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[STDs] Atlas of Gonorrhea

Gonorrhea, Atlas of Gonorrhea, Bacterial Sexually Transmitted Diseases, Color Atlas & Synopsis of Sexually Transmitted Diseases, Third Edition

Gonorrhea 


Gonorrhea is among the most common and most widely recognized sexually transmitted diseases (STDs) throughout the world. It is one of the five classical venereal diseases, with syphilis, chancroid, lymphogranuloma venereum, and donovanosis (granuloma inguinale). Neisseria gonorrhoeae, a Gramnegative diplococcus that in clinical material typically appears within polymorphonuclear leukocytes (PMNs), primarily infects the mucosal surfaces of the urethra or endocervix and secondarily those of the rectum and pharynx. Conjunctivitis can occur by exposure to infected secretions, including autoinoculation in patients with genital infection. Ascending infection in women results in gonococcal pelvic inflammatory disease (PID), the most common complication and an important cause of female infertility. Bacteremic dissemination causes a characteristic arthritis–dermatitis syndrome or septic arthritis, and rarely bacterial endocarditis or meningitis. Other complications are acute epididymitis and, in infants born to infected mothers, conjunctivitis (gonococcal ophthalmia neonatorum) that can result in corneal scarring and consequent blindness. Transmission occurs almost exclusively through sexual or perinatal exposure.

Evolution of antibiotic-resistant N. gonorrhoeae worldwide has rendered ineffective formerly recommended regimens of the sulfonamides, penicillins, tetracyclines, and fluoroquinolones. Ceftriaxone remains active, but relative resistance to cefixime and other oral cephalosporins has evolved in parts of Asia and likely will spread and rare ceftriaxone-resistant strains have been isolated in east Asia. Eventual dissemination of ceftriaxone resistant gonococci remains a distinct possibility, and the recommended dose of ceftriaxone has been raised from 125 to 250 mg. It has long been recommended that single-dose treatment with a cephalosporin or other recommended antibiotic be followed by azithromycin or doxycycline to treat simultaneous chlamydial infection, present in 15–30% of persons with gonorrhea. In order to help retard evolution of antibiotic resistance in N. gonorrhoeae, such dual therapy is now recommended by the Centers for Disease Control and Prevention (CDC) and other experts even if simultaneous chlamydial infection has been excluded. Clinicians should remain alert to possible frequent modifications in recommended treatments. As for chlamydial infection, 10–20% of patients with gonorrhea have persistent or recurrent infection when retested 3–6 months after treatment, and all patients with gonorrhea should be routinely rescreened for both N. gonorrhoeae and C. trachomatis. 


EPIDEMIOLOGY

Incidence and Prevalence
• In the United States, reported cases fell 78% from peak 1,013,436 (454 per 100,000 population) in 1978 to 301,174 cases (99 per 100,000) in 2009; true total probably is double the reported cases, i.e. ~600,000 infections annually
• Global incidence highly variable; generally low in industrialized countries, but widely underreported
• European Union had total 29,000 reported cases in 2007; <15 per 100,000 in all western European countries
• WHO estimates 170 million cases per year worldwide
• Strong associations in all societies with low socioeconomic status, population migration, societal disruption, armed conflict, commercial sex, and reduced access to health care
• Prevalence varies widely:
° Typically 5–20% of patients in many urban STD clinics and some corrections facilities
° Generally <1% of sexually active women in private physicians’ offices and most reproductive health clinics
° Usually 5–10% of men who have sex with men (MSM) seeking care for STD

Transmission
• Most cases are acquired by vaginal or anal intercourse; estimated transmission risk per unprotected
exposure 20–50%
• Less efficient transmission by fellatio, especially from pharynx to genitals, but explains most pharyngeal infections in women and MSM and up to 40% of urethral gonorrhea in MSM
• Least efficient by cunnilingus, accounting for rare pharyngeal infection

Age
• All ages susceptible
• In the United States, ~80% of cases occur in females aged 15–29 years and males aged 15–34 years

Sex
• In the United States, reported cases in females slightly outnumber those in men (ratio 1.2 to 1 in 2009), owing to more frequent screening of women; actual case rates are probably similar in heterosexual men and women, elevated in MSM
• Distribution by sex varies with success of case-finding in asymptomatic women, frequency of commercial sex, and local rates in MSM

Sexual Orientation
• Rising rates in cases of MSM in industrialized countries during 1998–2009
• Annual rate in MSM is several times higher than in heterosexuals
° In King County, Washington, estimated 2009 annual rate per 100,000 was 28 times higher in MSM (1,105 per 100,000) than heterosexual men (40 per 100,000) 

EPIDEMIOLOGY

Incidence and Prevalence
• In the United States, reported cases fell 78% from peak 1,013,436 (454 per 100,000 population) in
1978 to 301,174 cases (99 per 100,000) in 2009; true total probably is double the reported cases, i.e. ~600,000 infections annually
• Global incidence highly variable; generally low in industrialized countries, but widely underreported
• European Union had total 29,000 reported cases in 2007; <15 per 100,000 in all western European countries
• WHO estimates 170 million cases per year worldwide
• Strong associations in all societies with low socioeconomic status, population migration, societal disruption, armed conflict, commercial sex, and reduced access to health care
• Prevalence varies widely:
° Typically 5–20% of patients in many urban STD clinics and some corrections facilities
° Generally <1% of sexually active women in private physicians’ offices and most reproductive health clinics
° Usually 5–10% of men who have sex with men (MSM) seeking care for STD

Transmission
• Most cases are acquired by vaginal or anal intercourse; estimated transmission risk per unprotected
exposure 20–50%
• Less efficient transmission by fellatio, especially from pharynx to genitals, but explains most pharyngeal infections in women and MSM and up to 40% of urethral gonorrhea in MSM
• Least efficient by cunnilingus, accounting for rare pharyngeal infection

Age
• All ages susceptible
• In the United States, ~80% of cases occur in females aged 15–29 years and males aged 15–34 years

Sex
• In the United States, reported cases in females slightly outnumber those in men (ratio 1.2 to 1 in 2009), owing to more frequent screening of women; actual case rates are probably similar in heterosexual men and women, elevated in MSM
• Distribution by sex varies with success of case-finding in asymptomatic women, frequency of commercial sex, and local rates in MSM

Sexual Orientation
• Rising rates in cases of MSM in industrialized countries during 1998–2009
• Annual rate in MSM is several times higher than in heterosexuals
° In King County, Washington, estimated 2009 annual rate per 100,000 was 28 times higher in MSM (1,105 per 100,000) than heterosexual men (40 per 100,000) 

PHYSICAL EXAMINATION

Urethritis in Males
• Urethral discharge, usually overt; sometimes demonstrable only by “milking” urethra
• Discharge usually is frankly purulent, i.e. opaque, white or yellow in color; sometimes mucoid or mucopurulent
• Occasional meatal erythema
• Rarely penile edema or lymphangitis
• May be normal in men with subclinical infection

Urogenital Infection in Women
• Purulent or mucopurulent endocervical exudate; other signs of mucopurulent cervicitis 
• Sometimes purulent exudate expressible from the urethra, periurethral (Skene’s) glands, or Bartholin gland duct
• Uterine, adnexal, or abdominal tenderness or mass, suggesting PID
• Often entirely normal

Rectal Infection
• External examination usually normal
• Anoscopy may show mucosal erythema, punctate bleeding, purulent exudate
Pharyngeal Infection
• Usually normal
• Rarely erythema, purulent exudate, cervical lymphadenopathy

Localized and Systemic Complications
• Abdominal tenderness, pelvic adnexal tenderness, pelvic mass
• Testicular tenderness, enlargement (usually unilateral)
• Tenosynovitis, joint tenderness, and erythema
• Skin lesions: petechiae, papules, pustules (sometimes hemorrhagic)
• Conjunctival erythema, purulent exudate

LABORATORY DIAGNOSIS

Gram-Stained Smear
• PMNs with intracellular gram-negative diplococci (ICGND); test performance depends substantially on skills and experience of examiner 
• Highly accurate in symptomatic male urethritis: ≥90% sensitive, ≥95% specific (i.e., false-negative and false-positive results are rare)
• Insensitive for cervical, rectal, or asymptomatic urethral infection, detecting <50% of cases; but highly specific with experienced observer
• Not useful for pharyngeal infection

Nucleic Acid Amplification Tests
• NAAT is usual test of choice, including transcription-mediated amplification (TMA), e.g. Aptima, strand displacement assay (SDA), e.g. ProbeTec, or polymerase chain reaction (PCR), e.g. Amplicor†
• Combination NAATs detect both N. gonorrhoeae and C. trachomatis in single specimens
• NAAT detects 90–95% of infections in genital secretions (cervical, vaginal, or urethral swab, or urine) and rarely are false-positive
• Rectal and pharyngeal infection: TMA appears reliable

Culture
• Isolation on selective growth medium; preserves isolate for antimicrobial susceptibility testing or for confirmation for medicolegal purposes, when needed
• Sensitivity: urethra ≥95%; cervix 80–90%; rectum 70–80%; pharynx 60–70%

Other Tests
• Nonamplified DNA probe tests (e.g., Pace II) and antigen detection assays are less sensitive than
NAAT; false-positive results may be common in low-prevalence settings
• Only culture and NAAT are recommended to detect rectal or pharyngeal gonorrhea

TREATMENT

Principles
• Penicillin resistance: Resistant N. gonorrhoeae is prevalent worldwide, both plasmid-mediated β-  lactamase production and chromosomal
• Fluoroquinolones: Resistance is now prevalent worldwide
• Cephalosporins: Clinically significant resistance to oral cephalosporins has appeared in parts of Asia; to date uncommon elsewhere but increasing spread is anticipated; ceftriaxone resistance may be
increasing but currently rare
• Recommended single-dose regimens are ≥95% effective for urethral, cervical, and rectal infections
• Recommended regimens have variable and generally lower efficacy for pharyngeal infection 
• Treat all gonorrhea patients with azithromycin or doxycycline as recommended for C. trachomatis infection
• Dual therapy also may help retard selection of antibiotic-resistant N. gonorrhoeae and should be employed even when chlamydial infection has been excluded.

Uncomplicated Genital or Rectal Gonorrhea in Adults
Regimen of Choice
• Ceftriaxone 250 mg IM (single dose) and either azithromycin 1.0 g PO (single dose) or doxycycline
100 mg PO bid for 7 days
Primary Alternative if Ceftriaxone Cannot Be Given
• Cefixime 400 mg PO (single dose) and azithromycin or doxycycline, as above
Other Alternative Regimens
• Cefpodoxime 400 mg PO (single dose) and azithromycin or doxycycline, as above; or
• Cefuroxime 1.0 g PO (single dose) and azithromycin or doxycycline, as above; or
• Azithromycin 2.0 g PO (single dose)

Pharyngeal Gonorrhea
• Ceftriaxone and azithromycin or doxycycline, as above
• Other single-dose regimens have reduced efficacy when given alone, but probably are reliable in combination with azithromycin or doxycycline.

Pregnant Women
• Ceftriaxone or cefixime as above, and azithromycin 1.0 g PO
• Azitrhomycin 2.0 g PO (single dose) if cephalosporins contraindicated
• If azithromycin not available, use ceftriaxone or cefixime, and either amoxicillin or erythromycin as
recommended for C. trachomatis during pregnancy.

Disseminated Gonococcal Infection
• Ceftriaxone 1.0 g IM or IV every 24 hours until improved, then cefixime 400 mg PO bid to complete 7 days total therapy
• A fluoroquinolone (e.g., ciprofloxacin) may given initially or to complete 7 days therapy, i susceptibility testing demonstrates sensitivity
• For endocarditis, give parenteral cephalosporin therapy for 4 to 6 weeks

Gonococcal Conjunctivitis in Adults
• Ceftriaxone 1.0 g IM, single dose

Follow-up
• Retest all patients 3–6 months after treatment (rescreening); 10–20% of patients have either reinfection or delayed treatment failure
• Test of cure at 3–4 weeks:
° If therapeutic compliance is uncertain
° Pregnant women
° Following nonstandard treatment
° Do not retest with NAAT sooner than 3 weeks after treatment, due to possible persistence of gonococcal DNA despite successful eradication

MANAGEMENT OF SEX PARTNERS
• All sex partners in preceding month, as well as all likely source partners, should be tested for N. gonorrhoeae and treated (without awaiting test results)
• Expedited partner treatment (EPT) (e.g., patient-delivered partner treatment) is indicated whenever
partner compliance with direct health care is uncertain
° EPT is recommended by some experts as management of choice for all partners
° When practical, partners managed with EPT also should be examined, tested, and counseled

PREVENTION
Counseling
• Emphasize importance of preventing future infections and ensuring treatment of partners
• Encourage monogamy, condoms, selection of sex partners at low risk, and avoidance of concurrency (overlapping partnerships)
• Emphasize the substantially elevated risk of HIV infection in persons with gonorrhea
• Address lifestyle issues that are common risk markers for gonorrhea, including commercial sex, substance abuse, concurrency, abusive relationships, sexual coercion

Screening
• Formal recommendations for gonorrhea screening are lacking in the United States, but testing for N.
gonorrhoeae is the norm when screening for chlamydia
• Routinely test women in population groups and settings with high rates of gonorrhea whenever they
seek health care
• Screening men for urethral gonorrhea is of uncertain value, because asymptomatic urethral infection
is rare
• Test MSM for rectal and pharyngeal infection, depending on sites exposed

Reporting
• Report cases to health authorities according to local regulations 

4–1. Gonococcal urethritis
4–1. Gonococcal urethritis. a. Purulent urethral discharge. b. Gram-stained smear showing intracellular gram-negative diplococci.  


CASE 1

Patient Profile Age 22, carwash attendant

History Urethral discharge for 1 day, mild dysuria; vaginal intercourse with a new female partner 4 days earlier and with regular girlfriend 2 days ago

Examination Copious purulent urethral discharge

Differential Diagnosis Gonorrhea, nongonococcal urethritis

Laboratory PMNs with ICGND on urethral smear; urethral NAATs for N. gonorrhoeae and C. trachomatis (both positive); VDRL and HIV serology (both negative)

Diagnosis Gonococcal urethritis (with chlamydial infection)

Treatment Cefixime 400 mg PO plus azithromycin 1.0 g PO (both single dose, directly observed)

Follow-up Advised to return in 3 months for rescreening with urine NAAT for N. gonorrhoeae and C.trachomatis

Sex Partner Management Advised to refer partners; patient agreed to refer his new partner and opted for EPT for his regular partner, with cefixime and azithromycin

Comment Up to 25% of heterosexual men with gonorrhea also have urethral C. trachomatis infection.

onococcal cervicitis
4–2. Gonococcal cervicitis, with scant purulent exudate in os.  

CASE 2

Patient Profile Age 18, new partner of preceding patient

History Asymptomatic; no other partners in past 4 months; skin rash after receiving penicillin during
childhood

Examination Mucopurulent cervical exudate; otherwise normal

Differential Diagnosis Mucopurulent cervicitis; contact and referral history suggests gonorrhea;
20–30% probability of concomitant chlamydial infection

Laboratory Gram stain of cervical exudate showed PMNs without ICGND; cervical NAATs for N.
gonorrhoeae and C. trachomatis (both positive); VDRL and HIV serology negative

Diagnosis Gonococcal cervicitis (with chlamydial infection)

Treatment Cefixime 400 mg PO, single dose, directly observed; plus azithromycin 1.0 g PO, single dose

Follow-up Advised to return in 3 months for rescreening with urine NAAT for N. gonorrhoeae and C.trachomatis

Sex Partner Management The only partner at risk had been treated

Comment Although allergic cross reactivity can occur between penicillin and cephalosporins, it is uncommon and oral cefixime (or IM ceftriaxone) is considered safe by most experts.

4–3. a. Gonococcal conjunctivitis; compare with chlamydial conjunctivitis. 
b. Purulent discharge in gonococcal urethritis.  

CASE 3
Patient Profile Age 33, male, computer programmer, MSM, HIV positive, on antiretroviral therapy

History Urethral discharge for 3 days; increasingly severe left eye pain and photophobia for 2 days;
visited an urgent care clinic 1 day earlier for eye pain, treated with eye drops; one regular sex partner
who also has HIV; patient suspects partner has other partners 

Examination Marked conjunctival erythema, copious purulent exudate, subconjunctival hemorrhage;
purulent urethral discharge

Differential Diagnosis Urethritis, probably gonorrhea; rule out chlamydial infection and NGU; purulent conjunctivitis, rule out gonorrhea, other pyogenic infections, herpes, C. trachomatis

Laboratory PMNs with ICGND in both conjunctival and urethral exudate; both culture and NAAT from both sites positive for N. gonorrhoeae; urethral and conjunctival NAAT negative for C. trachomatis and negative by culture for herpes simplex virus (HSV); rectal NAAT and pharyngeal culture negative for N. gonorrhoeae; rectal NAAT negative for C. trachomatis; VDRL negative

Diagnosis Gonococcal urethritis and conjunctivitis

Treatment Ceftriaxone 250 mg IM, single dose, followed by doxycycline 100 mg PO bid for 7 days

Follow-up Scheduled to return after 2 days to assess conjunctivitis, which had markedly improved

Sex Partner Management Patient notified his partner, who was treated by his private physician

Comment Compare with chlamydial conjunctivitis (see Fig. 3–3); conjunctivitis may have resulted from autoinoculation from patient’s urethral infection, or from direct oropharyngeal exposure; some
HIV-infected MSM continue high-risk sex or have partners who do so.

Skin lesions in gonococcal arthritis–dermatitis syndrome.
4–4. Skin lesions in gonococcal arthritis–dermatitis syndrome. 
a. Early papular lesions of forearm. 
b. Hemorrhagic lesion of finger. 
c. Pustule with central eschar. 
d. Large hemorrhagic pustule of foot. 
(Parts a and b are from the case
described below. Parts c and d are from two other patients.)
Lesions typically begin as nonspecific papules or petechiae,
and then progress to pustules, often with a hemorrhagic component. 
The rulers in parts a, b, and d are metric.

CASE 4

Patient Profile Age 22, female, exotic dancer in a strip club

History Generalized aching of arms and legs and “red bumps” on all four extremities for 2 days; overt pain of several joints for 1 day; intermittent vaginal discharge for several months without recent change; currently menstruating; refused to give information about sex partners or sexual practices in connection with her work

Examination Afebrile; 15–20 papular, pustular, and hemorrhagic skin lesions on extremities; slight erythema and edema over left wrist, extending to dorsum of hand; pain on range of motion of left ankle, without visible abnormality; moderate effusion of right knee, with 20 mL slightly cloudy, straw-colored fluid withdrawn by needle aspiration; menstrual blood in vaginal vault, genital examination otherwise normal; normal cardiac examination 

Differential Diagnosis Disseminated gonococcal infection (arthritis–dermatitis syndrome); also consider reactive arthritis, hepatitis B prodrome, other immune-complex syndromes, meningococcemia, bacterial endocarditis, acute rheumatic fever, systemic lupus erythematosus, and other etiologies of acute arthritis

Laboratory Synovial fluid contained 8,500 leukocytes per mm3, 80% PMNs, no crystals, no bacteria observed by Gram stain; in pre-NAAT era, cultures for N. gonorrhoeae from cervix, anal canal, pharynx, synovial fluid, and blood (×3); cervical culture for C. trachomatis (negative); CBC showed 12,400 leukocytes, 80% PMNs, otherwise normal; chemistry panel normal, including liver function tests; VDRL, HIV, and hepatitis B serologies negative; N. gonorrhoeae isolated from cervix and pharynx; other cultures negative

Diagnosis Disseminated gonococcal infection with arthritis–dermatitis syndrome 

Treatment Ceftriaxone 1.0 g IM, repeated 1 day later; then ofloxacin 300 mg PO bid for 8 days (10 days total therapy)

Follow-up Followed daily for 3 days till completion of therapy; arthritis improved within 1 day and resolved by day 5; skin lesions were healed at 10 days

Sex Partner Management At first follow-up visit, health department counselor reinterviewed patient, without success in identifying partners

Comment Onset of DGI (disseminated gonococcal infection) during or near menses is typical. Many patients, like this one, are afebrile; high fever may be an indication for IV therapy and usually hospitalization. Synovial fluid cultures usually are negative in arthritis–dermatitis stage, but often positive if overt septic arthritis supervenes. Blood cultures may be positive or negative. Careful cardiac examination and close follow-up are indicated for first 2–3 days to evaluate for gonococcal endocarditis. This patient presented before fluoroquinolone-resistant N. gonorrhoeae was prevalent, and ofloxacin was selected for completion of therapy because of efficacy against both N. gonorrhoeae and C. trachomatis. DGI is associated with particular gonococcal strains that are currently uncommon in most geographic areas.

Periurethral furuncle due to N. gonorrhoeae
4–5. Periurethral furuncle due to N. gonorrhoeae. Patient presented with history of “pimple” at tip of penis, draining intermittently for 6 weeks, without urethral discharge or dysuria.
Pathogenesis may have been infection of a sebaceous gland or
other preexisting skin lesion. Gram stain of exudate showed PMNs
with ICGND, and culture was positive for N. gonorrhoeae.  


Mucopurulent exudate in gonorrhea
4–6. Mucopurulent exudate in gonorrhea. Some cases lack overtly
purulent discharge, and laboratory testing is required to confidently
distinguish gonococcal urethritis from NGU  


Copious purulent urethral exudate in gonorrhea
4–7. Copious purulent urethral exudate in gonorrhea  

Gonococcal urethritis with penile venereal edema.
4–8. Gonococcal urethritis with penile venereal edema.
When associated with gonorrhea, such edema has been
called “bull-headed clap.” Penile venereal edema can
also occur with genital herpes and chlamydial NGU  


Presumptive gonococcal ulcer of the penis in a patient with gonococcal urethritis;
4–9. Presumptive gonococcal ulcer of the penis in a
patient with gonococcal urethritis; N. gonorrhoeae
was isolated from the ulcer as well as the urethra;
darkfield microscopy, syphilis serology, and cultures
for HSV and Haemophilus ducreyi were negative. N.
gonorrhoeae is a rare cause of ulceration of the genitals or fingers; most 
cases probably represent secondary gonococcal infection of preexisting skin lesions.  


REFERENCES
H. Hunter Handsfield, MD, Color Atlas & Synopsis of Sexually Transmitted Diseases, Third Edition.

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Gonorrhea, Atlas of Gonorrhea, Bacterial Sexually Transmitted Diseases, Color Atlas & Synopsis of Sexually Transmitted Diseases, Third Edition
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