Gonorrhea

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Gonorrhea Ronald C Ballard

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Gonorrhea is caused by Neisseira gonorrhoeae, a Gramnegative diplococcus that infects columnar epithelial surfaces often resulting in extensive mucopurulent discharge In contrast to men, many women with gonococcal infection are asymptomatic or minimally symptomatic Gonorrhea is usually transmitted sexually Gonorrhea can cause urethritis, endocervical infection, pelvic inflammatory disease, proctitis, pharyngitis, ocular infection and disseminated infection Neonates can become infected by passage through the birth canal, and infected neonates may present with purulent ocular discharge (ophthalmia neonatorum) Diagnosis of gonococcal infection is usually based on syndromic recognition, or culture or non-culture assays Antibiotic resistance is problematic and of growing concern Treatment often involves the use of single dose parenteral ceftriaxone (to target gonorrhea) together with a 7-day course of a tetracycline or a macrolide antibiotic (to empirically treat possible chlamydial co-infection) Metronidazole is often added to the above regimwen to treat women with pelvic inflammatory disease (PID) Newborns with gonoccocal ophthalmia neonatorum need systemic parenteral treatment, usually with ceftriaxone Prevention of gonorrhea involves adherence to safer sex practices and tracing and treating of contacts and partners Individuals with gonorrhea should be evaluated and treated for other sexually transmitted diseases

INTRODUCTION Gonorrhea is caused by Neisseria gonorrhoeae, a Gram-negative diplococcus that can infect a variety of mucosal surfaces lined by columnar epithelial cells. It remains the second most commonly reported noti­ fiable disease in the USA. Following a significant decline in incidence during the last three decades of the 1990s, probably as a result of successful implementation of control activities, rates have essentially stabilized over the past 10 years. Elsewhere in the industrialized world, the decline in gonorrhea has also been precipitous, with the disease nearing eradication in some Scandinavian countries. Gonorrhea remains a significant public health problem in many developing countries.

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Gonorrhea is transmitted almost exclusively by sexual contact, with adults under 30 years of age who have unprotected sex with multiple sexual partners at highest risk of infection. The sites most affected are the urethra in men and the uterine cervix and urethra in women. Rectal infection is common in both women and men who have sex with men, and gonococcal pharyngitis can occur in both sexes following orogenital contact. Although gonococcal vulvovaginitis in prepubertal girls can be the result of contact with fomites, sexual transmission is the most frequent cause of infection, even in young children. Vertical transmission can result in conjunctivitis and infection of the pharynx, vagina and rectum of babies born to infected mothers.

ETIOLOGY Neisseria gonorrhoeae is a Gram-negative diplococcus that forms small, mucoid, oxidase-positive colonies on chocolate agar. It is differentiated from other species of Neisseria by its ability to ferment glucose, but not lactose, sucrose or maltose. Confirmatory tests include co-agglutination with monoclonal antibodies and DNA hybridization. The ultrastructure of the gonococcal cell envelope is similar to that of other Gram-negative bacteria. Notably, the cell wall contains a number of antigenic proteins, lipopolysaccharide and pili (which are filamentous structures that aid attachment to cell surfaces and enhance resistance to phagocytosis and killing by neutrophils).

ANTIGENS AND IMMUNITY The gonococcal pili, lipopolysaccharide and the outer membrane proteins are antigenic; IgG and IgA antibodies to homologous isolates have been detected in mucosal secretions following uncomplicated infections [1]. However, in practice, natural, uncomplicated gonococcal infections do not confer any significant immunity and re-infections are common. Patients with a congenital deficiency in one of the terminal components of complement (C7, C8, C9) may experience recurrent episodes of disseminated gonococcal infection. A variety of methods for gonococcal typing have been developed, including auxotyping (which is dependent upon determining requirements for growth), or protein I serotyping. By using both auxotyping and serovar analysis, gonococci have been divided into a large number of classes that have been widely used as a tool for the epidemiologic study of gonococcal infections. More recently, molecular methods, such as pulsed field gel electrophoresis, opa-typing and, particularly, Neisseria gonorrhoeae Multi-Antigen Sequence Typing (NG-MAST) have been used to elucidate the epidemiologic linkages of gonococcal infections in various sexual networks.

ANTIBIOTIC-RESISTANT STRAINS Plasmids encoding for the production of ß-lactamases were first demonstrated in gonococci in 1976. These penicillinase-producing N. gonorrhoeae (PPNG) are now commonly encountered around the world. High-level resistance to tetracyclines associated with the acquisition of a 25.2 MDa tet-M plasmid (TRNG) was initially detected in 1985 and has subsequently spread around the world [1]. In addition,

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gonococci may be resistant to many antibiotics as a result of chromosomal mutations. Strains showing chromosomal resistance to penicillin/ampicillin/amoxicillin may also show decreased susceptibility to cephalosporins, tetracycline and macrolide antibiotics. Decreased susceptibility and high-level chromosomal resistance of gonococcal strains to the fluoroquinolone antibiotics emerged more recently in many countries. Such resistance is thought to be the result of the acquisition of point mutations in genes encoding gonococcal DNA gyrase (gyrA) and topoisomerase IV (parC) enzymes, and changes in bacterial cell membrane permeability. These mechanisms of resistance can occur in combination, rendering most treatment options ineffective. Where fluoroquinolone resistance is common, the only class of antibiotic that can be used with confidence is the cephalosporins. Even here, problems have emerged with oral cephalosporin treatment failures being recorded in the Far East. It is clear that, barring the development of a new class of antibiotic active against N. gonorrhoeae, the era of single-dose, single-agent treatment for gonorrhea may be coming to an end, and that combination therapy may become routine in the near future.

CLINICAL MANIFESTATIONS

The severity of the condition may vary from being virtually asymptomatic to life-threatening. A profuse vaginal discharge, often with an offensive odor, is commonly noted and is often associated with dysuria. Abnormal uterine bleeding occurs in 35–40% of patients, probably as a result of endometritis. Patients with gonococcal pelvic inflammatory disease (PID) may have associated chlamydial infection, while anaerobic super-infection may contribute to disease etiology, particularly in severe cases [3]. Clinical findings include pyrexia, tachycardia, lower abdominal tenderness and pelvic, or even generalized, peritonitis. Vaginal examination reveals cervical excitation tenderness and, frequently, adnexal tenderness. Adnexal masses may be formed from tubo-ovarian abscesses or from omentum and bowel adherent to the inflamed tubes and ovaries. Occasionally, a patient may present in extremis, with features of generalized peritonitis, septicemic shock and disseminated intravascular coagulopathy. In some severe cases, the liver capsule can become inflamed and attached to the peritoneum by fine “violinstring” adhesions. This perihepatitis is also known as Fitz-Hugh-Curtis syndrome. Resolution of tubal infections may result in formation of fine scars that are associated with increased risk of ectopic pregnancy and tubal infertility.

URETHRITIS

GONOCOCCAL PROCTITIS

The clinical features of gonococcal urethritis in men are a urethral discharge, which is often profuse and purulent (Fig. 50.1), dysuria and frequency of micturition [2]. The onset of symptoms is often sudden following an incubation period of 1–10 days but, in a minority of cases, the disease may be asymptomatic. In rare cases, N. gonorrhoeae may spread to the epididymis and testis, the prostate, or Skene’s and Littré’s glands.

Most cases of gonococcal proctitis are asymptomatic, but may be associated with an anal discharge, blood and/or mucus in stools, and pain during defecation. Gonococcal proctitis is common in men who have sex with men who practice anal-receptive intercourse; the disease is frequently associated with other sexually acquired enteric infections. Women may acquire gonococcal proctitis from heterosexual anal intercourse or as a result of spread from the adjacent vagina.

ENDOCERVICAL INFECTION

GONOCOCCAL PHARYNGITIS

In contrast to men, most women with gonococcal infection are asymptomatic or minimally symptomatic. Those with symptoms may complain of a vaginal discharge or dysuria, which may be associated with infection of the urethra. On speculum examination, a purulent discharge may be seen arising from the endocervical canal but, in many cases, no visible endocervical mucus can be detected on visual inspection. If left untreated, these infections may progress to salpingitis without any obvious symptoms.

Pharyngeal gonococcal infection, in common with rectal infection, tends to be asymptomatic. However, a minority of patients may complain of a sore throat and, on examination, a mucopurulent exudate may be present. Pharyngeal infections occur in those patients practicing fellatio or cunnilingus.

GONOCOCCAL PELVIC INFLAMMATORY DISEASE Neisseria gonorrhoeae may ascend from the endocervical canal to the endometrium, fallopian tubes and, eventually, the peritoneal cavity, causing endometritis, salpingitis and pelvic peritonitis. Symptomatic patients may report lower abdominal pain which is usually bilateral.

FIGURE 50.1 Purulent urethral discharge associated with gonococcal urethritis.

OCULAR INFECTIONS Ocular infections occur in neonates born to infected mothers. It is characterized by edema of the lids and a profuse purulent discharge (Fig. 50.2). The incubation period is usually short (normally 1–4 days). Occasionally, a severe, purulent keratoconjunctivitis is seen in adults following accidental exposure of the eye to genital secretions. Both neonatal and adult eye infections require prompt diagnosis and treatment in order to prevent sight-threatening sequelae that may ensue as a result of corneal opacities, scarring, or panophthalmitis and perforation.

FIGURE 50.2 Gonococcal ophthalmia neonatorum.

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HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE

DISSEMINATED GONOCOCCAL INFECTION Disseminated gonococcal infection (DGI) occurs as a result of gonococcal bacteremia. The source of infection tends to be asymptomatic endocervical, pharyngeal, rectal or urethral disease. The most common form of DGI is the dermatitis-arthritis syndrome, in which patients, usually women, develop arthralgias and macular, pustular, hemorrhagic or necrotic skin lesions on the distal extremities. A minority of patients develops septic joints with a purulent effusion and associated fever. The disease normally affects isolated joints. Other manifestations of gonococcal bacteremia include endocarditis and meningitis. Fortunately, these complications are extremely rare.

LABORATORY DIAGNOSIS THE GRAM STAIN The finding of intracellular Gram-negative diplococci in Gram-stained smears of urethral or conjunctival material is generally regarded as sufficient evidence for a presumptive diagnosis of gonococcal infection in symptomatic men with acute urethritis and in patients with conjunctivitis (Fig. 50.3). However, whenever possible, the exudate should be cultured on a selective medium to confirm the diagnosis. Owing to the presence of large numbers of bacteria that can be mistaken for (or mask) N. gonorrhoeae in the female genital tract and rectum, or the presence of other Neisseria spp., especially in the oropharynx, Gram-stained smears of genital secretions from women and from the rectum or pharynx of patients with suspected gonococcal infection are of questionable diagnostic value.

CULTURE Urethral swabs should be taken from men and endocervical, urethral and rectal swabs from women to optimize isolation rates. Pharyngeal swabs should be taken from patients with a history of recent orogenital contact. Specimens for culture of N. gonorrhoeae should be plated directly onto a selective medium such as Thayer-Martin or New York City medium, each of which is composed of a gonococcal, or equivalent, agar base, with additional growth supplements and antibacterial and antifungal agents. If the specimen is obtained from a site that is usually sterile (e.g. blood or synovial fluid), it can be inoculated directly onto plates of nonselective chocolate agar. Inoculated plates can be stored at room temperature in a candle extinction jar for up to 6 hours without significant loss of viability. Alternatively, specimens may be sent to the laboratory in Stuart’s or Amies’ transport medium. After incubation for 24–48 hours at 35–36.5°C in an atmosphere of 10% carbon monoxide, in air, isolated colonies can provisionally be identified on

FIGURE 50.3 Gram-stained smear of urethral exudate showing Gramnegative intracellular diplococci.

the basis of a Gram stain, oxidase test and sugar fermentation reactions. Neisseria gonorrhoeae produces oxidase and ferments glucose, but not sucrose, lactose or maltose. Alternatively, isolated organisms can be identified by using monoclonal antibodies in commercial co-agglutination tests. While culture is largely being replaced by nonculture methods for the diagnosis of gonorrhea in many industrialized countries, it is essential to maintain culture capability for N. gonorrhoeae in order to perform antimicrobial susceptibility testing where necessary.

NONCULTURE TESTS Commercially available nonculture tests for the diagnosis of gonorrhea include antigen detection tests, for example ELISA assays, nonamplified nucleic add probes and nucleic acid amplification tests (NAATs), such as PCR, strand displacement amplification (SDA), transcription-mediated amplification (TMA) and real-time PCR tests. These amplified tests, although relatively expensive, are more sensitive than culture and have the advantage that they can be applied to “noninvasive” specimens, such as self-administered vaginal swabs in women and first-catch urine in men—making them ideal for screening applications. Despite the emergence of NAATs as the diagnostic tests of choice for gonorrhea, false-positive results are known to occur, particularly when testing specimens obtained from nongenital sites. It is therefore recommended that positive gonococcal NAAT results should be confirmed with another NAAT which uses an alternative target sequence in order to reduce the possibility of false-positive results that are known to occur with related Neisseria spp. Unfortunately, all nonculture tests share the disadvantage that they can detect nonviable N. gonorrhoeae. Therefore, they cannot be recommended for evaluation of tests of cure following treatment.

TREATMENT UNCOMPLICATED GONOCOCCAL INFECTIONS Single-dose therapy is preferred to overcome problems associated with patient compliance. However, in many countries where gonorrhea is common, the choice of treatment is limited by financial constraints and the availability of antibiotics. The likelihood of concurrent infection justifies the use of combination therapies active against all possible causes of the presenting disease “syndrome”. This “syndromic approach” to the management of sexually transmitted infections has been advocated by the World Health Organization (WHO) [4]. Since 1985, the treatment guidelines for gonorrhea published by the Centers for Disease Control (CDC) have recommended that singledose treatments effective for eradication of N. gonorrhoeae be automatically followed by a 7-day course of a tetracycline or a macrolide antibiotic, which would be expected to eradicate concomitant Chlamydia trachomatis infection and other causes of nongonococcal urethritis. In many countries with few laboratory facilities, routine treatment of acute urethritis in men is achieved with such dual therapy, while routine therapy of sexually acquired vaginal discharge and PID is achieved by addition of multidose metronidazole to this regimen to eradicate trichomoniasis, bacterial vaginosis and anaerobes associated with pelvic infection. In the few regions of the world where antimicrobial resistance of N. gonorrhoeae is not a problem, single-dose treatment with either ciprofloxacin 500 mg or ofloxacin 400 mg, by mouth, remains acceptable, followed by a 7-day course of doxycycline 100 mg twice daily or tetracycline 500 mg four times daily, both by mouth. In areas where fluoroquinolone resistance is common, cefixime 400 mg as a single oral dose or ceftriaxone 250 mg or spectinomycin 2 g as a single, intramuscular injection (IM) may precede the 7-day treatment for other infections. Less expensive, and possibly less effective, alternatives used in some developing countries include combining antichlamydial therapy with either kanamycin 2 g or gentamicin 240 mg as a single, intramuscular injection. Sexual partners of patients with gonorrhea should be treated simultaneously, regardless of the results of laboratory investigations.

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EPIDIDYMO-ORCHITIS As this is usually caused by N. gonorrhoeae or C. trachomatis, the treatment for this complication is identical to that of uncomplicated disease.

PELVIC INFLAMMATORY DISEASE (PID) AND OTHER GENITAL COMPLICATIONS Empirical therapy for PID is complicated by the diversity of organisms isolated from specimens obtained from the upper genital tract. The presence of N. gonorrhoeae in the endocervix does not automatically indicate that it is the main etiologic agent of any associated PID. Hospital admission is warranted for a temperature >38°C, pelvic or abdominal peritonitis, or pelvic masses, or when the diagnosis is in doubt. Outpatient therapies recommended by the WHO for treatment of PID in areas where gonococcal resistance is common include: single-dose therapy normally recommended for uncomplicated gonorrhea plus doxycycline, 100 mg orally twice daily, or tetracycline, 500 mg orally four times daily for 14 days, plus metronidazole, 400– 500 mg orally, twice daily for 14 days. In cases of severe PID requiring hospitalization, the spectrum of causative organisms is even broader. To provide adequate antimicrobial cover for N. gonorrhoeae, C. trachomatis, anaerobic bacteria (Bacteroides spp. and Gram-positive cocci), facultative Gram-negative rods, and Mycoplasma hominis, the WHO recommends one of the following treatment regimens [4]. 1. Ceftriaxone, 500 mg by IM injection, once daily, plus doxycycline, 100 mg orally or by intravenous (IV) injection, twice daily, or tetracycline, 500 mg orally four times daily, plus metronidazole, 400–500 mg orally or by IV injection, twice daily, or chloramphenicol, 500 mg orally or by IV injection, four times daily. 2. Clindamycin, 900 mg by IV injection, every 8 hours, plus gentamicin 1.5 mg/kg by IV injection every 8 hours. 3. Ciprofloxacin 500 mg orally, twice daily, or spectinomycin 1g by IM injection, four times daily, plus doxycycline, 100 mg orally or by IV injection, twice daily, or tetracycline, 500 mg orally, four times daily, plus metronidazole 400– 500 mg orally or by IV injection, twice daily, or chloramphenicol, 500 mg orally or by IV injection, four times daily. For all three regimens, therapy should be continued until at least 2 days after the patient has improved and should then be followed by either doxycycline 100 mg orally, twice daily for 14 days, or tetracycline, 500 mg orally, four times daily for 14 days. As intrauterine devices (IUDs) are recognized as a risk factor for PID, removal of the IUD is recommended soon after initiation of antimicrobial chemotherapy. When the IUD has been removed, appropriate contraceptive counseling should be provided.

DISSEMINATED GONOCOCCAL INFECTION Prolonged therapy with ceftriaxone or spectinomycin has been recommended by the WHO: ceftriaxone, 1g by IM or IV injection, once daily for 7 days; or spectinomycin, 2g by IM injection, twice daily for 7 days.

Repeated aspiration of fluid from any septic joint is recommended. For gonococcal meningitis and endocarditis, treatment with either of the above regimens is recommended, but the duration of therapy should be extended to 14 days in the case of meningitis and 4 weeks in the case of endocarditis.

GONOCOCCAL EYE INFECTIONS Ocular infections in adults should be treated as for uncomplicated infections of the genital tract. In addition, the eyes should be irrigated frequently with sterile saline to prevent accumulation of purulent discharge. Topical antibiotics alone are not considered sufficient therapy. Neonates with gonococcal ophthalmia should, ideally, be hospitalized and isolated for 24 hours after initiation of therapy. Ceftriaxone 50 mg/kg (maximum 125 mg), spectinomycin 25 mg/kg (maximum 75 mg) or kanamycin 25 mg/kg (maximum 75 mg) can all be given as a single IM injection. As with adults, the eyes of babies should be irrigated with sterile saline hourly to prevent accumulation of discharge. Topical antibiotic preparations alone are not sufficient for therapy. Both parents of neonates with gonococcal ophthalmia must receive appropriate treatment.

PREVENTION AND CONTROL Prevention strategies for gonorrhea are identical to those used for other sexually transmitted infections, namely, rapid diagnosis and provision of effective therapy together with early partner notification, condom promotion and patient education programs. In developing countries, targeted interventions, such as periodic preventive therapy and outreach aimed at high-risk populations, for example sex workers, military personnel and migrant workers, may be productive. Broadbased case-finding programs using noninvasive techniques, for example testing of self-administered vaginal swabs or first-catch urine for specific gonococcal nucleic acid sequences by PCR, SDA or TMA, may be cost-effective in more affluent settings. Gonococcal ophthalmia neonatorum may be prevented by the instillation of 1% silver nitrate eye drops at birth (Credé prophylaxis). However, as many cases of chemically- induced conjunctivitis have been recorded following this procedure, many centers routinely use topical tetracycline, chloramphenicol or erythromycin eye ointment for ocular prophylaxis.

REFERENCES 1. Sparling PF. Biology of Neisseria gonorrhoeae. In: Holmes KK, Sparling PF, Stamm WE, et al, eds. Sexually Transmitted Diseases, New York: McGraw-Hill; 2008:607–26. 2. Hook EW III, Handsfield HH. Gonococcal Infections in the Adult. In: Holmes KK, Sparling PF, Stamm WE, et al, eds. Sexually Transmitted Diseases, New York: McGraw-Hill; 2008: 627–45. 3. Ison CA, Lewis DA. Gonorrhea. In: Morse SA, Ballard RC, Holmes KK, Moreland AA, eds. Atlas of Sexually Transmitted Diseases and AIDS, 4th edn. London: Mosby; 2010. 4. World Health Organization. Guidelines for the Management of Sexually Transmitted Infections. Geneva: World Health Organization; 2010.

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