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Emerging Antimicrobial Resistance in Neisseria gonorrhoeae: Urgent Need to Strengthen Prevention Strategies FREE

Kimberly A. Workowski, MD; Stuart M. Berman, MD, ScM; and John M. Douglas Jr., MD
[+] Article and Author Information

From the National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, and Emory University, Atlanta, Georgia.


Disclaimer: The opinions expressed in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Acknowledgment: The authors thank Hillard Weinstock, Eileen Yee, and the many clinicians and laboratory personnel for their substantial contributions to the Gonococcal Isolate Surveillance Project. They also thank Lori Newman for her contribution in the development of the CDC's 2006 STD Treatment Guidelines (43).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Kimberly A. Workowski, MD, 10 Corporate Square, Corporate Square Boulevard, Mailstop E02, Atlanta, GA 30333; e-mail, kgw2@cdc.gov.

Current Author Addresses: Drs. Workowski, Berman, and Douglas: 10 Corporate Square, Corporate Square Boulevard, Mailstop E02, Atlanta, GA 30333.


Ann Intern Med. 2008;148(8):606-613. doi:10.7326/0003-4819-148-8-200804150-00005
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Prevention and control of gonorrhea is an important public health concern due to the high burden of disease, the recent increase in reported infection rates, and the reproductive and economic consequences of infection. Effective antibiotic treatment is one essential component of an integrated approach to gonorrhea control. Over the past 60 years, however, development of resistance in Neisseria gonorrhoeae to multiple antimicrobial classes challenges this component of gonorrhea control. An integrated, comprehensive prevention strategy should include enhancement of national and international surveillance systems to monitor antimicrobial resistance and new strategies to maximize the benefit and prolong the utility of antimicrobials, including combination regimens, implementation of screening recommendations for individuals at high risk for infection, and the assurance of prompt and effective treatment for infected persons and their sexual partners. Progress in controlling the epidemic and avoiding a resurgence as treatment options wane will require careful attention to all components of a comprehensive prevention strategy.

Neisseria gonorrhoeae infection can cause cervicitis, urethritis, proctitis, pelvic inflammatory disease with long-term sequelae (infertility, ectopic pregnancy, chronic pelvic pain), adverse outcomes of pregnancy, and increased susceptibility to and transmission of HIV infection (12). Neisseria gonorrhoeae infection is the second most common notifiable disease in the United States, with 358 366 cases reported in 2006 (3). However, reported cases probably represent an underestimate of the actual disease burden because of underdiagnosis and underreporting; it is estimated that there were approximately 718 000 incident gonorrhea cases in 2000 (4). After national implementation of gonorrhea control activities in the 1970s, the incidence of gonorrhea in the United States declined markedly, with a 74% reduction in rates from 1975 to 1997. Although rates have remained relatively stable over the past decade, in 2006 the national gonorrhea case rate (120.9 cases per 100 000 population) increased for the second consecutive year, particularly in the western United States (3, 5). Rates of gonorrhea remain high in the South and among African Americans, adolescents, young adults, and men who have sex with men. Recent reports have also documented high rates of gonorrhea among HIV-infected men who have sex with men (3). Because of increased infection rates, high burden of disease, and the reproductive and economic implications of gonorrhea infection, prevention and control of gonorrhea is an important public health concern (67). As current therapeutic options become more limited, we describe the emergent challenges to maintaining antimicrobial effectiveness and a comprehensive approach to gonorrhea control.

An essential element in gonorrhea control is the availability and provision of appropriate, effective antimicrobial therapy. Effective treatment not only eradicates infection in the affected individual and prevents the development of complications, it also has an important public health benefit of shortening the duration of infection, thus decreasing transmission and eliminating reservoirs of infection. However, over the past 60 years N. gonorrhoeae has developed resistance to multiple classes of antimicrobials (Appendix Figure). Sulfanilamides were used for gonococcal treatment after their introduction in 1936, but their efficacy was short-lived because of the rapid emergence of resistance by 1945 (8). Penicillin became the recommended antimicrobial regimen for the next 40 years. The progressive decline in susceptibility—initially associated with chromosomally mediated resistance (exhibited by a stepwise increase in resistance) and later by the acquisition and spread of plasmids containing genes for penicillinase production—required serial increases in the recommended dose of intramuscular procaine penicillin (with probenecid) from 50 000 units in 1945 to 4.8 million units by the early 1970s (9). In 1985, because of emerging penicillin resistance, ceftriaxone became a recommended regimen for the treatment of uncomplicated gonococcal infections (10). At the same time, tetracycline resistance (both plasmid and chromosomally mediated) was spreading to the extent that tetracycline was no longer a viable treatment option. By 1989, resistance to penicillin was sufficiently widespread that penicillin was no longer effective. Ceftriaxone then became the recommended regimen for gonorrhea therapy, with ciprofloxacin as an alternative treatment option (11). By 1993, on the basis of data regarding high efficacy, safety, and convenience as single-dose therapies, oral fluoroquinolones (ciprofloxacin, ofloxacin) were recommended as oral regimens for gonorrhea treatment, as was the oral third-generation cephalosporin cefixime (12).

Grahic Jump Location
Appendix Figure.
Historical perspective on antimicrobial resistance in the United States.

QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men.

Grahic Jump Location

In 1986, concerns about emerging gonococcal antimicrobial resistance lead to the development of the Gonococcal Isolate Surveillance Project (GISP), a national sentinel surveillance system that monitors antimicrobial susceptibility in the United States. Each year, approximately 6000 urethral gonococcal isolates from men attending 25 to 30 sexually transmitted disease (STD) clinics throughout the country are collected and analyzed to provide national data that help guide treatment recommendations. The GISP findings of notable importance include the continued high prevalence of penicillin and tetracycline resistance, which has remained greater than 15%; the increasing prevalence of isolates with decreased susceptibility to macrolides; the appearance of a limited number of multidrug-resistant isolates with decreased susceptibility to cefixime (3); and most important, the dramatic spread of quinolone-resistant N. gonorrhoeae.

Based in part on data from GISP, the emergence of quinolone-resistant N. gonorrhoeae was first identified in Hawaii in 1991, at about same time that it was recognized as a problem in Asia (13). Thereafter, sporadic occurrences of quinolone-resistant N. gonorrhoeae were noted in the United States throughout the 1990s. By 2000, quinolone-resistant N. gonorrhoeae was increasingly observed in persons who became infected in Asia, the Pacific Islands (including Hawaii), or California. As a result, fluoroquinolones were no longer recommended for treating gonorrhea acquired in those locales (1415). Over the next several years, GISP identified increased rates of quinolone-resistant N. gonorrhoeae among men who have sex with men. This finding prompted an advisory in 2004 that fluoroquinolones were no longer recommended for treating gonorrhea in men who have sex with men, regardless of locale (16). Most recently, data from GISP indicate that quinolone-resistant N. gonorrhoeae is widely dispersed in the United States and that in 2006 the infection accounted for 39% of gonococcal isolates in men who have sex with men and 7% in heterosexual men. On the basis of these cumulative data, the Centers for Disease Control and Prevention (CDC) announced that fluoroquinolones are no longer recommended for treating gonococcal infections and associated conditions, such as pelvic inflammatory disease or epididymitis, in any population in the United States (17).

The antimicrobial resistance data from GISP have provided a rational basis for recommended gonococcal treatment regimens. However, data from this sentinel surveillance system have limitations. The GISP data may not be representative of the total population with gonorrhea in the United States, because the current national surveillance system oversamples West Coast locations (where new resistant strains have been first detected), evaluates only male urethral isolates obtained from STD clinics, and samples only a minority of reported gonococcal infections. Dramatic differences in quinolone-resistant N. gonorrhoeae prevalence by geographic location and sexual orientation illustrate the challenge of achieving accurate representation (18). The rapid spread throughout the United States of quinolone-resistant N. gonorrhoeae in heterosexual men, as well as among men who have sex with men, makes defining remaining pockets of continued susceptibility of N. gonorrhoeae problematic. These limitations highlight the difficulty of defining an appropriate sentinel population and a frequency of sampling with sufficient representation to assure susceptibility in a particular locale. Thus, there is a need to monitor antimicrobial resistance at the local level, which would provide a more in-depth understanding of resistance trends and contribute to decisions that affect treatment recommendations in various locations (1920).

The epidemiology of antimicrobial resistance guides decisions about gonococcal treatment recommendations. As discussed, data from GISP are critical when evaluated along with other relevant data, such as those provided by the Gonococcal Antimicrobial Surveillance Program of the Western Pacific Regional Office of the World Health Organization (WHO) in Southeast Asia and the Pacific region. The CDC and the WHO have recommended a change in the treatment regimen when the prevalence of antimicrobial resistance exceeds 5% for a specific antibiotic, while taking into account the prevalence of gonorrhea in the community, the cost of diagnostic and treatment regimens, and the availability of antimicrobial susceptibility data (2123).

An accepted definition of gonococcal treatment efficacy requires a cure rate of over 95% with a lower bound of the 95% CI of at least 90% (24). At the time this criterion was proposed, many antimicrobial regimens met this standard, but in an attempt to reduce the risk for therapeutic failure and development of antimicrobial resistance, more stringent criteria were proposed by Moran and colleagues (25). Their criteria specified that efficacy exceed 95% in summed clinical trials, but required that the lower bound of the 95% CI also be at least 95%. In addition to efficacy data, decisions regarding treatment recommendations involve consideration of other factors. These include administration of at least twice the minimum dose to ensure therapeutic reserve, documentation that susceptibility is not lower among organisms recovered after treatment, and evidence that the serum or plasma concentration with the recommended dose is at least 4 times the minimum inhibitory concentration required to inhibit 90% of strains (MIC90) for 10 hours after the concentration peak (25). These stringent clinical efficacy criteria (95% efficacy with 95% CI) were used to determine the gonorrhea treatment regimens recommended in the CDC STD Treatment Guidelines since 1993.

However, it was recently suggested that these criteria be modified, given the propensity of N. gonorrhoeae to develop antimicrobial resistance to a wide variety of antibiotics, the paucity of novel antimicrobial agents being developed, and the decreased number of highly effective and available treatment regimens (22). Antimicrobials would now be recommended as “alternative treatment regimens” if their clinical efficacy is greater than 95% and the lower bound of the 95% CI is at least 90%; the more stringent criteria would be maintained as required criteria for the primary recommended gonorrhea treatment regimens.

Because of the emergence of quinolone-resistant N. gonorrhoeae in the United States, the current recommended gonorrhea treatment options are from a single class of antimicrobials—cephalosporins. Ceftriaxone, available only as an injection (125 mg intramuscularly), is the recommended regimen for uncomplicated urogenital and anorectal infection. Several other parenteral cephalosporins (ceftizoxime, cefoxitin, cefotaxime) are efficacious in treating gonorrhea but do not offer any substantial advantages over ceftriaxone. Cefixime, 400 mg, is the only oral regimen recommended for gonorrhea treatment. Single-dose oral regimens have potential benefits of convenience and reduced risk for needlestick injury in health care workers. However, as a result of the decision by the manufacturer to discontinue U.S. production, cefixime tablets have not been available in the United States since October 2002 (26). In 2004, Lupin (Mumbai, India) received approval from the U.S. Food and Drug Administration (FDA) to manufacture generic cefixime, currently available as a suspension (200 mg/5 mL), with approval of a tablet formulation anticipated in 2008. Several oral regimens for uncomplicated urogenital and anorectal gonococcal infections may be considered as alternative gonococcal therapies using the less stringent efficacy criterion (that is, lower bound of 95% CI ≥90%). Some evidence suggests that cefpodoxime, 400 mg, may be effective for treating urogenital and anorectal gonorrhea (22, 27). Cefuroxime axetil, 1 g, also meets the less stringent efficacy criteria, but it has poor pharmacodynamic characteristics that may select for stepwise increases in resistance, as has occurred with penicillin (28).

Because cephalosporins are the only currently recommended class of antimicrobials, it is critical that susceptibility to these drugs be actively monitored. Data from GISP indicate that the MIC90 distribution for ceftriaxone has remained relatively stable: Only 4 isolates identified since 1987 have had decreased susceptibility to ceftriaxone, and no resistant isolates have been identified (29). Cefixime susceptibility testing through GISP has demonstrated 48 isolates with decreased susceptibility since 1992 (29), with several isolates having possible epidemiologic links to Asia (30). Recent reports from Japan and several other countries in the WHO Western Pacific Region (Australia; Brunei; China; and Papua, New Guinea) suggest decreased susceptibility to cephalosporins, with the reported mechanism of resistance being alterations in penA genes (3033). Some N. gonorrhoeae strains demonstrating reduced cephalosporin susceptibility also have reduced susceptibility to multiple drug classes, including quinolones, macrolides, penicillins, and tetracyclines (30, 32). The emergence and dissemination of such strains is of particular concern.

Management of Cephalosporin Allergy

Allergy to antibiotics is another barrier to successful treatment. Many regard a history of penicillin allergy as a relative contraindication to cephalosporin administration (34). Allergic reactions to cephalosporin occur in approximately 5% to 10% of persons with a history of penicillin allergy. However, immediate (30 to 60 minutes after administration) and accelerated (1 to 12 hours after administration) IgE-mediated anaphylactic or urticarial reactions to cephalosporins are rare, relative to reactions associated with penicillin (3435). Although a cross-reactivity rate of 10% has been reported, this estimate is based on retrospective studies in which penicillin allergy was not routinely confirmed by skin testing. However, some of the reactions may have not been immune-mediated (35). Available data suggest an increased risk for cephalosporin reactions among persons with positive results on penicillin skin tests (34). Skin testing (major and minor penicillin determinants) is warranted for individuals who require cephalosporin treatment and have a history of penicillin allergy that is consistent with an IgE-mediated mechanism (36). However, skin testing is not feasible in many settings because benzylpenicilloyl polylysine is not currently available; a companion major and minor determinant mixture is anticipated in the future. Cephalosporin desensitization may also be considered in the management of persons who have had documented severe allergic reactions to a cephalosporin or to penicillin, but this is impractical in most clinical settings.

Alternative Treatment Options

Spectinomycin is another therapeutic option for persons with gonococcal urogenital infection who cannot tolerate cephalosporins. Of note, spectinomycin has limited effectiveness for the treatment of pharyngeal infection, limiting its utility in populations in which such infections are common, such as men who have sex with men. However, spectinomycin is not currently commercially available for gonococcal treatment but is expected to be available in the United States during 2008. Updated information regarding the availability of spectinomycin is available at http://www.cdc.gov/std/gonorrhea/arg(37). However, even if spectinomycin were available, it would probably remain an alternative treatment rather than a recommended one, because high levels of resistance developed when this antimicrobial was widely used in the mid-1980s (38).

Azithromycin, 2 g, taken orally is effective against uncomplicated gonococcal infection and is another option for persons who are allergic to cephalosporins. However, concerns about the development of antimicrobial resistance to macrolides with widespread use restrict current treatment recommendations to limited circumstances. Macrolide antibiotics, such as azithromycin and erythromycin, have been associated with the multiple transferable resistance efflux system (3940). Gonococcal isolates with reduced susceptibility or resistance to azithromycin have been documented in the United States and many other countries (29, 33). Of additional concern, the 2-g dose has been associated with adverse gastrointestinal effects, such as nausea, diarrhea, and vomiting, possibly due to the drug's effect on motilin receptors, as demonstrated with other macrolides (41). However, a recently developed extended-release microsphere formulation delivers 2 g of azithromycin in a single tablet. This has improved tolerability owing to release in the lower gastrointestinal tract and bypass of the motilin receptors in the upper tract (42).

A test of cure is not required after appropriate treatment for uncomplicated urogenital gonorrhea with any of the recommended or alternative regimens (43), but local jurisdictions may elect to perform such testing. Persons whose symptoms persist after a recommended regimen should be evaluated by culture and antimicrobial susceptibility testing; such cases should be reported to the local health department.

Given the possible emergence of cephalosporin resistance, other effective therapeutic regimens and new agents for gonorrhea treatment are urgently needed. Although aminoglycosides (kanamycin, gentamicin) have been widely used for syndromic treatment for urethral discharge in some settings (44), additional information is needed before such drugs can be considered. For example, data are limited on the prevalence of gonococcal resistance to aminoglycosides because there is no standard MIC that defines antimicrobial resistance. Furthermore, correlations between laboratory data and clinical outcome have not been established, aminoglycosides are administered only by injection, and resistance has developed with widespread use (44). Another drug that may be considered is rifampicin, which is widely available in many countries; however, resistance develops rapidly, and recent data from Indonesia suggest that resistance is prevalent (45). Other antimicrobials, including co-trimoxazole, chloramphenicol, and ertapenem, have been investigated to a limited extent. Concerns about emergence of resistance, cost, efficacy, and safety of each of these alternative regimens remain (22, 46).

New strategies are needed to maximize the benefit and prolong the utility of antimicrobials. Some have suggested that use of a limited number of treatment regimens may accelerate emergence or spread of antimicrobial resistance and should be avoided (47), but recent data have not supported this view (48). Use of combination therapy may reduce the selective pressure that monotherapy exerts on drug resistance; using different antimicrobial classes or combination regimens is analogous to the therapeutic approaches to tuberculosis and HIV infection. Macrolides combined with either aminoglycosides or rifampin are possible treatment options. For example, some have suggested that routine co-treatment for chlamydia with azithromycin may hinder the development of antimicrobial-resistant N. gonorrhoeae(43). Clinical and laboratory evaluation of the pharmacokinetics and pharmacodynamics of such combinations will help to identify efficacious regimens that deter antimicrobial resistance.

Antimicrobial treatment alone is inadequate in addressing emerging gonococcal antimicrobial resistance. Gonococcal resistance has emerged and spread from countries in which disease is highly prevalent, syndromic treatment algorithms (urethritis, cervicitis) are widely used, the capacity to identify asymptomatic reservoirs is lacking, and surveillance and prevention program activities are limited (46). The discovery of novel agents or a combination of antimicrobials is only one component of an integrated, global approach to gonorrhea prevention.

Prevention and control programs for STDs have been critical in achieving the substantial reduction in rates of gonorrhea infection in the United States over the past 30 years (6). Continuing progress in controlling this important STD requires a comprehensive approach to confront the considerable challenges presented by the high global burden of disease, an adaptable organism, emerging antimicrobial resistance, and sparse treatment options. A comprehensive prevention strategy must enhance global surveillance systems that monitor antimicrobial resistance, adapt screening recommendations for individuals at high risk for infection, and assure prompt and effective treatment for infected persons and their sexual partners (Table).

Table Jump PlaceholderTable.  Gonorrhea Prevention and Control
Surveillance for Resistance

Effective antimicrobial treatment is the foundation of our national gonorrhea prevention program; vigilant surveillance to identify emerging antimicrobial resistance is essential if treatment is to remain highly effective. The national sentinel gonococcal surveillance system (with close monitoring of cephalosporin MICs) must be strengthened, and collaboration with international partners must be enhanced to monitor emerging resistance globally. In addition, we must expand geographic information systems to track infections at the local level, evaluate risk factors associated with antimicrobial resistance, and heighten surveillance of treatment failures to identify emerging cephalosporin resistance. We must increase local capacity to monitor antimicrobial susceptibility, which requires the technical capacity to culture gonococci. However, the ability to perform a gonococcal culture and susceptibility testing is affected by the expansion of nucleic acid amplification testing for diagnosis of infection (20). The CDC has encouraged state and local health departments to maintain a capacity to perform culture and antimicrobial susceptibility testing or develop partnerships with experienced laboratories that can perform such testing (17).

Primary Screening

Another essential and well-established component of gonorrhea control is the screening of populations at risk for infection. Because gonococcal infections among women frequently are asymptomatic, screening of women at high risk is essential to detect reservoirs of infection. The U.S. Preventive Services Task Force recommends screening sexually active women (including pregnant women) and women at increased risk for infection. Risk factors include age younger than 25 years, previous gonorrhea infection or other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use (49). Screening low-risk women and men is not recommended.

Routine screening for gonorrhea and other common STDs is also recommended for sexually active men who have sex with men, including those with HIV infection (43). Specific screening recommendations include annual tests for gonorrhea and chlamydia on urethral or urine specimens, a test for gonococcal pharyngeal infection in men with orogenital exposure, and a test for gonorrhea and chlamydia rectal infection in men who have had receptive anal intercourse during the past year (43). More frequent screening (at 3- to 6-month intervals) may be indicated for men who have sex with men, who have multiple or anonymous partners, who have sex in conjunction with illicit drug use, who use methamphetamines, or whose partners participate in these activities. Adherence to these screening recommendations is an important strategy for gonorrhea control in sexually active men who have sex with men, because asymptomatic infection at pharyngeal and rectal sites is common and gonorrhea can be easily transmitted with insertive or receptive rectal intercourse and fellatio (3, 5052). Screening for pharyngeal infection among men who have sex with men is also important because this infection is more difficult to treat than urogenital or anorectal infection. Few antimicrobial regimens, including ceftriaxone, can eradicate more than 90% of gonococcal pharyngeal infections (22, 5354). Culture is the preferred method for detection of N. gonorrhoeae at the pharyngeal and rectal sites (43) because the FDA has not approved nucleic acid amplification tests for use at those sites. However, such tests have been used at the pharyngeal and rectal sites after local validation tests were done to meet Clinical Laboratory Improvement Amendment requirements (5051). In addition, all persons tested for gonorrhea should be evaluated for other STDs, including syphilis, chlamydia, and HIV infection (43).

Secondary Screening and Management of Sex Partners

Persons who have had gonorrhea and received appropriate treatment in the past several months have a high incidence of repeated infection (5557). Most of these infections result from reinfection rather than treatment failure, which indicates the importance of prevention counseling and partner referral. As a result, retesting—ideally at all exposed anatomical sites—is recommended 3 to 4 months after treatment for initial infection (43, 57). Prompt and effective evaluation and treatment of sexual partners is necessary to prevent reinfection and disrupt routes of transmission; therefore, partners whose last sexual contact was within 60 days before symptom onset or diagnosis of infection should be evaluated and treated for both gonorrhea and chlamydia (43). If medical evaluation, counseling, and treatment of partners are not possible, expedited partner therapy, in which partners of infected persons are treated without medical evaluation or prevention counseling, is a reasonable alternative for partners of heterosexual men or women (58). There is no documented experience with expedited partner therapy for gonorrhea or chlamydia infection among men who have sex with men.

Dependence on Commercial Interest in Drug Development

Despite the manifest need for additional antimicrobial agents with the recommended treatment options now limited to a single antimicrobial class, financial incentives for novel drug discovery and clinical evaluation of existing agents have not stimulated ongoing research by industry. The current problem with gonorrhea treatment regimens is part of a larger pattern of declining investment in antimicrobials. Many consider this trend to be a looming public health crisis and have proposed legislative and regulatory incentives to spur development of new therapies (59). Clinicians and public health officials must collaborate with the pharmaceutical industry to ensure the discovery and clinical development of new antimicrobials. Limited availability of drugs of proven benefit (cefixime and spectinomycin) for infections for which few other options exist is a serious threat to public health.

Although there have been great successes in gonorrhea control in the United States, gonococcal infection remains an important public health problem, disproportionally affecting such populations as African Americans, adolescents and young adults, and men who have sex with men. The provision of effective antimicrobial treatment not only eradicates infection in the affected individual, it prevents transmission, thus reducing disease rates. However, effective antimicrobial treatment should be seen as only one essential component of an integrated approach to gonococcal control. Further progress in controlling the epidemic, and avoiding a resurgence as treatment options wane, will require careful attention to all components of a comprehensive prevention strategy.

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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 of penicillinase-producing Neisseria gonorrhoeae. N Engl J Med. 1987; 317:272-8. PubMed
 
Johnson SR, Sandul AL, Parekh M, Wang SA, Knapp JS, Trees DL.  Mutations causing in vitro resistance to azithromycin in Neisseria gonorrhoeae. Int J Antimicrob Agents. 2003; 21:414-9. PubMed
 
Xia M, Whittington WL, Shafer WM, Holmes KK.  Gonorrhea among men who have sex with men: outbreak caused by a single genotype of erythromycin-resistant Neisseria gonorrhoeae with a single-base pair deletion in the mtrR promoter region. J Infect Dis. 2000; 181:2080-2. PubMed
 
Takeshita E, Matsuura B, Dong M, Miller LJ, Matsui H, Onji M.  Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol. 2006; 41:223-30. PubMed
 
Chandra R, Liu P, Breen JD, Fisher J, Xie C, LaBadie R. et al.  Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin. Clin Pharmacokinet. 2007; 46:247-59. PubMed
 
Centers for Disease Control and Prevention.  Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55:1-94. PubMed
 
Daly CC, Hoffman I, Hobbs M, Maida M, Zimba D, Davis R. 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
 
Sutrisna A, Soebjakto O, Wignall FS, Kaul S, Limnios EA, Ray S. et al.  Increasing resistance to ciprofloxacin and other antibiotics in Neisseria gonorrhoeae from East Java and Papua, Indonesia, in 2004—implications for treatment. Int J STD AIDS. 2006; 17:810-2. PubMed
 
Tapsall J.  Antibiotic resistance in Neisseria gonorrhoeae is diminishing available treatment options for gonorrhea: some possible remedies. Expert Rev Anti Infect Ther. 2006; 4:619-28. PubMed
 
Livermore DM.  Minimising antibiotic resistance. Lancet Infect Dis. 2005; 5:450-9. PubMed
 
Tapsall JW.  What management is there for gonorrhea in the postquinolone era? [Editorial]. Sex Transm Dis. 2006; 33:8-10. PubMed
 
U.S. Preventive Services Task Force.  Screening for gonorrhea: recommendation statement. Ann Fam Med. 2005; 3:263-7. PubMed
 
Kent CK, Chaw JK, Wong W, Liska S, Gibson S, Hubbard G. et al.  Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis. 2005; 41:67-74. PubMed
 
Morris SR, Klausner JD, Buchbinder SP, Wheeler SL, Koblin B, Coates T. et al.  Prevalence and incidence of pharyngeal gonorrhea in a longitudinal sample of men who have sex with men: the EXPLORE study. Clin Infect Dis. 2006; 43:1284-9. PubMed
 
Lafferty WE, Hughes JP, Handsfield HH.  Sexually transmitted diseases in men who have sex with men. Acquisition of gonorrhea and nongonococcal urethritis by fellatio and implications for STD/HIV prevention. Sex Transm Dis. 1997; 24:272-8. PubMed
 
Moran JS.  Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important? Sex Transm Dis. 1995; 22:39-47. PubMed
 
Moran J.  Gonorrhoea. Clin Evid. 2005; 2016-23. PubMed
 
Thomas JC, Weiner DH, Schoenbach VJ, Earp JA.  Frequent re-infection in a community with hyperendemic gonorrhoea and chlamydia: appropriate clinical actions. Int J STD AIDS. 2000; 11:461-7. PubMed
 
Gunn RA, Maroufi A, Fox KK, Berman SM.  Surveillance for repeat gonorrhea infection, San Diego, California, 1995-2001: establishing definitions and methods. Sex Transm Dis. 2004; 31:373-9. PubMed
 
RESPECT-2 Study Group.  High incidence of new sexually transmitted infections in the year following a sexually transmitted infection: a case for rescreening. Ann Intern Med. 2006; 145:564-72. PubMed
 
Centers for Disease Control and Prevention.  Expedited partner therapy in the management of sexually transmitted diseases: review and guidance. Atlanta: Centers for Disease Control and Prevention; 2006. Accessed athttp://www.cdc.gov/std/treatment/EPTFinalReport2006.pdfon 20 March 2008.
 
Antimicrobial Availability Task Force of the Infectious Diseases Society of America.  Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America Clin Infect Dis. 2006;42:657-68. [PMID: 16447111]
 

Figures

Grahic Jump Location
Appendix Figure.
Historical perspective on antimicrobial resistance in the United States.

QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men.

Grahic Jump Location

Tables

Table Jump PlaceholderTable.  Gonorrhea Prevention and Control

References

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Centers for Disease Control and Prevention (CDC).  Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep. 2007; 56:332-6. PubMed
 
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Dicker LW, Mosure DJ, Steece R, Stone KM.  Testing for sexually transmitted diseases in U.S. Public health laboratories in 2004. Sex Transm Dis. 2007; 34:41-6. PubMed
 
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Centers for Disease Control and Prevention (CDC).  Discontinuation of cefixime tablets—United States. MMWR Morb Mortal Wkly Rep. 2002; 51:1052. PubMed
 
Hall C, McElroy M, Samuel M, Guerry S, Ried C, Rietmeijer C, Philip S, Katz A, Bauer H, Newman L, Bolan G.  Single-dose Cefpodoxime proxetil effective treatment of uncomplicated urogenital and rectal gonorrhea. [Abstract]. Presented at the 17th International Society for STD Research, Seattle, Washington 29 July–1 August 2007: Abstract P-459.
 
North Thames Audit Group.  Which cephalosporin for gonorrhoea? Sex Transm Infect. 2004; 80:386-8. PubMed
 
Centers for Disease Control and Prevention (CDC).  Gonococcal Isolate Surveillance Project (GISP) Annual Report, 2006. Atlanta: Centers for Disease Control and Prevention; 2008.
 
Wang SA, Lee MV, O'Connor N, Iverson CJ, Ohye RG, Whiticar PM. et al.  Multidrug-resistant Neisseria gonorrhoeae with decreased susceptibility to cefixime-Hawaii, 2001. Clin Infect Dis. 2003; 37:849-52. PubMed
 
Ito M, Yasuda M, Yokoi S, Ito S, Takahashi Y, Ishihara 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; 48:3185-7. PubMed
 
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. PubMed
 
The WHO Western Pacific Gonococcal Antimicrobial Surveillance Programme.  Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific Region, 2006. Commun Dis Intell. 2008. [Forthcoming].
 
Kelkar PS, Li JT.  Cephalosporin allergy. N Engl J Med. 2001; 345:804-9. PubMed
 
Saxon A, Beall GN, Rohr AS, Adelman DC.  Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med. 1987; 107:204-15. PubMed
 
Joint Task Force on Practice Parameters.  The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005; 115:S483-523. PubMed
 
Centers for Disease Control and Prevention (CDC).  Notice to readers: discontinuation of spectinomycin. MMWR Morb Mortal Wkly Rep. 2006; 55:370.
 
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 of penicillinase-producing Neisseria gonorrhoeae. N Engl J Med. 1987; 317:272-8. PubMed
 
Johnson SR, Sandul AL, Parekh M, Wang SA, Knapp JS, Trees DL.  Mutations causing in vitro resistance to azithromycin in Neisseria gonorrhoeae. Int J Antimicrob Agents. 2003; 21:414-9. PubMed
 
Xia M, Whittington WL, Shafer WM, Holmes KK.  Gonorrhea among men who have sex with men: outbreak caused by a single genotype of erythromycin-resistant Neisseria gonorrhoeae with a single-base pair deletion in the mtrR promoter region. J Infect Dis. 2000; 181:2080-2. PubMed
 
Takeshita E, Matsuura B, Dong M, Miller LJ, Matsui H, Onji M.  Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol. 2006; 41:223-30. PubMed
 
Chandra R, Liu P, Breen JD, Fisher J, Xie C, LaBadie R. et al.  Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin. Clin Pharmacokinet. 2007; 46:247-59. PubMed
 
Centers for Disease Control and Prevention.  Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55:1-94. PubMed
 
Daly CC, Hoffman I, Hobbs M, Maida M, Zimba D, Davis R. 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
 
Sutrisna A, Soebjakto O, Wignall FS, Kaul S, Limnios EA, Ray S. et al.  Increasing resistance to ciprofloxacin and other antibiotics in Neisseria gonorrhoeae from East Java and Papua, Indonesia, in 2004—implications for treatment. Int J STD AIDS. 2006; 17:810-2. PubMed
 
Tapsall J.  Antibiotic resistance in Neisseria gonorrhoeae is diminishing available treatment options for gonorrhea: some possible remedies. Expert Rev Anti Infect Ther. 2006; 4:619-28. PubMed
 
Livermore DM.  Minimising antibiotic resistance. Lancet Infect Dis. 2005; 5:450-9. PubMed
 
Tapsall JW.  What management is there for gonorrhea in the postquinolone era? [Editorial]. Sex Transm Dis. 2006; 33:8-10. PubMed
 
U.S. Preventive Services Task Force.  Screening for gonorrhea: recommendation statement. Ann Fam Med. 2005; 3:263-7. PubMed
 
Kent CK, Chaw JK, Wong W, Liska S, Gibson S, Hubbard G. et al.  Prevalence of rectal, urethral, and pharyngeal chlamydia and gonorrhea detected in 2 clinical settings among men who have sex with men: San Francisco, California, 2003. Clin Infect Dis. 2005; 41:67-74. PubMed
 
Morris SR, Klausner JD, Buchbinder SP, Wheeler SL, Koblin B, Coates T. et al.  Prevalence and incidence of pharyngeal gonorrhea in a longitudinal sample of men who have sex with men: the EXPLORE study. Clin Infect Dis. 2006; 43:1284-9. PubMed
 
Lafferty WE, Hughes JP, Handsfield HH.  Sexually transmitted diseases in men who have sex with men. Acquisition of gonorrhea and nongonococcal urethritis by fellatio and implications for STD/HIV prevention. Sex Transm Dis. 1997; 24:272-8. PubMed
 
Moran JS.  Treating uncomplicated Neisseria gonorrhoeae infections: is the anatomic site of infection important? Sex Transm Dis. 1995; 22:39-47. PubMed
 
Moran J.  Gonorrhoea. Clin Evid. 2005; 2016-23. PubMed
 
Thomas JC, Weiner DH, Schoenbach VJ, Earp JA.  Frequent re-infection in a community with hyperendemic gonorrhoea and chlamydia: appropriate clinical actions. Int J STD AIDS. 2000; 11:461-7. PubMed
 
Gunn RA, Maroufi A, Fox KK, Berman SM.  Surveillance for repeat gonorrhea infection, San Diego, California, 1995-2001: establishing definitions and methods. Sex Transm Dis. 2004; 31:373-9. PubMed
 
RESPECT-2 Study Group.  High incidence of new sexually transmitted infections in the year following a sexually transmitted infection: a case for rescreening. Ann Intern Med. 2006; 145:564-72. PubMed
 
Centers for Disease Control and Prevention.  Expedited partner therapy in the management of sexually transmitted diseases: review and guidance. Atlanta: Centers for Disease Control and Prevention; 2006. Accessed athttp://www.cdc.gov/std/treatment/EPTFinalReport2006.pdfon 20 March 2008.
 
Antimicrobial Availability Task Force of the Infectious Diseases Society of America.  Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America Clin Infect Dis. 2006;42:657-68. [PMID: 16447111]
 

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Emerging Antimicrobial Resistance in Neisseria gonorrhoeae
Posted on May 11, 2008
Takashi Deguchi
Department of Urology, Graduate School of Medicine, Gifu University
Conflict of Interest: None Declared

Workowski and colleagues report the emerging antimicrobial resistance in Neisseria gonorrhoeae and the urgent need of an integrated, comprehensive approach to control gonorrhea (1). In particular, we agree with them in the importance of enhancement of national and international surveillance systems to monitor antimicrobial resistance. In Japan, nationwide surveillance of antimicrobial resistance of N. gonorrhoeae has not been conduced, and high priority has not been placed on funding for such surveillance. Antimicrobial resistance of N. gonorrhoeae has not been controlled in an efficient or timely manner to prolong the efficacy of existing antibiotics. As a consequence, effective oral regimens for treatment of gonorrhea have been lost.

In Japan, treatment failures with fluoroquinolones were first reported in 1994. Since the late 1990s, there has been an increase in clinical strains with decreased susceptibility to fluoroquinolones (2). In 1999, fluoroquinolones were excluded from recommendations and guidelines for treatment of gonococcal infections. As alternatives to fluoroquinolones, oral cephalosporins were commonly used. Since 2001, however, a decrease in susceptibility of clinical strains to them has also been observed (2). Such strains have a mosaic penicillin-binding protein 2 (PBP 2) composed of fragments of PBP 2 from Neisseria cinerea and Neisseria perflava (3). This mosaic PBP 2 is significantly associated with decreased susceptibility to oral cephalosporins. The emergence and spread of such strains forced exclusion of cefixime from the 2006 recommendations and guidelines. In Japan, a single oral 1-g dose of azithromycin is used for treatment of non-gonococcal urethritis but is not registered for treatment of gonorrhea. However, decreased susceptibility of clinical strains to azithromycin has been observed (4). Higher doses of azithromycin are not and will not be recommended. No longer are there oral regimens for treatment of gonorrhea in Japan. For spectinomycin and ceftriaxone, resistance is rare. Strains with the mosaic PBP 2 are still sensitive to ceftriaxone. Ceftriaxone is also effective against gonococcal pharyngeal infection. In Japan, therefore, ceftriaxone is the only agent recommended as the first-choice treatment for gonococcal infections.

In conclusion, global spread of N. gonorrhoeae strains against which oral regimens are not effective is a matter of serious concern, and emergence of N. gonorrhoeae strains with resistance to injectable agents is disastrous. As Workowski and colleagues describe (1), ideally, a coherent global surveillance system, which can generate the high-quality data on which decisions for treatment change are based, rather than regional surveillances in isolation, should be established before the disease becomes untreatable.

Takashi Deguchi, MD and Mitsuru Yasuda, MD Graduate School of Medicine, Gifu University Gifu, Japan Shin-ichi Maeda, MD Toyota Memorial Hospital, Toyota, Japan.

Potential Financial Conflicts of Interest: None disclosed.

References

1. Workowski KA, Berman SM, Douglas JM. Emerging antimicrobial resistance in Neisseria gonorrhoeae: urgent need to strengthen prevention strategies. Ann Intern Med. 2008;148:606-13. [PMID: 18413622]

2. Ito M, Yasuda M, Yokoi S, Ito S-I, Takahashi Y, Ishihara 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;48:3185-7. [PMID: 15273147]

3. Ito M, Deguchi T, Mizutani K-S, Yasuda M, Yokoi S, Ito S-I, 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. [PMID: 15616287]

4. Yasuda M, Hagiwara N, Ishihara S, Maeda S, Deguchi T. Remarkable increase of Neisseria gonorrhoeae with decreased susceptibility to cefixime and azithromycin. [Abstract]. Presented in the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California 27 September-30, 2006: Abstract L2-1230.

Conflict of Interest:

None declared

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