Sexually Transmitted Diseases (STDs) Chapter 72 PDF

Chapter 72: Sexually Transmitted Diseases Jeffery A. Goad, Karl M. Hess, Albert T. Bach Introduction Sexually transmitted diseases (STDs) are discussed in the earliest written records. However, only in the last several decades have the common STDs been differentiated from each other; unique STD syn...

Chapter 72: Sexually Transmitted Diseases Jeffery A. Goad, Karl M. Hess, Albert T. Bach Introduction Sexually transmitted diseases (STDs) are discussed in the earliest written records. However, only in the last several decades have the common STDs been differentiated from each other; unique STD syndromes continue to be described today. For example, of the common STDs, bacterial vaginosis (BV) was not described clearly as a syndrome (initially called Haemophilus vaginalis vaginitis) until the 1950s; herpes simplex virus (HSV) type 2 (the cause of genital herpes) was not differentiated from HSV type 1 until the 1960s; the spectrum of genital chlamydial infections was not defined until the 1970s; and the human immunodeficiency virus (HIV) as an STD was not recognized until the 1980s. Since 1980, eight additional sexually transmitted pathogens have been identified. They include the human papillomaviruses (HPV), human T-lymphotropic virus (HTLV-I and II), Mycoplasma genitalium, Mobiluncus species, HIV-1 and 2, and the human herpes virus type 8 (associated with Kaposi sarcoma).[] More recently, the Centers for Disease Control and Prevention (CDC) report while hepatitis C virus (HCV) infection is not efficiently transmitted through sexual contact, men who have sex with men (MSM) coinfected with HIV are more likely to transmit to HCV than through heterosexual contact.[] See http://www.cdc.gov/std/training/othertraining.htm for general resources from the Centers for Disease Control and Prevention for various sexually transmitted diseases. Gonorrhea Gonorrhea (see http://www.cdc.gov/std/training/-clinicalslides/slides-dl.htm for symptoms of this STD) is caused by Neisseria gonorrhoeae, a gram-negative diplococcus. Depending on the site of exposure, this disease can cause uncomplicated cervical, urethral, rectal, and oropharyngeal infections in both males and females. N. gonorrhoeae infection in women is also a major cause of pelvic inflammatory disease (PID). Disseminated gonococcal infection (DGI), the bactermic spread of N. gonorrhoeae to joints and other tissues, can lead to complicated gonorrhea infections that cause pustular acral skin lesions, tenosynovitis, polyarthralgia, or arthritis. DGI may lead to rare cases of perihepatitis, endocarditis, or meningitis. In the 1930s, sulfonamides became the first form of effective antimicrobial therapy for gonorrhea until penicillins and tetracyclines became the mainstays of therapy; however, the high levels of resistance to these two antimicrobial agents have eliminated their use in the treatment of this disease state. In the United States, the incidence of gonorrhea fell 74.3% between 1975 and 1997 after the establishment of national gonorrhea control programs. From 1996 to 2006, the rate fluctuated at around 115 cases per 100,000 individuals, and from 2006 to 2009, the rates declined to a historic low of 98.1 cases per 100,000 individuals in 2009.[],[] After slight rate increases each year from 2009, the national gonorrhea rate of 106.1 cases per 100,000 individuals in 2013 (representing a total of 333,004 cases) was a decrease from 107.5 in 2012.[] The current Healthy People 2020 goals for gonorrhea are 257 cases per 100,000 women aged 15 to 44 and 198 cases per 100,000 men aged 15 to 44 ().[] Although there was a decrease of 9.1% in gonorrhea rates among African Americans from 2009 to 2013, rates of gonorrhea remain the highest among African Americans compared to other race and ethnic groups. During this same time period, all other race and ethnic groups saw an increase in gonorrhea rates.[] The highest incidence of gonorrhea is in men aged 20 to 24 years and in women aged 15 to 24 years of age. Additional risk factors for women acquiring gonorrhea include a previous gonococcal or other STD infection, new or multiple sex partners, inconsistent condom use, or engaging in commercial sex work or drug use.[] Although the risk of gonorrhea was greater in homosexual men than in heterosexual men in the past, the incidence dropped in homosexual men during the 1980s AIDS epidemic, because of a reduction in sexual risk behaviors. Currently, the incidence of gonorrhea in MSM continues to rise, from 21.5% in 2006 to 35.1% in 2013.[] Uncomplicated Gonorrhea Transmission CASE 72-1 QUESTION 1: D.S., a 23-year-old male naval officer recently stationed in the Philippines, complains of dysuria, meatal pain, and a profuse yellow urethral discharge for 2 days. He admits to extramarital sex with a prostitute during the past week. He is accompanied by his pregnant wife, C.S., who is asymptomatic. D.S. engages in vaginal sex but there is no history of oral or anal sex with either partner. Assuming the prostitute has gonorrhea, what is the likelihood that D.S. and C.S. have been infected? After one or two episodes of unprotected vaginal intercourse with an asymptomatic infected prostitute, a man has approximately 50% risk of acquiring a urethral infection; the risk increases with repeated exposures and high prevalence among commercial sex workers.[] The prevalence of infection in women who are secondary sex contacts of infected men is as high as 80% to 90%.[] Therefore, the likelihood that D.S. and C.S. are infected is high. Because D.S. had sex with a prostitute, both D.S. and C.S. should also be tested for HIV infection. Signs and Symptoms: Males CASE 72-1, QUESTION 2: What signs and symptoms in D.S. are consistent with the diagnosis of gonorrhea? Describe D.S.’s anticipated clinical course if he remains untreated. In men, gonorrhea usually becomes clinically apparent 1 to 7 days after contact with an infected source. A purulent discharge associated with dysuria is the first sign of infection; D.S. exhibits both. The discharge, which is presumably caused by chemotactic factors such as C5a released when antigonococcal antibody binds complement, may become more profuse and blood tinged as the infection progresses. Some strains of gonorrhea have a propensity to cause asymptomatic or minimally symptomatic infection with negative Gram stain. Patients with asymptomatic or minimally symptomatic disease may serve as reservoirs for the infection, evading treatment for prolonged periods.[] At one time, only women were thought to have asymptomatic gonorrhea, but now it is known that men may be asymptomatic carriers as well.[] In the area before antimicrobials, gonococci occasionally spread to the epididymis, causing unilateral epididymitis; the prevalence was 5% or more in patients in some studies. Now epididymitis occurs in less than 1% of men with gonorrhea. Urethral stricture after repeated attacks and sterility after epididymitis are rare complications of gonococcal infection owing to the effectiveness of antibiotics. Diagnosis: Males CASE 72-1, QUESTION 3: Intracellular gram-negative diplococci were seen on the Gram stain of D.S.’s urethral exudate. Is any further diagnostic testing required? Demonstration of intracellular gram-negative diplococci in the gram-stained exudate confirms the diagnosis in symptomatic men. Until recently, some experts recommended that cultures be reserved for individuals with negative Gram stain of urethral exudate. However, today cultures are recommended for all patients to permit isolation and testing of the bacteria for antibiotic susceptibility. Cultures usually are performed on Thayer–Martin medium, an enriched chocolate agar to which vancomycin, colistimethate, and nystatin have been added. Cultures from the throat should be obtained if D.S. were exposed by cunnilingus to the prostitute. In D.S.’s case, a urethral culture is indicated. Signs and Symptoms: Females CASE 72-1, QUESTION 4: C.S., D.S.’s wife, is asymptomatic. What symptoms would be consistent with gonorrhea in C.S.? Do the symptoms differ because she is pregnant? What is the natural course of gonorrhea in women if left untreated? Urogenital gonococcal infections in women are commonly asymptomatic. Because the endocervical canal is the primary site of urogenital gonococcal infection in women, the most common symptom is vaginal discharge. Many women infected with gonorrhea have abnormalities of the cervix, including purulent or mucopurulent endocervical discharge, erythema, friability, and edema of the zone of ectopy.[] The incubation period for urogenital gonorrhea in women is variable.[] PID is a serious complication in 10% to 20% of women with acute gonococcal infection and can lead to infertility and chronic pelvic pain.[],[] The assessment of signs and symptoms in women with gonorrhea often is confounded by nonspecific signs and symptoms and a high prevalence of coexisting infection, especially with Chlamydia trachomatis or Trichomonas vaginalis. Although lower genital tract symptoms in women may disappear, they remain carriers of N. gonorrhoeae and should be treated. Complications of urogenital gonorrhea in pregnancy include spontaneous abortion, premature rupture of the fetal membranes, premature delivery, and acute chorioamnionitis.[],[],[] Other complications include gonococcal arthritis (see Case 72-4, Question 1) conjunctivitis, and ophthalmia neonatorum in the newborn.[] For these reasons, it is critical that C.S. be worked up thoroughly for gonorrhea. CASE 72-1, QUESTION 5: How should gonorrhea be ruled out in C.S.? Diagnosis: Females Nucleic acid amplification tests (NAATs), such as polymerase chain reaction, are recommended for the detection of N. gonorrhoeae at urogenital sites in men and women regardless if symptoms are present.[] Although NAATs are not FDA approved for the detection of N. gonorrhoeae at non-urogenital sites, laboratories should meet CLIA requirements and performance specifications for use with rectal and oropharyngeal specimens; NAATs are the recommended detection method for rectal and orophyaryngeal specimens. Although culture for N. gonorrhoeae is not ideal for routine diagnosis, cultures should be performed for isolation and identification, antibiotic susceptibility, and resistance surveillance. Cultures should also be performed in cases of suspected treatment failures, defined as those that have received CDC-recommended treatment and subsequently has a positive N. gonorrhoeae test result 7 days after treatment and did not engage in sexual activity during those 7 days.[] In C.S., a NAAT from anal specimen also could be performed because the rectum can serve as a reservoir for gonococci. Treatment CASE 72-1, QUESTION 6: Compare the various drug regimens used for uncomplicated gonorrhea. The CDC recommendations are summarized in. Many strains of N. gonorrhoeae exhibit plasmid-mediated resistance to penicillin and tetracycline (penicillinase-producing N. gonorrhoeae [PPNG] and/or tetracycline-resistant N. gonorrhoeae [TRNG], respectively (). In addition, significant levels of chromosomally mediated resistance to penicillin, tetracycline, and cefoxitin have been reported.[] In 2013, all isolates in the Gonococcal Isolate Surveillance Project (GISP) were susceptible to ceftriaxone; therefore, a single dose of intramuscular (IM) ceftriaxone 250 mg is preferred for the treatment of gonorrhea.[],[] Cefixime 400 mg orally (PO) as a single dose is no longer recommended as a first-line treatment by the CDC but as an alternative option when ceftriaxone cannot be used. Because of the emergence of high levels of quinolone-resistant N. gonorrhoeae (QRNG), the CDC no longer recommends the use of fluroquinolones, such as ciprofloxacin and ofloxacin, for the treatment of gonorrhea.[],[] Because a high percentage of patients with gonorrhea are also coinfected with C. trachomatis, a single dose of azithromycin is recommended to be taken concurrently for a presumed infection (see Case 72-1, Question 7).[],[] Table 72-1 CDC Recommendations for Treatment of Uncomplicated Gonorrhea Presentation Drugs of Choice (% Dosage Alternative Regimens Cured) Urethritis, cervicitis, Ceftriaxone (99.2) 250 mg IM Cephalosporin single dose rectala once regimensb Pharyngeala Ceftriaxone (98.9) 250 mg IM once aBecause a high percentage of patients with gonorrhea have coexisting Chlamydia trachomatis infections, many clinicians recommend treating all patients with gonorrhea with a single-dose azithromycin 1 g orally for treatment of Chlamydia. bAdditional cephalosporin regimens include cefixime 400 mg PO, ceftizoxime 500 mg IM, cefoxitin 2 g IM (administered with probenecid 1 g PO), and cefotaxime 500 mg IM. Adapted from Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137. Intramuscular spectinomycin, which traditionally had been used in individuals who could not tolerate fluoroquinolones or cephalosporins, is still unavailable from the manufacturer.[] Although limited data exists for treatment of gonorrhea in patients with cephalosporin or IgE-mediated penicillin allergy, potential alternative treatments are a single dose of gemifloxacin 320 mg PO plus azithromycin 2 g PO, or a single dose of gentamicin 240 mg intramuscularly plus azithromycin 2 g PO.[],[] Individuals who have either penicillin or cephalosporin allergies should be desensitized to cephalosporins before treatment begins.[] Ceftriaxone and Other Cephalosporins Ceftriaxone, a third-generation cephalosporin, is given as a single, small-volume IM injection that eradicates gonorrhea at all anatomic sites and is also safe in pregnancy (U.S. Food and Drug Administration [FDA] pregnancy category B). Ceftriaxone is ineffective against C. trachomatis and in the prevention of postgonococcal urethritis, whereas ofloxacin and levofloxacin for 7 days have similar efficacy to doxycycline.[] Other injectable cephalosporins (notably ceftizoxime, cefoxitin, and cefotaxime) have been found to be safe and highly effective, but they do not offer any advantage over ceftriaxone for urogenital infections, and their efficacy in pharyngeal infections is not as well-established. A single oral dose of cefixime 400 mg is also effective in curing 92.3% of uncomplicated urogenital and anorectal gonorrhea infections.[] However, in 2012, the CDC no longer recommended cefixime as a first-line regimen because of concerns about declining cefixime susceptibility among urethral N. gonorrhoeae isolates in the United States during 2006 to 2011.[] Other oral cephalosporins, such as cefpodoxime and cefuroxime, are not recommended because of inferior efficacy and less favorable pharmacodynamics; however, they are FDA approved to treat uncomplicated N. gonorrhoeae. Fluoroquinolones Fluoroquinolones have been routinely used since the 1990s for the treatment of gonorrhea; however, the GISP has continuously documented fluoroquinolone resistance in N. gonorrhoeae isolates, which has necessitated changes in the CDC Sexually Transmitted Disease treatment guidelines (). Because of this increased resistance, the CDC no longer recommends ciprofloxacin, levofloxacin, ofloxacin, or other fluoroquinolones for the treatment of gonorrhea. This recommendation also extends to the treatment of gonorrhea-associated conditions, such as PID.[],[] Prescribing Patterns The CDC’s 2013 Sexually Transmitted Disease Surveillance Program observed that 96.9% of treated patients received ceftriaxone 250 mg. The number of those treated with cefixime decreased from 5.3% in 2011 to 0.02% in 2013.[] This decrease in cefixime use was expected as CDC recommendations to avoid use of cefixime at any dose as first-line therapy was issued in 2012. Other most prescribed medications, followed in order by ceftriaxone, azithromycin, “other less frequently used drugs,” and cefixime (). Dual therapy with azithromycin or doxycycline was prescribed in 95.4% and 4% of those treated with ceftriaxone, respectively.[] CASE 72-1, QUESTION 7: How should D.S.’s urethritis be treated? Because C.S. is totally asymptomatic and the results of her cultures are pending, should she be treated empirically? If so, what drug(s) would you recommend? Because D.S. has gonococcal infection limited to the urethra (uncomplicated), a few treatment regimens are possible, as outlined in Case 72-1, Question 6. Ceftriaxone is the preferred treatment, with cefixime as an alternative, only if ceftriaxone is not available. Quinolones should be avoided because of increased resistance in N. gonorrhoeae and because D.S.’s infection was likely obtained in the Philippines, where quinolone resistance occurs in more than half of all isolates.[],[] Patients with gonorrhea may also be coinfected with Chlamydia and therefore presumptive cotreatment with azithromycin 1 g PO as a single dose could be initiated if coinfection is suspected.[],[] Although single-dose azithromycin 2 g monotherapy has been used to treat concurrent gonorrhea and Chlamydia, it is more expensive and poorly tolerated because of increased gastrointestinal (GI) side effects and may lead to macrolide-resistant N. gonorrhoeae, or treatment failure.[] Sexual Partners C.S. also should be treated even though she appears asymptomatic. All partners who have had sexual exposure to patients with gonorrhea within 60 days should be treated. If the patient has not been sexually active for 60 days, the most recent sexual partner should be treated. This is especially true when the partner is pregnant because gonorrhea during pregnancy is associated with chorioamnionitis and prematurity, as well as neonatal infection. Pregnant women can be treated safely with cephalosporins and azithromycin for gonorrhea and Chlamydia. Follow-Up CASE 72-1, QUESTION 8: How does one determine whether the drug therapy of gonorrhea has been effective in D.S. and C.S.? If recommended therapies are used for treatment of uncomplicated gonorrhea, a test-of-cure is not necessary for either C.S. or D.S. because cure rates are close to 100%.[] However, a test-of-cure should be done 14 days after treatment in those with pharyngeal infection treated with an alternative treatment regimen.[] If symptoms persist in D.S., who was treated with ceftriaxone, cultures should be done to determine antibiotic susceptibility, and to rule out other causes of urethritis. Antibiotic-Resistant Neisseria gonorrhoeae CASE 72-1, QUESTION 9: D.S. states that he was treated with penicillin in the past for a gonococcal infection. Why are penicillins not prescribed routinely today? Failure of penicillin to eradicate the gonococcus can be the result of plasmid (e.g., PPNG) or chromosomally mediated resistant Neisseria gonorrhea (CMRNG) antibiotic resistance. PPNG contain plasmids, which determine the production of lactamase, an enzyme that hydrolyzes the lactam ring of penicillin G or ampicillin. Chromosomally mediated resistance does not involve β-lactamase production and often is associated with increased resistance to other β-lactams. The clinical significance of CMRNG is questionable because serum levels of approved antibiotics are achieved far above the minimum inhibitory concentration, such that treatment failure is unlikely. However, to date, CMRNG remain largely susceptible to ceftriaxone. High-level tetracycline resistance is defined by gonococci that carry plasmid-encoded resistance to 16 g/mL or more of tetracycline. These strains are known as TRNG. Although not of major concern in the United States, development of resistance to alternative therapies is a continuing concern. The first cases of PPNG infection were reported in the United States in 1976. PPNG are especially prevalent in Southeast Asia, the Far East, and West Africa, where the prevalence often exceeds 50%. In the United States, the percent of PPNG strains reached a peak of about 11% in 1991; since then, cases have steadily declined to 0.4% in 2007, according to the CDC’s GISP ().[] Strains of TRNG were first identified in 1985, but fortunately most TRNG isolates still are sensitive to β-lactam antibiotics. The use of tetracycline was officially abandoned by the CDC in 1985 and penicillin was abandoned in 1987. In the late 1990s, the number of TRNG and PPNG plus TRNG cases plateaued at about 5% and 1%, respectively. Therefore, because approximately 21% of gonococcal isolates are resistant to tetracycline and/or penicillin within the United States, it is not acceptable to use these agents in the initial management of uncomplicated genital gonorrhea; IM ceftriaxone remains the drug of choice. Antibiotic susceptibility testing is recommended in cases of persistent infection after treatment. QRNG was first reported in 1990 and was reported to be 0.2% of isolates in the continental United States.[],[] In the 2013 GISP report, 11% of isolates from Honolulu, Hawaii, were QRNG, whereas among California sites, 31.8% to 44.4% of isolates were QRNG.[] N. gonorrhoeae resistance to quinolones has increased almost every year since reporting began in 1990 and has become widespread in the United States, resulting in the CDC recommending against using quinolones for the treatment of gonococcal or related conditions (e.g., PID) acquired in the United States.[],[] In 2013, 16.1% of all isolates collected by the GISP demonstrated resistance to ciprofloxacin.[] Resistance to fluoroquinolones is associated with mutations of GyrA and is commonly identified in strains that produce β-lactamase and strains exhibiting chromosomally mediated resistance to penicillin and tetracycline.[] N. gonorrhoeae strains may therefore exhibit decreased susceptibility or complete resistance to the recommended dose of quinolones, and the clinical importance of strains with decreased susceptibility is unknown.[] D.S. was likely infected with N. gonorrhoeae in the Philippines, and QRNG is highly likely; thus, an appropriate cephalosporin antibiotic such as IM ceftriaxone should be recommended. If he had been initially treated with ceftriaxone, the expectation would be that he would be free of gonococcal infection within 3 days. To date, ceftriaxone-resistant strains of N. gonorrhoeae have not been reported in the United States, but GISP data has documented decreased cefixime susceptibility among urethral N. gonorrhoeae isolates.[] Anorectal and Pharyngeal Gonorrhea Epidemiology CASE 72-2 QUESTION 1: M.B. is a 24-year-old, sexually active, homosexual man with a 2-month history of perianal itching, painful defecation, constipation, a bloody mucoid rectal discharge, and a sore throat. Sigmoidoscopy revealed rectal mucosal inflammation but no apparent ulcers or fissures. Stool examination for parasites was negative and a Venereal Disease Research Laboratory (VDRL) test was nonreactive. Both rectal and pharyngeal cultures revealed N. gonorrhoeae. How does gonorrhea in homosexual men compare with gonorrhea in heterosexual men? Rectal infection occurs rarely in strictly heterosexual men, whereas in the male homosexual population, anorectal (25%) and pharyngeal (10%–25%) gonococcal infections occur more often.[],[] Because pharyngeal[],[] and anorectal gonococcal infections are often asymptomatic, a large reservoir of carriers in the homosexual male population may exist and annually screening should be done if they have engaged in receptive oral or anal intercourse in the preceding year. By comparison, very few urethral gonococcal infections are asymptomatic. In addition, data indicate that pharyngeal infections may be an important source of urethral gonorrhea in homosexual men, spread by fellatio.[],[] Signs and Symptoms CASE 72-2, QUESTION 2: Are M.B.’s signs and symptoms consistent with gonorrhea? Rectal gonorrhea produces the syndrome of proctitis with anorectal pain, mucopurulent anorectal discharge, constipation, tenesmus, and anorectal bleeding. The differential diagnosis of proctitis in the homosexual male includes rectal infection with N. gonorrhoeae, C. trachomatis, HSV, and syphilis. Proctitis, limited to the distal rectum, should be differentiated from proctocolitis, which is often caused by Shigella species, Campylobacter species, or Entamoeba histolytica in homosexual men. The incidence of rectal gonorrhea and Chlamydia has risen dramatically since 1996.[] Rectal Chlamydia is often asymptomatic and observed more often than gonorrhea, necessitating testing for both pathogens.[] Although pharyngeal gonorrhea is often asymptomatic, a review of system and physical exam may reveal a sore throat, pharyngeal exudates, or cervical lymphadenitis. CASE 72-2, QUESTION 3: How should M.B.’s diagnosis be managed? Treatment The treatment of choice for patients such as M.B. with anorectal or pharyngeal gonorrhea is ceftriaxone 250 mg IM as a single dose ().[] Azithromycin should also be given to treat possible coexisting rectal chlamydial infection. Patients, such as M.B., with either anorectal or pharyngeal gonorrhea should be advised to avoid further unprotected sexual activity and should be counseled and tested for infection with HIV. CASE 72-2, QUESTION 4: What are the alternative regimens for patients with isolated anal or pharyngeal gonorrhea? Patients with anorectal gonorrhea alone should be treated with ceftriaxone. Oral cefixime is a recommended alternative, but it should not be used as a first-line agent. As with urogenital infections, alternative regimens for isolated anorectal infection include a single-dose cephalosporin regimen, such as ceftizoxime. Because spectinomycin is unavailable, patients with anorectal gonorrhea, who are allergic to penicillin or cephalosporins, should be desensitized before treatment is initiated. Patients with gonococcal infections of the pharynx should be treated with ceftriaxone; however, infections of this nature are more difficult to eradicate than infections at urogenital and anorectal sites. Treatment for gonorrheal infections at these sites should also be treated with azithromycin for presumptive Chlamydial coinfection.[] Prevention CASE 72-2, QUESTION 5: What measures have been used to prevent the sexual transmission of infection? Condoms, when used properly, seem to provide a high degree of protection against the acquisition and transmission of STDs.[],[] Previous studies indicated that the use of the spermicide nonoxynol-9 had activity against gonorrhea and Chlamydia; however, in light of recent evidence suggesting that nonoxynol-9 might actually increase the risk of acquiring HIV and other STDs, the FDA currently requires manufacturers of nonoxynol-9 products to include a warning statement on the product’s label that it does not protect against HIV or other STDs.[],[] Topical antibacterial agents, urinating, and washing after intercourse are of little value in preventing the transmission of STDs. Douching may increase the risk of other STDs, such as trichomoniasis.[] The prophylactic administration of antibiotics immediately before or soon after sexual intercourse is not recommended owing to increased costs and antimicrobial resistance. Use of rapid, specific tests and empiric symptomatic management enhances detection and treatment of gonorrhea. Pelvic Inflammatory Disease The term PID refers to a variety of inflammatory disorders of the upper female reproductive tract. This term does not denote the primary infection site (the fallopian tubes) nor the causative microorganisms. PID also has been used to connote an infection that occurs acutely when either vaginal or cervical micro-organisms traverse the sterile endometrium and ascend to the fallopian tubes. Acute salpingitis may also be used to describe an acute infection of the fallopian tubes. Therefore, the terms PID and salpingitis are used interchangeably in this discussion to denote an acute infection involving the fallopian tubes. PID affects approximately 1 million women annually in the United States.[] However, the National Disease and Therapeutic Index (NDTI) estimates that from 2002 to 2012, the number of initial visit to physicians for PID for women aged 15 to 44 decreased 39.8%.[] Many cases of acute PID occur by sexual transmission, especially in young women 16 to 24 years, who are more likely to have multiple sexual partners.[] Risk factors for the development of PID include unprotected sexual intercourse before age 15, douching, BV, sex while menstruating, and smoking.[] It is unclear whether an intrauterine device (IUD) increases the risk of PID, but it may be prudent to avoid placement when the patient has chlamydial or gonococcal cervicitis.[] Two-thirds of PID cases resulting in infertility are asymptomatic, and up to one-third are incorrectly diagnosed owing to low specificity of diagnostic techniques. In the United States, infertility occurs in about 12.1% of women after the first episode of PID.[] The estimated costs for treatment of PID and its sequelae exceeds $4.2 billion annually.[] Etiology Most cases of PID are caused by C. trachomatis and N. gonorrhoeae. Some microorganisms that make up the vaginal flora are also associated with PID, including Gardnerella vaginalis, H. influenzae, and Streptococcus agalactiae. Mycoplasma hominis, Ureaplasma urealyticum, M. genitalium, and cytomegalovirus (CMV) have also been associated with PID, but a causative role is unclear.[] Up to 70% of cases may be polymicrobial and include M. genitalium and BV.[] Facultative enteric gram-negative bacilli and a variety of anaerobic bacteria have also been isolated from the upper genital tract of up to 70% of women with acute PID.[] Women diagnosed with acute PID should be tested for C. trachomatis and N. gonorrhoeae using NAAT and screened for HIV.[] Signs and Symptoms The variations in presentation and nonspecific signs and symptoms of PID make it a complex disease to diagnosis. The onset of symptoms of abdominal pain attributable to PID caused by either gonococci or chlamydia often occurs soon after the menstrual period. Symptoms of PID, if present, are often nonspecific, which can create a delay in or failure of diagnosis. Vaginal discharge, menorrhagia, dysuria, and dyspareunia are commonly associated with PID. Pelvic examination findings include cervical motion tenderness, uterine tenderness, or adnexal tenderness. Temperatures greater than 101°F, abnormal cervical or vaginal mucopurulent discharge, white blood cells (WBC) on saline microscopy of vaginal secretions, elevated erythrocyte sedimentation rate, an elevated C-reactive protein, or laboratory documentation of cervical infection with N. gonorrhoeae or C. trachomatis support a diagnosis of PID.[] Clinical diagnosis has sensitivity for PID of about 65% to 90%, whereas laparoscopy and a newer technique, transvaginal Doppler ultrasound, are about 100% specific, resulting in the combination of laparoscopy and clinical impression serving as the gold standard.[],[],[] Unfortunately, laparoscopy and Doppler ultrasound are costly and often not readily available for acute cases and they are not diagnostic for endometritis; thus, clinical impression is critical. A key to reducing the incidence of PID may be through active screening of Chlamydia in young, sexually active women.[],[] Clinical Sequelae An abscess may form in the pelvic or abdominal cavity and in one or both fallopian tubes. Chronic abdominal pain develops in 18% of women with PID and may be the result of pelvic adhesions surrounding the tubes and ovaries. After a single episode of PID, tubal occlusion and fibrosis secondary to fallopian tube inflammation (salpingitis) result in 12% infertility, 25% infertility after two episodes, and 50% infertility after three or more episodes.[] Other sequelae include ectopic pregnancy (9%) and chronic pelvic pain (18%).[] The risk of ectopic pregnancy is increased approximately eightfold after one or more episodes of PID. Diagnosis and Treatment CASE 72-3 QUESTION 1: H.C., a 19-year-old, sexually active woman, complains of mild dysuria, a purulent vaginal discharge, fever, and moderately severe, bilateral, lower abdominal pain of 3 days duration. Examination confirms uterine and adnexal tenderness, a purulent cervical exudate, and a temperature of 39°C. Laboratory examinations show a nonreactive VDRL and negative urinalysis. A pregnancy test performed was negative. The peripheral WBC count was mildly elevated (11,000/mL) with 70% polymorphonuclear leukocytes. Does H.C. have PID? How should she be treated? Although fever and leukocytosis are often absent in mild or subacute PID, these findings in a woman with uterine and adnexal tenderness with cervical exudate increases the likelihood of acute PID. Recommended treatment regimens for PID are listed in and should be initiated immediately after diagnosis of PID to prevent clinical sequelae; confirmation of the actual pathogen rarely takes place. Patients such as H.C. with mild-to-moderate PID can be hospitalized and treated with parenteral antibiotics; however, clinical efficacy and overall outcomes are equal between parental and oral therapy, and H.C. could also be treated on an outpatient basis. For inpatient treatment, the CDC recommends either intravenous (IV) cefotetan 2 g every 12 hours or IV cefoxitin 2 g every 6 hours for at least 24 hours beyond the first signs of clinical improvement along with doxycycline 100 mg every 12 hours. Once clinical improvement is noted, parenteral therapy may be discontinued and PO doxycycline 100 mg every 12 hours can continue to complete 14 days of therapy. For outpatient treatment, the CDC guidelines recommend either IM ceftriaxone 250 mg as a single dose or IM cefoxitin 2 g as a single dose (with probenecid 1 g PO for one dose) plus PO doxycycline 100 mg twice a day for 14 days with or without PO metronidazole 500 mg twice daily for 14 days.[] A tetracycline derivative or an alternative agent that is active against C. trachomatis should be included in the treatment of PID; however, monotherapy with a tetracycline is not recommended because of the lack of activity against gram-negative aerobic and anaerobic organisms and N. gonorrhoeae. The addition of metronidazole, which covers anaerobic bacteria, should also be considered; anaerobes have been isolated from the upper reproductive tract of women with PID and may cause tubal and epithelial destruction.[],[] Metronidazole is widely used by clinicians, because BV is frequently associated with PID.[] Fluoroquinolones, such as levofloxacin and ofloxacin, are no longer recommended for the treatment of PID because of the increase in prevalence of QRNG in the United States.[] Table 72-2 Antimicrobial Regimens Recommended by the CDC for Treatment of Acute Pelvic Inflammatory Disease Treatment Setting, Advantage Disadvantage Clinical Drugs, Schedule Considerations Outpatient (Oral) Therapyc Regimen A Inpatient (Parenteral) Therapy Regimen A Cefotetan 2 g IV Optimal coverage of N. Possible suboptimal Penicillin-allergic every 12 hours OR gonorrhoeae (including anaerobic coverage patients may also cefoxitin 2 g IV every resistant strains) and C. be allergic to 6 hours PLUS trachomatis cephalosporins; doxycycline 100 mg doxycycline use IV or POa every 12 in pregnant hours Continue patients may doxycycline (100 mg cause reversible PO twice daily) after inhibition of discharge to complete skeletal growth in 14 days of therapy the fetus and discoloration of teeth in young children Regimen B Clindamycin 900 mg Optimal coverage of Possible suboptimal Patients with IV every 8 hours anaerobes and coverage of N. decreased renal PLUS gentamicin Gram-negative enteric gonorrhoeae and C. function may not loading dose IV or IM rods trachomatis be good (2 mg/kg) followed by candidates for a maintenance dose aminoglycoside of 1.5 mg/kg every 8 treatment or may hoursb need a dosage adjustment Alternative Regimen Ampicillin/sulbactam Optimal coverage of N. Inadequate coverage Not appropriate 3 g IV every 6 hours gonorrhoeae and C. of anaerobes in pregnancy or PLUS doxycycline trachomatis necessitates use of in young children 100 mg PO or IV metronidazole or every 12 hours ampicillin/sulbactam Ceftriaxone 250 mg Good to excellent Possible suboptimal Optimal IM in a single dose coverage of N. anaerobic coverage cephalosporin is PLUS doxycycline gonorrhoeae and optimal necessitating the unclear; more 100 mg PO twice coverage of C. addition of complicated daily for 14 days trachomatis metronidazole regimen requiring WITH or WITHOUT combination of metronidazole 500 parenteral and mg PO twice daily for oral therapies 14 days OR cefoxitin 2 g IM in a single dose and probenecid, 1 g PO administered concurrently in a single dose PLUS doxycycline 100 mg PO twice daily for 14 days WITH or WITHOUT metronidazole 500 mg PO twice daily for 14 days OR other parenteral third-generation cephalosporins (e.g., ceftizoxime or cefotaxime) PLUS doxycycline 100 mg PO twice daily for 14 days WITH or WITHOUT metronidazole 500 mg PO twice daily for 14 days aConsidering the oral bioavailability of doxycycline, PO therapy should be preferentially used over IV. bSingle daily dosing (3–5 mg/kg) may be substituted. cConsider for mild-to-moderate acute PID. Adapted from Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137. Both oral and IV doxycycline have similar bioavailability; therefore, doxycycline should be given PO whenever possible.[] Substantial clinical improvement is usually seen within 3 days after initiation of therapy. Clindamycin plus gentamicin can be used alternatively in penicillin-allergic and pregnant women.[] Because H.C. is sexually active, any sexual partners within the previous 60 days (or if >60 days, then the most recent sexual partner) should be empirically treated because of the risk of gonococcal or chlamydial urethritis as well as to reduce the risk of reinfection. Complicated Gonorrhea Disseminated Gonococcal Infection Signs and Symptoms CASE 72-4 QUESTION 1: S.P., a 28-year-old, sexually active woman, was seen for stiffness and pain of the right wrist and left ankle and fever (38°C). On physical examination, the knee and wrist joints were found to be hot, red, and swollen; papules and pustular lesions were observed on S.P.’s legs and forearms. A latex fixation test for rheumatoid factor was negative. A tap of the right knee yielded an effusion with a WBC count of 34,000/mL (80% polymorphonuclear leukocytes). Cultures of the skin lesions were negative, but N. gonorrhoeae was isolated from the throat, cervix, blood, and synovial fluid. A chest radiograph, echocardiogram, and electrocardiogram all were normal, and no murmur could be appreciated. Assess S.P.’s clinical presentation. S.P.’s signs, symptoms, and laboratory findings are consistent with gonococcal bacteremia, which today occurs in less than 1% of women and men with gonorrhea. The most common manifestation of gonococcemia is the gonococcal arthritis–dermatitis syndrome or DGI exhibited by S.P. Symptoms include fever, occasional chills, a mild tenosynovitis of the small joints, and skin lesions; the latter primarily involving the distal extremities are petechial, papular, pustular, and hemorrhagic in appearance.[] Diagnosis of DGI is made by NAAT or culture of specimen from routine sites of gonococcal infections (e.g., urethra, cervix, pharynx, and rectum), as well as culture from disseminated sites of infection (e.g., synovial fluid, blood, skin, and CNS). However, blood cultures are positive in only 33% of DGI cases, even when culture samples are obtained early in the course of the infection.[] The low positive yield from blood cultures may be attributable to the low inoculum or intermittent bacteremic period. Treatment CASE 72-4, QUESTION 2: How should S.P. be managed? How quickly will she respond to therapy? Patients like S.P. with gonococcal arthritis and bacteremia should be hospitalized for treatment with ceftriaxone 1 g IV or IM daily until substantial clinical improvement is sustained for 24 to 48 hours, at which time therapy may be switched to an oral agent guided by antimicrobial susceptibility for a total treatment course of at least 7 days ().[] Initiation of treatment should also include azithromycin 1 g PO in a single dose. Symptoms and signs of tenosynovitis should be improved markedly within 48 hours. Septic gonococcal arthritis with purulent synovial fluid may require repeated aspiration and resolves more slowly. Table 72-3 Treatment of Disseminated Gonococcal Infection No Penicillin Allergya Parenteral Recommendedb—Ceftriaxone 1 g IV or IM every 24 hours Alternativeb—Cefotaxime 1 g IV q8h or ceftizoxime 1 g IV every 8 hours Oralc Cefixime 400 mg PO twice daily aParenteral treatment should be continued for 24 to 48 hours beyond clinical improvement. bTreatment should include a single dose of Azithromycin 1 g PO. cTreat for 7 days after switching from parenteral therapy. Adapted from Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137. Treatment of Gonococcal Endocarditis and Meningitis CASE 72-4, QUESTION 3: How should gonococcal endocarditis and meningitis be treated? Gonococcal endocarditis and meningitis, occurring in only 1% to 3% of DGIs, require high-dose IV therapy, such as ceftriaxone (1–2 g IV every 12–24 hours), for 10 to 14 days in the case of meningitis and for at least 4 weeks in the case of endocarditis.[] Like other gonococcal infections, a single dose of azithromycin 1 g PO should be given. Neonatal Disseminated Gonococcal Infection: Treatment CASE 72-4, QUESTION 4: How should neonatal DGI and meningitis be managed? Neonatal DGI and meningitis can be treated with either ceftriaxone 25 to 50 mg/kg (IV or IM) daily or cefotaxime 25 mg/kg (IV or IM) every 12 hours. Treatment is for 7 days for DGI; however, meningitis requires 10 to 14 days of treatment.[] Although ceftriaxone is also effective in the treatment of neonatal DGI and meningitis, cefotaxime is considered a safer choice in the neonatal population. Chlamydia Trachomatis The rate of reported Chlamydia infections has climbed steadily each year since the 1980s, and it is the most commonly reported STD in the United States. During 1993 to 2012, the reported rate of chlamydial infections increased from 178 to 453.3 cases per 100,000 individuals.[] This increase may be attributable to the increased development and use of more sensitive screening tests, improved national reporting efforts, or a true increase in the incidence of disease.[] In 2013, the United States saw the rate of chlamydial infections decrease for the first time to 446.6 cases per 100,000.[] Women are 3 times more likely than men to be infected with Chlamydia—623.1 cases versus 262.6 cases per 100,000 individuals, respectively, in 2013. However, from 2009 to 2013, the infection rate among men increased 21% compared with 6.2% in women. The highest rate of infection is in women 15 to 19 years (3,043.3 cases per 100,000 females) and in men 20 to 24 years (1,325.6 cases per 100,000 males).[] If left untreated, chlamydial infection in women can lead to serious sequelae, such as PID, ectopic pregnancy, and infertility. Asymptomatic infection is also observed in both men and women; however, routine screening is recommended for sexually active women up to 25 years of age and older women with risk factors for infection (e.g., multiple sexual partners or having a new sexual partner). Screening sexually active men for C. trachomatis can be considered in settings or populations with a high prevalence of the infection (e.g., MSM populations).[] C. trachomatis, an intracellular obligate organism, can be diagnosed either by culture, direct immunofluorescence assay (DFA), enzyme immunoassay (EIA), or NAAT of endocervical or male urethral swabs.[] However, C. trachomatis is a difficult organism to demonstrate in clinical specimens because cell culture techniques are not readily available to the practitioner. Because few practitioners have access to facilities for isolation of C. trachomatis, most chlamydial infections are diagnosed and treated based on clinical impression and laboratory techniques. Nonculture diagnostic tests, such as NAATs, DFAs, and EIAs, are generally sensitive methods for detecting C. trachomatis. Ligase chain reaction and PCR are two NAATs with wide commercial availability, are relatively simple to use, can be performed using urine or genital swab specimens, and are more sensitive than non-NAATs.[] NAATs are approximately 20% to 35% more sensitive than EIAs and DFAs and are the recommended test method for detection of C. trachomatis in men and women with and without symptoms.[],[] A test-of-cure is not necessary unless patient compliance is questionable, symptoms persist, or reinfection is suspected. Repeat testing with NAATs fewer than 3 weeks after initiation of treatment is not recommended because false-negative results may occur as a result of undetectable C. trachomatis organisms. Moreover, false positives may occur with repeat NAATs with the continued excretion of dead organisms. A variety of clinical syndromes are caused by C. trachomatis, including cervicitis, urethritis, bartholinitis, endometritis, salpingitis, and perihepatitis in women, and urethritis, epididymitis, prostatitis, proctitis, and Reiter syndrome in men.[] The spectrum of chlamydial infections closely resembles those caused by the gonococcus, which is why many patients presenting with these syndromes are treated with drugs effective against both organisms. There is controversy in how C. trachomatis is cultured and what the in vitro results mean clinically, especially in the 10% to 15% of cases that fail treatment.[] The CDC thus uses cure rates instead of microbial susceptibilities to make treatment recommendations. Only azithromycin and doxycycline have 97% and 98% cure rates, respectively.[],[] Alternatives include erythromycin, ofloxacin, and levofloxacin. Other quinolones should not be used because they have not been evaluated adequately or are not reliably effective.[] Nongonococcal Urethritis Etiology CASE 72-5 QUESTION 1: T.K., a 26-year-old, sexually active man, complains of mild dysuria and a mucoid-like urethral discharge beginning 15 days after his last intercourse. He has no fever, lymphadenopathy, penile lesions, or hematuria. A Gram stain smear of an anterior urethral specimen showed 20 polymorphonuclear neutrophilic leukocytes (PMNs) per oil immersion (1,000) field and no gram-negative diplococci. What pathogens are associated with nongonococcal urethritis (NGU)? In the United States, NGU is the most common STD in men.[],[] C. trachomatis is a frequent cause of NGU, representing 15% to 40% of all cases. Other agents that have been associated with NGU include M. genitalium, T. vaginalis, HSV, and adenovirus; however, the cause for the majority of NGU cases is unknown.[] The variety of pathogens and disparity among identification techniques require sound clinical judgment and an algorithmic laboratory testing approach to accurately identify and treat the cause. A NAAT, if available, should be performed to rule out the presence of C. trachomatis and N. gonorrhoeae. Signs and Symptoms CASE 72-5, QUESTION 2: Describe the clinical presentation of a person with NGU. Is T.K.’s presentation consistent with NGU? How does one differentiate between NGU and gonococcal urethritis? T.K.’s presentation is typical. Compared with gonococcal urethritis, NGU typically produces less severe and less frequent dysuria and less penile discharge. Chlamydial urethral infection is completely asymptomatic more often than gonococcal urethral infection. The incubation period for gonococcal urethritis is 2 to 7 days, whereas the incubation period for NGU is typically 2 to 3 weeks. Nonetheless, NGU and gonococcal urethritis cannot be reliably differentiated solely on the basis of symptoms and signs. If there is objective evidence of a urethral discharge (expressed by milking the urethra), a Gram stain with ≥2 WBCs per oil immersion field in the urethral secretion, positive leukocyte esterase test demonstrating 10 WBCs per high-power field, the diagnosis of NGU is made by excluding the presence of N. gonorrhoeae by Gram stain and/or culture. Treatment CASE 72-5, QUESTION 3: How should T.K. be treated? If C. trachomatis cannot be ruled out, therapy with azithromycin 1 g PO for one dose or doxycycline 100 mg PO twice daily for 7 days should be ordered. Compared to doxycycline, M. genitalium responds better to azithromycin as doxycycline does not effectively eradicate M. genitalium.[] Azithromycin also has the advantage of a single-dose regimen, which may aid in patient compliance. Erythromycin base 500 mg PO 4 times a day or erythromycin ethylsuccinate 800 mg PO 4 times a day for 7 days are alternative CDC-approved regimens. Additionally, ofloxacin 300 mg PO twice daily or levofloxacin 500 mg PO every day for 7 days are other alternatives, but they offer no significant advantages compared with the previously mentioned agents, may not treat U. urealyticum adequately, and are significantly more expensive.[],[] Ciprofloxacin should be avoided because treatment failures have been reported.[] Patient counseling should emphasize the need for abstinence from sexual intercourse at least until the prescribed course of therapy has been completed (or 7 days after single-dose therapy) by the patient and his sexual partner(s).[] There is some indication that the proportion of NGU caused by C. trachomatis is declining, potentially being replaced by an increased proportion of U. urealyticum, which is variably cured at 2 weeks by azithromycin (73%) and doxycycline (65%).[] Recurrent Infection CASE 72-5, QUESTION 4: T.K. was treated with doxycycline 100 mg twice daily for 7 days. He remained asymptomatic for 14 days after completion of his therapy, when he again noticed similar symptoms of dysuria and a mucoid-like urethral discharge. How should T.K.’s recurrent infection be treated? The major problem encountered in the treatment of NGU is the high rate of recurrent infections. Men receiving treatment should follow-up if symptoms persist or recur after completion of therapy. Approximately 20% to 60% of patients experience recurrent or persistent urethritis within 1 to 2 weeks after treatment.[] The rate of recurrence is highest in patients with idiopathic urethritis, that is, those not infected with C. trachomatis or U. urealyticum. Recurrence suggests reexposure to an untreated partner, whereas persistent urethritis (without improvement during therapy) suggests the presence of other organisms, including M. genitalium, U. urealyticum, or T. vaginalis.[],[],[] NGU that persists or recurs should be retreated with the initial regimen if the patient was not compliant or the sexual partner was not treated. For patients with persistent symptoms, who were compliant with the initial regimen and were not reexposed, the CDC recommends using a single 1 g dose of azithromycin if not used for the initial episode, or moxifloxacin 400 mg PO daily for 7 days if the patient has failed azithromycin.[] Men with acute epididymitis often have chlamydial or gonococcal infection, particularly if they are younger than 35 years of age or have a urethral discharge. Escherichia coli and Pseudomonas species are common pathogens in homosexual men. In older men, sexually transmitted epididymitis is less common and is more commonly caused by urinary tract instrumentation, surgery, systemic disease, or immune suppression.[] If testicular tenderness is present with urethritis, and the clinical impression is consistent with epididymitis caused by Chlamydia or gonorrhea, the CDC recommend a single dose of ceftriaxone 250 mg IM plus doxycycline 100 mg PO twice for 10 days. For acute epididymitis caused by enteric organisms or with a negative gonococcal culture or NAAT, ofloxacin 300 mg PO twice daily or levofloxacin 500 mg PO once daily for 10 days may be used.[],[] In men who practice insertive anal sex, where the most likely cause of acute epididymitis is caused by Chlamydia, gonorrhea, and enteric organisms, the CDC recommends ceftriaxone 250 mg IM in a single dose plus levofloxacin 500 mg PO daily or ofloxacin 300 mg PO BID for 10 days.[] Sexual Partners CASE 72-5, QUESTION 5: A.C., T.K.’s girlfriend, comes into the clinic 3 weeks after T.K.’s last visit. She is worried that she may have a similar infection, although she has no signs or symptoms. What clinical manifestations of chlamydial infections are seen in women? Should A.C. be treated for suspected chlamydial infection? In the absence of cultures for Chlamydia, empirical treatment against chlamydia of women who are sexual partners of men with NGU is recommended. Many partners are asymptomatic but from 30% to 70% are culture positive if tested. A.C. should be examined carefully for mucopurulent cervicitis and salpingitis. Although many women with chlamydial infection of the cervix are asymptomatic, up to one-quarter have evidence of mucopurulent discharge.[] A Gram stain of appropriately collected mucopurulent endocervical discharge from patients with Chlamydia infection shows many PMNs and no gonococci. Regardless of findings, treatment should be initiated with the same azithromycin or doxycycline regimen used for NGU. However, if A.C. is pregnant, tetracyclines and fluoroquinolones should be avoided. Azithromycin 1 g PO as a single dose or amoxicillin 500 mg PO 3 times a day for 7 days could be used instead. Alternatively, either erythromycin base 500 mg PO 4 times a day for 7 days, erythromycin base 250 mg PO 4 times a day for 14 days, erythromycin ethylsuccinate 800 mg PO 4 times a day for 7 days, or erythromycin ethylsuccinate 400 mg PO 4 times a day for 14 days can be used.[] Erythromycin estolate should be avoided in pregnancy because of the increased risk of hepatotoxicity. Azithromycin is safe and effective during pregnancy.[],[] High rates of GI side effects limit the use of erythromycin. In pregnant women, a repeat NAAT is recommended 3 weeks after completion of therapy to ensure therapeutic cure.[] Coinfection with Chlamydia is common in heterosexual men and women with gonorrhea. Therefore, drug regimens effective against both organisms are recommended in patients with gonorrhea to prevent postgonococcal chlamydial morbidity (epididymitis, mucopurulent cervicitis, salpingitis) and to reduce the genital reservoir of C. trachomatis. Lymphogranuloma Venereum Etiology and Signs and Symptoms CASE 72-6 QUESTION 1: S.F., a 32-year-old male student who reports having sex with men, presents to the STD clinic with a chief complaint of pain and swelling in the groin. He reports the appearance of a small ulcer on his penis about 2 weeks ago, which resolved rapidly. On examination, he has a bubo (inflammatory swelling of one or more lymph nodes in the groin) with surrounding erythema on his right side. S.F. also has a fever (39°C). Laboratory findings are remarkable for a mild leukocytosis (WBC count, 12,000 cells/µL). What organisms are responsible for lymphogranuloma venereum (LGV)? Describe its clinical course. What subjective and objective manifestations in S.F. are consistent with LGV? LGV or Nicolas–Favre disease has historically been considered a rare disease in the United States and other developed nations; however, outbreaks have been recently reported in The Netherlands and Great Britain as well as in the United States in New York, Texas, and San Francisco.[],[] Since 2003, the number of cases of LGV, especially proctocolitis, in MSM in developed countries has been increasing.[],[] The cause of LGV is usually C. trachomatis serovars L1, L2, or L3, which are different from those serovars responsible for chlamydia urethritis.[] Three stages of LGV infection are recognized in heterosexual men.[] Stage I is characterized by a small genital papule or vesicle that appears between 3 and 30 days after exposure. The patient usually is asymptomatic; the ulcer heals rapidly and leaves no scar. This primary lesion is consistent with that reported by S.F. Many patients with LGV recall no primary lesion. Stage II is characterized by acute, painful lymphadenitis with bubo formation (the inguinal syndrome); it is often accompanied by pain and fever, as illustrated by S.F. Without treatment, the buboes may rupture, forming numerous sinus tracts that drain chronically. Adenopathy above and below the inguinal ligament results in the “groove sign.” Healing occurs slowly, and most patients suffer no serious sequelae. Patients in this stage may also present with an anogenitorectal syndrome, which is accompanied by proctocolitis and hyperplasia of intestinal and perirectal lymphatic tissue. Stage III is characterized by perirectal abscesses, rectovaginal fistulae (in women), rectal strictures, and genital elephantiasis.[] Appropriate treatment of stage II LGV usually prevents these late complications. An acute anorectal syndrome of LGV occurs in homosexual men who acquire the infection through rectal receptive intercourse. In these cases, a primary anal ulcer may be noted with associated inguinal adenopathy (anal lymphatics drain to inguinal nodes). Subsequently, acute hemorrhagic proctocolitis occurs with tenesmus, rectal pain, constipation, and a mucopurulent, bloody rectal discharge. Rectal biopsy may show granulomatous colitis, mimicking Crohn’s disease. Perirectal pelvic adenopathy also occurs. Treatment CASE 72-6, QUESTION 2: How should S.F. be treated? Current CDC recommendations for LGV include doxycycline 100 mg PO twice daily or erythromycin base 500 mg PO 4 times a day for 21 days.[] Surgical intervention may be needed for later forms of the disease. Azithromycin 1 g weekly for 3 weeks may be effective, as well as fluoroquinolones, but clinical data on its use are lacking.[] Syphilis Epidemiology Syphilis is caused by the spirochete, Treponema pallidum. The rates of primary and secondary syphilis in the United States increased in the late 1980s secondary to crack cocaine use (and associated unsafe sex practices), but from 1990 to 2000 the rates have decreased to those reported in 1941 when reporting began, representing a 89.7% decrease since 1990.[],[],[] However, the number of cases of primary and secondary syphilis have steadily risen since 2000, reaching a high of 17,375 cases in 2013.[] Another concern is that syphilis facilitates the transmission of HIV, and a high proportion of syphilis is reported in HIV-positive MSM.[],[] Since 2008, the rates of congenital syphilis have not increased until 2013, when 348 cases were reported to the CDC representing 8.7 cases per 100,000 individuals, a 0.3% increase from 2012 ().[] This increase was attributable to the increase in the rate of primary and secondary syphilis cases in the West among females during 2010 to 2013. The Healthy People 2020 (HP) goals for primary and secondary syphilis among women is 1.4 cases per 100,000 individuals and among men it is 6.8 cases per 100,000 individuals ().[] The clinical manifestations of syphilis have not changed appreciably since their first description. However, early diagnosis, treatment, and greater physician/patient awareness of the disease have reduced the incidence of its severe forms. Penicillin continues to be the mainstay of therapy. Clinical Stages CASE 72-7 QUESTION 1: D.M., a 27-year-old homosexual man, presents to the STD clinic with complaints of malaise, headache, and fever of 4 days’ duration. He also reveals that he had a sore on his penis about 8 weeks ago, but it has since resolved. Upon examination, he is afebrile and has a widespread maculopapular skin rash that involves the soles of his feet; general lymphadenopathy also is appreciated. Medical history is unremarkable except for one episode of gonorrhea 2 years ago that was treated with procaine penicillin. Laboratory findings include a normal peripheral WBC count, a negative serology for HIV antigen, and a positive rapid plasma reagin (RPR) test and fluorescent treponemal antibody absorption (FTA-ABS) test. Describe the clinical course of syphilis. Are D.M.’s symptoms consistent with this infection? Primary Stage The average incubation period for syphilis is 3 weeks and ranges from 10 to 90 days.[] During this incubation period, T. pallidum can be demonstrated in the lymph and blood. The primary chancre develops at the site of inoculation as a painless papule that becomes ulcerated and indurated. The ulcer is nontender and filled with spirochetes. The chancre usually involves the penis in the heterosexual male; the penis or anus in the homosexual male; and the vulva, perineum, or cervix in the female. Occasionally, the lip or tongue is involved. Regional lymph nodes are enlarged, firm, and nontender. Unfortunately, the typical chancre described earlier often is missed, particularly in women or homosexual men.[] Without treatment, the primary chancre resolves spontaneously, usually in 2 to 6 weeks. The differential diagnosis of genital ulcers also includes chancroid and genital herpes. Like chancroid, genital herpes produces painful, superficial, nonindurated ulcers with tender inguinal adenopathy. However, unlike chancroid, lesions of genital herpes characteristically proceed through a vesicular state and often are associated with urethritis, cervicitis, and constitutional symptoms, such as fever and chills. Syphilis can be differentiated from herpes by a nonpainful versus painful lesion, a papular versus vesicular appearance, and single versus multiple lesions. Chancroid is more difficult to differentiate from syphilis, although chancroid tends to have a more-tender lesion, jagged border, and striking inguinal lymphadenopathy.[] Secondary Stage Approximately 6 weeks after a chancre first appears, the untreated patient manifests signs and symptoms of the secondary stage of syphilis. This stage is currently evidenced by D.M. Skin lesions of secondary syphilis may erupt in a variety of patterns and are usually widespread in distribution. A macular lesion is often the earliest manifestation in this stage. The lesion is round or oval, occurs primarily on the trunk, and is rose or pink in color. As lesions mature, they become papular or nodular with scaling (the so-called papulosquamous rash). The differential diagnosis of diffuse papulosquamous rashes includes psoriasis, pityriasis rosea, and lichen planus. In syphilis, the palms and soles are characteristically involved, and oral lesions (mucous patches) may occur. Generalized lymphadenopathy usually is present, and patchy alopecia may be seen. The most infectious lesion of secondary syphilis is condyloma latum. Condylomata lata are characteristically wet, indurated lesions occurring primarily in the perineum or around the anus as a result of direct spread from the primary lesion. Laboratory studies sometimes reveal anemia, leukocytosis, or an increased erythrocyte sedimentation rate. Other manifestations of secondary syphilis include mild hepatitis, aseptic meningitis, uveitis, neuropathies, and glomerulonephritis.[] Latent Stage By definition, untreated, asymptomatic persons with serologic evidence for syphilis have latent syphilis. The latent stage is divided into two phases: the early latent (>1 year’s duration) and late latent (>1 year’s duration). In the Oslo study of patients with untreated syphilis, 25% experienced secondary relapses, usually within the first year.[] Patients who relapse to the secondary stage are infectious; those in the late latent stage are not infectious and are immune to reinfection with T. pallidum. Tertiary Stage Serious morbidity and mortality are caused by pathologic progresses involving the skin, bones, central nervous system, and cardiovascular system. Infectious granulomas (gummas), the characteristic lesions of tertiary syphilis, are observed infrequently. Most gummas respond quickly to specific therapy, although if critical organs are involved (heart, brain, liver), they can be fatal.[] The most common manifestations of syphilitic cardiovascular disease are aortic insufficiency and aortitis, with aneurysm of the ascending aorta. Neurosyphilis may be classified as asymptomatic early or late, meningeal, parenchymatous, or gummatous. Although neurosyphilis has been a rare complication for more than 40 years because of the widespread of use of penicillin, syphilitic meningitis, an early form of neurosyphilis, may be more common in HIV-positive patients.[],[] Late neurosyphilis may be asymptomatic or accompanied by a variety of manifestations; the most common syndromes are meningovascular syphilis, general paresis, tabes dorsalis (locomotor ataxia), and optic atrophy. In patients with asymptomatic neurosyphilis, examination of the cerebrospinal fluid (CSF) typically reveals mononuclear pleocytosis, an elevated protein concentration, and a positive VDRL reaction. Patients with asymptomatic neurosyphilis are at increased risk for experiencing neurologic disease. Meningovascular syphilis, accounting for almost 38% of all cases of neurosyphilis, typically begins abruptly with hemiparesis or hemiplegia, aphasia, or seizures.[] General paresis is characterized by extensive parenchymal damage and includes abnormalities associated with the mnemonic PARESIS (personality, affect, reflexes [hyperactive], eye [Argyll Robertson pupil], sensorium [hallucination, delusions, illusions], intellect [decreased recent memory, calculations, judgment], and speech). Tabes dorsalis occurs after demyelinization of the spinal cord. Symptoms observed include an ataxic, wide-based gait and foot slap; paresthesias; bladder irregularities; impotence; areflexia; and loss of position, deep pain, and temperature sensation. The Argyll Robertson pupil, seen in both paresis and tabes dorsalis, is a small, irregular pupil that reacts to accommodation but not to light. Laboratory Tests CASE 72-7, QUESTION 2: Evaluate D.M.’s laboratory findings. Dark-Field Examination Exudate expressed from the chancre or from condyloma latum is examined with a dark-field microscope. The diagnosis of syphilis is made if spirochetes with characteristic corkscrew morphology and mobility are present. Dark-field examination is the most specific and sensitive method but only with an experienced microscopist.[],[] Three dark-field examinations on consecutive days should be performed before considering the test negative in suspected primary syphilis. This technique and other methods, such as DFA and PCR, which detect T. pallidum directly from exudate or tissue are definitive diagnostic methods for syphilis. Serologic Tests Serologic tests become reactive during the primary stage, but they may be negative at the time of presentation with primary syphilis. When the history or examination suggests primary syphilis, a VDRL should be sent to the laboratory, or an RPR test should be performed in the clinic (see discussion on nontreponemal tests, next). If initial serology and dark-field examinations are negative, the serology should be repeated in 1 to 4 weeks to exclude primary syphilis. If the dark-field examination is positive, an RPR may still be ordered to establish a baseline for follow-up after treatment. Serologic tests are uniformly positive in secondary syphilis.[] Two types of tests are used for the serodiagnosis of syphilis: nontreponemal tests, which measure serum concentrations of reagin (antibody to cardiolipin), and treponemal tests, which detect the presence of antibodies specific for T. pallidum. Nontreponemal Tests Nontreponemal tests are not specific for T. pallidum but can be quantified. They are inexpensive and useful for screening large numbers of people. The most widely used nontreponemal tests are the VDRL test and the RPR Card Test. The RPR test is the most widely used because it is simpler to perform than the VDRL. Although they are equally valid assays, results of the VDRL and RPR are not interchangeable; thus, the same test should be used throughout the posttreatment monitoring period.[],[] The result reported in the quantitative VDRL test is the most dilute serum concentration with a positive reaction. This test may be used to follow the decline in VDRL titer after effective therapy (see Case 72-7, Question 5). In some individuals, a serofast reaction occurs in which nontreponemal antibodies may remain at a low titer for up to their entire lives. When false-positive tests occur, the titer usually is low (e.g., VDRL or RPR titer of 1:8).[] In secondary syphilis, sensitivity of the RPR and VDRL approach 100% owing to the high antibody concentrations.[] Treponemal Tests Specific treponemal tests, such as FTA-ABS, T. pallidum particle agglutination assay (TP-PA), and various EIAs, confirm a positive nontreponemal test. The FTA-ABS test is the most commonly used treponemal test. Because treponemal tests are relatively difficult and expensive to perform, they are not traditionally used for screening. Treatment CASE 72-7, QUESTION 3: How should D.M. be treated? The CDC recommends penicillin G for the treatment of all stages of syphilis ().[] Every effort should be made to rule out penicillin allergy before choosing alternative agents. Considering that penicillin-resistant T. pallidum has never been observed, treatment regimens for syphilis have changed relatively little during the years. Table 72-4 Treatment Guidelines for Syphilis Stage Recommended Alternative Regimen Regimen Early (primary, secondary, or Benzathine penicillin Doxycycline 100 mg early latent)a G 2.4 million-units PO BID for 14 days or single dose IM Tetracycline 500 mg PO QID for 14 days or Ceftriaxone 1 g IM/IV every day for 8 to 10 days or Azithromycin 2 g PO × 1 dose Late latent or latent syphilis of Lumbar puncture Lumbar puncture unknown duration If CSF normal: benzathine If CSF normal: penicillin G 2.4 doxycycline 100 mg million-units/week × 3 weeks IM PO BID for 28 days or Tetracycline 500 mg PO QID for 28 days If CSF abnormal: Treat as If CSF abnormal: treat neurosyphilis as neurosyphilis Neurosyphilisb (asymptomatic or Aqueous crystalline Procaine penicillin 2.4 symptomatic) penicillin G 18–24 million-units IM daily million-units IV every plus probenecid 500 day × 10–14 daysc mg PO QID, both for 10–14 days Congenital Aqueous crystalline If CSF normal: penicillin G benzathine penicillin G 100,000–150,000 50,000 units/kg/dose units/kg/day, IM in a single dose administered as 50,000 units/kg/dose IV q12h during the first 7 days of life, and every 8 hours thereafter for a total of 10 daysd Procaine penicillin G 50,000 units/kg/dose IM a day in a single dose for 10 days Syphilis in pregnancy According to stage According to stage aSome experts recommend repeating this regimen after 7 days for HIV-infected patients. bBecause of the shorter duration of therapy as compared with latent syphilis, some experts recommend giving benzathine penicillin G, 2.4 million-units/week for up to 3 weeks, after the completion of these neurosyphilis regimens to provide a comparable total duration of therapy. cAdministered as 3–4 million-units IV every 4 hours or continuous infusion. dAll infants born to women treated during pregnancy with erythromycin must be treated with penicillin at birth. Adapted from Workowski KA, Bolan GA; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1–137. As shown in , recommended therapy for primary, secondary, or latent syphilis (with negative findings in the CSF) of less than 1 year’s duration is a single, IM 2.4 million-unit dose of benzathine penicillin G. If penicillin is contraindicated, tetracycline 500 mg PO 4 times a day or doxycycline 100 mg PO twice a day for 14 days are the main alternatives. If the patient is allergic to penicillin, is not pregnant, and cannot receive tetracycline or doxycycline, a 10- to 14-day regimen of ceftriaxone 1 g IM or IV every day or a single 2 g dose of azithromycin are options.[] The use of erythromycin as an alternative is no longer recommended by the CDC because of its poor efficacy. The optimal dose, duration, and efficacy of these alternative regimens are not well-defined, necessitating close follow-up of patients. However, recent studies have shown that azithromycin 2 g PO as a 1-time dose is at least equivalent to benzathine penicillin G.[],[] Skin testing should be performed for individuals who claim allergy to penicillin. If the patient is truly allergic, he or she should be desensitized.[] Late latent syphilis (>1 year’s duration) and tertiary syphilis (gummas or cardiovascular syphilis) are treated with IM benzathine penicillin G (50,000 units/kg, up to 2.4 million-units) weekly for a total of 3 weeks.[] Neurosyphilis CASE 72-7, QUESTION 4: Would D.M.’s treatment differ if his CSF had tested positive for syphilis? Neurosyphilis can present at any stage of syphilis. When conventional IM doses of benzathine penicillin G are administered, measurable levels of penicillin are not obtainable in the CSF. However, this does not mean that penicillin does not concentrate in meningeal tissue.[] Treatment failures, as well as late clinical progression to neurosyphilis, can occur after treatment with the recommended IM regimen. After one dose, benzathine penicillin reaches peak plasma concentrations slower (13–24 hours) but with more prolonged treponemicidal plasma concentrations (7–10 days) when compared with procaine penicillin (1–4 hours to peak; 12–24 hour treponemicidal plasma concentrations).[] Reports of benzathine penicillin failures in the 1970s has resulted in the CDC recommending treatment with aqueous crystalline penicillin G, 3 to 4 million-units IV every 4 hours, or 18 to 24 million-units per day continuous infusion for 10 to 14 days. Alternatively, neurosyphilis can be treated with concurrent procaine penicillin (2.4 million-units IM daily) and probenecid (500 mg PO 4 times a day) for 10 to 14 days. Some experts add benzathine penicillin G (2.4 million-units IM once a week for up to 3 weeks) after the completion of aqueous penicillin G or procaine penicillin.[] Penicillin-allergic patients should be skin tested to confirm allergy and, if confirmed, the patient should be desensitized and treated with an appropriate penicillin regimen. Some data suggest that ceftriaxone 2 g IM or IV daily for 10 to 14 days can be used as an alternative in patients whose concern for cross-sensitivity between ceftriaxone and penicillin is negligible.[] Alternatively, the World Health Organization recommends penicillin-allergic nonpregnant patients receive either doxycycline 200 mg PO twice a day or tetracycline 500 mg PO 4 times a day for 30 days.[] Follow-Up CASE 72-7, QUESTION 5: D.M. was treated with a single IM dose of benzathine penicillin (2.4 million-units). How should his response to therapy be monitored? Physical examination and a quantitative VDRL or RPR test for primary and secondary syphilis should be repeated at least 6 and 12 months after therapy.[] Retreatment should be considered when the RPR or VDRL titer does not decline fourfold in 6 months. Patients with HIV coinfection should receive periodic serologic testing.[] Patients with latent syphilis should be retested 6, 12, and 24 months after treatment. Close serologic monitoring is necessary if antibiotics other than penicillin are used; CSF examination should be performed in these patients at their last follow-up visit. Patients with neurosyphilis should be monitored serologically every 6 months; CSF examinations should be repeated at 6-month intervals until normal. If still abnormal at 2 years, retreatment should be considered. Return of lesions, a fourfold increase in titer, or a titer of 1:8 that does not fall at least fourfold within 12 months necessitates retreatment. Suspected treatment failures, especially with abnormal CSF, should be treated as described for neurosyphilis. However, false-positive serologic results should be ruled out. Within 2 years, most patients with early syphilis become seronegative. However, if the disease is treated during the late stages, complete seroreversion may not occur. Patients treated with oral doxycycline or erythromycin are less likely to become seronegative.[] Therapy is considered adequate in patients who never become seronegative as long as the titer decreases fourfold. Although the disease process may be halted in patients with tertiary syphilis, existing damage to the cardiovascular or nervous systems cannot be reversed. Pregnancy CASE 72-8 QUESTION 1: N.W., a 27-year-old woman in her 19th week of gestation, has a positive VDRL and FTA-ABS. How should N.W. be managed? How would management be altered in the face of penicillin allergy? Although pregnancy may be associated with false-positive nontreponemal tests,[] the presence of both a positive treponemal test (e.g., FTA-ABS) and a nontreponemal test (e.g., RPR) virtually excludes a false-positive reaction.[] The next step is to determine whether N.W. already has been treated adequately. If she has previously received adequate treatment and follow-up and shows no evidence of persistence or recurrence of syphilis, then she requires no further therapy. Pregnancy has no known effect on the clinical course of syphilis.[] However, her infant should be observed carefully. If N.W. has not been treated previously for syphilis, then she should be treated with penicillin in the same doses recommended for nonpregnant women; some experts recommend a second dose 1 week later of 2.4 million-units of benzathine penicillin.[] The goal of therapy should be to treat the mother with syphilis as soon as possible. Syphilis transmission can occur transplacentally as early as 9 to 10 weeks’ gestation via direct contact with lesions in the birth canal.[],[] If the mother is left untreated, 70% to 100% of fetuses born to mothers with primary or 40% with secondary syphilis may be aborted, stillborn, or born with congenital syphilis (see Case 72-8, Question 3).[],[] There is no completely satisfactory alternative for the pregnant woman with an accelerated allergic reaction to penicillin. Tetracycline, as well as doxycycline, should be avoided during pregnancy, especially during the second or third trimester, because of tetracycline’s known effects on the fetus (tooth staining and inhibition of bone growth).[] Erythromycin has been used to treat pregnant patients with syphilis; however, the transplacental transfer rate of erythromycin is inadequate,[] potentially explaining the increased rate of aborted or stillborn infants in erythromycin-treated patients. Erythromycin and azithromycin are not recommended as alternative therapy for syphilis during pregnancy.[] A woman with a history of allergy to penicillin should be skin tested; if allergy is confirmed, she should be desensitized and treated with penicillin.[] It is possible that the newer cephalosporins may ultimately prove to be acceptable alternatives to penicillin G in the pregnant woman with syphilis, who is allergic to penicillin, but there is sufficient evidence for the CDC to recommend their use. Adequate treatment with penicillin can prevent up to 98% of fetal infections.[],[] Serologic titers, at a minimum should be followed up at 28 to 32 weeks’ gestation and at delivery. Monthly serologic titers may be considered in women at high risk for reinfection or those in geographical areas of high syphilis rates; thereafter, she should be followed up as any other patient with syphilis.[] Jarisch–Herxheimer Reaction CASE 72-8, QUESTION 2: N.W. was treated with an IM injection of 2.4 million-units of benzathine penicillin G. Six hours later, she complained of diffuse myalgias, chills, headache, and an exacerbation of her rash. She was tachypneic, but normotensive. What is this reaction? How should N.W. be managed? N.W. has developed the Jarisch–Herxheimer reaction (JHR), a usually benign, self-limited complication of antitreponemal antibiotic therapy that develops within hours after treatment of early syphilis.[] The cause of JHR is not well understood, but it is probably related to the release of cytokines.[] Clinical manifestations include fever, chills, myalgias, headache, tachycardia, and hypotension. The pathogenesis of the syndrome is uncertain, but the reaction should not be interpreted as an allergic reaction to penicillin. It typically begins within the first 24 hours after antibiotic administration and normally subsides spontaneously, generally subsiding even while antibiotics are continued.[],[] Notably, JHR can occur after administration of many antimicrobials and is not exclusive to penicillins, nor is it exclusive to syphilis treatment, occurring in other spirochetal diseases, such as Lyme disease and relapsing fever.[] Usually self-limiting in nonpregnant patients, the primary risk of this reaction in pregnant women is miscarriage, premature labor, or fetal distress.[],[] Pregnant women should seek medical attention if contractions or a change in fetal movements are noted. Close monitoring of JHR should be observed for patients with ophthalmic or neurologic syphilis. For these patients, prednisolone 10 to 20 mg 3 times a day for 3 days given 24 hours before syphilis treatment may prevent fever, but it will not control local inflammation.[] Tumor necrosis factor-α has been demonstrated to have some success in the prevention of JHR in spirochete disease.[] Although there is no proven effective preventive therapy, some experts still recommend antipyretics, hydration, and patient education; antibiotic therapy should not be discontinued. Neonatal Syphilis CASE 72-8, QUESTION 3: How should N.W.’s baby be treated if a diagnosis of congenital syphilis is confirmed? Infants born to mothers who have been treated for syphilis during pregnancy should be carefully examined at birth with a quantitative nontreponemal serologic test. If tests are reactive, the infant should be followed and have serologic testing every 2 to 3 months until nontreponemal tests are nonreactive.[] Newborn serology is difficult to interpret because of transplacental transfer of nontreponemal and treponemal immunoglobulin G to the infant. Treatment decisions are largely based on evidence of syphilis in the mother, adequacy of maternal treatment, comparison of maternal and neonatal nontreponemal serology, and/or presence of clinical or laboratory evidence of syphilis in the neonate. In addition, infants should be treated at birth, even if they are asymptomatic, when maternal treatment is unknown or inadequate, or when infant follow-up cannot be guaranteed. In most cases, a CSF examination should be performed before treatment is begun to rule out neurosyphilis. Chancroid Chancroid or soft chancre is a painful genital ulcer disease that is often associated with tender inguinal adenopathy. It is caused by Haemophilus ducreyi, a gram-negative bacillus. Chancroid is endemic in developing countries, but its incidence in the United States has steadily declined. In 2013, 10 cases of chancroid were reported in the United States, down from 28 cases in 2009.[] Chancroid and other genital ulcers have also been implicated in the acquisition and transmission of HIV. Signs and Symptoms CASE 72-9 QUESTION 1: T.G., a 31-year-old uncircumcised sexually active male, presents to the STD clinic with complaints of tender lesions on the penis and inguinal regions. He noticed the penile lesions on the external surface of the prepuce (foreskin) 2 days before his visit. The lesions were sharply demarcated but were not indurated; the base of the penile ulcer was covered by a yellow–gray purulent exudate. Right inguinal adenitis was present and extremely painful on palpation. A dark-field examination of the purulent exudate was negative. Gram stain revealed a mixture of gram-positive and gram-negative flora. T.G. claims to have an allergy to penicillin, but no other drug allergies are reported. What is the natural course of chancroid? Does T.G. have signs or symptoms consistent with chancroid? What diagnostic procedures are necessary? Uncircumcised men, as well as circumcised men, may have an increased risk of chancroid infection and may not respond to therapy. In fact, evidence suggests circumcision is protective against nearly all STDs, including HIV, as well as protecting women against T. vaginalis and BV.[] A painful genital ulcer appears 3 to 10 days after exposure and begins as a tender, red papule that becomes pustular and ulcerates within 2 days. Chancroid can be suspected if all of the following criteria are met: (1) one or more painful genital ulcers present, (2) regional lymphadenopathy, (3) no evidence of T. pallidum by dark-field examination, and (4) a negative HSV PCR test or HSV culture. As illustrated by T.G., the ulcer may be covered by a grayish or yellow exudate. A Gram stain can be misleading because of the polymicrobic nature of the ulcer and culture and because isolation of H. ducreyi is difficult, requiring specialized specimen collection and growth media.[] Treatment CASE 72-9, QUESTION 2: How should T.G.’s chancroid be treated? Most strains of H. ducreyi produce a TEM-type β-lactamase, and many strains are resistant to the antimicrobials that traditionally were used to treat chancroid, such as sulfonamides and tetracycline.[],[] Currently recommended CDC treatment regimens include azithromycin 1 g PO for 1 dose, ceftriaxone 250 mg IM once, ciprofloxacin 500 mg PO twice a day for 3 days, or erythromycin base 500 mg PO 3 times a day for 7 days. Ciprofloxacin is contraindicated in pregnant and lactating women. Because T.G. has a history of penicillin hypersensitivity, azithromycin as a single oral dose is a preferred treatment regimen. Treatment may not be as effective for patients who are coinfected with HIV or who are uncircumcised; therefore, HIV testing should occur at the time of chancroid diagnosis and if negative, should be repeated 3 months after the diagnosis. Follow-up should occur 3 to 7 days after treatment is initiated. Depending on the size of the ulcer, the time required until complete recovery will vary; larger ulcers may require longer than 2 weeks. Because T.G. is also sexually active, his sexual partner should be evaluated and treated if they had contact during the 10 days prior to the onset of symptoms. Vaginitis Approximately 10 million physician office visits are made annually in the United States for women seeking evaluation and treatment of vaginitis.[] The term vaginitis refers to such nonspecific vaginal symptoms as itching, burning, irritation, and abnormal discharge that may be caused by infection or other medical conditions. The most common vaginal infections are BV (22%–50% of cases), vulvovaginal candidiasis (VVC; 17%–39% of cases), and trichomoniasis (4%–35% of cases). However, approximately 30% of cases of vaginitis remain undiagnosed.[] Bacterial Vaginosis Bacterial vaginosis (BV) is the most common genital tract infection amongst reproductive aged women.[] While the exact prevalence of BV varies, one estimate places it at 29.2%. In addition, many sexually active women are infected with G. vaginalis, yet as much as 84% are asymptomatic.[] During an episode of BV, the normal vaginal lactobacillus flora is replaced by Mobiluncus species, Prevotella species, Ureaplasma species, Mycoplasma species, and increased numbers of G. vaginalis and is associated with an increased, malodorous vaginal discharge.[] The evidence for definitive risk factors in BV is inconclusive. Multiple sexual partners, a new sexual partner, douching, lack of condom use, and decreased concentrations of vaginal lactobacilli have been associated with BV. Non-sexually active women are rarely affected.[] In addition, studies among women who generally have sex with other women show evidence for sexual transmission.[] The routine treatment of male sexual partners is not recommended because a woman’s response to therapy or her likelihood of relapse or recurrence is not impacted by treatment of her sexual partner(s).[] Signs, Symptoms, and Diagnosis CASE 72-10 QUESTION 1: H.H. is a 24-year-old, sexually active woman with a 1-week history of moderate vaginal discharge that has a “fishy” odor, most notable after coitus. She has no complaints of vaginal pruritus or burning. On examination, the discharge appears thin, white, homogeneous, and notably malodorous. A wet mount of the vaginal secretion revealed few leukocytes and numerous “clue cells.” The vaginal pH was 4.8, and a characteristic fishy odor was noted when the discharge was mixed with 10% potassium hydroxide (KOH). Does H.H. have signs and symptoms consistent with BV? What diagnostic tests are required? H.H.’s signs and symptoms are typical of BV. The clinical diagnosis can be confirmed by a vaginal Gram stain that shows overgrowth of the vagina with G. vaginalis and other organisms as noted earlier. A 10% KOH solution mixed with the vaginal secretions yields a transient fishy odor because of the increased production of biogenic diamines (positive amine test). A wet preparation of the specimen reveals “clue cells” (exfoliated vaginal epithelial cells sometimes with adherent coccobacillary pathogens), vaginal pH greater than 4.5, and the characteristic KOH “whiff” test.[],[] If there are many white cells, other infections (e.g., T. vaginalis) should be suspected. Self-diagnosis is correct only about 3% to 4% of the time because most women attribute symptoms to poor hygiene.[] Treatment CASE 72-10, QUESTION 2: How should H.H. be treated? Nonpregnant women with symptomatic disease require treatment. CDC-recommended regimens include oral metronidazole 500 mg twice a day for 7 days, metronidazole gel 0.75% intravaginally daily for 5 days, or clindamycin cream 2% intravaginally at bedtime for 7 days.[] The FDA has approved metronidazole extended release 750 mg once daily for 7 days and a single dose of clindamycin intravaginal cream for the treatment of BV; however, limited data have been published comparing these regimens to established therapies. Alternatively, the CDC recommends either tinidazole 2 g PO every day for 2 days, tinidazole 1 g PO every day for 5 days, clindamycin 300 mg PO 2 times a day for 7 days, or clindamycin ovules 100 mg intravaginally once at bedtime for 3 days.[] Patients should be instructed to avoid consuming alcohol during treatment with metronidazole and for 72 hours afterward to avoid disulfiram-like reactions. Additionally, clindamycin cream is oil based and may weaken latex condoms or diaphragms. Alternative products include probiotics which have been evaluated in non-pregnant women and have shown to improve cure rates and reduce the reoccurrence of BV, although more studies are needed to establish their role in treatment.[],[] BV has been associated with preterm labor and premature delivery and treatment is recommended for all symptomatic women. The CDC recommends metronidazole 250 mg PO 3 times daily for 7 days or 500 mg PO twice a day for 7 days, or clindamycin 300 mg PO twice daily for 7 days. Teratogenic data suggest that metronidazole is not harmful to the fetus. More recent data suggest that the use of intravaginal clindamycin cream is also safe to use for pregnant women.[] Vulvovaginal Candidiasis Candida albicans is the causative organism of VVC in 80% to 92% of cases, with Candida glabrata and Candida tropicalis accounting for most of the remaining cases.[],[],[],[] The latter organisms have been identified increasingly as the causative agents of VVC during the past two decades. Approximately 75% of women will experience at least one episode of VVC during their reproductive years and 40% to 45% will have two or more episodes within their lifetime.[] Less than 5% of women who have VVC have recurrent candidal episodes (defined as four or more episodes of VVC in 1 year). Vulvovaginal candidiasis is not usually described as an STD because celibate women may also experience it; however, the incidence of VVC increases when women become sexually active.[] Because of this, VVC is often diagnosed during evaluation for a suspected STD when women present with vaginal symptoms. Assessing Self-Treatment CASE 72-11 QUESTION 1: L.L., a 23-year-old woman, purchases a nonprescription antifungal agent to relieve vaginal symptoms that she believes are caused by a vaginal yeast infection. L.L. asks the pharmacist for assistance in the selection of an antifungal agent. What information should be obtained from L.L. before a medication is recommended? The pharmacist should ask L.L. if this is her first episode of vaginitis or whether she has experienced similar symptoms previously that have been diagnosed as a vaginal yeast infection and treated by a physician. The nonprescription antifungal agents are indicated for the treatment of VVC in women who previously were diagnosed and treated by their physician. Additional questions that should be asked by the pharmacist include current symptoms, whether they are pregnant or not, other current medical conditions or medications, and allergies. Patients should be referred to a physician if any of the following are present: first episode of VVC, has had more than three episodes of VVC within the past 12 months, last episode was less than 2 months ago, is pregnant, is younger than 12, fever, lower abdominal, back, or shoulder pain, severe symptoms, or has a malodorous vaginal discharge.[] Signs and Symptoms CASE 72-11, QUESTION 2: L.L. has experienced two episodes of vaginal yeast infections, with the most recent case occurring approximately 1 year ago. On both occasions she was diagnosed as having VVC by her physician and responded to antifungal therapy. L.L. currently describes vaginal and vulvar itching, vaginal soreness, and vulvar burning accompanied by a thick, white vaginal discharge that has the consistency of cottage cheese. She has been unable to have sexual intercourse because of pain. These symptoms are similar to those she experienced with her previous vaginal yeast infections. L.L. has no underlying major health problems. Her current medications include oral tetracycline for acne and Ortho Tri-Cyclen for birth control. She has regular menstrual cycles and her last menstrual period ended 4 days ago. What clinical manifestations does L.L. exhibit that are consistent with VVC? What are the other common manifestations? L.L. exhibits signs and symptoms associated with VVC (i.e., vulvar and vaginal pruritus, vaginal soreness, vulvar burning, dyspareunia, and a thick, white vaginal discharge that appears to be curd-like). Women may also have vaginal discharge which is usually described as nonodorous, highly viscous, and white in color that may vary in consistency from curd-like to watery. Vulvar erythema may also be present.[] Differential Diagnosis CASE 72-11, QUESTION 3: How can VVC be differentiated from other vaginal infections? VVC should be differentiated from other vaginal infections because a nonprescription antifungal agent could delay the appropriate treatment of other vaginal infections. The physical appearance of the vaginal discharge may be useful in predicting VVC if it is a viscous, nonodorous, white, curd-like discharge and the patient has a normal vaginal pH (pH >4.5). The quantity of the discharge may be scanty to profuse. Some women with VVC exhibit only vaginal erythema with minimal discharge or an increased amount of normal vaginal secretion. characterizes the vaginal discharges associated with VVC, BV, and trichomoniasis. The vaginal discharge from a woman with signs and symptoms of VVC should be examined for the microscopic presence of Candida using a wet-mount preparation with 10% KOH or a Gram stain of the vaginal discharge. The use of KOH improves the visualization of yeast or pseudohyphae that are seen in approximately 70% of women diagnosed with VVC. If the wet mount is negative, the patient’s vaginal discharge should be cultured for Candida in an appropriate growth medium. Isolation of Candida without signs and symptoms should not result in treatment, because Candida is part of normal vaginal flora in approximately 10% to 20% of women. It is the proliferation of C. albicans or other yeasts that lead to vulvovaginitis symptoms. Nonprescription home screening tests are also available that measure pH levels within the vaginal epithelium (e.g., Vagisil Screening Kit and Fem-V), which are highly sensitive to pH changes but suffer from low specificity. Table 72-5 Characteristics of Vaginal Discharge Characteristics Normal Candidiasi Trichomoniasi Bacterial s s Vaginosis Color White or clear White Yellow–green White to