Neisseria gonorrhoeae

Monograph

Neisseria gonorrhoeae, the gonococcus, is a non-spore-forming, nonmotile bacterium that appears under the microscope as a Gram-negative coccus occurring in pairs (diplococci) with flattening of the adjacent sides. Gonococci are adapted to growth on mucous membranes and cannot tolerate drying. Their fragility limits their transmissibility to direct contact between mucous membranes or the direct exchange of infected secretions.

EPIDEMIOLOGY

The requirement for intimate contact to permit transmission makes gonorrhea a classic sexually transmitted infection. Sexual transmission via penile-vaginal, penile-rectal, or penile-pharyngeal contact accounts for the vast majority of cases. The most important means of non-sexual transmission is from mother to child during birth.  The gonococcus is a survivor. Despite its being too fragile to be transmitted by food, water, air, or (with very rare exceptions) fomites, it remained a very common infection in most of the world in the preantibiotic era despite sometimes strenuous efforts to control it. The introduction of antimicrobials led to control of gonorrhea in some populations, but despite the natural susceptibility of the gonococci to low concentrations of a wide variety of antimicrobials, 75 years after the discovery of penicillin gonorrhea remains a common infection in much of the world. In the United States, gonorrhea remains one of the most commonly reported infectious diseases with 116 cases per 100,000 population reported in 2003 (7). It is most common among adolescents and young adults, with a peak incidence among females at 15 to 19 years of age (635/100,000 in 2003) and a peak incidence among males at 20 to 24 years of age (466/100,000 in 2003).

CLINICAL MANIFESTATIONS

In males, urethral infection may be asymptomatic or present as a painful but ultimately self-limited urethral inflammation.  Acute gonococcal urethritis is characterized by an exuberant granulocytic inflammatory discharge.  Fortunately, therapy with an appropriate dose of an antimicrobial agent active against the infecting strain will reliably eradicate infection, obviating the need for a test of cure. Eradication from the urethra is rapid with no viable bacteria recoverable 24 hours after a single dose of antimicrobial (27). Gonococcal orchitis and epidymitis are infrequent complications of urethral infection.  Pharyngeal disease may be more common than previously appreciated and anal intercourse may lead to gonococcal proctitis; organisms that are increasingly resistant to conventional antibiotics have been isolated from rectal cultures.

In women, gonococci may cause asymptomatic or symptomatic endocervical infections, or upper genital tract disease.  Gonococcal infections of women are closely associated with infertility and as a result, females disproportionately suffer the consequences of infection.  

For both men and women, but more commonly in women, local gonococcal infection can progress to bacteremia with attendant septic arthritis.  In fact, gonococcal arthritis is the most common etiology of arthritis in young people.  When infection involves the eyes, especially in newborns, blindness can result if treatment is not prompt. Rarely, bacteremia results in dissemination to the joints, skin , endocardium or meninges. 

LABORATORY DIAGNOSIS

The only rapid test for gonococcal infection is microscopic examination of stained secretions. Detection of polymorphonuclear leucocytes with intracellular Gram-negative diplococci in urethral exudates is reliable for the diagnosis of gonorrhea in men with symptomatic urethritis. It has a sensitivity and specificity comparable to culture isolation followed by oxidase testing and Gram staining of the isolate (10). The Gram stain of cervical secretions is less sensitive for the diagnosis of gonorrhea in women and specificity is inadequate except in skilled hands. The CDC does not recommend the use of Gram stain for the detection of gonococcal infection in asymptomatic men, in women, or at any site other than the urethra (10).

Definitive diagnosis of N. gonorrhoeae infection takes time. Either culture or DNA detection techniques can be used. Culture can be relatively inexpensive and is highly specific when confirmatory tests are used. It is also highly sensitive but only when specimen collection and transport are optimal. The DNA tests, especially the amplified DNA tests, can be highly sensitive and specific but, unlike culture, they provide no specimen for antimicrobial sensitivity testing.

Tests that are not highly specific are often sufficient for making treatment decisions. However, for making decisions about contact notification more specific tests should be used and in cases where the isolation of N. gonorhoeae may be evidence of crime, culture should be used for diagnosis with confirmatory testing and preservation of the isolate.

PATHOGENESIS

N. gonorrhoeae (and N. meningitidis) are obligate human pathogens.  These organisms do not produce a specific product or "toxin" that accounts for the symptoms of gonorrhea.  Rather it is the ability of these organisms to multiply on mucosal surfaces and avoid host defenses that incites the vigorous host immune response that ultimately causes the disease pathology.  The capacity to multiply in vivo is a function of their ability to access growth-essential nutrients from the host, including efficiently scavenging growth-essential iron from human transferring, lactoferrin, or hemoglobin.   These organisms evade host defenses by avoiding antigenic detection through the production of a capsule or antigenic variation of surface proteins.  They also evade host defenses by invading columnar epithelial cells (e.g., endocervix, urethra, rectum, oropharynx, nasopharynx, and conjunctiva) (38a).  Host factors can also contribute as individuals with complement deficiencies are predisposed to infection by pathogenic Neisseria spp.

Gonococci attach primarily to columnar and cuboidal epithelium. After 24-48 hours, they penetrate between and through the cells to reach the submucosal tissues where they stimulate a marked neutrophilic response resulting in sloughing of the epithelium, microabscess formation, and the exudation of pus (54).

Gonococcal infection facilitates transmission of HIV-1.  In HIV infected individuals gonococcal urethritis greatly increases shedding of HIV in mucosal secretions and semen (29a).  In HIV-negative individuals, gonococcal infection recruits cells and cytokines capable of enhancing acquisition of HIV, and facilitates breaks in mucosal integrity leading to increased virus infectivity.

SUSCEPTIBILITY IN VITRO AND IN VIVO

The gonococcus is a model of adaptability, having developed resistance to sulfonamides, penicillins, tetracyclines, and, recently, to fluoroquinolones. Nevertheless, any individual gonococcal strain has a high probability of being susceptible to single-dose treatment with any of several antimicrobials and all gonococci remain susceptible to single doses of certain cephalosporins.

In Vitro Data

Table 1 shows some recent MIC values from around the world for the antimicrobials most useful against N. gonorrhoeae. The data have many geographical gaps and few studies have differentiated between isolates from men who have sex with men (MSM) and isolates from heterosexuals.  In the United States, fluoroquinolone resistance is much more common among MSM (8).

In Vivo Data

Relationship Between In Vitro Susceptibility and Clinical Outcome

Studies of human subjects experimentally infected withN. gonorrhoeae strains of known penicillin susceptibility and treated with varying doses of penicillin showed that eradication of urethral infections in men given single-dose therapy was associated with maintenance of plasma penicillin levels 3 to 4 times the MIC of the infecting strain for at least 7 to 10 hours (28). More recently it has been shown that high cure rates (>97.5%) in clinical trials of fluoroquinolones and cephalosporins for the treatment of urogenital and rectal infections are associated with serum or plasma antimicrobial concentrations of at least four times the MIC90 of the infecting strains persisting for at least 10 hours (42). For pharyngeal infection, high cure rates (≥80%) are associated with high serum or plasma antimicrobial levels that persist for at least 20 hours. 

Results of Clinical Trials

Table 2 summarizes the results of clinical trials of the most effective antigonococcal regimens. Reference (42) offers a more comprehensive summary of 87 separate regimens.

ANTIMICROBIAL THERAPY

Uncomplicated Urogenital and Rectal Infections

Criteria for Choosing Regimens for Routine Use

It is important that only regimens with an effectiveness of >95% in clinical trials be used. Less effective regimens would permit onward transmission and obligate the prescriber to reexamine patients after treatment to ensure that they were no longer infectious. Such follow up would be expensive and, in many cases, impossible. Fortunately, there are safe, single-dose regimens that cure nearly 100% of infections, obviating the need for a test of cure. With several safe and effective antigonococcal regimens to choose from, it was proposed that the minimal standard for uncomplicated urogenital or rectal infections should be a proven efficacy of >95% in summed clinical trials with a 95% confidence interval that excludes values <95% (42). However, with resistance to flouroquinolones spreading, such a high standard may be untenable.

In the single-dose regimens used for the treatment of gonorrhea, the recommended antimicrobials are all very safe; hypersensitivity reactions are the greatest concern but even these appear to be rare. The main consideration is oral versus intramuscular administration. Avoiding injections is especially desirable in STD clinics where a substantial proportion of patients may be HIV- or hepatitis B surface antigen-positive.

The cephalosporins and spectinomycin have few contraindications. Fluoroquinolones, on the other hand, are generally considered to be contraindicated for children <18 years of age and for pregnant women. These contraindications are based on extrapolation from animal studies and not on human studies or clinical experience. Studies of children with cystic fibrosis treated with prolonged courses of fluoroquinolones have shown no evidence of toxicity (22, 23, 52).

Cost is an important consideration, especially for public STD clinics and increasingly for all providers. In general, the fluoroquinolones can be purchased for a lower per treatment cost than can the cephalosporins or spectinomycin.

Efficacy against incubating syphilis is no longer an important consideration in the United States because 1) incubating syphilis appears to be uncommon among gonorrhea patients in the United States (44), 2) patients treated for gonorrhea should, in general, be treated presumptively for Chlamydia trachomatis infection as well and the recommended antichlamydia regimens are likely to eradicate incubating syphilis.

Regimens Recommended for the Routine Treatment of Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum in Adult Heterosexuals Unlikely to have Acquired Their Infection from a Foreign Source or in Hawaii or California

Several single-dose regimens have been shown to be safe and highly effective for the treatment of cervical, urethral and rectal infections among adult men and women and are recommended by the CDC for the treatment of infections from a heterosexual, domestic U.S. source: ceftriaxone (125 mg i.m.), cefixime (400 mg p.o.), ciprofloxacin (500 mg p.o.), ofloxacin (400 mg p.o.), or levofloxacin (250 mg p.o.) (9). Fluoroquinolones should not be used in California or Hawaii, to treat MSM, or to treat infections that may have been acquired abroad. All of these regimens should routinely be accompanied with a regimen effective against uncomplicated Chlamydia trachomatis genital infection unless chlamydial infection has been ruled out.

Ceftriaxone in a single injection of 125 mg provides sustained, high bactericidal levels in the blood. Extensive clinical experience indicates that it is safe and effective for the treatment of uncomplicated gonorrhea at all sites, curing 98.8% of uncomplicated urogenital and anorectal infections in published clinical trials. (A 250-mg dose is also acceptable, but so large a dose is unnecessary.)

Cefixime has an antimicrobial spectrum similar to that of ceftriaxone, but the 400-mg oral dose does not provide as high nor as sustained plasma levels as does 125 mg ceftriaxone. In published clinical trials, the 400 mg dose cured 97.3% of uncomplicated urogenital and anorectal infections. The advantage of cefixime is that it can be administered orally. An 800-mg dose may be slightly more effective but is less well tolerated.

Ciprofloxacin is very active against almost all strains of N. gonorrhoeae found in heterosexuals in the United States (excluding Hawaii and California) and, at a dose of 500 mg provides sustained bactericidal levels in the blood that have cured 99.8% of uncomplicated urogenital and anorectal infections in published clinical trials conducted in populations in which fluoroquinolone-resistant strains had not been reported. It is safe, relatively inexpensive, and can be administered orally. Numerous studies have shown that a 250-mg dose is also highly effective (curing 98.7% of uncomplicated urogenital and anorectal infections in published trials) and 250 mg is the dose approved by the Food and Drug Administration for the treatment of uncomplicated urethral and cervical gonorrhea. However, in view of the increasing spread of quinolone-resistant Neisseria gonorrhoeae (QRNG) and the fact that the 250-mg dose is not significantly safer, cheaper, or better tolerated than the 500-mg dose, the 500-mg dose is recommended (22). Because QRNG strains have become common in much of the world, quinolones should not be used to treat infections acquired from someone who may have been infected outside the United States. Quinolones should also not be used to treat infections in MSM.

Ofloxacin is also very active against most strains of N. gonorrhoeae and has favorable pharmacokinetics. The 400 mg oral dose has been very effective for the treatment of uncomplicated urogenital and anorectal infections, curing 98.6% in published clinical trials. Levofloxacin, the active l-isomer of ofloxacin, is twice as active as ofloxacin against N. gonorrhoeae in vitro. In vivo, a single 250-mg oral dose produces about the same peak serum concentration as does a 400-mg oral dose of ofloxacin (2.8 mg/mL compared with 2.9 mg/mL) and has a longer elimination half-life (7.3 hours compared with 4 to 5 hours). Levofloxacin can be used in place of ofloxacin (400 mg) in a single dose of 250 mg.

Patients who can tolerate neither cephalosporins nor fluoroquinolones, spectinomycin in a single 2-g i.m. dose is an acceptable alternative. Spectinomycin is expensive in the United States and must be given by intramuscular injection through a large bore (18 gauge) needle, but it has been effective in published clinical trials, curing 98.2% of uncomplicated urogenital and anorectal infections and resistance remains very rare in the United States (8) and uncommon elsewhere.

Pediatric Infection

Children have not been the subjects of recent clinical trials of gonorrhea therapy so the following recommendations from the CDC are based on clinical experience and expert opinion. Children who weigh 45 kg or more and have uncomplicated gonorrhea should be treated with one of the regimens recommended for adults. (Fluoroquinolones have not been recommended for person less than 18 years of age because they damage articular cartilage in young animals. However, in children treated with ciprofloxacin, no joint damage clearly attributable to quinolone therapy has been observed, even with multiple dose regimens (5). Children who weigh less than 45 kg who have uncomplicated vulvovaginitis, cervicitis, urethritis, pharyngitis, or proctitis should be treated with a single dose of ceftriaxone (125 mg i.m.). If ceftriaxone cannot be given, an acceptable alternative is spectinomycin (40 mg/kg [maximum 2 g] i.m.) in a single dose but this treatment is unreliable for pharyngeal infections. Some experts use cefixime to treat gonococcal infections in children because it can be administered orally; however, there are no published reports of its safety or effectiveness for this purpose.

Pharyngeal Infections

Gonococcal infections of the pharynx are more difficult to eradicate than are infections at urogenital and anorectal sites (41). Few antigonococcal regimens can be relied upon to cure them more than 90% of the time. The most effective are single doses ofceftriaxone (125 [or 250] mg i.m.) and, for infections not acquired in Asia, the Pacific, Hawaii, or California, ciprofloxacin (500 mg p.o.).

Children weighing ≥ 45 kg, may be treated with one of the regimens recommended for adults. For children weighing <45 kg., the CDC recommends ceftriaxone (125 mg i.m.) or, if ceftriaxone cannot be used, spectinomycin (40mg/kg [maximum 2 g] i.m.). Spectinomycin is unreliable against pharyngeal infections; a culture should be performed 3-5 days after treatment to ensure that the infection has been eradicated.

Eye Infections

Conjunctivitis in Adults and Adolescents

Only one study of the treatment of gonococcal conjunctivitis among adults has been published in recent years (26). In that study, all 12 patients responded well to a single 1-g injection of ceftriaxone. The CDC recommends that a single, 1-g dose of ceftriaxone be administered intramuscularly and suggests that lavaging the eye once with saline be considered (9).

Ophthalmia Neonatorum

CDC recommends that gonococcal neonatal ophthalmia be treated with ceftriaxone (25 50 mg/kg i.v. or i.m.) in a single dose, not to exceed 125 mg. Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely. Topical antibiotic therapy alone is inadequate and is unnecessary if systemic treatment is administered. Simultaneous infection with C. trachomatis should be considered when a patient does not respond satisfactorily (9).

Pelvic Inflammatory Disease

The syndrome of pelvic inflammatory disease (PID) results when infection ascends the reproductive tract from the cervix to the fallopian tubes and ovaries. Although PID is the most common complication of genital gonococcal infection, it can be caused by other microbes as well; therapy of PID should cover not only N. gonorrhoeae, but also C. trachomatis, anaerobes, Gram-negative facultative bacteria, and streptococci.

Pointing out the limited data comparing the efficacy of inpatient with outpatient treatment settings, the CDC proposes the following criteria for hospitalization based on observational data and theoretical concerns: surgical emergencies (e.g. appendicitis) cannot be excluded; the patient is pregnant; the patient does not respond clinically to oral antimicrobial therapy; the patient is unable to follow or tolerate an outpatient oral regimen; the patient has severe illness, nausea and vomiting, or high fever; or the patient has a tubo-ovarian abscess (9).

The CDC recommends the following parenteral regimens for the treatment of PID: (a) cefotetan 2 g i.v. every 12 h) orcefoxitin (2 g i.v. every 6 h), either accompanied by doxycycline (100 mg p.o. or i.v. every 12 h) Parenteral therapy can be discontinued 24 hours after a patient improves clinically; continuing oral therapy should consist of doxycycline (100 mg p.o. twice a day) to complete a total of 14 days of therapy. When tubo-ovarian abscess is present, many health-care providers use clindamycin ormetronidazole with doxycycline for continued therapy rather than doxycycline alone, because it provides more effective anaerobic coverage. (b) clindamycin (900 mg i.v. every 8 h) plus gentamicin (2 mg/kg i.v. or i.m. as a loading dose, followed by 1.5 mg/kg every 8 h) Parenteral therapy can be discontinued 24 hours after a patient improves clinically; continuing oral therapy should consist of doxycycline (100 mg p.o. twice a day) or clindamycin (450 mg p.o. four times a day) to complete a total of 14 days of therapy. When tubo-ovarian abscess is present, many health-care providers use clindamycin or metronidazole with doxycycline for continued therapy (9).

Alternative parenteral regimens are levofloxacin (500 mg i.v. once daily) or ofloxacin (400 mg i.v. every 12 h), plus doxycycline (100 mg p.o. or i.v. every 12 h). Either may be given with or without metronidazole (500 mg i.v. every 8 h) orampicillin/sulbactam (3 g i.v. every 6 h).

The CDC also recommends the following mainly oral regimens: (a) levofloxacin (500 mg p.o. once daily) or ofloxacin (400 mg p.o. twice a day for 14 days); either may be given with or without metronidazole (500 mg p.o. twice a day for 14 days), (b)ceftriaxone 250 mg i.m. once or cefoxitin 2 g i.m. once in combination with probenecid 1 g p.o. in a single concurrent dose) or a single dose of another parenteral, third-generation cephalosporin (e.g., ceftizoxime or cefotaxime); to any of these regimens should be added doxycycline 100 mg orally twice a day for 14 days. The doxycycline may be given with metronidazole (500 mg p.o. twice a day for 14 days).

Of the antimicrobials recommended for the treatment of PID, the third-generation cephalosporins (especially ceftriaxone) and the fluoroquinolones are the most active against N. gonorrhoeae (except where fluoroquinolone-resistant N. gonorrhoeae are common). However, all regimens are likely to eradicate N. gonorrhoeae, since they include multiple doses and combinations of antimicrobials with activity against gonococci.

Disseminated Gonococcal Infection (DGI)

Disseminated gonococcal infection (DGI) results from gonococcal bacteremia, often resulting in petechial or pustular, acral skin lesions, asymmetrical arthralgias, tenosynovitis or septic arthritis, and is rarely complicated by perihepatitis and, very rarely, by endocarditis or meningitis. No studies of the treatment of DGI have been published in the past 24 years. The CDC recommendations for the treatment of DGI are based on the opinions of experts. Despite the lack of experimental or even observational studies of the efficacy of the recommended regimens, it is reassuring to note that no reports of treatment failures have been published since these recommendations were first made by the CDC in 1989.

Adults

The CDC recommends hospitalization for initial therapy, especially for patients who cannot be relied on to comply with treatment, for those for whom the diagnosis is uncertain, and for those who have purulent synovial effusions or other complications. Patients should be examined for clinical evidence of endocarditis and meningitis. If endocarditis and meningitis are ruled out, patients should initially be treated with ceftriaxone 1 g i.m. or i.v. every 24 hours. Acceptable alternatives are cefotaxime (1 g i.v. every 8 hours),ceftizoxime (1 g i.v. every 8 hours), or spectinomycin (2 g i.m. every 12 hours). If the infecting organism is known to be susceptible to fluoroquinolones, ciprofloxacin (500 mg i.v. every 12 hours), ofloxacin (400 mg i.v. every 12 hours), or levofloxacin (250 mg i.v. daily), Parenteral treatment should be continued for 24 48 hours after improvement begins; then therapy may be switched to cefixime(400 mg p.o. 2 times a day) or ciprofloxacin (500 mg p.o. 2 times a day), ofloxacin (400 mg p.o. 2 times a day), or levofloxacin (500 mg p.o. once a day) to complete a full week of antimicrobial therapy. For gonococcal endocarditis or meningitis, initial therapy should be with 1 2 g of ceftriaxone (i.v. every 12 hours) and therapy should be continued for 10 14 days for meningitis and for at least 4 weeks for endocarditis.

Children

Children who have bacteremia or arthritis should be treated with ceftriaxone (50 mg/kg i.m. or i.v.) in a single dose daily for 7 days if they weigh >45 kg. If they weigh less, they should receive the same treatment except that the maximum daily dose should be no more than 1 g.

Underlying Diseases

HIV

Persons with HIV infection and gonococcal infection should receive the same treatment as persons not infected with HIV.

Pregnancy

There is no evidence that women respond less well to antigonococcal therapy during pregnancy. Two recent, randomized, controlled trials have addressed the treatment of gonococcal infection during pregnancy. In one trial, ceftriaxone (250 mg) cured 95.2% (95% CI 89.2% to 98.5%) of rectal and cervical infections and 100% (95% CI 54.1% to 100%) of pharyngeal infections while spectinomycin (2 g) cured 97.0% (95% CI 91.5% to 99.4%) of rectal and cervical infections and 83.3% (95% CI 35.9% to 99.6%) of pharyngeal infections (6). In the second trial, ceftriaxone (125 mg) cured 96.8% (95% CI 89.0% to 99.6%) of cervical and rectal infections and 100% (95% CI 47.8% to 100%) of pharyngeal infections; cefixime 400 mg cured 96.8% (95%CI 88.8% to 99.6%) of cervical and rectal infections and 100% (95% CI 54.1% to 100%) of pharyngeal infections (50). Because fluoroquinolones cause arthropathy in young animals their use is not recommended in pregnancy, although we found no reports of adverse effects of quinolones on pregnancy outcome in humans and a single, multicenter, prospective, controlled study of 200 exposed women found no evidence of adverse effects (34). Pregnant women infected with N. gonorrhoeae should be treated with a cephalosporin or, if they cannot tolerate a cephalosporin, with spectinomycin.

Allergy, Intolerance, or Adverse Reactions

Persons who cannot tolerate cephalosporins or quinolones should, in general, be treated with spectinomycin. Because spectinomycin is unreliable against pharyngeal infections (curing only 52% of infections in published studies), patients treated with spectinomycin and suspected or known to have pharyngeal infection should have a pharyngeal culture 3-5 days after treatment to verify eradication of infection.

Alternative Therapy

Alternative Cephalosporins

Single-dose alternatives to ceftriaxone and cefixime listed by the CDC are: ceftizoxime (500 mg i.m.), cefotaxime (500 mg i.m.), and cefoxitin (2 g i.m.) with probenecid (1 g p.o.). None of these regimens offers any advantage over ceftriaxone and there is less clinical experience with them for the treatment of uncomplicated gonorrhea. There are no acceptable oral cephalosporin alternatives to the 400-mg cefixime regimen. Neither cefuroxime axetil (1 g) nor cefpodoxime proxetil (200 mg) have been shown to cure more than 95% of uncomplicated urogenital and anorectal infections with a 95% confidence interval that excludes 95%.

Fluoroquinolones

Single-dose quinolone alternatives to ciprofloxacin, ofloxacin, and levofloxacin are gatifloxacin (400 mg p.o.), lomefloxacin (400 mg p.o.), and norfloxacin (800 mg p.o.). They are safe and effective for the treatment of uncomplicated gonorrhea but they are less well studied and none offers any advantage over the recommended fluoroquinolone regimens.

Macrolides

Azithromycin (2 gm p.o.) is highly effective against uncomplicated gonococcal infection but is expensive and too often causes gastrointestinal distress to be recommended for the treatment of gonorrhea. At an oral dose of one gram, azithromycin has cured 97.1% of subjects in published studies but is not recommended by the CDC because of concerns about the development of resistance.

Many other antimicrobials are also active against N. gonorrhoeae, but have no demonstrated advantage over those listed here.

Quinolone-Resistant N. gonorrhoeae (QRNG)

In the 17 years since strains of N. gonorrhoeae with decreased susceptibility to quinolones were first detected (29), strains with decreased susceptibility and strains resistant to quinolones (QRNG) have become common in parts of Asia and the Pacific, North America, and Europe. They appear to remain relatively rare in South America and Africa but surveillance is incomplete. In Asia, where strains with decreased susceptibility to the quinolones were first reported from the Philippines in 1988, QRNG made up 61% of 313 isolates tested in 1999, 54% of 399 tested in 2001 and 56% of 111 tested in 2003 (Table 3). Very high and increasing rates of QRNG are also reported in China, Vietnam, Japan, and Singapore (Table 3). In the nations of Oceania, the few surveillance data available indicate that 0 to 12% of isolates are resistant (Table 3). In most of Europe, surveillance for resistance has been less systematic than in Asia but a recent study found that of 1975 N. gonorrhoeae isolates collected in the United Kingdom 14.1% were fluoroquinolone-resistant and a further 1.6% showed decreased susceptibility (48). In the United States, QRNG remain relatively rare outside of California and Hawaii. Of the isolates collected by CDC's Gonococcal Isolate Surveillance Project (GISP) during 2003, 4.1% wereciprofloxacin resistant (minimum inhibitory concentrations (MICs) > 1.0 μg/mL to ciprofloxacin) but they were heavily concentrated in MSM (among whom 15% of isolates were resistant) and the states of California and Hawaii. Among isolates from heterosexuals outside of California and Hawaii, resistant isolates made up just 0.4% of the GISP sample (8). Elsewhere in the Western Hemisphere, QRNG is rarely reported. One fluoroquinolone-resistant isolate has been reported from South America (20).

Patients infected with QRNG will not necessarily fail to respond to a standard dose of a recommended fluoroquinolone. Resistance to ciprofloxacin, for example, is defined as exhibiting an MIC >1µg/mL but such patients are often cured by a single oral dose of 500 mg. The best data relating in vitro and in vivo susceptibility are from a population of female sex workers in the Philippines with a prevalence of ciprofloxacin resistance of 63%. Among 72 evaluable patients treated with 500 mg of ciprofloxacin, 24 (32%) failed therapy. Failure was related to pretreatment MICs: 2/18 (11%) for MICs <0.06 µg/mL, 0/4 for MICs of 0.125-0.5, 0/6 for MICs of 1-2, and 15/30 (50%) for MICs ≥4 (1).

Because of these and other data, quinolones are no longer recommended for the treatment of gonococcal infections in MSM, infections that may have been acquired in California, Hawaii, or outside the United States, or in sex partners of persons who may have acquired their infection from an MSM or in California, Hawaii, or outside the United States.

Combination Therapy

There are so many safe and effective single agent regimens that combination regimens, with their increased risk of adverse drug reactions, are unnecessary. For complicated infections, treatment with a higher dose of a single agent (e.g., 1 g instead of 125 mg of ceftriaxone for ophthalmia) or with multiple doses of a single agent (e.g., 4 weeks of therapy with ceftriaxone for endocarditis) is recommended, rather than adding a second antigonococcal agent.

Outcome

The anatomic site of infection is related to clinical outcome. A systematic review of published trials of various antimicrobial regimens for the biological cure of uncomplicated N. gonorrhoeae infection found that modern antigonococcal agents eradicate infections of the urethra, cervix and rectum more reliably than infection of the pharynx (41). Cure rates were 96.4% for the male urethra, 98.4% for the female urethra, 98.0% for the cervix, 97.9% for the female rectum, and 95.3% for the male rectum. Cure rates were significantly lower for infections of the pharynx: 83.7% in females and 79.2% in males. Nevertheless, there is a close relationship between efficacy at the pharynx and efficacy at other sites, so that the regimens most effective against urogenital and rectal infections generally are effective against pharyngeal infections as well. An exception to this relationship is spectinomycin (2 g i.m.) which is highly effective against urogenital and rectal infections but has poor efficacy against pharyngeal infection.

ADJUNCTIVE THERAPy

In the treatment of gonococcal ophthalmia, saline lavage of the affected eye may be considered in addition to definitive treatment with a parenteral antimicrobial.

For all gonococcal infections, the CDC recommends adding presumptive treatment for coexistent chlamydial infection to the antigonococcal regimen (see below).

ENDPOINTS FOR MONITORING THERAPY

The goals of therapy are to prevent complications and to render the individual non-infectious. For uncomplicated urogenital or rectal infections, the recommended regimens are so close to 100% effective that no follow up is needed if compliance is assured (i.e., treatment is directly observed) and symptoms resolve. For pharyngeal infections, only ciprofloxacin (500 mg) and (ceftriaxone 125 mg) are more than 90% effective (Table 2). However, most experts believe that pharyngeal infections are self-limited and not highly contagious so follow up cultures are not routinely recommended. For infections at other sites (e.g., the eye) and for disseminated infection, clinical resolution of signs and symptoms are used as endpoints since there is little concern about persistent, asymptomatic infection which would, in any case, not be readily transmissible.

Those persons with symptoms persisting after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility. Infections detected after treatment with one of the recommended regimens are more likely to be reinfections than treatment failures.

VACCINES

No antigonococcal vaccine is commercially available or in phase III clinical trials. Study of the immune response to the gonococcus continues to be an area of active research (51, 45).

PREVENTION OR INFECTION CONTROL MEASURES

The acquisition of gonococcal infection is prevented by avoiding unprotected sexual contact with an infected person. Because many infected persons have no signs or symptoms, it is prudent for persons having sex outside of mutually monogamous relationships to use condoms in order to protect themselves and their partners. 

CO-EXISTING STDS

Dual Therapy for Gonorrhea and Chlamydial Infection

Persons with gonorrhea are generally at high risk of being infected with Chlamydia trachomatis as well. Recent studies in the United States and United Kingdom found concurrent C. trachomatis in 7–14% of homosexual men with gonorrhea, in 20–30% of heterosexual men, and in 40-50% of women (14,25,30,36,38). The CDC recommends that persons being treated for N. gonorrhoeaeinfection be routinely treated with a regimen effective against genital C. trachomatis infection as well. Recommended antichlamydial regimens include doxycycline (100 mg p.o. 2 times a day for 7 days and azithromycin (1 gram p.o. once). Routine dual therapy without testing can clearly be cost-effective because chlamydia therapy is safe and costs so little (e.g., ≥$0.50 to 1.50 for doxycycline) compared with the cost of testing. Some experts believe that the routine use of dual therapy has contributed to significant decreases in the prevalence of chlamydial infection. In addition to its value as a strategy for the control of chlamydial infection, dual therapy may have a secondary benefit. Because most gonococci in the United States are susceptible to the antimicrobial regimens recommended for the treatment of uncomplicated C. trachomatis infection, routine co-treatment may hinder the evolution and spread of antimicrobial resistant N. gonorrhoeae.

Since the introduction of dual therapy, chlamydial infection prevalence has dropped in some populations and testing for chlamydial infection has become quicker, more sensitive, and more widely available. Where rates of co-infection are low, some clinicians may prefer to use a highly sensitive test for chlamydia rather than treat presumptively. However, presumptive treatment is indicated for patients who may not return for test results.

Screening for Other Sexually Transmitted Diseases

 Persons treated for gonorrhea are generally at increased risk for other STDs including HIV infection and should be counseled and screened as appropriate.

Disease Reporting

Gonorrhea is a reportable disease in all 50 states and the District of Columbia.

Management of Sex Partners

Recent sexual contacts of persons treated for gonorrhea and mothers of infected newborns should generally be tested for gonorrhea and treated presumptively. If found to be infected, they should be advised to refer their recent sex partners.

Resistance of N. gonorrhoeae to fluoroquinolones and other antimicrobials is expected to continue to spread which means that surveillance for antimicrobial resistance will continue to be important to guide therapy recommendations. The GISP, which samples approximately 3% of all gonococcal infections reported in men in the U.S. is a mainstay of surveillance. However, surveillance by clinicians is also important. Clinicians who diagnose N. gonorrhoeae infection in a person who was treated with a recommended regimen and who denies re-exposure should perform culture and susceptibility testing of relevant clinical specimens and should report the case to the local health department.

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Table 1 - In Vitro Activities of Selected Antimicrobials against Neisseria gonorrhoeae

Antimicrobial	MIC50(mg/L)	MIC90(mg/L)	MIC range (mg/L)	Number of strains	Source of isolates (country and year)*	Reference
Cephalosporins
Cefixime	0.008	0.030		6552	USA 2003	CDC 2003 (7)
	<0.002	0.008	<0.002-0.06	150	Germany 1988-92	Schäffer 1995
	<0.015	<0.015	<0.0015-0.12	104	London, United Kingdom n.r. >95	Lewis 1995
	<0.001	0.03	<0.001-8.0	328	Thailand 1990	Clendennen 1992a
	0.015	0.06	0.008-0.12	164	Nairobi, Kenya 1989-90	Plourde 1992
	0.03	0.25	0.002-0.5	211	Fukuoka City, Japan 2002	Tanaka 2004
Cefotaxime	<0.015	0.03	<0.0015-0.12	104	London, United Kingdom n.r. >95	Lewis 1995
	0.001	0.004	0.001-0.016	122	Indonesia 1996	Lesmana 2001
	0.031	0.125	0.004-0.25	79	Japan 1992-93	Tanaka 1995
	0.03	0.06	<0.001-8.0	333	Thailand 1990	Clendennen 1992a
	0.03	1	0.002->8	134	Philippines 1989	Clendennen 1992b
	0.008	0.015	0.004-0.06	130	Mwanza, Tanzania 1992	West 1995
Cefotetan	-	0.5	0.03-8	150	New Orleans, Louisiana, USA 1989	Youssef 1990
Cefoxitin	0.5	1	0.5-1.0	129	Philadelphia, USA 1987	Fekete 1989
	1.0	2	0.03-4	400	Spain 1992-99	Berron 2000
	0.250	1	0.016-2.0	122	Indonesia 1996	Lesmana 2001
	1	2	0.060-8.0	332	Thailand 1990	Clendennen 1992a
	1	4	0.06->8	134	Philippines 1989	Clendennen 1992b
Cefpodoxime	0.008	0.03	0.001-0.125	77	USA (n.r.) >91	Fekete 1991
	0.03	0.125	<0.004->4.0	331	Thailand 1990	Clendennen 1992a
	0.03	2	0.002->4	134	Philippines 1989	Clendennen 1992b
Ceftizoxime	0.004	0.016	0.001-0.016	89	Germany (n.r.) >89	Korting 1989
	0.015	0.03	<0.001->4.0	333	Thailand 1990	Clendennen 1992a
	0.008	0.25	<0.001->4	137	Philippines 1989	Clendennen 1992b
Ceftriaxone	0.004	0.015		6552	USA 2003	CDC 2003 (7)
	0.004	0.008	0.00025-0.016	81	Manaus, Brazil 1998	Dillon 2001a
	0.001	0.001	0.001 - 0.008	81	Buenos Aires, Argentina 1995-96	Famiglietti 2001
	0.004	0.016	0.002-0.064	507	Trinidad, Trinidad and Tobago1992	Swanston 1997
	0.003	0.01	0.0005-0.12	400	Spain 1992-99	Berron 2000
	<0.007	<0.007	<0.007-0.030	85	Berlin, Germany 1995-97	Wagner 2000
	0.03	2	0.016-2.048	91	Zhanjiang, China 1998-99	Guoming 2000
	0.0312	0.125	0.25-0.002	203	Guangzhoou, China 1997-98	Wenling 2000
	0.015	0.06	0.004-0.5	94	Dhaka, Bangledesh 1997	Bhuiyan 1999
	0.001	0.002	0.001-0.008	122	Jakarta, Indonesia 1996	Lesmana 2001
	0.008	0.03	<0.001-1.0	333	Thailand 1990	Clendennen 1992a
	0.008	0.06	<0.001->1.0	134	Philippines 1989	Clendennen 1992b
	0.004	0.008	0.002-0.060	139	Kigali, Rwanda 1999-2000	Van Dyck 2001
	<0.007	0.015	<0.007 - 0.06	354	Durban, South Africa 1997-2000	Moodley 2001a
	<0.002	0.004	<0.002-0.032	177	Nairobi, Kenya 1995-96	Claeys 1998
	0.015	0.06	0.002-0.25	110	Guanzhou, China 2001	Zheng 2005
	0.004	0.032	<0.001-0.063	91	Cuba 1995-98	Sosa 2003
	0.015	0.06	0.002-0.12	211	Fukuoka City, Japan 2002	Tanaka 2004
	0.004	0.016	0.004-0.03	413	New Zealand 2002	Heffernan 2004
	<0.001	0.008	<0.001-0.032	936	London, U.K. 2003	GRASP 2004
	0.02	0.004	<0.001-0.032	1039	England and Wales excluding London, U.K. 2003	GRASP 2004
cefuroxime	0.032	0.125	0.001 - 0.5	81	Buenos Aires, Argentina 1995-96	Famiglietti 2001
	0.064	0.128	0.008-1	506	Trinidad, Trinidad and Tobago1992	Swanston 1997
	0.03	0.125	<0.002-0.5	150	Germany 1988-92	Schäffer 1995
	0.5	1	0.06-4.0	94	Dhaka, Bangladesh 1977	Bhuiyan 1999
	0.5	1	<0.030->4.0	333	Thailand 1990	Clendennen 1992a
	0.125	2	0.015->8.0	135	Philippines 1989	Clendennen 1992b
	0.03	0.5	0.016-256	199	Dar es salaam, Tanzania 1993-95	Mbwana 1999
	0.06	0.25	0.008-1	130	Mwanza, Tanzania 1992	West 1995
quinolones
ciprofloxacin	0.004	0.008		6552	USA 2003	CDC 2003 (7)
	0.004	0.008	0.004-0.25	81	Manaus, Brazil 1998	Dillon 2001a
	0.008	0.032	0.001 - 0.5	81	Buenos Aires, Argentina 1995-1996	Famiglietti 2001.
	0.003	0.01	0.001-0.25	400	Spain 1992-99	Berron 2000
	0.007	4	<0.0015-64	81	Spain, 2001	New reference ARREAZA 2005
	<0.007	<0.007	<0.007-8.0	84	Berlin, Germany 1995-97	Wagner 2000
	<0.004	0.008	<0.004-0.06	104	London, United Kingdom n.r. >95	Lewis 1995
	<0.03	1.0	<0.03-4.0	56	Ulaanbaatar, Mongolia n.r. (2001)	Lkhamsuren 2001
	2	2	0.032-2.048	91	Zhanjiang, China 1998-99	Guoming 2000
	0.015	1.0	0.004-4.0	94	Dhaka, Bangladesh 1997	Bhuiyan 1999
	2	8	0.008-64	115	Philippines 1996-97	Aplaxca 2001
	0.004	0.016	0.001-0.016	122	Jakarta, Indonesia 1996	Lesmana 2001
	0.004	0.008	<0.001-2.0	329	Thailand 1990	Clendennen 1992a
	0.004	0.25	<0.001->2.0	135	Philippines 1989	Clendennen 1992b
	0.004	0.008	0.002-0.15	139	Kigali, Rwanda 1999-2000	Van Dyck 2001
	<0.007	0.015	<0.007 - 0.06	354	Durban, South Africa 1997-2000	Moodley 2001a
	<0.007	0.03	<0.007-0.06	204	Durban (urban), South Africa 1999	Moodley 2001b
	<0.007	0.015	<0.007-1.0	156	KwaZulu/Natal (rural), South Africa 1999	Moodley 2001b
	0.002	0.012	0.002-32	199	Dar es salaam, Tanzania 1993-95	Mbwana 1999
	0.004	0.008	0.002-0.015	251	Abidjan, Côte d=Ivoire 1992-93	Van Dyck 1997
	0.004	0.015	0.002-0.06	952	Kinshasa, Congo 1988-1993	Van Dyck 1997
	0.015	0.015	0.001-0.03	40	Nairobi, Kenya 1989-90	Plourde 1992
	0.004	0.015	0.001-0.06	1085	Kigali, Rwanda 1989-90	Van Dyck 1997
	2	8	0.03-32	110	Guangzhou, China 2001	Zheng 2005
	0.008	0.016	0.004-0.063	91	Cuba 1995-98	Sosa 2003
	4	32	0.002-64	211	Fukuoka City, Japan 2002	Tanaka 2004
	0.004	0.06	0.004-4	413	New Zealand 2002	Heffernan 2004
enoxacin	0.25	2	0.008-8.0	79	Japan 1992-93	Tanaka 1995
lomefloxacin	0.016	0.032	<0.008-0.063	196	Canada PCN-sensitive 1988	Talbot 1989
	0.125	1.0	0.004-2.0	79	Japan 1992-93	Tanaka 1995
norfloxacin	0.016	0.032	0.008-0.128	507	Trinidad, Trinidad and Tobago1992	Swanston 1997
	0.003	0.006	0.001-4	400	Spain 1992-99	Berron 2000
	0.25	16	0.016-32	157	Fukuoka City, Japan 1997-98	Tanaka 2000
	0.03	0.06	0.016-0.5	122	Jakarta, Indonesia 1996	Lesmana 2001
	0.06	0.125	<0.015->4.0	332	Thailand 1990	Clendennen 1992a
	<0.016	0.016	0.016-0.125	177	Nairobi, Kenya 1995-96	Claeys
	0.06	0.125	0.008-0.25	130	Mwanza, Tanzania 1992	West 1995
ofloxacin	0.0039	0.0078	0.002-0.015	100	Brooklyn, New York, USA (n.r.) >92	Glatt 1992
	0.016	0.032	0.002 - 0.5	81	Buenos Aires, Argentina 1995-1996	Famiglietti 2001
	0.03	0.03	0.002-1	400	Spain 1992-99	Berron 2000
	0.008	0.03	<0.002-0.25	150	Germany 1988-92	Schäffer 1995
	0.125	1	0.002-2.0	79	Japan 1992-93	Tanaka 1995
	0.038	0.075	<0.005-2.5	333	Thailand 1990	Clendennen 1992a
	0.038	0.625	0.005->5.0	139	Philippines 1989	Clendennen 1992b
	0.015	0.03	<0.007 - 4	354	Durban, South Africa 1997-2000	Moodley 2001a
	0.008	0.012	0.004-0.032	177	Nairobi, Kenya 1995-96	Claeys 1998
levofloxacin	0.007	0.003	0.002-0.5	400	Spain 1992-99	Berron 2000
	4	8	0.004-32	211	Fukuoka City, Japan 2002	Tanaka 2004
gatifloxacin	1	2	<0.001-8	211	Fukuoka City, Japan 2002	Tanaka 2004
miscellaneous
azithromycin	0.125	0.25		6552	USA 2003	CDC 2003 (7)
	0.125	0.25	0.032-0.5	81	Manaus, Brazil 1998	Dillon 2001a
	0.125	0.5	0.063-8.0	67	St. Vincent 1996	Dillon 2001b
	0.032	0.125	0.016 - 2	81	Buenos Aires, Argentina 1995-1996	Famiglietti 2001
	0.25	2.0	0.063-8.0	69	Georgetown, Guyana 1994-1995	Dillon 2001b
	0.25	0.5	<0.007-1.0	85	Berlin, Germany 1995-97	Wagner 2000
	0.023	0.047	<0.016-0.19	177	Nairobi, Kenya 1995-96	Claeys 1998
	0.25	0.5	0.063-4.0	91	Cuba 1995-98	Sosa 2003
	0.5	1	0.06-2	130	Mwanza, Tanzania 1992	West 1995
	0.12	0.25	0.008-2	211	Fukuoka City, Japan 2002	Tanaka 2004
	0.125	0.25	0.03-4	936	London, U.K. 2003	GRASP 2004
	0.125	0.5	0.03-2	1039	England and Wales excluding London, U.K. 2003	GRASP 2004
spectinomycin	16	16		187	USA 1989-90	Portilla 1992
	8	16	16-16	81	Manaus, Brazil 1998	Dillon 2001a
	8	16	2 - 16	81	Buenos Aires, Argentina 1995-1996	Famiglietti 2001
	32	32	0.5-32	507	Trinidad, Trinidad and Tobago1992	Swanston 1997
	16	16	4-32	400	Spain 1992-99	Berron 2000
	8	16	0.06-32	85	Berlin, Germany 1995-97	Wagner 2000
	16	128	8-128	90	Zhanjiang, China 1998-99	Guoming 2000
	8	16	4-16	197	Fukuoka City, Japan, 1997-98	Tanaka 2000
	8.0	16.0	4.0-32.0	94	Dhaka, Bangladesh 1977	Bhuiyan 1999
	64	64	8-128	305	Thailand 1990	Clendennen 1992a
	32	32	16->128	117	Philippines 1989	Clendennen 1992b
	32	32	16-32	139	Kigali, Rwanda 1999-2000	Van Dyck 2001
	8	32	<0.007 - >64	354	Durban, South Africa 1997-2000	Moodley 2001a
	4	8	3-12	177	Nairobi, Kenya 1995-96	Claeys
	8	32	8-32	199	Dar es salaam, Tanzania 1993-95	Mbwana 1999
	8	16	4-16	110	Guangzhou, China 2001	Zheng 2005
	16	16	8-16	91	Cuba 1995-98	Sosa 2003
	8	16	4-16	211	Fukuoka City, Japan 2002	Tanaka 2004
	16	32	2-64	936	London, U.K. 2003	GRASP 2004
	16	32	2-64	1039	England and Wales excluding London, U.K. 2003	GRASP 2004
	8	16	2-16	413	New Zealand 2002	Heffernan 2004

* n.r. indicates that dates of specimen isolations were not reported.  Number in parentheses is date of publication.

** indicates that lower limit of MIC range was not reported.

Table 2 -  Aggregated Results of Clinical Trials

	Pharyngeal infections			Urogenital & rectal infections
Drug regimen	% cured	95% C I		% cured	95% C I
Ceftriaxone 250 mg	99.0	94.4	100	99.2	98.8	99.5
Ciprofloxacin 500 mg*	97.2	85.5	99.9	99.8	98.7	100
Ciprofloxacin 250 mg	88.5	81.8	95.2	98.7	98.0	99.4
Ceftriaxone 125 mg	94.1	85.6	98.4	98.9	97.9	99.8
Ceftizoxime 500 mg	100	15.8	100	99.2	97.8	99.8
Ofloxacin 400 mg	88.7	68.8	97.8	98.6	97.8	99.4
Gatifloxacin 600 mg	100	82.3	100	99.6	97.7	100
Spectinomycin 2 g	51.8	38.7	64.9	98.2	97.6	99.9
Azithromycin 2 g	100	82.3	100	99.2	97.2	99.9
Gatifloxacin 400 mg	100	63.1	100	99.2	97.1	99.9
Cefoxitin 2g + probenecid 1 g				99.2	97.1	99.9
Cefotaxime 500 mg	45.4	16.7	76.2	97.9	96.7	99.1
Norfloxacin 800 mg	80.0	28.4	99.5	98.0	96.7	99.2
Azithromycin 1 g	100	39.8	100	97.1	95.2	99.0
Cefixime 800 mg	80.0	51.9	95.7	98.4	95.9	99.6
Cefixime 400 mg	92.3	74.9	99.1	97.4	95.9	98.6
Cefuroxime axetil 1 g	56.9	43.3	70.5	96.2	94.8	97.5
Cexpodoxime proxetil 200 mg	78.9	54.5	94.0	96.5	94.3	98.5

*Excludes two published clinical trials among subjects known to be at high risk of harboring fluoroquinolone-resistant strains; ciprofloxacin 500 mg cured only 48 of 72 cervical infections (67%) in one trial (1) and 41 of 66 (62%) in the other (47).

Table 3  -  Quinolone Resistance in Strains of Neisseria gonorrhoeae Isolated in Asia and Oceania in 1999, 2001, and 2003

	Number tested			Number less susceptible (%)			Number resistant (%)
Country	1999	2001	2003	1999	2001	2003	1999	2001	2003
ASIA
Brunei	53	52	50	4 (7.5)	1 (2.0)	5 (10.0)	5 (9.4)	10 (19.0)	31 (62.0)
China	591	748	1254	131 (22.1)	83 (11.1)		332 (52.8)	650 (86.9)	1171 (93.4)
Hong Kong SAR	2482	2575	3378	697 (28.1)	235 (9.1)	165 (4.9)	1653 (66.6)	2270 (88.2)	3167 (93.7)
Japan	246	300	200	80 (32.5)	42 (14.0)	17 (12.8)	56 (22.8)	192 (64.0)	154 (77.0)
Korea	86	177	212	61 (71.0)	94 (53.1)	39 (18.4)	14 (16.0)	70 (39.5)	166 (78.3)
Laos		187			11 (5.9)			42 (22.5)
Malaysia	54	30		0 (0)	2 (6.7)		0 (0)	7 (23.3)
Mongolia	56			5 (8.9)			14 (25.0)
Philippines	313	399	111	8 (2.5)	1 (0.2)	11 (9.9)	191 (61.0)	217 (54.3)	62 (55.9)
Singapore	768	741	200	37 (4.8)	35 (4.7)	9 (4.5)	131 (17.0)	207 (27.9)	103 (51.5)
Vietnam	194	168		27 (13.9)	33 (19.6)		69 (35.6)	71 (42.3)
OCEANIA
Australia	3658	3641	3772	500 (13.7)	149 (4.1)	77 (2.0)	128 (3.5)	489 (13.4)	452 (12.0)
New Caledonia	53	57	53	0 (0)		0 (0)	0 (0)		3 (5.7)
New Zealand	638	765	1113	8 (1.3)	20 (2.6)	31 (2.8)	14 (2.2)	77 (10.0)	96 (8.6)
Papua New Guinea	343	96	96	1 (0.3)	0 (0)	0 (0)	5 (1.5)	0 (0)	0 (0)

Data for 1999 are from “Quinolone resistance in strains of Neisseria gonorrhoeae isolated in 15 countries in the WHO WPR in 1999" published in Commun Dis Intell 2000;24:268-270; data for 2001 are from “Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the WHO Western Pacific Region, 2001" published in Commun Dis Intell 2002;26:541-545; and data for 2003 are from “Surveillance of antibiotic resistance in Neisseria gonorrhoeae in the World Health Organization Western Pacific Region, 2003" published in Commun Dis Intell 2005;29:62-64.

Table 4 -  Recommended Regimens for the Treatment of Gonococcal Infections in the United States

Diagnosis	Population	Treatment of choice	Alternative Regimen
Uncomplicated urogenital or rectal infection	Heterosexual adults and children >45 kg likely to have acquired infection from a U.S. domestic source outside California or Hawaii	Ceftriaxone 125 mg IM in a single dose OR Cefixime 400 mg orally in a single dose OR Ciprofloxacin 500 mg orally in a single dose OR Ofloxacin 400 mg orally in a single dose OR Levofloxacin 250 mg orally in a single dose   PLUS treatment for Chlamydia if chlamydial infection is not ruled out	Spectinomycin 2 g IM in a single dose   PLUS treatment for Chlamydia if chlamydial infection is not ruled out
	Homosexual adults and children >45 kg or adults and children>45 kg who may have acquired infection from a California, Hawaii, or foreign source	Ceftriaxone 125 mg IM in a single dose OR Cefixime 400 mg orally in a single dose   PLUS treatment for Chlamydia if chlamydial infection is not ruled out	Spectinomycin 2 g IM in a single dose   PLUS treatment for Chlamydia if chlamydial infection is not ruled out
	Children who weigh <45 kg	Ceftriaxone 125 mg IM in a single dose	Spectinomycin 40 mg/kg (maximum dose: 2 g) IM in a single dose
Pharyngeal infection	Heterosexual adults and children >45 kg likely to have acquired infection from a U.S. domestic source outside California or Hawaii	Ceftriaxone 125 mg IM in a single dose OR Ciprofloxacin 500 mg orally in a single dose   PLUS treatment for Chlamydia if chlamydial infection is not ruled out
	Homosexual adults and children >45 kg or adults and children ≥45 kg who may have acquired infection from a California, Hawaii, or foreign source	Ceftriaxone 125 mg IM in a single dose   PLUS treatment for Chlamydia if chlamydial infection is not ruled out
	Children who weigh <45 kg	Ceftriaxone 125 mg IM in a single dose	Spectinomycin 40 mg/kg (maximum dose: 2 g) IM in a single dose may be used, but this therapy is unreliable and should be followed with a test of cure
Eye infection	Adults	Ceftriaxone 1 g IM as a single dose
	Infants	Ceftriaxone 25–50 mg/kg IV or IM in a single dose, not to exceed 125 mg.
Pelvic Inflammatory Disease	Parenteral  therapy	Cefotetan 2 g IV every 12 h OR Cefoxitin 2 g IV every 6 h) PLUS Doxycycline 100 mg orally  or IV every 12 h OR Clindamycin 900 mg IV every 8h PLUS Gentamicin loading dose IV or IM (2 mg/kg of body weight) followed by a maintenance dose (1.5 mg/kg) every 8 h (Single daily dosing may be substituted.)	Ofloxacin 400 mg IV every 12 hours OR Levofloxacin 500 mg IV once daily  WITH OR WITHOUT Metronidazole 500 mg IV every 8 h OR Ampicillin/Sulbactam 3 g IV every 6 h PLUS Docycycline 100 mg orally or IV every 12 h)
	Oral therapy	Levofloxacin 500 mg orally once daily for 14 days or Ofloxacin 400 mg orally twice a day for 14 days WITH OR WITHOUT Metronidazole 500 mg orally twice a day for 14 days OR Ceftriaxone 250 mg IM in a single dose OR Cefoxitin 2 g IM in a single dose and Probenecid 1 g orally administered concurrently as a single dose OR other parenteral third generation cephalosporine PLUS Doxycycline 100 mg orally twice a day for 13 days  WITH OR WITHOUT Metronidazole 500 mg orally twice a day for 14 days
Disseminated infection	Adults and children >45 kg infected with organisms known to be susceptible to fluoroquinolones.	Ceftriaxone 1 g IM or IV every 24 hours Parenteral treatment should be continued for 24‑48 hours after improvement begins; then therapy may be switched to cefixime 400 mg orally twice a day OR ciprofloxacin 500 mg orally twice a day OR ofloxacin 400 mg orally twice a day OR levofloxacin 500 mg orally once a day to complete a full week of antimicrobial therapy.	Cefotaxime 1 g IV every 8 hours OR ceftizoxime 1 g IV every 8 hours OR ciprofloxacin 500 mg IV every 12 hours OR ofloxacin 400 mg IV every 12 hours OR levofloxacin 250 mg IV daily OR spectinomycin 2 g IM every 12 hours. Parenteral treatment should be continued for 24‑48 hours after improvement begins; then therapy may be switched to cefixime 400 mg orally twice a day OR ciprofloxacin 500 mg orally twice a day OR ofloxacin 400 mg orallyl twice a day OR levofloxacin 500 mg orally once a day to complete a full week of antimicrobial therapy.
	Adults and children >45 kg who may be infected with fluoroquinolone-resistant organisms	Ceftriaxone 1 g IM or IV every 24 hours Parenteral treatment should be continued for 24‑48 hours after improvement begins; then therapy may be switched to cefixime 400 mg orally twice a day to complete a full week of antimicrobial therapy.	Cefotaxime 1 g IV every 8 hours OR ceftizoxime 1 g IV every 8 hours OR spectinomycin 2 g IM every 12 hours. Parenteral treatment should be continued for 24‑48 hours after improvement begins; then therapy may be switched to cefixime 400 mg orally twice a day to complete a full week of antimicrobial therapy.
	Newborns	Ceftriaxone 25–50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10–14 days, if meningitis is documented OR Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration of 10–14 days, if meningitis is documented.

What's New

Kirkcaldy RD, et al.  Cephalosporin-Resistant Gonorrhea in North America.   JAMA 2013;309:185-187.

Schumacher CM, Ghanem KG.  Retreatment rates for uncomplicated gonorrhea infection: comparing ceftriaxone and azithromycin versus ceftriaxone and doxycycline.Sex Transm Dis. 2013;40:539-45.

Bolan GA, et al. The emerging threat of untreatable gonococcal infection. NEJM. 2012;366(6):485-7.

Mehta SD, Moses S, et al. Adult Male Circumcision Does Not Reduce the Risk of Incident Neisseria gonorrhoeae, Chlamydia trachomatis, or Trichomonas vaginalis Infection: Results from a Randomized, Controlled Trial in Kenya.J Infect Dis. 2009 Aug 1;200:370-378.

Moncada J, Donegan E, et al.  Evaluation of CDC-Recommended Approaches for Confirmatory Testing of PositiveNeisseria gonorrhoeae Nucleic Acid Amplification Test Results. J Clin Microbiol 2008;46:1614-1619.

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CDC. Quinolones not recommended in the U.S.

Newman LM, Moran JS, Workowski KA.  Update on the Management of Gonorrhea in Adults in the United States.  Clin Infect Dis 2007;44:S84-101.

CDC. Cost minimizing strategies for treatment of gonorrhea. Emerg Infect Dis, Aug 2005. 

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