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Gonococcal Resistance: Are Cephalosporins Next?

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Abstract

The development of resistance to multiple antibiotics has limited treatment options for gonorrhea in many countries. Currently, the Centers for Disease Control and Prevention only recommend cephalosporin antibiotics for treatment of uncomplicated gonorrhea. Although the cephalosporins remain effective, the demonstrated ability of Neisseria gonorrhoeae to develop resistance has raised concerns about the possibility of multidrug-resistant N. gonorrhoeae strains, which include cephalosporin resistance. This article provides a review of global trends in cephalosporin susceptibility among gonococcal isolates, recent findings that deepen our understanding of genetic mechanisms of resistance, and the public health and clinical implications of the potential emergence of cephalosporin-resistant gonorrhea.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect. 1999;75(1):3–17.

    Article  PubMed  CAS  Google Scholar 

  2. World Health Organization. Global prevalence and incidence of selected curable sexually transmitted infections: overview and estimates. Geneva: WHO; 2001.

    Google Scholar 

  3. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Surveillance, 2008. Atlanta, GA: US Department of Health and Human Services; November 2009.

    Google Scholar 

  4. • Workowski KA, Berman SM, Douglas JM. Emerging antimicrobial resistance in Neisseria gonorrhoeae: urgent need to strengthen prevention strategies. Ann Intern Med. 2008;148(8):606–13. These authors review the history of antimicrobial resistance in N. gonorrhoeae, current treatment recommendations, and key components of gonorrhea prevention and control.

    PubMed  Google Scholar 

  5. Tapsall JW. Antibiotic resistance in Neisseria gonorrhoeae. CID. 2005;41 Suppl 4:S263–8.

    Article  CAS  Google Scholar 

  6. CDC. Sexually Transmitted Disease Surveillance 2003 Supplement: Gonococcal Isolate Surveillance Project Annual Report—2003. Atlanta: US Department of Health and Human Services, November 2004.

  7. CDC. Increases in fluoroquinolone-resistance Neisseria gonorrhoeae—Hawaii and California, 2001. MMWR Morb Mortal Wkly Rep. 2002;51(46):1041–4.

    Google Scholar 

  8. CDC. Increases in Fluoroquinolone-Resistant Neisseria gonorrhoeae among Men who have sex with men—United States, 2003, and Revised Recommendations for Gonorrhea Treatment, 2004. MMWR Morb Mortal Wkly Rep. 2004;53(16):335–8.

    Google Scholar 

  9. CDC. Update to CDC’s Sexually Transmitted Disease Treatment Guidelines, 2006: Fluoroquinolones No Longer Recommended for Treatment of Gonococcal Infections. MMWR Morb Mortal Wkly Rep. 2007;56(14):332–6.

    Google Scholar 

  10. • CDC. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR Morb Mortal Wkly Rep 2010. http://www.cdc.gov/std/treatment/2010/default.htm. Updated recommendations for treatment of gonorrhea and other STDs based on best available evidence and expert opinion. Changes in recommendations for the treatment of uncomplicated gonorrhea include an increase in the dose of ceftriaxone from 125 mg to 250 mg and routine co-treatment of gonorrhea with treatment for chlamydia (previous recommendations were to treat for chlamydia if chlamydia not ruled out). Rationales for these changes include enhanced treatment efficacy for undiagnosed pharyngeal gonorrhea and potential decreased likelihood of antibiotic resistance.

  11. Akasaka S, Muratani T, Yamada Y, et al. Emergence of cephem- and aztreonam-high-resistant Neisseria gonorrhoeae that does not produce β-lactamase. J Infect Chemother. 2001;7(1):49–50.

    Article  PubMed  CAS  Google Scholar 

  12. 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. 2003;9:35–9.

    Article  PubMed  CAS  Google Scholar 

  13. Yokoi S, Deguchi T, Ozawa T, et al. Threat to Cefixime Treatment for Gonorrhea. Emerg Infect Dis. 2007;13(8):1275–7.

    PubMed  Google Scholar 

  14. Lo JYC, Ho KM, Leung AOC, et al. Ceftibuten Resistance and Treatment Failure of Neisseria gonorrhoeae Infection. Antimicrob Agents Chemother. 2008;52(10):3564–7.

    Article  PubMed  CAS  Google Scholar 

  15. Clinical and Laboratory Standards Institute. January 2010. Approved standard M100-S20,30(1). Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement.

  16. 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. 2004;48(8):3185–7.

    Article  PubMed  CAS  Google Scholar 

  17. Sho T, Murantani T, Kobayashi T, et al. Antimicrobial susceptibilities of various antibiotics against Neisseria gonorrhoeae isolates in western part of Japan [abstract]. 18th ISSTDR, London 2009. Abstract OS3.2.01.

  18. Su X, Jiang F. Quimuge, et al.: Surveillance of antimicrobial susceptibilities in Neisseria gonorrhoeae in Nanjing, China, 1999–2006. Sex Transm Dis. 2007;34(12):995–9.

    PubMed  CAS  Google Scholar 

  19. World Health Organization 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, 2007–2008. Comm Dis Intell 2010; 34(1):1–7.

    Google Scholar 

  20. Cao V, Ratsima E, Van Tri D, et al. Antimicrobial Susceptibility in Neisseria gonorrhoeae strains isolated in 2004–2006 in Bangui, Central African Republic; Yaoundé, Cameroon; Antananarivo, Madagascar; and Ho Chi Minh Ville and Nha Trang, Vietnam. Sex Transm Dis. 2008;35(11):941–5.

    Article  PubMed  CAS  Google Scholar 

  21. Srifeungfung S, Rungpisuthipong A, Asavapiriyanot S, et al. Prevalence of antimicrobial susceptibility of Neisseria gonorrhoeae: an update in Thailand [abstract]. IUSTI 2009, Cape Town, South Africa. Abstract P.1.2.34.

  22. Bala M, Ray K, Gupta SM. Antimicrobial resistance pattern of Neisseria gonorrhoeae isolates from peripheral health centres and STD clinic attendees of a tertiary care centre in India. Int J STD AIDS. 2008;19:378–80.

    PubMed  CAS  Google Scholar 

  23. Australian Gonococcal Surveillance Programme (AGSP). Annual report of the Australian Gonococcal Surveillance Programme, 2009. Comm Dis Intell. 2010;34(2):89–95.

    Google Scholar 

  24. Tapsall JW, Read P, Carmody C, et al. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhea verified by molecular microbiological methods. J Med Microbiol. 2009;58:683–7.

    Article  PubMed  CAS  Google Scholar 

  25. GRASP Steering Group. Gonococcal Resistance to Antibiotics Surveillance Programme (GRASP) Steering Group. GRASP 2008 Report: Trends in Antimicrobial Resistant Gonorrhoeae. London: Health Protection Agency 2009.

  26. 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. Eurosurveill. 2010;15(14):1–5.

    Google Scholar 

  27. Tzelepi E, Avgerinou H, Flemetakis A, et al. Changing figures of antimicrobial susceptibility and serovar distribution in Neisseria gonorrhoeae isolates in Greece. Sex Transm Dis. 2010;37(2):115–20.

    Article  PubMed  Google Scholar 

  28. Cole MJ, Chisholm SA, Hoffmann S, et al. European surveillance of antimicrobial resistance in Neisseria gonorrhoeae. Sex Transm Infect. 2010;86:427–32.

    Article  PubMed  Google Scholar 

  29. Golparian D, Hellmark B, Fredlund H, et al. Emergence, spread and characteristics of Neisseria gonorrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden. Sex Transm Infect. 2010;86:454–60.

    Article  PubMed  Google Scholar 

  30. • de Vries HJ, van der Helm JJ, van der Loeff MFS, van Dam AP. Multidrug-resistant Neisseria gonorrhoeae with reduced cefotaxime susceptibility is increasingly common in men who have sex with men, Amsterdam, the Netherlands. Eurosurveill. 2009;14(37):1–6. The authors reported that MSM were more likely than men who have sex with women to harbor isolates with elevated MICs to cephalosporins. This finding has important implications for Western industrialized countries, and raises the possibility that MSM infected with gonorrhea may be at high-risk for strains with decreased cephalosporin susceptibility, as was the case during the introduction of QRNG.

    Google Scholar 

  31. • Unemo M, Golparian D, Syversen G, et al. Two cases of verified clinical failures using internationally recommended first-line cefixime for gonorrhoea treatment, Norway, 2010. Eurosurv. 2010;15(47):9–11. The authors reported the first cases of confirmed oral cephalosporin treatment failures reported outside of Japan. The cases were not epidemiologically linked and neither reported recent travel to Japan, although reported travel to Asia (Philippines). This is a very concerning development.

    Google Scholar 

  32. Wang SA, Lee MV, O’Connor N, et al. Multidrug-resistant Neisseria gonorrhoeae with decreased susceptibility to cefixime—Hawaii, 2001. CID. 2003;37:849–52.

    Article  CAS  Google Scholar 

  33. Ito M, Deguchi T, Mizutani K-S, 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. 2005;49:137–43.

    Article  PubMed  CAS  Google Scholar 

  34. Ochiai S, Sekiguchi S, Hayashi A, et al. Decreased affinity of mosaic-structure recombinant penicillin-binding protein 2 for oral cephalosporins in Neisseria gonorrhoeae. J Antimicrob Chemother. 2007;60:54–60.

    Article  PubMed  CAS  Google Scholar 

  35. 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. 2008;14:195–203.

    Article  PubMed  CAS  Google Scholar 

  36. Ameyama S, Onodera S, Takahata M, et al. Mosaic-like structure of penicillin-binding 2 gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob Agents Chemother. 2002;46:3744–9.

    Article  PubMed  CAS  Google Scholar 

  37. • 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. 2007;51:2117–22. The authors characterized 18 gonococcal isolates with reduced susceptibility to ceftriaxone and cefixime collected in Sweden, the United Kingdom, and the United States. Although a majority (61%) had nearly identical penA mosaic alleles, the remaining 39% did not have mosaic penA alleles but contained alterations in the C-terminal region of the transpeptidase domain of penA.

    Article  PubMed  CAS  Google Scholar 

  38. Whiley DM, Limnios EA, Ray S, et al. Diversity of penA alterations and subtypes in Neisseria gonorrhoeae strains from Sydney, Australia that are less susceptible to ceftriaxone. Antimicrob Agents Chemother. 2007;51:3111–6.

    Article  PubMed  CAS  Google Scholar 

  39. • 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. 2010;65:1615–8. Among 76 gonococcal isolates from Australia with reduced susceptibility to ceftriaxone and lacking the mosaic penA allele, 64 contained an amino acid substitution in penicillin-binding protein 2: 39 at position 542, 26 at position 551, and 9 at position 501. Among 98 isolates from a previous study re-analyzed for this paper, substitutions at positions 542 and 551 were significantly associated with higher MICs to ceftriaxone.

    Article  PubMed  CAS  Google Scholar 

  40. 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 Agents. 2006;27:20–6.

    Article  PubMed  CAS  Google Scholar 

  41. • Lee S-G, Lee H, Jeong SH, 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. Among 46 gonococcal isolates from Korea with reduced susceptibility to ceftriaxone or cefixime, only one contained a mosaic penA mutation. A majority (28) contained an amino acid substitution at position 501 of penicillin-binding protein 2. In addition, all isolates contained mtrR and penB mutations.

    Article  PubMed  CAS  Google Scholar 

  42. • Zhao S, Duncan M, Tomberg J, et al. Genetics of chromosomally mediated intermediate resistance to ceftriaxone and cefixime in Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2009;53:3744–51. In order to determine relative contributions of different mutations to the reductions in susceptibility to ceftriaxone and cefixime, recombinant N. gonorrhoeae strains were created through transformation, with each strain containing both the mosaic penA allele and another of three mutations from a donor strain with reduced susceptibility to cefixime and ceftriaxone. Addition of mosaic penA had the greatest impact on increase in MIC of cefixime, with additional contributions to increasing MICs from mtrR and penB. For ceftriaxone, contributions to increases in MICs were equivalent for penA and for mtrR and penB. A strain containing all four mutations had increased MICs to cefixime and ceftriaxone, but not to the level of the donor strain, suggesting that there are additional unknown mutations that are important in cephalosporin resistance.

    Article  PubMed  CAS  Google Scholar 

  43. 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. 2007;13:302–4.

    Article  PubMed  CAS  Google Scholar 

  44. Ohnishi M, Watanabe Y, Ono E, et al. Spread of a chromosomal cefixime-resistant penA gene among different Neisseria gonorrhoeae lineages. Antimicrob Agents Chemother. 2010;54:1060–7.

    Article  PubMed  CAS  Google Scholar 

  45. Whiley DM, Limnios EA, Ray S, et al. Further questions regarding the role of mosaic penA sequences in conferring reduced susceptibility to ceftriaxone in Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2007;51:802–3.

    Article  PubMed  CAS  Google Scholar 

  46. 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. 2009;53:4032–4.

    Article  PubMed  CAS  Google Scholar 

  47. 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. 2010;54:554–6.

    Article  PubMed  CAS  Google Scholar 

  48. Takahata S, Senju N, Osaki Y, et al. Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae. Antimicrob Agents Chemother. 2006;50:3638–45.

    Article  PubMed  CAS  Google Scholar 

  49. Ochiai S, Ishiko H, Yasuda M, Deguchi T. Rapid detection of the mosaic structure of the Neisseria gonorrhoeae penA gene, which is associated with decreased susceptibilities to oral cephalosporins. J Clin Microbiol. 2008;46:1804–10.

    Article  PubMed  CAS  Google Scholar 

  50. Unemo M, Fasth O, Fredlund H, et al. 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. 2009;63:1142–51.

    Article  PubMed  CAS  Google Scholar 

  51. Newman LM, Moran JS, Workowski KA. Update on the management of gonorrhea in adults in the United States. CID. 2007;44 Suppl 3:S84–101.

    Article  CAS  Google Scholar 

  52. Muratani T, Inatomi H, Ando Y, et al. Single dose 1 g ceftriaxone for urogenital and pharyngeal infection caused by Neisseria gonorrhoeae. Int J Urol. 2008;15:837–42.

    Article  PubMed  CAS  Google Scholar 

  53. Deguchi T, Yasuda M. Lack of nationwide surveillance of antimicrobial resistance in Neisseria gonorrhoeae in Japan. Ann Intern Med. 2008;149:363–4.

    PubMed  Google Scholar 

  54. Tapsall JW. Failure of azithromcin therapy in gonorrhea and dis-correlation with laboratory test parameters. Sex Transm Dis. 1998;25:505–8.

    Article  PubMed  CAS  Google Scholar 

  55. Chandra R, Liu P, Breen JD, et al. Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin. Clin Pharmacokinet. 2007;46:247–59.

    Article  PubMed  CAS  Google Scholar 

  56. Boslego JW, Tramont EC, Takafuji ET, et al. Effect of spectinomycin use on the prevalence of spectinomycin-resistant and of penicillinase-producing Neisseria gonorrhoeae. N Engl J Med. 1987;317:272–8.

    Article  PubMed  CAS  Google Scholar 

  57. Daly CC, Hoffman I, Hobbs M, et al. Development of an antimicrobial susceptibility surveillance system for Neisseria gonorrhoeae in Malawi: comparison of methods. J Clin Microbiol. 1997;35:2985–8.

    PubMed  CAS  Google Scholar 

  58. Hira SK, Attili VR, Kamanga J, et al. Efficacy of gentamicin and kanamycin in the treatment of uncomplicated gonococcal urethritis in Zambia. Sex Transm Dis. 1985;12(1):52–4.

    Article  PubMed  CAS  Google Scholar 

  59. Tan NJ, Rajan VS, Pang R, Sng EH. Gentamicin in the treatment of infections due to penicillinase-producing gonococci. Br J Vener Dis. 1980;56(6):394–6.

    PubMed  CAS  Google Scholar 

  60. Lule G, Behets FM, Hoffman IF, et al. STD/HIV control in Malawi and the search for affordable and effective urethritis therapy: a first field evaluation. Genitourin Med. 1994;70(6):384–8.

    PubMed  CAS  Google Scholar 

  61. Felarca AB, Laqui EM, Ibarra LM. Gentamicin in gonococcal urethritis of Filipino males: dosage and response. J Infect Dis. 1971;124(Supplement):S287–92.

    PubMed  Google Scholar 

  62. Morrison GD, Reeves DS. Gentamicin in the treatment of gonococcal urethritis. A microbiological, pharmacological, and clinical study. Br J Vener Dis. 1973;49(6):513–6.

    PubMed  CAS  Google Scholar 

  63. Hantschke D, Strauss P, Linzenmeier G, et al. Treatment of gonorrhoea with single injections of gentamicin. Br J Vener Dis. 1973;49(1):62–4.

    PubMed  CAS  Google Scholar 

  64. Brown LB, Krysiak R, Kamanga G, et al. Neisseria gonorrhoeae antimicrobial susceptibility in Lilongwe, Malawi, 2007. Sex Transm Dis. 2010;37(3):169–72.

    Article  PubMed  Google Scholar 

  65. Tapsall J. Antibiotic resistance in Neisseria gonorrhoeae is diminishing available treatment options for gonorrhea: some possible remedies. Expert Rev Anti Infect Ther. 2006;4(4):619–28.

    Article  PubMed  CAS  Google Scholar 

  66. Golden M, Kerani R, Shafii T, et al. Does azithromycin co-treatment enhance the efficacy of oral cephalosporins for pharyngeal gonorrhea? [abstract P2.95] Presented at the 18th International Society for STD Research. London, UK. June 28–July 1, 2009.

  67. Sathia L, Ellis B, Phillip S, et al. Pharyngeal gonorrhea—is dual therapy the way forward? Int J STD AIDS. 2007;18(9):647–8.

    Article  PubMed  Google Scholar 

  68. US Preventive Services Task Force (USPSTF). Screening for gonorrhea: recommendation statement. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ), 2005.

  69. World Health Organization. Consultation on the Strategic Response to the Threat of Untreatable Neisseria gonorrhoeae and Emergence of Cephalosporin Resistance in Neisseria gonorrhoeae. Manila, WHO; 2010. Available at: http://www.wpro.who.int/internet/resources.ashx/HSI/report/GASP+Consultation+Report_April+2010.pdf. Accessed December 2010.

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Conflicts of interest: R.D. Kirkcaldy—none; R.C. Ballard—none; and D. Dowell—none.

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Kirkcaldy, R.D., Ballard, R.C. & Dowell, D. Gonococcal Resistance: Are Cephalosporins Next?. Curr Infect Dis Rep 13, 196–204 (2011). https://doi.org/10.1007/s11908-011-0169-9

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