N. gonorrhoeae, the causative agent of gonorrhea, is a gram-negative, nonmotile, non-spore-forming organism that grows singly and in pairs (i.e., as diplococci).
The ~311,000 cases reported in the United States in 2012 probably represent only half the true number of cases because of underreporting, self-treatment, and nonspecific treatment without a laboratory diagnosis.
60% of reported cases in the United States occur in 15- to 19-year-old women and 20- to 24-year-old men.
Gonorrhea is transmitted from males to females more efficiently than in the opposite direction, with 50–70% of women acquiring gonorrhea during a single unprotected sexual encounter with an infected man. Roughly two-thirds of all infected men are asymptomatic.
Drug-resistant strains are widespread. Penicillin, ampicillin, and tetracycline are no longer reliable therapeutic agents, and oral cephalosporins and fluoroquinolones are no longer routinely recommended. In addition, strains highly resistant to ceftriaxone have been isolated in Japan and some European countries.
Except in disseminated disease, the sites of infection typically reflect areas involved in sexual contact.
Urethritis and cervicitis have an incubation period of 2–7 days and ~10 days, respectively. See above for details.
Anorectal gonorrhea can cause acute proctitis in women (due to the spread of cervical exudate to the rectum) and MSM.
Pharyngeal gonorrhea is usually mild or asymptomatic and results from oral–genital sexual exposure (typically fellatio). Pharyngeal infection almost always coexists with genital infection, resolves spontaneously, and is rarely transmitted to sexual contacts.
Ocular gonorrhea is typically caused by autoinoculation and presents as a markedly swollen eyelid, hyperemia, chemosis, and profuse purulent discharge.
Gonorrhea in pregnancy can have serious consequences for both the mother and the infant.
– Salpingitis and PID are associated with fetal loss.
– Third-trimester disease can cause prolonged rupture of membranes, premature delivery, chorioamnionitis, funisitis, and neonatal sepsis.
– Ophthalmia neonatorum, the most common form of gonorrhea among neonates, is preventable by prophylactic ophthalmic ointments (e.g., containing erythromycin or tetracycline), but treatment requires systemic antibiotics.
Gonococcal arthritis results from dissemination of organisms due to gonococcal bacteremia. Pts present during a bacteremic phase (relatively uncommon) or with suppurative arthritis involving one or two joints (most commonly the knees, wrists, ankles, and elbows), with tenosynovitis and skin lesions. Menstruation and complement deficiencies of the membrane attack complex (C5–C9) are risk factors for disseminated disease.
NAATs, culture, and microscopic examination (for intracellular diplococci) of urogenital samples are used to diagnose gonorrhea; NAAT of urine samples is most sensitive. A single culture of endocervical discharge has a sensitivity of 80–90%.
See Table 83-2.
TABLE 83-2RECOMMENDED TREATMENT FOR GONOCOCCAL INFECTIONS: ADAPTED FROM THE 2010 GUIDELINES OF THE CENTERS FOR DISEASE CONTROL AND PREVENTION ||Download (.pdf) TABLE 83-2RECOMMENDED TREATMENT FOR GONOCOCCAL INFECTIONS: ADAPTED FROM THE 2010 GUIDELINES OF THE CENTERS FOR DISEASE CONTROL AND PREVENTION
|Diagnosis ||Treatment of Choicea |
|Uncomplicated gonococcal infection of the cervix, urethra, pharynxb, or rectum || |
|First-line regimen ||Ceftriaxone (250 mg IM, single dose) |
| ||plus |
| ||Treatment for Chlamydia if chlamydial infection is not ruled out: |
| ||Azithromycin (1 g PO, single dose) |
| ||or |
| ||Doxycycline (100 mg PO bid for 7 days) |
|Alternative regimensc ||Cefixime (400 mg PO, single dose) |
| ||or |
| ||Ceftizoxime (500 mg IM, single dose) |
| ||or |
| ||Cefotaxime (500 mg IM, single dose) |
| ||or |
| ||Spectinomycin (2 g IM, single dose)d, e |
| ||or |
| ||Cefotetan (1 g IM, single dose) plus probenecid (1 g PO, single dose)d |
| ||or |
| ||Cefoxitin (2 g IM, single dose) plus probenecid (1 g PO, single dose)d |
|Epididymitis ||Ceftriaxone (250 mg IM once) followed by doxycycline (100 mg PO bid for 10 days) is effective for epididymitis due to Chlamydia trachomatis or Neisseria gonorrhoeae. |
|Pelvic inflammatory disease ||See Chap. 163 in HPIM-19 |
| Outpatient || |
Ceftriaxone (250 mg IM once)
Doxycycline (100 mg PO bid for 14 days)
Metronidazole (500 mg PO bid for 14 days)
| Inpatient || |
Cefotetan (2 g IV q12h) or cefoxitin (2 g IV q6h)
doxycycline (100 mg IV/PO q12h)
Clindamycin (900 mg IV q8h)
gentamicin (loading dose of 2.0 mg/kg IV/IM followed by 1.5 mg/kg q8h)
|Gonococcal conjunctivitis in an adult ||Ceftriaxone (1 g IM, single dose)f |
|Ophthalmia neonatorumg ||Ceftriaxone (25–50 mg/kg IV, single dose, not to exceed 125 mg) |
|Disseminated gonococcal infectionh || |
| Initial therapyi || |
| Pt tolerant of β-lactam drugs || |
Ceftriaxone (1 g IM or IV q24h; recommended)
Cefotaxime (1 g IV q8h)
Ceftizoxime (1 g IV q8h)
| Pts allergic to β-lactam drugs ||Spectinomycin (2 g IM q12h)d |
| Continuation therapyi ||Cefixime (400 mg PO bid) |
|Meningitis or endocarditis ||Ceftriaxone (1–2 g IV bid) for 10–14 days (meningitis) or ≥4 weeks (endocarditis)j |
INFECTIONS WITH CHLAMYDIA TRACHOMATIS
C. trachomatis organisms are obligate intracellular bacteria that are divided into two biovars: trachoma and LGV. The trachoma biovar causes ocular trachoma and urogenital infections; the LGV biovar causes lymphogranuloma venereum.
The World Health Organization (WHO) estimates that >106.4 million cases of C. trachomatis infection occur annually worldwide; it is the most prevalent of all bacterial STIs. The estimated 2–3 million cases per year that occur in the United States make C. trachomatis infection the most commonly reported infectious disease in this country.
80–90% of women and >50% of men with C. trachomatis genital infections lack symptoms; other pts have very mild symptoms.
Urethritis, epididymitis, cervicitis, salpingitis, PID, and proctitis are all discussed above.
Reactive arthritis (conjunctivitis, urethritis or cervicitis, arthritis, and mucocutaneous lesions) occurs in 1–2% of NGU cases, many of which are due to C. trachomatis. More than 80% of pts have the HLA-B27 phenotype.
LGV is an invasive, systemic STI that—in heterosexual individuals—presents most commonly as painful inguinal lymphadenopathy beginning 2–6 weeks after presumed exposure. Progressive periadenitis results in fluctuant, suppurative nodes with development of multiple draining fistulas. Spontaneous resolution occurs after several months. See Table 83-1 for additional clinical details.
NAATs of urine or urogenital swabs are the diagnostic tests of choice. Serologic testing may be helpful in the diagnosis of LGV and neonatal pneumonia caused by C. trachomatis, but it is not useful in diagnosing uncomplicated urogenital infections.
TREATMENT: INFECTIONS WITH CHLAMYDIA TRACHOMATIS
See “Specific Syndromes,” above.
LGV should be treated with doxycycline (100 mg PO bid) or erythromycin base (500 mg PO qid) for at least 3 weeks.
INFECTIONS DUE TO MYCOPLASMAS
Microbiology and Epidemiology
Mycoplasmas are the smallest free-living organisms known and lack a cell wall. M. hominis, M. genitalium, Ureaplasma parvum, and U. urealyticum cause urogenital tract disease. These organisms are commonly present in the vagina of asymptomatic women.
Ureaplasmas are a common cause of Chlamydia-negative NGU. M. hominis and M. genitalium are associated with PID; M. hominis is implicated in 5–10% of cases of postpartum or postabortal fever.
PCR is most commonly used for detection of urogenital mycoplasmas; culture is possible but can be done primarily at reference laboratories. Serologic testing is not helpful.
TREATMENT: INFECTIONS DUE TO MYCOPLASMAS
Recommendations for treatment of NGU and PID listed above are appropriate for genital mycoplasmas.
Microbiology and Epidemiology
Treponema pallidum subspecies pallidum—the cause of syphilis—is a thin, spiral organism with a cell body surrounded by a trilaminar cytoplasmic membrane. Humans are the only natural host, and the organism cannot be cultured in vitro.
Cases are acquired by sexual contact with infectious lesions (chancre, mucous patch, skin rash, condyloma latum); nonsexual acquisition through close personal contact, infection in utero, blood transfusion, and organ transplantation is less common.
There are ~12 million new infections per year worldwide.
– In the United States, 31,575 cases were reported in 2000.
– The reported cases of primary and secondary syphilis combined (which better indicate disease activity) increased from <6000 in 2000 to >14,000 in 2012, primarily affecting MSM, 20–70% of whom were co-infected with HIV.
One-third to one-half of sexual contacts of persons with infectious syphilis become infected—a figure that underscores the importance of treating all recently exposed sexual contacts.
T. pallidum penetrates intact mucous membranes or microscopic abrasions and, within hours, enters lymphatics and blood to produce systemic infection and metastatic foci. After a median incubation period of ~21 days (range, 2–6 weeks), the primary lesion (chancre) appears at the site of inoculation, persists for 4–6 weeks, and then heals spontaneously. Generalized parenchymal, constitutional, and mucocutaneous manifestations of secondary syphilis appear 6–8 weeks later despite high antibody titers, subsiding in 2–6 weeks. After a latent period, one-third of untreated pts eventually develop tertiary disease (syphilitic gummas, cardiovascular disease, neurologic disease).
Syphilis progresses through three phases with distinct clinical presentations.
Primary syphilis: A chancre at the site of inoculation (penis, rectum or anal canal, mouth, cervix, labia) is characteristic but often goes unnoticed. See Table 83-1 for clinical details. Regional adenopathy can persist long after the chancre heals.
Secondary syphilis: The protean manifestations of the secondary stage usually include mucocutaneous lesions and generalized nontender lymphadenopathy.
– Skin lesions can be subtle but are often pale red or pink, nonpruritic macules that are widely distributed over the trunk and extremities, including the palms and soles.
– In moist intertriginous areas, papules can enlarge and erode to produce broad, highly infectious lesions called condylomata lata.
– Superficial mucosal erosions (mucous patches) and constitutional symptoms (e.g., sore throat, fever, malaise) can occur.
– Less common findings include hepatitis, nephropathy, arthritis, and ocular findings (e.g., optic neuritis, anterior uveitis, iritis).
Latent syphilis: Pts without clinical manifestations but with positive syphilis serology have latent disease. Early latent syphilis is limited to the first year after infection, whereas late latent syphilis is defined as that of ≥1 year’s (or unknown) duration.
Tertiary syphilis: The classic forms of tertiary syphilis include neurosyphilis, cardiovascular syphilis, and gummas.
– Neurosyphilis represents a continuum, with asymptomatic disease occurring early after infection and potentially progressing to general paresis and tabes dorsalis. Symptomatic disease has three main presentations, all of which are now rare (except in pts with advanced HIV infection). Meningeal syphilis presents as headache, nausea, vomiting, neck stiffness, cranial nerve involvement, seizures, and changes in mental status within 1 year of infection. Meningovascular syphilis presents up to 10 years after infection as a subacute encephalitic prodrome followed by a gradually progressive vascular syndrome. Parenchymatous involvement presents at 20 years for general paresis and 25–30 years for tabes dorsalis. A general mnemonic for paresis is personality, affect, reflexes (hyperactive), eye (Argyll Robertson pupils, which react to accommodation but not to light), sensorium (illusions, delusions, hallucinations), intellect (decrease in recent memory and orientation, judgment, calculations, insight), and speech. Tabes dorsalis is a demyelination of posterior columns, dorsal roots, and dorsal root ganglia, with ataxic, wide-based gait and footslap; paresthesia; bladder disturbances; impotence; areflexia; and loss of position, deep pain, and temperature sensations.
– Cardiovascular syphilis develops in ~10% of untreated pts 10–40 years after infection. Endarteritis obliterans of the vasa vasorum providing the blood supply to large vessels results in aortitis, aortic regurgitation, saccular aneurysm, and coronary ostial stenosis.
– Gummas are usually solitary lesions showing granulomatous inflammation with central necrosis. Common sites include the skin and skeletal system; however, any organ (including the brain) may be involved.
Congenital syphilis: Syphilis can be transmitted throughout pregnancy, but fetal disease does not become manifest until after the fourth month of gestation. All pregnant women should be tested for syphilis early in pregnancy.
Serologic tests—both nontreponemal and treponemal—are the mainstays of diagnosis; changes in antibody titers can also be used to monitor response to therapy.
Nontreponemal serologic tests that measure IgG and IgM antibodies to a cardiolipin–lecithin–cholesterol antigen complex (e.g., rapid plasma reagin [RPR], Venereal Disease Research Laboratory [VDRL]) are recommended for screening or for quantitation of serum antibody. After therapy for early syphilis, a persistent fall in titer by ≥4-fold is considered an adequate response.
Treponemal tests, including the agglutination assay (e.g., the Serodia TP-PA test), the fluorescent treponemal antibody–absorbed (FTA-ABS) test, and treponemal enzyme or chemiluminescence immunoassays (EIAs/CIAs), are used to confirm results from nontreponemal tests and should not be used as a screening test because of high false-positive rates. Results remain positive even after successful treatment.
LP is recommended for pts with syphilis and neurologic signs or symptoms, an RPR or VDRL titer ≥1:32, or suspected treatment failure and for HIV-infected pts with a CD4+ T cell count <350/μL.
Pts with syphilis should be evaluated for HIV disease.
See Table 83-3 for treatment recommendations.
The Jarisch-Herxheimer reaction is a dramatic reaction to treatment that is most common with initiation of therapy for primary (~50% of pts) or secondary (~90%) syphilis. The reaction is associated with fever, chills, myalgias, tachycardia, headache, tachypnea, and vasodilation. Symptoms subside within 12–24 h without treatment.
Response to treatment should be monitored by determination of RPR or VDRL titers at 6 and 12 months in primary and secondary syphilis and at 6, 12, and 24 months in tertiary or latent syphilis.
– HIV-infected pts should undergo repeat serologic testing at 3, 6, 9, 12, and 24 months, irrespective of the stage of syphilis.
– Re-treatment should be considered if serologic responses are not adequate (a persistent antibody fall by ≥4-fold) or if clinical signs persist or recur. For these pts, CSF should be examined, with treatment for neurosyphilis if CSF is abnormal and treatment for late latent syphilis if CSF is normal.
– In treated neurosyphilis, CSF cell counts should be monitored every 6 months until normal. In adequately treated HIV-uninfected pts, an elevated CSF cell count falls to normal in 3–12 months.
TABLE 83-3RECOMMENDATIONS FOR THE TREATMENT OF SYPHILISa ||Download (.pdf) TABLE 83-3RECOMMENDATIONS FOR THE TREATMENT OF SYPHILISa
|Stage of Syphilis ||Patients without Penicillin Allergy ||Patients with Confirmed Penicillin Allergyb |
|Primary, secondary, or early latent ||CSF normal or not examined: Penicillin G benzathine (single dose of 2.4 mU IM) ||CSF normal or not examined: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 2 weeks |
| ||CSF abnormal: Treat as neurosyphilis ||CSF abnormal: Treat as neurosyphilis |
|Late latent (or latent of uncertain duration), cardiovascular, or benign tertiary || |
CSF normal or not examined: Penicillin G benzathine (2.4 mU IM weekly for 3 weeks)
CSF abnormal: Treat as neurosyphilis
CSF normal and pt not infected with HIV: Tetracycline HCl (500 mg PO qid) or doxycycline (100 mg PO bid) for 4 weeks
CSF normal and pt infected with HIV: Desensitization and treatment with penicillin if compliance cannot be ensured
CSF abnormal: Treat as neurosyphilis
|Neurosyphilis (asymptomatic or symptomatic) || |
Aqueous crystalline penicillin G (18–24 mU/d IV, given as 3–4 mU q4h or continuous infusion) for 10–14 days
Aqueous procaine penicillin G (2.4 mU/d IM) plus oral probenecid (500 mg qid), both for 10–14 days
|Desensitization and treatment with penicillinc |
|Syphilis in pregnancy ||According to stage ||Desensitization and treatment with penicillin |
HERPES SIMPLEX VIRUS INFECTIONS
Microbiology and Epidemiology
HSV is a linear, double-strand DNA virus, with two subtypes (HSV-1 and HSV-2).
Exposure to HSV at mucosal surfaces or abraded skin sites permits viral entry into cells of the epidermis and dermis, viral replication, entry into neuronal cells, and centrifugal spread throughout the body.
More than 90% of adults have antibodies to HSV-1 by age 40; 15–20% of the U.S. population has antibodies to HSV-2, with a higher prevalence in low-income countries.
Unrecognized carriage of HSV-2 and frequent asymptomatic reactivations of virus from the genital tract foster the continued spread of HSV disease.
Genital lesions caused by HSV-1 have lower recurrence rates in the first year (~55%) than those caused by HSV-2 (~90%).
See Table 83-1 for clinical details. First episodes of genital herpes due to HSV-1 and HSV-2 present similarly and can be associated with fever, headache, malaise, and myalgias. More than 80% of women with primary genital herpes have cervical or urethral involvement. Local symptoms include pain, dysuria, vaginal and urethral discharge, and tender inguinal lymphadenopathy.
Isolation of HSV in tissue culture or demonstration of HSV antigens or DNA in scrapings from lesions is the most accurate diagnostic method. PCR is increasingly being used for detection of HSV DNA and is more sensitive than culture at mucosal sites. Staining of scrapings from the base of the lesion with Wright’s, Giemsa’s (Tzanck preparation), or Papanicolaou’s stain to detect giant cells or intranuclear inclusions is well described, but most clinicians are not skilled in these techniques, which furthermore do not differentiate between HSV and VZV.
TREATMENT: HSV GENITAL INFECTIONS
First episodes: Oral acyclovir (400 mg tid), valacyclovir (1 g bid), or famciclovir (250 mg bid) for 7–14 days is effective.
Symptomatic recurrent episodes: Oral acyclovir (800 mg tid for 2 days), valacyclovir (500 mg bid for 3 days), or famciclovir (750 or 1000 mg bid for 1 day, 1500 mg once, or 500 mg stat followed by 250 mg q12h for 3 days) effectively shortens lesion duration.
Suppression of recurrent episodes: Oral acyclovir (400–800 mg bid) or valacyclovir (500 mg qd) is given. Pts with >9 episodes per year should take valacyclovir (1 g qd or 500 mg bid) or famciclovir (250–500 mg bid). Daily valacyclovir appears to be more effective at reducing subclinical shedding than daily famciclovir.
CHANCROID (HAEMOPHILUS DUCREYI INFECTION)
H. ducreyi is the etiologic agent of chancroid, an STI characterized by genital ulceration and inguinal adenitis. In addition to being a cause of morbidity in itself, chancroid increases the efficiency of transmission of and degree of susceptibility to HIV infection. See Table 83-1 for clinical details. Culture of H. ducreyi from the lesion confirms the diagnosis; PCR is starting to become available. In the setting of a compatible clinical presentation (including one or more painful genital ulcers) and negative tests for syphilis and HSV infection, a probable diagnosis of chancroid can be made.
TREATMENT: CHANCROID (HAEMOPHILUS DUCREYI INFECTION)
Regimens recommended by the Centers for Disease Control and Prevention (CDC) include azithromycin (1 g PO once), ciprofloxacin (500 mg PO bid for 3 days), ceftriaxone (250 mg IM once), and erythromycin base (500 mg tid for 1 week).
Sexual partners within 10 days preceding the pt’s onset of symptoms should be identified and treated, regardless of symptoms.
DONOVANOSIS (KLEBSIELLA GRANULOMATIS INFECTION)
Microbiology and Epidemiology
Also known as granuloma inguinale, donovanosis is caused by K. granulomatis. The infection is endemic in Papua New Guinea, parts of southern Africa, India, the Caribbean, French Guyana, Brazil, and Aboriginal communities in Australia; few cases are reported in the United States.
See Table 83-1 for clinical details. Four types of lesions have been described: (1) the classic ulcerogranulomatous lesion that bleeds readily when touched; (2) a hypertrophic or verrucous ulcer with a raised irregular edge; (3) a necrotic, offensive-smelling ulcer causing tissue destruction; and (4) a sclerotic or cicatricial lesion with fibrous and scar tissue. The genitals are affected in 90% of pts and the inguinal region in 10%.
Diagnosis is often based on identification of typical Donovan bodies (gram-negative intracytoplasmic cysts filled with deeply staining bodies that may have a safety-pin appearance) within large mononuclear cells in smears from lesions or biopsy specimens. PCR is also available.
TREATMENT: DONOVANOSIS (KLEBSIELLA GRANULOMATIS INFECTION)
Pts should be treated with azithromycin (1 g on day 1, then 500 mg qd for 7 days or 1 g weekly for 4 weeks); alternative therapy consists of a 14-day course of doxycycline (100 mg bid), trimethoprim-sulfamethoxazole (960 mg bid), erythromycin (500 mg qid), or tetracycline (500 mg qid). If any of the 14-day treatment regimens are chosen, the pt should be monitored until lesions have healed completely.
HUMAN PAPILLOMAVIRUS (HPV) INFECTIONS
Papillomaviruses are nonenveloped, double-strand DNA viruses. More than 125 HPV types are recognized, and individual types are associated with specific clinical manifestations. For example, HPV types 16 and 18 have been most strongly associated with cervical and anal cancers, causing 70–85% and ~90% of cases, respectively; HPV types 6 and 11 cause genital warts (condylomata acuminata).
Epidemiology and Clinical Manifestations
HPV is transmitted by sexual intercourse, by oral sex, and possibly by touching of a partner’s genitalia.
The interval between initial infection and the diagnosis of HPV-associated cancer may be >20 years, with HIV infection accelerating this progression.
The physical appearance of warts varies with their anatomic location, ranging from soft, whitish papules on the vulva to raised, keratotic, pigmented plaques on the penis.
Although subclinical cervical HPV infections are common, pts with cervical cancer present early on with eroded carcinomas that bleed easily; more advanced carcinomas present as ulcerated lesions or as an exophytic lesion.
Anal cancer typically presents as rectal bleeding and pain or a mass sensation, although 20% of pts are asymptomatic.
Most visible warts are diagnosed correctly by history and physical examination alone. The primary method used for cervical cancer screening is cytology via Pap smear every 3 years beginning at age 21; for women ≥30 years of age, the testing interval can be lengthened to 5 years if co-testing for HPV DNA is negative. There is no clear consensus regarding screening for anal cancer.
TREATMENT: HUMAN PAPILLOMAVIRUS INFECTIONS
Many lesions resolve spontaneously. Current treatment is not completely effective, and some agents have significant side effects.
Provider-administered therapy can include cryotherapy, surgical excision, intralesionally administered interferon, or laser surgery.
Pt-administered therapy consists of podophyllotoxin (0.05% solution or gel or 0.15% cream applied bid for 3 days; can be repeated up to 4 times with 4 days between treatment courses); imiquimod (5% or 3.75% cream applied 3 times per week for up to 16 weeks); and sinecatechins (15% ointment applied tid for up to 4 months).
A quadrivalent vaccine (Gardasil, Merck) containing HPV types 6, 11, 16, and 18 and a bivalent vaccine (Cervarix, GlaxoSmithKline) containing HPV types 16 and 18 are available. The CDC recommends administration of the quadrivalent vaccine to all boys and girls at 11–12 years of age as well as to young men and women 13–26 years of age who have not previously completed the full series.
For a more detailed discussion, see Marrazzo JM, Holmes KK: Sexually Transmitted Infections: Overview and Clinical Approach, Chap. 163, p. 869; Ram S, Rice PA: Gonococcal Infections, Chap. 181, p. 1003; Murphy TF: Haemophilus and Moraxella Infections, Chap. 182, p. 1010; O’Farrell N: Donovanosis, Chap. 198e; Lukehart SA: Syphilis, Chap. 206, p. 1132; Hardy RD: Infections Due to Mycoplasmas, Chap. 212, p. 1163; Gaydos CA, Quinn TC: Chlamydial Infections, Chap. 213, p. 1165; Corey L: Herpes Simplex Virus Infections, Chap. 216, p. 1175; and Ermel AC, Brown DR: Human Papillomavirus Infections, Chap. 222, p. 1197, in HPIM-19.