After completing this continuing education article, the pharmacist should be able to:
Sexually transmitted diseases (STDs) are among the most common infectious diseases worldwide, and they are of significant public health importance. Over the years, a variety of new pathogens transmitted through sexual contact have been identified. Today, human immunodeficiency virus (HIV) is the most frequently occurring STD in the United States. Because of the wide range of clinical manifestations, potential complications, and the frequency of cotransmission of multiple STDs, the diagnosis and management of individuals with STDs remains challenging.
The most current information on the epidemiology, prevention, diagnosis, and management of STDs was provided by the Centers for Disease Control and Prevention (CDC) in guidelines updated in 2002.1 The purpose of this article is to review these recommendations and to discuss the potential role of the pharmacist in the counseling and education of patients with or at risk for STDs.
Several factors contribute to the prevalence of STDs. Cultural, demographic, and economic factors, combined with sexual behavior, help define the frequency of STDs in the United States. Age is among the most important demographic factors contributing to their incidence. The majority of STD cases occur in patients in their teens and twenties when they are at the peak years of sexual activity.2
The single greatest risk factor for contracting an STD is the number of sexual partners.2,3 As the number of sexual partners increases, so too does the risk of exposure to a person infected with an STD. Sexual preference also may contribute to the risk of transmission of STDs. For all major STDs, the incidence is much greater in men who have sex with other men than in the heterosexual population.4 In addition, prostitution and illicit drug use have been associated with a higher incidence of STDs.
For a number of STDs, the clinical manifestations overlap significantly, thus preventing a definitive diagnosis without microbiologic examination. To aid in narrowing the differential diagnosis, STDs are commonly categorized based on clinical presentation. This article will focus on diseases characterized by genital ulcers, as well as those characterized by urethritis and cervicitis. The CDC guidelines mentioned above provide a review of the STDs not discussed in this article.
Diseases Characterized by Genital Ulcers
In the United States, most sexually active individuals who have genital ulcers of an infectious etiology have genital herpes, syphilis, or chancroid.3 Genital herpes is the most prevalent. The distribution of these diseases throughout the country differs, based on geography and patient population. Importantly, each has been associated with an increased risk of acquiring other sexually transmitted diseases, including HIV infection. This article will deal specifically with the presentation, manifestations, and treatment of genital herpes and syphilis.
The word herpes comes from the Greek, meaning "to creep," and it has been used in medicine since antiquity. Genital herpes is caused by the herpes simplex virus (HSV) serotype 1 or 2. The majority of cases are caused by HSV-2. Infection with HSV-2 is lifelong, and currently antiviral therapy is not curative.5
Epidemiology of Genital Herpes
Humans are the only natural reservoir for this family of DNA viruses.5 In large population-based serologic testing, antibodies to HSV-2 are first identified after puberty and are correlated with the onset of sexual activity. In the United States, it has been shown that the seroprevalence of HSV-2 has increased from 16% to 22.7% in adults.6
Routes of Transmission of Genital Herpes
HSV is transmitted by direct contact with an infected person. This contact includes sexual contact with a person with active lesions or, more commonly, sexual contact with one who is asymptomatic but is shedding virus in genital secretions. Other modes of transmission include autoinoculation and neonatal transmission. It is important to note that the overwhelming majority of genital herpes is transmitted when a person feels well and appears normal but is asymptomatically shedding virus.7
Pathogenesis of Genital Herpes
HSV enters the susceptible host and replicates locally in cells of mucous membranes (Figure 1). Cells lyse, new virions are released, and these virions travel via lymph to nodes. Depending on a variety of host factors, the virus either will disseminate through the blood and seed viscera or the central nervous system (CNS), or it will remain latent in local nerve roots. Infection is lifelong, because the virus cannot be eradicated from the body.5,8 Disease manifestations are due to cellular destruction caused by the presence of the virus. Histopathology classically shows multinucleated giant cells with intranuclear inclusions.
The virus becomes latent and can periodically reactivate. Recurrences of genital herpes are to be expected, but currently there is no way to predict for an individual patient when or how often such recurrences will appear.9 In some patients, such factors as stress, sunlight, menses, or trauma may precipitate recurrences.10
Clinical Manifestations of Genital Herpes
Patients experiencing their first episode of genital herpes will note the presence of a vesicular eruption (Figure 2). The incubation period for genital herpes can be highly variable, ranging from 7 days to several years. The lesion will progress and rupture over the course of the next week to become a cluster of moist, shallow ulcers. New lesions may appear simultaneously as well. The ulcers begin to heal within 2 weeks, forming dry crusts. By day 21, lesions are generally healed, and viral shedding has decreased significantly.11 The ulcerative lesions are accompanied by regional, painful lymphadenopathy (in contrast with the presentation of primary syphilis; see Syphilis section).
Frequently, patients with their first outbreak can have systemic symptoms, including low-grade fever, headache, and constitutional symptoms. Recurrent genital herpes outbreaks are heralded with prodromal symptoms that include burning at the site of recurrence.12 Recurrent lesions appear within 24 hours and heal within 7 days.9
Treatment of Genital Herpes
Antiviral chemotherapy offers clinical benefit to most symptomatic patients. The major benefit of antiviral therapy is derived in patients with their first outbreak of genital herpes, and all such individuals should be offered treatment. 1,5,13 Treating recurrences can achieve a modest benefit (healing of ulcers 1 day sooner than in controls) and is not routinely recommended.1,5,14 Patients with recurrences benefit only if antiviral therapy is initiated within 24 hours of the recurrence. Antiviral agents also have been used as suppressive therapy on a chronic daily basis to partially control or reduce the signs and symptoms of herpes. It is important to note, however, that these drugs do not eradicate latent virus, nor do they affect the risk, frequency, or severity of recurrences after the drug is discontinued.1,14 See Table 1 for specific recommendations for the use of antiviral agents to treat genital herpes.1
Syphilis is a complex systemic illness caused by the spirochete Treponema pallidum. It holds a special place in the story of Western medicine, and its history makes for very fascinating reading, because many famous and infamous individuals have contracted the disease over the years.15
Syphilis is most commonly transmitted via sexual contact, but it also can be transmitted by close, direct, nonsexual contact, by congenital transmission, or as a blood-borne pathogen.16 A patient is most infectious early in the disease, especially when a chancre or mucous patch is present.
In all states, syphilis is a reportable disease. The number of cases of syphilis in the United States has consistently declined over the past 6 decades, after reaching a peak during World War II.2,3 National case rates reached an all time low in 1999-2000, but there has since been a small increase, in particular in the southeastern United States from Maryland to Florida.3
Pathogenesis of Syphilis
T pallidum is inoculated via 1 of the routes described above. The infectious dose varies from patient to patient, but in rabbits as few as 4 treponemes can establish infection.17 Within hours to days, spirochetes disseminate from the local inoculation site via the bloodstream and lymphatics. Lesions will appear once 10 7 organisms per gram of tissue have been achieved.17 The incubation period varies, depending on the inoculum size.
Stages of Infection with Syphilis
Primary Infection. This stage of infection encompasses the development of the primary lesion (called a chancre). This lesion occurs at the inoculation site. On average, the incubation period is 21 days (range, 9-90 days).18,19 The chancre itself is a painless ulcer with a clean base, rolled or raised edges, and no exudates. It usually presents as a single lesion unless the patient is immunocompromised. The lesion may be accompanied by painless regional lymphadenopathy. The chancre will heal with scarring within 2 to 8 weeks, regardless of whether a patient receives effective antimicrobial treatment.18,19
Secondary Infection. If untreated, a primary infection will progress to a secondary or disseminated stage of infection. Manifestations of secondary syphilis usually occur 2 to 12 weeks after the appearance of the chancre and between 1 and 6 months after inoculation.18,19 This stage of infection is characterized by the greatest number of spirochetes in the body. It has been referred to as "the great imitator" because it can manifest itself in a variety of ways involving any organ system. Manifestations include a rash that can present as macular, papular, maculopapular, papulopustular, or pustulosquamous. These manifestations never are vesicular. The distribution of these lesions can be anywhere on the body, including the palms and soles of the feet.
In addition, lesions (called condylomata lata) may be seen in the moist intertriginous areas of the body as gray-white plaques, or silvery-gray mucous patches may appear on any mucous membrane. Some individuals experience patchy alopecia. These lesions can persist for days to weeks. When they are scraped and examined microscopically, many spirochetes will be visible.
Exposed lesions are infectious. Other symptoms associated with this stage of infection include low-grade fever, malaise, pharyngitis, and CNS symptoms. Relapses of secondary syphilis can occur up to 4 years after the initial infection in untreated patients.5,18,19
Latent Infection. After the signs and symptoms of secondary disease subside, untreated patients enter a latent period, in which disease can be diagnosed only by serologic testing. Latent syphilis is divided into early and late latent stages. Early latent syphilis is defined as occurring in an asymptomatic patient with syphilis of less than 1 year's duration. Relapses of syphilis are most likely to occur during this stage of syphilis. Late latent infection has been defined as occurring in an asymptomatic patient with syphilis of >1 year's duration or in patients with an unknown duration of infection. Relapses rarely occur during this stage, and individuals with late latent disease are not considered infectious to others.5,18,19
Late or Tertiary Syphilis
This stage of disease refers to clinically apparent or inapparent disease that develops in up to one third of untreated patients. Most of the lesions involve the aorta or the arteries of the CNS. Granulomatous lesions (called gummas) can present in any area of the body as well. Neurosyphilis also is included as part of tertiary disease. It can be characterized as meningovascular disease, manifesting as a stroke or seizure (occurring 5-10 years after infection); parenchymatous disease, manifesting as a combination of psychiatric abnormalities and neurologic deficits (usually 15-20 years after infection); or tabes dorsalis, manifesting as a "footslap" with a wide gait and incontinence (25-30 years after infection).20,21
Treatment of Syphilis
Although there has never been a well-controlled, prospective study to determine the optimal dose and duration of therapy, penicillin is the treatment of choice for all stages of syphilis infection, based on well-established efficacy over many years of clinical use.1,5 The use of other antimicrobial agents to treat syphilis has been complicated by the fact that T pallidum cannot be cultivated by typical microbiologic culture techniques.22 As such, a wide range of antimicrobial agents have not been subjected to in vitro assessment of their activity against this organism. The current recommendations for the treatment of syphilis are outlined in Table 2.1 It is important to note that pregnant women and HIVinfected individuals with syphilis who are allergic to penicillin should undergo desensitization and be treated with penicillin therapy.1 Guidance for monitoring the response to treatment is provided in Table 3.1
Adverse Reactions Associated with the Treatment of Syphilis
A reaction called the Jarisch-Herxheimer reaction can occur after treatment of syphilis. This reaction typically occurs within 1 to 2 hours after the initial treatment and is most common in patients treated with penicillin-based regimens.23 It manifests with an abrupt onset of fever, chills, myalgias, headache, tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. It is most commonly seen in those treated for secondary syphilis, but it can occur in any stage of disease.5 The reaction is self-limited and lasts from 12 to 24 hours. Patients should be warned of the reaction prior to treatment. Treatment for the reaction includes a nonsteroidal anti-inflammatory drug or acetaminophen for 24 to 48 hours after treatment. A single 60-mg dose of prednisone can abort the reaction and should be recommended for patients with cardiovascular or symptomatic neurosyphilis and for pregnant patients to avoid catastrophic consequences.24
Diseases Characterized by Urethritis and Cervicitis Disease Presentation
Neisseria gonorrhoeae is a gram-negative diplococcus organism estimated to cause up to 1 million infections per year in the United States.3 Gonococcal urethritis, if untreated, spontaneously resolves after several weeks, and almost all patients are symptom-free within 6 months.25 Asymptomatic patients serve as carriers of infection. Complications of gonococcal urethritis include sterility and epididymitis, but they are rare due to the availability of effective antimicrobial therapy.
Other sites of gonococcal infection include the anus, rectum, pharynx, and eye. Anorectal and pharyngeal gonococcal infections often occur in men who have sex with other men.26 Up to 90% of these infections are asymptomatic, resulting in a substantial number of asymptomatic carriers.27 Gonococcal infection of the pharynx is more difficult to eradicate than infection at urogenital and anorectal sites. Few antimicrobial regimens reliably cure >90% of infections.1
Chlamydia trachomatis is an obligate intracellular parasite, which accounts for up to 50% of nongonococcal urethritis (NGU).3 NGU typically produces less severe and less frequent dysuria and discharge. In addition, chlamydial infections are more often asymptomatic than is gonococcal urethritis.28 Unfortunately, the 2 pathogens cannot be reliably differentiated, based on clinical manifestations. In addition, it is estimated that coinfection with Chlamydia occurs in up to 60% of patients with gonorrhea.28
Urethritis is the most common manifestation in men and is characterized by dysuria and urinary frequency followed by profuse urethral discharge. Asymptomatic infections are common. The most significant bacterial pathogens in men who have urethritis are N gonorrhoeae and C trachomatis.3
The most common manifestation of C trachomatis in women is mucopurulent cervicitis, defined as a purulent endocervical exudate visible in the endocervical canal or in a swab specimen. Symptoms tend to be nonspecific and may include vaginal discharge (most commonly), dysuria, urinary frequency, and abnormal discharge. Infection often is asymptomatic, however. Infection may extend to the endometrium or fallopian tubes in more than 15% of women, causing abdominal pain and pelvic tenderness.29
Serious chlamydial infections are the most common cause of "silent" pelvic inflammatory disease (PID). They also are associated with ectopic pregnancy and infertility. Of particular concern are new data suggesting that chlamydial cervicitis increases the risk of transmission of HIV.30 Complications of gonorrheal infections include disseminated gonococcal infections and PID involving the joints and CNS. During pregnancy, gonococcal infection may lead to spontaneous abortion, premature rupture of fetal membranes, and premature delivery.31,32
Treatment of Urethritis and Cervicitis
Coinfection with C trachomatis often occurs among patients with gonococcal infection. Therefore, treatment of such patients for chlamydial infection is appropriate and cost-effective when diagnostic tools are unavailable. The CDC recommends dual therapy, because the cost to treat a patient for chlamydial infection is less than the cost of testing.1 Table 4 provides the CDC-recommended regimens for the treatment of uncomplicated gonococcal infections of the cervix, urethra, and rectum.1
The cephalosporins recommended include cefixime and ceftriaxone. Extensive experience continues to support the use of ceftriaxone when given as a single intramuscular (IM) injection for the treatment of uncomplicated gonorrhea at all anatomic sites.33 The only oral cephalosporin recommended is cefixime.1 It possesses in vitro activity similar to ceftriaxone but is unable to reach and sustain the same bactericidal levels. The advantage over ceftriaxone lies in the ease of oral administration. Alternative single-dose cephalosporin regimens include ceftizoxime 500 mg IM, cefoxitin 2 g IM with 1 g of oral probenecid, and cefotaxime 500 mg IM. These cephalosporins offer no advantage over ceftriaxone.
Fluoroquinolones also are recommended for the treatment of gonorrhea.1 A single oral dose of ciprofloxacin, ofloxacin, or levofloxacin is effective in treating infection from >95% of gonococcal strains.34 Alternative fluoroquinolone regimens include gatifloxacin 400 mg, norfloxacin 800 mg, and lomefloxacin 400 mg. Spectinomycin 2 g IM is useful for patients who cannot tolerate cephalosporins or fluoroquinolones, but it is expensive.
Quinolone-Resistant Neisseria Gonorrhoeae (QRNG)
Since 1993, the CDC has recommended the use of fluoroquinolones in the treatment of gonorrhea.35 QRNG, however, continues to be identified more frequently, most commonly in Asia and the Pacific region.36 In Hawaii, the CDC's Gonococcal Isolate Surveillance Project determined that QRNG accounted for 20% of all gonococcal isolates tested.36 In addition, several sites in California (San Francisco, Long Beach, Orange County, and San Diego) have reported increasing prevalence of QRNG.36 The CDC recommends that fluoroquinolones continue to be used as first-line agents in the United States as long as QRNG isolates remain <1%.1,36
In July 2002, Wyeth Pharmaceuticals announced the discontinuation of the production of cefixime in the United States.37 Cefixime remains the only oral regimen that has maintained consistent activity against N gonorrhoeae.
The discontinuation of US cefixime production has prompted the CDC to evaluate additional oral alternatives for the treatment of uncomplicated gonorrhea.38 The agent should cure >95% of urogenital infections in order to be recommended as a viable treatment option. Treatment with either cefuroxime or cefpodoxime (200 mg) fails to meet the criteria for efficacy for urogenital infections, and their efficacy in pharyngeal infections is unacceptable. Data are limited regarding the use of a higher dose of cefpodoxime (400 mg) as well as ceftibuten. A 2-g dose of azithromycin is effective in the treatment of both urogenital and pharyngeal infections but is not recommended because of the cost and an unacceptable gastrointestinal (GI) side-effect profile. As a result, either ceftriaxone or a fluoroquinolone remains the alternative of choice in the absence of cefixime. In addition, where QRNG is prevalent, IM ceftriaxone remains the only CDC-recommended alternative.
Table 5 provides the CDC-recommended regimens for the treatment of chlamydial infections. The results of clinical trials indicate that azithromycin and doxycycline are equally effective, although the single-dose azithromycin regimen has the advantage of improved compliance.39,40
Alternative regimens include erythromycin, ofloxacin, or levofloxacin. Erythromycin is less effective than both azithromycin and doxycycline, and its GI side effects preclude its routine use. Ofloxacin is equally effective but more expensive and offers no advantage over the other agents. Clinical data with levofloxacin are lacking, but the similarity of its pharmacology and in vitro activity to those of ofloxacin suggest its efficacy. Other fluoroquinolones either lack data or have not been shown to be effective against C trachomatis.
Pregnancy and Gonococcal Infection. Pregnant women infected with N gonorrhoeae should be treated with a recommended or alternative cephalosporin because fluoroquinolones are contraindicated in pregnancy. Women who cannot tolerate a cephalosporin should be given a 2-g IM dose of spectinomycin.
Pregnancy and Chlamydial Infection. Tetracyclines and fluoroquinolones are contraindicated during pregnancy. The CDC recommends erythromycin base 500 mg qid for 7 days or amoxicillin 500 mg tid for 7 days. In addition, clinical experience along with limited data suggests that a 1-g dose of azithromycin is safe and effective in this setting.41,42 Repeat testing 3 weeks after completion of therapy is recommended for all pregnant women, because these regimens may be less effective and the extended durations of erythromycin and amoxicillin may result in poor compliance.1
Management of Sex Partners. Patients should be instructed to refer their sex partners for evaluation and treatment. All sex partners who have N gonorrhoeae or C trachomatis infections should be evaluated and treated for both infections if their last sexual contact with the patient was within 60 days before the onset of symptoms or diagnosis of infection. The most recent sex partner should be evaluated even if the time of last contact exceeds 60 days. Both parties should be instructed to abstain from sexual intercourse until both have completed therapy. Abstinence should be continued until 7 days after a single-dose regimen or until completion of a 7-day regimen.1
Follow-Up. Except for pregnant women, a test-of-cure visit is not necessary for patients treated with a CDC-recommended regimen unless noncompliance is suspected. Patients who have symptoms that persist despite therapy, however, should be reevaluated. Reinfection is more common than treatment failure, indicating a clear need for patient education with emphasis on treatment of sex partners and abstinence during treatment.
In addition to the effective treatment of STDs, preventing these infections and their transmission is equally important.43 Pharmacists can play a critical role in the counseling and education of patients who are at increased risk for STDs.
Effective communication between the pharmacist and patients is essential in building a successful relationship. This relationship allows for the delivery of prevention messages that are patient-specific, identifying behaviors that place patients at increased risk for STDs. Treating patients with respect and compassion and without passing judgment are important skills in successful patient counseling. The pharmacist can promote the appropriate use of various prevention methods?such as condoms, spermicides, and abstinence? as well as compliance during treatment.44,45
The most obvious way to avoid transmission of STDs is to abstain from sexual intercourse. Other than complete abstinence, the most effective way to prevent STD transmission is to maintain a mutually monogamous relationship with an uninfected partner. Vaccination also is an effective means to prevent the transmission of certain STDs. Because the hepatitis B virus often is transmitted through sexual intercourse, vaccination is recommended for all persons being evaluated for an STD.1 The hepatitis A vaccine also is recommended for men who have sex with other men and for illegal drug users.1
Male latex condoms, when used appropriately, are effective in preventing sexual transmission of HIV infection and reducing the risk for other STDs. Their overall efficacy is 98%.1,45 In order to be effective, however, male condoms must be used consistently and correctly to prevent STDs.
When a male condom cannot be used, sex partners may consider using a female condom. The female condom is an effective barrier to viruses, such as HIV.46 Limited studies have evaluated the efficacy of the female condom in preventing STDs. Soper et al demonstrated that compliant use of the female condom resulted in the prevention of vaginal trichomoniasis.47 Two other studies have shown no clear enhancement of STD prevention through the use of the female condom.48,49 If used appropriately, the female condom may reduce the risk of transmission of STDs.
The use of spermicides alone is not recommended for STD prevention. Recent data indicate that vaginal spermicides are ineffective in preventing STDs, such as gonorrhea, Chlamydia infection, or HIV.50 The use of nonoxynol-9 has resulted in the development of genital lesions, which may be associated with an increased risk of transmission of HIV.1,51
In addition, condoms lubricated with spermicides are no more effective than other lubricated condoms in preventing the transmission of HIV and other STDs. In fact, they are more costly and have been associated with the development of urinary tract infections in women.1,52
Neither vaginal sponges nor diaphragms should be used to protect women against HIV infection. The sponge may protect against gonorrhea and Chlamydia infection but is associated with an increased risk of vaginal candidiasis.1,53 Diaphragm use may protect against gonorrhea, Chlamydia infection, and trichomoniasis, but no concrete data exist.54 Contraceptive methods such as hormonal contraception are not mechanical or chemical barriers and offer no protection against HIV or other STDs. Women who use hormonal contraception should be encouraged to use a barrier method to protect against STDs.
When patients are prescribed medications for the treatment of an STD, the pharmacist also can provide counseling on the side effects associated with the specific STD therapy, as well as promoting abstinence during treatment. Cotransmission of HIV with other STDs is becoming increasingly more common. With HIV being the most common STD today, pharmacists may encourage patients to consider HIV testing if their specific behaviors place them at an increased risk.
STDs continue to be an important health care issue. As new pathogens are identified, the management of patients with a sexually transmitted infection remains challenging. Pharmacists as health care professionals should remain abreast of current treatment issues in order to provide appropriate education to patients.
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Valid for credit through May 31, 2007.
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Treatment of Sexually Transmitted Diseases
(Based on the article starting on page 96.) Choose the 1 most correct answer.
1. Human immunodeficiency virus (HIV) is the most frequently occurring sexually transmitted disease (STD) in the United States.
2. Genital herpes, syphilis, and chancroid have each has been associated with an increased risk of acquiring other sexually transmitted diseases, including HIV infection.
3. Which of the following is the treatment of choice for a woman with mucopurulent cervicitis who is not pregnant and has no drug allergies?
4. A 26-year-old man presents to the local clinic for evaluation of painful genital lesions. He has a history of genital herpes, with approximately 1 to 2 outbreaks per year. He noted a prodrome prior to this most recent eruption that was consistent with his previous bouts with genital herpes. Which of the following is the preferred regimen to treat this patient's episode of genital herpes?
5. Which of the following STDs can be prevented by vaccination?
6. Which of the following is the treatment of choice for syphilis at any stage in a pregnant woman who has a severe allergy to penicillin?
7. What side effect can be commonly seen within hours of the treatment of a patient with syphilis?
8. During what stage of syphilis is the chancre present?
9. Which of the following diseases is associated with a painful genital ulcer and painful inguinal adenopathy?
10. For which of the following disease pairs is clinical presentation indistinguishable and should empiric therapy be provided to treat both diseases?
11. Which of the following diseases is the most common cause of "silent" pelvic inflammatory disease that can lead to infertility in women?
12. Which of the following is the single greatest risk factor for contracting STDs?
13. Which of the following is the most common viral cause of genital ulcers?
14. Which of the following is the most correct statement regarding genital HSV?
15. A 40-year-old native of Hawaii is seen in the clinic for dysuria, urinary frequency, and discharge. Gram stain reveals white blood cells containing intracellular gram-negative diplococci. A diagnosis of gonococcal urethritis is made. He has no known drug allergies. Which of the following regimens is most appropriate to treat his infection?
16. Which of the following is an alternative option recommended by the Centers for Disease Control and Prevention for the oral treatment of uncomplicated gonococcal infection in the absence of cefixime?
17. Which of the following regimens would you recommend for a pregnant patient with suspected cervicitis who has no known drug allergies?
18. Vaginal sponges and diaphragms should not be used to protect women against HIV infection.
19. Which of the following should not be a task performed by a pharmacist in STD prevention?
20. Which of the following prevention methods has been shown to be the most effective in decreasing the transmission of STDs?
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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