a. Pregnant women—Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnant women.
The 2006 CDC treatment guidelines recommend either amoxicillin, 500 mg orally three times daily for 7 days, or azithromycin, 1g single dose orally, in this patient population (see Table 13–4). Erythromycin, previously a first-line agent in the 2002 CDC treatment guidelines, is
now listed as a alternative agent in the 2006 guidelines (see Table 13-4). Azithromycin was moved to a first-line agent in the 2006 guidelines because: 1) recent clinical trials of azithromycin versus comparator regimens (erythromycin or amoxicillin) in chlamydia-infected pregnant women have demonstrated azithromycin to be safe and just as or more efficacious as the comparator regimens, 2) anecdotal experience and discussion with experts suggested azithromycin was far more widely used than erythromycin or amoxicillin in these patients, and 3) erythromycin is poorly tolerated in pregnant women, which leads to greater noncompliance and lower efficacy.
All three antibiotics are pregnancy category B drugs.
b. Adolescents—Although there is some evidence for development of bone and joint disease in juvenile ani- mals treated with fluoroquinolones, there is sufficient clinical experience in human adolescents (especially those
>45 kg) to support use of the alternatively recommended fluoroquinolone regimens for chlamydia if doxycycline or azithromycin cannot be used.
c. HIV-infected individuals—There are no data to suggest that the efficacy of recommended antimicrobial regimens for chlamydia are altered in HIV-infected indi- viduals, and the CDC recommends the same regimens in these patients.
Table 13–4.Antimicrobial therapy for uncomplicated genital chlamydial infection.
Recommended Regimen Alternative Regimen
Nonpregnant patients Azithromycin, 1 g PO in a single dose Ofloxacin, 300 mg PO twice daily for 7 d
or or
Doxycycline, 100 mg PO twice daily Levofloxacin, 500 mg PO once daily for 7 d
for 7 d or
Erythromycin base, 500 mg PO 4 times daily for 7 d
or
Erythromycin ethylsuccinate, 800 mg PO 4 times daily for 7 d
Pregnant patients Azithromycin, 1 g PO in a single dosea Erythromycin ethylsuccinate, 800 mg PO 4 times daily for 7 d
or or
Amoxicillin, 500 mg PO 3 times daily Erythromycin ethylsuccinate, 400 mg PO
for 7 d 4 times daily for 14 d
or
Erythromycin base, 250 mg PO 4 times daily for 14 d
or
Erythromycin base, 500 mg PO 4 times daily for 7 d
aRecent literature supports the efficacy and safety of this regimen, and anecdotal experience suggests it is used far more widely than either erythromycin or amoxicillin for chlamydia-infected pregnant women.
Based on Centers for Disease Control and Prevention; Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006.MMWR Recomm Rep2006;55(RR-11):1–94.
82 / CHAPTER 13
B. OTHERMANAGEMENTCONSIDERATIONS
1. Sexual activity—To prevent transmission to unin- fected individuals, it is recommended that chlamydia- infected patients be instructed to abstain from sexual activity until completion of a recommended treatment regimen (ie, 7 days after receiving single-dose azithromycin or after finishing a 7-day course of doxy- cycline). For those persons unlikely to abstain during this period, strict compliance with condom use should be reinforced to prevent further transmission. Patients should also use these prevention measures until their sex partners have completed therapy.
2. Management of sex partners—Treatment of sex part- ners of chlamydia-infected patients is important, both to prevent reinfection of the patient and to prevent further transmission to other susceptible individuals. Traditionally, chlamydia-infected patients have been instructed by providers to notify their partners that they have been exposed to chlamydia and should themselves be seen by a provider for testing and treatment. However, high rates of chlamydia reinfection suggest such partner notification practices often do not lead to treatment of the sex partner.
Recent studies have explored the feasibility and effi- cacy (in preventing recurrence of chlamydia) of patients or providers delivering medication or a prescription directly to the sex partner (ie, expedited partner therapy [EPT]). Although further studies are needed, it appears that EPT is feasible and may decrease rates of chlamydia recurrence. There are, however, some concerns with EPT. One concern is the risk for an allergic reaction to the EPT in the sex partner, but serious drug reactions to doxycycline or azithromycin are very rare. There is some concern about the legality of EPT, as this issue is not clearly addressed in most states. However, anecdotal evi- dence and discussion with other experts suggests EPT is already a widespread clinical practice. An additional concern centers on the delivery of medication by male patients to female sex partners who have subclinical PID;
providing EPT to these partners might deter them from seeking evaluation by a health care provider, thus lead- ing to treatment for PID that may be insufficient.
However, many of these female partners might not have sought provider evaluation anyway, and EPT may pro- vide some benefit. Finally, another potential concern with EPT is reduced opportunities to screen partners for other STDs, including HIV infection, and to provide risk reduction education. Clinicians who use EPT are encouraged to provide educational materials for the partners and encourage them to seek evaluation, which will allow examination for clinical evidence of complica- tions and testing for other STDs.
3. Follow-up and “test of cure”—Nonpregnant patients with uncomplicated genital chlamydial infection do not need repeat clinical or diagnostic evaluation after completion of therapy unless symptoms or signs of
infection persist or recur. However, test of cure following treatment of uncomplicated genital chlamydial infec- tions—usually more than 3 weeks after treatment—is recommended for pregnant women, a population in which treatment failures could lead to both maternal and neonatal complications.
4. Approach to treatment failure—Chlamydia-infected patients with symptoms or signs of infection that persist or recur within a short time period (<4 weeks) after treat- ment are often labeled as “treatment failures.” The first step in managing such patients is to repeat the clinical and diagnostic evaluation. This is done to confirm the presence of C trachomatisand to rule out other STDs. It is recommended that patients with clinical findings sug- gestive of chlamydial infection (urethritis, cervicitis, etc) receive empiric treatment with one of the CDC-recom- mended treatment regimens. Most cases of “treatment failure” are a result of reinfection of the patient by an untreated partner. Therefore, the next step is to ensure that sex partners receive treatment and both the patient and partner abstain until treatment is complete.
No studies have definitely proved that treatment failure in the absence of reexposure to an infected partner occurs following recommended chlamydia treatment regimens, but there is indirect evidence suggesting it may. There is also no strong evidence to support that treatment failure is due to resistant C trachomatisisolates. Antibiotic resistance can be induced in vitro in C trachomatis, but wild-type resistance does not appear to be common in clinical iso- lates or to result in sustained transmission.
5. “Repeat testing” to identify chlamydia recurrence—
Recurrence of chlamydial infection is common in women, occurring in 10–20% within 6 months of a prior chlamy- dial infection. The rate of recurrence in men is unclear, but our clinical experience suggests it is common. Recurrence of chlamydial infection can lead to upper genital tract complications in men and women, and may serve as a reservoir for repeated chlamydial infections.
The current CDC treatment guidelines advise that all women with chlamydial infections be retested for chlamydial infection in about 3 months after treatment to rule out reinfection, and we believe that strong con- sideration should also be given to rescreening high-risk men following chlamydial infection if resources permit.
Clinicians should have a system in place to recall patients treated for chlamydial infection for retesting in about 3 months. Some researchers are evaluating the feasibility of having patients repeat chlamydial testing by home self-collection and then mail in specimens (urine in men and vaginal swabs or urine in women).
Centers for DiseccControl and Prevention; Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006.
MMWR Recomm Rep 2006;55(RR-11):1–94. [PMID:
16888612] (These widely accepted guidelines, developed in
GENITAL CHLAMYDIAL INFECTIONS / 83
consultation with professionals knowledgeable in the field of STDs, provides recommendations for management of chlamy- dial infections).
Geisler WM. Approaches to the management of uncomplicated genitalChlamydia trachomatisinfections.Exp Rev Anti Infect Ther2004;2:771–785. [PMID: 15482239] (Reviews current and future approaches to management of chlamydia).
Golden MR. Expedited partner therapy for sexually transmitted diseases.Clin Infect Dis2005;41:630–633. [PMID: 16080085]
(Informative editorial that includes a summary of the ran- domized, controlled trials of EPT for chlamydial infection.) Suchland RJ, Geisler WM, Stamm WE. Methodologies and cell
lines used for antimicrobial susceptibility testing of Chlamydia spp. Antimicrob Agents Chemother2003;47:636–642. [PMID:
12543671] (This article provides a basis for standardizing the methodologic approach and interpretation of antimicrobial testing of Chlamydia, and is one of the few studies to date assessing correlation of clinical outcomes in chlamydial infec- tions with results of susceptibility testing).
When to Refer to a Specialist
Patients who present with recurrent C trachomatisinfec- tions and who deny reexposure to an untreated sex part- ner may benefit from referral to a specialist. Chlamydia genotyping is a tool we and other researchers have utilized to determine with a reasonable certainty whether the chlamydia strains in such patients with recurrent chlamydia are the same or a different genotype (the latter likely representing new infection). In those presenting with recurrent infection with the same chlamydial geno- type, antimicrobial susceptibility testing may also be considered. However, such testing currently lacks a stan- dardized methodology and is performed by us and only a few other researchers. Finally, referral to a urologist or gynecologist may also be of benefit in evaluating whether an upper genital tract infection (in men, prostatitis or epididymitis; in women, PID) may be present and serving as a nidus for reinfecting the lower genital tract.
Prognosis
Initiation of appropriate antimicrobial therapy leads to improvement and eventual resolution of symptoms and
signs of uncomplicated genital chlamydial infection within the first few days of therapy and to clinical and microbiologic cure after the completion of therapy in most patients. The key to prevention of recurrent chlamy- dial infection is ensuring patient compliance with treat- ment, achieving treatment of sex partners, providing STD education, and reenforcing the use of barrier pre- cautions. With the availability of highly sensitive diag- nostic tests for chlamydia (ie, NAATs), continued efforts toward sex partner treatment, rescreening chlamydia- infected women in a few months, and routine yearly chlamydia screening in women, we anticipate further decline in the prevalence of chlamydial infection and its associated complications in the United States.
Relevant Web Sites
[Centers for Disease Control and Prevention fact sheet on chlamydia:]
http://www.cdc.gov/std/chlamydia/STDFact-Chlamydia.htm
PRACTICE POINTS
• Up to 50% or more of women with endocervical chlamydial infection have concomitant urethral infection and may present with painful urination or urinary frequency, or both.
• NAATs are the preferred and recommended means for detecting C trachomatisinfection.
• Clinicians should have a system in place to recall patients treated for chlamydial infection for retesting in about 3 months.
84 General Considerations
Herpes simplex virus (HSV) infections are endemic in the United States and are a cause of recurrent genital and oral ulcerative disease. Genital herpes infection can be caused by type 2 virus (HSV-2), or less frequently by type 1 (HSV-1). Although most infections are asympto- matic, genital HSV infection, whether type 1 or 2, can cause vesicular and ulcerative disease in adults and severe systemic disease in neonates and immunocompromised individuals. Genital HSV infection increases the risk of HIV acquisition in infected persons.
HSV-2 transmission is almost always sexual, whereas HSV-1 is usually transmitted through nonsexual skin- to-skin contact. Current estimates place the incidence of HSV-2 infection at more than 1.5 million cases annu- ally. In the general population, HSV-2 seroprevalence is low for persons younger than 12 years of age, rises sharply following onset of sexual activity, and peaks by the early 40s. HSV-2 seroprevalence in the United States rose 30% between 1978 and 1991 to 21.7%. The over- whelming majority of individuals with genital HSV infection have undiagnosed initial infections and unrec- ognized recurrences. Orolabial HSV-2 infection is rare and is almost always associated with genital infection.
HSV-1 infection frequently occurs as orolabial infec- tion in childhood, and approximately 20% of children younger than 5 years of age are seropositive. The sero- prevalence of HSV-1 rises almost linearly with increas- ing age to approximately 70%. In the general population over the past decade, HSV-1 has become an increasingly common cause of genital infection, with an estimated 50% of newly acquired genital herpes attributable to it in some populations.
Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105–1111. [PMID: 9329932] (Classic article.)
Pathogenesis
Primary HSV infection occurs at mucosal sites of inoc- ulation (see Figure 14–1), with retrograde infection propagating to sensory nerve ganglia. Following resolu- tion of primary infection, HSV enters a latent state in sensory nerve ganglia from which reactivation may occur to cause active infection at any mucosal sites innervated by the nerve ganglia.
During primary HSV infection, natural killer cells are important effectors of immunity. Their activation depends on the production of several cytokines in response to the infection. These cytokines also have direct and indirect effects that are important for limit- ing replication of the virus. As the immune response matures, HSV clearance from infected tissues is T-cell mediated, involving cytokine-mediated effector mecha- nisms and direct cytolysis of virus-infected cells. In mice and humans, both CD4 and CD8 T cells are important in resolution of infection. Antibody may play a limited role in controlling HSV infection as well.
The efficiency of the immune response appears to influence the quantity of virus establishing latency in the ganglia. Although the elements contributing to this control are incompletely known, interferon-γ(IFN-γ) is likely to be important. IFN-γ activates antiviral genes that inhibit HSV replication and may be required for early decrease in local HSV viral titers. However, it appears from murine models that both IFN-γ and T-cell
Peter Leone, MD
14
Genital Herpes
ESSENTIALS OF DIAGNOSIS
• Most individuals with genital herpes are unaware of the infection but are able to transmit it to others.
• Type-specific serology allows reliable differentia- tion of chronic type 1 from type 2 infection.
• Clinical diagnosis should be confirmed by diag- nostic testing of the genital lesion (culture or polymerase chain reaction [PCR]) or a type-specific serologic assay.
Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use.
GENITAL HERPES / 85
response can maintain viral latency and clear peripheral infections.
Prevention
There are multiple proven ways to prevent the acquisi- tion and transmission of genital herpes. There are no
“right” answers for prevention, and each patient must determine those best suited for his or her lifestyle. All patients diagnosed with genital herpes should be edu- cated to recognize genital herpes outbreaks and given the option of daily suppressive therapy as a means to reduce genital herpes transmission. Measures for reducing transmission and acquisition of genital herpes include:
1. Disclosure of genital herpes infection to new part- ners. Although it may be difficult at first for patients to inform new partners that they have genital her- pes, medical providers should encourage this important and necessary step to allow sex partners to make informed choices and, if appropriate, modify sexual practices to reduce the risk of transmission.
2. Abstinence during outbreaks. Once educated about the typically mild signs and symptoms of outbreaks, most patients are able to recognize symp- tomatic outbreaks.
3. Correct and consistent condom use. Male latex condom use can reduce transmission, especially during the first 6–12 months after initial infection.
4. Selection of partners with similar HSV serologic status or a history of genital herpes.
5. Chronic suppressive therapy. A recent major study demonstrated a 70% reduction in HSV transmission by infected patients using daily suppressive therapy.
The reduction in disease and infection transmis- sion may be attributable to both reduction of gen- ital herpes recurrences and reduction of subclinical shedding.
Clinical Findings A. SYMPTOMS ANDSIGNS
Genital infection with HSV can be differentiated into five categories: first recognized episode, primary first episode, nonprimary first episode, recurrent episode, and subclinical shedding. Symptoms and signs charac- teristic of each are described below.
1. First recognized episode—The clinical diagnosis of a first episode versus recurrent episodes is unreliable. For the patient, the first recognized episode is an “initial”
infection, whether it is a first episode or recurrent infec- tion. The only way to classify a first episode with certainty is to document serologic conversion, but such classifica- tion usually serves little clinical purpose. All first recog- nized episodes can be safely managed as a newly acquired infection given the safety profile of currently recom- mended oral antiviral medications for HSV. Although both increased frequency of outbreaks and viral shed- ding are more likely with recent acquisition of infection, recommendations for daily suppressive therapy are based on the patient’s desire to control disease (ie, out- breaks) or reduce the risk of transmission, or both.
2. Primary first episode—This refers to infection with either HSV-1 or HSV-2 in an individual who has never had infection with a herpes simplex virus. In immuno- competent hosts, this event often goes unrecognized.
After an incubation period of several days (average, 4 days; range, 1–14 days), a small papule appears that quickly evolves into a vesicle within 24 hours. Vesicles can be clear or pustular, are multiple, and rapidly evolve into shallow, nonindurated, painful ulcers (see Figure 14–2).
The appearance of lesions can be associated with dysuria, inguinal lymphadenitis, vaginal discharge, and cervicitis.
In primary infection, systemic symptoms including myal- gias, malaise, fever, and other “flu-like” symptoms may be associated with the appearance of genital lesions. In the typical presentation, signs or symptoms are minimal and usually are not recognized as primary genital herpes.
Crops of lesions may occur over 1–2 weeks, and crust- ing and healing of lesions requires an additional 1–2 weeks (see Figure 14–3).
3. Nonprimary first episode—This refers to infection in individuals who have had a previous infection with either HSV type. The typical scenario is an individual Figure 14–1.Primary genital herpes of the vulva.
(Reproduced, with permission, from Holmes KK, et al.
Sexually Transmitted Diseases,3rd ed. McGraw-Hill, 1999, Figure 28.)
86 / CHAPTER 14
is more rapid than with a primary first episode. The first episode usually resolves within 5–7 days. Nonprimary first episodes are clinically similar to recurrent disease and are often mistaken for recurrent genital herpes, if they are recognized at all.
4. Recurrent episode—Recurrent genital herpes refers to the second or subsequent episodes of genital herpes with the same virus type. HSV-2 is much more likely to recur then HSV-1 and accounts for more than 90% of recurrent genital herpes. The median number of recur- rences is four per year, but up to 38% of individuals have six or more recurrences per year. Recurrences are, in general, clinically fairly mild and are often unrecog- nized. The outbreak usually is not associated with sys- temic symptoms but may be preceded by a prodrome of local paresthesia or dysesthesia.
Recurrent genital herpes may occur as a cluster of localized vesiculopustular or ulcerative lesions. Lesions tend to lateralize to one side of the midline. “Atypical”
lesions are common and may be mistaken for excoriation or irritation. The predominant locations of lesions are on the glans penis or penile shaft in men (see Figure 14–4), the vaginal introitus or labia in women, and the but- tocks and anal area in both sexes. A neuropathic pro- drome characterized by pain or a burning sensation may occur 6–24 hours prior to the appearance of lesions.
5. Subclinical shedding—Subclinical shedding refers to the detection of virus in the absence of visible lesions.
Our understanding of the natural history of genital her- pes has shifted from that of intermittent outbreaks to one of low-grade frequent shedding of virus that can be with prior HSV-1 orolabial infection who subsequently
acquires new genital HSV-2 infection. Typically, the first genital herpes outbreak tends to be less severe clinically than a true primary episode due to an existing, partial humoral and cellular immunity. Fewer lesions appear, pain and systemic symptoms are less, and lesion resolution
B
C
Figure 14–2.A:Vesicular lesions of genital herpes simplex virus (HSV) infection of the vulva.B:Genital ulceration resulting from HSV infection of the penile shaft.C:HSV infection of the posterior thigh.
Figure 14–3.Primary HSV infection showing intact vesicles and pustules with surrounding erythema together with an earlier lesion, which is crusted and healing.(Reproduced, with permission, from Holmes KK, et al.Sexually Transmitted Diseases,3rd ed. McGraw-Hill, 1999, Figure 26.)