Gonorrhea 

Updated: Sep 07, 2018
Author: Brian Wong, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD 

Overview

Practice Essentials

Gonorrhea is a purulent infection of the mucous membrane surfaces caused by Neisseria gonorrhoeae. N gonorrhoeae is spread by sexual contact or through transmission during childbirth. The Centers for Disease Control (CDC) recommends that all patients with gonorrheal infection also be treated for presumed co-infection with Chlamydia trachomatis.[1] See the image below.

This patient presented with gonococcal urethritis, This patient presented with gonococcal urethritis, which became systemically disseminated, leading to gonococcal conjunctivitis of the right eye. Courtesy of the CDC/Joe Miller, VD.

See 20 Signs of Sexually Transmitted Infections, a Critical Images slideshow, to help make an accurate diagnosis.

Signs and symptoms

History

In women, the major genitourinary symptoms of gonorrhea include the following:

  • Vaginal discharge: The most common presenting symptom of gonorrhea, vaginal discharge from endocervicitis is usually described as thin, purulent, and mildly odorous; however, many patients have minimal or no symptoms from gonococcal cervicitis

  • Dysuria

  • Intermenstrual bleeding

  • Dyspareunia (painful intercourse)

  • Mild lower abdominal pain

If the infection progresses to pelvic inflammatory disease (PID), symptoms may include the following:

  • Lower abdominal pain: Most consistent symptom of PID

  • Increased vaginal discharge or mucopurulent urethral discharge

  • Dysuria: Usually without urgency or frequency

  • Cervical motion tenderness

  • Adnexal tenderness (usually bilateral) or adnexal mass

  • Intermenstrual bleeding

  • Fever, chills, nausea, and vomiting (less common)

In males, the major genitourinary symptoms of gonorrhea include the following:

  • Urethritis: The major manifestation of gonococcal infection in men; initial characteristics include burning upon urination and a serous discharge; a few days later, the discharge usually becomes more profuse, purulent, and, at times, tinged with blood

  • Acute epididymitis: Usually unilateral and often occurs in conjunction with a urethral exudate

  • Urethral strictures: Have become uncommon in the antibiotic era, but they can present with a decreased and abnormal urine stream, as well as with the secondary complications of prostatitis and cystitis

  • Rectal infection: May present with pain, pruritus, discharge, or tenesmus

In males and females, the classic presentation of disseminated gonococcal infection (DGI) is an arthritis-dermatitis syndrome. Joint or tendon pain is the most common presenting complaint in the early stage of infection. The second stage of DGI is characterized by septic arthritis. The knee is the most common site of purulent gonococcal arthritis.

In neonates, in whom bilateral conjunctivitis (ophthalmia neonatorum) often follows vaginal delivery from an untreated mother with a gonococcal infection, symptoms of gonococcal conjunctivitis include the following:

  • Eye pain

  • Redness

  • Purulent discharge

Physical examination

Look for the following genitourinary symptoms during physical examination in females:

  • Mucopurulent or purulent vaginal, urethral, or cervical discharge

  • Vaginal bleeding; vulvovaginitis in children

  • Cervical friability - Tendency to bleed upon manipulation

  • Cervical motion tenderness during bimanual pelvic examination

  • Fullness and/or tenderness of the adnexa, unilateral or bilateral (eg, ovaries, fallopian tubes)

  • Lower abdominal pain/tenderness, with or without rebound tenderness

  • Possible low back pain - More common in progression to PID

  • Upper right abdominal tenderness (with perihepatitis)

Look for the following genitourinary symptoms during physical examination in males:

  • Mucopurulent or purulent urethral discharge: Obtained by milking the urethra along the shaft of the penis

  • Possible epididymitis: Unilateral epididymal tenderness and edema, with or without penile discharge or dysuria

  • Penile edema without other overt inflammatory signs

  • Urethral stricture: Uncommon; more often seen in the preantibiotic era with urethral irrigation using caustic liquids

See Clinical Presentation for more detail.

Diagnosis

Culture is the most common diagnostic test for gonorrhea, followed by the deoxyribonucleic acid (DNA) probe and then the polymerase chain reaction (PCR) assay and ligand chain reaction (LCR). The DNA probe is an antigen detection test that uses a probe to detect gonorrhea DNA in specimens.

Specific culture of a swab from the site of infection is a criterion standard for diagnosis at all potential sites of gonococcal infection. Cultures are particularly useful when the clinical diagnosis is unclear, when a failure of treatment has occurred, when contact tracing is problematic, and when legal questions arise.

In patients who may have DGI, all possible mucosal sites should be cultured (eg, pharynx, cervix, urethra, rectum), as should blood and synovial fluid (in cases of septic arthritis). Three sets of blood cultures should also be obtained.

See Workup for more detail.

Management

For uncomplicated urogenital, anorectal, and pharyngeal gonococcal infection, a drug regimen using ceftriaxone plus either azithromycin or doxycycline may be used. Antimicrobial drugs used alone or in various combinations in other gonococcal infections include the following:

  • Gonococcal arthritis: Ceftriaxone

  • Gonococcal conjunctivitis: Ceftriaxone

  • Gonorrhea contributing to PID: Cefoxitin, ceftriaxone, doxycycline, metronidazole, cefotetan, clindamycin, gentamicin

  • Gonococcal epididymitis: Ceftriaxone, doxycycline

  • DGI: Ceftriaxone, cefotaxime, ceftizoxime

  • Gonococcal meningitis and endocarditis: Ceftriaxone

See Treatment and Medication for more detail.

Background

Gonorrhea, an important public health problem and the second most common notifiable disease in the United States, is a purulent infection of mucous membrane surfaces caused by the gram-negative diplococcus Neisseria gonorrhoeae. Although gonorrhea (known colloquially as the clap and the drip) is most frequently spread during sexual contact, it can also be transmitted from the mother's genital tract to the newborn during birth, causing ophthalmia neonatorum and systemic neonatal infection. (See Etiology.)

In women, the cervix is the most common site of gonorrhea, resulting in endocervicitis and urethritis, which can be complicated by pelvic inflammatory disease (PID). In men, gonorrhea causes anterior urethritis. Gonorrhea can also spread throughout the body to cause localized and disseminated disease. Complications also include ectopic pregnancy and increased susceptibility to human immunodeficiency virus (HIV) infection. Most commonly, the term gonorrhea refers to urethritis and/or cervicitis in a sexually active person. (See Pathophysiology, Prognosis, Presentation, and Workup.)

Gonococcal infections following sexual and perinatal transmission are a major source of morbidity worldwide. In the developed world, where prophylaxis for neonatal eye infection is standard, the vast majority of infections follow genitourinary mucosal exposure. (See Pathophysiology, Etiology, and Prognosis, and Treatment.)

In the pediatric population, the importance of gonorrhea is 3-fold, as follows:

  • As a common and preventable sexually transmitted disease (STD) in the sexually active teenage population

  • As a perinatal infection at childbirth

  • As a forensic aid in investigating sexual abuse

Gonococcemia

Gonococcemia is defined as the presence of N gonorrhoeae in the bloodstream, which can lead to the development of disseminated gonococcal infection (DGI). Gonococcemia occurs in about 0.5-3% of patients with gonorrhea (see the image below). (See Pathophysiology and Prognosis.)

This patient presented with gonococcal urethritis, This patient presented with gonococcal urethritis, which became systemically disseminated, leading to gonococcal conjunctivitis of the right eye. Courtesy of the CDC/Joe Miller, VD.

The clinical manifestations of this process are biphasic, with an early bacteremic phase consisting of tenosynovitis, arthralgias,[2] and dermatitis, followed by a localized phase consisting of localized septic arthritis. Other potentially severe clinical complications include osteomyelitis, meningitis, endocarditis, adult respiratory distress syndrome (ARDS),[3, 4] and fatal septic shock.[5] Polymyositis is also a rare complication of gonococcemia. (See Pathophysiology, Prognosis, and Presentation.)

Patients who are pregnant or menstruating may be particularly prone to gonococcemia. Other populations at risk of infection include women and individuals with complement deficiencies, HIV disease, or systemic lupus erythematosus (SLE). DGI is an important, potentially life-threatening, and easily treatable clinical entity that remains the most common cause of acute septic arthritis in young, sexually active adults.

Pathophysiology

The pathophysiology of N gonorrhoeae and the relative virulence of different subtypes depend on the antigenic characteristics of the respective surface proteins. Certain subtypes are able to evade serum immune responses and are more likely to lead to disseminated (systemic) infection.

Well-characterized plasmids commonly carry antibiotic-resistance genes, most notably penicillinase. Plasmid and nonplasmid genes are transmitted freely between different subtypes. The ensuing exchange of surface protein genes results in high host susceptibility to reinfection. The exchange of antibiotic resistance genes has led to extremely high levels of resistance to beta-lactam antibiotics. Fluoroquinolone resistance has also been documented on multiple continents and in widespread populations within the United States.[6]

Infection of the lower genital tract, the most common clinical presentation, primarily manifests as male urethritis and female endocervicitis. Infection of the pharynx, rectum, and female urethra occur frequently but are more likely to be asymptomatic or minimally symptomatic. Retrograde spread of the organisms occurs in as many as 20% of women with cervicitis, often resulting in pelvic inflammatory disease (PID), with salpingitis, endometritis, and/or tubo-ovarian abscess. Retrograde spread can lead to frank abdominal peritonitis and to a perihepatitis known as Fitz-Hugh-Curtis syndrome.

Long-term sequelae of PID, such as tubal factor infertility, ectopic pregnancy, and chronic pain, may occur in up to 25% of affected patients. Epididymitis or epididymo-orchitis may occur in men after gonococcal urethritis. Lower genital infection is a risk factor for the presence of other sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV).

Conjunctivitis can occur in adults, as well as children, following direct inoculation of organisms (usually as a result of hand-eye inoculation in adults) and can lead to blindness.

Disseminated gonococcal infection

Disseminated gonococcal infection (DGI) occurs following approximately 1% of genital infections. Patients with DGI may present with symptoms of rash, fever, arthralgias, migratory polyarthritis, septic arthritis, tendonitis, tenosynovitis, endocarditis, or meningitis.

N gonorrhoeae organisms spread from a primary site, such as the endocervix, the urethra, the pharynx, or the rectum, and disseminate to the blood to infect other end organs. Usually, multiple sites, such as the skin and the joints, are infected. Neisserial organisms disseminate to the blood due to a variety of predisposing factors, such as host physiologic changes, virulence factors of the organism itself, and failures of the host's immune defenses.[7]

For example, changes in the vaginal pH that occur during menses and pregnancy and the puerperium period make the vaginal environment more suitable for the growth of the organism and provide increased access to the bloodstream. (Three fourths of the cases of DGI occur in women; susceptibility is increased if the primary mucosal infection occurs during menstruation or pregnancy.)[8, 9]

Defects in the host's immune defenses are also involved in the pathophysiology, with certain patients more likely to develop bacteremia. Specifically, patients with deficiency in terminal complement components are less able to combat infection, as complement plays an important role in the killing of neisserial organisms. As many as 13% of patients with DGI have a complement deficiency.

A study of 22 patients with DGI revealed that total serum complement activity was greater than 25% below the normal mean. Other causes of immunocompromise (eg, HIV, SLE) also predispose to dissemination of infection.

In addition, certain strains of gonorrhea causing asymptomatic genital infections are seen in association with DGI.[10]

Etiology

N gonorrhoeae is a gram-negative, intracellular, aerobic diplococcus; more specifically, it is a form of diplococcus known as the gonococcus. N gonorrhoeae is spread by sexual contact or through vertical transmission during childbirth. It mainly affects the host’s columnar or cuboidal epithelium. Virtually any mucous membrane can be infected by this microorganism. The physiologic ectopy of the squamocolumnar junction onto the ectocervix in the adolescent female is one factor that causes particular susceptibility to this infection.

Many factors influence the manner in which gonococci mediate their virulence and pathogenicity. Pili help in attachment of gonococci to mucosal surfaces and contribute to resistance by preventing ingestion and destruction by neutrophils. Opacity-associated (Opa) proteins increase adherence between gonococci and phagocytes, promote invasion into host cells, and possibly down-regulate the immune response.

Porin channels (porA, porB) in the outer membrane play key roles in virulence. Gonococcal strains with porA may have inherent resistance to normal human serum and an increased ability to invade epithelial cells, explaining their association with bacteremia.

Certain acquired plasmids and genetic mutations enhance virulence. TEM-1–type beta-lactamase (penicillinase) affects penicillin binding and efflux pumps and confers resistance to penicillin.[11, 12] TetM protects the ribosome and confers resistance to tetracycline. Alterations in gyrA and parC genes result in fluoroquinolone resistance by efflux activation and decreased antibiotic cell permeation.[11]

Gonococci attach to the host mucosal cell (pili and Opa proteins play major roles) and, within 24-48 hours, penetrate through and between cells into the subepithelial space. A typical host response is characterized by invasion with neutrophils, followed by epithelial sloughing, formation of submucosal microabscesses, and purulent discharge. If left untreated, macrophage and lymphocyte infiltration replaces the neutrophils. Some gonococcal strains cause an asymptomatic infection, leading to an asymptomatic carrier state in persons of either sex.

The ability to grow anaerobically allows gonococci, when mixed with refluxed menstrual blood or attached to sperm, to secondarily invade lower genital structures (vagina and cervix) and progress to upper genital organs (endometrium, salpinx, ovaries).

Gonococcal infection usually follows mucosal inoculation during vaginal, anal, or oral sexual contact or perinatally.

Sexually transmitted infection

Gonococcal infection usually follows mucosal inoculation during vaginal, anal, or oral sexual contact. It also may be caused by inoculation of mucosa by contaminated fingers or other objects. Transmission through penile-rectal contact is fairly efficient.

The risk of transmission of N gonorrhoeae from an infected woman to the urethra of her male partner is approximately 20% per episode of vaginal intercourse and rises to 60-80% after 4 or more exposures. In contrast, the risk of male-to-female transmission approximates 50-70% per contact, with little evidence of increased risk with more sexual exposures.

Persons who have unprotected intercourse with new partners frequently enough to sustain the infection in a community are defined as core transmitters.

Neonatal and pediatric gonococcal infection

Neonatal gonococcal infection may follow conjunctival infection, which is obtained during passage through the birth canal. In addition, direct infection may occur through the scalp at the sites of fetal monitoring electrodes.

In children, infection may occur from sexual abuse by an infected individual or possibly nonsexual contact in the child's household or in institutional settings.

Autoinoculation

Autoinoculation can occur when a person touches an infected site (genital organ) and contacts skin or mucosa.

Risk factors

Risk factors for gonorrhea include the following:

  • Sexual exposure to an infected partner without barrier protection (eg, failure to use a condom or condom failure)[13]

  • Multiple sex partners

  • Male homosexuality

  • Low socioeconomic status

  • Minority status - Blacks, Hispanics, and Native Americans have the highest rates in the United States

  • History of concurrent or past STDs

  • Exchange of sex for drugs or money

  • Use of crack cocaine

  • Early age of onset of sexual activity

  • Pelvic inflammatory disease (PID) - Use of an intrauterine device (IUD)

Epidemiology

Occurrence in the United States

An estimated 820,000 new gonococcal infections occur annually in the United States, with a significant number of cases likely unreported.[14] Per the CDC, gonorrhea is the second most commonly reported communicable disease.[15] The national average in 2009 was 99.1 cases per 100,000 population, a 10.5% decrease from 2008, with considerable state-to-state variation (see the figure below).[16, 17] Men were apparently less likely than women to be tested for gonorrhea, 20.7% vs 50.9%, respectively.[18] However, the infection rates between men and women were similar (105.8 vs 108.7 cases per 100,000).[19]

Gonorrhea rates, United States, 1941-2016. Courtes Gonorrhea rates, United States, 1941-2016. Courtesy of the Centers for Disease Control and Prevention (CDC).

One report estimated the annual cost of gonorrhea and its complications to be $162.1 million (range, $81.1 million to $243.2 million).[20]

In the United States, the number of gonococcal infections peaked in the 1970s, the era of the sexual revolution. With the onset of the HIV epidemic and the practicing of safe sex techniques, the incidence dramatically decreased from 468 cases per 100,000 population in 1975 to 100-150 cases per 100,000 population at the turn of the century. The rate of reported gonorrhea cases was at its lowest in 2009 but has been increasing overall since then.[21] Since 2016, more than 450,000 cases have been reported to the CDC, with a rate of 145.8 cases per 100,000 people, an increase of 18.5% from 2015.[22] The increased numbers have been attributed to increased cases in males and persistently high rates in adolescents, young adults, and certain racial/ethnic groups in defined geographic areas.[22]

Within the United States, carriage rates highly depend on the geographic area, the racial and ethnic group, and sexual preferences. The rate of gonorrhea is much higher in African Americans than in other racial groups[23] and is much higher in the rural southeastern United States and in inner cities, presumably because of an association with socioeconomic and behavioral factors, as well as with social networks.

In 2016, rates of infection ranged from about 479.9 cases per 100,000 population in the District of Columbia to 20.1 cases per 100,000 population in Vermont.[24] The CDC supports a campaign (Healthy People 2020) that targets a decreased incidence rate of 251.9 cases per 100,000 population among females aged 15-44 years and 194.8 per 100,000 population among males of the same age by the year 2020.

Rates of gonococcal infection per 100,000 by state Rates of gonococcal infection per 100,000 by state and outlying regions (2016). Courtesy of the Centers for Disease Control and Prevention (CDC).

In children who have been sexually abused, rates of recovery of gonorrhea range from 1% to 30%. In female adolescents who are sexually active, asymptomatic carriage of gonorrhea occurs in 1-5%.

Resistant gonorrhea

The incidence of antibiotic-resistant strains of N gonorrhoeae has been rising since the late 1940s. Of greatest concern is the rise in the percentage of cases due to N gonorrhoeae with higher minimum inhibitory concentrations (MICs) to ceftriaxone, the current treatment of choice. In 2016, the Gonococcal Isolate Surveillance Project (GISP) found 0.3% of the tested isolates had elevated ceftriaxone MICs.[25]

In May 2016, the first cluster of highly resistant gonorrhea infections in the United States was identified in Hawaii. Most of the isolates showed decreased susceptibility to ceftriaxone, and all cases had very high-level resistance to azithromycin.[26]

International occurrence

An estimated 98 million new cases of gonorrhea occur annually, according to World Health Organization estimates. In comparison, an estimated 62 million new cases occurred in 1999 and 88 million in 2005. In 1999, the number of new cases of gonococcal infection diagnosed in North America was 1.56 million; in Western Europe, 1.11 million; in South and Southeast Asia, 27.2 million; and in Latin America and the Caribbean, 7.27 million.

Gonorrhea was the most common STD worldwide for at least most of the 20th century, although since the mid-1970s, public health initiatives in the industrialized world have resulted in declining incidence of the disease. As noted earlier, however, gonococcal infection is still the second most common notifiable disease in the United States, and Western European rates approximate those in the United States.[27, 28, 29]

Although the frequency data are unknown in most developing nations, these countries are considered to have the highest rates of gonorrhea and its complications. Gonococcal infection rates in pregnant women in the Central African Republic and South Africa were found to be 3.1% and 7.8%, respectively.

Resistant gonorrhea

The incidence of antibiotic-resistant strains has been rising since the late 1940s. Of greatest concern historically has been the high percentage of cases due to penicillinase-producing N gonorrhoeae. However, fluoroquinolone resistance has increased rapidly over the past decade on most continents and within the United States. The CDC reported fluoroquinolone resistance in 6.8% of 2004 isolates, 9.4% of 2005 isolates, and 13.3% of 2006 isolates.[6]

Race-related demographics

All sexually active populations are at risk for gonococcal infection, and the level of risk rises with the number of sexual partners and the presence of other STDs.

Although race has no intrinsic effect on susceptibility to gonorrhea, the frequency of gonorrhea in the United States is increased among urban dwellers, individuals of lower socioeconomic status, and minorities of any population. This may be due to decreased access to diagnosis and treatment; lack of adequate care (ie, education, diagnosis, and treatment), leading to increased transmission rates; and/or reflection bias due to data collection site preference (eg, urban emergency departments [EDs] and STD clinics), as well as true differences in prevalence.

Overall, the African American–to–white ratio of gonococcal infections declined from 23:1 in 2002 to 18:1 in 2006. Infection rates have been trending downward since 1998. However, between 2005 and 2006, the CDC noted a 6.3% increase in the rate of gonococcal infections in African Americans. Subsequently, rates have begun to downtrend once again. (See the figure below.)

Gonorrhea rates by race/ethnicity, United States, Gonorrhea rates by race/ethnicity, United States, 2012-2016. Courtesy of the Centers for Disease Control and Prevention (CDC).

Compared with reported incidence in whites, the rate of reported cases was 8.6 times higher in blacks, 3 times higher in native Hawaiians/Pacific Islanders, 1.7 times higher in Hispanics, and 0.5 times higher in Asians.[21] From 2012-2016, the rate of gonorrhea increased among all races and ethnic groups.

Sex-related demographics

The male-to-female ratio for gonorrhea is approximately 1:1.4; however, females may be asymptomatic, whereas males are rarely asymptomatic. From 2015 to 2016, rates among males increased approximately 22%, while rates in females increased 13.8%. The large increase in diagnosis in males has been attributed to either increased transmission or increased case documentation (increased extra-genital screening) among men who have sex with men (MSM).[21]

Serious sequelae are much more common in women, in whom pelvic inflammatory disease (PID) may lead to ectopic pregnancy or infertility and in whom DGI is more likely, owing to menstruation, pregnancy, and a higher incidence in occult infection.

Age-related demographics

The highest incidence of gonococcal infection in the United States in 2016 was among adults aged 20-24 years, in both men and women.[16, 17] This is likely due to the following (see the figure below):

  • Increased numbers of sexual partners
  • Decreased access to or use of health care
  • Physiologic ectopy of the squamocolumnar junction in females
  • Decreased use of barrier contraceptives
Rates of reported gonorrhea cases by age group and Rates of reported gonorrhea cases by age group and sex, United States, 2016. Courtesy of the Centers for Disease Control and Prevention (CDC).

Infection in children is a marker for child sexual abuse and should be reported as such, although a 2007 review provided some support for nonsexual transmission between children and for transmission from adults to children related to poor hand hygiene.[30, 31]

Gonococcemia remains an important disease in the adolescent and young adult population, with a peak incidence in males aged 20-24 years and in females aged 15-19 years.

Prognosis

With adequate early therapy, complete cure and return to normal function are the rule. Most gonococcal infections respond quickly to cephalosporin therapy. Late, delayed, or inappropriate therapy may lead to significant morbidity or, on rare occasions, death.

Complications in males

Urethral strictures secondary to gonococcal infection in men are less common than previously thought. Some strictures in the preantibiotic era likely resulted from treatment by urethral irrigation using caustic compounds rather than from the gonorrhea itself.

Other complications, such as penile lymphangitis, periurethral abscess, acute prostatitis, seminal vesiculitis, and infection of the Tyson and Cowper glands, are now rare.

Complications in females

Tubal scarring and infertility are the major complications of gonococcal infection in females. The incidence of involuntary infertility is estimated at 15% after one attack of pelvic inflammatory disease (PID) and approximately 50%-80% after 3 attacks. (However, infertility may be more common after chlamydial PID than after gonococcal PID, presumably because the more acute inflammatory signs associated with gonorrhea prompt women to seek diagnosis and treatment sooner.) Despite clinical and microbiological cure of infection, one study showed 13% infertility rates in females with PID due to N gonorrhoeae infection.[32]

Failure to diagnose PID can result in acute morbidity, including tuboovarian abscess, endometritis, Fitz-Hugh-Curtis syndrome (perihepatitis), and other chronic sequelae. Perihepatitis secondary to gonorrhea presents as right upper quadrant pain and nausea.

The incidence of ectopic pregnancy is increased from 7-fold to 10-fold in women with previous salpingitis, with resultant increased fetal and maternal mortality rates.

Gonococcal infections in women may also manifest as gonococcal urethritis or infection of periurethral (Skene) or Bartholin glands.

Pelvic inflammatory disease

PID is generally the most feared complication of gonococcal infection, because it is one of the leading causes of female infertility and often leads to hospitalization. This can be devastating to any woman, especially an adolescent who potentially has many years of childbearing ahead of her. In a 2011 study, female adolescents with PID were more likely than older women to have a rapid recurrence of PID or to become pregnant despite reporting more consistent condom use.[33] Ten to twenty percent of patients diagnosed with cervical gonorrhea may develop PID.

Tubo-ovarian abscess and, rarely, tubal perforation with peritonitis and death, can occur, especially if the tubo-ovarian abscess was recurrent. Females with recurrent PID have high rates of ectopic pregnancy and infertility.

Epididymitis and orchitis

Epididymitis and orchitis occur infrequently in males who go untreated. These conditions usually respond well to the same antibiotics used for uncomplicated urethritis, but the drugs are administered for a longer course.

Arthritis

Gonorrhea is the most common cause of arthritis in the adolescent. However, arthritis (septic or reactive) is a rare complication of this disease.

Because it mimics septic arthritis, excluding the possibility of gonococcal infection in any adolescent with acute onset of pyogenic arthritis is important. Adequate diagnosis may require culturing extraarticular sites for N gonorrhoeae.

Endocarditis

Endocarditis is a rare but serious complication of disseminated gonococcal infection, affecting 1%-2% of cases. Prior to the era in which antibiotics were the primary treatment, median survival was 6-8 weeks.

Additional complications

Complications of gonococcal infections also include the following[34] :

  • Corneal scarring after ocular gonococcal infections

  • Destruction of cardiac valves in gonococcal endocarditis

  • Death from congestive heart failure related to endocarditis

  • Central nervous system (CNS) complications of gonococcal meningitis

It has been suggested that a person with a gonococcal infection may be at a 3- to 5-fold increased risk of acquiring HIV infection, if exposed to the virus.

DGI is an acute illness that causes fever, asymmetrical polyarthralgias, and skin pustules overlying small joints in patients with gonorrhea. Disseminated infection may also lead to meningitis or endocarditis.

In newborns, vertical transmission can cause conjunctivitis, known as ophthalmia neonatorum, and permanent damage and blindness, if untreated.

Oral sex with an infected partner can result in pharyngitis, and, similarly, anal infection can arise from anal sex or local spread from a vaginal source.

Patient Education

Discuss safe sexual practices with all individuals in whom gonorrhea is suspected. Proper education to prevent gonorrhea may be more effective than simplistic instructions to avoid sex, especially in the teenaged population. Teenagers involved with abstinence-only campaigns have unchanged STD rates and disproportionately acquire anal and oral infections, rather than vaginal infections (the perception being that if an activity is not vaginal sex, it is not sex). Stress that oral or anal sex can also transmit disease.

Patients should know the method of disease transmission and the adverse impact of recurrent infections on future fertility, they should be counseled about the risks of complications following gonococcal infection and the risk of other STDs, and they should always be instructed to refer any sex partners for prompt evaluation and treatment.

In addition, these individuals should be aware that they should avoid sexual contact until medication is finished and until their partners are fully evaluated and treated. Thereafter, they should avoid unprotected contact.

The discussion of responsible sexual behavior should not be limited or withheld because of personal religious or moral views, because these may not be shared by the patient, and teenagers are notorious for sexual experimentation; evidence suggests that offering only limited discussion does the teenage population a huge disservice. This advice is especially pertinent in states where sexual education is almost nonexistent in the school system because of abstinence-only teaching, which is misleading and factually inaccurate.

In one study in Peru, a bundle of interventions that included extensive public health efforts, including training of local medical personnel, specific and presumptive treatment, outreach to female sex workers, and supply of barrier contraception, may have been effective at reducing the prevalence of several STDs, although the effect did not reach statistical significance overall.

The effects were more greatly pronounced (and significant) among female sex workers and young adult women. The study was hampered by several methodologic limitations, such as comparing different cities as controls, which made drawing conclusions from the data difficult.[35]

Abstinence education

Although the most effective STD prevention is abstinence from sex, this is oftentimes an unrealistic expectation, especially in the teenaged population. In fact, 88% of teenagers who pledged abstinence in middle and high school still engaged in premarital sex. Moreover, they tend to have riskier, unprotected sex because of their lack of education. Those who pledge before having sex have been found to have a 33% higher prevalence rate of STDs than have those who had sex and then retrospectively pledged, with nonpledgers falling in between. This is despite a lower number of partners and an older age at first intercourse in pledgers.

Moreover, pledgers are less likely to be aware of their STD status and are less likely to seek testing, even if their STD rates are similar overall (again, highlighting a lack of appropriate sexual education).

Of course, abstinence should be explained to be the best option, but a more practical expectation is abstinence from sex with someone known or suspected of having an STD until treatment is obtained and completed. In light of the difficulty of knowing a potential partner's sexual history (or honesty), strongly recommend the use of condoms as a reasonable alternative to abstinence.[13]

Risks of unprotected sex

Patients should also be counseled about the additional risks of unprotected sex, including the acquisition of more serious or lifelong infections such as herpes, hepatitis B, and HIV, and, of course, about the risks of pregnancy. The emotional aspect of sexual relationships may also need to be addressed, especially in teenage girls. Teenagers are vulnerable in that they are sexually mature but not yet emotionally mature.

For patient education information, see the Sexual Health Center, as well as Sexually Transmitted Diseases, Gonorrhea, and Chlamydia.

Patient education materials are also available at The Centers for Disease Control and Prevention (CDC) Website (Sexually Transmitted Diseases – Gonorrhea) and from many local public health departments.

 

Presentation

History

The incubation period for gonorrhea is usually 2-7 days after exposure to an infected partner. In all patients who present with a possible STD, the history should include the following:

  • Past history of STDs (including HIV infection and viral hepatitis)
  • Treatment history for known STDs
  • Known symptoms of STDs in current or past sexual partners
  • Type of contraception used
  • Any history of sexual assault

In women, the history should also include the date of the last menstrual period and the details of parity, including any history of ectopic pregnancies.

Female genitourinary tract

The most common site of gonococcal infection in women is the endocervix (80%-90%), followed by the urethra (80%), rectum (40%), and pharynx (10%-20%). If symptoms develop, they often manifest within 10 days of infection.

Major symptoms include vaginal discharge, dysuria, intermenstrual bleeding, dyspareunia (painful intercourse), and mild lower abdominal pain.

When gonococcal cervicitis is either asymptomatic or unrecognized, the patient may progress to PID, often in proximity to a menstrual period. PID may also be asymptomatic or silent and occurs in 10-20% of infected women. Symptoms of PID include the following:

  • Lower abdominal pain (most consistent symptom of PID)
  • Increased vaginal discharge or mucopurulent urethral discharge
  • Dysuria (usually without urgency or frequency)
  • Cervical motion tenderness
  • Adnexal tenderness (usually bilateral) or adnexal mass
  • Intermenstrual bleeding
  • Fever, chills, nausea, and vomiting (less common)

Acute perihepatitis (Fitz-Hugh-Curtis syndrome) occurs primarily through direct extension of N gonorrhoeae or Chlamydia trachomatis from the fallopian tube to the liver capsule and overlying peritoneum. Acute perihepatitis is more commonly associated with C trachomatis. Patients with this syndrome may report right upper quadrant pain, nausea, vomiting, and fever, and friction rub may be heard along the right anterior costal margin. Cases tend to occur in individuals with PID and therefore should be among the differential diagnoses of right upper quadrant pain in young sexually active women.

Vaginal discharge from endocervicitis is the most common presenting symptom of gonorrhea and is usually described as thin, purulent, and mildly odorous. Many patients have minimal or no symptoms from gonococcal cervicitis. Dysuria or a scant urethral discharge may be due to urethritis accompanying cervicitis.

Gonorrheal infection of the Bartholin glands (glands near the labia) is asymptomatic in one third of cases but may manifest as perilabial pain, edema, tenderness, and discharge.

Pelvic or lower abdominal pain suggests ascending infection of the endometrium, fallopian tubes, ovaries, and peritoneum. Pain may be midline, unilateral, or bilateral. Fever, nausea, and vomiting may be present. Pelvic examination usually demonstrates bilateral adnexal tenderness, possible tenderness over the uterine fundus, and possible cervical motion tenderness. Abdominal examination elicits lower quadrant tenderness. PID related to gonococcal infection may follow the onset of menses by a few days. The possibility of ectopic pregnancy should always be considered in patients with pelvic or lower abdominal pain.

Rectal infection is often asymptomatic, but rectal pain, pruritus, tenesmus, and rectal discharge may be present if the rectal mucosa is infected. Bloody diarrhea may also occur. Rectal infection may occur from anal intercourse or, in women, by local spread of the organism.

Male genitourinary tract

In men, urethritis is the major manifestation of gonococcal infection. Initial characteristics include burning upon urination and a serous discharge. A few days later, the discharge usually becomes more profuse, purulent, and, at times, blood-tinged.

Acute epididymitis may also be caused by N gonorrhoeae or C trachomatis, especially in men younger than 35 years. This is usually unilateral and often occurs in conjunction with a urethral exudate. The classic presentation of epididymitis is of unilateral pain and swelling localized posteriorly within the scrotum.

Urethral strictures due to gonococcal infection are now uncommon in the antibiotic era, but they can present with a decreased and abnormal urine stream, as well as with the secondary complications of prostatitis and cystitis.

Another manifestation of gonorrhea, rectal infection, may present with pain, pruritus, discharge, or tenesmus.

Sex-independent manifestations

Men and women may exhibit gonococcal infection of the pharynx, rectum, and eye.

Gonococcal pharyngitis is most commonly acquired during orogenital contact, with fellatio predisposing to infection more so than cunnilingus. Pharyngitis is often asymptomatic; however, it may present as exudative pharyngitis with cervical lymphadenopathy. Most cases of pharyngeal infection resolve spontaneously and are believed to be less transmissible than rectal or genital gonorrhea.

Although rectal cultures are positive for gonorrhea in up to 40% of women with cervical gonorrhea (a similar percentage noted in infected homosexual men), symptoms of proctitis are unusual. When symptoms do occur, males are more likely to exhibit symptoms, since trauma during anal intercourse or inoculum size may play a role.

Eye involvement in adults occurs by autoinoculation of gonococci into the conjunctival sac from a primary site of infection, such as the genitals, and is usually unilateral. The most common form of presentation is a purulent conjunctivitis, which may rapidly progress to panophthalmitis and loss of the eye unless promptly treated. Gonococcal conjunctivitis is often reported to be painful and may exhibit photophobia and purulent drainage.

Neonates

In neonates, bilateral conjunctivitis (ophthalmia neonatorum) often follows vaginal delivery from an untreated, infected mother. However, transmission to the newborn can also occur in utero or in the postpartum period.

Symptoms of gonococcal conjunctivitis include eye pain, redness, and a purulent discharge. Neonates may also acquire pharyngeal, respiratory, or rectal infection or disseminated gonococcal infection (DGI).

The organism can cause permanent injury to the eye very quickly. Prompt recognition and treatment are essential to avoid blindness. Blindness due to neonatal gonococcal infection is a serious problem in developing countries but is now uncommon in the United States and in other countries where neonatal conjunctival prophylaxis with antimicrobial therapy is routine. Nevertheless, infants of mothers with untreated infections, poor prenatal care, and unmonitored births continue to be at risk.

Direct infection with N gonorrhoeae in neonates may also occur through the scalp at the sites of fetal monitoring electrodes.

Disseminated gonococcal infection

The symptoms of DGI vary greatly from patient to patient. By the time the symptoms of DGI appear, many patients no longer have any localized symptoms of mucosal infection.

The classic presentation of DGI is an arthritis-dermatitis (tenosynovitis) syndrome. Joint or tendon pain is the most common presenting complaint in the early stage of infection. About 25% of patients with DGI complain of pain in a single joint, but many other patients describe migratory polyarthralgia, especially of the knees, elbows, and more distal joints. Patients may also have tenosynovitis; the early tenosynovitis most commonly affects the flexor tendon sheaths of the wrist or the Achilles tendon ("lovers' heels").

Skin rash is a presenting complaint in approximately 25% of patients, but a careful examination will reveal a rash in most patients with DGI. The rash is usually found below the neck and may also involve the palms and soles.

The dermatitis consists of lesions varying from maculopapular to pustular, often with a hemorrhagic component. Lesions usually number 5-40, are peripherally located, and may be painful before they are visible. Lesions are transient, lasting less than four days. Fever is common but rarely exceeds 39°C.

The second stage of DGI is characterized by septic arthritis, by which time the skin lesions have disappeared and blood culture results are nearly always negative. The knee is the most common site of purulent gonococcal arthritis.

Rare complications of DGI include gonococcal meningitis, pericarditis, and endocarditis. Headache, neck pain and stiffness, fever, and decreased sensorium may indicate gonococcal meningitis. This disease may be clinically indistinguishable from meningococcal meningitis on presentation, although the course of gonococcal meningitis is usually less rapid.

Gonococcal endocarditis is more common in men than in women. Patients with collagen vascular disease (especially those with systemic lupus erythematosus) may also be more prone to this complication. The aortic valve is affected most commonly. A subacute onset of fever, chills, sweats, and malaise may indicate the presence of gonococcal endocarditis. Patients with endocarditis may develop atypical chest pain, cough, and dyspnea and may also develop the arthralgias and rash typical of DGI. Gonococcal endocarditis can cause severe valvular damage and death if not recognized and treated rapidly.

Physical Examination

N gonorrhoeae infection may be recognized by the typical signs and symptoms of the disease, but it is important to remember that, by the time disseminated or upper reproductive tract disease is present, the primary site of mucosal infection may be normal in appearance, and the patient may have no localized signs or symptoms.

With oropharyngeal infection, pharyngitis (usually mild) may be occur. With rectal infection, mucopurulent or purulent discharge may be present.

The physical examination should also always include scrutiny for signs of herpes simplex, syphilis, chancroid, lymphogranuloma venereum, and genital warts.

Neonates

In neonates, look for purulent discharge from the eyes or other infected sites. The discharge from the eyes is usually bilateral in ophthalmia neonatorum, while in older patients, the condition most often is unilateral when secondary to self-inoculation.

Also examine neonates for temperature instability (fever, hypothermia), which can result from disseminated sepsis

Female genitourinary tract

Look for the following in females:

  • Mucopurulent or purulent vaginal, urethral, or cervical discharge

  • Vaginal bleeding; vulvovaginitis in children

  • Cervical friability - Tendency to bleed upon manipulation

  • Cervical motion tenderness during bimanual pelvic examination

  • Fullness and/or tenderness of the adnexa, unilateral or bilateral (eg, ovaries, fallopian tubes)

  • Lower abdominal pain/tenderness, with or without rebound tenderness

  • Possible low back pain - More common in progression to pelvic inflammatory disease (PID)

  • Upper right abdominal tenderness (with perihepatitis)

  • Fever

Male genitourinary tract

Look for the following in males:

  • Mucopurulent or purulent urethral discharge - Obtained by milking the urethra along the shaft of the penis

  • Possible epididymitis - Unilateral epididymal tenderness and edema, with or without penile discharge or dysuria

  • Penile edema without other overt inflammatory signs

  • Urethral stricture - Uncommon; more often seen in the preantibiotic era with urethral irrigation using caustic liquids

Rectal symptoms

Rectal symptoms of gonorrhea include the following:

  • Mucopurulent or purulent discharge with or without rectal bleeding

  • Mucopurulent exudate and inflammatory in the rectal mucosa

  • Rectal abscess (less common)

Ocular and periocular symptoms

Ocular and periocular manifestations of gonorrhea include the following:

  • Anterior chamber - Cellular reaction, hypopyon, endophthalmitis

  • Conjunctiva - Chemosis, acute purulent exudate, hemorrhages (see the image below)

    This patient presented with gonococcal urethritis, This patient presented with gonococcal urethritis, which became systemically disseminated, leading to gonococcal conjunctivitis of the right eye. Courtesy of the CDC/Joe Miller, VD.
  • Cornea - Punctate epithelial keratitis; marginal, sterile stromal infiltrates; epithelial defects; infectious stromal infiltrates; stromal ulcerations; descemetocele; perforation; opacification

  • Lids - Erythema, edema

Disseminated gonococcal infection

DGI may present with any of the following findings:

  • Fever - Usually a temperature of less than 39°C

  • Skin - Maculopapular, pustular, necrotic, or vesicular rash, typically occurring on the torso, limbs, palms, and soles may be present; the rash usually spares the face, scalp, and mouth; hemorrhagic lesions, erythema nodosum, urticaria, and erythema multiforme occur less frequently; the skin lesions are usually in different stages of development at the time of clinical presentation (see the image below)

    Disseminated gonococcemia, acral pustules. Disseminated gonococcemia, acral pustules.
  • Joints - Most patients may have polyarthralgia with joint tenderness, decreased range of motion, and erythema; less often, purulent arthritis may affect a single joint with severe pain, tenderness, edema, erythema, and decreased range of motion

  • Tenosynovitis - Presents as erythema and local tenderness along a tendon sheath, with pain on active or passive range of motion; tenosynovitis most often occurs in the hands but may be found in the tendons of the lower extremities as well

  • Central nervous system - Patients with gonococcal meningitis may present with meningismus or decreased mental status

  • Cardiac - Patients with gonococcal endocarditis may have a new murmur, tachycardia, and fever; embolic lesions may be present.; the aortic valve tends to be the main valve affected

  • Muscle - DGI can cause abscess formation within the soft tissues, presenting as localized tenderness, edema, and pain with motion

Certain patient populations, such as patients infected with HIV, can experience involvement of unusual joints, such as the sternoclavicular joint and the hips, and the arthritis may have a more aggressive course, with potential destruction of the joint.

 

DDx

Diagnostic Considerations

When evaluating a female patient with suspected gonococcal infection, also consider bacterial vaginosis, vaginitis, ectopic pregnancy, pregnancy, tubo-ovarian abscess, endometriosis, and mucopurulent cervicitis. In men, consider epididymitis, orchitis, and testicular torsion.

Other conditions that should be considered include the following:

  • Urinary tract infections
  • Pharyngitis; hepatitis
  • Herpes simplex urethritis
  • Rat-bite fever
  • Inflammatory and septic arthritis
  • Nongonococcal conjunctivitis, endocarditis, meningitis, and urethritis

Differential diagnosis of DGI

Other causes of arthritis and dermatitis may display a clinical picture similar to that of disseminated gonococcal infection (DGI), with some notable differences. Certain risk factors for disseminated infection should be kept in mind, such as acquired complement deficiencies (C5, C6, C7, C8), underlying systemic lupus erythematosus, pregnancy, and recent menstruation.

Reactive arthritis

Reactive arthritis is a human leukocyte antigen B27 (HLA-B27)–associated condition that predominantly occurs in young men and has the clinical triad of urethritis, conjunctivitis, and arthritis. However, the distribution of the arthritis is different, occurring predominantly in the joints of the axial skeleton. The clinical picture is less acute, occurring over the course of weeks rather than days and with less severe fever. This syndrome does not respond to antibiotic therapy, and it does not have the associated dermatitis that occurs in gonococcemia.

Nongonococcal septic arthritis

Nongonococcal septic arthritis can be caused by a variety of organisms, but it presents with an acute onset of joint swelling and pain. Culture of joint fluid commonly reveals organisms. This type of arthritis is a destructive form of arthritis that is usually monoarticular. It most frequently occurs in children and elderly persons. Immediate treatment with antibiotics is indicated.

Rheumatic fever

Rheumatic fever is a rare illness in the modern era and can present with high fever, rash, arthritis, and endocarditis. This condition follows a streptococcal infection and requires long, emergent intravenous (IV) antibiotic therapy for endocarditis; it also responds well to anti-inflammatory medications.

Syphilis

Syphilis, an STD that commonly occurs in sexually active young adults, can also produce a rash, symptoms of arthritis, and genital lesions. However, genital involvement is usually in the form of an ulcer and not urethritis, and the rash can involve the palms and the soles. Laboratory tests, including rapid plasma reagin (RPR) titers, can aid in distinguishing syphilis from gonococcemia.

Other

Other conditions to consider in a patient with arthritis and skin lesions include the following:

  • Meningococcemia
  • Hepatitis
  • Bacterial endocarditis
  • Systemic lupus erythematosus (SLE)
  • Tenosynovitis (eg, de Quervain disease, infectious)
  • Other seronegative arthritides - Eg, ankylosing spondylitis, Sweet syndrome, and related dermal vasculitides

Additional considerations

Other conditions to consider in the differential diagnosis of N gonorrhoeae infection include the following:

  • Sexual abuse
  • Enuresis
  • Sexual assault
  • Testicular torsion
  • Trichomoniasis
  • Endometritis
  • Vaginitis
  • Acanthosis nigricans
  • Cutaneous manifestations of hepatitis C
  • Lyme disease
  • Meningococcemia
  • Psoriatic arthritis
  • Syphilis
 

Workup

Approach Considerations

Culture is the criterion standard test in the workup of gonorrheal infections. Bacterial culture has high sensitivity and high specificity, is relatively low cost, is suitable for different types of specimen sources, and can be used for epidemiologic and resistance testing purposes. However, culturing for Neisseria is problematic because it is difficult to maintain the bacteria’s viability during transport and storage in various settings. Another drawback is that 24-72 hours is needed before a preliminary culture result may return.

Based on CDC guidelines and the USPS Task Force recommendations, nucleic acid amplification test (NAAT) assay is the test of choice to evaluate for urogenital infections in both males and females, whether symptomatic or asymptomatic.[36, 37]

One benefit of NAAT assay is that it does not require live organisms yet can yield a positive result with minimal genetic material available, using specimens such as first catch urine and vaginal swabs. Sensitivity for detection exceeds 90%, and specificity is 99% or higher. NAAT assays approved for use with vaginal swabs may also be approved for use with patient-collected vaginal specimens. Among patients engaging in oral or anal receptive sexual intercourse, NAAT assays may be useful to detect gonorrheal infection. However, NAAT assays using specimens collected from extragenital sites have not been approved by the US Food and Drug Administration (FDA).[38]

For specific CDC screening recommendations based on sex and health state, see the 2015 Sexually Transmitted Diseases Treatment Guidelines.

For the clinical guideline summary from the US Preventive Services Task Force, see the Screening for Gonorrhea: Recommendation Statement.

Culture and nonculture testing for N gonorrhoeae

Perform a culture or nonculture detection test for N gonorrhoeae on endocervical, urethral, pharyngeal, or rectal discharge. Because organisms are intracellular, attempt to obtain specimens in a manner that will contain mucosal cells and not merely discharge (similar to a Papanicolaou smear).

Nonculture tests are less accurate in the presence of blood or during menses. Use culture instead at these times.

Culture is performed on Thayer-Martin plates that must be stored refrigerated but warmed to room temperature before obtaining a sample. The plate is then incubated in a carbon dioxide atmosphere. Poor technique drastically reduces test sensitivity.

Medicolegal cases (eg, child abuse, rape) require culture due to the possibility of false-positive results with nonculture methods. However, performing the more sensitive PCR assay-based tests to raise the likelihood of detecting an infection and then following up with culture to produce admissible evidence is appropriate.

Complete blood count

Patients with gonococcemia may have an elevated white blood cell (WBC) count, in the range of 10,000-15,000/µL.

Erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR) is usually mildly elevated, with values from 20-50 in most patients. Less than 50% of patients have an ESR of higher than 50.

Serologic tests

These tests include latex agglutination, ELISA, immunoprecipitation, and complement fixation tests. Because of their lower sensitivity and specificity, especially in populations with a low prevalence of disease, these tests are not routinely used for diagnosis, but they can be used as adjuncts to the other laboratory tests and may help in making the diagnosis.

Echocardiography

Because of the potential severity of pericarditis and endocarditis, a cardiologic examination, including echocardiography, is recommended, even though these conditions are rare.

Suspected disseminated gonococcal infection

Gram stains, cultures, and nucleic acid amplification tests (NAATs) of genital, rectal, conjunctival, pharyngeal secretions and/or other extragenital sites, as applicable, should also be obtained when DGI is suspected. Specimens from disseminated sites of infection, such as skin, synovial fluid, blood, and CSF, are recommended. Perihepatitis is also an occasional complication.

The highest yield of N gonorrhoeae organisms in gonococcemia is from mucosal sites, including the pharynx, urethra, cervix, or rectum. Urethral and cervical cultures are typically the most revealing. Blood cultures yield positive culture results in 10-30% of patients and joint fluid in 20-30% of patients. Skin lesions yield organisms in only about 10% of patients. Immunofluorescence studies may improve the effectiveness in skin and joint fluid. Gram stain of material from unroofed skin lesions may show typical organisms.

Other STDs

Other tests that may be indicated are those for concurrent STDs. For example, the Preventive Services Task Force recommends that women at increased risk of gonorrhea also be screened for chlamydia, HIV, and syphilis.[39]

Patients in whom gonococcal disease is suspected should be evaluated for syphilis infection, as well as for infection with C trachomatis (high rate of asymptomatic carriage), HIV (with counseling), hepatitis B virus, herpes simplex virus, and any STDs that are suggested by the history and physical examination findings. Administer hepatitis B vaccination to these individuals unless they have received the full vaccine series.

Rapid HIV test technology makes testing in the emergency department (ED) and referral more practical than enzyme-linked immunosorbent assay (ELISA). The need for additional testing depends on the situation; they are often performed as a battery of tests in suspected rape and child abuse cases.

HIV testing in cases of rape or new-onset abuse does not acutely diagnose a new infection but does establish a baseline status of the patient such that subsequent seroconversion might be linked back to the event in question.

Smears With Gram Stain

Urethritis in males

The presence of typical gram-negative intracellular diplococci and polymorphonuclear leukocytes on Gram stain from a specimen collected from a symptomatic male establishes a diagnosis of gonorrhea (sensitivity, >95%; specificity, >99%).[36] A negative Gram stain result is not sufficient for excluding neisserial infections in asymptomatic men. Results are considered equivocal if typical morphotypes not associated with neutrophils are present or if cell-associated, but morphologically atypical, organisms are observed.

Urine

In men, urethritis can be diagnosed using either of 2 methods of Gram staining. The first is via a urine sample. Preferably, examine the patient at least 2 hours after micturition or before his first morning void. The patient should provide a first-morning void, with the first 10-15mL of the urine being saved. The urine is centrifuged so that the sediment may be analyzed microscopically under high power or oil immersion. The presence of 10 or more polymorphonuclear leukocytes (PMNs) seen under high power suggests urethritis.

Urethral exudate

The second method is a Gram stain of urethral exudate. The presence of 4 or more PMNs per oil-immersion field is diagnostic for urethritis. In symptomatic males, Gram staining of urethral exudate yields a sensitivity of 90-98% and a specificity of 95-98%. However, in asymptomatic males, the sensitivity of the Gram stain is only 60%. Therefore, culture studies are recommended if an asymptomatic gonococcal infection is suggested.

Cervicitis in females

In women with positive cervical culture results, the Gram stain results from the endocervix are 50-60% sensitive and 82-97% specific. In addition, the presence of more than 10 PMNs per high-power field on an endocervical smear is consistent with cervicitis. In women who lack a cervix because of hysterectomy, use urethral culture to make the diagnosis.

Emergency department use

Gram stain is a rapid and inexpensive test available in many emergency departments (EDs). The positive predictive value is high for urethral infection, but a negative Gram stain does not rule out infection in asymptomatic men. Collect specimens from the urethra, endocervix, pharynx, rectum, conjunctiva, urine, or blood.

A Gram stain of urethral or cervical discharge may show gram-negative intracellular diplococci (diagnostic in the male) and PMNs. This is very useful if the physician has easy access to a microscope, because the diagnosis may be made without waiting for culture results.

The sensitivity and specificity of the Gram stain are lower for endocervical and rectal specimens. Gram stains from these sites are not recommended for routine use in the ED. In addition, Gram staining is not useful for the diagnosis of pharyngeal infection, because the oropharynx may be colonized by other Neisseria species that can lead to false-positive results.

Isolation Via Culture

Specific culture of a swab from the site of infection is a criterion standard for diagnosis at all potential sites of infection. Bacterial culture has high sensitivity and specificity, is relatively low cost, and is suitable for different types of specimen sources. Cultures are particularly useful when the clinical diagnosis is unclear, when a failure of treatment has occurred, when contact tracing is problematic, and when legal questions arise. However, culturing for Neisseria is problematic because the bacteria’s viability is difficult to maintain during transport and storage in various settings. Another drawback is the time; 24-72 hours may be needed before a preliminary culture result is available. Therefore, empiric treatment is often necessary in patients awaiting diagnosis via culture.[40]

A small percentage (approximately 5%) of isolated gram-negative diplococci from genital, rectal, and pharyngeal cultures are actually Neisseria meningitidis, which can cause clinical disease that is identical to gonococcal infections of the urethra, cervix, or rectum. Hence, speciation from samples from pharyngeal and rectal sites should be standard, while samples from genital sites are recommended.

Antimicrobial susceptibility testing is generally unnecessary except in cases of resistance surveillance testing or cases of disseminated infection.

N gonorrhoeae is a fastidious organism that requires an enriched medium, such as Thayer-Martin or Martin-Lewis medium, and must be incubated at 35-36.5°C with supplemental 5% CO2. Poor technique, failure to store collected specimens appropriately, and slow transport to the microbiology laboratory drastically reduce test sensitivity.

If multiple specimens are to be collected from one anatomic site, it is recommended that the N gonorrhoeae culture specimen be obtained first, as this will increase likelihood of successful culture.[36] Gonorrheal cultures should be obtained with a plastic or wire shaft with rayon, Dacron, or calcium alginate tip, as wooden shafts and cotton-tip swabs might be inhibitory and may prevent optimal recovery of the organism. Culture swabs should be inserted 2-3 cm into the male urethra or 1-2 cm into a female endocervical canal followed by 2-3 rotations of the swab. If there is urethral discharge, exudate collection is adequate for gonorrheal culture.

Sensitivity

A single culture on most selective media yields a sensitivity of 95% or more for urethral specimens from men with symptomatic urethritis. A sensitivity rate of about 80-90% is found for endocervical infections in women. For maximized yield in cervical specimens, simultaneous inoculation on selective and nonselective media is recommended. Culture may take several days to weeks.

Specimen collection

Although the urethra is commonly infected in women with gonorrhea, culturing urethral specimens does not materially increase the diagnostic yield except in women who lack a cervix because of hysterectomy.

Patients with possible disseminated gonococcal infection (DGI) should have culture samples taken from all possible mucosal sites (ie, pharynx, urethra, cervix, rectum) and from blood and synovial fluid. Rectal and pharyngeal specimens are inoculated onto selective medium only.

When collecting specimens in males, any discharge present at the meatus can be easily recovered for examination. If no discharge is present at the meatus, urethral material must be recovered by inserting and rotating a small swab 2-3 cm into the urethra. A calcium alginate or Rayon swab on a metal shaft is recommended.

When collecting specimens in women, the exocervix is first wiped of exudate. A swab is then placed into the external os and rotated for several seconds. However, take care to avoid contact with vaginal mucosa or secretions, as vaginal fluids are inadequate.

Cultures of the conjunctiva

Chocolate agar in a carbon dioxide–enriched environment is the best medium. Blood agar, MacConkey medium, and phenylethyl alcohol with 5% sheep blood also are good media.

Isolation through other bodily fluid cultures

In patients who may have DGI, all possible mucosal sites should be cultured (eg, pharynx, cervix, urethra, rectum), as should blood and synovial fluid (in cases of septic arthritis). Three sets of blood cultures should also be obtained. Specimens from any mucosal site should be inoculated immediately in selective media for gonorrheal organisms, such as modified Thayer-Martin, or on chocolate agar at room temperature, which should be incubated in an enriched carbon dioxide environment. The growth of typical oxidase-positive colonies that consist of gram-negative diplococci strongly suggests gonorrhea.

Samples from normally sterile sites (eg, blood, cerebrospinal fluid [CSF], synovial fluid) should be plated on nonselective and broth mediums. On the other hand, rectal and pharyngeal specimens, locations where commensal Neisseria may be present, should be inoculated onto selective medium only.

Synovial fluid aspirations in patients with septic arthritis usually yield greater than 50,000 leukocytes/µL, while synovial fluid culture is variably positive. Blood cultures, at this point, are often negative.

Gram stain and culture of vesicular or pustular skin lesions were found to have a diagnostic yield of less than 5%. Immunofluorescent techniques may be used to achieve better results.

Blood cultures

When disseminated gonococcal infection is suspected, a minimum of three sets of blood cultures should be obtained, given that bacteremia is intermittent.

If a patient is suspected of having gonococcal arthritis-dermatitis, gonococci may be recovered in blood culture.

Imaging Studies

Plain radiography

Chest radiography may show hemidiaphragm elevation in Fitz-Hugh-Curtis syndrome. Joint plain films to evaluate septic joints are often unrevealing but may help to rule out fracture or other disease processes.

Ultrasonography or CT scanning

Ultrasonography may be indicated in women to investigate suspected pelvic inflammatory disease (PID) and to visualize the appendix and ovaries as other possible causes of the symptoms. Pelvic ultrasonography or computed tomography (CT) scanning may demonstrate thick, dilated fallopian tubes or abscess formation.

PID is uncommon in pregnancy when the cervical mucus plug may provide some protection to the upper tract. Ultrasonography should be used to rule out ectopic pregnancy whenever a pregnant patient has signs and symptoms of possible PID.

Abdominal imaging may give indications of peri-hepatic adhesions or abdominal loculated fluid collections or help to exclude other diagnoses.

Nucleic Acid Amplification Tests

NAATs amplify genetic sequences (DNA or ribonucleic acid [RNA]) from a few copies to millions in a short period of time. One of the key benefits of NAATs is that a wide variety of specimen types may be sampled, including swabs from the endocervix, vagina, urethra (men), and urine (men and women). Variations of this process include ligase chain reaction tests and strand displacement amplification.

These tests are very sensitive; they are also more rapid than culture, more specific than immunoassays, and do not require viable organisms.[41] However, they are expensive, and results must be interpreted carefully because of false-positive results in certain settings.[42, 43]

NAATs may be of particular use when examination and mucosal swab are difficult (in children or extremely apprehensive patients) and urine specimens are more easily obtained. However, although these tests can be used on eye secretions, their performance is less well validated. In addition, NAATs are not all recommended for rectal and pharyngeal specimens at this time.

Clinicians should be familiar with specimen collection guidelines and performance parameters of the test available at their own hospitals.

NAATs of genital, rectal, conjunctival, and pharyngeal secretions should also be obtained, regardless of presenting symptoms or exposure history, when disseminated gonococcal infection (DGI) is suspected, even if the patient has no localized symptoms at any of those sites.

Pharyngeal gonococcal infections can occur in heterosexual men diagnosed with urethritis. Screening for pharyngeal colonization by N gonorrhoeae and C trachomatis using validated NAATs has been recommended for heterosexual men diagnosed with urethritis.[44]

PCR and LCR

PCR and ligand chain reaction (LCR) are gene amplification techniques that markedly increase the sensitivity of specimen testing. Both techniques amplify the genetic fingerprint of specimens with very few organisms present in order to more easily detect and identify the organisms.

These methods have a high sensitivity and a high specificity (78.6% and 96.4%, respectively). They are easily performed on urethral specimens and can even be performed on first-void urine specimens. PCR and LCR are noninvasive, rapid, sensitive, and specific, and they have facilitated the diagnosis of gonococcal infection.[45] However, they cannot report antibiotic sensitivities; therefore, these techniques do not eliminate the need for culture in these patients.

In addition, specific molecular tests may produce erroneous results.[43] In certain circumstances, it may be advisable, in consultation with a medical microbiologist, to take a sample for culture or to perform a second molecular test aimed at a different part of the bacterial genome.

N gonorrhoeae was identified as the causative agent in a case of culture-negative dermatitis-arthritis syndrome using real-time PCR.[46] This technology can improve the speed and sensitivity of diagnosis and consequent management of patients with this syndrome.

Some studies have been shown promise in the use of DNA polymerase chain reaction (PCR) assay for porA pseudogene detection, possibly even in nongenital sites.[47]

Nucleic Acid Probe Signal Amplification

Nucleic acid probe signal amplification (NAPSA) detects DNA sequences using RNA probes. Located sequences are then coated with detection antibodies, which allow detection. One commercial product uses a single test to detect gonorrhea and chlamydia. More study is needed to evaluate the sensitivity of this technique compared with that of NAAT.

Consider verifying positive urogenital nucleic acid detection test results (PCR, LCR, strand displacement amplification, ribosomal RNA or DNA sequence amplification tests) when false-positive results are likely. In 2002, the CDC recommended testing a second specimen with a different test to confirm the positive results.[48] Australia and the United Kingdom have proposed guidelines to test the initial specimen with supplementary tests using different target sequences. The recommendations were that a result be reported as positive only if both test results were positive.[49]

Be aware that nonculture tests do not provide antimicrobial susceptibility results. Thus, in scenarios in which resistance or treatment failure is considered, culture and antimicrobial susceptibility testing may be warranted.

Antibody-Antigen Testing

The immunochromatographic strip test (IST) combines antibodies from a patient’s specimen (secretions or urine) and N gonorrhoeae antigens on a nitrocellulose strip. One study showed that this technique yielded a sensitivity of 70% and specificity of 97%.[50]

Optical immunoassay (OIA) also uses antigen-antibody reactions (monoclonal), but on a silicon wafer; a positive reaction is evidenced by a color change. A sensitivity of 60% and specificity of 90% was reported.

Both rapid tests yield results within 30 minutes and require minimal training to use. Initial test results show some promise, but additional verification of their utility in appropriate settings is still needed.[51]

Procedures

Laparoscopy

In women with symptoms and signs suggestive of pelvic inflammatory disease (PID) who are difficult to diagnose clinically, laparoscopy may be indicated to rule out (and, if need be, to treat) appendicitis, ovarian torsion, ectopic pregnancy, or other surgical emergencies. When evaluating perihepatitis, laparoscopy may demonstrate the classic "violin string" adhesions seen between the liver capsule and the parietal peritoneum.

Imaging studies such as ultrasonography are obviously a less invasive means of obtaining diagnostic information, but potentially emergent cases may require a more definitive examination, which permits rapid intervention if required.

Culdocentesis

In PID, culdocentesis, although rarely indicated, may demonstrate free purulent exudate and provide material for Gram stain and culture.

Arthrocentesis

In septic arthritis cases, arthrocentesis may show purulence and/or causative organisms.

Lumbar puncture

Perform lumbar puncture and joint aspiration, if indicated by clinical findings. Rarely would CSF fluid yield positive results in cases of meningitis secondary to gonorrhea.

Histologic Findings

Exudate of PMNs is typical. Gram-negative intracellular diplococci are seen microscopically (see the image below). In pelvic inflammatory disease (PID), loss of ciliated columnar epithelium from the fallopian tubes may occur. Tubes, pelvic mesentery, and ovaries may be bound together with dense fibrosis and abscess formation.

Cytologic smear of cutaneous acral pustule showing Cytologic smear of cutaneous acral pustule showing gram-negative, intracellular diplococci.

Testing for Gonorrhea in Males

According to the latest US Preventive Task Force (USPTF) statement, there are insufficient data to assess the balance of benefits and harms of screening for gonorrhea in males.[37] However, when testing a male for gonococcal infection, NAAT assay testing of urine specimens is the recommended first-line method for diagnosing gonorrheal genitourinary infections. Evidence has shown that the first catch urine specimen is as good as, if not better than, urethral swabs specimens in the detection of genitourinary gonorrheal infections.[52] Urethral swab specimen collection is recommended in patients in whom CDC-recommended initial therapy has failed based on repeat positive NAAT assay results 7 days or more days after treatment and who are not believed to have been re-exposed to gonorrhea after the treatment course. The specimen should be sent for antibiotic susceptibility to evaluate for antimicrobial resistance.

Testing for Gonorrhea in Females

According to the USPTF recommendation, sexually active women younger than 25 years and older women at increased risk for gonococcal infection (defined by the CDC as those who have a new sex partner, more than one sex partner, a sex partner with concurrent partners, or a sex partner who has an STI) should be screened annually. Other medical governing bodies have also suggested other risk factors for gonorrhea, including prior gonococcal infection, other concurrent sexually transmitted infections, inconsistent condom use, commercial sex work, and illicit drug use.

The preferred method to screen for genitourinary gonorrhea is collection of vaginal swab specimens sent for NAAT assay testing. Studies have shown that the sensitivity of vaginal swab specimens is equal to that of cervical swab specimens.[53] In addition, patient-collected vaginal specimens also have the same sensitivity and specificity as clinician-collected specimens.[54, 55]

If the patient needs a concurrent pelvic examination, an endocervical swab is reasonable. However, in contrast with workup in males, first catch urine specimens to detect gonorrhea may detect about 10% fewer infections when compared with vaginal and endocervical swab specimens.

In patients in whom CDC-recommended initial therapy has failed based on repeat positive NAAT assay results 7 or more days after treatment and are not believed to have been re-exposed to gonorrhea after the treatment course, an endocervical swab for N gonorrhoeae should be obtained and sent for antibiotic susceptibility to evaluate for antimicrobial resistance.

Testing for Gonorrhea at Extragenital Sites

Extragenital gonorrheal infections (pharyngeal and rectal infections) are often asymptomatic and are not uncommon in certain populations, such as men who have sex with men (MSM). Annual screening of extragenital sites in the MSM population is recommended by the CDC. While NAAT assay is the test of choice for extragenital gonorrheal infection screening, NAAT assays have not been approved by the FDA for pharyngeal and rectal specimens. Laboratories are recommended to process extragenital NAAT assay screens in compliance with Clinical Laboratory Improvement Amendments (CLIA) guidelines.[56] It is also important to be aware that certain NAAT assays may detect commensal Neisseria species and thereby yield false-positive results. In this situation, alternative testing methods may be needed for increased accuracy. If a patient has received a CDC-recommended antibiotic course with a repeat positive NAAT assay result 7 or more days after treatment and is not believed to have been re-exposed to gonorrhea after the treatment course, a rectal and/or oropharyngeal swab specimen for N gonorrhoeae culture should be obtained and evaluated for antibiotic susceptibility.

 

Treatment

Approach Considerations

As discussed in the Workup section, females with diagnosed or suspected sexually transmitted diseases (STDs) should have a concomitant pregnancy test. This guides further care and allows treatment with medications that are not approved for use in pregnancy.

Identification and treatment of the patient's partner and any partners of the partner are important to prevent reinfection and complications.

Prevention of neonatal disease is with the use of silver nitrate, erythromycin, ciprofloxacin, gentamicin, or erythromycin eye drops.

Inpatient versus outpatient treatment

The main decision once a diagnosis of gonorrhea has been made, either definitively or presumptively, is whether to treat the patient as an outpatient or to hospitalize him or her.

For males, treatment is always outpatient for genital infection; however, admission may be necessary for complications such as disseminated gonococcal infection (DGI) or gonococcal arthritis.

In females, the decision is much more difficult, because the risk of complications is much higher. In light of high rates of noncompliance, reinfection, and poor follow-up, some clinicians advocate admitting a female patient whenever a question of a complication such as pelvic inflammatory disease (PID) is present, particularly in the adolescent population.

Many institutions have attempted to quantify abnormalities found on pelvic examination (ie, the PID score) in an attempt to admit those patients with a higher likelihood of complications.

In cases in which future fertility is at risk, most physicians are fairly aggressive, especially in situations in which the patient is very young or unfamiliar to them.

Many physicians admit patients who have corneal involvement for treatment with IV antibiotics. These patients can be discharged once the infection is under control and the corneal infection is improving.

Surgical care

Septic joints should be aspirated to make the initial diagnosis and to remove inflammatory exudate. Open drainage is rarely indicated, except in infections of the hip in children. Most authorities recommend removal of intrauterine devices in women with PID.

Pharmacologic Treatment Regimens

Because of resistance with oral cephalosporins, only 1 regimen, dual treatment with ceftriaxone and azithromycin, is recommended for treatment of gonorrhea in the United States. Dual therapy with ceftriaxone and azithromycin should be administered together on the same day, preferably simultaneously and under direct observation. In addition, persons infected with N gonorrhoeae frequently are coinfected with C trachomatis; this finding has led to the longstanding recommendation that persons treated for gonococcal infection also be treated with a regimen that is effective against uncomplicated genital C trachomatis infection, further supporting the use of dual therapy that includes azithromycin.[1]

Combination with azithromycin, versus doxycycline, is preferred because of the more convenient dosing, likely better patient compliance, and reports of increasing resistance to tetracyclines in some Gonococcal Isolate Surveillance Project (GISP) samples.

Uncomplicated urogenital, anorectal, and pharyngeal gonococcal infection

First-line dual drug therapy regimen is as follows[1] :

  • Ceftriaxone 250 mg intramuscular (IM) single dose plus
  • Azithromycin 1 g PO single dose

The 250-mg IM dose of ceftriaxone is now recommended over the 125-mg dose, given concern for resistance, prior lower-dose ceftriaxone dose failures, and seemingly improved efficacy in pharyngeal infections. No benefit has been found for ceftriaxone dosing greater than 250 mg. Ceftriaxone is safe and effective in pregnant women and probably destroys incubating syphilis. Its major drawback is the necessity for IM administration.

A review of the recommendations for antimicrobial treatment of uncomplicated gonorrhea in 11 East European countries showed ceftriaxone (250-1000 mg IM once) was a first-line antimicrobial in all of them.[57] (However, many of the second-line and alternative treatments were less than ideal, with regionally manufactured antimicrobials predominantly used.)

Data have indicated that the 400-mg oral dose of cefixime does not provide a bactericidal level that is as high or as sustained as that of the 250-mg dose of ceftriaxone and provided a lower cure rate for pharyngeal gonorrhea. The oral cephalosporins cefpodoxime and cefuroxime seem to be inferior and have less desirable pharmacodynamics.[58, 59] In addition, based on findings from the Gonococcal Isolate Surveillance Project (GISP), reported July 2011, from 2009-2010 a decreasing susceptibility to cefixime was found.[60] In response, the CDC issued revised guidelines that do not include oral cephalosporins as first-line treatment.[61]

Because of the persistent increase in multidrug-resistant gonorrhea, the 2015 CDC treatment recommendations are as follows[1] :

  • Treat gonorrhea at any anatomic site with a single intramuscular injection of 250 mg ceftriaxone plus azithromycin 1 g PO as a single dose
  • If ceftriaxone is unavailable, patients can be given a single oral dose of cefixime 400 mg plus a single dose of azithromycin 1 g PO

Alternative treatment options

Per CDC guidelines, single-dose injectable cephalosporin regimens (other than ceftriaxone 250 mg IM) that are safe and generally effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg IM), cefoxitin (2 g IM with probenecid 1 g PO), and cefotaxime (500 mg IM).[62] None of the above regimens offers any additional benefits for urogenital infection and may be more questionable in the treatment of pharyngeal infection.[58, 63]

In patients who are cephalosporin allergic, consider alternant dual therapy with single doses of gemifloxacin PO 320 mg plus azithromycin 2 g PO, or gentamicin 240 mg IM plus azithromycin 2 g PO.[64] Note that, while both of the above regimens seemed to have treated the few extragenital infections in the population studied, it was not powered to give reliable estimates of regimen efficacy. Be aware of treatment-limiting adverse gastrointestinal adverse effects (eg, vomiting) of both of the cephalosporin-allergic regimens, 7.7% and 3.3%, respectively.

Another alternative regimen for patients intolerant of cephalosporins include is spectinomycin (2 g IM). Spectinomycin may be costly and is currently unavailable in the United States.

If azithromycin allergic, doxycycline (100 mg PO BID for 7 days) can be used in place of azithromycin as an alternative second antimicrobial when used in combination with ceftriaxone or cefixime. However, be aware of the rising prevalence of tetracycline resistance among GISP isolates.

The CDC recommends that patients should return for a test of cure in 1 week. The CDC advises that clinicians should perform susceptibility testing in patients who fail to respond to treatment and notify their local public health STD program.[65]

Monotherapy with azithromycin is no longer recommended because of concerns over the ease with which N gonorrhoeae can develop resistance to macrolides, and because several studies have documented azithromycin treatment failures. Strains of N gonorrhoeae circulating in the United States are not adequately susceptible to penicillins, tetracyclines, or older macrolides (eg, erythromycin); thus, use of these antimicrobials cannot be recommended.[1]

Gonococcal pharyngeal infections may be more challenging to eradicate than infections involving urogenital and anorectal areas.[66]

Investigational and future treatment options

In a clinical trial conducted by the CDC and NIH, 2 new antibiotic regimens successfully treated gonorrhea infections. The 2 regimens consist of gentamicin IV plus azithromycin PO, and gemifloxacin PO plus azithromycin PO. The study was conducted to identify new treatment options in the face of growing antibiotic resistance.[67, 68] While the study results offer successful treatment options, the CDC is not recommending a change in current guidelines due to the severe gastrointestinal side effects reported by trial participants. However, providers may consider using the regimens studied in this trial as alternative options when ceftriaxone cannot be used.[69]

The study of these antibiotic regimens included 401 men and women ranging in age from 15 years to 60 years. The combination treatments were highly effective in curing genital gonorrhea infections. The gentamicin plus azithromycin was found to be 100% effective and the gemifloxacin plus azithromycin was 99.5% effective. Both combinations cured 100% of gonococcal infections of the throat and rectum.[67, 68]

Although highly effective, the regimens frequently caused adverse GI effects. Of the 202 participants in the gentamicin plus azithromycin arm, 28% experienced nausea, 19% experienced diarrhea, and 7% experienced either abdominal discomfort/pain or vomiting. Of the 199 participants in the gemifloxacin plus azithromycin arm, 37% experienced nausea, 23% experienced diarrhea, and 11% experienced abdominal discomfort/pain.[67, 68]

Because of the emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) N gonorrhoeae, combinations of available medications have been tested to maximize treatment response. Two combinations showed some promise in vitro: (1) gentamicin plus ertapenem and (2) gentamicin plus cefixime. Further investigation of these two combination regimens for treatment of drug-resistant gonorrhea is necessary prior to mainstream use.[70]

The novel experimental oral antibiotic ETX0914 (Entasis Therapeutics) was found to be safe and efficacious in treating uncomplicated urogenital gonorrhea in a phase 2 clinical trial. The FDA has designated ETX0914 a Qualified Infectious Disease Product and awarded the drug fast-track status.[26]

Drugs that are not primary treatment options

Prior to 2007, fluoroquinolones were the preferred class of antimicrobials for the treatment of gonorrhea; however, reports surfaced of N gonorrhoeae infection with decreasing susceptibilities and frank resistance. In addition, United States gonococcal strains with elevated MICs to cefixime also are likely to be resistant to tetracyclines but susceptible to azithromycin. Consequently, only 1 regimen, dual treatment with ceftriaxone and azithromycin, is recommended for treatment of gonorrhea in the United States.[1]

In August 2012, the CDC announced changes to 2010 sexually transmitted disease guidelines for gonorrhea treatment. The Gonococcal Isolate Surveillance Project (GISP) described a decline in cefixime susceptibility among urethral N gonorrhoeae isolates in the United States during 2006-2011. Because of cefixime’s susceptibility, new guidelines were issued that no longer recommend oral cephalosporins for first-line gonococcal infection treatment.[61]

In April 2007, the CDC updated treatment guidelines for gonococcal infection and associated conditions. Fluoroquinolone antibiotics were no longer recommended to treat gonorrhea in the United States. The recommendation was based on analysis of new data from the CDC's aforementioned GISP. The data showed the proportion of gonorrhea cases in heterosexual men that were fluoroquinolone-resistant (QRNG) reached 6.7%, an 11-fold increase from 0.6% in 2001.[6]

However, if a patient has an absolute contraindication to cephalosporin and other viable antibiotic options are limited, a fluoroquinolone may still have a role in treatment. In these situations, sensitivity testing would be necessary in the event of treatment failure.

Tetracyclines are no longer acceptable first-line therapy for gonorrhea because of the prevalence of tetracycline-resistant strains. Doxycycline 100 mg PO BID for 7 days can be used in place of azithromycin as an alternative second antimicrobial when used in combination with ceftriaxone or cefixime (also second-line therapy). Furthermore, as cefixime becomes less effective, continued used of cefixime might hasten the development of resistance to ceftriaxone, a safe, well-tolerated, injectable cephalosporin and the last antimicrobial known to be highly effective in a single dose for treatment of gonorrhea at all anatomic sites of infection. Other oral cephalosporins (eg, cefpodoxime and cefuroxime) are not recommended because of inferior efficacy and less favorable pharmacodynamics. The frequency of such gonococcal strains is increasing, having climbed to 5-15% in various US cities.[1]

Gonococcal arthritis

Recommended therapy is with ceftriaxone at 1 g daily IV/IM plus a single dose of azithromycin 1 g PO. Initial IV/IM treatment should be continued for 1-2 days after symptoms improve.

Alternative regimens include cefotaxime or ceftizoxime 1 g IV every 8 hours plus a single dose of azithromycin 1 g PO.[1]

When treating an arthritis-dermatitis syndrome, CDC guidelines allow for switch to an oral antibiotic, when guided by susceptibility testing, after 1-2 days of significant clinical improvement is documented to complete a total course of at least 7 days.[62]

Gonococcal conjunctivitis

Treatment recommendations for adults are single doses of ceftriaxone 1 g IM plus azithromycin 1 g PO with saline irrigation.[1, 71] Topical antibiotic solutions may also be considered. If the cornea is involved or if corneal involvement cannot be excluded due to lid swelling or chemosis, some physicians treat with a 3-day course of IV antibiotics (eg, ceftriaxone 1 g IV q12-24h).[72]

Gonorrhea contributing to pelvic inflammatory disease

All regimens used to treat PID should also be effective against N gonorrhoeae and C trachomatis because endocervical screening that is negative for these organisms does not rule out upper-reproductive–tract infection.

The preferred regimen is a single dose of ceftriaxone 2 g IM plus doxycycline 100 mg PO BID for 14 days with or without metronidazole 500 mg PO BID for 14 days.

Other regimens are also effective and should take into consideration severity of PID and if tubo-ovarian abscess is present.[1]

Gonococcal epididymitis

Recommended therapy includes ceftriaxone 250 mg IM as a single dose with doxycycline 100 mg orally twice daily for a total of 10 days.

Disseminated gonococcal infection

In disseminated infection, it is important to evaluate for evidence of meningitis and endocarditis. Inpatient management and consultation with an infectious disease specialist to decide upon initial regimen are recommended, especially in patients who may be noncompliant with therapy, in whom the diagnosis is uncertain, who have purulent arthritis, or who have other complications.

Gonococcal meningitis and endocarditis

Current recommendations in the treatment of gonococcal meningitis and endocarditis are to use ceftriaxone 1-2 g IV every 12-24 hours plus azithromycin 1 g PO for 1 dose. The exact duration of therapy and any alteration in antibiotics should be discussed with an infectious disease specialist. Of key importance are antimicrobial susceptibility testing and the patient's clinical response to empiric therapy. The 2015 CDC guidelines recommend 10-14 days of parenteral therapy for meningitis and at least 4 weeks of parenteral therapy for endocarditis.[62]

See the 2015 CDC STD treatment guidelines for treatment of gonococcal infection in children and newborns.[62]

Consultations

The following consultations should be made in cases of gonococcal infections:

  • Gynecologist - Should be consulted for patients with severe pelvic inflammatory disease (PID) and for any pregnant patient with an STD

  • Pediatrician - Should be consulted for any child with an STD

  • Ophthalmologist - Should be consulted for every patient with gonococcal conjunctivitis, as this disease may progress rapidly and can cause permanent loss of vision

  • Infectious disease specialist - May be of benefit in cases of disseminated gonococcal infection (DGI) or complicated disease courses

In cases of suspected rape or abuse in pediatric patients, seeking specialist help (in the form of specialist nurses or physicians) to interview and collect specimens (if necessary) for testing is prudent. Careful documentation of physical findings, even if apparently normal, is crucial for medicolegal reasons. Notification of child-protective services is required if abuse is suspected.

Monitoring

Per the 2015 CDC Sexually Transmitted Diseases Treatment Guidelines, a test-of-cure is no longer needed for patients with uncomplicated urogenital or rectal gonorrhea who are treated with recommended or alternative regimens.

However, patients with pharyngeal gonorrhea treated with an alternative regimen should be rested for 14 days after treatment and be tested for cure with NAAT assay or culture. Confirmatory testing of the repeat NAAT assays that are positive and further antimicrobial susceptibility testing may be needed.

In many cases, "treatment failure" may result from reinfection from sexual partners who have not received appropriate therapy.

Reevaluation 3 months after treatment is recommended by the CDC. This is distinct and different from immediate test of cure. If 3-month retesting is not possible, the patient should undergo repeat screening at the next medical encounter, within 12 months of treatment.

Instruct patients with uncomplicated gonococcal infections to follow up with a primary care physician or public health provider to reduce the risk of future infection.

Early follow-up care and culture with antibiotic sensitivities are indicated in patients with unresolved or recurrent symptoms despite therapy.

Patients with disseminated gonococcal infection (DGI) or pelvic inflammatory disease (PID) who are treated in an outpatient setting must receive follow-up care within 24 hours.

Deterrence and Prevention

In an effort to minimize transmission of gonorrhea, patients should refrain from all sexual activity for at least 7 days after treatment, and all sexual partners should also undergo appropriate treatment.

The prevention of gonococcal infections is based on education, mechanical or chemical prophylaxis, and early diagnosis and treatment. Condoms offer partial protection, while effective antibiotics taken in therapeutic doses immediately before or soon after exposure can mediate an infection. Several studies have shown that male circumcision status had no statistically significant impact on susceptibility to or acquisition of gonorrhea.[73, 74]

The US Preventive Services Task Force (2008) found that behavioral counseling interventions in multiple sessions conducted in STD clinics and primary care settings effectively reduces the occurrence of STDs in at-risk adults and adolescents. However, they determined that additional studies are needed for evaluation of lower-intensity behavioral counseling interventions and behavioral counseling in lower-risk patient populations.[75]

Preventive measures also include attention to partner notification. Patients should be encouraged to notify their sexual partners of their exposure and encourage them to seek medical care; this is patient referral. If patients are unwilling or unable to notify their partners, then the assistance of state and local departments of public health can be enlisted; this is provider referral.

The American College of Obstetricians and Gynecologists (ACOG) has released guidelines on expedited partner therapy for chlamydial and gonorrheal sexually transmitted diseases (STDs).[76, 77] While designed to prevent reinfection with chlamydia and gonorrhea, the recommendations can also be applied to other STDs. The ACOG recommendations include the following:

  • Expedited partner therapy to prevent reinfection, with legalization of expedited partner therapy
  • Counsel partners to undergo screening for HIV infection and other STDs
  • Expedited partner therapy contraindicated in cases of suspected abuse or compromised patient safety; pretreatment evaluation for abuse potential recommended
  • Expedited partner therapy medications and protocols based on CDC, state, and/or local guidelines

Screening

Because of the health risks from asymptomatic gonorrhea, the US Preventive Services Task Force recommends gonorrhea screening women who are at increased risk for infection, including the following[78] :

  • Patients with previous gonorrheal infection

  • Patients with other STDs

  • Patients with new or multiple sex partners

  • Patients who engage in inconsistent condom use

  • Patients who engage in commercial sex work and drug use

  • Patients living in communities with a high prevalence of disease

Because the prevalence of asymptomatic gonorrhea in men is low, evidence was insufficient for the task force to either recommend or not recommend routine screening of men at increased infection risk.

Prophylaxis in neonates

All infants born to mothers with untreated gonococcal infection should be treated prophylactically with a single dose of ceftriaxone (25-50 mg/kg IV/IM, not to exceed 125 mg). All neonates should undergo prophylaxis for ophthalmia neonatorum with silver nitrate (1%) aqueous solution in both eyes once or erythromycin (0.5%) ophthalmic ointment in both eyes once.

Research

Several factors, including the lack of an animal model and the diverse antigenic variability of gonorrhea, have made creation of a gonococcal vaccine difficult. Based on rabbit studies, a pilin target was the most likely vaccine candidate. Early tests in military recruits and in volunteers met with some success, but protection was strain-limited, once again because of high antigenic variation of pili. A vaccine toward porins was also evaluated, but induced anti-porin antibodies were not bactericidal.[29]

PRO-2000, an antimicrobial gel for the potential prevention of HIV infection, is in phase III trial for the prevention of sexually transmitted infections, including HIV, herpes, chlamydia, and gonorrhea, in Africa.[79]

HIV Infection

Patients with HIV infection should undergo the same medical and surgical therapy as patients without HIV infection.

 

Guidelines

WHO Guidelines on the Treatment of Neisseria gonorrhoeae Infection

Guidelines on the treatment of Neisseria gonorrhoeae by the World Health Organization (WHO) are summarized below.[80]

Genital and anorectal gonococcal infections

Treatment recommendations by the WHO for genital and anorectal gonococcal infections are as follows:

  • Ceftriaxone 250 mg IM as a single dose plus azithromycin 1 g PO as a single dose
  • Cefixime 400 mg PO as a single dose plus azithromycin 1 g PO as a single dose
  • Single-drug therapy (one of the following, based on recent local resistance data confirming susceptibility to the antimicrobial): Ceftriaxone 250 mg IM as a single dose; cefixime 400 mg PO as a single dose; or spectinomycin 2 g IM as a single dose

Oropharyngeal gonococcal infections

In adults and adolescents with gonococcal oropharyngeal infections, the WHO suggests dual therapy over single therapy.

Dual therapy options are as follows:

  • Ceftriaxone 250 mg IM as a single dose PLUS azithromycin 1 g PO as a single dose or
  • Cefixime 400 mg PO as a single dose PLUS azithromycin 1 g PO as a single dose

Single-drug therapy (based on recent local resistance data confirming susceptibility to the antimicrobial) consists of ceftriaxone 250 mg IM as single dose.

Re-treatment of gonococcal infections after treatment failure

If treatment failure occurs after a WHO recommended dual therapy, re-treat with one of the following dual therapies:

  • Ceftriaxone 500 mg IM as a single dose plus azithromycin 2 g PO as a single dose or
  • Cefixime 800 mg orally as a single dose plus azithromycin 2 g PO as a single dose or
  • Gentamicin 240 mg IM as a single dose plus azithromycin 2 g PO as a single dose or
  • Spectinomycin 2 g IM as a single dose (if not an oropharyngeal infection) PLUS azithromycin 2 g PO as a single dose

Gonococcal conjunctivitis in neonates

In neonates with gonococcal conjunctivitis, the WHO STI guidelines suggest one of the following treatment options:

  • Ceftriaxone 50 mg/kg (maximum 150 mg) IM as a single dose or
  • Kanamycin 25 mg /kg (maximum 75 mg) IM as a single dose or
  • Spectinomycin 25 mg/kg (maximum 75 mg) IM as a single dose

For ocular prophylaxis, the WHO guidelines suggest one of the following options for topical application to both eyes immediately after birth:

  • Tetracycline hydrochloride 1% eye ointment or
  • Erythromycin 0.5% eye ointment or
  • Povidone iodine 2.5% solution (water-based) or
  • Silver nitrate 1% solution or
  • Chloramphenicol 1% eye ointment

CDC Guidelines on the Treatment of Gonorrhea

The CDC treatment guidelines on gonorrhea infections are as follows:[1]

  • Uncomplicated gonorrhea infections of the urethra, cervix, pharynx, and rectum: Ceftriaxone 250 mg IM as a single dose plus azithromycin 1 g PO as a single dose
  • Gonococcal conjunctivitis: Ceftriaxone 250 mg IM as a single dose plus azithromycin 1 g PO as a single dose
  • Disseminated gonococcal infections with arthritis and/or dermatitis: Ceftriaxone 1 g IV or IM every 24 hours plus azithromycin 1 g PO as a single dose
  • Gonococcal meningitis and endocarditis: Ceftriaxone 1-2 g IV every 12-24 hours plus azithromycin 1 g PO as a single dose
 

Medication

Medication Summary

Rapid cure of gonorrhea is critical to curtail transmission. Because of emerging resistance that has resulted in limited choices for antibiotics, it is imperative to follow treatment guidelines to avoid further resistance and to obtain optimal treatment results. For more information, see CDC Sexually Transmitted Diseases Treatment Guidelines, 2015.

Antibiotics, Other

Class Summary

Medical therapy requires dual antibiotic treatment with efficacy against N gonorrhoeae. Until several years ago, the treatment of choice involved oral medication for as long as 10 days or an injection; however, patients tend to be poorly compliant with medications for various reasons, and the availability of newer medications has allowed in-office single-doses of ceftriaxone IM plus azithromycin PO treatment to ensure compliance.

After obtaining specimens for diagnosis, many practitioners presumptively treat patients based on history and examination, because of the risk of poor follow-up, complications, and continuing disease spread to other partners. In addition, because gonorrhea is often simultaneously diagnosed with chlamydia, many practitioners treat patients for both diseases when treating for either one beyond the newborn period.

Disseminated or complicated infections (eg, endocarditis, meningitis) require more prolonged, inpatient therapy. For these cases, an infectious disease consultation is essential.

N gonorrhoeae in the United States is not adequately susceptible to penicillins, fluoroquinolones, or erythromycin for these antimicrobials to be recommended.

Ceftriaxone (Rocephin)

Ceftriaxone is part of the dual-drug regimen (along with azithromycin) for treating gonorrhea because of the attainment of high, sustained bactericidal levels in the blood. Ceftriaxone binds to penicillin-binding proteins, inhibiting bacterial cell wall growth.

Azithromycin (Zithromax, Zmax)

Azithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. It is part of the first-line preferred dual-drug regimen for gonococcal infections plus ceftriaxone IM.

Cefixime (Suprax)

Cefixime, a cephalosporin, inhibits bacterial cell wall synthesis by binding to 1 or more of the penicillin-binding proteins. It is not used first-line and it is an alternant therapy for uncomplicated gonorrhea if ceftriaxone is unavailable. For this situation, patients can be given a single oral dose of cefixime 400 mg plus a single dose of azithromycin 1 g PO.

Doxycycline (Vibramycin, Doxy)

Doxycycline inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Doxycycline 100 mg PO BID for 10-14 days may be used in addition to a single dose of ceftriaxone 250 mg IM for gonococcal epididymitis or pelvic inflammatory disease.

Erythromycin ophthalmic (Ilotycin Ophthalmic)

Erythromycin is the only antibiotic ophthalmic ointment recommended for use in neonates for prophylaxis of gonococcal ophthalmia neonatorum. Silver nitrate and tetracycline ophthalmic ointments are no longer manufactured in the United States, bacitracin is not effective, and povidone iodine has not been studied adequately. Gentamicin ophthalmic ointment has been associated with severe ocular reactions in neonates and should not be used for ocular prophylaxis.

 

Questions & Answers

Overview

What is gonorrhea?

What are the signs and symptoms of gonorrhea in females?

What are the symptoms of gonorrhea that has progressed to pelvic inflammatory disease (PID)?

What are the signs and symptoms of gonorrhea in males?

What is the classic presentation of disseminated gonococcal infection (DGI)?

What are symptoms of gonococcal conjunctivitis in neonates?

Which physical findings suggest gonorrhea in females?

Which physical findings suggest gonorrhea in males?

How is gonorrhea diagnosed?

How should cultures be obtained for the diagnosis of disseminated gonococcal infection (DGI)?

What are the treatment options for gonorrhea?

What is gonorrhea?

What is the progression of gonorrhea in females?

What are the common routes of transmission for gonococcal infections?

How is gonorrhea infection transmitted in pediatric populations?

What is gonococcemia and how is it defined?

Which factors increase the risk of gonorrhea infection?

What is the pathophysiology of gonorrhea?

What is the pathophysiology of disseminated gonococcal infection (DGI)?

What causes gonorrhea?

What causes sexually-transmitted gonorrhea?

What causes gonococcal infection in neonates and children?

What is autoinoculation of gonorrhea infection?

What are the risk factors for gonorrhea infection?

What is the incidence of gonorrhea in the US?

What is the prevalence of antibiotic-resistant gonorrhea in the US?

What is the global incidence of gonorrhea?

What is the global prevalence of anti-biotic-resistant gonorrhea?

What are the racial predilections of gonorrhea?

How does the incidence of gonorrhea vary by sex?

Which age groups are at highest risk for gonorrhea infection?

What is the prognosis of gonorrhea?

What are complications of gonorrhea in males?

What are complications of gonorrhea in females?

What is the prognosis of pelvic inflammatory disease (PID) due to gonorrhea?

What is the prognosis of epididymitis and orchitis due to gonorrhea?

In which patient group is gonorrhea a common cause of arthritis?

What is the prevalence of endocarditis in gonorrhea?

What are serious complications of gonococcal infections?

What should be included in patient education about gonorrhea?

How effective is abstinence education in the prevention of gonorrhea?

What are the other risks of unprotected sex that should be included in patient education about gonorrhea?

Presentation

What should be the focus of the history for patients with suspected gonorrhea?

What are the signs and symptoms of gonorrhea infection in females?

What are the signs and symptoms of gonorrhea in males?

What are the extragenital manifestations of gonorrhea?

What are the signs and symptoms of gonorrhea in neonates?

What are the signs and symptoms of disseminated gonococcal infection (DGI)?

What should be included in the physical exam for gonorrhea?

Which physical findings are characteristic of gonorrhea in neonates?

Which physical findings are characteristic of gonorrhea in females?

Which physical findings are characteristic of gonorrhea in male?

What are the rectal symptoms of gonorrhea?

What are the ocular and periocular symptoms of gonorrhea?

Which physical findings are characteristic of disseminated gonococcal infection (DGI)?

DDX

Which conditions should be included in the differential diagnoses for gonorrhea in females?

Which conditions are included in the differential diagnosis of disseminated gonococcal infection (DGI)?

How is gonococcal arthritis differentiated from reactive arthritis?

How are nongonococcal and gonococcal septic arthritis differentiated?

How is rheumatic fever differentiated from gonococcal endocarditis?

How is syphilis differentiated from gonorrhea?

Which conditions with arthritis and skin lesions are included in the differential diagnoses of gonorrhea?

Which conditions should be included in the differential diagnoses of gonorrhea?

Workup

What are the CDC guidelines for gonorrhea screening?

How is N gonorrhoeae identified for the diagnosis of gonorrhea?

Which complete blood count (CBC) count suggests gonorrhea?

Which erythrocyte sedimentation rate suggests gonorrhea?

Which serologic tests are indicated in the workup of gonorrhea?

When is echocardiography indicated in the workup of gonorrhea?

What is included in the workup for suspected disseminated gonococcal infection (DGI)?

Which other STDs should be screened for during the evaluation of gonorrhea?

What is the role of gram stain smear in the diagnosis of gonorrhea in males?

What is the role of gram stain smear in the diagnosis of gonorrhea in females?

What is the role of gram stains in the emergency department (ED) evaluation of gonorrhea?

What is the criterion standard for diagnosis of gonorrhea?

What is the sensitivity of a single culture for the diagnosis of gonorrhea?

How are culture specimens collected for diagnosis of gonorrhea?

Which media are used for cultures of the conjunctiva in the workup of gonorrhea?

How are culture specimens collected for diagnosis of disseminated gonococcal infection (DGI)?

When are blood cultures indicated in the workup of gonorrhea?

What is the role of plain radiography in the workup of gonorrhea?

What is the role of ultrasonography or CT scanning in the workup of gonorrhea?

What is the role of nucleic acid amplification tests in the workup of gonorrhea?

What is the role of polymerase chain reaction (PCR) and ligand chain reaction (LCR) in the workup of gonorrhea?

When is nucleic acid probe signal amplification (NAPSA) indicated in the workup of gonorrhea?

When is antibody-antigen testing indicated in the workup of gonorrhea?

What is the role for laparoscopy in the workup of gonorrhea?

What is the role of culdocentesis in the workup of gonorrhea?

What is the role of arthrocentesis in the workup of gonorrhea?

What is the role of lumbar puncture in the workup of gonorrhea?

Which histologic findings are characteristic of gonorrhea?

What are the US Preventive Task Force (USPTF) recommendations for gonorrhea screening in males?

What are the US Preventive Task Force (USPTF) recommendations for gonorrhea screening in females?

What are the CDC recommendations for gonorrhea screening at extragenital sites?

Treatment

What are prevention considerations when treating a patient with gonorrhea?

When is inpatient treatment of gonorrhea indicated?

When is surgical intervention indicated in the treatment of gonorrhea?

What are pharmacologic treatment options for gonorrhea?

What is the first-line pharmacologic treatment for uncomplicated gonococcal infection?

What are the CDC guidelines for pharmacologic treatment of gonorrhea?

What are investigational treatments for gonorrhea?

Which drugs are not primary treatment options for gonorrhea?

What are the pharmacologic treatment options for gonococcal arthritis?

What are the pharmacologic treatment options for gonococcal conjunctivitis?

What are the pharmacologic treatment options for pelvic inflammatory disease (PID) due to gonorrhea?

What is the pharmacologic treatment for gonococcal epididymitis?

What is the pharmacologic treatment for disseminated gonococcal infection (DGI)?

How are gonococcal meningitis and endocarditis treated?

Which specialist consultations are helpful in the treatment of gonorrhea?

What is included in monitoring following treatment for gonorrhea?

How is gonorrhea prevented?

What are the US Preventive Services Task Force recommendations for gonorrhea screening?

When is gonorrhea prophylaxis indicated for neonates?

What progress has been made in the development of a vaccine against gonococcal?

How is gonorrhea treated in patients with comorbid HIV infection?

Guidelines

What are the WHO treatment guidelines for genital and anorectal gonorrhea?

What are the WHO treatment guidelines for pharyngeal gonococcal infections?

What are the WHO guidelines for retreatment of gonorrhea after treatment failure?

What are the WHO treatment guidelines for gonococcal conjunctivitis in neonates?

What are the CDC treatment guidelines for gonorrhea?

Medications

What actions help ensure optimal treatment outcomes for patients with gonorrhea?

Which medications in the drug class Antibiotics, Other are used in the treatment of Gonorrhea?