DGI is a relatively rare manifestation of infection with N gonorrhoeae. Most cases occur in persons with asymptomatic mucosal infection and may be due to infection by a distinct strain that is prone to systemic dissemination. Host factors are important for develop- ment of DGI. In women, about 70% of disseminated gonococcal disease occurs during menses. Patients with terminal component complement deficiency are par- ticularly susceptible to systemic infection with both N gonorrhoeaeandNeisseria meningitidis.
The bacteremia of DGI typically causes skin lesions.
The lesions begin as papules and pustules and sometimes
Figure 16–2.Gonococcal ophthalmia neonatorum with crusting and lid edema.
102 / CHAPTER 16
include a hemorrhagic component with surrounding erythema (see Figure 16–4). Lesions are present in 50–75% of patients, but number fewer than 30 lesions in most cases. Other manifestations of DGI include arthritis, pericarditis, endocarditis, and meningitis (each of which is seen in fewer than 3% of patients with DGI). A later manifestation of the DGI-associated arthritis-dermatitis syndrome consists of migratory arthralgias followed by progressive arthritis in one or two joints.
B. LABORATORYFINDINGS
Definitive diagnosis for N gonorrhoeaecan be made by Gram stain, culture, molecular probe assays, or nucleic acid amplification tests (NAATs). Test performance, available technology, cost, and prevalence of gonorrhea must be taken into account when selecting diagnostic tests to be used for identification of gonococcal infections.
Ideally, the test should be highly sensitive, specific, rapid, and inexpensive.
Figure 16–3.Bartholin gland infections may occur as manifestations of gonorrhea in women. Incision and drainage may be required along with antibiotic therapy.
Figure 16–4. The hemorrhagic lesions of disseminated gonococcal infection are similar to those seen in other bacteremias. Culture of these lesions is usually not helpful in establishing the diagnosis.
GONORRHEA / 103 1. Gram stain—Low cost and rapidity of diagnosis
make Gram stain of urethral specimens an important test for the evaluation of gonorrhea, especially in men.
A Gram stain is considered positive for N gonorrhoeaeif neutrophils with intracellular gram-negative diplococci are observed under microscopy (see Figure 16–5). A Gram stain is considered negative in the absence of gram-negative intracellular diplococci, and is equivocal following the observation of extracellular gram-negative or morphologically atypical-appearing organisms.
The sensitivity and specificity of the Gram stain smear varies, depending on the site of infection and the presence or absence of symptoms. For symptomatic urethritis in men, the high sensitivity and specificity (95% and 98%, respectively), suffices for diagnosis. In asymptomatic men, sensitivity is significantly lower and requires culture or other diagnostic tests to rule out gonococcal infection.
Lower sensitivity (40–60%) also occurs in Gram stains of endocervical samples from symptomatic women, although it retains a high specificity in these cases. A presumptive diagnosis of gonorrhea can be made on the basis of a positive smear in women.
However high intraobserver variability in preparing and reading endocervical Gram stains renders the finding of a negative Gram stain unreliable. Gram-stained smear of specimens from the rectum, pharynx, and other sites should be used only in conjunction with other diagnostic tests to confirm the diagnosis.
2. Culture—The “gold standard” for detection of N gonorrhoeaeis culture, although widespread use of NAATs may signify a change in this long-standing standard.
The main benefits of culture are high specificity and the ability to perform antimicrobial susceptibility testing on culture isolates. The disadvantages of culture can be substantial in many areas because of stringent storage and transport requirements of culture media, fastidious growth requirements of N gonorrhoeae, and delays in obtaining results.
The yield of gonococcal culture is largely dependent on the anatomic site cultured and the culture media.
Selective media contain several antibiotics to prevent the overgrowth of genitourinary, enteric, and oral flora.
Modified Thayer-Martin (MTM) is probably the most widely used selective medium, with an overall sensitivity of 80–95% for isolation of N gonorrhoeae. Other selective media include NYC (New York City), Martin-Lewis, and GC-Lect. Nonselective media can be used for ure- thral specimens from men with symptomatic urethritis due to the high concentration of gonococci relative to that of other genital flora.
In women, a single culture of the endocervix is usu- ally sufficient for isolation of gonococci because infec- tion usually involves the cervix. For women who have undergone a hysterectomy, urethral cultures are indi- cated. Consideration of culturing the accessory gland ducts, pharynx, and rectum should be based on clinical presentation, site of sexual contact, and cost.
The overall yield of blood cultures is less than 30% for DGI, and decreases with duration of clinical illness. This may be due to intermittent, low levels of bacteremia, the extraordinary nutritional requirements of the dissemi- nated gonorrhea strain, and the role of immune complex deposition as a cause of local inflammation. To confirm
Figure 16–5.Gram-negative intracellular diplococci are visible within the polymorphonuclear cells on this urethral Gram stain.
104 / CHAPTER 16
the diagnosis of DGI, cultures should be obtained from all mucosal sites. In over 80% of patients, gonococci can be isolated from genital, rectal, or pharyngeal cultures. In cases where cultures are negative from all mucosal sites, isolation of N gonorrhoeaefrom sex partners may be the only means of confirming the diagnosis.
3. Molecular methods—Gonococcal infections can be diagnosed with other methods, including immunofluo- rescence assays and DNA probes. These diagnostic methods can offer quicker results and higher sensitivity than culture. DNA probe assays for N gonorrhoeaehave reported sensitivity of 93–99% and specificity of 98–99.5%.
NAATs for N gonorrhoeae involve amplification of specific DNA or RNA sequences by polymerase chain reaction, strand displacement assay (SDA), or transcription-mediated assay (TMA). Commercially developed ligase chain reaction tests for N gonorrhoeae are no longer available.
The sensitivity and specificity of NAATs are compa- rable to urethral and endocervical culture. Advantages of NAATs are multiple and include decreased time to results; use with noninvasive urine specimens and self- collected vaginal swabs; identification of coinfecting C trachomatis (depending on manufacturer); and, for TMA and SDA, excellent performance diagnosing anorectal and pharyngeal infections. Urine-based testing permits screening of populations in nontraditional set- tings and may be more acceptable to patients. Self- collected vaginal swabs have also demonstrated good sensitivity and increased patient acceptability.
The primary disadvantage of NAATs is the inability to perform antimicrobial susceptibility testing for N gon- orrhoeaefrom clinical specimens. In the future, commer- cially available NAATs may identify resistance genes.
With specificity less than 100%, NAATs can gener- ate false-positive results when screening is performed in low prevalence populations. Caution must therefore be given to the interpretation of results when screening asymptomatic persons in low prevalence populations.
Garlan SM, Tabrizi SN. Diagnosis of sexually transmitted infections using self-collected noninvasive specimens. Sex Health 2004;1:121–126. [PMID: 16334994]. (Good review of the utility of self-collected specimens for various STDs.) Katz AR, Effler PV, Ohye RG, et al. False positive gonorrhea test
results with a nucleic acid amplification test: The impact of low prevalence on positive predictive value. Clin Infect Dis 2004;38:814–818. [PMID: 14999624] (Demonstration of the importance of STD history and knowledge of local gon- orrhea prevalence for interpretation of positive results in patients in whom the positive result was unexpected.) Phipps W, Stanley H, Kohn R, et al. Syphilis, chlamydia and gon-
orrhea screening in HIV-infected patients in primary care, San Francisco, California, 2003. AIDS Patient Care STDS 2005:19:495–498. [PMID: 16124843]. (Excellent demon- stration of the importance of screening for disease and obtaining specimens from multiple anatomic sites.)
Stary A, Ching SF, Teodorwicz L, et al. Comparison of ligase chain reaction and culture for detection of Neisseria gonorrhoeae in genital and extragenital specimens. J Clin Microbiol1997;
35:239–242. [PMID: 8968915]. (One of the earliest reports demonstrating the superior sensitivity of NAAT methods compared with culture for genitourinary and extragenitouri- nary gonorrhea.)
Differential Diagnosis
The differential diagnosis for patients presenting with signs or symptoms of gonorrhea include other STDs and genitourinary syndromes (C trachomatis, Trichomonas vaginalis, Mycoplasma genitalium, Ureaplasma ure- alyticum). For women, the list also includes bacterial vaginosis, cervical herpes simplex infection, and can- didiasis. Coinfection with other STDs further complicates the differential diagnosis.
For women presenting with vaginal or cervical symp- toms, noninfectious causes to be considered in the dif- ferential diagnosis include retained foreign body, chemical irritation, allergic reaction, endocervical polyp, physical trauma, vesicovaginal or rectovaginal fistula, carcinoma, and leukorrhea of pregnancy. Additionally, hormones, age, and other factors can influence the pres- entation of vaginal discharge.
The differential diagnosis for men presenting with urethritis should include and urinary tract infection or prostatitis in men aged 35 years or older. The causes of prostatitis and prostadynia are beyond the scope of this chapter. Another genitourinary syndrome that can accompany urethritis in men in epididymitis, which may result from STDs, trauma or chemical irritation.
Consultation with a urologist may be indicated.
For women presenting with PID, the differential diagnosis remains broad and includes ectopic preg- nancy, urinary tract infection, pyelonephritis, appen- dicitis, proctocolitis, and endometriosis.
The differential diagnosis for patients presenting with DGI is extensive and must include meningococcemia, ecthyma gangrenosum, and other causes of bacteremia.
Classic signs associated with bacteremia (high fever, leukocytosis, systemic toxicity) are usually absent in DGI.
The arthritis of DGI can be difficult to distinguish clinically from other causes of infectious arthritides (eg, staphylococcal, streptococcal). Synovial fluid cultures are usually sterile but demonstrate cell counts and chemistries consistent with septic arthritis. The chances of a positive culture increase when the synovial fluid is purulent.
Complications
PID requires prompt treatment to reduce the incidence of chronic infection and infertility (see When to Refer to a Specialist, later). The likelihood of infertility increases with the number of episodes of PID: 11% among women with one episode, 23% with two episodes, and
GONORRHEA / 105 75% with three or more episodes of PID. Other sequelae
include chronic pelvic pain and ectopic pregnancy.
Other urogenital complications from gonorrhea in women include perihepatitis (Fitz-Hugh-Curtis syn- drome). This syndrome presents as acute right or bilateral upper quadrant tenderness, frequently with signs and symptoms of PID.
Ocular infection with gonorrhea in adults can threaten sight. Gonococcal conjunctivitis usually occurs with concomitant, or at least recent, genitourinary gon- orrhea. Gonococcal ophthalmia resulting from accidental inoculation has shown excellent response to ceftriaxone, 1.0 g intramuscularly as a single dose.
Gonococcal arthritis, the most common compli- cation of DGI, can present as monoarticular or
pauciarticular arthritis. An important clinical f inding that can distinguish gonococcal arthritis from other infectious causes is an accompanying tenosynovitis, which often occurs over the involved joint and may include erythema.
Bardin T. Gonococcal arthritis. Best Pract Res Clin Rheumatol 2003;17:201–208. [PMID: 12787521]. (Concise review of the clinical and diagnostic issues of gonococcal arthritis.)
Treatment
Treatment regimens for uncomplicated gonorrhea should cure at least 95% of genitourinary infections by a single dose of therapy (see Table 16–1).
Table 16–1.Recommended treatment regimens for gonorrhea based on US and European STD treatment guidelines.
Drug Special Considerations
Uncomplicated Ceftriaxone, 125 mg IM as a Co-treat for Chlamydiaunless excluded (cervical, urethral, single dosea Any of these regimens may be used for
rectal) infection or gonococcal pharyngitis; few regimens reliably
Cefpodoxime, 400 mg PO as a cure >90% pharyngeal gonorrhea single dose
or
Ciprofloxacin, 500 mg PO as a single doseb
or
Cefixime, 400 mg PO as a single dosec
Pregnant women Ceftriaxone, 125 mg IM as a Co-treat for Chlamydiausing:
single dose • Azithromycin, 1 g PO as a single dose or
• Erythromycin base, 500 mg PO 4 times daily
or
• Amoxicillin 500 mg PO 3 times daily unless excluded
Use spectinomycin for women who cannot receive ceftriaxone
Obtain “test of cure”>7 d after treatment Alternative Spectinomycin, 2.0 g IM as Spectinomycin is not effective against
regimens a single dosec pharyngeal gonorrhea
or
Kanamycin, 2.0 g IM as a single dose
or
Gentamicin, 240 mg IM as a single dose
aOther single-dose second- and third-generation cephalosporins have no advantage over cef triaxone.
bOther single-dose fluoroquinolones have no advantage over ciprofloxacin, although data regarding their use for gonorrhea is limited. Fluoroquinolones are not recommended for use in patients in California and Hawaii, or in men who have sex with men, due to increased incidences of fluoroquinolone-resistant N gonorrhoeaein these populations.
cLimited availability in the United States in 2006.
106 / CHAPTER 16
A. ANTIMICROBIALRESISTANCE
Reduced susceptibility to antimicrobials has been reported since the early 1950s and has continued to evolve and spread since that time. The reasons for the development of resistance are complex but can be attrib- uted to four major factors: (1) poor compliance with prescribed therapy, (2) inadequate dosing of antibiotics, (3) circumstances causing low or inadequate antibiotic serum levels, and (4) conditions favoring the selection of resistance mutations (eg, widespread use of antimicrobial agents).
Treatment with penicillin and tetracycline is unreli- able in much of the world due to the appearance of penicillinase-producing N gonorrhoeae, plasmid-mediated high-level tetracycline-resistant N gonorrhoeae, and chromosomally mediated penicillin and tetracycline- resistant N gonorrhoeae.
In reaction to widespread penicillin and tetracycline resistance, the Centers for Disease Control and Prevention in 1987 ceased to recommend these agents for treatment of gonorrhea and began advocating the use of third-generation cephalosporins and selected flu- oroquinolones. Ceftriaxone continues to be effective, with no reported resistance. The only currently available oral third-generation cephalosporin in the US is cefpo- doxime. Some oral second-generation cephalosporins may be used for therapy of uncomplicated gonorrhea (see Relevant World Wide Web Sites).
Fluoroquinolone resistance has been noted in the Far East, Australia, Africa, Europe, and, most recently, the United States. Ciprofloxacin-resistant strains are becom- ing more widespread throughout the United States. In 2006, fluoroquinolones are not recommended for gon- orrhea treatment in Hawaii and California, nor are they recommended in MSM.
B. TREATMENTRECOMMENDATIONS
1. Uncomplicated infections—Specific treatment rec- ommendations for uncomplicated gonococcal infec- tions in patients are shown in Table 16–1. Because pharyngeal infections with N gonorrhoeaecan be diffi- cult to eradicate, few regimens reliably cure more than 90% of these infections.
All sex partners who have had contact with the infected patient (within 60 days of diagnosis) should be examined and treated. Additionally, patients and their sexual contacts should be offered HIV counseling and testing at the time of gonorrhea diagnosis. Routine “test of cure” is not indicated following treatment for uncom- plicated gonorrhea with currently recommended cephalosporin regimens; however, patients who remain symptomatic after treatment should be reexamined and tested. Patients treated with a fluoroquinolone in areas with increased levels of fluoroquinolone resistance should also have a test of cure. All patients diagnosed with gonorrhea should be tested to rule out repeat infection
3–4 months after treatment. Unless coinfection with C trachomatis has been excluded, treatment for chlamydia is recommended as a part of all gonorrhea treatment regimens.
2. PID—Most PID is caused by N gonorrhoeae, C tra- chomatis, or gram-negative bacilli. Therapy should include drugs active against these organisms as well as anaerobes. Most women receive outpatient therapy that should be limited to nonpregnant, compliant women with mild to moderate disease. Women treated with outpatient regimens should be advised to return within 3 days to follow up response to therapy. Inpatient man- agement of PID should begin with intravenous antibi- otics that may be switched ultimately to an oral regimen.
3. Ophthalmia neonatorum—Gonococcal ophthalmia neonatorum can be prevented by routine screening for endocervical infection during pregnancy and by the pro- phylactic use of 1% silver nitrate, erythromycin, or tetra- cycline ophthalmic solution. These agents may not be available in developing countries. A single application of 2.5% povidone–iodine is an inexpensive alternative with a broad spectrum of activity against chlamydia, gonor- rhea, HIV, and herpes simplex. Given the high rates of tetracycline-resistant N gonorrhoeae, tetracycline may no longer be adequate as prophylactic therapy.
4. DGI—Patients with DGI require hospitalization for observation of response to therapy and to assure adherence with the treatment regimen. The recom- mended initial regimen for DGI is ceftriaxone, 1 g intra- muscularly or intravenously every 24 hours for 7 days. In patients with a prompt clinical response to therapy and whose adherence is likely, therapy can be completed on an outpatient basis. If a patient is allergic to cephalosporins, consultation with an infectious dis- ease specialist is recommended (see When to Refer to a Specialist, later).
Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med 1995;332:562–566. [PMID: 7838190]. (Classic article demonstrating the effectiveness of the less-expensive povidone-iodine solution for prevention of this serious gono- coccal complication.)
Woods CR. Gonococcal infections in neonates and young children.
Semin Pediatr Infect Dis 2005;16:258–270. [PMID:
16210106]. (Good review of gonorrheal infections in chil- dren, with a discussion of some of the medicolegal aspects involved in caring for infected children.)
When to Refer to a Specialist
Most uncomplicated genitourinary gonorrhea responds well to single-dose therapy. Consultation with an infec- tious disease specialist should be obtained for infections suspected of antimicrobial resistance, poor therapeutic response, or requiring repeated courses of oral or intra- venous therapy, or when serious sequelae have developed.
GONORRHEA / 107 Inpatient management of PID or of pregnant women
with other complications of gonococcal infection should be carried out in conjunction with an infectious disease or obstetrician-gynecologist consultant to prevent fur- ther complications or adverse outcomes for the fetus.
Most women with PID who have demonstrated clinical improvement (afebrile for 24 hours, able to tolerate oral regimens) may be switched to an oral regimen. Therapy should be continued to complete a 14-day course.
Ocular infections that do not respond to single-dose therapy should be referred immediately for ophthalmo- logic evaluation because of the risk of severe ulcerative keratitis and potential for visual impairment.
Patients with suppurative arthritis from gonorrhea should be hospitalized and managed in consultation with infectious disease and orthopedic specialists, espe- cially in instances where the diagnosis is in doubt.
Effusions may require frequent aspirations until they have ceased to accumulate.
Rare manifestations of DGI, meningitis, and endo- carditis with N gonorrhoeaerequire high-dose intravenous therapy with a highly active agent that achieves adequate tissue levels in the site of infection. These systemic mani- festations of gonorrhea infection should be managed in conjunction with an infectious disease specialist.
Prognosis
In general, cure rates for uncomplicated genitourinary gonorrhea exceed 95% with single-dose treatments. An important part of this high cure rate includes concomi- tant treatment of sex partners to prevent reinfections.
However, it must be understood that high-risk sexual behaviors will continue to put the patient at risk of gon- orrhea and other STDs, including HIV. Reinfection with
N gonorrhoeaeis possible, because there is no conferred immunity from prior infections. Patients should be counseled on risk-reduction methods to prevent subse- quent infections. Resolution of symptoms of PID or DGI usually occurs within 24–48 hours of initiation of therapy.
PRACTICE POINTS
• All patients diagnosed with gonorrhea should be tested to rule out repeat infection 3–4 months after treatment. Unless coinfection with C tra- chomatis has been excluded, treatment for chlamydia is recommended as a part of all gon- orrhea treatment regimens.
Relevant Web Sites
[American Social Health Organization:]
http://www.ashastd.org
[Centers for Disease Control and Prevention, Division of STD Prevention:]
http://www.cdc.gov/std
[National Institute of Allergy and Infectious Disease, Division of Microbiology and Infectious Diseases:]
http://www.niaid.nih.gov/dmid/stds/
[World Health Organization, Sexually Transmitted Diseases Diagnostics Initiative:]
http://www.who.int/std_diagnostics/