1236 PART 5 Infectious Diseases

that show a porin-specific TH2-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 may

noncompetitively inhibit binding of porin and LOS antibodies because

of the proximity of these structures in the gonococcal outer membrane.

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 Agents It 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 and became ineffective within a decade. Penicillin was then

used as the drug of choice for the treatment of gonorrhea. By 1965, 42%

of gonococcal isolates had developed low-level resistance to penicillin

G. 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 highlevel 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 2007, chromosomal mutations accounted for resistance to penicillin, tetracycline, or both in

~16% of strains surveyed in the United States.

β-Lactamase (penicillinase)–producing strains of N. gonorrhoeae

(PPNG) carrying β-lactamase plasmids had rapidly spread worldwide

by the early 1980s. N. gonorrhoeae strains with plasmid-borne tetracycline resistance (TRNG) can mobilize some β-lactamase plasmids,

and PPNG and TRNG occur together, sometimes along with strains

exhibiting chromosomally mediated resistance (CMRNG). Penicillin,

ampicillin, and tetracycline are no longer reliable for the treatment of

gonorrhea and should not be used.

Quinolone-containing regimens also were recommended for treatment of gonococcal infections; the fluoroquinolones offered the advantage of antichlamydial activity when administered for 7 days. However,

quinolone-resistant N. gonorrhoeae (QRNG) appeared soon after

these agents were first used to treat gonorrhea. QRNG is particularly

common in the Pacific Islands (including Hawaii) and Asia, where, in

certain areas, all gonococcal strains are now resistant to quinolones.

At present, QRNG is also common in parts of Europe and the Middle

East. In the United States, QRNG has been identified in all areas but

predominantly in states on the Pacific coast, where resistant strains

were first seen. Alterations in DNA gyrase and topoisomerase IV have

been implicated as mechanisms of fluoroquinolone resistance.

Resistance to spectinomycin, which has been used in the past as an

alternative agent, has been reported. Because this agent usually is not

associated with resistance to other antibiotics, spectinomycin can be

reserved for use against multidrug-resistant strains of N. gonorrhoeae.

Nevertheless, outbreaks caused by strains resistant to spectinomycin

have been documented in Korea and England when the drug has been

used for primary treatment of gonorrhea.

Third-generation cephalosporins have remained highly effective as

single-dose therapy for gonorrhea, but the recent isolation of strains

highly resistant to ceftriaxone (minimal inhibitory concentrations [MICs],

2 μg/mL) in Japan and some European countries is cause for concern.

Even though the MICs of ceftriaxone against certain strains may reach

0.015–0.125 μg/mL (higher than the MICs of 0.0001–0.008 μg/mL for fully

susceptible strains), these levels are greatly exceeded in the blood, the

urethra, and the cervix when the routinely recommended parenteral

dose of ceftriaxone is administered. The rising MICs of oral cefixime

(the previously recommended alternative oral third-generation cephalosporin) against N. gonorrhoeae, combined with this drug’s limited

capacity to reach levels sufficiently higher than MICs in the blood, the

urethra, the cervix, and especially the pharynx, have resulted in the

removal of cefixime from the list of first-line agents for treatment of

uncomplicated gonorrhea. N. gonorrhoeae strains with reduced susceptibility to ceftriaxone and cefixime (i.e., cephalosporin-intermediate/

resistant strains) contain mutations in (1) the penA allele, which is the

principal resistance determinant and encodes a penicillin-binding protein (PBP2) whose sequence can differ in up to 60–70 amino acids from

that of wild-type PBP2; (2) the multiple transferable resistance regulator

(mtrR) gene that results in increased drug efflux through the MtrCDE

efflux pump; and (3) penB, which decreases drug influx through PorB.

Resistance to azithromycin can result from alterations of the ribosomal binding target by azithromycin and—as with cephalosporins—

the over- and underexpression of efflux and influx systems. Combined

resistance to cephalosporins and azithromycin has been reported in

several instances throughout the world.

■ CLINICAL MANIFESTATIONS

Gonococcal Infections in Men Acute urethritis is the most common clinical manifestation of gonorrhea in male patients. The usual

incubation period after exposure is 2–7 days, although the interval can

be longer and most men remain asymptomatic. Strains of the PorB.1A

serotype tend to cause a greater proportion of cases of mild and

asymptomatic urethritis than do PorB.1B strains. When they occur,

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. Gram’s

staining of the urethral discharge may reveal PMNs and gram-negative

intracellular monococci and diplococci (Fig. 156-1). The clinical manifestations of gonococcal urethritis are usually more severe and overt

than those of nongonococcal urethritis, including urethritis caused by

Chlamydia trachomatis (Chap. 189); 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,

many cases do not have a specific etiologic agent identified. Certain

clones of Neisseria meningitidis, the second member of the pathogenic

FIGURE 156-1 Gram’s stain of urethral discharge from a male patient with

gonorrhea shows gram-negative intracellular monococci and diplococci. (Source:

© All rights reserved. Canadian Guidelines on Sexually Transmitted Infections.

Public Health Agency of Canada, modified 2020. Adapted and reproduced with

permission from the Minister of Health, 2021.)

1237CHAPTER 156 Gonococcal Infections

Neisseria species, have been associated with urethritis in men who have

sex with men (MSM) in Europe and in heterosexual men in the southern and midwestern United States.

Most symptomatic men 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. Before the antibiotic era, symptoms

of urethritis persisted for ~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 fistula, inflammation or abscess of Cowper’s gland, and seminal vesiculitis. Balanitis may develop in uncircumcised men.

Gonococcal Infections in Women •  GONOCOCCAL CERVICITIS

Mucopurulent cervicitis is a common STI diagnosis in American

women and may be caused by N. gonorrhoeae, C. trachomatis, and

other organisms, including Mycoplasma genitalium (Chap. 188).

Cervicitis may coexist with candidal or trichomonal vaginitis. N. gonorrhoeae primarily infects the columnar epithelium of the cervical os.

Bartholin’s glands occasionally become infected.

Women infected with N. gonorrhoeae usually develop symptoms.

However, women who either remain asymptomatic or have only minor

symptoms may delay seeking medical attention. These minor symptoms may include scant vaginal discharge issuing from the inflamed

cervix (without 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 reveals a mucopurulent discharge

(mucopus) issuing from the cervical os or a reddened (inflamed) cervix even in the absence of reported symptoms. 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 “Laboratory

Diagnosis,” below). Edematous and friable cervical ectopy and endocervical bleeding induced by gentle swabbing are more often seen in

chlamydial infection. 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 pelvic inflammatory

disease (PID) and to administer treatment for that disease (Chaps. 136

and 189).

N. gonorrhoeae may also be recovered from the urethra and rectum

of women with cervicitis, but these are rarely the only infected sites.

Urethritis in women may produce symptoms of internal dysuria, which

is often attributed to “cystitis.” Pyuria in the absence of bacteriuria

visible on Gram’s stain of unspun urine, accompanied by urine cultures that fail to yield >102

 colonies of bacteria usually associated with

urinary tract infection, signifies the possibility of urethritis usually

due to C. trachomatis. Urethral infection with N. gonorrhoeae also may

occur in this context, but in this instance, urethral cultures are usually

positive.

GONOCOCCAL VAGINITIS The vaginal mucosa of healthy women

is lined by stratified squamous epithelium and is rarely 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 epithelium is 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 often

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.

Anorectal Gonorrhea Because 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 MSM,

the frequency of gonococcal infection, including rectal infection, fell by

≥90% throughout the United States in the early 1980s, A resurgence of

gonorrhea among MSM has been documented in several cities since

the 1990s, the estimated rates of reported cases having more than doubled in a recent 3-year period. Gonococcal isolates from the rectum of

MSM tend to be more resistant to antimicrobial agents than are gonococcal isolates from other sites. Gonococcal isolates with a mutation

in mtrR or in the promoter region of the gene that encodes for this

transcriptional regulator develop increased resistance to antimicrobial

hydrophobic agents such as bile acids and fatty acids in feces and thus

are found with increased frequency in MSM. 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 Gonorrhea Pharyngeal 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. In certain female adolescent

populations in the United States, pharyngeal gonorrhea has become as

common as genital gonorrhea. 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.

Pharyngeal colonization with N. meningitidis needs to be differentiated

from that with other Neisseria species. Because commensal oropharyngeal neisseriae are often resistant to antimicrobials, horizontal gene

transfer between these organisms and N. gonorrhoeae may be important in the development of antimicrobial resistance of N. gonorrhoeae.

Ocular Gonorrhea in Adults Ocular gonorrhea in an adult usually results from autoinoculation of N. gonorrhoeae 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 be attributable to 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 also should be performed.

Gonorrhea in Pregnant Women, Neonates, and Children

Gonorrhea in pregnancy can have serious consequences for both the

mother and the infant. Recognition of gonorrhea early in pregnancy

also identifies a population at risk for other STIs, particularly chlamydial infection, syphilis, and trichomoniasis. The risks of salpingitis and

PID—conditions associated with a high rate of fetal loss—are highest

during the first trimester. Pharyngeal infection, most often asymptomatic, may be more common during pregnancy because of altered sexual

practices. 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 newborn’s gastric aspirate during delivery) are common complications of maternal

gonococcal infection at term. Other conditions and microorganisms,

including Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma

urealyticum, C. trachomatis, and bacterial vaginosis (often accompanied by infection with Trichomonas vaginalis), have been associated

with similar complications.

1238 PART 5 Infectious Diseases

FIGURE 156-2 Characteristic skin lesions in patients with proven gonococcal bacteremia. The lesions are in various

stages of evolution. A. Very early petechia on finger. B. Early papular lesion, 7 mm in diameter, on lower leg. C. Pustule

with central eschar resulting from early petechial lesion. D. Pustular lesion on finger. E. Mature lesion with central

necrosis (black) on hemorrhagic base. F. Bullae on anterior tibial surface. (Reprinted with permission from TF Murphy,

GI Parameswaran: Clin Infect Dis 49:124, 2009, with permission. © 2009 Infectious Diseases Society of America.)

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 eye

drops or ophthalmic preparations containing erythromycin or tetracycline) prevents ophthalmia neonatorum but is not

effective for its treatment, which requires

systemic antibiotics. The clinical manifestations are acute and usually begin

2–5 days after birth. An initial nonspecific conjunctivitis with a serosanguineous discharge is followed by tense edema

of the 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 onset usually comes at

3–21 days of age, and polyarticular involvement is common. Sepsis,

meningitis, and pneumonia are seen in rare instances.

Any STI in children beyond the neonatal period raises the possibility of sexual abuse. 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 upper genital tract are rarely involved. All children with

gonococcal infection should also be evaluated for chlamydial infection,

syphilis, and possibly HIV infection.

Gonococcal Arthritis Disseminated gonococcal infection (DGI;

gonococcal arthritis) results from gonococcal bacteremia. In the

1970s, DGI occurred in ~0.5–3% of persons with untreated gonococcal

mucosal infection. The lower incidence of DGI at present is probably

attributable to a decline in the prevalence of particular strains that

are likely to disseminate. Nonetheless, sporadic outbreaks of DGI still

occur in North America. 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. Strains

recovered from DGI cases in the 1970s were often of the PorB.1A

serotype, were highly susceptible to penicillin, and had special growth

requirements—including arginine, hypoxanthine, and uracil—that

made 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, and persons with more than one episode

of DGI should be screened with an assay for total hemolytic complement activity. DGI is also associated with the use of the complement

C5–blocking monoclonal antibody eculizumab.

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 chills more frequently accompany their fever. Painful

joints are common and often occur together 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 (Fig. 156-2; see also Fig. A1-43).

Other manifestations of noninfectious dermatitis, such as nodular

lesions, urticaria, and erythema multiforme, have been described.

These lesions are usually on the extremities and number between 5 and

40. The differential diagnosis of the bacteremic stage of DGI includes

reactive arthritis, 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 reactive arthritis differs from that in DGI (Fig. 156-3), as do the skin and

genital manifestations (Chap. 362).

Suppurative arthritis involves one or two joints, most often the

knees, wrists, ankles, and elbows (in decreasing order of frequency);

other joints occasionally are 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 Chap. 130. Rarely, osteomyelitis complicates septic arthritis

involving small joints of the hand.

Gonococcal endocarditis, although rare today, was a relatively

common complication of DGI in the preantibiotic era, accounting for

about one-quarter of reported cases of endocarditis. Another unusual

complication of DGI is meningitis.

Gonococcal Infections in HIV-Infected Persons The association between gonorrhea and the acquisition of HIV has been

demonstrated in several well-controlled studies, mainly in Kenya

and Zaire. The nonulcerative STIs enhance the transmission of

HIV three- to fivefold; transmission of HIV-infected immune cells

and increased viral shedding by persons with urethritis or cervicitis may contribute (Chap. 202). HIV has been detected by polymerase chain reaction (PCR) more commonly in ejaculates from

HIV-positive men with gonococcal urethritis than in those from HIVpositive men with nongonococcal urethritis. PCR positivity diminishes

1239CHAPTER 156 Gonococcal Infections

Disseminated gonococcal infection

(N = 102)

Reactive arthritis

(N = 173)

60 50 40 30 20 10 0 10 20 30 40 50 60

Hand and fingers

Wrist

Elbow

Shoulder

Sternal*

Spine and SI†

Hip

Knee

Ankle

Foot and toes

Percent of patients

FIGURE 156-3 Distribution of joints with arthritis in 102 patients with disseminated

gonococcal infection and 173 patients with reactive arthritis. *

Includes the

sternoclavicular joints. †

SI, sacroiliac joint.

twofold after appropriate therapy for urethritis. Not only does gonorrhea enhance the transmission of HIV, but it may also increase the

individual’s risk for acquisition of HIV. A proposed mechanism is the

significantly greater number of CD4+ T lymphocytes and dendritic

cells that can be infected by HIV in endocervical secretions from

women with nonulcerative STIs than in those from women with ulcerative STIs.

■ LABORATORY DIAGNOSIS

A rapid diagnosis of gonococcal infection in men may be obtained

by Gram’s staining of urethral exudates (Fig. 156-1). The detection of

gram-negative intracellular monococci and 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 ThayerMartin 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 (Chap. 189).

PMNs are often seen in the endocervix on a Gram’s stain, and an

abnormally increased number (≥30 PMNs per field in five 1000×

oil-immersion microscopic fields) establishes the presence of an

inflammatory discharge. Unfortunately, the presence or absence of

gram-negative intracellular monococci or 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 ~80–90%. 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.

Several nucleic acid amplification tests (NAATs), including the

Roche COBAS AMPLICOR, Gen-Probe Aptima Combo 2, and BD

ProbeTec ET, are now widely available on semiautomated or fully

automated platforms and are commonly employed diagnostic tests for

gonorrhea. These tests also detect C. trachomatis and are more sensitive than culture for identification of either N. gonorrhoeae or C. trachomatis. The Gen-Probe and BD tests offer the advantage that urine

samples can be tested with a sensitivity similar to or greater than that

obtained when urethral or cervical swab samples are assessed by other

non-NAATs or culture, respectively. A point-of-care NAAT-based test

(Binx io) for gonorrhea and chlamydia with a 30-minute turnaround

time is now approved by the U.S. Food and Drug Administration

(FDA). In MSM, it is important to screen the rectum and pharynx

because screening urine alone will miss the majority of cases. A disadvantage of non-culture-based assays is that N. gonorrhoeae cannot

be grown from the transport systems. Thus, a culture-confirmatory

test and formal antimicrobial susceptibility testing, if needed, cannot

be performed.

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 in children. Although 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,

NAATs from these sites are preferred for diagnostic evaluation in adult

victims of suspected sexual abuse, especially if the NAATs have been

evaluated by the local laboratory and found to be superior. Cultures

should be obtained from the pharynx and anus of both girls and boys,

the urethra of boys, and the vagina of girls; cervical specimens are not

recommended for prepubertal girls. 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.

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.

TREATMENT

Gonococcal Infections

Treatment failure 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. Single-dose regimens have been developed

for uncomplicated gonococcal infections. Treatment guidelines for

gonococcal infections from the Centers for Disease Control and

Prevention (CDC) were revised in 2020, and are summarized in

Table 156-1. The third-generation cephalosporin ceftriaxone is

now recommended as the first-line regimen for use at twice the

previous dose (now, 500 mg IM, single dose) based on doubling

of mean inhibitory concentrations (MICs) of current strains compared with MICs 20 years ago. The development of decreased

sensitivity to ceftriaxone throughout the world will require the

development of new effective regimens. Azithromycin, which had

been recommended to provide additional treatment of gonorrhea

(also to include treatment of chlamydial infection) is no longer

recommended as part of a first line regimen. Resistance to azithromycin of U.S. isolates of N. gonorrhoeae, which had been less than

0.6% over a number of years, has increased more than sevenfold to

4.6% in the most recent year in which it was reported. If chlamydial

infection cannot be excluded, concurrent treatment with doxycycline (100 mg orally twice a day for 7 days) is recommended. The

recommendations for uncomplicated gonorrhea apply to HIVinfected as well as HIV-uninfected patients.

1240 PART 5 Infectious Diseases

The currently recommended regimen for the treatment of

uncomplicated gonococcal infection of the urethra, cervix, rectum,

or pharynx (a single IM dose of ceftriaxone) almost always results

in an effective cure. Quinolone-containing regimens are no longer

recommended in the United States as first-line treatment because

of widespread resistance. Rising MICs of cefixime worldwide have

led the CDC to discontinue its recommendation of this agent as

first-line treatment for uncomplicated gonorrhea. Multicenter trials

of treatment for uncomplicated gonorrhea in the United States have

shown ≥99.5% efficacy of two combination regimens and 96% efficacy in one single-agent regimen: gemifloxacin (320 mg, single oral

dose) plus azithromycin (2 g, single oral dose); gentamicin (a single

IM dose of 240 mg or, in individuals who weigh ≤45 kg, 5 mg/kg)

plus azithromycin (2 g, single oral dose), and zoliflodacin (2 or

3 g, single oral dose). At this time, however, none of these regimens

is recommended by CDC as first-line treatment; gentamicin plus

azithromycin is recommended as an alternative regimen.

Co-infection with C. trachomatis occurs frequently; concurrent

treatment with doxycycline (100 mg orally twice daily for 7 days)

is effective against chlamydial infection. Spectinomycin has been

used as an alternative agent for the treatment of uncomplicated

gonococcal infections in penicillin-allergic persons outside the

United States but is not currently available in the United States. Of

note, the limited effectiveness of spectinomycin for the treatment of

pharyngeal infection reduces its utility in populations among whom

such infection is common, such as MSM.

Persons with uncomplicated genital or rectal infections who

receive ceftriaxone or an alternative regimen do not need a test of

cure; however, 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. Persons with pharyngeal infection should undergo a test of

cure regardless of the treatment regimen, 7–14 days after treatment

to ensure eradication or detection of a possible treatment failure.

Symptomatic gonococcal pharyngitis is more difficult to eradicate

than genital infection. Persons who cannot tolerate cephalosporins

may be treated with an alternative regimen. Treatment with spectinomycin results in a cure rate of ≤52%; persons given spectinomycin should have a subsequent pharyngeal sample cultured early

(3–5 days) following treatment as a test of cure. A single 2-g dose

of azithromycin may be used if the infecting organism is known to

be sensitive or in areas where rates of resistance to azithromycin are

low. Quinolones may be used if the infecting organism is known to

be sensitive. If culture is not readily available and NAAT is positive,

every effort should be made to perform a confirmatory culture. All

isolates from test-of-cure cultures should undergo antimicrobial

susceptibility testing. Because of high rates of reinfection with

N. gonorrhoeae (and C. trachomatis) within 6–12 months, persons

previously treated for gonorrhea should be retested 3 months after

treatment.

Treatments for gonococcal epididymitis and PID are discussed

in Chap. 136. 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, particularly the joint-localized stage with suppurative

arthritis, may require higher dosages and longer durations of therapy

(Table 156-1). Hospitalization is indicated if the diagnosis is uncertain, if the patient has localized suppurative arthritis 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 clinical improvement of affected joints.

Gonococcal meningitis and endocarditis should be treated in the

hospital with high-dose IV ceftriaxone (1–2 g IV every 12–24 h);

therapy should continue for 10–14 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 CONTROL

Condoms, 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

TABLE 156-1 Recommended Treatment for Gonococcal Infections:

Adapted from the 2020 Guidelines for Gonococcal Infection of the

Centers for Disease Control and Prevention

DIAGNOSIS TREATMENT OF CHOICEa

Uncomplicated gonococcal infection of

the cervix, urethra, pharynxb

, or rectum

First-line regimen Ceftriaxone (500 mg IM, single dose)

plus

Doxycycline (100 mg orally twice a day

for 7 days) for treatment of chlamydial

infection if chlamydial infection cannot

be excluded

 Alternative regimens if ceftriaxone is

not available

Gentamicin (240 mg IM, single dose)

plus azithromycin (2 g orally as a single

dose)c

Cefixime (800 mg PO, single dose) or

spectinomycin (2 g IM, single dose)d,e

plus

Doxycycline (100 mg orally twice a day

for 7 days) for treatment of chlamydial

infection if chlamydial infection cannot

be excluded

Epididymitis See Chap. 136

Pelvic inflammatory disease See Chap. 136

Gonococcal conjunctivitis in an adult Ceftriaxone (1 g IM, single dose)f

Ophthalmia neonatorumg Ceftriaxone (25–50 mg/kg IV, single

dose, not to exceed 125 mg)

Disseminated gonococcal infectionh

Initial therapyi

 Patient tolerant of β-lactam drugs Ceftriaxone (1 g IM or IV q24h;

recommended) or cefotaxime (1 g IV

q8h) or ceftizoxime (1 g IV q8h)

 Patients allergic to β-lactam drugs Spectinomycin (2 g IM q12h)d

Continuation therapyj Cefixime (400 mg PO bid)

Meningitis or endocarditis See text for specific recommendationsk

a

True failure of treatment with a recommended regimen is rare and should

prompt an evaluation for reinfection, infection with a drug-resistant strain, or an

alternative diagnosis. b

Ceftriaxone is the most reliable agent recommended for

treatment of pharyngeal infection. c

In vitro synergistic killing of N. gonorrhoeae

of gentamicin plus azithromycin is mild to moderate; azithromycin is for treatment

chlamydial infection, primarily. d

Spectinomycin is unavailable in the United States;

in uncomplicated gonococcal infection it should be used at a higher dose (4 g IM,

single dose) in areas of the world where increased resistance to spectinomycin

exists. e

Spectinomycin may be ineffective for the treatment of pharyngeal

gonorrhea. f

Plus lavage of the infected eye with saline solution (once). g

Prophylactic

regimens are discussed in the text. h

Hospitalization is indicated if the diagnosis

is uncertain, if the patient has the joint-localized stage with suppurative arthritis,

or if the patient cannot be relied on to adhere to treatment. i

All initial regimens

should also include doxycycline (100 mg orally twice a day for 7 days) for treatment

of chlamydial infection if chlamydial infection cannot be excluded; j

gonococcal

therapy should be continued for 24–48 h after clinical improvement begins, at

which time the switch may be made to an oral agent (e.g., cefixime) if antimicrobial

susceptibility can be documented by culture of the causative organism. If no

organism is isolated and the diagnosis is secure, then treatment with ceftriaxone

should be continued for at least 1 week. k

Hospitalization is indicated to exclude

suspected meningitis or endocarditis.