SEXUALLY TRANSMITTED DISEASES (STD)

General Goal: To know the major cause(s) of these diseases, how they are transmitted, and the major manifestations of the diseases.

Specific Educational Objectives: The student should be able to:

1. identify the common cause of each of the STD's discussed in this handout and the next two STD handouts. Know the common or pathognomonic signs of the diseases.

2. describe the major manifestations of each disease and differentiate it from other diseases in the course.

2. use serology in diagnosing syphilis. You should be familiar with the pathogenesis of syphilis. You do not have to know all the information in the handout about neurosyphilis.

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)

OVERVIEW

It is important to understand at least five key points about all STD's in this country today:

1. STD's affect men and women of all backgrounds and economic levels. They are most prevalent among teenagers and young adults. Nearly two-thirds of all STD's occur in people younger than 25 years of age.

2. The incidence of STD's is rising, in part because in the last few decades, young people have become sexually active earlier yet are marrying later. In addition, divorce is more common. The net result is that sexually active people are more likely to have multiple sex partners and are more likely to acquire STD's.

3. Usually STD's cause no symptoms. This is especially true in women. If symptoms develop, they may be confused with those of other diseases not transmitted through sexual contact. Even when an STD causes no symptoms a person who is infected may be able to pass the disease on to a sex partner (ex. genital herpes, HIV).

4. Health problems caused by STD's tend to be more severe and more frequent for women than for men. This is because of the increased frequency of asymptomatic infections. As a result many women do not seek care until serious problems develop.

• Some STD's can spread into the uterus and fallopian tubes to cause pelvic inflammatory disease (PID), which in turn is the major cause of  both involuntary infertility and ectopic (tubal) pregnancy.
• STD's in women also may be associated with cervical cancer (e.g. Papillomavirus infections).
• STD's can be passed from a mother to her baby before, during, or immediately after birth. Some of these infections of the newborn can be cured easily (ex. opthalmia neonatorium), but others may cause a baby to be permanently disabled (ex. congenital syphilis or CMV) or even die (e.g. Herpes Simplex virus, HIV).

STD Prevention

The prevention and control of STDs is based on the following five major concepts: 

1. education and counseling of persons at risk on ways to adopt safer sexual behavior; 

2. identification of asymptomatically infected persons and of symptomatic persons unlikely to seek diagnostic and treatment services;

3. effective diagnosis and treatment of infected persons; 

4. evaluation, treatment, and counseling of sex partners of persons who are infected with an STD; and 

5. preexposure vaccination of persons at risk for vaccine-preventable STDs (Hep A and B)

Prevention of STDs begins with changing the sexual behaviors that place persons at risk for infection. Since STD control activities reduce the likelihood of transmission to sex partners, treatment of infected persons constitutes primary prevention of spread within the community.

Sexual Transmission

The most reliable way to avoid transmission of STDs is to abstain from sexual intercourse (i.e., oral, vaginal, or anal sex) or to be in a long-term, mutually monogamous relationship with an uninfected partner. Counseling that encourages abstinence from sexual intercourse is essential for patients who are being treated for an STD or whose partners are undergoing treatment and for persons who wish to avoid the possible consequences of sexual intercourse (e.g., STD/HIV and unintended pregnancy).

If two people wish to become sexually active the following can lower the chances a person will acquire a STD.

• Test both partners for STDs, including HIV, before initiating sexual intercourse.
• If a person chooses to have sexual intercourse with a partner whose infection status is unknown or who is infected with HIV or another STD, a new condom should be used for each act of insertive intercourse.

Preexposure Vaccination

Preexposure vaccination is one of the most effective methods for preventing transmission of Hepatitis A and B infections. Hepatitis B virus infection frequently is sexually transmitted, hepatitis B vaccination is recommended for all unvaccinated persons being evaluated for an STD. In addition, hepatitis A vaccine is currently licensed and is recommended for men who have sex with men (MSM) and illegal drug users (both injection and non-injection).

Prevention Methods

Male Condom

When condoms are used consistently and correctly, they are effective in preventing the sexual transmission of HIV infection and can reduce the risk for other STDs (i.e., gonorrhea, chlamydia, and trichomoniasis). Since, condoms do not cover all exposed areas, they are more effective in preventing infections transmitted by fluids from mucosal surfaces (e.g., gonorrhea, chlamydia, trichomoniasis, and HIV) than in preventing those transmitted by skin-to-skin contact (e.g., herpes simplex virus [HSV], HPV, syphilis, and chancroid).

Female Condoms

Laboratory studies indicate that the female condom is an effective mechanical barrier to viruses, including HIV. If used consistently and correctly, the female condom may substantially reduce the risk for STDs. When a male condom cannot be used properly, sex partners should consider using a female condom.

Vaginal Spermicides, Sponges, and Diaphragms

Recent evidence has indicated that vaginal spermicides containing nonoxynol-9 (N-9) are not effective in preventing cervical gonorrhea, chlamydia, or HIV infection. Frequent use of spermicides containing N-9 has resulted in genital lesions, which may be associated with an increased risk of HIV transmission. Spermicides alone are not recommended for STD/HIV prevention.

The vaginal contraceptive sponge appears to protect against cervical gonorrhea and chlamydia, but its use increases the risk for candidiasis. Diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis. Neither vaginal sponges nor diaphragms should be relied on to protect women against HIV infection. Diaphragm and spermicides have been associated with an increased risk of bacterial urinary tract infection in women.

Condoms and N-9 Vaginal Spermicides

Condoms lubricated with spermicides are no more effective than other lubricated condoms in protecting against the transmission of HIV and other STDs.

Rectal Use of N-9 Spermicides

Recent studies have demonstrated that N-9 may increase the risk of HIV transmission during vaginal intercourse. Although similar studies have not been conducted among men who use N-9 spermicide during anal intercourse with other men, N-9 can damage the cells lining the rectum, thus providing a portal of entry for HIV and other sexually transmissible agents. Therefore, N-9 should not be used as a microbicide or lubricant during anal intercourse.

Nonbarrier Contraception, Surgical Sterilization, and Hysterectomy

Women who are not at risk for pregnancy might incorrectly perceive themselves to be at no risk for STDs, including HIV infection. Contraceptive methods that are not mechanical or chemical barriers offer no protection against HIV or other STDs.

The STD's will be divided into 5 different groups based on their clinical presentations:

1. Diseases Characterized by Genital Ulcers

2. Diseases Characterized by Urethritis and Cervicitis

3. Diseases Characterized by Vaginal Discharge

4. Other STD's

   • Pelvic inflammatory Disease

   • Genital Warts (Human Papillomavirus Infections)

   • Epididymitis

   • Proctitis, Proctocolitis, and Enteritis

5. Ectoparasitic Infections

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.(45th week of 2000 there have been 293,917 cases). However since a number of these infections are asymptomatic or not reported it is estimated that there are 1-2 x 10⁶ 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).

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, defotaxime or ceftizoxime).

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.

II. Pelvic inflammatory disease (PID) is a disease of women defined as the clinical syndrome resulting from the ascending spread of microorganisms from the vagina and endocervix to the endometrium, the fallopian tubes and/or to contiguous structures.

PID is caused by more than one organism. May include endometritis, salpingitis, tuba-ovarian abscess, and pelvic peritonitis.

A. Etiology

1. N. gonorrhoeae most common
2. C. trachomatis most common- there are 4-8 million chlamydial infections per year in the U.S. (number includes men and women; week 45 of 2000 there have been 561,649 reported cases. not all cases result in PID.)
3. Anaerobic bacteria (ex. Bacteroides)
4. Facultative Gram negative rods (ex. E. coli)
5. Mycoplasma hominis
6. Actinomyces israelii (often seen in women with long-standing intrauterine devices (IUD).

The exact events taking place are as yet unclear, however, it is believed that:

• prior infections of the fallopian tubes (usually of N. gonorrhoeae or C. trachomatis) take place resulting in damage to the ciliary cells lining the fallopian tubes;
• another infection ensues and the organisms are able to ascend the fallopian tubes and cause infections in contiguous structures.

1. The morbidity produced by PID is greater than that of any other serious infection. In the U.S. about 850,000 women, requiring more than 212,000 hospital admissions and 115,000 surgical procedures are reported each year.

2. Risk factors include:

• Multiple sex partners
• History of previous PID
• Menstruation.
• IUD use (oral contraceptives however decrease the risk)
• Marital status (single women are at higher risk)
• Asymptomatic gonococcal infection in either sexual partner.

1. Moderate fever (generally above 99°F)
2. Bilateral lower abdominal pain that is maximal in the region of the fallopian tubes and generally lasts no longer than 14 days.
3. Increased vaginal discharge
4. Irregular bleeding
5. Tenderness on cervical motion
6. Tender adnexal mass(es)
7. Purulent endocervical discharge
8. Nausea and vomiting

E. Sequelae

1. The most common cause of involuntary infertility in women.
2. Dissemination to liver resulting in a perihepatitis.
3. Fitz-Hugh-Curtis syndrome; "Violin Strings" form between the abdominal wall and liver capsule (may occur in both gonococcal and nongonococcal types of PID).
4. Unilateral or bilateral ovarian abscesses (image 2).
5. Tubal occlusion, scarring, and adhesions (the adhesions can result in chronic abdominal pain).
6. Death due to rupture of the ovarian abscesses.

1. Definitive Dx consists of direct visualization of inflamed fallopian tube(s) on laparoscopy, laparotomy, or biopsy evidence of salpingitis (laparoscopic image of salpingitis)(sonograph of salpingitis). Only a confirmed culture of a biopsy of the fallopian tube positively identifies the etiology of salpingitis.
2. A presumptive Dx can be made on clinical grounds alone.

1. Positive culture for N. gonorrhoeae or C. trachomatis from the cul-de-sac or endocervix.   PCR tests are available.
2. Positive Gram stain for intracellular gonococci from the cul-de-sac or endocervix.
3. Elevated white blood cell count.
4. Elevated erythrocyte sedimentation rate.
5. A "recent recommendation" is to check sexually active adolescent females twice a year for C. trachomatis. This is due to the high prevalence (29%) of infection with this organism.

1. Can be treated on an outpatient basis only if their temperature is <38^oC, WBC <11,000/mm³, there is minimal evidence of peritonitis, active bowel sounds, and they are able to tolerate oral nourishment and treatment.
2. Hospitalize the patient if:
• the patient fails the first set of tests in item number 1
• the Dx is uncertain
• surgical emergencies such as appendicitis and ectopic pregnancy must be excluded
• a pelvic abscess is suspected
• severe illness precludes outpatient management e. the patient is pregnant
• the patient is unable to follow or tolerate outpatient regimen
• the clinical follow-up after 48-72 hours of starting antibiotics cannot be arranged
3. Unfortunately, no single antibiotic will be active against all possible pathogens.
4. Hospitalized patients
• Parenteral Cefotetan or Cefoxitin AND doxycycline
• OR Clindamycin and gentamicin.
5. Ambulatory therapy:
• Ceftriaxone and doxycycline 14 days for both
• OR Ofloxicin and metronidazole 14 days for both

1. Close medical follow-up is essential in PID patients due to the higher failure rates of therapeutic regimens.
2. Evaluation of patient 2-3 days after start of therapy for symptomatic improvement, drug reactions, and compliance.
3. Repeat exam and endocervical and rectal cultures 4-7 days after completing therapy.
4. Confirmation of clinical resolution by repeating exam and endocervical culture 4-6 weeks after completing therapy.
5. Sex partners should be check for STD's.
6. Removal of IUD (this can take place during therapy).

Nongonococcal urethritis (NGU) is the most frequent cause of urethritis in heterosexual men. 45% of the cases of gonorrhea also have NGU. A number of organisms can cause NGU and they include:

1. Chlamydia trachomatis- most common
2. Ureaplasma urealyticum- most common
3. Gardnerella vaginalis
4. Trichomonas vaginalis
5. Herpes Simplex virus
6. 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. C. trachomatis and U. urealyticum are the major causes of NGU.
2. Mycoplasma genitalium
3. 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.
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 that will be discussed in more detail later on this week.

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 15 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. Doxycycline for at least 7 days OR Erythromycin for 7 days OR single treatment with a single 1 g dose of azithromycin.
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.