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Gonococcal Infections

DEFINITION

Gonorrhea is a sexually transmitted infection of epithelium and commonly manifests as cervicitis, urethritis, proctitis, and conjunctivitis. If untreated, infections at these sites can lead to local complications such as endometritis, salpingitis, tuboovarian abscess, bartholinitis, peritonitis, and perihepatitis in the female; periurethritis and epididymitis in the male; and ophthalmia neonatorum in the newborn. Disseminated gonococcemia is an uncommon event whose manifestations include skin lesions, tenosynovitis, arthritis, and (in rare cases) endocarditis or meningitis.Neisseria gonorrhoeae is a gram-negative, nonmotile, non-spore-forming organism that grows in pairs (diplococci). Each individual organism is shaped like a coffee bean, with adjacent concave sides seen on Gram's stain. Gonococci, like all other Neisseria spp., are oxidase positive. They are distinguished from other neisseriae by their ability to grow on selective media and to utilize glucose but not maltose, sucrose, or lactose.

EPIDEMIOLOGY

The incidence of gonorrhea has declined significantly in the United States, but there were still ~362,000 newly reported cases in 2002. Gonorrhea remains a major public health problem worldwide, is a significant cause of morbidity in developing countries, and may play a role in enhancing transmission of HIV.Gonorrhea predominantly affects young, nonwhite, unmarried, less educated members of urban populations. The number of reported cases probably represents half of the true number of cases—a discrepancy resulting from underreporting, self-treatment, and nonspecific treatment without a culture-proven diagnosis. The number of reported cases of gonorrhea in the United States rose from ~250,000 in the early 1960s to a high of 1.01 million in 1978. The peak recorded incidence of gonorrhea in modern times was reported in 1975, with 468 cases per 100,000 population in the United States. This peak was attributable to the interaction of several variables, including improved accuracy of diagnosis, changes in patterns of contraceptive use, and changes in sexual behavior. The incidence of the disease has since gradually declined and is currently estimated at 120 cases per 100,000, a figure that is still the highest among industrialized countries. A further decline in the overall incidence of gonorrhea in the United States over the past decade may reflect increased condom use resulting from public health efforts to curtail HIV transmission. Presently, the attack rate in the United States is highest in the 20- to 24-year age group, in which 75% of all cases occur. With adjustment for sexual experience, the risk is highest among sexually active 15- to 19-year-old women. In terms of ethnicity, rates are highest among African Americans and lowest among persons of Asian or Pacific Island descent.The incidence of gonorrhea is highest in developing countries. The exact incidence of any of the sexually transmitted diseases (STDs) is difficult to ascertain in developing countries because of limited surveillance and variable diagnostic criteria. For example, in Kenya, it was estimated in 1987 that 10% of all live births were adversely affected by STDs, and gonococcal ophthalmia neonatorum reportedly affected 4% of all live-born infants. The median prevalence of gonorrhea in unselected populations of pregnant women has been estimated at 10% in Africa, 5% in Latin America, and 4% in Asia. Studies in Africa have clearly demonstrated that nonulcerative STDs such as gonorrhea are an independent risk factor for the transmission of HIV Gonorrhea is transmitted from males to females more efficiently than in the opposite direction. The rate of transmission to a woman following a single unprotected sexual encounter with an infected man is on the order of 40 to 60%. Oropharyngeal gonorrhea occurs in ~20% of women who practice fellatio with infected partners. Transmission in either direction by cunnilingus is rare.There exists in any population a small minority of individuals who have high rates of new-partner acquisition. These “core-group members” or “high-frequency transmitters” are vital in sustaining STD transmission at the population level. Another instrumental factor in sustaining gonorrhea in the population is the large number of infected individuals who are asymptomatic or have minor symptoms that are ignored. These persons, unlike symptomatic individuals, do not cease sexual activity and therefore continue to transmit the disease. This situation underscores the importance of contact tracing and empirical treatment of sex partners of index cases.

PATHOGENESIS, IMMUNOLOGY, AND ANTIMICROBIAL RESISTANCE

Outer-Membrane ProteinsPILIFresh clinical isolates of N. gonorrhoeae initially form piliated (fimbriated) colonies distinguishable on translucent agar. Pilus expression is rapidly switched off with unselected subculture because of rearrangements in pilus genes. This change is a basis for phase variation of gonococci. Piliated strains adhere better to cells derived from human mucosal surfaces and are more virulent in organ culture models and human inoculation experiments than nonpiliated variants. In a fallopian tube explant model, pili mediate gonococcal attachment to nonciliated columnar epithelial cells. This event initiates gonococcal phagocytosis and transport through these cells to intercellular spaces near the basement membrane or directly into the subepithelial tissue. Damage to nearby ciliated columnar epithelial cells, which is caused by the release of cytokines, results in loss of cilia and sloughing of ciliated cells and diminishes the integrity of the fallopian tube. Nonpiliated gonococci cause epithelial damage at a much slower rate. CD46 (membrane cofactor protein) is present on urogenital epithelial cells in both men and women and has been determined to be a receptor for PilC; this subunit is located at the tip of the pilus molecule and is critical in mediating adherence. Pili are also essential for genetic competence and transformation of N. gonorrhoeae, which permit horizontal transfer of genetic material between different gonococcal lineages in vivo.

OPACITY-ASSOCIATED PROTEIN

Another gonococcal surface protein that is important in adherence to epithelial cells is opacity-associated protein (Opa, formerly called protein II). Opa contributes to intergonococcal adhesion, which is responsible for the opaque nature of gonococcal colonies on translucent agar and the organism's adherence to a variety of eukaryotic cells, including polymorphonuclear leukocytes (PMNs). Certain Opa variants promote invasion of epithelial cells, and this effect has been linked with the ability of Opa to bind vitronectin, glycosaminoglycans, and several members of the carcinoembryonic antigen–related cell adhesion molecule (CEACAM, previously known as CD66) receptor family. Each strain of N. gonorrhoeae possesses as many as 11 different opa genes, but usually no more than three types are expressed at any given time. Isolates from normally sterile sites such as the fallopian tube and synovial fluid usually fail to express Opa, while isolates from mucosal sites usually form opaque colonies. Female commercial sex workers with antibodies to Opa may be less likely to develop pelvic inflammatory disease (PID) than women without such antibodies. N. gonorrhoeae Opa proteins that bind CEACAM 1, which is expressed by primary CD4+ T lymphocytes, suppress the activation and proliferation of these lymphocytes. This phenomenon may serve to explain the transient decrease in CD4+ T-lymphocyte counts associated with gonococcal infection. PORINPorin (previously designated protein I) is the most abundant gonococcal surface protein, accounting for >50% of the organism's total outer-membrane protein. Porin molecules exist as trimers that provide anion aqueous channels through the otherwise-hydrophobic outer membrane. Porin shows stable interstrain antigenic variation and forms the basis for gonococcal serotyping. Two main serotypes have been identified: Por1A strains are often associated with disseminated gonococcal infection (DGI), while Por1B strains usually cause local genital infections only. DGI strains are generally resistant to the killing action of normal human serum, do not incite a significant local inflammatory response, and therefore may not cause symptoms at genital sites. These characteristics may be related to the ability of Por1A strains to bind to complement-downregulatory molecules, resulting in a diminished inflammatory response. Porin can translocate to the cytoplasmic membrane of host cells—a process that could initiate gonococcal endocytosis and invasion. In addition, porin is an immunologic target of bactericidal and opsonophagocytic antibodies that may arise in response to immune stimulation resulting from infection or immunization with porin-containing vaccine candidates.

OTHER OUTER-MEMBRANE PROTEINS

Other notable outer-membrane proteins include H.8, a lipoprotein that is present in high concentration on the surface of all gonococcal strains and is an excellent target for antibody-based diagnostic testing. Transferrin-binding proteins (Tbp1 and Tbp2) and lactoferrin-binding protein are required for scavenging iron from transferrin and lactoferrin in vivo. Transferrin and iron have been shown to increase attachment of iron-deprived N. gonorrhoeae to human endometrial cells. Studies with volunteers have demonstrated that gonococci deficient in transferrin- and lactoferrin-binding proteins cannot establish infection in men. IgA1 protease is produced by N. gonorrhoeae and may protect the organism from the action of mucosal IgA.LipooligosaccharideGonococcal lipooligosaccharide (LOS) consists of a lipid A and a core oligosaccharide that lacks the repeating O-carbohydrate antigenic side chain seen in other gram-negative bacteria. Gonococcal LOS possesses marked endotoxic activity and contributes to the local cytotoxic effect in the fallopian tube model. LOS core sugars undergo a high degree of antigenic variation under different conditions of growth; this variation reflects genetic regulation and expression of glycotransferase genes that dictate the carbohydrate structure of LOS. These phenotypic changes may affect interactions of N. gonorrhoeae with elements of the humoral immune system (antibodies and complement) and may also influence direct binding of organisms to both professional phagocytes and nonprofessional phagocytes (epithelial cells). For example, gonococci that are sialylated at their LOS sites bind complement factor H and downregulate the alternative pathway of complement. LOS sialylation may also mask bactericidal antibody–binding epitopes on LOS and porin and may decrease opsonophagocytosis and inhibit the oxidative burst in PMNs. While sialylation of LOS confers on the bacteria the ability to attenuate the inflammatory response and evade the innate immune system, experiments in male volunteers suggest that sialylated gonococci may be less capable of establishing infection than their unsialylated counterparts. This difference could be explained by the observation that the unsialylated terminal lactosamine residue of LOS binds to an asialoglycoprotein receptor on male epithelial cells that would otherwise facilitate binding and subsequent gonococcal invasion of these cells.Host FactorsIn addition to gonococcal structures that interact with epithelial cells, host factors seem to be important in mediating entry of gonococci into nonphagocytic cells. Activation of phosphatidylcholine-specific phospholipase C and acidic sphingomyelinase by N. gonorrhoeae, which results in the release of diacylglycerol and ceramide, is a requirement for the entry of N. gonorrhoeae into epithelial cells. Ceramide accumulation within cells leads to apoptosis, which may disrupt epithelial integrity and facilitate entry of gonococci into subepithelial tissue. Release of chemotactic factors as a result of complement activation contributes to inflammation, as does the toxic effect of LOS in provoking the release of inflammatory cytokines.The importance of humoral immunity in host defenses against neisserial infections is best illustrated by the predisposition of persons deficient in terminal complement components (C5 through C9) to recurrent bacteremic gonococcal infections and to recurrent meningococcal meningitis or meningococcemia. Gonococcal porin induces T cell–proliferative responses in persons with urogenital gonococcal disease. A significant increase in porin-specific interleukin (IL) 4–producing CD4+ as well as CD8+ lymphocytes is seen in individuals with mucosal gonococcal disease. A portion of these lymphocytes that show a porin-specific T_H2-type response could traffic to mucosal surfaces and play a role in immune protection against the disease. Few data clearly indicate that protective immunity is acquired from a previous gonococcal infection, although bactericidal and opsonophagocytic antibodies to porin and LOS may offer partial protection. On the other hand, women who are infected and acquire high levels of antibody to another outer-membrane protein, Rmp (reduction modifiable protein, formerly called protein III), may be especially likely to become reinfected with N. gonorrhoeae because Rmp antibodies block the effect of bactericidal antibodies to porin and LOS. Rmp shows little, if any, interstrain antigenic variation; therefore, Rmp antibodies potentially may block antibody-mediated killing of all gonococci. The mechanism of blocking has not been fully characterized, but Rmp antibodies noncompetitively inhibit binding of porin and LOS antibodies because of the proximity of these structures in the gonococcal outer membrane. Less well understood is how blocking antibody may divert complement binding to the gonococcal surface or otherwise hasten inactivation of complement. In male volunteers who have no history of gonorrhea, the net effect of these events may influence the outcome of experimental challenge with N. gonorrhoeae. Because Rmp bears extensive homology to enterobacterial OmpA and meningococcal class 4 proteins, it is possible that these blocking antibodies result from prior exposure to cross-reacting proteins from these species and also play a role in first-time infection with N. gonorrhoeae.Gonococcal Resistance to Antimicrobial AgentsIt is no surprise that N. gonorrhoeae, with its remarkable capacity to alter its antigenic structure and adapt to changes in the microenvironment, has become resistant to numerous antibiotics. The first effective agents against gonorrhea were the sulfonamides, which were introduced in the 1930s. Within a decade, antibiotic resistance emerged, resulting in treatment failures in one-third of patients. Penicillin was then employed as the drug of choice for the treatment of gonorrhea. By 1965, 42% of gonococcal isolates had developed low-level resistance to penicillin G. To prevent treatment failures, the Centers for Disease Control and Prevention (CDC) at that time recommended doubling the dose of penicillin for the treatment of gonorrhea. Resistance due to the production of penicillinase arose later.Gonococci become fully resistant to antibiotics either by chromosomal mutations or by acquisition of R factors (plasmids). Two types of chromosomal mutations have been described. The first type, which is drug specific, is a single-step mutation leading to high-level resistance. The second type involves mutations at several chromosomal loci that combine to determine the level as well as the pattern of resistance. Strains with mutations in chromosomal genes were first observed in the late 1950s. As recently as 1997, strains with chromosomal resistance (CMRNG) accounted for resistance to penicillin, tetracycline, or both in ~20% of strains surveyed in the United States.β-Lactamase (penicillinase)–producing strains of N. gonorrhoeae (PPNG) carrying plasmids with the Pc^rdeterminant were seen almost simultaneously in the United States, England, western Africa, and the Philippines in the late 1970s. PPNG strains have since spread worldwide and by the early 1980s accounted for >50% of all gonococcal isolates in some parts of the developing world. The average prevalence of PPNG in the United States dropped by two-thirds after most penicillin use was discontinued and is now on the order of 4%, with higher rates reported from certain areas. N. gonorrhoeae strains with plasmid-borne tetracycline resistance (TRNG) can mobilize some β-lactamase plasmids, and PPNG and TRNG occur together, sometimes along with CMRNG. Penicillin, ampicillin, and tetracycline are no longer reliable agents for the treatment of gonorrhea and should not be used. Third-generation cephalosporins have remained highly effective as single-dose therapy for gonorrhea. Even though the minimal inhibitory concentrations (MICs) of ceftriaxone for certain strains may reach 0.015 to 0.125 mg/L (higher than MICs of 0.0001 to 0.008 mg/L for fully susceptible strains), these levels are greatly exceeded in blood, the urethra, and the cervix when the routinely recommended ceftriaxone and cefixime regimens are administered (see below). These regimens almost always result in an effective cure.Quinolone-containing regimens are also recommended for treatment of gonococcal infections; the fluoroquinolones offer the advantage of antichlamydial activity when administered for 7 days. Serum concentrations following therapeutic dosages of the quinolones exceed the MIC for N. gonorrhoeae by ~100-fold. However, quinolone-resistant N. gonorrhoeae (QRNG) appeared soon after these agents were first used to treat gonorrhea, particularly in Southeast Asia. QRNG strains have been reported recently in the United States, mostly in the far western states. Alterations in DNA gyrase and topoisomerase IV have been implicated as mechanisms of fluoroquinolone resistance.Resistance to spectinomycin, which is used as an alternative agent, has been reported, but resistance to this agent is usually not associated with resistance to other antibiotics. Therefore, spectinomycin can be reserved for use against multiresistant strains of N. gonorrhoeae. Nevertheless, outbreaks caused by strains resistant to spectinomycin have been documented in Korea and England when the drug was used as a primary agent to treat gonorrhea. CLINICAL MANIFESTATIONSGonococcal Infection in MalesAcute urethritis is the most common clinical manifestation of gonorrhea in males. The usual incubation period following exposure is 2 to 7 days, although the interval can be longer and some men remain asymptomatic. Strains of the Por1A serotype, with nutritional requirements for arginine, hypoxanthine, and uracil (i.e., the AHU auxotype), tend to cause a greater proportion of cases of mild and asymptomatic urethritis than Por1B strains. Urethral discharge and dysuria, usually without urinary frequency or urgency, are the major symptoms. The discharge initially is scant and mucoid but becomes profuse and purulent within a day or two. The clinical manifestations of gonococcal urethritis are usually more severe and overt than those of nongonococcal urethritis, including urethritis caused by Chlamydia trachomatis; however, exceptions are common, and it is often impossible to differentiate the causes of urethritis on clinical grounds alone. The majority of cases of urethritis seen in the United States today are not caused by N. gonorrhoeae and/or C. trachomatis. Although a number of other organisms may be responsible, most cases do not have a specific etiologic agent identified. Most symptomatic males with gonorrhea seek treatment and cease to be infectious. The remaining men, who are largely asymptomatic, accumulate in number over time and constitute about two-thirds of all infected men at any point in time. Together with men incubating the organism (who shed the organism but are asymptomatic), they serve as the source of spread of infection. Prior to the antibiotic era, symptoms of urethritis persisted for about 8 weeks. Epididymitis is now an uncommon complication, and gonococcal prostatitis occurs rarely, if at all. Other unusual local complications of gonococcal urethritis include edema of the penis due to dorsal lymphangitis or thrombophlebitis, submucous inflammatory “soft” infiltration of the urethral wall, periurethral abscess or fistulae, inflammation or abscess of Cowper's gland, and seminal vesiculitis. Balanitis may develop in uncircumcised men. After a decline in gonococcal infections among homosexual men early in the era of AIDS, a disturbing increase in gonorrhea was observed among young homosexual men in the 1990s, probably related to decreased condom use. The clinical features of anorectal and pharyngeal gonorrhea are discussed below.Gonococcal Infections in Females GONOCOCCAL CERVICITISMucopurulent cervicitis is the most common STD diagnosis in American women and may be caused by N. gonorrhoeae, C. trachomatis, and other organisms. Cervicitis may coexist with candidal or trichomonal vaginitis. N. gonorrhoeae primarily infects the cervical os but can also infect more peripheral areas of the cervix where columnar epithelium meets stratified squamous epithelium. Except in rare instances, the vaginal mucosa, which is lined by stratified squamous epithelium, does not become infected. Bartholin's glands occasionally become infected.Women infected with N. gonorrhoeae usually develop symptoms. However, the women who either remain asymptomatic or have only minor symptoms may delay in seeking medical attention. These symptoms may include scant discharge from the vagina that may issue forth from the inflammed cervix (not vaginitis or vaginosis per se) and dysuria (often without urgency or frequency) that may be associated with gonococcal urethritis. Although the incubation period of gonorrhea is less well defined in women than in men, symptoms usually develop within 10 days of infection and are more acute and intense than those of chlamydial cervicitis.The physical examination may reveal a mucopurulent discharge (mucopus) issuing from the cervical os. The examiner may check for mucopurulent discharge by swabbing a sample of mucus from the endocervix and observing its color against the white background of the swab; yellow or green mucus suggests mucopus. However, only 35% of women with gonococcal cervicitis actually have a mucopurulent discharge defined by these criteria. Because Gram's stain is not sensitive for the diagnosis of gonorrhea in women, specimens should be submitted for culture or a nonculture assay (see below). Edematous and friable cervical ectopy as well as endocervical bleeding induced by gentle swabbing are more often seen in chlamydial infection.N. gonorrhoeae may be recovered from the urethra and rectum of women with cervicitis, but these are rarely the sole infected sites. Urethritis in women may produce symptoms of internal dysuria, which is often attributed to “cystitis.” Pyuria in the absence of bacteriuria seen on Gram's stain of unspun urine, accompanied by urine cultures that fail to yield >10⁵ colonies of bacteria usually associated with urinary tract infection, signifies the possibility of urethritis due to C. trachomatis. Urethral infection with N. gonorrhoeae may also occur in this context, but in this instance urethral cultures will usually be positive. Compression of the urethra through the anterior vaginal wall against the symphysis pubis may express urethral exudate.

COMPLICATIONS OF GONOCOCCAL CERVICITIS

Gonococcal infection may extend deep enough to produce dyspareunia and lower abdominal or back pain. In such cases, it is imperative to consider a diagnosis of PID and to administer treatment for that disease. Ascending infection of the genital tract follows ~20% of cases of gonococcal cervicitis and may result in acute endometritis accompanied by abnormal menstrual bleeding, midline lower abdominal pain and tenderness, and dyspareunia. Spread to the fallopian tubes results in acute salpingitis, whose symptoms may be accompanied by signs of cervical motion tenderness and abnormal adnexal mass on pelvic examination. Patients may be febrile, and leukocytosis and an elevated erythrocyte sedimentation rate or C-reactive protein level may be detected. Co-infection with C. trachomatis may increase the risk of PID, which is the clinical counterpart of endometritis and salpingitis. Tubal scarring leading to infertility is the most devastating sequela of salpingitis; the increased risk of ectopic pregnancy is also significant. Prompt and appropriate antibiotic therapy for gonococcal salpingitis (prior to the development of an adnexal mass) can prevent tubal infertility in nearly all cases. Bilateral tubal damage occurs in ~20% of women with an adnexal mass. More than half of women with tubal infertility give no history of PID. These women with “silent salpingitis” may report abdominal or pelvic discomfort (such as dysmenorrhea or dyspareunia) that may be attributed to other diagnoses (such as endometriosis). Spread of infection to the pelvis may result in pelvic peritonitis characterized by nausea and vomiting. Spread of gonococci—or, more commonly, of chlamydiae—via the peritoneal cavity to the upper abdomen may cause perihepatitis (Fitz-Hugh–Curtis syndrome;.

GONOCOCCAL VAGINITIS

The vaginal mucosa of healthy women is lined by stratified squamous epithelium and is usually not infected by N. gonorrhoeae. However, gonococcal vaginitis can occur in anestrogenic women (e.g., prepubertal girls and postmenopausal women), in whom the vaginal stratified squamous epithelial layers are often thinned down to the basilar layer, which can be infected by N. gonorrhoeae. The intense inflammation of the vagina makes the physical (speculum and bimanual) examination extremely painful. The vaginal mucosa is red and edematous, and an abundant purulent discharge is present. Infection in the urethra and in Skene's and Bartholin's glands often accompanies gonococcal vaginitis. Inflamed cervical erosion or abscesses in nabothian cysts may also occur. Coexisting cervicitis may result in pus in the cervical os.Differential Diagnosis of Genital Gonococcal InfectionsThe clinical features of uncomplicated gonococcal infections closely resemble those of genital infections caused by C. trachomatis. Although the symptoms produced by chlamydial infections tend to be milder, the two infections are often indistinguishable on clinical grounds alone. Co-infection with N. gonorrhoeae and C. trachomatis is seen in up to 40% of cases. The differential diagnosis of urethritis, epididymitis, and proctitis in men; of cervicitis and PID in women; and of vaginitis in prepubertal girls is discussed.Anorectal GonorrheaBecause the female anatomy permits the spread of cervical exudate to the rectum, N. gonorrhoeae is sometimes recovered from the rectum of women with uncomplicated gonococcal cervicitis. The rectum is the sole site of infection in only 5% of women with gonorrhea. Such women are usually asymptomatic but occasionally have acute proctitis manifested by anorectal pain or pruritus, tenesmus, purulent rectal discharge, and rectal bleeding. Among homosexual men, the frequency of gonococcal infection, including rectal infection, fell by ≥90% throughout the United States in the early 1980s, but a resurgence of gonorrhea among homosexual men was documented in several cities during the 1990s. Gonococcal isolates from the rectum of homosexual men tend to be more resistant than other gonococcal isolates to antimicrobials. Gonococcal isolates with a mutation in mtrR (multiple transferable resistance repressor) or in the promoter region of the gene that encodes for this transcriptional repressor develop increased resistance to antimicrobial hydrophobic agents such as bile acids and fatty acids in feces and thus are found with increased frequency in homosexual men. The mutation, which curtails the production of a DNA-binding protein called MtrR, results in derepression of the expression of other mtr genes that encode the production of an energy-dependent efflux pump, thereby resulting in increased resistance to hydrophobic agents. This situation may have been responsible for higher rates of failure of treatment for rectal gonorrhea with older regimens consisting of penicillin or tetracyclines.Pharyngeal GonorrheaPharyngeal gonorrhea is usually mild or asymptomatic, although symptomatic pharyngitis does occasionally occur with cervical lymphadenitis. The mode of acquisition is oral-genital sexual exposure, with fellatio being a more efficient means of transmission than cunnilingus. It is important to solicit a sexual history as part of the evaluation of pharyngitis so that appropriate cultures for N. gonorrhoeae can be performed. Acute HIV infection should also be considered in the differential diagnosis of pharyngitis in persons with appropriate risk factors. Most cases resolve spontaneously, and transmission from the pharynx to sexual contacts is rare. Pharyngeal infection almost always coexists with genital infection. Swabs from the pharynx should be plated directly onto gonococcal selective media. Because pharyngeal colonization with N. meningitidis needs to be differentiated from that with other Neisseria species, the diagnosis of pharyngeal gonorrhea is more expensive and difficult than that of anogenital gonorrhea.Ocular Gonorrhea in AdultsOcular gonorrhea in an adult usually results from autoinoculation from an infected genital site. As in genital infection, the manifestations range from severe to occasionally mild or asymptomatic disease. The variability in clinical manifestations may result from differences in the ability of the infecting strain to elicit an inflammatory response.Infection may result in a markedly swollen eyelid, severe hyperemia and chemosis, and a profuse purulent discharge. The massively inflamed conjunctiva may be draped over the cornea and limbus. Lytic enzymes from the infiltrating PMNs occasionally cause corneal ulceration and rarely cause perforation.Prompt recognition and treatment of this condition are of paramount importance. Gram's stain and culture of the purulent discharge establish the diagnosis. Genital cultures should also be performed.Gonorrhea in Pregnant Women, Neonates, and ChildrenGonorrhea in pregnancy can have serious consequences for both the mother and the infant. Therefore, early detection and eradication of the disease in the mother are extremely important. Recognition of gonorrhea early in pregnancy also identifies a population at risk for other STDs, particularly chlamydial infection and syphilis. These women should be monitored closely for these infections throughout pregnancy. The incidence of gonorrhea in pregnancy ranges from rare to ~10%, depending upon the population surveyed. Salpingitis and PID can occur during the first trimester and are associated with a high rate of fetal loss. In the second and third trimesters, the relative impermeability of the cervical mucus (under the influence of progesterone) and the obliteration of the intrauterine cavity (resulting from the attachment of the chorion to the endometrial decidua by around the twelfth week of gestation) pose physical barriers that usually prevent ascending infection. Pharyngeal infection, most often asymptomatic, may be more common during pregnancy because of altered sexual practices. Acquisition of gonococcal infection late in pregnancy can adversely affect labor and delivery as well as the well-being of the fetus. Prolonged rupture of the membranes, premature delivery, chorioamnionitis, funisitis (infection of the umbilical cord stump), and sepsis in the infant (with N. gonorrhoeae detected in the gastric aspirate of the newborn during delivery) are common complications of maternal gonococcal infection at term. Hazards to the fetus include spontaneous abortion, perinatal death, premature delivery, perinatal distress, and premature rupture of membranes. Other microorganisms and conditions, including Mycoplasma hominis, Ureaplasma urealyticum, C. trachomatis, and bacterial vaginosis, have been associated with similar complications.The most common form of gonorrhea in neonates is ophthalmia neonatorum, which results from exposure to infected cervical secretions during parturition. Ocular neonatal instillation of a prophylactic agent (e.g., 1% silver nitrate eyedrops or ophthalmic preparations containing erythromycin or tetracycline) is a cost-effective measure for the prevention of ophthalmia neonatorum but is not effective for its treatment, which requires systemic antibiotics. The clinical manifestations are acute and begin 2 to 5 days after birth. A small inoculum of organisms, low virulence of the infecting strain, or partial suppression by ophthalmic prophylaxis can result in a more indolent course. Therefore, gonococcal infection must be ruled out by culture in every case of conjunctivitis in infants. An initial nonspecific conjunctivitis with a serosanguineous discharge is followed by tense edema of both eyelids, chemosis, and a profuse, thick, purulent discharge. Corneal ulcerations that result in nebulae or perforation may lead to anterior synechiae, anterior staphyloma, panophthalmitis, and blindness. Infections described at other mucosal sites in infants, including vaginitis, rhinitis, and anorectal infection, are likely to be asymptomatic. Pharyngeal colonization has been demonstrated in 35% of infants with gonococcal ophthalmia, and coughing is the most prominent symptom in these cases. Septic arthritis (see below) is the most common manifestation of systemic infection or DGI in the newborn. The primary focus of DGI in most of these cases is uncertain. The onset usually comes at 3 to 21 days of age, and polyarticular involvement is common. Sepsis, meningitis, and pneumonia are seen in rare instances.Any STD in children beyond the neonatal period raises the possibility of sexual abuse. In most cases of abuse, the perpetrator is a male assailant known to the child. Gonococcal vulvovaginitis is the most common manifestation of gonococcal infection in children beyond infancy. Anorectal and pharyngeal infections are common in these children and are frequently asymptomatic. The urethra, Bartholin's and Skene's glands, and the upper genital tract are rarely involved. All children with gonococcal infection should also be evaluated for chlamydial infection, syphilis, and possibly HIV infection. All cases of suspected and confirmed child abuse should be reported to the appropriate social service agency in the county where the child resides.Gonococcal Arthritis (DGI)DGI or gonococcal arthritis results from gonococcal bacteremia. In the 1970s, DGI occurred in ~0.5 to 3% of persons with untreated gonococcal mucosal infection. The lower incidence at present is probably attributable to a decline in the prevalence of particular strains that are likely to disseminate and has resulted in fewer cases that present in the bacteremic stage of the disease (see below). DGI strains resist the bactericidal action of human serum and generally do not incite inflammation at genital sites, probably because of limited generation of chemotactic factors. These strains are often of the Por1A serotype, are highly susceptible to penicillin, and have special growth requirements (i.e., the AHU auxotype) that makes the organism more fastidious and more difficult to isolate. Menstruation is a risk factor for dissemination, and approximately two-thirds of cases of DGI are in women. In about half of affected women, symptoms of DGI begin within 7 days of onset of menses. Complement deficiencies, especially of the components involved in the assembly of the membrane attack complex (C5 through C9), predispose to neisserial bacteremia. Up to 13% of patients with DGI have complement deficiencies, and persons with more than one episode of DGI should be screened with an assay for total hemolytic complement activity.The clinical manifestations of DGI have sometimes been classified into two stages: a bacteremic stage, which is less common today, and a joint-localized stage with suppurative arthritis. A clear-cut progression usually is not evident. Patients in the bacteremic stage have higher temperatures, and their fever is more frequently accompanied by chills. Painful joints are common and often occur in conjunction with tenosynovitis and skin lesions. Polyarthralgias usually include the knees, elbows, and more distal joints; the axial skeleton is generally spared. Skin lesions are seen in ~75% of patients and include papules and pustules, often with a hemorrhagic component. These lesions are usually on the extremities and number between 5 and 40. The differential diagnosis of the bacteremic stage of DGI includes Reiter's syndrome, acute rheumatoid arthritis, sarcoidosis, erythema nodosum, drug-induced arthritis, and viral infections (e.g., hepatitis B and acute HIV infection). The distribution of joint symptoms in Reiter's syndrome differs from DGI, as do the skin and genital manifestations.Suppurative arthritis involves one or two joints, most often (in decreasing order of frequency) the knees, wrists, ankles, and elbows. The occurrence of arthritis in the absence of signs and symptoms of the bacteremic stage has led to the suggestion that these are separate syndromes. Other joints, such as the small joints of the hands and feet and the sternoclavicular and temporomandibular joints, are occasionally involved. Most patients who develop gonococcal septic arthritis do so without prior polyarthralgias or skin lesions; in the absence of symptomatic genital infection, this disease cannot be distinguished from septic arthritis caused by other pathogens. The differential diagnosis of acute arthritis in young adults is discussed in. Rarely, osteomyelitis complicates septic arthritis involving small joints of the hand.Although it has been postulated that the initial arthritis and skin lesions are due to direct tissue invasion by N. gonorrhoeae, the organism has been recovered from <5% of skin lesions cultured. This low isolation rate has been attributed to either a small inoculum of infecting organisms or the fastidious growth requirements of N. gonorrhoeae strains that disseminate. Gonococcal antigens have been identified in “sterile” skin lesions by immunofluorescent staining techniques. There is also evidence that immune-mediated or hypersensitivity phenomena caused by gonococcal antigens account for skin lesions. Other manifestations of noninfectious dermatitis, such as nodular lesions, urticaria, and erythema multiforme, have been described. Gonococcal endocarditis, although rare today, was relatively common in the preantibiotic era, causing about one-quarter of reported cases of endocarditis. Another unusual complication of DGI is meningitis.Gonococcal Infection in HIV-Infected PersonsThe association between gonorrhea and the acquisition of HIV has been demonstrated in several well-controlled studies, mainly in Kenya and Zaire. The nonulcerative STDs enhance the transmission of HIV by three- to fivefold, possibly because of increased viral shedding in persons with urethritis or cervicitis. HIV has been detected by polymerase chain reaction (PCR) more commonly in ejaculates from HIV-positive men with gonococcal urethritis than in those from HIV-positive men with nongonococcal urethritis. PCR positivity diminishes by twofold following appropriate therapy for urethritis. Not only does gonorrhea enhance the transmission of HIV, it may also increase the individual's risk for acquisition of HIV. A proposed mechanism is the significantly greater number of CD4+ lymphocytes and dendritic cells that can be infected by HIV in endocervical secretions of women with nonulcerative STDs than in those of women with ulcerative

STDs. LABORATORY DIAGNOSISA rapid diagnosis of gonococcal infection in men may be obtained by Gram's staining of urethral exudates. The detection of gram-negative intracellular diplococci is usually highly specific and sensitive in diagnosing gonococcal urethritis in symptomatic males but is only ~50% sensitive in diagnosing gonococcal cervicitis. Samples should be collected with Dacron or rayon swabs. Part of the sample should be inoculated onto a plate of modified Thayer-Martin or other gonococcal selective medium for culture. It is important to process all samples immediately because gonococci do not tolerate drying. If plates cannot be incubated immediately, they can be held safely for several hours at room temperature in candle extinction jars prior to incubation. If processing is to occur within 6 h, transport of specimens may be facilitated by the use of nonnutritive swab transport systems such as Stuart or Amies medium. For longer holding periods (e.g., when specimens for culture are to be mailed), culture media with self-contained CO₂-generating systems (such as the JEMBEC or Gono-Pak systems) may be used. Specimens should also be obtained for the diagnosis of chlamydial infection.PMNs are often seen in the endocervix on a Gram's stain, and an abnormally increased number [≥30 PMNs per field in five 1000X oil-immersion (microscopic) fields] establishes the presence of an inflammatory discharge. Unfortunately, the presence or absence of gram-negative intracellular diplococci in cervical smears does not accurately predict which patients have gonorrhea, and the diagnosis in this setting should be made by culture or another suitable nonculture diagnostic method. The sensitivity of a single endocervical culture is ~80 to 90%, with the precise figure depending on the quality of the medium and the adequacy of the clinical specimen. The yield can be enhanced by culture of a second cervical specimen. If a history of rectal sex is elicited, a rectal wall swab (uncontaminated with feces) should be cultured. A presumptive diagnosis of gonorrhea cannot be made on the basis of gram-negative diplococci in smears from the pharynx, where other Neisseria species are components of the normal flora.Nucleic acid probe tests are sometimes substituted for culture for the direct detection of N. gonorrhoeae in urogenital specimens. A common assay employs a nonisotopic chemiluminescent DNA probe that hybridizes specifically with gonococcal 16S ribosomal RNA. Studies assessing the utility of the nucleic acid probe system in high-risk outpatients undergoing screening for STDs have revealed that it is at least as sensitive as conventional culture techniques and may be a cost-effective alternative to culture, especially in high-risk males. A disadvantage of non-culture-based assays in general is that specimens submitted in probe-transport systems cannot be cultured subsequently. Therefore, a culture-confirmatory test is not possible, and formal antimicrobial susceptibility testing, if needed, cannot be performed. Low-cost point-of-care tests are under development for use in resource-poor settings, where specific diagnosis often gives way to syndromic management. Nucleic acid amplification tests (NAATs, including Roche Amplicor, Gen-Probe APTIMA, and BDProbeTec) have been cleared by the U.S. Food and Drug Administration (FDA) and offer the advantage of testing urine samples with a sensitivity similar to that of culture and other non-NAATs on urethral or cervical swab samples.Because of the legal implications, the preferred method for the diagnosis of gonococcal infection in children is a standardized culture. Two positive NAATs, each targeting a different nucleic acid sequence, may be substituted for culture of the cervix or the urethra as legal evidence of infection; however, cervical specimens are not recommended for prepubertal girls. Nonculture tests for gonococcal infection have not been approved by the FDA for use with specimens obtained from the pharynx and rectum of infected children. Cultures should be obtained from the pharynx and anus of both girls and boys, the vagina of girls, and the urethra of boys. For boys with a urethral discharge, a meatal specimen of the discharge is adequate for culture. Presumptive colonies of N. gonorrhoeae should be identified definitively by at least two independent methods (e.g., biochemical, enzyme substrate, or serologic).Blood should be cultured in suspected cases of DGI. The use of Isolator blood culture tubes may enhance the yield. The probability of positive blood cultures decreases after 48 h of illness. Synovial fluid should be inoculated into blood culture broth medium and plated onto chocolate agar rather than selective medium because this fluid is not likely to be contaminated with commensal bacteria. Gonococci are infrequently recovered from early joint effusions containing <20,000 leukocytes/µL but may be recovered from effusions containing >80,000 leukocytes/µL. The organisms are seldom recovered from blood and synovial fluid of the same patient.TREATMENTAlthough clinical isolates of N. gonorrhoeae vary in their antimicrobial susceptibility patterns in different parts of the world, they remain susceptible to a wide variety of agents. Because failure of treatment can lead to continued transmission and the emergence of antibiotic resistance, the importance of adequate treatment with a regimen that the patient will adhere to cannot be overemphasized. Thus highly effective single-dose regimens have been developed for the treatment of uncomplicated gonococcal infections. The 2002 CDC treatment guidelines for gonococcal infections are summarized in Table 1; the recommendations for uncomplicated gonorrhea apply to HIV-infected as well as HIV-uninfected patients.

The third-generation cephalosporins cefixime (given orally) and ceftriaxone (given intramuscularly), both as a single dose, have been the mainstay of therapy with this class of antibiotics for uncomplicated gonococcal infection of the urethra, cervix, rectum, or pharynx. The recent discontinuation of cefixime production in the United States has prompted further examination of alternative oral options for urogenital and pharyngeal gonococcal infections. To be considered as a recommended treatment for uncomplicated gonorrhea, an antimicrobial regimen should cure >95% of urogenital infections. (The therapeutic efficacy for anorectal infection is typically comparable to that for urogenital infection.) Studies documenting efficacy should have sufficient sample size so that the lower limit of the confidence interval (CI) of the cure rate is also >95%. The available data do not demonstrate that any single-dose oral antimicrobial regimen other than cefixime or a fluoroquinolone (see below) meets these efficacy criteria for urogenital gonococcal infection; published data on the efficacy of alternative oral regimens in treating pharyngeal gonococcal infection are even more limited. Single doses of ciprofloxacin, ofloxacin, or levofloxacin are effective first-line regimens. Other quinolones, such as gatifloxacin, norfloxacin, and lomefloxacin, are probably efficacious for treating uncomplicated gonorrhea, but data regarding their use are also limited, and they offer no advantage over the other recommended quinolones. Because of resistance to fluoroquinolones in several parts of Asia and the Pacific (including Hawaii), these agents should not be used to treat gonorrhea acquired in these regions. Several states, including California, are now recommending the curtailment of quinolone treatment for gonorrhea infection altogether, and in these regions ceftriaxone should be used.Because co-infection with C. trachomatis occurs frequently, initial treatment regimens must incorporate an agent (e.g., azithromycin or doxycycline) effective against chlamydial infection. Routine dual therapy without testing for Chlamydia can be cost-effective for populations where chlamydial infection accompanies 10 to 30% of gonococcal infections. Pregnant women with gonorrhea should receive concurrent treatment with a macrolide antibiotic for possible chlamydial infection; doxycycline should not be used during pregnancy. A single 1-g dose of azithromycin, which is effective therapy for uncomplicated chlamydial infections, results in an unacceptably low cure rate (93%) for gonococcal infections and should not be used alone.Uncomplicated gonococcal infections in penicillin-allergic persons who cannot tolerate quinolones may be treated with a single dose of spectinomycin.Persons with uncomplicated infections who receive a recommended regimen need not return for a test of cure. Cultures for N. gonorrhoeae should be performed if symptoms persist after therapy with an established regimen, and any gonococci isolated should be tested for antimicrobial susceptibility.Symptomatic gonococcal pharyngitis is more difficult to eradicate than genital infection. Few regimens result in cure rates of >90%. Persons who cannot tolerate cephalosporins or quinolones can be treated with spectinomycin, but this agent results in a cure rate of ≤52%. Therefore, persons given spectinomycin should have a pharyngeal culture performed 3 to 5 days after treatment as a test of cure.Treatments for gonococcal epididymitis and PID. Ocular gonococcal infections in older children and adults should be managed with a single dose of ceftriaxone combined with saline irrigation of the conjunctivae (both undertaken expeditiously), and patients should undergo a careful ophthalmologic evaluation that includes a slit-lamp examination.DGI may require higher dosages and longer durations of therapy. Hospitalization is indicated if the diagnosis is uncertain, if the patient has localized joint disease that requires aspiration, or if the patient cannot be relied on to comply with treatment. Open drainage is necessary only occasionally—e.g., for management of hip infections that may be difficult to drain percutaneously. Nonsteroidal anti-inflammatory agents may be indicated to alleviate pain and hasten improvement of affected joints. Gonococcal meningitis and endocarditis should be treated in the hospital with high-dose intravenous ceftriaxone (1 to 2 g every 12 h); therapy should continue for 10 to 14 days for meningitis and for at least 4 weeks for endocarditis. All persons who experience more than one episode of DGI should be evaluated for complement deficiency.PREVENTION AND CONTROLCondoms, if properly used, provide effective protection against the transmission and acquisition of gonorrhea as well as other infections that are transmitted to and from genital mucosal surfaces. Spermicidal preparations used with a diaphragm or cervical sponges impregnated with nonoxynol 9 offer some protection against gonorrhea and chlamydial infection. However, the frequent use of preparations that contain nonoxynol 9 is associated with mucosal disruption that paradoxically may enhance the risk of HIV infection in the event of exposure. All patients should be instructed to refer sex partners for evaluation and treatment. All sex partners of persons with gonorrhea should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections if their last contact with the patient took place within 60 days before the onset of symptoms or the diagnosis of infection in the patient. If the patient's last sexual encounter was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. Greater emphasis must be placed on prevention by public health education, individual patient counseling, and behavior modification. Sexually active persons, especially adolescents, should be offered screening for STDs. For males, a NAAT on urine or a urethral swab may be used for screening. Preventing the spread of gonorrhea may help reduce the transmission of HIV. No effective vaccine for gonorrhea is yet available, but efforts to test a porin vaccine candidate are under way.

ACKNOWLEDGEMENTThe authors acknowledge the contributions of Dr. King K. Holmes and Dr. Stephen A. Morse to the chapter on this subject in earlier editions of Harrison's.

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