#98721: Bacterial Sexually Transmitted Infections

Records of new chlamydia cases began in 1984. Since then, case rates gradually increased, with 251.4 per 100,000 population reported in 2000, 405.3 per 100,000 population in 2009, and a peak of 539.9 per 100,000 population in 2018 [1]. Since 2018, the rates have decreased. In 2020, the rate was 481.3 cases per 100,000 population, a decrease of 13% compared with the rate in 2019 [1]. Chlamydial infection is diagnosed more than twice as often in women than men, and rates are highest among adolescents and young adults.

Population rates of gonorrhea rose from 1941 levels (146.7 per 100,000 population) to peak in 1976 (460.6 per 100,000 population), declined to an all-time low in 2009 (98.1 per 100,000 population), but are rising again as of 2020 (206.5 per 100,000 population) [1]. In 2020, the reported case rate (per 100,000) of gonorrhea was higher among men (250) than among women (150). The higher rate of infection among men compared to women is likely because cases are readily identified not only in men who have sex with women but also in men who have sex with men (MSM) [1].

Population rates of syphilis infection were the highest recorded in 1943 (447.0 per 100,000 population), slowly declining until 1978 (29.2 per 100,000 population), and then doubling by 1990 (54.3 per 100,000 population). Rates then began declining again until 2005 (11.2 per 100,000 population), following which case rates have risen every year, reaching 40.6 per 100,000 in 2020, a 6.8% increase over that for 2019 [1]. Preliminary data for 2021 shows that total reported cases of syphilis increased from 133,955 in 2020, to 171,074 in 2021, a 27.7% increase [90]. Primary and secondary syphilis, the most infectious stages, increased from 41,665 to 52,354. Young MSM are disproportionately impacted, accounting for the majority (53%) of all male syphilis cases in 2020.

Chancroid rates rose from 1941 levels (2.5 per 100,000 population) to peak in 1947 (6.7 per 100,000 population), declined until 1978 (0.2 per 100,000 population) and rose again until 1987 (2.1 per 100,000 population), but declined again to remain at historic lows in 2020 (<0.1 per 100,000 population) [1].

Practical strategies for risk assessment and counseling are provided in the CDC treatment guidelines document [4]. Health providers should use simple, direct language when asking these questions, taking care to exhibit respect, compassion, and a nonjudgmental attitude. Organizations such as the National Network of STI/HIV Prevention Training Centers, a CDC-funded group, can help providers enhance skills in counseling individuals about prevention. Resources can be found on the organization's website at https://www.cdc.gov/std/treatment/resources.htm.

All sexually active adolescents are considered at increased risk for STIs and should be counseled. Other at-risk groups include adults with current or past-year STIs with multiple sex partners or who use condoms inconsistently. As noted, Black Americans have the highest STI prevalence of any racial/ethnic group, and STI prevalence is higher in American Indians, Alaska Natives, and Latino/as than in white populations. Increased STI prevalence rates are also found in MSM, persons with low incomes living in urban settings, current or former inmates, military recruits, persons who exchange sex for money or drugs, persons with mental illness or a disability, current or former injecting drug users, persons with sexual abuse history, and patients of public STI clinics [7].

Behavioral counseling interventions can reduce the risk of acquiring an STI. Interventions ranging in intensity from 30 minutes to more than two hours of contact time are beneficial; evidence of benefit increases with intervention intensity [7]. Interventions can be delivered by primary care clinicians or through referral to trained behavioral counselors. Successful interventions provide basic information on STIs and STI transmission; assess patient risk for transmission; and provide pertinent skills training, such as condom use, communication about safe sex, problem solving, and goal setting. Many successful interventions aim to increase motivation or commitment to safe sex practices [7].

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because communication with patients and families is considered an essential aspect of care, it is each practitioner's responsibility to ensure that information regarding goals and potential outcomes are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

Uncontrolled studies found that diaphragms protected against cervical gonorrhea, chlamydia, and trichomoniasis, but controlled studies found that compared with external condoms, diaphragms plus lubricant did not reduce rates of chlamydia or gonorrhea [20]. Diaphragms should not be solely relied on for protection against HIV/STIs [21,22].

Contraceptive methods that are not mechanical barriers provide no protection against HIV or other STIs. Sexually active patients who use hormonal contraception, nonhormonal intrauterine devices, or have been surgically sterilized or undergone a hysterectomy should be advised to use condoms to reduce risks for STIs [15].

Vaginal washing and douching after sexual exposure are ineffective and may increase the risk for bacterial vaginosis, some STIs, and HIV infection [4,23].

With disk diffusion testing, antibiotic-impregnated paper disks determine antimicrobial resistance of a bacterial isolate. The disks are placed on a lawn of bacterial growth, and micro-organisms that grow closer to a disk are more resistant to the antibiotic on the disk [33].

Broth dilution and agar dilution methods test a bacterial isolate against a range of antimicrobial concentrations. These are similar to disk diffusion but use plastic strips with an antibiotic gradient indicating the antibiotic concentration at different points on the strip. The minimal inhibitory concentration (MIC), the lowest concentration of drug that inhibits organism growth, is read at the point where the border of growth inhibition intersects the strip [33].

Common symptoms in women include vaginal discharge, post-coital and intermenstrual bleeding, dysuria, lower abdominal pain, and deep dyspareunia. Physical exam can reveal pelvic and/or cervical motion tenderness; cervicitis (yellow, mucopurulent exudate with/without contact bleeding); or cervical ectopy (expansion of red endocervical epithelium onto vaginal surfaces of cervix) [36,38].

Symptoms in men include urethral discharge, dysuria, urethritis (acute severe onset dysuria, frequency, and copious, purulent discharge mimicking gonococcal urethritis), and possible progression to epididymitis [36,38].

Doxycycline is contraindicated in the second and third trimesters, and animal studies have raised concerns over ofloxacin and levofloxacin [46]. Azithromycin is safe and effective as an alternative drug for chlamydia in pregnancy [47,48]. All pregnant women diagnosed with chlamydia should be retested three months after treatment. Women younger than 25 years of age and those at increased risk for chlamydia should be rescreened during the third trimester [49].

Amoxicillin (500 mg orally three times per day for seven days) is the preferred alternative therapy in pregnancy with persistent chlamydial symptoms following exposure to penicillin-class antibiotics [50]. Gastrointestinal side effects from erythromycin can lead to nonadherence, and lower-dose 14-day regimens can mitigate gastrointestinal intolerance. The potential hepatotoxicity of erythromycin estolate contraindicates its use in pregnancy [4].

Recommended and alternative treatment approaches for all gonorrheal infection sites and stages are summarized in Table 4. Ceftriaxone plus azithromycin is the only first-line recommendation for urogenital, endocervical, anorectal, and oropharyngeal gonorrheal infection and for gonorrheal infection in pregnant women and patients with HIV [34,58]. This arose from efforts by the CDC to prevent development of cephalosporin resistance, following evidence during 2006–2011 suggesting decreasing efficacy with cefixime against N. gonorrhoeae [34]. Prior to December 2020, the CDC recommended dual ceftriaxone/azithromycin therapy. However, it shifted to a recommendation for ceftriaxone monotherapy to help combat increasing resistance to azithromycin [63]. Cefixime was removed as a first-line treatment of gonorrhea in 2012 [57]. Single-dose ceftriaxone should be combined with doxycycline, 100 mg daily for seven days, unless chlamydia infection has been excluded [4].

Single-injection ceftriaxone 500 mg provides sustained, high bactericidal levels in the blood. In clinical trials, ceftriaxone showed cures in 99.2% of uncomplicated urogenital and anorectal infections and 98.9% of pharyngeal infections [61,62]. Other single-dose injectable cephalosporins are available but not recommended as gonorrhea treatment. Gentamicin is solely recommended for use when ceftriaxone is unavailable.

Patients with a history of IgE-mediated beta-lactam allergy, including anaphylaxis, should be considered for penicillin skin testing, although cross-reactivity to third-generation cephalosporins (ceftriaxone) is very low [64,65,66].

Dispense on-site and observe first dosing for all prescribed treatment. If medications are not available when treatment is indicated, linkage to an STI treatment facility should be provided for same-day treatment [4].

All sex partners within 60 days of diagnosis should be evaluated and presumptively treated for N. gonorrhoeae and C. trachomatis infections. If the last potential exposure was more than 60 days previous, the most recent sex partner should be treated. Patients and sex partners should abstain from condomless sexual activity for seven days after treatment and until sex partners are adequately treated [4]. Under current guidelines, every effort should be made to ensure that a patient's sex partners are evaluated and treated with the recommended regimen (a single dose of ceftriaxone 500 mg IM). If a healthcare provider cannot ensure an infected patient's partner will be promptly linked to care, expedited partner therapy with a single 800-mg dose of cefixime may be delivered to the partner by the patient, a disease investigation specialist, or collaborating pharmacy [4,32]. If a chlamydia infection in the patient has not been excluded, doxycycline 100 mg twice daily for seven days should be added to the sex partner's regimen. When cephalosporin treatment failure is suspected, the treating clinician should consult an infectious disease specialist, an STI/HIV Prevention Training Center clinical expert, the local or state health department STI program, or the CDC for advice [67].

All patients should be retested within three months of initial treatment [34]. A test-of-cure using either culture or NAAT is recommended in patients with pharyngeal gonorrhea 14 days after treatment with an alternative regimen. If the NAAT is positive, confirm by culture testing before retreatment. All positive test-of-cure cultures should include antimicrobial susceptibility testing. Symptoms that persist after treatment should be evaluated by culture, with or without NAAT, and any gonococci isolated should be tested for antimicrobial susceptibility [4].

Gonococcal conjunctivitis is uncommon and research data on gonococcal conjunctivitis treatment in adults are limited. Consider one-time lavage of the infected eye with saline solution and consultation with an infectious disease specialist [4].

Disseminated gonococcal infection frequently appears as petechial or pustular acral skin lesions, asymmetric polyarthralgia, tenosynovitis, or oligoarticular septic arthritis. The infection can be complicated by perihepatitis and rarely by endocarditis or meningitis. Some N. gonorrhoeae strains that cause disseminated infection are associated with minimal genital inflammation [68]. If disseminated gonococcal infection is suspected, use NAAT or culture specimens from urogenital and extragenital sites, and specimens from disseminated infection sites such as the skin, synovial fluid, blood, and central nervous system (CNS). Test all N. gonorrhoeae isolates for antimicrobial susceptibility [4].

Hospitalization and consultation with an infectious disease specialist are initially recommended, especially when treatment adherence is doubted, diagnosis uncertain, or purulent synovial effusions or other complications are present. Examine for evidence of endocarditis and meningitis [4].

When treating the arthritis-dermatitis syndrome, switch to an oral agent according to antimicrobial susceptibility testing 24 to 48 hours after substantial clinical improvement, for total treatment of at least seven days [4].

The optimal treatment and duration for disseminated gonococcal infection is poorly studied. Antimicrobial susceptibility results direct the treatment of disseminated gonococcal infection, but pending susceptibility results, treatment should be guided by the clinical presentation. Meningitis treatment should continue for 10 to 14 days. Parenteral antimicrobial therapy for endocarditis should continue for more than four weeks [4].

After an average incubation of 21 days (range: 9 to 90 days), a painless chancre or ulcer appears at the anogenital infection site, with regional lymphadenopathy. The ulcer resolves in three to eight weeks by local immune clearance, after the bacteria have widely disseminated through blood and lymphatic systems.

Rash, mucocutaneous lesions, and generalized lymphadenopathy, the "classical triad" reflecting multisystem involvement, develop 4 to 10 weeks after the initial chancre [71]. Roughly 1% to 2% of patients develop neurologic complications during secondary syphilis.

The disease becomes asymptomatic following spontaneous resolution of secondary syphilis 3 to 12 weeks from onset. The first year is termed early latent, and afterward, late latent. Early latent syphilis is considered infectious because secondary disease recurs in 25% of patients [70].

Tertiary (late) syphilis occurs 10 to 40 years after initial infection in 33% of untreated patients. Inflammatory lesions can develop in bone (osteitis), skin (gummatous lesions), connective tissues of the cardiovascular system (aortitis, coronary vessel disease), and less often, in the respiratory tract, reproductive organs, lymph nodes, liver, or brain/CNS. This stage is potentially fatal.

Neurosyphilis results from CNS infection by T. pallidum and can occur at any syphilis stage. Early neurosyphilis manifests in the initial months or years of infection in cranial nerve dysfunction, meningitis, stroke, altered mental status, and auditory or ophthalmic abnormalities. Late neurosyphilis manifests 10 to 30 years after primary disease as progressive dementia or paralysis with brain and/or spinal cord involvement; optical involvement manifests as syphilitic uveitis, neuroretinitis, optic neuritis, and possibly blindness.

Infection of the visual system (ocular syphilis) or auditory system (otosyphilis) can occur at any stage of syphilis but is commonly identified during the early stages and can present with or without additional CNS involvement [4]. Ocular syphilis often presents as panuveitis, but limited forms are common, including conjunctivitis, anterior uveitis, posterior uveitis, optic neuropathy, and retinal vasculitis. Otosyphilis presents with combined cochlear and vestibular symptoms, including tinnitus, vertigo, and sensorineural hearing loss (unilateral or bilateral, rapid onset and progression).

Darkfield examinations and molecular tests for detecting T. pallidum directly from lesion exudate or tissue are definitive methods for diagnosing early syphilis [4]. In later stages or when lesions are absent, infection is diagnosed using serologic assays that detect antibodies in serum or cerebrospinal fluid (CSF). Different tests are used for detecting treponemal-specific antibodies against T. pallidum or nontreponemal antibodies against T. pallidum and similar infection. Both types of tests are required for diagnostic accuracy. The use of only one type of serologic test (nontreponemal or treponemal) is insufficient for diagnosis and can result in false-negative results among persons tested during primary syphilis and false-positive results among persons without syphilis or those previously treated [4]. Aside from patients with suspected neurosyphilis, other testing is not needed. Antibody tests may also be used to measure treatment response [30,72].

Patients may be negative for antibodies against T. pallidum in primary syphilis, especially in the first two weeks after symptom onset. With progression into secondary syphilis, antibodies to T. pallidum reach peak titers and may persist indefinitely regardless of disease state or prior therapy. To help differentiate active from past syphilis infection, tests are used to detect antibodies against nontreponemal antigens such as cardiolipin, a lipid antigen released by host cells damaged by T. pallidum. Nontreponemal antibodies are typically positive during current infection and negative following treatment or during late/latent syphilis [73].

Nontreponemal antibody tests are highly sensitive but low in specificity to T. pallidum, and false-positives can result from other conditions such as autoimmune disease, tuberculosis, or HIV. For the diagnosis of syphilis, a positive test result must be confirmed by a treponemal test. Common nontreponemal antibody tests include [30,72,74]:

Treponemal antibody tests are highly specific to T. pallidum. The majority of patients who test positive will have reactive treponemal tests for the remainder of their lives, regardless of adequate treatment and independent of disease activity [4]. However, 15% to 25% of patients treated during the primary stage revert to being serologically nonreactive after two to three years. Treponemal antibody titers do not predict treatment response and should not be used for this purpose. Nontreponemal antibodies disappear around three years after successful treatment, and positive treponemal tests require NNT confirmation to distinguish active infection (or reinfection) from previous resolved illness. Treponemal antibody tests include [30,70,72,74]:

Immunoassays may also be used to diagnose syphilis. Options include enzyme, multiplex flow, chemiluminescent, and microbead immunoassays.

Historically, serologic testing for syphilis used initial NNT screens such as the RPR, with positive results followed by FTA-ABS or TP-PA for confirmation. Although accurate, this analytic process is labor intensive and requires subjective interpretation by laboratory personnel [73].

Using enzyme or multiplex flow immunoassay to detect immune antibodies produced against T. pallidum (IgG, IgM, or IgG/IgM) is more popular today. These assays are highly sensitive and specific and allow objective interpretation of results and higher throughput [73,74].

The Mayo Clinic now performs syphilis screening by first using multiplex flow immunoassay to detect T. pallidum-specific IgG antibodies. IgG antibodies to syphilis can remain elevated despite appropriate antimicrobial treatment, and a reactive result does not distinguish recent from past infection. A positive multiplex flow immunoassay is followed by NNT testing using RPR; this provides supplemental serologic data, and indicators of syphilis disease state and treatment history [73].

Latent Syphilis

Latent syphilis is often identified after positive serologic testing in a patient without other obvious signs of disease. All such patients should be evaluated for secondary stage disease, including physical examination of accessible mucosal surfaces (e.g., oral cavity, perianal area, perineum and vagina in women, underneath the foreskin in uncircumcised men) for mucosal lesions [69].

Tertiary Syphilis

Limited information is available concerning clinical response and follow-up of patients with tertiary syphilis. They should be managed in consultation with an infectious disease specialist [4].

Neurosyphilis

Serologic testing is used to support a neurosyphilis diagnosis, but no single test has uniform specificity. Diagnosis is based on the combination of CSF abnormalities (e.g., CSF cell count, protein abnormality, reactive CSF-VDRL), systemic serologic test results, and neurologic signs and symptoms [75].

Patients of any syphilis stage and HIV status should be followed closely for new-onset symptoms and signs of neurologic (e.g., cognitive dysfunction, motor or sensory deficits, meningitis, stroke, hearing loss, cranial nerve palsies) or ophthalmic (e.g., uveitis, iritis, neuroretinitis, optic neuritis) disease. Evaluate suspected patients with CSF analysis, otologic exam, and ocular slit-lamp ophthalmologic exam [70,72].

When ocular manifestations are present, CSF examination is warranted even if other clinical neurologic findings are negative. Patients with known or suspected ocular syphilis should be referred to an ophthalmologist and treated for neurosyphilis even with normal CSF findings. In cases of ocular syphilis and abnormal CSF parameters, follow-up CSF studies are helpful in assessing response to treatment [4].

In early-stage syphilis, CSF abnormalities have been observed in association with negative clinical neurologic findings. In this context, abnormal CSF findings do not alter recommended treatment protocols [70,72].

Comorbid HIV Infection

HIV infection does not change treponemal and NNT diagnostics, but patients with advanced HIV infection/immunosuppression are more likely to have clinical and CSF abnormalities consistent with neurosyphilis [69].

Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin [4]. The desensitization process will be discussed in more detail later in this course.

CDC guidelines recommend follow-up clinical and serologic evaluation at 6 and 12 months after treatment; more frequent evaluation should be considered if opportunity is uncertain or repeat infection is a concern [4]. Patients with HIV should be clinically and serologically evaluated at 3, 6, 9, 12, and 24 months post-therapy, and in all patients with neurosyphilis, at 6, 12, 18, and 24 months post-therapy [82,83]. Treatment failure or re-infection is likely in patients with persistent or re-emerging signs or symptoms or a fourfold (or greater) increase in nontreponemal test titer for more than two weeks. Patients should be treated, HIV infection retested, and a CSF exam performed to help distinguish treatment failure from reinfection [4].

Optimal management with a less than fourfold decline in post-treatment titers is unclear. At a minimum, one should provide additional clinical and serologic follow-up and retest for HIV infection. Other considerations include a repeat course of treatment when follow-up cannot be ensured, and CSF exam to rule out unrecognized CNS infection. With negative CSF results, weekly injection of benzathine penicillin G 2.4 million units IM for three weeks is recommended [4].

By 6 to 12 months post-treatment, failure of nontreponemal test titers to decline fourfold can indicate treatment failure. However, at one-year post-treatment, 15% to 20% of treated primary and secondary syphilis patients will not achieve the fourfold decline in nontreponemal titer that defines response [81,86].

After 24 months, if nontreponemal titers fail to decline fourfold, CSF exam can be considered and treatment administered accordingly, although low initial titers (<1:8) might not decline [86,87,88].

When serologic titers fail to decline despite repeated courses of therapy for primary, secondary, or latent syphilis and negative CSF exams, the need for additional therapy or repeat CSF exam is unclear but is generally not recommended. Serologic response to treatment is also influenced by syphilis stage (with earlier stages more likely to decline fourfold and become negative), initial nontreponemal antibody titers (with lower titers less likely to decline fourfold than higher titers), and previous syphilis treatment (in whom nontreponemal titers decline more slowly) [86,87,88].

The appropriate course of action is also unclear for a missed weekly penicillin dose. Clinical experience suggests a 10- to 14-day interval between benzathine penicillin doses for latent syphilis may be acceptable before restarting the injection sequence. Pharmacologic considerations suggest a seven- to nine-day interval between doses, if feasible, is more optimal [77,78,79]. Missed doses are unacceptable in pregnant women treated for latent syphilis, and the full therapy course must be repeated with any missed dose [89].

Clinical follow-up and repeat nontreponemal antibody test assays at 6, 12, and 24 months, and CSF exam if observing the following [81]:

Data from studies cited in CDC guidelines indicate that, among immunocompetent persons and persons with HIV infection who are on effective antiretroviral therapy, normalization of the serum RPR titer predicts normalization of abnormal CSF parameters after neurosyphilis treatment [4,83,84]. Therefore, repeated CSF examinations are unnecessary when such patients exhibit serologic and clinical responses after treatment. Otherwise, if a satisfactory response to treatment is in question, repeat CSF examination may be prudent at six-month intervals. If CSF parameters have not normalized within 24 months, a repeat course of penicillin should be considered.

Sexual transmission of T. pallidum is thought to occur when mucocutaneous syphilitic lesions are present, which this is uncommon after the first year of infection. Persons sexually exposed to a patient diagnosed with primary, secondary, or early latent syphilis should be evaluated clinically and serologically and treated [4]. Anyone exposed to a sex partner within 90 days of diagnosis should be treated presumptively for early syphilis, even when serologic testing is negative. Anyone exposed to a sex partner more than 90 days before diagnosis should be treated presumptively for early syphilis if serologic test results are not immediately available and follow-up opportunity uncertain. If serologic tests are negative, no treatment is needed. If serologic tests are positive, deliver treatment based on clinical and serologic evaluation and syphilis stage.

Fluoroquinolone-based treatments might be effective, but optimal treatment duration has not been evaluated. Pregnant and lactating women should be treated with erythromycin. Use of doxycycline in pregnancy might be associated with discoloration of teeth, but the risk is not well defined; doxycycline is compatible with breastfeeding. Azithromycin 1 g orally once weekly for three weeks is probably effective based on its antimicrobial activity with chlamydia, but data are lacking on its use in lymphogranuloma venereum during pregnancy [4,46].

Persistent or recurrent bacterial vaginosis is common. Metronidazole gel can reduce the incidence of multiple recurrences, but efficacy may be lost when treatment is discontinued [111]. A sequential approach is suggested, with daily oral metronidazole or tinidazole, followed by daily intravaginal boric acid, and then suppressive long-term metronidazole gel [112]. Suppressive therapy with monthly oral metronidazole plus oral fluconazole can reduce bacterial vaginosis incidence and promote colonization with normal vaginal flora [113]. Persons with HIV infection have greater recurrence rates of bacterial vaginosis [114].

With allergy or intolerance to metronidazole or tinidazole, intravaginal clindamycin cream is preferred. Intravaginal metronidazole gel is helpful for those who lack allergy but do not tolerate oral metronidazole [4].

Treatment is recommended for all symptomatic pregnant women. Tinidazole should be avoided, but vaginal clindamycin is safe for pregnant women [115]. Treat symptomatic pregnant women with oral or vaginal metronidazole or clindamycin regimens used for nonpregnant women [116].

In men diagnosed with acute sexually transmitted epididymitis from chlamydial or gonorrheal infection, all sex partners within 60 days of symptom onset should be referred for evaluation, testing, and presumptive treatment. If the last sexual contact was more than 60 days previous, the most recent sex partner should be treated. Female partners should be linked to care; arrange expedited partner therapy and enhanced referral if delay is expected [121,122].

Following exposure, a papule develops and rapidly progresses to one or more pustular lesions, which rupture to form painful, purulent, shallow ulcers with a granulomatous base that bleeds readily. Multiple ulcers are common, particularly in women. Around 30% of patients develop painful inguinal lymphadenitis that may suppurate, become fluctuant, and spontaneously rupture. Spread beyond the genital tract is rare. Lesions tend to appear in the following sites [124]:

Diagnosis should first rule out other causes of genital ulcer disease. Definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media not widely available from commercial sources. Painful genital ulcer with tender suppurative inguinal adenopathy suggests a diagnosis of chancroid [123,125]. Probable diagnosis of chancroid can be made if all four of the following criteria are met:

Successful chancroid treatment cures the infection, resolves clinical symptoms, and prevents transmission. Advanced chancroid can result in scarring despite successful therapy. Ciprofloxacin has a cure rate of more than 90%, and azithromycin or ceftriaxone have advantages as single-dose therapy (Table 9). Chancroid culture is not routinely performed, which limits the information available on the current prevalence of antimicrobial resistance in the United States [4,126,127].

Uncircumcised men and patients with HIV are less responsive to treatment than circumcised or HIV-negative patients, and HIV testing should be performed when chancroid is diagnosed. Patients should be tested for HIV at the time chancroid is diagnosed. If the initial HIV test results were negative, the provider can consider the benefits of offering more frequent testing and HIV prophylaxis therapy to persons at increased risk for HIV infection [4].

Treatment During Pregnancy

Ciprofloxacin has low risk to the fetus during pregnancy but is potentially toxic during breastfeeding; alternate drugs should be used during pregnancy and lactation [46]. No adverse effects on pregnancy outcomes from chancroid have been reported [4].

Re-examine patients three to seven days after starting therapy. Ulcer symptoms usually improve by three days and objectively by seven days after successful therapy. Without improvement, clinicians should consider differential diagnosis, patient co-infection with another STI or HIV, treatment non-adherence, or an antimicrobial-resistant strain of H. ducreyi. Time to complete healing depends on ulcer size and location; large ulcers can require more than two weeks, and healing is slower in uncircumcised men with ulcers under the foreskin [4]. Patients with fluctuant buboes will experience symptomatic relief from drainage by needle aspiration, which may need to be repeated [123].

Management of Sex Partners

Even with symptom absence, sex partners should be examined and treated if they had sexual contact with the patients with chancroid in the 10 days preceding symptom onset [4].

Granuloma inguinale is characterized by slowly progressive, painless, red, raised, and ulcerated skin lesions. Regional lymphadenopathy is uncommon. Common sites of infection include [128,129]:

Following a 1- to 12-week incubation, the nodule slowly enlarges, becoming a raised, beefy-red, moist, smooth, foul-smelling lesion. The lesion slowly enlarges, often ulcerates, and may spread to other skin areas. Lesions heal slowly, with scarring. Secondary infections with other bacteria are common and can cause extensive tissue destruction. Occasionally, granuloma inguinale becomes systemic and spreads to the bones, joints, or liver; without treatment, anemia, wasting, and uncommonly death may occur [129,130].

Granuloma inguinale is suspected in patients with travel history from endemic areas with characteristic lesions. Diagnosis is confirmed microscopically by the presence of dark-staining Donovan bodies on tissue crush preparation of fluid from scrapings from the edge of lesions. Biopsy specimens are taken if the diagnosis is unclear or if adequate tissue fluid cannot be obtained because lesions are dry, sclerotic, or necrotic. The bacteria do not grow on ordinary culture media [128,130].

A limited number of studies suggest several antimicrobial regimens are effective for the treatment of granuloma inguinale (Table 10) [129]. Treatment can halt the progression of lesions. Healing typically proceeds inward from the ulcer margins, and prolonged therapy is usually required to permit granulation and re-epithelialization of ulcers. Relapse can occur 6 to 18 months after an apparently curative therapy response [4]. All patients should be followed until signs and symptoms have resolved.

First identified in the early 1980s, Mycoplasma genitalium causes nongonococcal urethritis in men. It is detected in 10% to 30% of men presenting with nonchlamydial nongonococcal urethritis and up to 40% with chronic nongonococcal urethritis [131]. The recent emergence and spread of M. genitalium are concerning because of increasing antimicrobial resistance to macrolides, the preferred mode of antibiotic treatment. The penicillins, cephalosporins, and other beta-lactam antibiotics disrupt bacterial cell wall synthesis and are ineffective against M. genitalium, which lacks a cell wall [132]. The prevalence of resistance to oral single-dose azithromycin 1 g (the common first-line treatment of urogenital M. genitalium) ranges from 44% to 90% in the United States, Canada, and Western Europe [4,131].

Despite growing concern over M. genitalium, there is little known of the long-term clinical consequences of infection. M. genitalium colonization/infection in men is associated with a 5.5-fold increased risk of nongonococcal urethritis. In women, M. genitalium has been linked to cervicitis, endometritis, PID, infertility, HIV, and adverse birth outcomes. The prevalence of M. genitalium in the United States among women is around 1%, compared with N. gonorrhoeae (0.4%) and C. trachomatis (3%). In contrast to previous contradictory findings associating M. genitalium and female genital tract pathology, more recent studies have confirmed this association. For example, 33% to 50% of PID cases are associated with N. gonorrhoeae and/or C. trachomatis, but many cases have unidentified etiology. Advances in detecting M. genitalium by NAAT are raising concerns that M. genitalium may play an important pathogenic role in cases in which other STIs are not identified. This issue is further complicated by several studies identifying M. genitalium treatment resistance among infected women [133].

Mycoplasma genitalium is a slow-growing organism. Culture can take up to six months, and few laboratories are able to recover clinical isolates. NAAT for M. genitalium is FDA-cleared for use with urethral, penile meatal, endocervical, and vaginal swab specimens [4]. More recently available is a diagnostic test using analyte-specific reagents to target M. genitalium. Any lab that performs in-house validation of the assay can use it for M. genitalium testing [134].

CDC guidelines recommend two-stage therapy approaches, using resistance-guided therapy when macrolide-resistance testing is available. Resistance-guided therapy has reported cure rates >90% [4]. In this approach, doxycycline, 100 mg twice daily for seven days is administered as initial (first-stage) empiric therapy, which reduces bacterial load and facilitates clearance. For patients with macrolide-sensitive M. genitalium infection, the second stage consists of high-dose azithromycin 1 gram orally then 500 mg once daily for three days. For those patients with macrolide-resistant infection, the second phase regimen is moxifloxacin 400 mg orally once daily for seven days [4]. If M. genitalium is detected by NAAT and resistance testing is not available, recommended treatment is doxycycline, 100 mg two times daily for seven days, followed by moxifloxacin 400 mg once daily for seven days [4]. When use of moxifloxacin is not feasible, an alternative regimen is initial stage doxycycline followed by azithromycin (1 g orally on day 1 then 500 mg once daily for 7 days) and a clinical test of cure 21 days after completion of therapy.

Recommended PID treatment regimens, which include doxycycline, are not effective against M. genitalium. If this organism is detected, and following initial empiric therapy for PID, a regimen of moxifloxacin 400 mg once daily for 14 days has been effective in eradicating the organism [4]. In settings in which M. genitalium testing is available, persons with persistent urethritis, cervicitis, or PID accompanied by detection of M. genitalium should be treated with moxifloxacin.

Fluoroquinolones other than moxifloxacin are not recommended for the treatment of M. genitalium. Microbiologic treatment failure (persistent bacterial detection) ranges from 30% to 67% after levofloxacin and 66% after ofloxacin. In contrast, cure rates for moxifloxacin range from 70% to 100%. The fourth-generation quinolones gatifloxacin and sitafloxacin have somewhat better efficacy against M. genitalium than levofloxacin and ofloxacin but are not available in the United States. However, treatment failures have been reported for both the 7- and 10-day moxifloxacin regimens, with few studies evaluating longer duration of treatment [134].

Over the years, gonorrhea has developed resistance to nearly every drug used to treat it, including sulfonamides, penicillin, tetracycline, and fluoroquinolones. Due to widespread resistance to these antibiotics, by 2007, only cephalosporins—including the oral antibiotic cefixime and the injectable antibiotic ceftriaxone—were left to effectively treat gonorrhea [28,58].

In 1986, the Gonococcal Isolate Surveillance Project (GISP) was initiated by the CDC to closely monitor how N. gonorrhoeae responds to antibiotics. These data are the early warning signs of resistance to recommended treatments. The marker for antibiotic response is the MIC, the lowest concentration of drug needed to stop bacterial growth and an indicator of susceptibility to treatment with a given antibiotic. An increase in MIC over time means greater antibiotic dose levels are required for effective treatment and that resistant strains have appeared and propagated [4,28,58].

The epidemiology of antimicrobial resistance has guided decisions about gonococcal treatment recommendations, which have evolved to circumvent changing antimicrobial resistance patterns [4,28,58]:

In 2012, evidence of emerging cefixime resistance led the CDC to issue new guidelines recommending against the use of cefixime in gonorrhea treatment. This change helped slow the emergence of cephalosporin resistance, but the only remaining recommended treatment option for gonorrheal infection is ceftriaxone IM combined with oral azithromycin [28,58].

This regimen continues to be generally effective, but CDC data indicate that resistance to azithromycin is emerging. During 2013–2014, the percentage of gonorrhea samples with elevated MICs of azithromycin increased by more than 300% (from 0.6% to 2.5%), the largest increase since azithromycin monitoring began. Gonorrhea remains more susceptible to azithromycin than other antibiotics such as penicillin (16.2% with elevated MICs in 2014) or tetracycline (25.3% with elevated MICs in 2014). Azithromycin with ceftriaxone remains effective against gonorrhea, but the data suggest time may be running out [28,58,146].

Azithromycin has shown efficacy in the treatment of primary and secondary syphilis. However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in multiple geographic areas in the United States. Concerns over emerging azithromycin resistance have discouraged its prescribing in STIs other than gonorrhea, except when recommended treatment options are not feasible [4].

When a candidate for treatment is skin-test positive to one of the penicillin determinants, the patient should be desensitized to penicillin, using a standard desensitization protocol, before proceeding with a specific penicillin regimen. This straightforward, relatively safe procedure can be performed with oral or intravenous penicillin. Oral desensitization is safer and easier to perform. Desensitization should take place in a hospital so serious IgE-mediated allergic reactions, which may occur, are rapidly treated. After the procedure is completed, the first penicillin dose is administered. Following desensitization, penicillin should be maintained continuously for the prescribed duration of the therapy course. After completion of a course of therapy, the desensitization procedure would need to be repeated if penicillin is required in the future [144,145].