General Goal: To know the major cause(s) of these infections, how they are transmitted, and the major manifestations of the infections.
Specific Educational Objectives: The student should be able to:
1. identify the common cause of each of the STI's discussed in this handout and the next two STI handouts. Know the common or pathognomonic signs of the infections.
2. describe the major manifestations of each infection and differentiate it from other infections in the course.
3. describe how you diagnose, treat and prevent these infections.
Reading: MEDICAL MICROBIOLOGY by P.R. Murray, K.S. Rosenthal, G.S. Kobayashi and M.A. Pfaller, 6th Edition. depends on the organism.
F.S. Southwick, Infectious Diseases A Clinical Short Course, 2nd edition, McGraw Hill. p. 231-255.
Lecture: Dr. Neal R. Chamberlain
Burstein GR, Zenilman JM. Nongonococcal urethritis--a new paradigm. Clin Infect Dis 1999 Jan;28 Suppl 1:S66-73
CDC. The national plan to eliminate syphilis from the United States. Atlanta, Georgia: US Department of Health and Human Services, CDC, National Center for HIV, STD, and TB Prevention, 1999:1--84.
Sexually Transmitted Disease Guidelines 2006.( http://www.cdc.gov/std/treatment/)
Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2006: Fluoroquinolones No Longer Recommended for Treatment of Gonococcal Infections. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5614a3.htm
Management of male patients who have urethritis - Urethritis is an infection characterized by urethral discharge of mucopurulent or purulent material and sometimes by dysuria or urethral pruritus. The patient will have dysuria without increases in urinary urgency or frequency helping to differentiate these infections from cystitis. Asymptomatic infections are common. The most common pathogens in men with urethritis are Neisseria gonorrhoeae and Chlamydia trachomatis. Testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are conditions that are reportable to state health departments. If diagnostic tools (e.g., Gram stain and microscope) are unavailable, patients should be treated for both infections. The additional antibiotic exposure and expense of treating a person who has nongonococcal urethritis (NGU) for both infections should encourage the health-care provider to make a specific diagnosis. Nucleic acid amplification tests (NAAT) enable detection of N gonorrhoeae and C trachomatis on all specimens. These tests are more sensitive than traditional culture techniques for C trachomatis and are the preferred method for the detection of this organism. Gonococcal urethritis, chlamydial urethritis, and nongoncoccal, nonchlamydial urethritis may facilitate HIV transmission.
Confirming a Case of Urethritis- Urethritis can be documented on the basis of any of the following signs.
Mucopurulent or purulent discharge.
Gram stain of urethral secretions demonstrating >5 WBC’s per oil immersion field. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis. It is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of leukocytes containing intracellular Gram-negative diplococci.
Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine demonstrating >10 WBCs per high power field.
Empiric treatment of symptoms without documentation of urethritis is recommended only for patients at high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated for gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated.
Management of female patients who have mucopurulent cervicitis (MPC) - MPC is a purulent or mucopurulent endocervical exudate visible in the endocervical canal or in an endocervical swab specimen. Some specialists also diagnose MPC on the basis of easily induced cervical bleeding. MPC is frequently asymptomatic however, some women have an abnormal vaginal discharge and vaginal bleeding (e.g., after sexual intercourse). MPC is usually caused by C trachomatis or N gonorrhoeae; however, in many cases neither organism can be isolated. MPC can persist despite repeated courses of antimicrobial therapy. Because relapse or reinfection with C trachomatis or N gonorrhoeae usually does not occur in persons with persistent cases of MPC, other non-microbiologic determinants (e.g., inflammation in the zone of ectopy) might be involved. Patients who have MPC should be tested for C trachomatis and for N gonorrhoeae with the most sensitive and specific test available. However, MPC is not a sensitive predictor of infection with these organisms; most women who have C trachomatis or N gonorrhoeae do not have MPC.
Urethral syndrome/dysuria in females- infections of the cervix and vagina (vaginitis- mentioned later) can spread to the urethral opening and into the urethra causing dysuria (external dysuria). Contrast this with “internal dysuria” which is an infection of the urinary bladder and the urethra (discussed above). Oftentimes, the patient with cystitis will also have urgency and increases in urinary frequency. Urgency and increases in urinary frequency are less common in patients with urethritis/urethral syndrome or “external dysuria”. Taken together these findings, internal vs. external dysuria and the presence or lack of urgency/frequency, can help the clinician differentiate cystitis from urethritis/urethral syndrome.
This section of the handout will cover the following diseases- gonorrhea, nongonorrheal urethritis (NGU) and chlamydial infections.
Gonorrhea is a sexually transmitted disease involving infection of columnar and transitional epithelium by Neisseria gonorrhoeae. N gonorrhoeae is a small gram-negative diplococcus which has flattened surfaces between the adjacent individual cocci (i.e., kidney-bean or coffee-bean shaped). These organisms are fragile and fastidious organisms; this is important for three reasons. One, they are not transmitted by fomites because they die rapidly in the outside environment. Two, conventional cotton swabs contain fatty acids which inhibit growth of the organisms and require sampling with other types of swabs (i.e., calcium alginate). Three, to grow the organisms requires a rich medium that contains antibiotics to inhibit overgrowth of the normal flora (i.e., Thayer Martin medium- chocolate agar containing vancomycin, colistin and nystatin or New York City medium- a translucent medium containing vancomycin, colistin, nystatin, and trimethoprim). N gonorrhoeae does not grow on blood plates.
Gonococcal infection in heterosexual men usually involves only the urethra. It causes approximately 1/3 of all cases of urethritis in U.S. Males with gonorrhea present with a profuse purulent urethral discharge and dysuria. Following an incubation period of 2-7 days, symptoms include inflammation and erythema around the opening of the urethra, a purulent urethral discharge and dysuria. Symptomatic men usually seek treatment so the disease does not usually progress. Some men remain asymptomatic, or they ignore early manifestations and are more likely to develop complications that include inguinal lymphadenitis, urethral stricture, local abscess formation and inflammation of neighboring structures (i.e., epididymitis, prostatitis) or disseminated gonococcemia with skin lesions.
In homosexual men, infection involves the urethra, anal canal, and pharynx. Anorectal infection is manifested by rectal pain and mucopurulent rectal discharge. Pharyngeal infection is important as a cause of sore throat due to pharyngitis, tonsillitis and gingivitis. It is also a principal origin of gonococcemia (see below for signs and symptoms of gonococcemia).
In females’ gonorrhea is asymptomatic approximately 30% of the time. Many other cases present with only vague, nonspecific symptoms so women oftentimes do not seek treatment. The usual site of infection is the cervix, and this is manifested by signs of regional inflammation (i.e., cervicitis). Infection of the cervix frequently leads to contiguous spread along mucous membranes to the urethral opening and rectum resulting in anorectal infection manifested by pain, purulent discharges, and rectal bleeding, urethral infection manifested by purulent exudates, dysuria and/or bartholinitis.
About 10-20% of cervical infections result in pelvic inflammatory disease (PID) due to upward spread of the bacteria resulting in endometritis, salpingitis, tuboovarian abscesses, pelvic peritonitis, and other local complications. PID will be discussed later in this handout. The Fitz-Hugh-Curtis syndrome is associated with PID and is a form of perihepatitis resulting from direct inoculation of gonococci on the surface of the liver.
Disseminated gonococcal infections occur in about 1-3% of cases and typically these patients are asymptomatic relative to urogenital or pharyngeal infection. Manifestations include low grade fever, migratory polyarthralgia involving the large joints and septic arthritis, increased pain and swelling, purulent synovial fluids, joint destruction, tenosynovitis, and petechial skin lesions.
Gonorrhea in children and infants- During childbirth, gonococci can infect the conjunctiva, pharynx, respiratory tract and gastrointestinal tract of the body. Conjunctival infections (i.e., ophthalmia neonatorum) can rapidly cause irreversible damage to the eye resulting in blindness. The most severe manifestations of N gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, including arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and inflammation at sites of fetal monitoring.
Humans are the only known host and infection is almost always via sexual contact.
There are about 300,000-500,000 reported cases/year in the U.S. However since a number of these infections are asymptomatic or not reported it is estimated that there are 600,000 total cases/year in the U.S.
The national rate of reported gonorrhea cases reached an historic low in 2009, but increased each year during 2009–2012. After a temporary decrease in 2013, the gonorrhea rate increased again in 2014.
This increase in 2014 was largely attributable to an increase among men. High gonorrhea rates persist in certain geographic areas, among adolescents and young adults, and in some racial/ ethnic groups.
The risk of contracting gonorrhea via heterosexual vaginal intercourse is 50% for women and about 20% for men following a single exposure.
The pathogenesis of gonorrhea is related to the ability of gonococci to attach to columnar epithelial cells and then cause these cells to transcytose the bacteria to the basolateral surface of the epithelial cells. Once on the basolateral surface of the epithelial cell these bacteria induce a strong phagocytic cell influx.
Pili and LOS bind to the columnar epithelial cells lining the urethra and cervix. The opacity associated proteins (Opa) also bind to the columnar epithelial cells and then cause the cytoskeleton of the cell to engulf the bacteria bound to the surface of the host cell. Opa proteins can also cause the bacterial cell to be transported from the apical surface of the columnar epithelial cell to the basolateral surface of the cell.
Once transported to the basolateral side of the columnar epithelial cells the bacteria induce an intense inflammatory response. Many PMN’s come to the site of the infection and attempt to phagocytize the bacteria. N gonorrhoeae produces extracellular secretory IgA proteases that clip the Fc portion of the IgA molecules off but allows the Fab portions to remain bound to the bacterial cell surface. Thus, decorating the bacteria with host protein and preventing opsonization by phagocytes. Those bacteria that are phagocytized by the PMN’s are protected from intracellular killing by the bacterial PorB protein. PorB prevents the fusion of the lysosome with the phagosome and allows the bacteria to, for a time, survive in the PMN.
Those bacteria not phagocytized need to acquire iron to survive. Most of the iron in the submucosa is chelated by host proteins. Iron is acquired by the bacteria through their use of a hemoglobin receptor, heme uptake protein, and a transferrin-binding protein. The ability to resist the killing by complement in the serum is important to the N gonorrhoeae once they arrive at the basolateral side of the columnar epithelial cells and if they gain entry into the bloodstream. A bacterial enzyme then sialylates LOS and allows binding of factor H a host inhibitor of complement activation and gives the bacteria resistance to the killing effects of human serum. LOS is also an important activator of host inflammatory cytokines (e.g., interleukin 1, tumor necrosis factor) that cause much of the damage seen in patients with gonococcemia (e.g., hemorrhagic skin lesions, arthritis).
Evaluate the patient’s presenting signs and symptoms and their sexual history. Sample the affected area with swabs (not cotton swabs). In males depending on the site affected throat, rectal or urethral swab samples can be obtained. In females depending on the site affected throat, rectal, urethral and/or endocervical swab samples can be obtained.
Culture the exudates obtained using the swabs for N gonorrhoeae. Specimens should be plated on selective media (Thayer Martin medium and/or New York City medium) or evaluated by nucleic acid amplification techniques (NAAT).
Gram stained urethral smears from males can give a rapid presumptive diagnosis of gonorrhea. Swab samples should also be sent for culture for N gonorrhoeae or NAAT for N gonorrhoeae to get a definitive diagnosis.
Urethral swabs containing exudates are smeared on glass slides, stained by Gram stain and then viewed. Three results are possible. The smear is positive for gonorrhea if gram-negative diplococci are seen within PMN’s. The smear is questionable if only extracellular Gram-negative diplococci are seen. The smear is negative if no gram-negative diplococci are seen.
However, gram stained urethral smears from females are NOT recommended because of the large number of organisms present around the urethral opening from the vaginal mucosa. In females, urethral swabs should be sent for culture for N gonorrhoeae or NAAT testing for N gonorrhoeae to get a definitive diagnosis.
Treatment and Prevention
Many strains of this bacterium are resistant to penicillin (PPNG- penicillinase producing N gonorrhoeae) therefore injectable cephalosporins are now commonly used to treat this infection. The drugs of choice for uncomplicated cases of cervicitis, pharyngitis, urethritis, and proctitis are: a single intramuscular dose of ceftriaxone plus a single dose of azithromycin orally.
Disseminated infections (i.e., bacteremias, meningitis, endocarditis, septic arthritis) require a parenteral antibiotic treatment with ceftriaxone until 24-48 hours after improvement begins. Then oral treatment with cefixime can be given for at least one week.
Ophthalmia neonatorum can be treated with ceftriaxone. Routine prophylaxis with 1% AgNO4 or 0.5% erythromycin or 1% tetracycline applied directly to the eye following birth prevents ophthalmia neonatorum.
Preventing spread to others rests on better education, proper reporting, follow-up of patients and their contacts, use of condoms, and chemoprophylaxis to prevent neonatal gonococcal conjunctivitis. Culturing pregnant women for gonorrheal infection before delivery and treating those that are infected can prevent gonorrheal infections of the newborn.
NONGONOCOCCAL URETHRITIS (NGU)
NGU is the most frequent cause of urethritis in heterosexual men. Forty-five percent of patients with gonorrheal urethritis also have NGU. NGU is diagnosed if gram-negative intracellular diplococci cannot be identified on urethral smears.
The etiology of most cases of NGU is not known however, Chlamydia trachomatis serovars D-K is a frequent cause (15%--55% of cases). The prevalence differs by age group, with fewer infections associated with this organism among older men. The number of NGU cases caused by Chlamydia has been gradually decreasing.
A number of other organisms can cause NGU and they include Ureaplasma urealyticum, Mycoplasma genitalium, Trichomonas vaginalis, Gardnerella vaginalis, Herpes Simplex virus and other as yet unknown organisms.
The patient usually has a history of urethral discharge, pain on urination and itch in the meatal region, or a history of a genital infection in a male or female partner. The discharge is a clear serous discharge rather than the purulent discharge seen in gonorrhea.
Urethral inflammation may be diagnosed by the presence of one of the following criteria;
a visible abnormal urethral discharge (a clear serous (mucopurulent) rather than a purulent discharge),
a positive leukocyte esterase test from a male aged less than 60 years who does not have a history of kidney disease or bladder infection, prostate enlargement, urogenital anatomic anomaly, or recent urinary tract instrumentation,
or microscopic evidence of urethritis (greater than or equal to 5 white blood cells per high-power field) on a gram stain of a urethral smear.
Complications of NGU among men infected with C trachomatis include epididymitis and Reiter's syndrome (reactive arthritis). Reactive arthritis consists of conjunctivitis, urethritis, arthritis and psoriasis-like mucocutaneous lesions. Skin lesions can occur on the palms and hands. Initially the lesions are papules with a yellow center that may produce keratoderma blenorrhagicum or circinate balanitis (painless).
Accurate data on the overall incidence of NGU is presently not available.
Men between the ages of 15 and 30, with multiple sex partners, are most at risk.
In the U.S. it is likely that well in excess of 50% of the cases of urethritis are nongonococcal.
In over 50% of the cases of NGU no etiologic agent is found.
The incidence of NGU is highly dependent on the population being served. Gonococcal urethritis is more common in the inner city and in homosexual populations. However, in heterosexual populations such on college campuses and in suburban or rural populations up to 80-90% of the urethritis is nongonococcal.
NGU is unusual in monogamous relationships. Most cases occur if the male or his partner has had one or more new partners in the preceding months.
NGU is spread almost exclusively through sexual contact involving penis to vagina or penis to rectum contact.
Diagnosis requires demonstration of a PMN response and exclusion of an N gonorrhoeae infection. No evidence of N gonorrhoeae infection by culture, gram stain of a smear of the discharge, or antigen or nucleic acid detection. Urethritis should be documented. Urethritis can be documented on the basis of any of the following signs; mucopurulent (NGU) or purulent (gonorrhea) discharge, gram stain of urethral secretions demonstrating ≥5 WBCs per oil immersion field, positive leukocyte esterase test on first-void urine, or microscopic examination of first-void urine demonstrating ≥10 WBCs per high power field. The gram stain is the preferred rapid diagnostic test for evaluating urethritis. It is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection.
Treatment and Prevention
Patients with NGU due to Chlamydia trachoma, Ureaplasma urealyticum, or Mycoplasma genitalium can be treated with doxycycline or azithromycin. Patients should be advised to return to their physician if symptoms persist or recur. All sex partners should be examined for STI’s and promptly treated. If NGU is persistent or recurrent look for untreated or noncompliant sex partners. If the sex partners have been treated and complain check for less common causes of urethritis. Mycoplasma genitalium and Ureaplasma urealyticum infections resistant to doxycycline can be treated with moxifloxacin. Trichomonas vaginalis infections should be treated with metronidazole or tinidazole plus azithromycin.
In the U.S., chlamydial genital infection is the most frequently reported notifiable infectious disease.
The cause of this infection is Chlamydia trachomatis. Eight oculogenital serovars D-K are the cause of these sexually transmitted infections. Three serovars D, E, and F are the most common ones causing genital infections in the U.S.
Asymptomatic infection is common among both men and women. Symptomatic females are rare and have mucopurulent cervicitis (MPC) and or urethritis. Symptomatic and asymptomatic female patients with a chlamydial infection can, if not treated, develop several severe sequelae. These sequelae include pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. Adolescent and young women are more likely to develop PID. Some women who have apparently uncomplicated cervical infection already have subclinical upper-reproductive--tract infection. Screening and treatment of cervical infection can reduce the likelihood of PID due to chlamydial infections.
Symptomatic males usually have urethritis (NGU mentioned above). Epididymitis is rare.
Complications of C trachomatis include Reiter's syndrome (reactive arthritis). Reactive arthritis consists of conjunctivitis, urethritis (or in females’ cervicitis), arthritis and psoriasis-like mucocutaneous lesions. Skin lesions can occur on the palms and hands. Initially the lesions are papules with a yellow center that may produce keratoderma blenorrhagicum and in males a painless circinate balanitis.
Chlamydia continues to be the most commonly reported nationally notifiable disease with 1,441,789 cases reported in 2014.
During 2013–2014, rates of reported chlamydia increased 2.8% overall, but decreased 4.2% among females aged 15–19 years.
Unfortunately, both test positivity and the number of reported cases of C. trachomatis infections remain high among most age groups, racial/ethnic groups, geographic areas, and both sexes.
Racial differences also persist; reported case rates and prevalence estimates among blacks continue to be substantially higher than among other racial/ethnic groups.
Sensitive and specific methods used to diagnose chlamydial infections include both tissue culture and nonculture tests. C trachomatis urogenital infections can be diagnosed in women by testing urine or swab specimens collected from the endocervix or vagina. Diagnosis of urethral infection in men can be performed by testing a urethral swab or urine specimen. Rectal infections in persons that engage in receptive anal intercourse can be diagnosed by testing a rectal swab specimen. Culture, direct immunofluorescence, enzyme immunoadsorbent assay (EIA), nucleic acid hybridization tests, and nucleic acid amplification tests (NAATs) are available for the detection of C trachomatis. NAATs are the most sensitive tests for these specimens and can be used with urine. NAAT and nucleic acid hybridization tests can also be used for detection of C trachomatis using rectal swab specimens.
Treatment and Prevention
Patients with this bacterial infection can be treated with doxycycline or azithromycin. Treating infected patients prevents transmission to sex partners. In addition, treatment of chlamydia in pregnant women usually prevents transmission of C trachomatis to infants during birth. Treatment of sex partners helps to prevent reinfection of the index patient and infection of other partners.
Sexually active adolescent women should be screened for chlamydial infection at least annually, even if symptoms are not present. Annual screening of all sexually active women aged 20--25 years is also recommended, as is screening of older women with risk factors (e.g., those who have a new sex partner and those with multiple sex partners). Screening and treatment of women positive for chlamydial infection has lowered the incidence of infections with this organism in the communities that have instituted annual screening programs. Annual screening of males has not yet been shown to lower the incidence of chlamydial infections. However, screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STI clinics).
CHLAMYDIAL INFECTIONS AMONG INFANTS
Prenatal screening of pregnant women can prevent C trachomatis infection among neonates. Pregnant women aged <25 years are at high risk for infection.
C trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix. Neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C trachomatis from mother to infant. However, ocular prophylaxis with those agents does prevent gonococcal ophthalmia.
Initial C trachomatis perinatal infection involves mucous membranes of the eye, oropharynx, urogenital tract, and rectum. C trachomatis infection in neonates is most often recognized by conjunctivitis that develops 5-12 days after birth. A chlamydial etiology should be considered for all infants aged <30 days who have conjunctivitis. C trachomatis is the most frequent identifiable infectious cause of ophthalmia neonatorum.
C trachomatis is also a common cause of subacute, afebrile pneumonia with onset from 1-3 months of age. Characteristic signs of chlamydial pneumonia in infants include a repetitive staccato cough with tachypnea and hyperinflation and bilateral diffuse infiltrates on a chest radiograph. Wheezing is rare, and infants are typically afebrile. Peripheral eosinophilia (>400 cells/mm3) occurs frequently. Asymptomatic infections can occur in the oropharynx, genital tract, and rectum of neonates.
Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., direct fluorescent antibody tests, enzyme immunoassays, and nucleic acid amplification tests). Specimens must contain conjunctival cells, not exudate alone. Specimens for culture isolation and nonculture tests should be obtained from the everted eyelid using a dacron-tipped swab. Ocular exudate from infants being evaluated for chlamydial conjunctivitis should also be tested for N gonorrhoeae.
Specimens for chlamydial testing of neonatal pneumonia should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (e.g., EIA, direct fluorescent antibody [DFA], and nucleic acid amplification [NAATs]) can be used, however these tests of nasopharyngeal specimens produce are not as specific or sensitive as culturing ocular specimens. Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C trachomatis. Because of the delay in obtaining test results for chlamydia, the decision to include an agent in the antibiotic regimen that is active against C trachomatis must frequently be based on clinical and radiological findings.
Treatment and Prevention
Erythromycin is the antibiotic of choice for treating both the conjunctivitis and pneumonia. Topical antibiotic therapy alone is inadequate for treatment of chlamydial eye infections and is not needed when systemic treatment is given. A specific diagnosis of C trachomatis infection confirms the need for treatment not only for the neonate, but also for the mother and her sex partner(s).
Test pregnant women for chlamydial infection (as described above) and treat those that are infected with azithromycin or amoxicillin. Also test their sexual partners and treat those that are infected to prevent reinfection. Test the pregnant patient again 3 weeks after completion of treatment to ensure they no are longer infected.
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