Gonorrhea

 

Salient features

 

·       Gonorrhea is the most common reportable STI in high-income countries

 

·       It is caused by Neisseria gonorrhoeae, which infects the mucosal surfaces of the human genital tract (as well as the anus, rectum and mouth) after direct – usually sexual – contact with an infected person

 

·       Cutaneous pustules as well as systemic symptoms such as arthritis and fever can result from hematogenous dissemination, which occurs in only a small percentage of infected individuals

 

·       Over the past few decades, resistance of N. gonorrhoeae to various antimicrobials has increased in frequency

 

Introduction

 

Gonorrhoea is a bacterial infection caused by Neisseria gonorrhoeae that principally causes purulent inflammation of the genital mucous membranes. It is primarily sexually transmitted but vertical transmission during childbirth is important. It is the second most commonly reported bacterial sexually transmitted infection (STI) after Chlamydia infection.

 

Gonorrhoea results in a number of clinical syndromes including urethritis, cervicitis, epididymo‐orchitis, pelvic inflammatory syndrome, disseminated gonococcal infection and ophthalmia neonatorum.

 

Epidemiology

 

Age

 

Peak age in males is 20–24 years and in females is 16–19 years.

 

Sex

 

Gonorrhoea is reported 2–3 times more frequently in men than women and one‐third of the infections in males are homosexually acquired.

 

Associated diseases

 

Individuals diagnosed with an STI are at risk of other coexistent STIs, therefore a sexual health assessment is warranted. Currently guidelines recommend empirical treatment to cover Chlamydia in anyone diagnosed with gonorrhoea.

 

Transmission

N. gonorrhoeae is a pathogen restricted to humans as its only host and transmitted primarily by sexual contact. The most efficient transmission occurs by vaginal or anal intercourse where there is physical contact with the mucosal surface of a sexual partner with an asymptomatic or mildly symptomatic infection. It can also be transmitted vertically from mother to child during normal vaginal birth, characteristically causing an inflammatory eye infection (ophthalmia neonatorum).

 

Causative organisms

 

Gonorrhoea is caused by the Gram‐negative, aerobic, intracellular diplococcus, Neisseria gonorrhoeae that typically grow in pairs and principally infects host columnar epithelium; stratified and squamous epithelia are more resistant to attack. The outer membrane structure of N. gonorrhoeae is typical for Gram-negative bacteria but, in contrast to N. meningitidis, it lacks the polysaccharide capsule that is responsible for the virulence of meningococci. Surface molecules on the outer membrane are involved in attachment, invasion and host injury, and they also represent important antigenic structures, especially the fibrillar pili (composed of 18 kD a pilin subunits). Outside the human host the organism is delicate and susceptible to drying, but within the body it has a large capability to effect antigenic variation, which helps it evade the host immune response and to develop antimicrobial resistance.

Certain gonococcal strains are more often associated with disseminated gonococcal infection (DGI) and tend to cause little genital inflammation and thereby escape detection. These include those with specific nutritional requirements (auxotype ahu, which requires arginine, hypoxanthine and uracil for growth) or contain low‐molecular‐weight protein 1a (porin serotype 1A) or fail to express outer membrane protein II. These all affect attachment of the gonococci to cells and phagocytes and results in them being more resistant to the bactericidal effects of human serum.

 

Pathogenesis

 

Although there is increasing knowledge about the pathogenicity of this microorganism, the exact molecular mechanisms of invasion of gonococci into the host cell are still unknown. Pathogenesis involves bacterial attachment to columnar epithelial cells. The most common sites of attachment include the mucosal cells of the male and female urogenital tracts. The gonococci attach to host mucosal cells with the aid of pili, which cover the entire outer cell surface, and outer membrane proteins. Several virulence factors are involved in the processes of adherence, inflammation and mucosal invasion. Because pili increase adhesion to the host cell, they also play an important role in pathogenesis; this may explain why non-piliated gonococci have a reduced ability to cause infections in humans. Pili undergo antigenic variation in which strains change their antigenic type. The gonococci then penetrate between cells into the subepithelial space. Gonococci are also being able to multiply and divide intracellularly, where they are immune to host defense mechanisms. The host mounts an acute inflammatory response that leads to epithelial sloughing, submucosal micro abscesses and purulent discharge. Strains that have the ability to resist the activity of antibodies and complement predispose to dissemination.

 

Gonococci have the ability to cause tissue destruction by production of a variety of enzymes and lipids such as phospholipase, peptidases, and lipid A. This plays a role in their damage of fallopian tubes and the development of post inflammatory arthritis.

 

Clinical features

 

 

 

N. gonorrhoeae infection tends to involve mucous membranes predominantly lined by columnar epithelial cells. The urethra, cervix, rectum, pharynx, and conjunctiva are the areas most commonly involved. Gonorrhea has a broad spectrum of clinical manifestations in both men and women, including asymptomatic infections, local symptomatic mucosal infections (with or without local complications), and systemic dissemination. Symptoms vary according to the site of infection and strain of organism.

CLINICAL MANIFESTATIONS OF GONORRHEA

Disseminated infection

1.   Arthritis 2.   Fever 3.   Tenosynovitis 4.   Acral cutaneous pustules 5.   Scalp abscesses (in neonates at sites of fetal scalp monitor electrodes) 6.   Endocarditis 7.   Meningitis

Direct mucosal infection

1.   Urethritis 2.   Cervicitis 3.   Proctitis 4.   Pharyngitis 5.   Vulvovaginitis (children) 6.   Ophthalmia neonatorum

Local extension

1.   Prostatitis 2.   Vesiculitis 3.   Epididymitis 4.   Salpingitis 5.   Oophoritis 6.   Pelvic inflammatory disease

 

Localized Disease (Men)

The incubation period in men is typically from 2 to 8 days, although it may rarely be longer since most infections are symptomatic by 2 weeks following exposure. Only about 10% of infections are asymptomatic in men. The most common clinical presentation of gonococcal infection in men is an acute anterior urethritis. There is rapid onset of severe burning dysuria accompanied by a urethral discharge that is typically purulent and profuse with meatal erythema and swelling. In about one-quarter of infected men, develop a scant or minimally purulent discharge, similar to those of non-gonococcal urethritis, and appear only after urethral manipulation (“stripping”). In some cases, there is so much soft tissue inflammation that the entire distal penis becomes swollen, so-called “bull head clap.”  Local complications can include inflammation of the Cowper and Tyson glands; ascension of the infection may lead to epididymitis, prostatitis, and vesiculitis. Patients with gonococcal epididymitis present with unilateral testicular pain and swelling accompanied by urethritis. However, epididymitis is more commonly caused by Chlamydia trachomatis or by combined infection with N. gonorrhoeae.

 

Localized Disease (Women)

In about 50% of infected women, gonococcal infection is asymptomatic and therefore remains unnoticed; when symptoms occur, it is usually > 14 days since exposure.

Appropriate screening, prompt diagnosis, and treatment are crucial in women due to serious complications that can result in sterility. The primary site of gonococcal infection in women is the endocervical canal, with associated clinical symptoms consisting of increased vaginal discharge, deep dyspareunia, postcoital bleeding and intermenstrual bleeding. Clinical inspection shows purulent cervical discharge with erythema, edema and contact mucosal bleeding. Urethral colonization is present in 70–90% of infected women and is the usual site of infection in women who have had a hysterectomy. Symptoms of urethritis include mucopurulent discharge and dysuria. However, vaginitis does not occur except in prepuberal girls or postmenopausal women because the vaginal epithelium of sexually mature women does not support growth of N. gonorrhoeae. Occasionally, inflammation of Bartholin glands is observed, with acute swelling of the labial folds and appearance of purulent discharge when pressure is applied to the gland. Organisms may invade the upper genital tract, including the uterus, fallopian tubes, and ovaries, resulting in pelvic inflammatory disease (PID).

 

Extragenital gonorrhea

 

Pharyngeal gonorrhea

This can occur in both men and women after oral sexual exposure. Because it is usually asymptomatic, the infection typically goes undetected and spontaneously resolves within a few weeks. However, pharyngeal gonorrhea may be an important source of urethral gonorrhea in MSM and for disseminated gonococcal disease. Infection of the oro‐pharynx may present with exudative pharyngitis and cervical lymphadenopathy. The incidence of gonococcal pharyngitis is higher in women than that in men due to the common practice of fellatio, especially among adolescents.

 

Rectal gonorrhea

Rectal gonorrhea is mainly seen in men who have sex with men and in heterosexual women who practice receptive anal intercourse. Women may also develop proctitis through autoinoculation from cervical discharge. Rectal gonorrhea is asymptomatic in at least 50% of patients, but it may result in gonococcal proctitis. Symptoms may include a rectal mucopurulent discharge, pain on defecation, constipation, and tenesmus. As a result of gonococcal proctitis, MSM are at a higher risk of acquiring HIV infection due to both damaged anorectal epithelial integrity and local recruitment of HIV-target cell types (CCR5/CD4+ T cells and DC-SIGN+ dendritic cells).

 

Gonococcal ophthalmia (including ophthalmia neonatorum)

Gonococcal ophthalmia is uncommon in adults but still represents a major cause of blindness in some low-income countries. Primarily due to autoinoculation of the organism from infected ano‐genital sites and unusual sexual practices, that leads to acute conjunctivitis. This presents as an acutely painful red eye with purulent discharge and, if left untreated, may progress to panophthalmitis and loss of vision.

Gonococcal infection in newborns is caused by inoculation with N. gonorrhoeae during delivery through an infected birth canal, and most often it presents with purulent conjunctivitis (ophthalmia neonatorum) in the first week after birth. Due to preventive application of antimicrobial ointment (usually erythromycin) immediately after birth, the rate of this gonococcal infection is currently low.

 

Complications and co‐morbidities

 

Complications may occur as a result of local abscess formation and from ascending infections and from hematogenous spread. Figure shows the main sites of gonococcal infection.

 

 

 Points of entry and route of dissemination of gonococci

 

Periurethral abscess may occur in either sex and lead to fistula formation and subsequent urethral stricture. In males, it may cause a saxophone penis deformity. Gonorrhoea should also be considered as a possible cause for a Bartholin abscess.

Ascending infection in men causes acute prostatitis, with symptoms of urinary frequency, stranguria and back or perineal pain. It may also present as unilateral or bilateral painful testicular swelling resulting from acute epididymo‐orchitis.

In women, ascending infections cause pelvic inflammatory disease (PID). PID occurs in about 10%–40% of uncomplicated gonorrheal infections in women. This is usually acute in onset with fever, lower abdominal and back pain, vomiting, vaginal bleeding, dyspareunia and marked adnexal and cervical motion tenderness on bimanual pelvic examination. Sequelae of untreated infection include tubo-ovarian abscesses, subsequent ectopic pregnancies, chronic pelvic pain, and infertility due to chronic inflammation with resultant scarring. Symptoms tend to occur or worsen at the time of menses and cannot be distinguished from nongonococcal etiologies.  Acute perihepatitis (Fitz‐Hugh–Curtis syndrome), with inflammation of the adjacent peritoneal area, is an infrequent complication of gonorrhoea, Chlamydia or mixed infections. It presents as fever and right upper quadrant pain and tenderness with abnormal liver function tests that mimic acute cholecystitis. Perihepatitis, resulting from inflammation of the liver capsule, generally occurs in much younger women than those who typically suffer from cholecystitis. Periappendicitis, which may also be caused either by gonorrhoea or chlamydial infection, has a similar pathogenesis.

Pregnancy complications may include premature rupture of the membranes, premature delivery and acute chorioamnionitis. PID is less likely than in the non‐pregnant state.

 

Disseminated gonococcal infection [Arthritis–dermatosis syndrome (gonococcemia)]

 

Spread of infection from the primary site of inoculation to other parts of the body through the blood stream leads to disseminated gonococcal infection (DGI), also known as gonococcemia. DGI occurs in 0.5–3% of patients as a result of hematogenous spread from the mucous membranes. It is facilitated by host and microbial factors, and may follow gonococcal infection at any ano‐genital or extragenital site. Risk factors for disseminated gonococcal infection include:

·        Female.

·        Men who have sex with men.

·        Pregnancy.

·        Menstruation (with the majority of cases in women developing during or immediately following menses)

·        Systemic lupus erythematosus.

·        Complement deficiency (C5–C9).

·        Intravenous drug use.

·        HIV infection.

 

The most common clinical manifestation of gonococcal bacteremia is a classic triad of dermatitis, migratory polyarthritis, and tenosynovitis. The classic syndrome consists of fever, joint pain and a paucilesional eruption of hemorrhagic pustules.

Joint or tendon pain is the most common accompanying feature. Pain and swelling may occur in a single joint or in multiple joints asymmetrically. Tenosynovitis often affects the hands and fingers. It may be accompanied by a migratory polyarthralgia, affecting the knees, elbows, wrists, metacarpophalangeal joints and ankle joints. There is a high yield of positive blood cultures in such cases.

The cutaneous lesions consist of scattered pustules, often necrotic, due to an embolic septic vasculitis. The skin lesions are small, tender and initially maculopapular. A central vesicle or pustule appears and hemorrhage and necrosis commonly ensue. Lesions occur in crops, usually between 5 and 40, and are most commonly seen peripherally on the distal portions of the extremities near affected joints, on the palms and soles or on the trunk. The concurrence of some degree of hemorrhage and necrosis led to the term “gun metal gray” to describe the cutaneous lesions of DGI. On the palms and soles, lesions may be tender, but in other sites they tend to be both nonpruritic and painless. Skin lesions disappear after appropriate treatment has been administered. Cutaneous lesions may be present in 40%–70% of cases of disseminated disease. Histologically, perivascular neutrophilia, dermal vasculitis, and epidermal neutrophil infiltration may be seen.

 

Later, one‐third of cases will develop a suppurative arthritis, which most commonly affects the knee. By this stage, skin lesions have usually disappeared and blood cultures are often negative. Rarely, pericarditis and endocarditis may also occur at this later stage. The latter is more common in men, usually affects the aortic valve, and presents with a subacute onset of chest pain, fever, chills and malaise. Meningitis, similar to that caused by meningococci, but with a less rapid course, is rare but well recognized.

 

Prognosis and Clinical Course

Most infected men seek treatment resulting from symptoms early enough to prevent serious sequelae, but not to prevent transmission to others. Most infected women have no recognizable symptoms until complications such as PID, tubal scarring, infertility, or ectopic pregnancy occur. DGI more common in women with asymptomatic cervical, endometrial, or tubal infection, and homosexual men with asymptomatic rectal or pharyngeal gonorrhea.

Without treatment, clinical symptoms of uncomplicated urethritis disappear in 95% patients after about 6 months. However, the rate of complications may be >20%. Similarly, pharyngeal infection has a spontaneous rate of clearance close to 100% at 12 weeks. Prognosis is excellent because the uncomplicated infections treated with appropriate antimicrobial therapy resolve completely. Previously treated gonococcal infection does not reduce the risk of reinfection. Urethral strictures, common in the pre‐antibiotic era, are now rare.

Those with ascending and systemic infection including epididymo‐orchitis, PID and disseminated gonococcal infection require longer courses of treatment to cure the infection. DGI has a good prognosis if treated appropriately and before permanent damage to joints or organs occurs.

 

Laboratory Diagnosis

Laboratory diagnosis is based on the identification of N. gonorrhoeae in secretions from infected mucous membranes by using stained smears, cultures and/or molecular biologic techniques. Samples are typically obtained from the endocervical canal in women (after wiping off exudate), the urethra in men (and occasionally in women who have had a hysterectomy), and (when indicated) the posterior pharynx. For diagnosis by nucleic acid amplification methods, a vaginal swab or urine sample can also be used. Anorectal specimens should be obtained via direct visualization using anoscopy if possible.

 

Staining methods

Direct detection of Gram-negative diplococci within neutrophils in Gram- or methylene blue-stained smears provides an immediate diagnosis, which is especially helpful in symptomatic individuals. Gram-stained urethral exudate detects between 95% and 98% of symptomatic infections in men, whereas Gram-stained cervical smears have a sensitivity of about 50%. The specificity of Gram-stained exudates depends primarily on the experience of the microscopist and on proper collection, and it may approach 100% in an optimal setting. However, because of its lower sensitivity in asymptomatic individuals, a negative Gram stain should not be considered sufficient for excluding infection in such patients. Smears are not helpful for detection of rectal and pharyngeal gonorrhea due to the presence of a large number of other bacteria. Vaginal specimens are never recommended for diagnostic purposes, since the vaginal mucosa resists gonococcal invasion. Of note, Gram-negative diplococci may occasionally be seen in smears of the contents of pustules in disseminated gonococcal infections.

 

Culture techniques

Isolation of N. gonorrhoeae by culture is still considered to be the gold standard for the diagnosis of gonococcal infections, and positive results obtained by stained smears should be confirmed by culture. Culture is currently the only acceptable method for cases of rape or other medicolegal situations, and it also allows antimicrobial sensitivity testing. Pustular lesions due to gonococcemia should be punctured for culture.

Depending on the symptomatic status of the infected person, currently available antibiotic-containing selective media (Thayer–Martin) have a sensitivity of 80–95% for genital samples directly plated at the time of collection. Sensitivity is much lower for extragenital specimens such as those from the rectal area (<50%). The specificity of the culture is reported to be ~95% in the case of isolation from the genital region.

 

Nucleic acid amplification tests

Nucleic acid amplification tests (NAATs) for the diagnosis of gonorrhoea are commonly combined with those for Chlamydia in commercial assays. With respect to overall sensitivity, specificity and ease of specimen transport, NAATs outperform other tests that are currently available for the diagnosis of infections due to Chlamydia trachomatis (CT) and N. gonorrhoeae (NG). NAATs used to detect gonococcal DNA or RNA, often in addition to chlamydial DNA or RNA. Overall, nucleic acid amplification tests are highly sensitive and specific and may be able to detect even the presence of one organism. Advantages of these tests include use of “non-invasive” sample types (e.g. urine and vaginal or introital swabs) and avoidance of problems with storage and transport (e.g. in field settings where culture facilities are not available). In asymptomatic patients and in samples from extragenital sites, amplification methods surpass the sensitivity of culture.

In DGI, cultures, and if available, nucleic acid amplification testing should be done on blood, joint fluid, and skin lesions. Synovial fluid from affected joints must be analyzed for cell count, Gram stain, and culture. Of necessity, diagnosis may rely on clinical suspicion and pertinent findings, because tests for DGI yield positive results only in a small number of cases.

 

Treatment

Although many antibiotics can be used for the treatment of gonorrhea, selection of therapy depends on the susceptibility of the organism that is isolated (or regional patterns), the anatomic site(s) of the infection, clinical symptoms, and the cost (especially in resource-poor settings) as well as potential side effects of the drug. Over the past few decades, strains of gonorrhea resistant to a number of antibiotics, including sulfonamides, penicillin, tetracyclines, erythromycin, spectinomycin, and more recently quinolones, have emerged. Antibiotic resistance of N. gonorrhoeae clearly represents an urgent public health threat.

Over the years, the development of different types of resistance has led to regular revisions of gonococcal treatment recommendations.  In 2007, the CDC recommended that fluoroquinolones are no longer recommended for the routine treatment of any gonococcal infections due to the increased prevalence of antimicrobial resistance. Currently, third-generation cephalosporins are the antibiotics of choice for gonococcal infections; however, treatment failures (especially with oral cephalosporins in Asian countries) have been described. Therefore, the current CDC treatment guidelines for uncomplicated gonococcal infections consist of dual therapy with ceftriaxone (250 mg intramuscularly in a single dose) plus azithromycin (1 g orally in a single dose). In addition, persons infected with N. gonorrhoeae are frequently co-infected with C. trachomatis, further supporting the use of dual therapy that includes azithromycin.

 

Treatment failures or infections in penicillin‐allergic patients are usually treated with intramuscular spectinomycin.

Patients with DGI may require hospitalization due to septic arthritis, meningitis, or endocarditis. The recommended regimen for DGI is ceftriaxone, 1 g intramuscularly (IM) or intravenously (IV) every 24 hours, continuing for 24–48 hours after clinical improvement is noted. Treatment may then be switched to oral doses of the antibiotic such as cefixime. Treatment of gonococcal meningitis should consist of ceftriaxone, 1–2 g IV every 12 hours for 10–14 days. Gonococcal ophthalmia neonatorum should be treated with ceftriaxone, 25–50 mg/kg IV or IM, not to exceed 125 mg in a single dose.

Sexual partners of those found to have gonococcal infections should be evaluated. However, since this is not always feasible, empiric treatment may be advisable.

Treatment is indicated if gonorrhoea is diagnosed or if there is a history of contact with a person known to be infected. Patients with gonorrhoea should always be fully assessed and screened for other STIs and HIV. They should be asked to abstain for sexual contact for 7 days after they and their partners have received treatment and their symptoms have resolved. A test of cure using a NAAT should be undertaken 2 weeks after the completion of treatment.

In complicated infections, more prolonged courses of treatment are employed.

 

TREATMENT RECOMMENDATIONS FOR GONOCOCCAL INFECTIONS

Uncomplicated gonococcal infections of the urethra, cervix, rectum or pharynx

Recommended regimens: ·        Ceftriaxone 500 mg IM + azithromycin 2 g PO as single dose

Alternative regimen: Cefixime, 400 mg po as single dose, PLUS azithromycin, 2 g po as single dose

·

Disseminated gonococcal infection

Recommended regimen:

Ceftriaxone, 1 g IM or IV q24h PLUS azithromycin, 1 g po as single dose   Ceftriaxone administered until 24–48 hours after improvement begins, then cefixime, 400 mg po BID, to complete at least 1 week of therapy

Alternative regimens: Cefotaxime or ceftizoxime, 1 g IV q24h, PLUS azithromycin, 1 g po as single dose Cephalosporin administered until 24–48 hours after improvement begins, then cefixime as above

Neonatal infections

Disseminated gonococcal infection and gonococcal scalp abscesses in newborns

1.   Ceftriaxone, 25–50 mg/kg IV or IM qd for 7 days (10–14 if meningitis) or 2.   Cefotaxime, 25 mg/kg IV or IM q12h for 7 days (10–14 if meningitis)

Ophthalmia neonatorum or asymptomatic neonate born to mother with untreated gonorrhea

1.   Ceftriaxone, 25–50 mg/kg IV or IM as single dose, not to exceed 125 mg

 

Complicated infection

Gonococcal epididymoorchitis

·        Ceftriaxone 500 mg IM + azithromycin 2 g PO single doses, followed by doxycycline 100 mg PO twice daily for 10–14 days

Gonococcal PID

·        Ceftriaxone 500 mg IM + azithromycin 2 g PO single doses, followed by doxycycline 100 mg PO twice daily + metronidazole 400 mg twice daily for 14 days

Gonococcal conjunctivitis

Ceftriaxone, 1 g IM as single dose, PLUS azithromycin, 1 g po as single dose