, Tapsall JW et al. Alterations of the pilQ gene in Neisseria gonorrhoeae are unlikely contributors to decreased susceptibility to ceftriaxone and cefixime in clinical gonococcal strains. J. Antimicrob. Chemother.65,2543–2547 (2010).
  Medline CASGoogle Scholar
• 98  Zhao S, Tobiason DM, Hu M, Seifert HS, Nicholas RA. The penC mutation conferring antibiotic resistance in Neisseria gonorrhoeae arises from a mutation in the PilQ secretin that interferes with multimer stability. Mol. Microbiol.57,1238–1251 (2005).
  Medline CASGoogle Scholar
• 99  Helm RA, Barnhart MM, Seifert HS. pilQ missense mutations have diverse effects on PilQ multimer formation, piliation, and pilus function in Neisseria gonorrhoeae. J. Bacteriol.189,3198–3207 (2007).
  Medline CASGoogle Scholar
• 100  Nakayama SI, Tribuddharat C, Prombhul S et al. Molecular analyses of TEM genes and their corresponding penicillinase-producing Neisseria gonorrhoeae isolates in Bangkok, Thailand. Antimicrob. Agents Chemother.56,916–920 (2012).
  Medline CASGoogle Scholar
• 101  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.85,256–258 (2009).
  Medline CASGoogle Scholar
• 102  Bignell C. 2009 European (IUSTI/WHO) guideline on the diagnosis and treatment of gonorrhoea in adults. Int. J. STD AIDS20,453–457 (2009).
  Medline CASGoogle Scholar
• 103  Japanese Society of Sexually Transmitted Infection. Gonococcal infection. Sexually transmitted infections, diagnosis and treatment guidelines 2011. Jpn J. Sex. Transm. Dis.22(Suppl. 1),52–59 (2011).
  Google Scholar
• 104  Muratani T, Inatomi H, Ando Y, Kawai S, Akasaka S, Matsumoto T. Single dose 1 g ceftriaxone for urogenital and pharyngeal infection caused by Neisseria gonorrhoeae. Int. J. Urol.15,837–842 (2008).
  Medline CASGoogle Scholar
• 105  Handsfield HH, McCormack WM, Hook EW III et al. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. The Gonorrhea Treatment Study Group. N. Engl. J. Med.325,1337–1341 (1991).
  Medline CASGoogle Scholar
• 106  Centers for Disease Control and Prevention (CDC). Update to CDC’s Sexually Transmitted Diseases Treatment Guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb. Mortal. Wkly Rep.61,590–594 (2012).
  MedlineGoogle Scholar
• 107  Furuya R, Nakayama H, Kanayama A et al.In vitro synergistic effects of double combinations of beta-lactams and azithromycin against clinical isolates of Neisseria gonorrhoeae. J. Infect. Chemother.12,172–176 (2006).
  Medline CASGoogle Scholar
• 108  Sathia L, Ellis B, Phillip S et al. Pharyngeal gonorrhoea – is dual therapy the way forward? Int. J. STD AIDS18,647–648 (2007).
  MedlineGoogle Scholar
• 109  Palmer HM, Young H, Winter A, Dave J. Emergence and spread of azithromycin-resistant Neisseria gonorrhoeae in Scotland. J. Antimicrob. Chemother.62,490–494 (2008).
  Medline CASGoogle Scholar
• 110  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.54,3812–3816 (2010).
  Medline CASGoogle Scholar
• 111  Starnino S, Stefanelli P, Neisseria gonorrhoeae Italian Study Group I. Azithromycin-resistant Neisseria gonorrhoeae strains recently isolated in Italy. J. Antimicrob. Chemother.63,1200–1204 (2009).
  Medline CASGoogle Scholar
• 112  Galarza PG, Abad R, Canigia LF et al. New mutation in 23S rRNA gene associated with high level of azithromycin resistance in Neisseria gonorrhoeae. Antimicrob. Agents Chemother.54,1652–1653 (2010).
  Medline CASGoogle Scholar
• 113  Katz AR, Komeya AY, Soge OO et al.Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States. Clin. Infect. Dis.54,841–843 (2012).
  Medline CASGoogle Scholar
• 114  Boslego JW, Tramont EC, Takafuji ET et al. Effect of spectinomycin use on the prevalence of spectinomycin-resistant and penicillinase-producing Neisseria gonorrhoeae. N. Engl. J. Med.317,272–278 (1987).
  Medline CASGoogle Scholar
• 115  Discontinuation of spectinomycin. Morbidity and Mortality Weekly Report, 7 April (2006).
  Google Scholar
• 116  Brown LB, Krysiak R, Kamanga G et al.Neisseria gonorrhoeae antimicrobial susceptibility in Lilongwe, Malawi, 2007. Sex. Transm. Dis.37,169–172 (2010).
  MedlineGoogle Scholar
• 117  Ross JD, Lewis DA. Cephalosporin resistant Neisseria gonorrhoeae: time to consider gentamicin? Sex. Transm. Infect.88,6–8 (2012).
  Medline CASGoogle Scholar
• 118  Chisholm SA, Quaye N, Cole MJ et al. An evaluation of gentamicin susceptibility of Neisseria gonorrhoeae isolates in Europe. J. Antimicrob. Chemother.66,592–595 (2011).
  Medline CASGoogle Scholar
• 119  Dowell D, Kirkcaldy RD. Effectiveness of gentamicin for gonorrhoea treatment: systematic review and meta-analysis. Sex. Transm. Infect. doi:10.1136/sextrans -2012-050604 (2012) (Epub ahead of print).
  MedlineGoogle Scholar
• 120  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.56,2739–2742 (2012).
  Medline CASGoogle Scholar
• 121  Llano-Sotelo B, Dunkle J, Klepacki D et al. Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. Antimicrob. Agents Chemother.54,4961–4970 (2010).
  Medline CASGoogle Scholar
• 122  Still JG, Schranz J, Degenhardt TP 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.55,1997–2003 (2011).
  Medline CASGoogle Scholar
• 123  Roblin PM, Kohlhoff SA, Parker C, Hammerschlag MR. In vitro activity of CEM-101, a new fluoroketolide antibiotic, against Chlamydia trachomatis and Chlamydia (Chlamydophila) pneumoniae. Antimicrob. Agents Chemother.54,1358–1359 (2010).
  Medline CASGoogle Scholar
• 124  Waites KB, Crabb DM, Duffy LB. Comparative in vitro susceptibilities of human mycoplasmas and ureaplasmas to a new investigational ketolide, CEM-101. Antimicrob. Agents Chemother.53,2139–2141 (2009).
  Medline CASGoogle Scholar
• 125  Unemo M, Golparian D, Limnios A 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.56,3603–3609 (2012).
  Medline CASGoogle Scholar
• 126  Burkhardt O, Derendorf H, Welte T. Ertapenem: the new carbapenem 5 years after first FDA licensing for clinical practice. Expert Opin. Pharmacother.8,237–256 (2007).
  Medline CASGoogle Scholar
• 127  Congeni BL. Ertapenem. Expert Opin. Pharmacother.11,669–672 (2010).
  Medline CASGoogle Scholar
• 128  Deshpande LM, Gales AC, Jones RN. GAR-936 (9-t-butylglycylamidominocycline) susceptibility test development for streptococci, Haemophilus influenzae and Neisseria gonorrhoeae: preliminary guidelines and interpretive criteria. Int. J. Antimicrob. Agents18,29–35 (2001).
  Medline CASGoogle Scholar
• 129  Falagas ME, Karageorgopoulos DE, Dimopoulos G. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of tigecycline. Curr. Drug Metab.10,13–21 (2009).
  Medline CASGoogle Scholar
• 130  Nix DE, Matthias KR. Should tigecycline be considered for urinary tract infections? A pharmacokinetic re-evaluation. J. Antimicrob. Chemother.65,1311–1312 (2010).
  Medline CASGoogle Scholar
• 131  Alexander BT, Marschall J, Tibbetts RJ, Neuner EA, Dunne WM Jr, Ritchie DJ. Treatment and clinical outcomes of urinary tract infections caused by KPC-producing Enterobacteriaceae in a retrospective cohort. Clin. Ther.34,1314–1323 (2012).
  Medline CASGoogle Scholar
• 132  Novak R. Are pleuromutilin antibiotics finally fit for human use? Ann. NY Acad. Sci.1241,71–81 (2011).
  Medline CASGoogle Scholar
• 133  Novak R, Shlaes DM. The pleuromutilin antibiotics: a new class for human use. Curr. Opin. Investig. Drugs11,182–191 (2010).
  Medline CASGoogle Scholar
• 134  Bradbury BJ, Pucci MJ. Recent advances in bacterial topoisomerase inhibitors. Curr. Opin. Pharmacol.8,574–581 (2008).
  Medline CASGoogle Scholar
• 135  Then RL, Sahl HG. Anti-infective strategies of the future: is there room for species-specific antibacterial agents? Curr. Pharm. Des.16,555–566 (2010).
  Medline CASGoogle Scholar
• 136  Golparian D, Shafer M, Ohnishi M, Unemo M. Inactivation of the MtrCDE, MacAB, and NorM efflux pumps in Neisseria gonorrhoeae strains with clinical resistance to extended-spectrum cephalosporins make them susceptible to several antimicrobials. Presented at: 18th International Pathogenic Neisseria Conference. Wurzburg, Germany, 9–14 September 2012.
  Google Scholar
• 137  Swanson S, Lee C-J, Liang X, Toone E, Zhou P, Nicholas R. LpxC inhibitors as novel therapeutics for treatment of antibiotic-resistant Neisseria gonorrhoeae. Presented at: 18th International Pathogenic Neisseria Conference. Wurzburg, Germany, 9–14 September 2012.
  Google Scholar
• 138  Bucki R, Leszczyńska K, Namiot A, Sokołowski W. Cathelicidin LL-37: a multitask antimicrobial peptide. Arch. Immunol. Ther. Exp. (Warsz.)58,15–25 (2010).
  Medline CASGoogle Scholar
• 139  Wetzler LM. The development of a gonococcal vaccine: fact or fiction? Int. J. STD AIDS12(Suppl. 2),12 (2001).
  Google Scholar
• 140  Zhu W, Chen CJ, Thomas CE, Anderson JE, Jerse AE, Sparling PF. Vaccines for gonorrhea: can we rise to the challenge. Front. Microbiol.2,124 (2011).
  MedlineGoogle Scholar
• 141  Hadad R, Jacobsson S, Pizza M et al. Novel meningococcal 4CMenB vaccine antigens – prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae. APMIS120,750–760 (2012).
  Medline CASGoogle Scholar
• 142  Hobbs MM, Sparling PF, Cohen MS, Shafer WM, Deal CD, Jerse AE. Experimental gonococcal infection in male volunteers: cumulative experience with Neisseria gonorrhoeae strains FA1090 and MS11mkC. Front. Microbiol.2,123 (2011).
  MedlineGoogle Scholar
• 143  Guiliani MM, Adu-Bobie J, Comanducci M et al. A universal vaccine for serogroup B meningococcus. Proc. Natl Acad. Sci. USA103,10834–10839 (2006).
  MedlineGoogle Scholar
• 144  Borges O, Lebre F, Bento D, Borchard G, Junginger HE. Mucosal vaccines: recent progress in understanding the natural barriers. Pharm. Res.27,211–223 (2010).
  Medline CASGoogle Scholar
• 145  Goire N, Sloots TP, Nissen MD, Whiley DM. Protocol for the molecular detection of antibiotic resistance mechanisms in Neisseria gonorrhoeae. Methods Mol. Biol.903,319–328 (2012).
  Medline CASGoogle Scholar
• 146  Unemo M, Olcén P, Fredlund H, Thulin S. Real-time PCR and subsequent pyrosequencing for screening of penA mosaic alleles and prediction of reduced susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae. APMIS116,1004–1008 (2008).
  Medline CASGoogle Scholar
• 147  Whiley SM, Bates J, Limnios A, Nissen MD, Tapsall J, Sloots TP. Use of a novel screening PCR indicates presence of Neisseria gonorrhoeae with a mosaic penA gene sequence in Australia. Pathology39,445–446 (2007).
  MedlineGoogle Scholar
• 148  Ochiai S, Ishiko H, Yasuda M, Deguchi T. Rapid detection of the mosaic structure of the Neisseria gonorrhoeaepenA gene, which is associated with decreased susceptibilities to oral cephalosporins. J. Clin. Microbiol.46,1804–1810 (2008).
  Medline CASGoogle Scholar
• 149  Goire N, Ohnishi M, Limnios AE 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.67,902–905 (2012).
  Medline CASGoogle Scholar
• 150  Unemo M, Dillon JA. Review and international recommendation of methods for typing Neisseria gonorrhoeae isolates and their implications for improved knowledge of gonococcal epidemiology, treatment, and biology. Clin. Microbiol. Rev.24,447–458 (2011).
  MedlineGoogle Scholar
• 201  WHO. Global incidence and prevalence of selected curable sexually transmitted infections – 2008. www.who.int/reproductivehealth/publications/rtis/2008_STI_estimates.pdf (Accessed 6 October 2012)
  Google Scholar
• 202  WHO, Department of Reproductive Health and Research. Global action plan to control the spread and impact of antimicrobial resistance in Neisseria gonorrhoeae. www.who.int/reproductivehealth/publications/rtis/9789241503501 (Accessed 6 October 2012)▪▪ WHO global action plan describing essential actions to control the spread and impact of gonococcal antimicrobial resistance and possible emergence of untreatable gonorrhea.
  Google Scholar
• 203  European Centre for Disease Prevention and Control. Response plan to control and manage the threat of multidrug-resistant gonorrhoea in Europe. www.ecdc.europa.eu/en/publications/Publications/1206-ECDC-MDR-gonorrhoea-response-plan.pdf (Accessed 6 October 2012)
  Google Scholar
• 204  Centers for Disease Control and Prevention. Cephalosporin-resistant Neisseria gonorrhoeae public health response plan (2012). www.cdc.gov/std/gonorrhea/default.htm (Accessed 6 October 2012)
  Google Scholar
• 205  European Centre for Disease Prevention and Control. Gonococcal antimicrobial susceptibility surveillance in Europe – 2010. www.ecdc.europa.eu/en/publications/Publications/1206-Gonococcal-AMR.pdf (Accessed 6 October 2012)
  Google Scholar
• 206  NG-MAST. Query global sequence and ST database. www.ng-mast.net (Accessed 26 October 2012)
  Google Scholar
• 207  WHO. Strategies and laboratory methods for strengthening surveillance of sexually transmitted infections. www.who.int/iris/bitstream/10665/75729/1/9789241504478_eng.pdf (Accessed 6 October 2012)
  Google Scholar