The overall incidence of Neisseria gonorrhoeae infection has been slowly decreasing during the past decade (Figure 1). Gonorrhea continues to be a commonly encountered disease, with over 700,000 cases reported in 1990 (personal correspondence from Centers for Disease Control, 1991).
Although gonorrhea is a disease usually limited to mucosal surfaces, in 0.5 to 3 percent of cases, hematogeous spread results in disseminated infection. [1,2] The classic triad of features consists of arthritis, many patients do not have all of these features. The clinician should consider the diagnosis when any of these findings is present and cannot be attributed to other causes. The clinician should also keep in mind that the initial mucosal infection can be asymptomatic and that patients may not manifest signs of clinical toxicity such as high fever and leukocytosis.  Furthermore, although disseminated infection is most common in young sexually active persons, the diagnosis should be considered in sexually active persons of any age, as illustrated in the following case report.
A 66-year-old man reported to the emergency department with a four-day history of arthralgia, which had developed two days after he had returned from a business trip to Indonesia. His first symptoms were throbbing pain, redness and swelling of the first metatarsophalangeal (MTP) joint of the left foot. Twelve hours later, similar symptoms developed in the left wrist. Over the next 24 hours, pain continued in the MTP joint and the wrist, and similar symptoms developed in the right knee. Movement of the involved joints was painful.
The patient did not report fever, chills, nausea, diarrhea, conjunctivitis, urethral discharge or dysuria, and he denied possible exposure to sexually transmitted diseases. He had no previous history of arthritis or connective tissue disease.
The patient appeared mildly ill on physical examination. His temperature was 38.4[degrees]C (101.2[degrees]F). The affected joints were swollen, warm and tender. Passive range of motion was painful and limited in these joints. Heart murmur, skin lesions and penile discharge were not noted.
Laboratory examination revealed a white blood cell count of 14,500 per [mm.sup.3] (14.5 X [10.sup.9] perL), with a differential of 70 percent (.70) granulocytes, 19 percent (.19) lymphocytes and 7 percent (.07) monocytes. The erythrocyte sedimentation rate was 6 mm per hour. The patient had a non-reactive tuberculin skin test, a normal uric acid level and a negative test for rheumatoid factor. The rapid plasma reagin test was negative.
An arthrocentesis of the right knee effusion yielded yellow, turbid synovial fluid with a red blood cell count of 600 per [mm.sup.3] (0.6 X [10.sup.9] per L) and a white blood cell count of 9,400 per [mm.sup.3] (9.4 X [10.sup.9] per L), of which 94 percent (.94) were neutrophils. No crystals were present, and no organisms were detected on gram stain. Synovial fluid, blood and urethral cultures were performed. Cultures of the throat and rectum were not obtained.
The patient was admitted to the hospital and empirically started on intravenous ceftriaxone (Rocephin) and gentamicin (Garamycin). On the third day after admission, N. gonorrhoeae was isolated from the synovial fluid. Blood and urethral cultures showed no growth. Treatment with ceftriaxone was continued for seven days. A seven-day course of doxycycline (Vibramycin) was given to treat potential coexisting chlamydial infection. Passive range-of-motion exercises were begun to prevent ankylosis of the involved joints.
On further questioning, the patient continued to deny sexual exposure. The Department of Preventive Medicine was contacted to conduct appropriate notification of the patient's sexual contacts. The patient was seen as an outpatient two weeks later and had fully recovered.
Disseminated gonococcal infection occurs most commonly in young adults, with the incidence decreasing sharply with age. This pattern parallels the overall incidence of gonorrhea, with the highest rates occurring in men 20 to 24 years of age and women 15 to 19 years of age. Figure 2 illustrates the differences in age-specific rates for men and women. Disseminated gonococcal
Characeristics of Disseminated Gonococcal Infection
Derived from Hook (1) and Handsfield (2).
infection has uncommonly been reported in persons 60 to 80 years of age. [3-5]
Before the antibiotic era, disseminated gonococcal infection, like uncomplicated gonorrhea, occurred more frequently in men than in women; however, up to 80 percent of cases now occur in women. [2,6] This change in epidemiology has been attributed to the fact that the initial mucosal infection in women is more commonly asymptomatic and may this progress unnoticed to hematogenous dissemination. [2,6,7]
In women, symptoms of disseminated infection commonly appear several days after the start of a menstrual period. [8-10] Infection may become disseminated at this time because sloughing of the endometrium exposes submucosal vessels to the infecting organism. [6,10] Pregnancy may also be a risk factor for the development of disseminated infection. [8-10]
Disseminated gonococcal infection should be considered a possibility in any person presenting with arthritis and either tenosynovitis or dermatitis. The complete triad of arthritis, dermatitis and tenosynovitis occurrs infrequently.
Arthritis develops in only 30 to 40 percent of cases and is usually migratory, with one joint healing as the next joint becomes affected.  Less commonly, the arthritis is additive. Joint involvement is usually asymmetric and most commonly includes the knee, elbow, wrist, metacarpophalangeal and ankle joints. 
Dermatitis, occurring predominantly on distal extremities, is seen in 50 to 75 percent of cases. The classic lesion is a painful necrotic pustule on an erythematous base; however, a macular, papular or petechial rash may occur. [1,2,6,9] Dermatitis is less commonly seen if arthritis is present. 
Tenosynovitis is present in up to 65 percent of cases. Its distribution is usually asymmetric, affecting predominantly the dorsal tendons of the hand and wrist.  Table 1 summarizes the common features of disseminated gonococcal infection. [1,2,11]
[TABULAR DATA OMITTED]
Potential complications include endoarditis, meningitis, perihepatitis and permanent joint damage. [3,5,12] Gonococcal endocarditis occurs in 1 to 2 percent of patients and is characterized by rapid destruction of the aortic valve. [1,2,5,9] Gonococcal meningitis is less common, with fewer than 25 cases reported since 1924. [1,2,12] Although uncommon, these complications can rapidly lead to death.
Hematogenous spread of gonococci can also result in intraperitoneal seeding and the formation of adhesions between the peritoneum and the parietal surface of the liver. This phenomenon is known as Fitz-Hugh-Curtis syndrome, or gonococcal perihepatitis. 
The differential diagnosis of disseminated gonococcal infection includes Reiter's syndrome, rheumatic fever, rheumatoid arthritis, secondary syphilis, gout, pyogenic arthritis and tuberculous arthritis. [6,13] Differentiating features of these entities are listed in Table 2. [1,2]
Diagnosis of disseminated gonococcal infection can be classified as proven (based on a positive blood or synovial fluid culture), probable (based on a positive primary mucosal site culture) or possible (based on response to antibiotic therapy). [1,7] The diagnosis is often difficult to prove. As a result, numerous sites should be cultured to provide the best chance for a definitive diagnosis.
Culture sites should include the blood, synovial fluid, endocervical canal, urethra, rectum and pharynx. Sexual contacts should be encouraged to seek evaluation and culture. [3,9] Cultures taken from the columnar epithelium of the rectum and endocervix yield better results than those taken from the epithelium of the vagina and anus, which are more likely to be contaminated with other organisms.  Less than 50 percent of blood or synovial fluid cultures are possitive in cases of disseminated infection, whereas 80 percent of mucosal cultures are positive. [1,2]
N. gonorrhoeae is a fastidious organism that dies quickly; therefore, cultures should be plated immediately on chocolate and Thayer-Martin agar, and incubated and 37[degrees]C (98.6[degrees]F) with a carbon dioxide concentration of 5 percent. 
Blood cultures will become positive in approximately 30 percent of patients within four days of the initial onset of symptoms. [4,8] After four days, the infection moves out of the bloodstream and into the synovial compartments and skin.
In persons with purulent joint effusions, arthrocentesis should be performed, both for therapeutic and diagnostic purposes. Synovial fluid analysis can help rule out noninfectious causes of joint effusions, such as gout and calcium pyrophosphate deposition disease. Microscopic findings of synovial fluid usually include a white blood cell count of 50,000 to 200,000 cells per [mm.sup.3] (50.0 to 200.0 X [10.sup.9] per L), with a differential of more than 90 percent (.90) neutrophils.  a low level of glucose is often observed in the synovial fluid.  Gram stains of synovial fluid are positive in 25 to 30 percent of cases, showing the characteristic gram-negative diplococci within polymorphonuclear leukocytes. [7,11] Synovial fluid cultures are positive in 30 to 50 percent of cases. [4,11]
Vesicular fluid from skin lesions may be cultured, but the diagnostic yield is less than 5 percent. [7,8] Better results from skin lesions have been obtained using immunofluorescent staining techniques. 
When disseminated gonococcal infection is strongly suspected, empiric treatment should be started. The treatment guidelines are frequently updated because of evolving patterns of antibiotic resistance. Before 1980, most strains of gonococci causing disseminated infection were penicillin-sensitive. [14,15] Since 1980, numerous cases caused by penicillin-resistant strains have been reported. [16,17] This increase corresponds with the overall increase in the incidence of antibiotic-resistant N. gonorrhoeae infections, as shown in Figure 3.
The CDC currently recommends one
Treatment Options for Disseminated
Gonococal Infection (Seven-Day Course)
Adapted from CDC. (18)
of several third-generation cephalosporins as first-line therapy. Initial therapy should be administered parenterally, with the intravenous route preferred. Treatment should be continued for a total of seven days. In certain patients, treatment may be completed with an appropriate oral antibiotic on an outpatient basis after resolution of symptoms. A summary of CDC recommendations is given in Table 3. 
Characteristically, more than 90 percent of patients show clinical improvement within 48 hours of appropriate antibiotic therapy.  Current CDC guidelines recommend that persons who are allergic to beta-lactam antibiotics be treated with spectinomycin (Trobicin), 2g intramuscularly every 12 hours.  This recommendation may change as evidence accumulates regarding the use of quinolone antibiotics in N. gonorrhoeae infection; verification of current CDC guidelines is therefore recommended. 
Persons who are treated for disseminated gonococcal infection should be tested for coexisting Chalmydia trachomatis infection. The incidence of coexisting chlamydial infection has been estimated to be as high as 50 percent. [18,20] For this reason, empiric treatment with doxycycline, 100 mg orally twice a day for seven days, is recommended.  The combination of high-dose ceftriaxone and doxycycline is believed to be effective against incubating syphilis as well. Syphilis was recently reported to be a coexistent infection in one of every 1,250 men with gonorrhea--and the incidence of syphilis is rapidly increasing. [20,21]
Involved joints should be immobilized in the most functional position. When a large effusion is present, arthrocentesis should be repeated until the joint is no longer tense.  Passive range-of-motion exercises should be started as early as possible. 
Patient education regarding the prevention and recognition of sexually transmitted diseases is important. This counseling should include the advice that use of latex condoms containing the bactericidal spermicide nonoxynol-9 is the most effective means of preventing the spread of sexually transmitted organisms.  Sexual contacts of the patient should also be evaluated.
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 Handsfield HH. Neisseria gonorrhoeae. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and practice of infectious diseases. 3d ed. New York: Churchill Livingstone, Inc., 1990:1622-3.
 Shapira O, Bar-On E, Sagiv S, Malkin C. Disseminated gonococcal infection. J Am Geriatr Soc 1990;38:678-9.
 Korting HC, Abeck D, Neubert U. Cultural proof of Neisseria gonorrhoeae in synovial fluid in disseminated gonococcal infection. Dermatologica 1983;167:204-7.
 Wall TC, Peyton RB, Corey GR. Gonococcal endocarditis: a new look at an old disease. Medicine 1989;68:375-80.
 Al-Suleiman SA, Grimes EM, Jonas HS. Disseminated gonococcal infections. Obstet Gynecol 1983;61:48-51.
 Masi AT, Eisenstein BI. Disseminated gonococcal infection (DGI) and gonococcal arthritis (GCA): II. Clinical manifestations, diagnosis, complications, treatment, and prevention. Semin Arthritis Rheum 1981;10:173-97.
 O'Brien JP, Goldenberg DL, Rice PA. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology of 49 patients and a review of pathophysiology and immune mechanisms. Medicine 1983;62:395-406.
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 Britigan BE, Cohen MS, Sparling PF. Gonococcal infection: a model of molecular pathogenesis. N Engl J Med 1985;312:1683-94.
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 Anan TJ, Culik DA. Neisseria gonorrhoeae dissemination and gonococcal meningitis. J Am Board Fam Pract 1989;2(2):123-5.
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KAREN. KERLE, CPT, USAF, MC is a first-year resident in family medicine at Malcolm Grow U.S. Air Force Medical Center, Andrews Air Force Base, Md. Dr. Kerle is a graduate of the Uniformed Services University of the Health Sciences, Bethesda, Md.
JOHN R. MASCOLA, LCDR, MC, USN is part of the clinical staff in infectious disease at the National Naval Medical Center, Bethesda, where he is also an instructor in medicine at the Uniformed Services University of the Health Sciences. Dr. Mascola graduated from Georgetown University School of Medicine, Washington, D.C. He completed a residency in internal medicine at the Naval Hospital, San Diego.
THOMAS A. MILLER, CDR, MC, USN is a member of the Department of Family Practice at the Naval Hospital, Jacksonville, Fla. He is a clinical assistant professor of family practice at the Uniformed Services University of the Health Sciences. Dr. Miller graduated from the University of Washington School of Medicine, Seattle. He completed a family practice residency at the Naval Hospital, Camp Pendleton, Calif., and a faculty development fellowship at the University of North Carolina at Chapel Hill.
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