SEXUALLY TRANSMITTED INFECTIONS (STI) II

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, 3rd Edition. depends on the organism.

F.S. Southwick, Infectious Diseases in 30 Days, 1^st edition, McGraw Hill. p. 289-318.

Lecture: Dr. Neal R. Chamberlain

References: 

1. Burstein GR, Zenilman JM. Nongonococcal urethritis--a new paradigm. Clin Infect Dis 1999 Jan;28 Suppl 1:S66-73
2. Hoeprich, PD., MC. Jordan, and AR. Ronald. Infectious Diseases: A Treatise of Infectious Processes. 5th edition. 1994. J.B. Lippincott Company, Philadelphia, PA.
3. 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.
4. Primary and Secondary Syphilis --- United States, 1999. MMWR. 50(01);113-117.
5. Sexually Transmitted Disease Guidelines 2002. Recommendations and Reports
   May 10, 2002/Vol. 51/No.RR-6 (http://www.cdc.gov/std/treatment/TOC2002TG.htm)
6. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2002 Supplement, Chlamydia Prevalence Monitoring Project. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, October 2003.

Diseases Characterized by Urethritis and Cervicitis

Management of Male Patients Who Have Urethritis

Urethritis is caused by an infection characterized by urethral discharge of mucopurulent or purulent material and sometimes by dysuria or urethral pruritis. Asymptomatic infections are common. 

The most common pathogens in men who have urethritis are N. gonorrhoeae and C. 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., a 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 also should encourage the health-care provider to make a specific diagnosis. Nucleic acid amplification tests 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 WBCs 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 WBCs 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 Patients Who Have Mucopurulent Cervicitis (MPC)

MPC is characterized by 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 often is asymptomatic, but some women have an abnormal vaginal discharge and vaginal bleeding (e.g., after sexual intercourse). 

MPC can be caused by C. trachomatis or N. gonorrhoeae; however, in most 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.

This handout will cover the following diseases.

1.      Gonorrhea

2.      Nongonorrheal urethritis (NGU)

3.   Chlamydial infections 

1. Gonorrhea

I. Gonorrhea is a sexually transmitted disease involving infection of columnar and transitional epithelium by Neisseria gonorrhoeae.

A. Important characteristics of N. gonorrhoeae:

1. Gonococci are small Gram-diplococci which characteristically have flattened surfaces between the adjacent individual cocci.
2. Major virulence mechanisms:
• Pili are small hair-like protein projections from the cell which are important as adherence structures.
• Production of an IgAase.
• Ability to scavenge iron.
• LPS is important.
3. Gonococci are very fragile and fastidious organisms; this is important for three reasons:
• They are not transmitted by fomites because they die rapidly in the outside environment.
• You should use calcium alginate swabs to collect clinical samples because unsaturated fatty acids present in regular cotton swabs will inhibit gonococci.
• Gonococci are usually isolated on Thayer Martin medium (chocolate agar with added Vancomycin, Colistin and Nystatin) or New York City medium (a translucent selective medium containing V, C, N, and trimethoprim).
4. Gonococci generally have little tendency to develop resistance to antibiotics but the emergence of plasmid-directed penicillinase-producing N. gonorrhoeae stains is an important exception; we refer to these as PPNG.

1. Man is the only known host and infection is almost always via sexual contact.
2. 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..
3. The risk of contracting gonorrhea via conventional intercourse is 50% for women and about 20% for men following a single exposure.

1. 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 profuse purulent urethral discharge and associated dysuria.
• Following an incubation period of 2-7 days, symptoms include:
1.  inflammation and erythema around the opening of the urethra
2.  a very purulent urethral discharge
3.  dysuria or painful urination
• Symptomatic men generally seek treatment so the disease does not progress; some men remain asymptomatic, however, or they ignore early manifestations and thus are open to further complications including:
1. inguinal lymphadenitis
2. urethral stricture
3. local abscess formation and inflammation of neighboring structures (epididymitis, prostatitis)
4. disseminated gonococcemia (skin lesions)
2. In homosexual men, infection involves the urethra, anal canal, and pharynx.
• Anorectal infection is manifested by:
1. rectal pain
2. mucopurulent rectal discharge
• Pharyngeal infection is important as a cause of sore throat due to pharyngitis, tonsillitis and/or gingivitis; also it is the principal origin of gonococcemia.
3. In females gonorrhea is completely asymptomatic approximately 30% of the time; many other cases present with only vague, nonspecific symptoms so the women do not seek treatment.
• The usual site of infection is the cervix, and this is manifested by signs of regional inflammation (cervicitis; image 1 and image 2).
• Infection of the cervix frequently leads to contiguous spread along mucous membranes to the urethral and anal areas resulting in:
• anorectal infection manifested by pain, purulent discharges, and rectal bleeding
• urethral infection manifested by purulent exudates, dysuria and increased frequency
• bartholinitis
• About 10-20% of cervical infections result in gonococcal pelvic inflammatory disease (PID) due to upward spread of the bacteria resulting in endometritis, salpingitis, tubovarian abscesses; image 1 and image 2, pelvic peritonitis and other local complications. PID will be discussed later.
• The Fitz-Hugh-Curtis syndrome is a form of perihepatitis resulting from direct inoculation of gonococci on the surface of the liver.
4. Disseminated gonococcal infections result in about 1-3% of cases and typically these patients are asymptomatic relative to urogenital and/or pharyngeal infection; manifestations include:
• Low grade fever
• Migratory polyarthralgias involving the large joints; septic arthritis
• Increased pain and swelling
• Purulent synovial fluids
• Joint destruction
• Tenosynovitis
• Skin rashes
5. Gonorrhea in children and infants
• During childbirth, gonococci infect the conjunctivitis, pharynx, respiratory tract and gastrointestinal tract of the body.
• Routine prophylaxis with 1% AgNO₄ or 0.5% erythromycin or 1% tetracycline applied directly to the eye following birth prevents ophthalmia neonatorum.

The pathogenesis of gonorrhea is related to the ability of gonococci to attach to mucosal cells via their pili, then penetrate to submucosal areas to induce a strong PMN cell influx.

E. Diagnosis

Diagnosis of gonorrhea involves a three-fold approach including:

1. evaluation of the presenting symptoms and sexual history;
2. gram stain of urethral exudates; and
3. culturing for N. gonorrhoeae.
• Specimens are taken with calcium alginate swabs.
• Specimens are plated on selective media (Thayer Martin medium and/or New York City medium).
4. Nucleic acid amplification techniques

1. It is positive for gonorrhea if Gm(-) diplococci are seen within PMNs.
2. It is questionable if only extracellular Gram(-) diplococci are seen.
3. It is negative if no Gram(-) diplococci are seen.

The drugs of choice for uncomplicated cases of cervicitis, pharyngitis, urethritis, and proctitis are: 

Cefixime 400 mg orally in a single dose,
     OR
Ceftriaxone 125 mg IM in a single dose,
     OR
Ciprofloxacin 500 mg orally in a single dose,
     OR
Ofloxacin 400 mg orally in a single dose,
     OR
Levofloxacin 250 mg orally in a single dose,
     PLUS,
IF CHLAMYDIAL INFECTION IS NOT RULED OUT
Azithromycin 1 g orally in a single dose
      OR
Doxycycline 100 mg orally twice a day for 7 days.

Disseminated infections (bacteremias, meningitis, endocarditis, septic arthritis) require parenteral antibiotic (Ceftriaxone 1 g IM or IV every 24 hours.).

Pharyngeal infections 

Ceftriaxone 125 mg IM in a single dose
     OR
Ciprofloxacin 500 mg orally in a single dose
     PLUS,
IF CHLAMYDIAL INFECTION IS NOT RULED OUT
Azithromycin 1 g orally in a single dose
     OR
Doxycycline 100 mg orally twice daily for 7 days.

Opthalmia neonatorum

Ceftriaxone 25--50 mg/kg IV or IM in a single dose, not to exceed 125 mg.

G. Prevention

1. Vaccines, most of which are composed of gonococcal pili, were not protective.

2. Control rests on better education, proper reporting, follow-up of patients and their contacts, use of condoms, and chemoprophylaxis to prevent neonatal gonoccocal conjunctivitis (opthalmia neonatorum (Silver nitrate (1%) aqueous solution in a single application, OR Erythromycin (0.5%) ophthalmic ointment in a single application, OR Tetracycline ophthalmic ointment (1%) in a single application).

2. Nongonococcal urethritis (NGU)

Nongonococcal urethritis (NGU) is the most frequent cause of urethritis in heterosexual men. 45% of the cases of gonorrhea also have NGU. NGU is diagnosed if Gram-negative intracellular diplococci cannot be identified on urethral smears. C. trachomatis is a frequent cause (i.e., 15%--55% of cases); however, the prevalence differs by age group, with lower prevalence of this organism among older men. The proportion of NGU cases caused by chlamydia has been declining gradually. Complications of NGU among men infected with C. trachomatis include epididymitis and Reiter's syndrome. 

A number of other organisms can cause NGU and they include:

1. Ureaplasma urealyticum
2. Mycoplasma genitalium
3. Trichomonas vaginalis
4. Herpes Simplex virus
5. and other as yet unknown organisms.

A. Important characteristics of the known cause of NGU

1. C. trachomatis types D-K is an obligate intracellular bacteria which requires tissue culture to grow in the laboratory. 
2. U. urealyticum is a prokaryote that lacks a cell wall and can be cultured in the lab. However, this organism is often seen in normal individuals and culturing the organism has questionable value in diagnosing NGU.
3. Mycoplasma genitalium is a bacterium lacking a cell well. This organism is also oftentimes seen in normal individuals and culturing the organism has questionable value.
4. G. vaginalis is a rod shaped gram variable bacteria which more commonly causes vaginitis but can on occasion cause NGU in males.
5. T. vaginalis is a eukaryotic parasite. 

1. Accurate data on the overall incidence of NGU is presently not available.
2. Men between the ages of 15 and 30, with multiple sex partners, are most at risk.
3. In the U.S. it is very likely that well in excess of 50% of the cases of urethritis are nongonococcal.
4. In up to 50% of the cases of NGU no etiologic agent is found.
5. The incidence of NGU is highly dependent on the population being served. In the inner city and in the homosexual population primarily you will see gonococcal urethritis. However, in primarily heterosexual populations such as Student Health Services or private practices up to 80-90% of the urethritis is nongonococcal.
6. NGU is very unusual in monogamous relationships. Most cases occur if the male or his partner has had one or more new partners in the preceding months.
7. NGU is spread almost exclusively through sexual contact involving penis to vagina or penis to rectum contact.

C. Symptoms and Signs

Urethral inflammation that is not the result of infection with Neisseria gonorrhoeae. Urethral inflammation may be
diagnosed by the presence of one of the following criteria (1996 case definition):

1. A visible abnormal urethral discharge,
2. or 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
3. 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

D. Diagnosis

No evidence of N. gonorrhoeae infection by culture, Gram stain, or antigen or nucleic acid detection. 

1.  Diagnosis requires demonstration of a PMN response and exclusion of N. gonorrhoeae.
2. The optimal time to evaluate the patient is in the morning prior to voiding, however examination 4 or more hours after the last urination is a useful compromise. The whole genital region should be examined for lesions and rashes. The inguinal lymph nodes should be palpated. Collect the first voided urine.
3. Specimens from the urethra should be obtained using a endourethral swab (calcium alginate swabs are best in that fatty acids present in cotton swabs are lethal to N. gonorrhoeae and C. trachomatis). The swab is then used to culture for the organisms and followed by preparation of a gram stain or methylene blue stained slide. PMN can be counted and the presence of intracellular diplococci can be seen if the infection is gonococcal. Five fields are scanned and a mean of greater than 4 PMN indicates urethritis.
4. The first 10 to 15 mls of the first voided urine can also be used to look for PMNs. Centrifuge the PMN and examine the sediment for PMNs. The presence of 10 or more PMNs in one or more fields appears to be the best cutoff.
5. Culture of the various organisms is appropriate in all cases except NGU caused by U. urealyticum. Many times this organism is seen in normal individuals and culturing U. urealyticum is of little value.
6. C. trachomatis requires tissue culture because it is an obligate intracellular pathogen. One looks for inclusion bodies using specific antisera in the tissue culture cell. Serology is not particularly useful in sexually active patients, however, serology in patients experiencing their first episode of urethritis is useful.
7. A modified Diamond media is useful for T. vaginalis. Laboratory diagnosis for the other causes of NGU is rarely done.

E. Treatment

1. Azithromycin 1 g orally in a single dose
        OR
   Doxycycline 100 mg orally twice a day for 7 days.
2. Patients should be advised to return if symptoms persist or recur.
3. All sex partners should be examined for STD and promptly treated.
4. Persistent or recurrent NGU. Look for untreated or noncompliant sex partners. If the sex partners have been treated and complain check for less common causes of urethritis.

3. Chlamydial Infections

In the United States, chlamydial genital infection occurs frequently among sexually active adolescents and young adults. In 2002, 834,555 chlamydial infections were reported to the CDC. The reported rate of infection is 455.5 per 100,000. The state specific median rate of 15- to 24 year old females positive for chlamydial infection was 7.5 percent in 2002 (range: 1.5 to 14.4 percent).  

Asymptomatic infection is common among both men and women. Symptomatic males usually have urethritis (mucopurulent; serous rather than purulent discharge- NGU). Epididymitis is rare. Symptomatic females are rare and may have mucopurulent cervicitis (MPC).

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). 

Chlamydial Infections in Adolescents and Adults

Several important sequelae can result from Chlamydia trachomatis infection in women; the most serious of these 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. A recent investigation of patients in a health maintenance organization demonstrated that screening and treatment of cervical infection can reduce the likelihood of PID.

Diagnosis

Sensitive and specific methods used to diagnose chlamydial infections include both tissue culture and nonculture tests (e.g., direct fluorescent antibody tests, enzyme immunoassays, and nucleic acid amplification tests).

Treatment

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.

Azithromycin 1 g orally in a single dose
     OR
Doxycycline 100 mg orally twice a day for 7 days.

Chlamydial Infections Among Infants

Prenatal screening of pregnant women can prevent Chlamydia 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. The prevalence of C. trachomatis infection among pregnant women does not vary by race/ethnicity or socioeconomic status. 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 and therefore should be continued.

Manifestations

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. Chlamydia is the most frequent identifiable infectious cause of ophthalmia neonatorum. 

C. trachomatis also is a common cause of subacute, afebrile pneumonia with onset from 1--3 months of age. 

Asymptomatic infections also can occur in the oropharynx, genital tract, and rectum of neonates.

Opthalmia Neonatorum Caused by C. trachomatis

A chlamydial etiology should be considered for all infants aged <30 days who have conjunctivitis.

Diagnosis

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 or the swab specified by the manufacturer's test kit. 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). Ocular exudate from infants being evaluated for chlamydial conjunctivitis should also be tested for N. gonorrhoeae.

Therapy

Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into four doses daily for 14 days. Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection and is unnecessary when systemic treatment is administered.

Infant Pneumonia Caused by C. trachomatis

Characteristic signs of chlamydial pneumonia in infants include a) a repetitive staccato cough with tachypnea and b) hyperinflation and bilateral diffuse infiltrates on a chest radiograph. Wheezing is rare, and infants are typically afebrile. Peripheral eosinophilia sometimes occurs in infants who have chlamydial pneumonia. Because clinical presentations differ, initial treatment and diagnostic tests should include C. trachomatis for all infants aged 1--3 months who possibly have pneumonia.

Diagnosis

Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (e.g., EIA, direct flourescent antibody [DFA], and nucleic acid amplification [NAATs]) can be used, although nonculture tests of nasopharyngeal specimens produce lower sensitivity and specificity than nonculture tests of 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

Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into four doses daily for 14 days.