Neisseria gonorrhoeae (Gonococcus)

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Chapter 185 Neisseria gonorrhoeae (Gonococcus)

Neisseria gonorrhoeae produces several forms of gonorrhea, an infection of the genitourinary tract mucous membranes and rarely of the mucosa of the rectum, oropharynx, and conjunctiva. Gonorrhea transmitted by sexual contact or perinatally is 2nd only to chlamydial infections in the number of cases reported to the Centers for Disease Control and Prevention (CDC) in the USA. This high prevalence and the development of antibiotic-resistant strains have produced significant morbidity in adolescents.

Etiology

N. gonorrhoeae is a nonmotile, aerobic, non–spore-forming, gram-negative intracellular diplococcus with flattened adjacent surfaces. Optimal growth occurs at 35-37°C and at pH 7.2-7.6 in an atmosphere of 3-5% carbon dioxide. The specimen should be inoculated immediately onto fresh, moist, modified Thayer-Martin or specialized transport media because gonococci do not tolerate drying. Thayer-Martin medium contains antimicrobial agents that inhibit hardier normal flora present in clinical specimens that may otherwise overgrow gonococci. Presumptive identification may be based on colony appearance, Gram stain appearance, and production of cytochrome oxidase. Gonococci are differentiated from other Neisseria species by the fermentation of glucose but not maltose, sucrose, or lactose. Gram-negative diplococci are seen in infected material, often within polymorphonuclear leukocytes.

Like all gram-negative bacteria, N. gonorrhoeae possesses a cell envelope composed of an inner cytoplasmic membrane, a middle layer of peptidoglycan, and an outer membrane. The outer membrane contains lipo-oligosaccharides (endotoxin), phospholipid, and a variety of proteins that contribute to cell adherence, tissue invasion, and resistance to host defenses. The 2 systems primarily used to characterize gonococcal strains are auxotyping and serotyping. Auxotyping is based on genetically stable requirements of strains for specific nutrients or cofactors as defined by an isolate’s ability to grow on chemically defined media. The most widely used serotyping system is based on a porin called PorI, a trimeric outer membrane protein that makes up a substantial part of the gonococcal envelope structure. Antibodies generated to PorI have been used to serotype gonococci (e.g., PorIA-4 and PorIB-12), and changes in PorI proteins present in a community are believed to occur, at least in part, as a result of selective immune pressure.

Epidemiology

N. gonorrhoeae infection occurs only in humans. The organism is shed in the exudate and secretions of infected mucosal surfaces and is transmitted through intimate contact, such as sexual contact or parturition, and rarely by contact with fomites. Gonococcal infections in the newborn period are generally acquired during delivery. Gonorrhea is the most common sexually transmitted infection found in sexually abused children. Rarely, N. gonorrhoeae may be spread by sexual play among children, but the index patient is likely to be a victim of sexual abuse. Gonococcal infections in children are acquired rarely through household exposure to infected caretakers. In such cases, the possibility of sexual abuse should be seriously considered.

The number of reported cases of gonorrhea increased steadily in the USA from 1964 to 1977, fluctuated through the early 1980s, and increased until 1987, when reported rates were 323/100,000. Rates decreased annually from 1987 to 1996, when reported rates were 123/100,000 population. Since 1996, rates declined or were stable, although in 2005 the national rate (116/100,000 population) increased for the first time since 1999. The decline in gonorrhea prevalence may be attributed to recommendations by the CDC that only highly effective antimicrobial agents be used to treat gonorrhea. The incidence of gonorrhea is highest in high-density urban areas among persons < 24 yr of age who have multiple sex partners and engage in unprotected sexual intercourse. Increases in gonorrhea prevalence have been noted among men who have sex with men (MSM). Risk factors include nonwhite race, homosexuality, increased number of sexual partners, prostitution, presence of other sexually transmitted infections, unmarried status, poverty, and failure to use condoms. Auxotyping and serotyping techniques and, more recently, molecular typing methods have been used to analyze the spread of individual strains of N. gonorrhoeae within a community.

Maintenance and subsequent spread of gonococcal infections in a community require a hyperendemic, high-risk core group such as prostitutes or adolescents with multiple sexual partners. This observation reflects the fact that most persons who have gonorrhea cease sexual activity and seek care, unless economic need or other factors (e.g., drug addiction) drive persistent sexual activity. Thus, many core transmitters belong to a subset of infected persons who lack or ignore symptoms and continue to be sexually active, underscoring the importance of seeking out and treating the sexual contacts of infected persons who present for treatment.

Gonococcal infection of neonates usually results from peripartum exposure to infected exudate from the cervix of the mother. An acute infection begins 2-5 days after birth. The incidence of neonatal infection depends on the prevalence of gonococcal infection among pregnant women, prenatal screening for gonorrhea, and neonatal ophthalmic prophylaxis.

Pathogenesis and Pathology

N. gonorrhoeae infects primarily columnar epithelium, because stratified squamous epithelium is relatively resistant to invasion. Mucosal invasion by gonococci results in a local inflammatory response that produces a purulent exudate consisting of polymorphonuclear leukocytes, serum, and desquamated epithelium. The gonococcal lipo-oligosaccharide (endotoxin) exhibits direct cytotoxicity, causing ciliostasis and sloughing of ciliated epithelial cells. Once the gonococcus traverses the mucosal barrier, the lipo-oligosaccharide binds bactericidal immunoglobulin M (IgM) antibody and serum complement, causing an acute inflammatory response in the subepithelial space. Tumor necrosis factor and other cytokines are thought to mediate the cytotoxicity of gonococcal infections.

Gonococci may ascend the urogenital tract, causing urethritis or epididymitis in postpubertal males and acute endometritis, salpingitis, and peritonitis (collectively termed acute pelvic inflammatory disease or PID) in postpubertal females. Dissemination from the fallopian tubes through the peritoneum to the liver capsule results in perihepatitis (Fitz-Hugh–Curtis syndrome). Gonococci that invade the lymphatics and blood vessels may cause inguinal lymphadenopathy; perineal, perianal, ischiorectal, and periprostatic abscesses; and disseminated gonococcal infection (DGI).

A number of gonococcal virulence and host immune factors are involved in the penetration of the mucosal barrier and subsequent manifestations of local and systemic infection. Selective pressure from different mucosal environments probably leads to changes in the outer membrane of the organism, including expression of variants of pili, opacity or Opa proteins (formerly protein II), and lipo-oligosaccharides. These changes may enhance gonococcal attachment, invasion, replication, and evasion of the host’s immune response.

For infection to occur, the gonococcus must first attach to host cells. A gonococcal IgA protease inactivates IgA1 by cleaving the molecule in the hinge region and may be an important factor in colonization or invasion of host mucosal surfaces. Gonococci adhere to the microvilli of nonciliated epithelial cells by hairlike protein structures (pili) that extend from the cell wall. Pili are thought to protect the gonococcus from phagocytosis and complement-mediated killing. Pili undergo high-frequency antigenic variation that may aid in the organism’s escape from the host immune response and may provide specific ligands for different cell receptors. Opacity proteins, most of which confer an opaque appearance to colonies, are also thought to function as ligands to facilitate binding to human cells. Gonococci that express certain Opa proteins adhere to and are phagocytosed by human neutrophils in the absence of serum.

Other phenotypic changes that occur in response to environmental stresses allow gonococci to establish infection. Examples include iron-repressible proteins for binding transferrin or lactoferrin, anaerobically expressed proteins, and proteins that are synthesized in response to contact with epithelial cells. Gonococci may grow in vivo under anaerobic conditions or in an environment with a relative lack of iron.

Approximately 24 hr after attachment, the epithelial cell surface invaginates and surrounds the gonococcus in a phagocytic vacuole. This phenomenon is thought to be mediated by the insertion of gonococcal outer membrane protein I into the host cell, causing alterations in membrane permeability. Subsequently, phagocytic vacuoles begin releasing gonococci into the subepithelial space by means of exocytosis. Viable organisms may then cause local disease (i.e., salpingitis) or disseminate through the bloodstream or lymphatics.

Serum IgG and IgM directed against gonococcal proteins and lipo-oligosaccharides lead to complement-mediated bacterial lysis. Stable serum resistance to this bactericidal antibody probably results from a particular type of porin protein expressed in gonococci (most contain PorIA), predisposing to disseminated disease. N. gonorrhoeae differentially subverts the effectiveness of complement and alters the inflammatory responses elicited in human infection. Isolates from cases of DGI typically resist killing by normal serum (i.e., are serum resistant), inactivate more C3b, generate less C5a, and result in less inflammation at local sites. PID isolates are serum sensitive, inactivate less C3b, generate more C5a, and result in more inflammation at local sites. IgG antibody directed against gonococcal reduction-modifiable protein (Rmp) blocks complement-mediated killing of N. gonorrhoeae. Anti-Rmp blocking antibodies may harbor specificity for outer membrane protein sequences shared with other neisserial species or Enterobacteriaceae, may be directed against unique Rmp upstream cysteine loop–specific sequences, or both. Preexisting antibodies directed against Rmp facilitate transmission of gonococcal infection to exposed women; Rmp is highly conserved in N. gonorrhoeae, and the blocking of mucosal defenses may be one of its functions. Gonococcal adaptation also appears to be important in the evasion of killing by neutrophils. Examples include sialylation of lipo-oligosaccharides, increases in catalase production, and changes in the expression of surface proteins.

Host factors may influence the incidence and manifestations of gonococcal infection. Prepubertal girls are susceptible to vulvovaginitis and, rarely, experience salpingitis. N. gonorrhoeae infects noncornified epithelium, and the thin noncornified vaginal epithelium and alkaline pH of the vaginal mucin predispose this age group to infection of the lower genital tract. Estrogen-induced cornification of the vaginal epithelium in neonates and mature females resists infection. Postpubertal females are more susceptible to salpingitis, especially during menses, when diminished bactericidal activity of the cervical mucus and reflux of blood from the uterine cavity into the fallopian tubes facilitate passage of gonococci into the upper reproductive tract.

Populations at risk for DGI include asymptomatic carriers; neonates; menstruating, pregnant, and postpartum women; homosexuals; and immunocompromised hosts. The asymptomatic carrier state implies failure of the host immune system to recognize the gonococcus as a pathogen, the capacity of the gonococcus to avoid being killed, or both. Pharyngeal colonization has been proposed as a risk factor for DGI. The high rate of asymptomatic infection in pharyngeal gonorrhea may account for this phenomenon. Women are at greater risk for development of DGI during menstruation, pregnancy, and the postpartum period, presumably because of the maximal endocervical shedding and decreased peroxidase bactericidal activity of the cervical mucus during these periods. A lack of neonatal bactericidal IgM antibody is thought to account for the increased susceptibility of neonates to DGI. Persons with terminal complement component deficiencies (C5-C9) are at considerable risk for development of recurrent episodes of DGI.

Clinical Manifestations

Gonorrhea is manifested by a spectrum of clinical presentations from asymptomatic carriage, to the characteristic localized urogenital infections, to disseminated systemic infection (Chapter 114).

Asymptomatic Gonorrhea

The incidence of asymptomatic gonorrhea in children has not been ascertained. Gonococci have been isolated from the oropharynx of young children who have been abused sexually by male contacts; oropharyngeal symptoms are usually absent. Most genital tract infections produce symptoms in children. However, as many as 80% of sexually mature females with urogenital gonorrhea infections are asymptomatic in settings in which most infections are detected through screening or other case-finding efforts. This situation is in contrast to that in men, who are asymptomatic only 10% of the time. Asymptomatic rectal carriage of N. gonorrhoeae has been documented in 40-60% of females with urogenital infection. Most persons with positive rectal culture results are asymptomatic. Most pharyngeal gonococcal infections are asymptomatic. The importance of documenting pharyngeal infection is debated. Most cases resolve spontaneously, transmission from the pharynx to other patients is uncommon, and the pharynx is rarely the only site of infection. Nevertheless, asymptomatic pharyngeal infection may lead to systemic infection and is occasionally the source of transmission to sexual partners.

Uncomplicated Gonorrhea

Genital gonorrhea has an incubation period of 2-5 days in men and 5-10 days in women. Primary infection develops in the urethra of males, the vulva and vagina of prepubertal females, and the cervix of postpubertal females. Neonatal ophthalmitis occurs in both sexes.

Urethritis is usually characterized by a purulent discharge and by dysuria without urgency or frequency. Untreated urethritis in males resolves spontaneously in several weeks or may be complicated by epididymitis, penile edema, lymphangitis, prostatitis, or seminal vesiculitis. Gram-negative intracellular diplococci are found in the discharge.

In prepubertal females, vulvovaginitis is usually characterized by a purulent vaginal discharge with a swollen, erythematous, tender, and excoriated vulva. Dysuria may occur. In postpubertal females, symptomatic gonococcal cervicitis and urethritis are characterized by purulent discharge, suprapubic pain, dysuria, intermenstrual bleeding, and dyspareunia. The cervix may be inflamed and tender. In urogenital gonorrhea limited to the lower genital tract, pain is not enhanced by moving the cervix, and the adnexa are not tender to palpation. Purulent material may be expressed from the urethra or ducts of the Bartholin gland. Rectal gonorrhea is often asymptomatic but may cause proctitis with symptoms of anal discharge, pruritus, bleeding, pain, tenesmus, and constipation. Asymptomatic rectal gonorrhea may not be due to anal intercourse but may represent colonization from vaginal infection.

Gonococcal ophthalmitis may be unilateral or bilateral and may occur in any age group after inoculation of the eye with infected secretions. Ophthalmia neonatorum due to N. gonorrhoeae usually appears from 1 to 4 days after birth (Chapter 618). Ocular infection in older patients results from inoculation or autoinoculation from a genital site. The infection begins with mild inflammation and a serosanguineous discharge. Within 24 hr, the discharge becomes thick and purulent, and tense edema of the eyelids with marked chemosis occurs. If the disease is not treated promptly, corneal ulceration, rupture, and blindness may follow.

Disseminated Gonococcal Infection

Hematogenous dissemination occurs in 1-3% of all gonococcal infections, more frequently after asymptomatic primary infections than symptomatic infections. Women account for the majority of cases, with symptoms beginning 7-30 days after infection and within 7 days of menstruation. The most common manifestations are asymmetric arthralgia, petechial or pustular acral skin lesions, tenosynovitis, suppurative arthritis, and, rarely, carditis, meningitis, and osteomyelitis. The most common initial symptom is acute onset of polyarthralgia with fever. Only 25% of patients complain of skin lesions. Most deny genitourinary symptoms; however, primary mucosal infection is documented by genitourinary cultures. Results of approximately 80-90% of cervical cultures are positive in women with DGI. In males, urethral culture results are positive in 50-60%, pharyngeal culture results are positive in 10-20%, and rectal culture results are positive in 15% of cases.

DGI has been classified into 2 clinical syndromes that have some overlapping features. The 1st and more common is the tenosynovitis-dermatitis syndrome, which is characterized by fever, chills, skin lesions, and polyarthralgia predominantly involving the wrists, hands, and fingers. Blood culture results are positive in approximately 30-40% of cases, and results of synovial fluid cultures are almost uniformly negative. The 2nd syndrome is the suppurative arthritis syndrome, in which systemic symptoms and signs are less prominent and monarticular arthritis, often involving the knee, is more common. A polyarthralgia phase may precede the monarticular infection. In cases of monarticular involvement, synovial fluid culture results are positive in approximately 45-55%, and synovial fluid findings are consistent with septic arthritis. Blood culture results are usually negative. DGI in neonates usually occurs as a polyarticular suppurative arthritis.

Dermatologic lesions usually begin as painful, discrete, 1- to 20-mm pink or red macules that progress to maculopapular, vesicular, bullous, pustular, or petechial lesions. The typical necrotic pustule on an erythematous base is distributed unevenly over the extremities, including the palmar and plantar surfaces, usually sparing the face and scalp. The lesions number between 5 and 40, and 20-30% may contain gonococci. Although immune complexes may be present in DGI, complement levels are normal, and the role of the immune complexes in pathogenesis is uncertain.

Acute endocarditis is an uncommon (1-2%) but often fatal manifestation of DGI that usually leads to rapid destruction of the aortic valve. Acute pericarditis is a rarely described entity in patients with disseminated gonorrhea. Meningitis with N. gonorrhoeae has been documented. Signs and symptoms are similar to those of any acute bacterial meningitis.

Diagnosis

It is not possible to distinguish gonococcal from nongonococcal urethritis on the basis of symptoms and signs alone. Gonococcal urethritis and vulvovaginitis must be distinguished from other infections that produce a purulent discharge, including β-hemolytic streptococci, Chlamydia trachomatis, Mycoplasma hominis, Trichomonas vaginalis, and Candida albicans. Rarely, infection with human herpes simplex virus type 2 may produce symptoms similar to those of gonorrhea.

In males with symptomatic urethritis, a presumptive diagnosis of gonorrhea can be made by identification of gram-negative intracellular diplococci (within leukocytes) in the urethral discharge. A similar finding in females is not sufficient because Mima polymorpha and Moraxella, which are normal vaginal flora, have a similar appearance. The sensitivity of the Gram stain for diagnosing gonococcal cervicitis and asymptomatic infections is also low. The presence of commensal Neisseria species in the oropharynx prevents the use of the Gram stain for diagnosis of pharyngeal gonorrhea. Nonpathogenic Neisseria organisms are not found intracellularly.

Specific testing for N. gonorrhoeae is recommended because a specific diagnosis might enhance partner notification. Highly sensitive and specific testing methods are available. Culture, nucleic acid hybridization tests, and nucleic acid amplification tests (NAATs) are available for the detection of genitourinary infection. Culture and nucleic acid hybridization tests require female endocervical or male urethral swab specimens. NAATs offer the widest range of testing specimen types; they are cleared by the U.S. Food and Drug Administration (FDA) for use with endocervical swabs, vaginal swabs, male urethral swabs, and female and male urine. However, product inserts for each NAAT vendor must be carefully examined to assess current indications. Nonculture tests are not FDA cleared for use with specimens from the rectum and pharynx or for use with specimens obtained from the oropharynx, rectum, or genital tract of children. Nonculture gonococcal tests for gonococci (e.g., gram-stained smear, nucleic acid hybridization tests, and NAATs) should not be used without standard culture in children because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child. Nonculture tests cannot provide antimicrobial susceptibility results, so in cases of persistent gonococcal infection after treatment, clinicians should perform both culture and antimicrobial susceptibility testing.

Material for cervical cultures is obtained as follows: After the exocervix is wiped, a swab is placed in the cervical os and rotated gently for several seconds. Male urethral specimens are obtained by placement of a small swab 2-3 cm into the urethra. Rectal swabs are best obtained by passing of a swab 2-4 cm into the anal canal; specimens that are heavily contaminated by feces should be discarded. For optimal culture results, specimens should be obtained with noncotton swabs (e.g., a urethrogenital calcium alginate–tipped swab [Calgiswab, Puritan Medical Products, Guilford, ME]), inoculated directly onto culture plates, and incubated immediately. The choice of anatomic sites to culture depends on the sites exposed and the clinical manifestations. Samples from the urethra should be cultured for heterosexual men, and samples from the endocervix and rectum should be cultured for all females, regardless of a history of anal intercourse. A pharyngeal culture specimen should be obtained from both men and women if symptoms of pharyngitis are present or in the case of oral exposure to a person known to have genital gonorrhea. In a suspected case of child sexual abuse, rectal, pharyngeal, and urethral (males) or vaginal (females) swabs should be cultured. Culture of the endocervix should not be attempted until after puberty.

Specimens from sites that are normally colonized by other organisms (e.g., cervix, rectum, pharynx) should be inoculated on a selective culture medium, such as modified Thayer-Martin medium (fortified with vancomycin, colistin, nystatin, and trimethoprim to inhibit growth of indigenous flora). Specimens from sites that are normally sterile or minimally contaminated (i.e., synovial fluid, blood, cerebrospinal fluid) should be inoculated on a nonselective chocolate agar medium. If DGI is suspected, blood, pharynx, rectum, urethra, cervix, and synovial fluid (if involved) should be cultured. Cultured specimens should be incubated promptly at 35-37°C in 3-5% carbon dioxide. When specimens must be transported to a central laboratory for culture plating, a reduced, non-nutrient holding medium (i.e., Amies modified Stuart medium) preserves specimens with minimal loss of viability for up to 6 hr. When transport may delay culture plating by more than 6 hr, it is preferable to inoculate the sample directly onto a culture medium and transport it at an ambient temperature in a candle jar. The Transgrow and JEMBEC (John E. Martin Biological Environmental Chamber) systems of modified Thayer-Martin medium are alternative transport systems.

Gonococcal arthritis must be distinguished from other forms of septic arthritis as well as from rheumatic fever, rheumatoid arthritis, inflammatory bowel disease, and arthritis secondary to rubella or rubella immunization. Gonococcal conjunctivitis in the newborn period must be differentiated from chemical conjunctivitis caused by silver nitrate drops as well as from conjunctivitis caused by C. trachomatis, Staphylococcus aureus, group A or B streptococcus, Pseudomonas aeruginosa, Streptococcus pneumoniae, or human herpes simplex virus type 2.

Treatment

All patients who are presumed or proven to have gonorrhea should be evaluated for concurrent syphilis, hepatitis B, HIV, and C. trachomatis infection. The incidence of Chlamydia co-infection is 15-25% among males and 35-50% among females. Patients beyond the neonatal period should be treated presumptively for C. trachomatis infection unless a negative chlamydial NAAT result is documented at the time treatment is initiated for gonorrhea. However, if chlamydial test results are not available or if a non-NAAT result is negative for Chlamydia, patients should be treated for both gonorrhea and Chlamydia infection (Chapter 218.2). Sexual partners exposed in the preceding 60 days should be examined, culture specimens should be collected, and presumptive treatment should be started.

Because of the prevalence of penicillin-resistant N. gonorrhoeae, ceftriaxone (a 3rd-generation cephalosporin) is recommended as initial therapy for all ages. Antimicrobial resistance in N. gonorrhoeae occurs as plasmid-mediated resistance to penicillin and tetracycline and chromosomally mediated resistance to penicillins, tetracyclines, spectinomycin, and fluoroquinolones. As a consequence of widespread fluoroquinolone-resistant gonorrhea in the USA, this class of antibiotics is no longer recommended for the treatment of gonorrhea in this country.

Adolescent and Adult Infections

A single dose of ceftriaxone (125 mg intramuscularly [IM]) eradicates pharyngeal and uncomplicated urogenital gonococcal infections. Ceftriaxone is safe and effective in pregnant women and probably aborts incubating syphilis. Alternative regimens include cefixime (400 mg by mouth [PO]) in a single dose. The efficacy of cefixime against incubating syphilis is uncertain. Other single-dose cephalosporin therapies that are considered alternative treatment regimens for uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime 500 mg IM; cefoxitin 2 g IM, administered with probenecid 1 g PO; and cefotaxime 500 mg IM. Some evidence indicates that cefpodoxime 400 mg and cefuroxime axetil 1 g might be oral alternatives. Spectinomycin (40 mg/kg, maximum dose 2 g) in a single IM dose remains highly effective for genital and rectal gonorrhea in the USA but is ineffective for pharyngeal infection and does not inhibit Treponema pallidum. Regardless of the regimen chosen, treatment should be followed by a regimen active against C. trachomatis unless Chlamydia infection is ruled out by a negative chlamydial NAAT result. The recommended regimen is doxycycline (100 mg PO twice daily for 7 days) or azithromycin (1g PO in a single dose). Adolescents and adults who are asymptomatic after treatment need not under culture for confirmation of cure.

Pregnant women should not be treated with quinolones or tetracyclines. Those infected with N. gonorrhoeae should be treated with a recommended or alternate cephalosporin. Either azithromycin or amoxicillin is recommended for treatment of presumptive or proven C. trachomatis infection during pregnancy.

The initial management of DGI includes hospitalization and parenteral administration of ceftriaxone (1 g/day). Alternative cephalosporins include cefotaxime (1 g intravenously [IV] every 8 hr) and ceftizoxime (1g IV every 8 hr). Patients should be examined for clinical evidence of endocarditis and meningitis. Treatment may be switched to oral regimens after 24-48 hr and as clinical improvement is obvious. Oral regimens include cefixime (400 mg PO bid) and cefpodoxime (400 mg PO bid) to complete 7 days of therapy. Fluoroquinolones may be an alternative treatment option if antimicrobial susceptibility to these agents can be documented by culture.

Gonococcal conjunctivitis should be treated with ceftriaxone (1g IM in a single dose) with lavage of the infected eye with saline. Meningitis is treated with ceftriaxone (1-2 g IV every 12 hr) for 10-14 days. Endocarditis is treated for >4 wk with ceftriaxone (1-2 g IV every 12 hr). Concurrent therapy for treatment of genital Chlamydia infection is important.

Infant and Pediatric Infections

Uncomplicated gonococcal infections in children should be treated with ceftriaxone in a single dose (50 mg/kg IM, not to exceed 125 mg). Children who have bacteremia or arthritis should be treated with ceftriaxone (50 mg/kg/day, maximum 1 g/day if <45 kg) for a minimum of 7 days. Meningitis should be treated for 10-14 days, and endocarditis for a minimum of 28 days, with ceftriaxone (50 mg/kg/dose every 12 hr with maximum of 1-2 g IV every 12 hr). Neonatal gonococcal ophthalmia is treated effectively with a single dose of ceftriaxone (50 mg/kg IM, not to exceed 125 mg); a single dose of cefotaxime (100 mg/kg IM) is an acceptable alternative. The conjunctivae should be irrigated frequently with physiologic saline solution. Infants born to mothers who have gonococcal infection should also receive a single dose of ceftriaxone (50 mg/kg IM, not to exceed 125 mg). Neonatal sepsis should be treated parenterally for a minimum of 7 days, and meningitis for a minimum of 10 days. Cefotaxime is recommended for infants with hyperbilirubinemia, because ceftriaxone competes for bilirubin binding sites on albumin. Neonates with gonococcal ophthalmitis must be hospitalized and evaluated for DGI.

Pelvic Inflammatory Disease

PID encompasses a spectrum of infectious diseases of the upper genital tract due to N. gonorrhoeae, C. trachomatis, and endogenous flora (streptococci, anaerobes, gram-negative bacilli). For women with more severe symptoms, parenteral therapy should be initiated in the hospital. A commonly recommended therapeutic regimen is cefoxitin (2g IV every 6 hr) or cefotetan (2g IV every 12 hr) plus doxycycline (100 mg PO or IV every 12 hr). Alternative regimens include clindamycin (900 mg IV every 8 hr) plus a loading dose of gentamicin (2 mg/kg IV) followed by maintenance gentamicin (1.5 mg/kg every 8 hr), and ampicillin/sulbactam (3 g IV every 6 hr) plus doxycycline (100 mg PO or IV every 12 hr). Clinical experience should guide transition to oral therapy, which usually can be initiated within 24 hr of improvement. Thereafter, oral doxycycline is given to complete 14 days of total therapy.

Parenteral therapy and oral therapy appear to be similar in clinical efficacy for women with PID of mild to moderate severity. Clinical response to outpatient treatment is similar among younger and older women. The decision to hospitalize adolescents with acute PID should be based on clinical criteria used for older women. Those who do not show response to oral therapy within 72 hr should be reevaluated to confirm the diagnosis and then should receive parenteral therapy. Recommended oral regimens are as follows: a single dose of ceftriaxone (250 mg IM) plus doxycycline (100 mg PO bid) with or without metronidazole (500 mg PO bid) for 14 days; and single doses of cefoxitin (2 g IM) and probenecid (1 g PO) plus doxycycline (100 mg PO bid) with or without metronidazole (500 mg PO bid) for 14 days. If the patient has an intrauterine device, it must be removed and an alternative form of birth control used. Sexual partners should be examined and treated for uncomplicated gonorrhea. Follow-up culture (test of cure) after cephalosporin-doxycycline therapy of gonococcal infection is not recommended owing to the low treatment failure rate. A follow-up examination and culture are recommended in 1-2 mo to evaluate the possibility of re-infection or, rarely, treatment failure.

Complications

Complications of gonorrhea result from the spread of gonococci from a local site of invasion. The interval between primary infection and development of a complication is usually days to weeks. In postpubertal females, endometritis may occur, especially during menses, and may progress to salpingitis and peritonitis (PID). Manifestations of PID include signs of lower genital tract infection (e.g., vaginal discharge, suprapubic pain, cervical tenderness) and upper genital tract infection (e.g., fever, leukocytosis, elevated erythrocyte sedimentation rate, and adnexal tenderness or mass). The differential diagnosis includes gynecologic diseases (ovarian cyst, ovarian tumor, ectopic pregnancy) and intra-abdominal disorders (appendicitis, urinary tract infection, inflammatory bowel disease).

Once inside the peritoneum, gonococci may seed the liver capsule, causing a perihepatitis with right upper quadrant pain (Fitz-Hugh–Curtis syndrome), with or without signs of salpingitis. Perihepatitis may also be caused by C. trachomatis. Progression to PID occurs in about 20% of cases of gonococcal cervicitis, and N. gonorrhoeae is isolated in approximately 40% of cases of PID in the USA. Untreated cases may lead to hydrosalpinx, pyosalpinx, tubo-ovarian abscess, and eventual sterility. Even with adequate treatment of PID, the risk for sterility due to bilateral tubal occlusion approaches 20% after 1 episode of salpingitis and exceeds 60% after 3 or more episodes. The risk for ectopic pregnancy is increased approximately sevenfold after 1 or more episodes of salpingitis. Additional sequelae of PID include chronic pain, dyspareunia, and increased risk for recurrent PID.

Urogenital gonococcal infection acquired during the 1st trimester of pregnancy carries a high risk for septic abortion. After 16 wk, infection leads to chorioamnionitis, a major cause of premature rupture of the membranes and premature delivery.

Prognosis

Prompt diagnosis and correct therapy ensure complete recovery from uncomplicated gonococcal disease. Complications and permanent sequelae may be associated with delayed treatment, recurrent infection, metastatic sites of infection (meninges, aortic valve), and delayed or topical therapy of gonococcal ophthalmia.

Prevention

Efforts to develop a gonococcal pilus vaccine have been unsuccessful thus far. The high degree of interstrain and intrastrain antigenic variability of pili poses a formidable deterrent to the development of a single effective pilus vaccine. Other gonococcal surface structures, such as the porin protein, stress proteins, and lipo-oligosaccharides, may prove more promising as vaccine candidates. In the absence of a vaccine, prevention of gonorrhea can be achieved through education, use of barrier contraceptives (especially condoms and spermicides), intensive epidemiologic and bacteriologic surveillance (screening sexual contacts), and early identification and treatment of infected contacts.

Gonococcal ophthalmia neonatorum can be prevented by instilling 2 drops of a 1% solution of silver nitrate into each conjunctival sac shortly after birth (Chapter 618). Erythromycin (0.5%) or tetracycline (1%) ophthalmic ointment may also be used.

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