Katherine Hsu, Sanjay Ram, Toni Darville
Neisseria gonorrhoeae is the causative agent of gonorrhea , an infection of the genitourinary tract mucous membranes and of the mucosa of the rectum, oropharynx, and conjunctiva. Gonorrhea transmitted by sexual contact or perinatally is second only to chlamydial infections in the number of cases reported to the U.S. Centers for Disease Control and Prevention (CDC). This high prevalence and the development of antibiotic-resistant strains have led to significant morbidity.
Neisseria gonorrhoeae is a nonmotile, aerobic, non–spore-forming, gram-negative diplococcus with flattened adjacent surfaces. Optimal growth occurs at 35-37°C (95-98.6°F) 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 from mucosal sites 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 spp. by the fermentation of glucose but not maltose, sucrose, or lactose. Gram-negative diplococci are seen in infected material, often within polymorphonuclear leukocytes (PMNs).
As with 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 lipooligosaccharide (LOS ; also called endotoxin ), phospholipid, and a variety of proteins that contribute to cell adherence, tissue invasion, and resistance to host defenses. Systems previously used to characterize gonococcal strains included 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. Serotyping systems were based on specific monoclonal antibodies directed against a porin protein called PorB (formerly Protein I or PorI), a trimeric outer membrane protein that makes up a substantial part of the gonococcal envelope structure. Changes in PorB proteins present in a community are believed to result, at least in part, from selective immune pressure. DNA-based typing methods have now supplanted auxo- and serotyping. Older gel-based DNA-based typing methods that included restriction fragment length polymorphism (RFLP) analysis of genomic DNA or rRNA (ribotyping), or typing of genes encoding opacity protein (opa ) were labor intensive and sometimes lacked the ability to accurately discriminate among strains. Methods currently used include the Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST ), which examines the sequences of the variable internal fragments of 2 highly polymorphic N. gonorrhoeae genes (porB encoding PorB and tbpB encoding subunit B of transferrin-binding protein), and multilocus sequence typing (MLST ), which analyzes the sequences of 7 chromosomal housekeeping genes.
Since gonorrhea became a nationally notifiable disease in 1944, U.S. rates have ranged between a historic high of 467.7 cases per 100,000 population in 1975 and a historic low of 98.1 per 100,000 in 2009. However, rates have increased almost every year since 2009, with a total of 555,608 cases and a rate of 171.9/100,000 reported in 2017. Rates of reported gonorrhea are also highest in the South (194.0/100,000); among young adults age 20-24 (684.8 cases per 100,000 females age 20-24; 705.2 cases per 100,000 males age 20-24); among males (169.7/100,000 males vs 120.4/100,000 females); and among blacks (548.1/100,000 vs 66.4/100,000 among whites). During 2013–2017, the rate among males increased 86.3% and the rate among females increased 39.4%, suggesting either increased transmission or increased case ascertainment (e.g., through increased extragenital screening) among gay, bisexual, and other men who have sex with men (MSM).
Molecular typing methods (e.g., NG-MAST, MLST) are used to analyze the spread of individual strains of N. gonorrhoeae within a community. Maintenance and subsequent spread of gonococcal infections in a community are sustained through continued transmission by asymptomatically infected people and also by a hyperendemic, high-risk core group such as commercial sex workers, MSM, or adolescents with multiple sexual partners. This latter observation reflects 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. Oral sex has a role in sustaining gonorrhea in MSM by providing a pool of untreated asymptomatic pharyngeal infections and may account for as much as one third of symptomatic gonococcal urethritis in MSM.
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.
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 PMNs, serum, and desquamated epithelium. The gonococcal LOS (endotoxin) exhibits direct cytotoxicity, causing ciliostasis and sloughing of ciliated epithelial cells. Tumor necrosis factor (TNF) and other cytokines are thought to mediate the cytotoxicity of gonococcal infections. LOS activates complement, which also contributes to the acute inflammatory response.
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 LOS. 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. Gonococci adhere to the microvilli of nonciliated epithelial cells by hairlike protein structures (pili) that extend from the cell wall. 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, function as ligands for members of the carcinoembryonic antigen–related cell adhesion molecule (CEACAM ) family of proteins or heparin sulfate proteoglycans (HSPGs) to facilitate binding to human cells. Interactions between complement receptor 3 (CR3) on cervical epithelial cells and iC3b, pili, and PorB on the gonococcal surface facilitates cellular entry of gonococci in women. In contrast, the interaction between LOS and asialoglycoprotein receptor (ASGP-R) permits gonococcal entry into male urethral epithelial cells. Gonococci that express certain Opa proteins adhere to CEACAM3 and are phagocytosed by human neutrophils in the absence of serum. The interaction of Opa with CEACAM1 on CD4+ T lymphocytes may suppress their activation and proliferation and contribute to the immunosuppression associated with gonorrhea. A gonococcal IgA protease inactivates IgA1 by cleaving the molecule in the hinge region and could contribute to colonization or invasion of host mucosal surfaces.
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 the gonococcal outer membrane PorB 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 LOS activate complement on gonococci. Gonococci have evolved several mechanisms to dampen complement activation. Scavenging cytidine monophospho-N -acetyl neuraminic acid (CMP-Neu5Ac, the donor molecule for sialic acid) to sialylate its LOS is one such example, which reduces binding of bactericidal antibodies and simultaneously enhances binding of a complement inhibitor called factor H (FH). This property is often lost on subculturing gonococci on media that lacks CMP-Neu5Ac and is thus termed “unstable serum resistance.” In contrast, “stable serum resistance”(complement resistance independent of LOS sialylation) is often seen in gonococci that express particular porin proteins (most PorB.1As and select PorB.1Bs),which enables them to bind to complement inhibitors such as FH and C4b-binding protein (C4BP). Such strains are often associated with 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 are “stably” serum resistant, show less C3b deposition on their surface, inactivate C3b more rapidly, generate less C5a, and result in less inflammation at local sites. PID isolates are serum sensitive, deposit more C3b on their surface, inactivate C3b relatively slowly, 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 (e.g., OmpA) sequences shared with other Neisseria spp. or Enterobacteriaceae, may be directed against a unique Rmp sequence upstream of the OmpA-shared region that includes a cysteine loop, 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 LOS, 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; MSM; and individuals with defects in complement. 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.
Gonorrhea is manifested by a spectrum of clinical presentations from asymptomatic carriage, to the characteristic localized mucosal infections, to disseminated systemic infection (see Chapter 146 ).
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 26–68% of females with urogenital infection. Most persons with positive rectal culture results are asymptomatic. Most pharyngeal gonococcal infections are asymptomatic, although rarely acute tonsillopharyngitis or cervical lymphadenopathy can occur. Pharyngeal gonorrhea is easily acquired through fellatio and may account for a significant proportion of urethral gonorrhea in MSM. Pharyngeal gonorrhea is increasingly prevalent, particularly among adolescents and young adults, and associated with overall increasing prevalence of oral sex behaviors.
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 (ophthalmia neonatorum) 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 MSM, the rectal mucosa can become infected after receptive anal intercourse. Symptoms range from painless mucopurulent discharge and scant rectal bleeding to overt proctitis with associated rectal pain and tenesmus.
In prepubertal females, vulvovaginitis is usually characterized by a purulent vaginal discharge with a swollen, erythematous, tender, and excoriated vulva. Dysuria may occur. Gonococcal infection should be considered in any girl with vaginal discharge, even when sexual abuse is not suspected; sexual abuse must be considered strongly when gonococcal infection is diagnosed in prepubertal children beyond the neonatal period. 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 from anal intercourse but may represent translocation of infected secretions from cervicovaginal 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 caused by N. gonorrhoeae usually appears from 1-4 days after birth (see Chapter 652 ). 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.
Hematogenous dissemination occurs in 1–3% of all gonococcal infections, more frequently after asymptomatic primary infections than symptomatic infections. Women previously accounted for the majority of cases, with symptoms beginning 7-30 days after infection and within 7 days of menstruation in about one half of cases, but more recent case series describe more male than female cases. 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 is classified into 2 clinical syndromes that have some overlapping features. The more common tenosynovitis-dermatitis syndrome 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. In the suppurative arthritis syndrome , systemic symptoms and signs are less prominent, and monoarticular arthritis is more common, often involving the knee. A polyarthralgia phase may precede the monoarticular infection. In cases of monoarticular 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, 1-20 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 (1–3%) 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, and signs and symptoms are similar to those of any acute bacterial meningitis.
Laboratory confirmation of gonococcal infection is essential, given the legal implications of potential sexual abuse in children and the need to refer sex partners of adolescents and adults for treatment. Given the advent of highly sensitive and specific nucleic acid amplification tests (NAATs), the use of less sensitive, nonamplified test technologies is no longer justified, such as nucleic acid hybridization/probe tests, nucleic acid genetic transformation tests, or enzyme immunoassays. Culture and susceptibility testing capability still need to be maintained, both because data are insufficient to recommend nonculture tests in cases of sexual assault in prepubescent boys and extragenital anatomic site exposure in prepubescent girls, and because culture is necessary to evaluate suspected cases of gonorrhea treatment failure and to monitor developing resistance to current treatment regimens.
Gram stains can be useful in the initial evaluation of patients with suspected gonococcal infection. 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 spp. in the oropharynx prevents the use of the Gram stain for diagnosis of pharyngeal gonorrhea.
Culture can be performed of any site, including nongenital sites. Advantages of culture include the availability of an isolate for further studies, including antibiotic susceptibility testing. Disadvantages of culture include more stringent transport and growth requirements, lower sensitivity than NAATs, and a delay in availability of results. 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. If symptoms are present, samples from the urethra and rectum can be cultured for men, and samples from the endocervix and rectum can 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 with a history of recent oral exposure, or oral exposure to a person known to have genital gonorrhea. In a suspected case of child sexual abuse , culture remains the recommended method of detection for N. gonorrhoeae in urethral specimens from boys and for extragenital sites (conjunctiva, pharynx, and rectum) from all children because NAATs have not yet been sufficiently evaluated for these populations and sample sites. 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 (95-98.6°F) in 3–5% carbon dioxide. When specimens must be transported to a central laboratory for culture plating, a reduced, nonnutrient 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 >6 hr, it is preferable to inoculate the sample directly onto a culture medium and transport it at an ambient temperature in CO2 -enriched atmosphere. The Transgrow and JEMBEC (John E. Martin Biological Environmental Chamber) systems of modified Thayer-Martin medium are alternative transport systems.
The U.S. Food and Drug Administration (FDA) has approved NAATs for use with endocervical swabs, vaginal swabs, male urethral swabs, and female and male first-catch urine. Advantages of using NAATs include less stringent transport conditions, more rapid turnaround time, flexibility in sampling source (providing additional feasibility of testing in settings where physical exam is not done), and patient preference for less invasive sampling. However, NAATs cannot provide antimicrobial susceptibility results, so in cases of persistent gonococcal infection after treatment, clinicians should perform both culture and antimicrobial susceptibility testing. Although urine specimens are acceptable for women, the sensitivity for screening appears to be lower than with vaginal or endocervical swab samples. In contrast, the sensitivity and specificity of urine and urethral swab specimens from men are similar, so first-catch urine is the recommended sample type for urethral screening in men. Product inserts for each NAAT vendor must be carefully examined to assess current indications and allowable specimens. NAATs are not FDA cleared for use with specimens from the rectum, pharynx, conjunctiva, joint fluid, blood, or cerebrospinal fluid. However, most commercial and public health laboratories have established performance specifications to satisfy Centers for Medicare and Medicaid Services (CMMS) regulations for FDA Clinical Laboratory Improvement Amendments (CLIA) compliance in testing and reporting results for rectal and pharyngeal swab specimens, facilitating their use for clinical management (gonorrhea screening of rectal and pharyngeal sites with NAATs is recommended at least annually in MSM reporting rectal or pharyngeal receptive intercourse).
Data on use of NAATs are limited in children. In a multicenter study of NAATs using strand displacement amplification or transcription-mediated amplification in children being evaluated for sexual abuse, urine from prepubertal girls was a reliable alternative to vaginal culture for detection for N. gonorrhoeae . However, culture still remains the recommended method for testing for all other sample sites among prepubertal children. Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, all positive specimens should be retained for additional confirmatory testing.
All patients who are presumed or proven to have gonorrhea should be evaluated for concurrent syphilis, 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 Chlamydia 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 (see Chapter 253.2 ). Persons who receive a diagnosis of gonorrhea should be instructed to abstain from sexual activity for 7 days after treatment and until all sex partners are adequately treated (7 days after receiving treatment and resolution of symptoms, if present). Sexual partners exposed in the preceding 60 days should be examined, specimens collected, and presumptive treatment started.
N. gonorrhoeae has progressively developed resistance to the antibiotics used to treat it over the years. Antimicrobial resistance in N. gonorrhoeae occurs as plasmid-mediated resistance to penicillin and tetracycline and chromosomally mediated resistance to penicillins, tetracyclines, spectinomycin, fluoroquinolones, cephalosporins, and azithromycin. Emergence of cephalosporin resistance worldwide has prompted designation of N. gonorrhoeae as antibiotic resistance threat level “Urgent” by the CDC. Surveillance data from the CDC Gonococcal Isolate Surveillance Project reveal concerning fluctuations in minimum inhibitory concentration (MIC) for the oral cephalosporin cefixime and the injectable third-generation cephalosporin ceftriaxone , leading the CDC to revise its U.S. gonorrhea treatment guidelines in 2012 to dual therapy in an attempt to preserve the last commercially available effective treatment. A theoretical basis exists for using 2 antimicrobials with different molecular targets to improve treatment efficacy and potentially delay emergence and spread of resistance to cephalosporins.
Table 219.1 summarizes first-line treatment regimens for neonate, child (weight ≤45 kg), adolescent, and adult gonococcal regimens. Mucosal, localized infections are treatable with single doses; disseminated infections are treated for a minimum of 1 wk. Although dual therapy is not recommended for neonatal and childhood infections, it is recommended for all adult and adolescent infections (inclusive of children >45 kg). The use of azithromycin as the 2nd antimicrobial is preferred to doxycycline because of the convenience and compliance advantages of single-dose therapy and the higher prevalence of gonococcal resistance to tetracycline compared to azithromycin among gonococcal surveillance isolates, particularly in strains with elevated MIC to cefixime.
Table 219.1
Recommended Treatment of Gonococcal Infections
| INFECTION | TREATMENT REGIMEN | LENGTH OF THERAPY | |
|---|---|---|---|
| Neonates | Ophthalmia neonatorum | Ceftriaxone,* 25-50 mg/kg IV or IM (max 250 mg), plus lavage infected eye frequently until discharge eliminated | Once |
|
Disseminated infection Scalp abscess Septic arthritis |
Ceftriaxone,* 25-50 mg/kg IV or IM qd or Cefotaxime, 25-50 mg/kg IV or IM q8–12h † |
7 days | |
| Meningitis |
Ceftriaxone,* 25-50 mg/kg IV or IM qd or Cefotaxime, 25-50 mg/kg IV or IM q8-12h † |
10-14 days | |
| Endocarditis |
Ceftriaxone,* 25-50 mg/kg IV or IM qd or Cefotaxime, 25-50 mg/kg IV or IM q8-12h † |
Minimum 28 days | |
| Children ≤45 kg |
Pharyngeal infection Anorectal infection Urogenital infection |
Ceftriaxone, 25-50 mg/kg IV or IM (max 250 mg) | Once |
| Conjunctivitis | Ceftriaxone, 50 mg/kg IM (max 1 g) ‡ | Once | |
|
Disseminated infection Septic arthritis |
Ceftriaxone, 50 mg/kg IV or IM qd (max 1 g daily) | 7 days | |
| Meningitis | Ceftriaxone, 50 mg/kg IV or IM q12-24h (max 4 g daily) | 10-14 days | |
| Endocarditis | Ceftriaxone, 50 mg/kg IV or IM q12-24h (max 4 g daily) | Minimum 28 days | |
| Adults, adolescents, and children >45 kg |
Pharyngeal infection Anorectal infection Urogenital infection |
Ceftriaxone, 250 mg IM plus Azithromycin, 1 g PO |
Once |
| Conjunctivitis |
Ceftriaxone, 1 g IM plus Azithromycin, 1 g PO ‡ |
Once | |
|
Disseminated infection Septic arthritis |
Ceftriaxone, 1 g IV or IM qd § plus |
7 days | |
| Azithromycin, 1 g PO | Once | ||
| Meningitis |
Ceftriaxone, 1-2 g IV q12-24h plus |
10-14 days | |
| Azithromycin, 1 g PO | Once | ||
| Endocarditis |
Ceftriaxone, 1-2 g IV q12-24h plus |
Minimum 28 days | |
| Azithromycin, 1 g PO | Once |
* When available, cefotaxime should be substituted for ceftriaxone in neonates with hyperbilirubinemia (particularly those who are premature) and in those <28 days old if receiving calcium-containing intravenous fluids. Consult neonatal dosing references.
† Dose and/or dosing frequency change after postnatal age >7 days. Consult neonatal dosing references.
‡ Plus lavage of the infected eye with saline solution (once).
§ Ceftriaxone should be continued for 24-48 hr after clinical improvement begins, at which time the switch may be made to an oral agent (e.g., cefixime or a quinolone) if antimicrobial susceptibility is documented by culture. If no organism is isolated and the diagnosis is secure, treatment with ceftriaxone should be continued for at least 7 days.
IM, Intramuscularly; IV, intravenously; PO, orally (by mouth); qd, every day; q8-12h, every 8 to 12 hours.
From Hsu KK, Wangu Z: Neisseria gonorrhoeae. In Long SS, Prober CG, Fischer M, editors: Principles and practice of pediatric infectious diseases, ed 5, Philadelphia, 2018, Elsevier, Table 126.1.
Alternative regimens exist for adolescents and adults but are extremely limited. For patients with cephalosporin allergy, the combination of gentamicin (240 mg intramuscularly [IM]) plus azithromycin (2 g orally [PO]) cured 100% of uncomplicated urogenital cases in a trial of U.S. patients age 15-60 yr; the combination of gemifloxacin (320 mg PO) (not licensed for use in those <18 yr old) plus azithromycin (2 g PO) cured >99% of uncomplicated urogenital cases in the same trial but was limited by 8% of patients vomiting within 1 hr of dual–oral drug administration. For patients with azithromycin allergy, doxycycline (100 mg PO twice daily for 7 days) can be used in place of azithromycin as an alternative 2nd antimicrobial. If ceftriaxone is not available, alternative cephalosporins to be used in combination with azithromycin or doxycycline for uncomplicated anorectal and urogenital infection include oral cefixime (400 mg PO), which does not provide as high, or as sustained, bactericidal blood levels as a 250 mg IM dose of ceftriaxone and has limited efficacy for pharyngeal gonorrhea, and other single-dose injectable cephalosporin regimens, such as ceftizoxime (500 mg IM), cefoxitin (2 g IM) with probenecid (1 g PO), or cefotaxime (500 mg IM), none of which offers any advantage over ceftriaxone for urogenital infection, and their efficacy against pharyngeal infection is less certain.
Pregnant women with gonococcal infection should be treated with standard adult dual therapy. If allergy precludes standard treatment, consultation with an infectious disease specialist is recommended. HIV–co-infected patients with gonococcal infection are treated the same as HIV-negative patients.
Follow-up test-of-cure is not recommended for persons diagnosed with uncomplicated urogenital or rectal gonorrhea receiving recommended or alternative regimens. However, any person with pharyngeal gonorrhea who is treated with an alternative regimen should return 14 days after treatment for a test-of cure using culture, NAAT, or both, because pharyngeal gonorrhea is more difficult to eradicate. Symptoms persisting after treatment should be evaluated by culture for N. gonorrhoeae (with or without simultaneous NAAT), and any gonococci isolated should be tested for antimicrobial susceptibility. Treatment failure should be considered in (1) persons whose symptoms do not resolve within 3–5 days after appropriate treatment and who report no sexual contact during posttreatment follow-up and (2) persons with a positive test-of-cure (i.e., positive culture >72 hr or positive NAAT ≥7 days after receiving recommended treatment) who report no sexual contact during posttreatment follow-up.
Prompt diagnosis and correct therapy ensure complete recovery from uncomplicated gonococcal disease. Complications of gonorrhea result from the spread of gonococci from a local site of invasion. 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.
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, tuboovarian abscess, 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 intraabdominal disorders (appendicitis, urinary tract infection, inflammatory bowel disease). Although N. gonorrhoeae and C. trachomatis are implicated in many cases of PID, this syndrome encompasses a spectrum of infectious diseases of the upper genital tract caused by N. gonorrhoeae, C. trachomatis, and endogenous flora (streptococci, anaerobes, gram-negative bacilli). Treatment must therefore be broad. For women with more severe symptoms (inability to exclude surgical emergency, presence of tuboovarian abscess, severe illness, nausea, vomiting or high fever), pregnancy, or lack of response to outpatient therapy within 72 hr, parenteral therapy should be initiated in the hospital. The decision to hospitalize adolescents with acute PID should be based on the same criteria used for older women, because the clinical response to outpatient treatment is similar among younger and older women.
Recommended parenteral regimens are cefotetan (2 g intravenously [IV] every 12 hr [q12h]) or cefoxitin (2 g IV q6h) plus doxycycline (100 mg PO or IV q12h), or clindamycin (900 mg IV q8h) plus a loading dose of gentamicin (2 mg/kg IV or IM) followed by maintenance gentamicin (1.5 mg/kg q8h). An alternative parenteral regimen is ampicillin-sulbactam (3 g IV q6h) plus doxycycline (100 mg PO or IV q12h). Clinical experience should guide transition to oral therapy, which usually can be initiated within 24 hr of improvement. Thereafter, oral clindamycin (450 mg PO 4 times daily [qid]) or doxycycline (100 mg PO twice daily [bid]) is given to complete 14 days of total therapy, unless tuboovarian abscess is present, in which case clindamycin (450 mg PO qid) or metronidazole (500 mg PO bid) should be added to doxycycline to complete 14 days of therapy with more effective anaerobic coverage. Parenteral therapy and intramuscular/oral therapy appear to be similar in clinical efficacy for younger and older women with PID of mild to moderate severity. Recommended 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.
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 approximately 20% of cases of gonococcal cervicitis, and N. gonorrhoeae is isolated in approximately 40% of cases of PID in the United States. Untreated cases may lead to hydrosalpinx, pyosalpinx, tuboovarian abscess, and eventual sterility. Even with adequate treatment of PID, the risk for sterility from 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 7-fold 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 first trimester of pregnancy carries a high risk for septic abortion. After 16 wk of pregnancy, infection leads to chorioamnionitis , a major cause of premature rupture of the membranes and premature delivery.
In males, without treatment, gonococcal urethritis usually resolves spontaneously over several weeks to months. Epididymitis and acute or chronic prostatitis are uncommon complications; most men with gonococcal epididymitis also have overt urethritis. Even more unusual complications include penile edema associated with penile dorsal lymphangitis or thrombophlebitis, periurethral abscess or fistulas, seminal vesiculitis, and balanitis in uncircumcised men.
Efforts to develop gonococcal vaccines that confer broad cross-protection have been unsuccessful thus far. A pilus vaccine elicited an antibody response and conferred protection against challenge with the homologous strain but did not protect against disease in a trial involving 3,250 volunteers. The high degree of interstrain and intrastrain antigenic variability of pili poses a formidable barrier to the development of a single effective pilus vaccine. An outer membrane vaccine that was enriched in PorB also elicited an antibody response but failed to protect male volunteers against challenge with the homologous strain, likely because small amounts of Rmp present in the vaccine preparation elicited subversive antibodies. A formalin-killed whole cell vaccine trial in 62 volunteers in an Inuvik population in Canada also failed to provide any protection. Gonococcal surface structures, such as the porin protein (isolated without contaminating Rmp), proteins expressed under various stress conditions that may be encountered in vivo and have been identified by proteomic and transcriptomic approaches, and lipooligosaccharides, may prove more promising as vaccine candidates.
In the absence of a vaccine, prevention of gonorrhea in adolescents and adults can be achieved through education , use of barrier protection (especially condoms), screening of high-risk populations as recommended by the U.S. Preventive Services Task Force (PSTF) and CDC (e.g., sexually active women ≤24 yr old, MSM, individuals previously infected with gonorrhea), and early identification and treatment of contacts—all sex partners within the 60 days preceding symptom onset or gonorrhea diagnosis, or, if none, the most recent sex partner, should be examined and treated presumptively. For heterosexual patients, expedited partner therapy (EPT) with cefixime (400 mg) and azithromycin (1 g) can be delivered to partners by the patient, a disease investigation specialist, or a collaborating pharmacy, as permitted by law (https://www.cdc.gov/std/ept/legal/ ). EPT has been shown to be safe and effective in prevention of reinfection with gonorrhea and is endorsed by the American Academy of Pediatrics, American Academy of Family Physicians, and Society of Adolescent Health and Medicine, as well as other clinical organizations, for use when in-person evaluation and treatment of the partner is impractical or unsuccessful. (Because of the high risk for coexisting undiagnosed sexually transmitted infections such as HIV, EPT is not considered a routine partner management strategy for MSM.)
An infant born to a woman with cervical gonococcal infection has an approximately 30% risk of acquiring ophthalmic infection, compared to a <5% risk if ocular prophylaxis is given. Gonococcal ophthalmia neonatorum can be prevented by instilling erythromycin (0.5%) ophthalmic ointment into the conjunctival sac (see Chapter 652 ). If erythromycin ointment is unavailable, infants at risk for N. gonorrhoeae (especially those born to a mother with untreated gonococcal infection or with no prenatal care) can be administered ceftriaxone 25-50 mg/kg IV or IM, not to exceed 250 mg, in a single dose.