Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents

INTRODUCTION — Gonorrhea, or infection with the gram-negative coccus Neisseria gonorrhoeae, is a major cause of morbidity among sexually active individuals worldwide. In the United States, it is the second most commonly reported communicable disease, with more than 600,000 cases reported annually [1], with probably an equal number of cases that remain unreported [2]. Gonorrhea is a major cause of urethritis in males and cervicitis in females; the latter can result in pelvic inflammatory disease (PID), infertility, ectopic pregnancy, and chronic pelvic pain. Extragenital infections of the pharynx and rectum are prevalent in certain groups, such as men who have sex with men (MSM). Invasive infections with N. gonorrhoeae, including disseminated gonococcal infection, endocarditis, and meningitis, are uncommon but can result in serious morbidity. Gonococcal resistance to several classes of antimicrobial agents is widespread. The growing threat of antimicrobial resistance in N. gonorrhoeae highlights the importance of ensuring the availability of appropriate diagnostic modalities for surveillance.

This topic discusses the clinical manifestations and diagnosis of gonorrhea in adults and adolescents. The epidemiology, pathogenesis, and treatment of gonorrhea are discussed in detail elsewhere. (See "Epidemiology and pathogenesis of Neisseria gonorrhoeae infection" and "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents".)

In addition, cutaneous manifestations of gonorrhea, disseminated gonorrhea, and gonorrhea in the newborn are discussed separately. (See "Cutaneous manifestations of gonorrhea" and "Disseminated gonococcal infection" and "Gonococcal infection in the newborn".)

INFECTION OF THE FEMALE UROGENITAL TRACT — Genital infections are the most common infections associated with N. gonorrhoeae. In individuals with female anatomy, cervical infection can ascend to involve the reproductive organs, causing pelvic inflammatory disease and/or complications of pregnancy.

Cervicitis — The uterine cervix is the most common site of mucosal infection with N. gonorrhoeae in females (picture 1). Most females with cervical gonococcal infection, up to 70 percent in some series, are asymptomatic [3]. Thus, the incubation period of gonorrhea is less well characterized in females than males. When present, genital symptoms develop in most females within 10 days of exposure [4]. Symptomatic infection typically manifests as vaginal pruritus and/or a mucopurulent discharge. Some females may complain of intermenstrual bleeding or menorrhagia. Pain is atypical in the absence of upper tract infection [5]. Abdominal pain and dyspareunia should raise suspicion for upper genital tract disease [6] (see 'Pelvic inflammatory disease' below). On examination, the cervix may appear normal or show signs of frank discharge. The cervical mucosa is often friable.

Importantly, these symptoms and signs of gonococcal cervical infection, when present, are indistinguishable from those observed with acute cervicitis of other causes. (See "Acute cervicitis".)

Urethritis — N. gonorrhoeae can be isolated from the urethra in up to 90 percent of females with gonococcal cervicitis [5], although urethral infection can uncommonly occur without concomitant cervical involvement. Additionally, among females who have undergone hysterectomy, the urethra is the main site of genital gonococcal infection [7].

As with gonococcal cervicitis, urethral involvement is typically asymptomatic. The main symptom, when present, is dysuria. Urinary urgency or frequency may also be present.

Pelvic inflammatory disease — Pelvic inflammatory disease (PID) occurs in approximately 10 to 20 percent of females with cervical gonorrhea, and N. gonorrhoeae is estimated to be the causative organism in 40 percent of cases of PID [8]. (See "Pelvic inflammatory disease: Pathogenesis, microbiology, and risk factors".)

Given the high incidence of asymptomatic gonococcal infection in females, PID can be the first presenting complaint. Symptoms of PID include pelvic/abdominal pain, abnormal vaginal bleeding, and dyspareunia. Often these symptoms occur with the onset of menses. Females with PID due to gonorrhea may appear more acutely ill and may be more likely to be febrile than females with nongonococcal salpingitis, but the extent of tubal inflammation and scarring appear to be similar [9]. Significant scarring and inflammation due to PID may be present in the absence of fulminant symptoms.

Signs of PID on examination include abdominal tenderness, uterine tenderness, adnexal or cervical motion tenderness, but these do not distinguish between gonococcal and nongonococcal etiologies. These are discussed in detail elsewhere. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

Perihepatitis (Fitz-Hugh-Curtis syndrome) — Perihepatitis is an inflammation of the Glisson’s capsule surrounding the liver and can be associated with PID. Its association with gonococcal infection was first described in 1934 [10], and is now known to be most commonly associated with Chlamydia trachomatis infection. The exact incidence of this syndrome in the setting of PID associated with N. gonorrhoeae is not entirely clear. In a study of 117 adolescents with mild to moderate PID, perihepatitis was reported in four percent overall [11]. When associated with STIs, it is noted almost exclusively in females. Cases in males have been reported [12].

Symptoms and signs include sharp pleuritic pain localized to the right upper quadrant, which may be accompanied by nausea, vomiting, and fever. A friction rub may be heard along the right anterior costal margin. Liver function tests are frequently normal or only mildly elevated. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Perihepatitis'.)

Bartholinitis — Symptomatic involvement of Bartholin’s glands, located behind the labia, may occur in up to 6 percent of females with genital gonococcal infection, while asymptomatic involvement of the glands may occur in up to a third [13]. Symptoms, when present, include perilabial pain and discharge, and signs may include edema of the labia and enlargement and tenderness of the gland (picture 2).

C. trachomatis and other nonsexually transmitted pathogens may also cause this syndrome and presentation. (See "Bartholin gland masses", section on 'Types of masses'.)

Complications of pregnancy — Urogenital gonococcal infections have been associated with chorioamnionitis, premature rupture of membranes, preterm birth, low birth weight or small for gestational age infants, and spontaneous abortions in pregnant females [14-18]. The risk of these complications in the setting of gonococcal infection has been reported as approximately two to five times greater than uninfected controls [14,19].

In addition, transmission of N. gonorrhoeae from an untreated infected mother to her baby may occur in 30 to 50 percent of cases [20]. Infants born to infected mothers may have neonatal conjunctivitis ("ophthalmia neonatorum"), pharyngitis, arthritis, and gonococcemia [21-23]. This is discussed in detail elsewhere. (See "Gonococcal infection in the newborn".)

INFECTION OF THE MALE UROGENITAL TRACT — Symptomatic urogenital gonococcal infections in individuals with male anatomy include urethritis and epididymitis.

Urethritis — N. gonorrhoeae is a common cause of urethritis, particularly in urban areas. Disproportionately higher rates of infection are reported from sexually transmitted infection (STI) clinics compared with private sector settings, in part due to diagnostic and reporting characteristics in public settings. STI clinic-based studies suggest that the majority of infected males are symptomatic [24]. In contrast, population-based studies, suggest that up to 60 percent of males may be asymptomatic or have very mild symptoms [25,26]. Of symptomatic males, the incubation period for N. gonorrhoeae is most commonly described as two to five days, although one study of 228 males with a known date of infection found a mean incubation period of eight days [27]. Others have estimated that symptoms of urethritis develop in 75 percent of males within four to eight days of genital infection with N. gonorrhoeae and in 80 to 90 percent within two weeks [28].

Males with gonococcal urethritis may present with any combination of symptoms. In one study that reported on 1615 episodes of gonococcal urethritis, discharge was present in 82 percent of cases and dysuria in 53 percent [27]. The discharge is often present spontaneously at the urethral meatus, purulent or mucopurulent in color, and copious in amount (picture 3). However, the discharge may also be indistinguishable on appearance from the more subtle manifestations that can be seen with nongonococcal urethritis. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Urethritis' and "Urethritis in adult males", section on 'Clinical manifestations'.)

Rare complications of gonococcal urethritis can include penile lymphangitis, penile edema ("bull-headed clap"), periurethral abscesses, and postinflammatory urethral strictures (this last complication is especially rare in the antibiotic era).

Urethritis is defined by characteristic signs or microscopic findings on urethral swab and/or urine specimens that indicate urethral inflammation. However, in one study of males attending an urban STI clinic, up to 5 percent of males diagnosed with gonorrhea had no Gram stain evidence of urethral inflammation [29]. Diagnostic criteria for urethritis are discussed in detail elsewhere. (See "Urethritis in adult males", section on 'Diagnosis'.)

Epididymitis — Acute unilateral epididymitis can be a complication of gonococcal infection, although it is more commonly due to C. trachomatis infection, especially in patients less than 35 years of age [30-32]. Combined gonococcal and chlamydial infections of the epididymis are more frequent than epididymal infections caused by N. gonorrhoeae alone [31].

Unilateral testicular pain and swelling may be the sole presenting complaints of males with epididymitis, with concomitant urethritis often discovered during the history and physical examination. The clinical manifestations of acute infectious epididymitis are discussed in detail elsewhere. Additional testing may be warranted to distinguish infectious causes of epididymitis from other causes of acute testicular pain (eg, torsion, trauma). (See "Acute scrotal pain in adults".)

EXTRAGENITAL INFECTION — N. gonorrhoeae can infect the rectum and pharynx, although infections at these sites are typically asymptomatic. Rarely, bacteremic spread from a mucosal site and resultant disseminated infection can occur. Additionally, N. gonorrhoeae can cause an aggressive conjunctivitis in adults and adolescents that can be transmitted through nonsexual contact.

Proctitis — In males, anorectal gonococcal infections typically occur among men who have sex with men (MSM) who engage in anal receptive intercourse; they are uncommon in males who have sex with only females. In one review of studies evaluating extragenital gonococcal infection, the prevalence of rectal infection ranged from 0.2 to 24 percent (median 6 percent) among MSM, in contrast to 0 to 5.7 percent (median 3 percent) among males who have sex with females [33]. In one multicenter study of over 11,000 MSM presenting to a sexually transmitted infection (STI) clinic and tested for rectal gonorrhea, 10 percent tested positive [34]. Anorectal gonorrhea may be the only site of infection in up to 40 percent of MSM [35,36]. These observations are particularly concerning because gonococcal proctitis in MSM is associated with an approximately threefold increase in the risk of acquisition of HIV infection [37].

In females, N. gonorrhoeae can be transmitted to the anal canal via a genital infection due to the proximity of the vagina, even in the absence of receptive anal intercourse. Prevalence of infection may be high in females reporting receptive anal intercourse. In the review of studies evaluating extragenital gonococcal infection, the prevalence of rectal infection among females ranged from 0.6 to 36 percent (median 2 percent) [33]. As an example, in one study of 2084 females at a STI clinic, three percent were found to have rectal gonorrhea; of those, 30 percent did not have concomitant genital infection [38].

Although anal intercourse is associated with rectal gonococcal infection, it is often detected in the absence of such reported risk behaviors.

Most cases of anorectal gonococcal infection are asymptomatic [39,40]. Symptoms and signs of proctitis, when present, include tenesmus, anorectal pain, rectal fullness, constipation, anorectal bleeding, and mucopurulent discharge [41]. Gonococcal proctitis cannot be distinguished from other infectious causes of proctitis by symptoms alone. (See 'Differential diagnosis' below.)

Pharyngitis — Gonococcal infection of the pharynx is usually acquired by oral sexual exposure [42]; it is acquired more efficiently by fellatio than by cunnilingus [27,42].

In a review of studies evaluating extragenital gonococcal infections, the prevalence of pharyngeal infections varied by population, and infection was often detected in the absence of reported risk behaviors (eg, receptive oral intercourse) [33]:

●Among females: 0 to 30 percent (median 2 percent)

●Among MSM: 0.5 to 17 percent (median 5 percent)

●Among males who have sex with only females: 0.4 to 15.5 percent (median 2 percent)

The majority of oropharyngeal infections with N. gonorrhoeae are asymptomatic, although sore throat, pharyngeal exudates, and/or cervical lymphadenitis are present in some cases. In a study of 192 individuals seeking care for sore throat in a general medicine setting, one percent overall had a positive throat culture for N. gonorrhoeae [43].

Although bacterial concentrations in the pharynx are generally lower than in the rectum and genitals, the pharynx is thought to be the site where horizontal transfer of gonococcal antimicrobial resistance genes commonly occurs [44].

Disseminated gonococcal infection — Bacteremic spread of N. gonorrhoeae from the initial site of infection is thought to occur in 0.5 to 3 percent of infected patients. Host factors and microbial factors may be responsible for dissemination. Most strains of gonorrhea that disseminate do not cause urethritis, but infection at a mucosal site usually precedes cases of disseminated gonococcal infection (DGI) [45].

Dissemination often leads to one of two clinical syndromes: purulent arthritis or a triad of tenosynovitis, dermatitis, and polyarthralgias [46]. Other manifestations of disseminated bacterial infection, such as endocarditis, meningitis, and osteomyelitis, are rare. These are discussed in detail elsewhere. (See "Disseminated gonococcal infection", section on 'Clinical manifestations'.)

Conjunctivitis — Gonococcal conjunctivitis mainly affects infants born to untreated mothers [20] (see "Gonococcal infection in the newborn"). In adults and adolescents, sporadic cases can occur as a result of autoinoculation from an anogenital source (picture 4). Outbreaks of gonococcal conjunctivitis have also been described [47,48]. In such outbreak settings, transmission via person-to-person nonsexual contact, fomites, or vectors (flies) has been reported.

Gonococcal conjunctivitis ranges from mild pauci-symptomatic infections to aggressive infections characterized by conjunctival injection, purulent discharge, and periorbital edema, which, if untreated, can progress to corneal ulceration, perforation, and blindness [49]. Infectivity ceases within hours of appropriate antibiotic therapy; as such, isolation of infected persons may be discontinued 24 hours after treatment. (See "Conjunctivitis", section on 'Hyperacute bacterial conjunctivitis'.)

DIFFERENTIAL DIAGNOSIS — Other sexually transmitted pathogens, including C. trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium, as well as herpes simplex virus (HSV) and syphilis can cause infections similar to N. gonorrhoeae [50]. Nonsexually transmitted pathogens and even non-infectious processes can also cause urogenital, pharyngeal, and rectal symptoms similar to N. gonorrhoeae.

The differential diagnosis of gonococcal infections depends on the particular clinical syndrome. These are discussed separately:

●(See "Acute cervicitis", section on 'Epidemiology and etiology'.)

●(See "Pelvic inflammatory disease: Pathogenesis, microbiology, and risk factors", section on 'Microbiology'.)

●(See "Urethritis in adult males", section on 'Epidemiology and microbiology' and "Urethritis in adult males", section on 'Differential diagnosis'.)

●(See "Acute scrotal pain in adults".)

●(See "Conjunctivitis", section on 'Classification and epidemiology'.)

●(See "Evaluation of acute pharyngitis in adults", section on 'HIV and other sexually transmitted infections'.)

●(See "Evaluation of anorectal symptoms in men who have sex with men", section on 'Proctitis'.)

DIAGNOSTIC APPROACH — The clinical syndromes associated with N. gonorrhoeae are typically diagnosed by history and physical examination, but a microbiologic diagnosis is required due to the lack of sensitivity and specificity of the clinical diagnosis. In general, nucleic acid amplification testing (NAAT) is the test of choice for the initial microbiologic diagnosis of N. gonorrhoeae infection, although culture remains an important diagnostic tool when antibiotic resistance is suspected.

If NAAT methods are unavailable, microscopy (for males), culture, antigen detection, and genetic probe methods can be used with endocervical or urethral swabs to diagnose urogenital gonorrhea. When no specific diagnostic tests are available, the diagnosis of gonorrhea remains presumptive when symptoms and signs of the clinical syndromes associated with gonorrhea are present in young or sexually active patients.

Sexually active individuals who are not in a long term mutually monogamous relationship should also be screened at genital and extragenital mucosal sites for gonorrhea even if asymptomatic if they reside in a location where N. gonorrhoeae is routinely diagnosed. Several mucosal sites may harbor infection without causing symptoms and therefore represent an ongoing source of infection in the community.

The following outlines the specific diagnostic approach by clinical scenario.

Initial evaluation — The specifics of diagnostic testing for N. gonorrhoeae at initial evaluation depend on the patient population and presentation, but it generally consists of NAAT of a self-collected specimen. In many cases, treatment of N. gonorrhoeae urogenital infection is empiric and initiated prior to the results of NAAT or other diagnostic tests. Nevertheless, establishing a microbiologic diagnosis is important for further management (eg, determining the need for repeat testing), partner management, and public health reasons.

In general, when a diagnostic test for N. gonorrhoeae is performed, testing for co-infections, specifically C. trachomatis, should also be performed. (See 'Evaluation for coinfection' below.)

Males with urogenital symptoms — Any sexually active man presenting with signs and symptoms of urethritis or epididymitis, or other urogenital symptoms consistent with gonorrhea should undergo diagnostic testing for N. gonorrhoeae [51]. NAAT of the first-catch urine is the diagnostic test of choice. For the first-catch urine specimen, approximately 20 to 30 mL of the initial urinary stream should be collected without pre-cleansing of the genital areas. A urethral swab is also an acceptable specimen for NAAT. (See 'Performance on urogenital specimens' below.)

If a urethral swab has been collected to evaluate microscopically for urethritis in a symptomatic man, the presence of polymorphonuclear leukocytes with intracellular gram-negative diplococci on Gram stain of the urethral specimen (picture 5) is sufficient to establish the diagnosis of N. gonorrhoeae. In such cases, NAAT for N. gonorrhoeae does not need to be sent. Microscopy of a urethral specimen can also be used for diagnosis if NAAT is not available. Otherwise, culture, antigen detection, and genetic probe methods can be used with urethral swabs to diagnose urogenital gonorrhea. (See 'Culture' below and 'Other tests' below.)

In addition, because of the significant prevalence of extragenital infections in MSM and the frequency of asymptomatic infections, MSM with a history of unprotected anal or oral sex who are not in a long-term mutually monogamous relationship should be screened for oral and rectal gonorrhea even in the absence of symptoms at these sites [50]. Testing can be performed with NAAT on self-collected pharyngeal and rectal swabs. (See 'Performance on extragenital specimens' below.)

Females with urogenital symptoms — Any sexually active female presenting with signs and symptoms of cervicitis or pelvic inflammatory disease, or other urogenital symptoms consistent with gonorrhea should undergo diagnostic testing for N. gonorrhoeae [51]. NAAT of a self- or clinician-collected vaginal swab is the preferred diagnostic test. An endocervical swab is an equally appropriate alternative specimen for NAAT if a speculum exam is already being performed. Urine and liquid Pap smear medium are also acceptable specimens for NAAT. (See 'Performance on urogenital specimens' below.)

If NAAT methods are unavailable, culture, antigen detection, and genetic probe methods can be used with endocervical swabs to diagnose urogenital gonorrhea. (See 'Culture' below and 'Other tests' below.)

Patients with extragenital symptoms — Sexually active individuals with symptoms and signs of proctitis, even in the absence of self-reported anal sexual exposure, should undergo diagnostic testing for N. gonorrhoeae. For patients who present with symptoms of pharyngitis, a history of unprotected oral sex should prompt testing for N. gonorrhoeae. NAAT of a rectal or pharyngeal swab, which can be collected by the patient, is the preferred diagnostic test for these sites. Of note, false positives may rarely occur due to non-gonococcal Neisseria species at this site, so a positive test should be carefully interpreted if the pre-test probability of gonorrhea was low. (See 'Performance on extragenital specimens' below.)

If NAAT is unavailable, culture, which has lower sensitivity, can also be used with pharyngeal and rectal swabs. (See 'Culture' below.)

For patients who are suspected to have gonococcal conjunctivitis based on exposure or symptoms, microbiological diagnosis is made by Gram stain and culture of conjunctival discharge.

Transgender or gender-diverse individuals — Testing for N. gonorrhoeae in gender-diverse individuals depends on the specific anatomy. Individuals with a vagina and cervix who have urogenital symptoms are tested in the same way as females; those with a penis are tested in the same way as males. Patients with a neovagina are tested with NAAT on first-catch urine and/or a neovaginal swab. Those with gender-affirming penile reconstruction are tested with an NAAT on first-catch urine. The optimal testing modality among transgender persons is yet to be determined.

Asymptomatic patients — Because a large number of gonococcal infections are asymptomatic, routine screening with NAAT should be offered to sexually active patients at high risk of infection and complications from gonorrhea who present to care for other reasons. Details on whom to screen for gonorrhea are discussed in detail elsewhere. (See "Screening for sexually transmitted infections", section on 'Screening recommendations'.)

Diagnostic testing for urogenital gonorrhea in asymptomatic patients is generally the same as for symptomatic patients (ie, NAAT of first-catch urine for males and vaginal swab for females). Urethral Gram stain can also be used for males, although it is less sensitive in the absence of symptoms. Thus, if the Gram stain is negative in an asymptomatic man, NAAT should also be performed if gonorrhea is suspected due to risk factors. (See 'Males with urogenital symptoms' above and 'Females with urogenital symptoms' above.)

In addition, because of the significant prevalence of extragenital infections in MSM and the frequency of asymptomatic infections, routine screening for oropharyngeal and rectal gonorrhea is warranted in MSM [50]. Testing can be performed with NAAT on self-collected pharyngeal and rectal swabs. (See 'Performance on extragenital specimens' below.)

Recent exposure — In patients who present within one to two weeks of a potential or known exposure to gonorrhea, diagnostic testing should not be used to inform the decision to treat. Such patients should be treated empirically [50]. Nevertheless, because establishing a microbiologic diagnosis is important for other reasons, diagnostic testing for N. gonorrhoeae (and other STIs) should still be performed at the site of exposure, as for symptomatic patients. (See 'Males with urogenital symptoms' above and 'Females with urogenital symptoms' above and 'Patients with extragenital symptoms' above.)

Persistent symptoms — Primary treatment failure is possible in patients with confirmed gonococcal infection who have persistent symptoms after appropriate therapy with good adherence and lack of re-exposure. In such patients, antibiotic-resistant gonorrhea should be suspected and tested for with culture and antimicrobial susceptibility testing as the preferred diagnostic modality (with or without NAAT performed at the same time) [50]. Culture requires endocervical, urethral, pharyngeal, or rectal swabs with specific handling. (See 'Culture' below.)

Recurrent symptoms — Recurrence of symptoms after initial resolution should lead to a repeat evaluation for gonorrhea and other sexually transmitted infections that cause urethritis or cervicitis, including chlamydia, bacterial vaginosis, and other pathogens. NAAT of first catch urine in males and vaginal swab in females remains the test of choice to evaluate for reinfection in the setting of symptom recurrence [50].

DIAGNOSTIC TECHNIQUES — N. gonorrhoeae can be identified using several diagnostic modalities. The sensitivity and specificity of these techniques vary widely. Overall, nucleic acid amplification testing (NAAT) is the most accurate and thus the preferred diagnostic test for both genital and extragenital infection. An additional advantage is that NAAT retains accuracy with patient-collected specimens (vaginal swab in females and urine in males, and rectal and pharyngeal swabs [52]). Additional diagnostic tests include culture, microscopy, and other nucleic acid-based tests (eg, probe hybridization).

The specific test and specimen to use depends on the clinical scenario. (See 'Diagnostic approach' above.)

Nucleic acid amplification — Use of nucleic acid amplification testing (NAAT) is recommended as the optimal method for the diagnosis of genital and extragenital infections caused by N. gonorrhoeae (and C. trachomatis, a frequent co-pathogen) in individuals with and without symptoms [50,53]. Compared with culture, commercially available NAAT offers rapid results (within hours) and enhanced sensitivity. Additionally, the ability to use NAAT for self-collected specimens [54] or urine samples represents an important improvement compared with conventional methods like culture, which require a pelvic examination in females or a urethral swab in males. The main drawback to NAAT methodology is that does not enable determination of antimicrobial susceptibility, which is paramount if antibiotic resistant infection is suspected.

Although NAAT tests may be individually more expensive than culture or other tests, high-volume laboratories may consider "pooling" techniques to identify a positive sample (made up of aliquots from several clinical specimens); a pooled sample that is "positive" is subsequently parsed to find the single positive clinical specimen.

Methodology — NAAT methodology consists of amplifying N. gonorrhoeae DNA or RNA sequences using various techniques, such as polymerase chain reaction (PCR), transcription-mediated amplification (TMA), or strand displacement amplification (SDA). NAAT can theoretically detect as little as one organism per sample, while the detection threshold of other methods is approximately 1000 organisms. Although the sensitivity of NAAT is generally better than culture, the sensitivity of the individual NAAT (eg, PCR-based versus TMA-based versus SDA-based testing) varies by NAAT and specimen type.

Performance on urogenital specimens — NAAT can be performed on a wide variety of urogenital samples including endocervical (including thin prep cervical cancer screening medium) and vaginal samples, urine samples (from males and females), and urethral samples (from males only). The preferred specimens are a first-catch urine for males and a vaginal swab for females [53]. An endocervical swab is appropriate if the patient was already undergoing speculum exam for other reasons.

NAAT testing on vaginal swabs performs as well as on cervical swabs [54]. The main reason to use vaginal swabs is that they can be obtained by the patient, through noninvasive self-collection. The sensitivity of testing on urine in females appears to be slightly lower compared with vaginal samples.

In contrast, the sensitivity and specificity of NAAT on urine or urethral specimens are similar in males. As an example, in a large study that included 683 males with gonorrhea, NAAT had a sensitivity of 99 percent with urethral swab specimens and 98 percent with urine specimens when compared with culture; the specificity of NAAT was also similar with either sample, at 96 percent.

Performance on extragenital specimens — NAAT has superior sensitivity for the detection of N. gonorrhoeae at extragenital sites, such as the oropharynx and rectum. As with urine and vaginal swabs, patient-collected rectal and pharyngeal swabs have been shown to perform comparably to clinician-collected swabs [55-57].

NAATs are cleared by the US Food and Drug Administration (FDA) for use at extragenital sites. Several studies have demonstrated that they have significantly higher sensitivity than culture-based testing at these sites [58-60]. The main concern has been their specificity at detecting gonorrhea given the presence of nonpathogenic Neisserial species in extragenital sites. A study tested the specificity of six different NAATs using 450 characterized clinical culture isolates of N. gonorrhoeae (n = 216), nongonococcal Neisseria species (n = 218), and some closely related non-Neisseria species (n = 16) [61]. All six assays tested displayed some false-positive results due to cross-reactions, but most demonstrated only sporadic low-level false positive results. A subsequent study performed on a subset of the assays did not demonstrate any cross-reactions [62], suggesting that performance characteristics of these assays are dependent on the testing environment. As such, all laboratories that offer NAAT testing of extragenital specimens must establish performance specifications for NAAT testing on nongenital samples. As with all tests that lack perfect specificity, in low prevalence settings, there is an increased probability that a positive test may be a false positive (ie, a low positive predictive value for the test).

In a cross-sectional study of 2598 participants, three assays from different manufacturers were compared against each other using a novel study design, a "Master Protocol" to determine diagnostic performance at the pharynx and rectum [63]. Agreement among the assays ranged from 85 to 97 percent for positive tests and 99 to 100 percent for negative tests, depending on the anatomic site and assay comparisons.

Gram stain (microscopy) — The main role of microscopy is in the diagnosis of urethritis in a symptomatic man. Due to its high specificity, a Gram stain of a male urethral specimen that demonstrates polymorphonuclear leukocytes with intracellular gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in males (picture 5).

In one study, a Gram stain diagnosed 94 percent of cases in symptomatic males; the sensitivity dropped to 81 percent in asymptomatic subjects [27]. Older reports have shown that performance of Gram stain in a man is similar to that of culture, with sensitivities of 89 to 94 percent and specificities of 94 to 97 percent [64]. Thus, in symptomatic males, urethral Gram stain is sensitive, specific, and cost effective. However, if the Gram stain is negative in an asymptomatic man, additional testing should be performed if gonorrhea is suspected due to risk factors.

A Gram stain has low specificity in females compared with males due to the possible presence of other nonpathogenic gram-negative diplococci in cervical secretions [65]; thus, other diagnostic methods are preferred in females.

A Gram stain cannot be used reliably for extragenital infections since other nonpathogenic gram-negative diplococci can be present; therefore, a Gram stain of pharyngeal or rectal specimens is not recommended. When Gram stain is used for the diagnosis of conjunctival infections, confirmation with culture should also be obtained.

An alternative to Gram stain, a methylene blue/gentian violet stain can also identify WBC and gonococcal forms on urethral swab specimens, but can be performed more rapidly than the Gram stain. Results correlate with those of a Gram stain, although N. gonorrhoeae appear as dark purple on the methylene blue/gentian violet stain [66].

Culture — The main advantage of culture is to assess antibiotic susceptibilities, which is of particular importance when antibiotic resistant infection is suspected. Resistance of the gonococcus to several classes of antibiotics and the emergence of gonococcal resistance to the currently recommended classes of antibiotics (cephalosporins and macrolides) has highlighted the importance of maintaining culture capacity. In the United States, the CDC recommends that a gonococcal culture be obtained and testing for antimicrobial susceptibility be performed whenever treatment failure is suspected [50]. Most large commercial laboratories and most large public health laboratories have maintained culture capacity for gonorrhea.

The reported sensitivity of culture ranges from 72 to 95 percent, depending upon the comparison assay, site sampled, and patient population. The major disadvantage to culture is that results are not usually available until 48 hours, and the sensitivity of culture declines in asymptomatic infection to only 65 to 85 percent [67]. In contrast, the sensitivity of NAAT is much higher.

Cultures for N. gonorrhoeae are processed on Thayer-Martin agar, which prevents the overgrowth of other endogenous flora. Culture specimens should be obtained with swabs that have plastic or wire shafts and rayon, Dacron, or calcium alginate tips, since other materials (eg, wooden shafts and cotton tips) may be toxic to N. gonorrhoeae [53]. If the specimen is also being used to test for chlamydia, calcium alginate tips should also be avoided.

●Urethral swabs are obtained by inserting a male urethral swab 2 to 3 centimeters into the urethral meatus and rotating 360 degrees two to three times.

●Cervical specimens are collected by inserting the tip of a swab 1 to 2 centimeters into the cervical os and rotating 360 degrees two to three times.

●Rectal specimens may be obtained by inserting the swab 3 to 4 cm into the rectal vault

●Pharyngeal specimens are procured from the posterior pharynx with a swab

Problems with culture can arise due to the fastidious nature of the organism. The specimen should be inoculated immediately onto the appropriate medium and transported rapidly to the microbiology laboratory. The organism should be incubated at 35º to 37ºC in a CO₂-enriched environment.

Costs are moderate compared with more expensive DNA amplification techniques. However, this must be weighed against need for a CO₂-enriched environment for transport, personnel time to read the cultures at 48 hours, and the fastidious nature of the organism that can result in false negative results.

Other tests — Other tests are used less commonly, generally when NAAT or culture are not available.

●Rapid tests — Three point-of-care tests have been cleared by the FDA, and several more are being developed for the rapid diagnosis of gonorrhea. Although NAAT is considered the "gold standard", same-day results for most NAAT are not usually available because they are classified as being of moderate to high complexity, usually requiring one to two days for results to become available.

One rapid NAAT assay that uses a modular-cartridge based platform for testing each specimen using PCR can be performed on-site in laboratories [68,69]. It detects nucleic acid of C. trachomatis and N. gonorrhoeae and can process up to 96 specimens in less than two hours. The performance measures of this assay are comparable to those of other NAAT. Another molecular point-of-case test that can be performed by non-laboratory-trained personnel in clinical settings can detect C. trachomatis and N. gonorrhoeae within 30 minutes [70]. For gonorrhea, sensitivity estimates were 100.0 percent (95% CI 92.1-100.0 percent) for females and 97.3 percent (95% CI 90.7-99.3 percent) for males. Specificity estimates were 99.9 percent (95% CI 99.5-100.0 percent) for females and 100 percent (95% CI 95.5-100.0 percent) for males.

Other basic point-of-care tests can also provide diagnostic information. The Gram stain is cheap, universally available, and has good sensitivity and specificity when used in symptomatic males (see 'Gram stain (microscopy)' above). The leukocyte esterase urine test detects an enzyme found in certain white blood cells and has been used for the diagnosis of gonorrhea in a number of countries for many years. In a meta-analysis of nine studies, the median sensitivity of this test was 71 percent and the median specificity was 70 percent [71].

Immunochromatographic tests to detect N. gonorrhoeae are also being developed as point-of-care tests. These immunoassays work via capillary action flow along a nitrocellulose membrane allowing an interaction between the antigen and a colorimetric particle. Depending on the assay, sensitivities ranged from 60 percent to 94 percent, and specificities ranged from 89 percent to 97 percent [71].

●Nucleic acid hybridization (nucleic acid probe) tests — Because they do not involve amplification of genetic targets, available genetic probe methods require invasive testing using a direct swab from the endocervix or urethra [72]. The main advantage of these tests is their low cost; however, because their sensitivity is considerably lower than NAAT and because NAAT have become more cost-competitive, these tests are not used as frequently as in the past. Nucleic acid hybridization tests use DNA probes labeled with a chemiluminescent marker to identify a specific nucleic acid sequence of the organism. One advantage of the probe assays is that sample storage and transport are less critical than culture. Culture generally requires that the sample be sent to the laboratory within 24 hours, while sample stability for DNA probe assays is up to seven days at room temperature [73].

●Antigen detection — An enzyme immunoassay (EIA) was developed to detect gonococcal antigens from cervical swab or urine specimens but is not widely used because its positive predictive value is only acceptable in populations with a high prevalence of infection.

EVALUATION FOR COINFECTION — It is important to note that N. gonorrhoeae not only causes similar clinical syndromes as C. trachomatis but also coexists in a significant proportion of patients with chlamydial infection. Thus, any testing for N. gonorrhoeae should also prompt testing for C. trachomatis. (See "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Diagnosis of chlamydial infections'.)

Additionally, presence of risk factors for gonorrhea in adults and adolescents also signifies a potential risk of other sexually transmitted pathogens, such as HIV and syphilis. Screening for other sexually transmitted infections is indicated in patients being evaluated for gonorrhea. (See "Screening for sexually transmitted infections".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)

SUMMARY AND RECOMMENDATIONS

●Infection of the female urogenital tract – Most genital gonococcal infections in females are asymptomatic. Symptomatic cervical infection can present with typical findings of cervicitis, including vaginal pruritus and a mucopurulent cervical discharge (picture 1). Some females may also have symptomatic involvement of the urethra (dysuria) or Bartholin’s glands (perilabial pain) (picture 2). Pelvic inflammatory disease is a complication of untreated urogenital infection and can lead to infertility. (See 'Infection of the female urogenital tract' above.)

●Infection of the male urogenital tract – Gonococcal infection in males is frequently asymptomatic, although it is more likely symptomatic than in females. Symptomatic urethritis often manifests with dysuria and copious purulent discharge (picture 3), although more subtle findings are not uncommon. Acute unilateral epididymitis, with testicular pain and swelling, can be a complication of genital gonococcal infection. (See 'Infection of the male urogenital tract' above.)

●Extragenital infection – This includes infection of the rectum and pharynx. Most are asymptomatic although can rarely present as proctitis, with anorectal pain with defecation and discharge, or as pharyngitis, with sore throat and pharyngeal exudate. (See 'Extragenital infection' above.)

●Disseminated infection – Bacteremic spread of N. gonorrhoeae from the initial site of infection occurs in a small minority of patients. Disseminated infection often manifests as purulent arthritis or a triad of tenosynovitis, dermatitis, and polyarthralgia. This is discussed in detail elsewhere. (See "Disseminated gonococcal infection", section on 'Clinical manifestations'.)

●Differential diagnosis – The clinical syndromes caused N. gonorrhoeae cannot be reliably distinguished from those caused by other pathogens on the basis of signs and symptoms alone. Other sexually transmitted pathogens, including Chlamydia trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium, as well as herpes simplex virus (HSV) and syphilis, can cause similar symptoms. (See 'Differential diagnosis' above.)

●Diagnostic methods

•NAAT as preferred test – Nucleic acid amplification testing (NAAT) has superior accuracy and can be used with various specimen types. For urogenital infections, vaginal swabs in females (clinician-collected and self-collected) and first-catch urine in males are the preferred specimens for NAAT. Preferred urogenital specimens for gender-diverse individuals depend on the specific anatomy. For extragenital infections, NAAT, used on pharyngeal and rectal swabs, is also the preferred test. (See 'Diagnostic approach' above and 'Nucleic acid amplification' above.)

•Microscopy for urethritis in males – In symptomatic males who have undergone urethral swab for microscopic evaluation for urethritis, the presence of polymorphonuclear leukocytes with intracellular gram-negative diplococci on Gram stain of the specimen (picture 5) is sufficient to establish the diagnosis of N. gonorrhoeae. (See 'Diagnostic approach' above and 'Gram stain (microscopy)' above.)

•Limited role for culture – Culture remains important for its ability to assess antibiotic susceptibilities of the isolate when resistance is suspected. Patients with confirmed gonococcal infection who have persistent symptoms after appropriate therapy with good adherence and lack of re-exposure should be tested for antibiotic resistant N. gonorrhoeae with culture and susceptibility testing. Culture requires endocervical, urethral, pharyngeal, or rectal swabs with specific handling. (See 'Diagnostic approach' above and 'Culture' above.)

●Testing for chlamydia – N. gonorrhoeae not only causes similar clinical syndromes as C. trachomatis but also coexists in a significant proportion of patients with chlamydial infection. Thus, any testing for N. gonorrhoeae should also prompt testing for C. trachomatis. (See 'Evaluation for coinfection' above and "Clinical manifestations and diagnosis of Chlamydia trachomatis infections", section on 'Diagnosis of chlamydial infections'.)