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GON(E)orrhea or Here to Stay:
The Emergence of an Unrelenting "Clap"

Kelly Daniels, Pharm. D., Eugene Kreys, Pharm. D., & Jennifer Seltzer, Pharm. D.

September 28, 2011

Gonorrhea, caused by Neisseria gonorrhoeae, is the second most commonly reported communicable disease in the United States (U.S.), as well as the second most prevalent bacterial sexually transmitted disease in the world. More than 700,000 cases occur annually in the U.S., but infection rates have been declining since the 1970's.1 Since there is currently no vaccine available for gonorrhea prevention, timely detection and appropriate antibiotic therapy are essential to control the spread of infection and prevent complications.2

Gonorrhea is defined as the presence of N. gonorrhoeae in the body, mainly at mucosal sites. Infection most commonly manifests as urethritis in men, causing painful urination and discharge from the penis.3 These symptoms usually lead patients to seek treatment relatively quickly. Infection in women may manifest as vaginal discharge or a burning sensation during urination, but most women are asymptomatic. Absence of early detection and treatment may result in disease transmission and complications.1 ,3 Gonorrhea is associated with significant morbidity in women, such as urethritis and cervicitis, which may ultimately lead to pelvic inflammatory disease, infertility, ectopic pregnancy, and pelvic pain.1

In previous years, multiple antibiotic drug classes were available for gonorrhea treatment, including penicillins, fluoroquinolones, macrolides, tetracyclines, and first and second generation cephalosporins. Due to the emergence of antimicrobial resistance, these agents are no longer considered first-line treatment for gonorrhea. It is estimated that nearly one-fifth of all isolates of N. gonorrhoeae are resistant to tetracycline, penicillin, or both, and the prevalence of fluoroquinolone-resistant N. gonorrhoeae is as high as 20 percent in certain parts of the U.S.4, 5 Susceptibility to extended-spectrum cephalosporins has also declined worldwide. Resistance to these agents has been reported in several countries around the world, with highest prevalence occurring in Japan.6-8 Treatment failures with cefixime prompted the removal of cefixime from the 2006 Japanese guidelines for gonorrhea prevention.2 The first high-level ceftriaxone-resistant gonococcal strain (H041) was recently isolated in Kyoto, Japan with a reported minimum inhibitory concentration (MIC) = 2 g/ml.9 Only one other ceftriaxone-resistant strain has been isolated (MIC = 0.5 g/ml).9 Reduced extended-spectrum cephalosporin susceptibility is most likely attributable to an alteration of the penA gene, which is responsible for encoding the penicillin-binding protein (PBP 2).11-13 Other mutations in the repressor gene allow for over-expression of the N. gonorrhoeae efflux pump, resulting in decreased susceptibility.12,14

Even with the emergence of cephalosporin-resistant N. gonorrhoeae, resistance to third generation cephalosporins, such as ceftriaxone or cefixime, is still uncommon. A single dose of ceftriaxone 250 mg intramuscularly is recommended as the treatment of choice by the Centers for Disease Control and Prevention (CDC) guidelines due to its safety, effectiveness, and administration convenience. An alternative regimen is oral cefixime 400 mg as a single dose, although bactericidal levels are not as high and sustained with this treatment compared to those produced by ceftriaxone.1 However, because cefixime has worse cure rates in pharyngeal infections, ceftriaxone remains the preferred agent.15 N. gonorrhoeae also remains susceptible to spectinomycin, an injectable antibiotic, that is reliably effective for gonorrhea treatment. Unfortunately, this agent is not currently available in the U.S.1, 16  In addition, the CDC also recommends dual therapy since patients are commonly co-infected with Chlamydia trachomatis, which is treated either with doxycycline or azithromycin. Since N. gonorrhoeae is commonly susceptible to doxycycline and azithromycin, dual therapy also further impedes the development of resistance.1 Ertapenem has also been proposed as an alternative treatment for gonorrhea due to availability as a single-dose regimen, but cost and the potential for inducing resistance, similar to other beta-lactams, limit its use.17 Trimethoprim/sulfamethoxazole, rifampin, and chloramphenicol treatment regimens may be potential alternatives, yet efficacy of these regimens have not been well-established.9,18,19

REFERENCES

  1. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59:1-110.

  2. Tapsall JW, Ndowa F, Lewis DA, Unemo M. Meeting the public health challenge of multidrug- and extensively drug-resistant Neisseria gonorrhoeae. Exp Rev Anti Infect Ther. 2009;7:821-34.

  3. Tapsall JW. Antibiotic resistance in Neisseria gonorrhoeae is diminishing available treatment options for gonorrhea: some possible remedies. Exp Rev Anti Infect Ther. 2006;4(4):619-28.

  4. Fox KK, Knapp JS, Holmes KK, et al. Antimicrobial resistance in Neisseria gonorrhoeae in the United States, 1988-1994: the emergence of decreased susceptibility to the fluoroquinolones. J Infect Dis. 1997;175:1396.

  5. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance, 2003. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, November 2004.

  6. Barry PM, Klausner JD. The use of cephalosporins for gonorrhea: the impending problem of resistance. Expert Opin Pharmacother. 2009;10:555-77.

  7. Kirkcaldy RD, Ballard RC, Dowell D. Gonococcal resistance: are cephalosporins next? Curr Infect Dis Rep. 2011;13:196–204.

  8. Lewis DA. The gonococcus fights back: is this time a knock out? Sex Transm Infect. 2010;86:415–21.

  9. Ohnishi M, Saika T, Hoshina S, et al. Ceftriaxone-resistant Neisseria gonorrhoeae, Japan. Emerg Infect Dis. 2011;17:148–9.

  10. 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.

  11. 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. 2002;46:3744–9.

  12. 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. 2010;86:454–60.

  13. 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. 2005;49:137–143.

  14. Hagman KE, Pan W, Spratt BG, et al. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology. 1995;141:611–622.

  15. Moran J. Gonorrhoea. Clin Evid. 2005;(13):2016–23.

  16. Deguchi T, Nakane K, Yasuda M, Maeda S. Emergence and spread of drug resistant Neisseria gonorrhoeae. J Urol. 2010;184:851-8.

  17. Livermore DM, Alexander S, Mardsen B, et al. Activity of ertapenem against Neisseria gonorrhoeae. J Antimicrob Chemother 2004;54(1):280-1.

  18. Alessi E, Monti M, Santambrogio A. Treatment of gonorrhea with thiamphenicol. Sex Transm Dis. 1984;11(4 Suppl):407-9.

  19. Sattler FR, Ruskin J. Therapy of gonorrhea. Comparison of trimethoprim-sulfamethoxazole and ampicillin. JAMA. 1978;240(21):2267-70.

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Last Reviewed: September 28, 2011
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