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Urethritis, Vulvovaginitis, and Cervicitis 51

51 Urethritis, Vulvovaginitis, and Cervicitis


Paula K. Braverman

URETHRITIS associated with urethritis.15,17–24 Further analysis has revealed that within
biovar 2, only specific subtypes may be independently associated with
Urethritis is inflammation of the urethra. The clinical presentation NGU.18
includes dysuria, urinary frequency, and urethral discharge or itching. T. vaginalis traditionally was considered a less common cause of ure-
Neutrophils usually are found in urethral secretions.1 According to the thritis in men. However, a nucleic acid amplification testing (NAAT) such
Centers for Disease Control and Prevention (CDC), urethritis is docu- as polymerase chain reaction (PCR) and transcription-mediated ampli-
mented by one of the following: visibly abnormal urethral discharge, a fication (TMA) demonstrate that T. vaginalis is associated with 10% to
positive leukocyte esterase (LE) test result for a man younger than 60 20% of cases of urethritis.10,15,25–27 T. vaginalis can be demonstrated in
years of age without other urinary tract disease that could cause pyuria, males without clinical signs of urethritis and commonly is associated
Gram stain of a urethral smear showing at least 2 white blood cells per with other STIs.15,28–30
high-power field (WBCs/HPF), and a positive LE test result for the first- Herpes simplex virus (HSV) is a less common cause of urethritis in
void urine or 10 or more WBCs/HPF in the first-void urine sediment.2,3 men.5,11,31 Urethritis develops in 30% of men with primary HSV infection
However, studies have demonstrated that symptoms of urethritis can and is found in 2% to 3% of cases of NGU.15 Studies reported in 2006
occur without microscopic evidence of pyuria on the Gram stain of found that HSV-1 was responsible for more cases of NGU than HSV-2
urethral swab specimens or in the first-void urine samples.4,5 and that HSV-1 was more likely to be associated with men engaging in
It may be difficult to establish the diagnosis of urethritis in women oral-genital sex and men with male partners.5,11 Infrequent causes of
because they may not have localized symptoms and some pathogens urethritis in men include adenoviruses, Haemophilus species, and Neis-
simultaneously infect multiple genital areas.6 In the absence of a docu- seria meningitidis; coliforms can be an etiologic agent in men who have
mented urinary tract infection, female dysuria can represent vulvar sex with men (MSM).1,5,11,15 Identification of some pathogens associated
inflammation from vaginitis or vulvar dermatoses, interstitial cystitis, or with urethritis suggests that infection with oropharyngeal flora, which
urethral infection with a sexually transmitted infection (STI).6,7 are normal nonpathogenic organisms in monogamous partners, is
possible.11
Etiologic Agents Nonsexually transmitted NGU is associated with urinary tract infec-
tion (UTI), bacterial prostatitis, urethral stricture, phimosis, and urethral
Infectious Causes catheterization.1 In 25% to 40% of cases, the cause of NGU in male
patients remains unknown.15
Organisms associated with STIs are the most significant etiologic agents Female Patients.  Urethritis in female patients can be caused by N.
in urethritis. Newer, more sensitive molecular diagnostic testing modali- gonorrhoeae, C. trachomatis, HSV, and M. genitalium. T. vaginalis typically
ties for STIs have advanced the understanding of specific pathogens that causes vaginitis in women but is known to infect the urethra and is
cause urethritis. associated with pyuria.6,7,10,29,32–36
Male Patients.  Chlamydia trachomatis and Neisseria gonorrhoeae are
common causes of urethritis in men.1 N. gonorrhoeae is estimated to Noninfectious Causes
cause one third of acute urethritis cases and is differentiated from other
agents, which cause nongonococcal urethritis (NGU).8 NGU is the most In men and women, urethritis can accompany noninfectious systemic
common clinical STI syndrome in men. Rates of specific etiologic agents diseases such as Stevens-Johnson syndrome, or it can result from chemi-
vary by geography, socioeconomic factors, age, race, and sexual orienta- cal irritation.1,6
tion or practices.1,5,8–14 Coinfection with multiple pathogens can occur,
and in 25% to 40% of cases, no pathogen is identified.15 Approximately Epidemiology
15% to 40% of NGU in men is caused by C. trachomatis, 15% to 25% by
Mycoplasma genitalium, 10% to 20% by Trichomonas vaginalis, and 10% One half of new STIs occur in adolescents and young adults between the
to 20% by Ureaplasma urealyticum.15,16 ages of 15 and 24 years.37 Population-based data for this age group
There has been confusion in the literature regarding the role of U. derived from the National Health and Nutrition Examination Survey
urealyticum as a cause of nongonococcal, nonchlamydial infection in (NHANES) showed the prevalence of C. trachomatis was 1.7% among
men.2,5,11,15,17–23 The genus Ureaplasma has two types: biovar 1 (U. parvum) males and 3.2% among females (2005–2008 data); prevalence of N.
and biovar 2 (U. urealyticum). Biovar 2 is the biotype most likely gonorrhoeae was 0.3% among males and 0.6% among females (1999–2008

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION G  Genitourinary Tract Infections

data); and prevalence of T. vaginalis was 0.9% among males and 1.5% hematuria, and urgency are uncommon in urethritis. However, if the
among females (2001–2004 data).37 male adolescent is sexually active, pyuria is more likely to be caused by
Other studies have demonstrated that prevalence rates of T. vaginalis urethritis than UTI because UTI is uncommon in this age group. A
infection increase with age; they are highest among black women, lower focused STI history (see Chapter 49) and thorough medical history can
among black men, and lowest among whites.38,39 Similar ethnic or racial help establish relative risks of urethritis and UTI.
differences have been found for C. trachomatis and N. gonorrhoeae.40 Data In adolescent girls, dysuria is the cardinal feature of urethritis, which
from several studies, including the CDC’s 2013 sexually transmitted must be differentiated from acute bacterial cystitis and vulvovaginitis
disease (STD) surveillance report, illustrate that the STI rates vary by (Table 51.2). The literature differentiates internal and external dysuria.
specific populations.25,38,40,41 Youth in correctional facilities and the Internal dysuria is pain that is felt internally during voiding. External
National Job Training Program have among the highest STI rates.2,40,41 dysuria is discomfort that is felt as urine passes over the labia.7 Internal
Sexual practices and behavior can influence the epidemiology of dysuria, urinary frequency, and isolation of more than 102 uropathogens
urethritis. Urethritis due to C. trachomatis, N. gonorrhoeae, or HSV per milliliter of voided urine suggest acute bacterial cystitis; isolation of
among adolescent women correlates with having new sex partners.6 102 or fewer uropathogens per milliliter suggests acute urethritis due to
Adenovirus and HSV-1 have been associated with oral-genital contact STI pathogens.6 Pain that is felt internally only at the end of urination is
and having a male partner, whereas M. genitalium and C. trachomatis consistent with bacterial cystitis.7 External dysuria can occur with vulvo-
have been associated with vaginal sex.5 In one study, N. gonorrhoeae and vaginitis. Female adolescents can have vaginitis alone or a concurrent
U. urealyticum urethritis were found in heterosexual men, C. trachomatis UTI and may not be able to adequately distinguish between internal and
urethritis was associated with MSM, and T. vaginalis was more common external dysuria.7,44 Any female patient suspected of having urethritis
in men older than 30 years of age.42 requires an STI-directed history and physical examination to identify
Urethritis due to STI pathogens also can occur in prepubertal boys other STIs or STI syndromes (e.g., pelvic inflammatory disease [PID]).
and, less frequently, in prepubertal girls. In this age group, transmission In prepubertal boys and girls, urethritis due to STI pathogens can
commonly results from sexual abuse with genital-to-genital contact (see manifest with dysuria and urethral or vaginal discharge. There may be
Chapter 54). vague lower abdominal pain, unwillingness to void, and in boys, irritation
in the distal urethra or meatus. Dysuria in a prepubertal child is much
Clinical Manifestations and Differential Diagnosis more likely to be caused by UTI than urethritis associated with STI.
Urethritis is more probable in the setting of a discharge or a history of
Symptomatic urethritis in adolescent males is characterized by dysuria, sexual abuse, especially if genital-to-genital contact has occurred.
urethral discharge, or urethral pruritus. Discharge can be mucoid,
mucopurulent, or purulent. Gonococcal urethritis compared with NGU
usually has a shorter incubation period, more acute onset, and more
Laboratory Findings and Diagnosis
profuse discharge (Table 51.1).1 Discharge in patients with NGU can be Male Patients.  For male patients, specimens are obtained to document
so scant that it is only noticed in the morning or is apparent as crusting urethritis and to detect common causes such as N. gonorrhoeae and C.
on the meatus or as stains in underwear.1 Urethral infection with N. trachomatis. The definitive diagnosis is enhanced if the patient has not
gonorrhoeae and the various organisms causing NGU also can be voided recently; examination in the morning before voiding is ideal.1 A
asymptomatic.43 meatal swab specimen of a discharge can be taken for Gram stain; the
Urethritis must be differentiated from UTI, particularly in adolescent finding of gram-negative intracellular diplococci of the typical kidney
boys with dysuria but no discharge. In contrast to UTI, frequency, bean morphology pattern (Fig. 51.1) or at least 2 neutrophils per oil
immersion field (×1000) is diagnostic of urethritis.1,2 A Gram stain smear
is sensitive and specific in diagnosing gonococcal urethritis if intracel-
TABLE 51.1  Clinical Manifestations of Nongonococcal and lular diplococci are detected. If the Gram stain is equivocal, negative, or
Gonococcal Urethritis unavailable and the criteria for urethritis are met, NAAT for N. gonor-
rhoeae and C. trachomatis is indicated.2
Nongonococcal Gonococcal
In all patients, regardless of whether N. gonorrhoeae is suspected by
Characteristic Urethritis Urethritis
Gram stain, a first-voided urine or urethral specimen should be obtained
Incubation period 2–3 weeks 2–6 days for detection of C. trachomatis by NAAT. The optimal specimen from
Onset Insidious Abrupt male patients is a first-voided urine.2,45 NAAT for N. gonorrhoeae and C.
trachomatis may detect infection in male patients with symptoms of
Dysuria +, may wax and wane ++, continuous urethritis but no objective evidence of urethral inflammation.2
Discharge Scant to moderate, Profuse, absent The diagnosis of T. vaginalis in men is more challenging than in
may be absent in <10% women. Wet mount preparation of a urethral smear detects only 30% of
+, modest discomfort; ++, more severe discomfort.
T. vaginalis infections in men.28 Culture can be performed on urine,
semen, or urethral specimens and appears to yield better results if

TABLE 51.2  Distinguishing Features of Urethritis, Acute Bacterial Cystitis, and Vulvovaginitis in Adolescent Females
Feature Urethritis Acute Bacterial Cystitis Vulvovaginitis
Symptoms Internal dysuria Internal dysuria, frequency, urgency, External dysuria, vaginal discharge,
hematuria vulvar burning, itching
Duration of symptoms Often ≥7 days Usually ≤4 days Varies with cause
Signs Mucopurulent cervicitis Suprapubic tenderness Vulvar lesions and inflammation,
Vulvar lesions vaginal discharge
Epidemiologic associations New sex partner Previous cystitis History of genital herpes
Previous STI Onset of symptoms within 24 hours Sex partner with genital herpes
Sexual partner with STI of intercourse Antibiotic use
Use of diaphragm Previous vulvovaginitis
Use of a spermicide Candidiasis
STI, sexually transmitted infection.
Modified from Holmes KK, Stamm WE, Sobel JD. Lower genital tract infection syndromes in women. In: Holmes KK, Sparling PF, Mardh P-A, et al. (eds). Sexually Transmitted Diseases, 4th ed. New
York, McGraw-Hill, 2008, pp. 987–1016.

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Urethritis, Vulvovaginitis, and Cervicitis 51
available. Specific testing of men for T. vaginalis should be considered for
cases of nongonococcal urethritis in high-prevalence areas or
populations.2
Cultures for U. urealyticum are not available readily, and M. genitalium
is difficult to isolate.1,32,51 In research studies, both are diagnosed and
evaluated using NAAT. However, these tests are not cleared for use by the
US Food and Drug Administration (FDA), and management relies on the
clinical presentation and exclusion of other causes.2
Female Patients.  Endocervical or vaginal and urethral specimens
should be obtained for NAAT for N. gonorrhoeae and C. trachomatis in
adolescent girls with urethritis because concurrent infection is common.2,6
Urinalysis and urine culture also are indicated because simultaneous UTI
and STI can occur in sexually active females.7 Urine testing using NAAT
for C. trachomatis and N. gonorrhoeae is not as sensitive as endocervical
specimen testing.2,45 Studies using NAAT for vaginal specimens have
shown good correlation with cervical specimens, and the vaginal speci-
A mens can be collected by the healthcare personnel or the patient.2,45
T. vaginalis can be diagnosed by a variety of methods, including wet
mount preparation, culture, nucleic acid probe, immunochromato-
graphic capillary flow dipstick technology, and NAAT.2,25,48,49,52,53 As for
male patients, wet mount microscopy has poor sensitivity compared with
other methods.2 NAAT for T. vaginalis (e.g., strand displacement ampli-
fication [SDA]), and TMA are FDA cleared for use in women for endo-
cervical, vaginal, or urine specimens.2,48,52

Treatment
Initial treatment for male patients can be based on Gram stain results
(Table 51.3).2 Patients with evidence of N. gonorrhoeae by Gram stain
should be treated with dual single-dose therapy, including intramuscular
ceftriaxone and oral azithromycin to reduce the development of
antimicrobial-resistant N. gonorrhoeae. Although oral cefixime can be
substituted for ceftriaxone, it is not the first-line drug due to resistance
patterns and poor efficacy if there is a concomitant pharyngeal
infection.2
B
All patients with negative Gram stain results should be tested for C.
trachomatis and treated if positive. For NGU, a single dose of azithromy-
cin may be preferred over a 1-week course of doxycycline in adolescents
because of adherence.2 Single-dose azithromycin is also preferred because
it is most effective in treating M. genitalium, which is the most common
cause of persistent and recurrent NGU.2 Confirmed cases of N. gonor-
rhoeae or C. trachomatis must be reported to the local health authorities,
and sexual partners should be contacted for assessment and treatment.
Immediate follow-up and repeat testing for N. gonorrhoeae or C. tra-
chomatis urethritis in adolescents are not recommended routinely if
appropriate treatment is completed, signs and symptoms disappear, and
no re-exposure to an untreated partner occurs. However, because of the
high rate of reinfection after initial treatment, repeat testing for N. gonor-
rhoeae and C. trachomatis is recommended in 3 months.2 If symptoms
persist despite good adherence and no re-exposure and the person meets
diagnostic criteria for persistent or recurrent NGU, further management
C is indicated. Treatment without signs for urethral inflammation has not
been demonstrated to be effective.2,54,55
FIGURE 51.1  (A) Gram stain of urethral discharge from an male adolescent with M. genitalium is the most common cause of persistent or recurrent
urethritis shows multiple neutrophils and intracellular diplococci with the kidney- NGU.2 If doxycycline was used initially, single-dose azithromycin should
bean morphology typical of Neisseria gonorrhoeae (magnification ×1000). (B) Gram be tried because it is more effective than multidose doxycycline for this
stain of vaginal fluid from an adolescent with bacterial vaginosis shows clue cells organism.2 However, resistance has developed to azithromycin, and
and squamous vaginal epithelial cells covered with coccobacilli, which gives them studies have demonstrated treatment failure in men treated with both
a stippled or granular appearance. Notice the absence of rods with blunt ends single-dose and extended-dosing regimens of azithromycin, possibly
(i.e., lactobacilli) (magnification ×2000). (C) Wet mount of vaginal secretions from related to the selection of resistant organisms with the common use of
a female adolescent with bacterial vaginosis shows clue cells. Notice the stippled single-dose azithromycin for treatment of N. gonorrhoeae and C. tracho-
epithelial cells with ragged (i.e., bacteria-covered), ill-defined borders (magnification matis. Seven days of moxifloxacin (400 mg daily) is effective for treatment
×200).
failures for M. genitalium.2,16,51,54–57 Fluoroquinolone resistance has also
been demonstrated.57,58
multiple sites are tested.2,29,46 The InPouch culture system (BioMed For male patients with persistent urethritis, culture of a urethral speci-
Diagnostics, San Jose, CA) is equivalent to the gold standard Diamond men or first-void urine for T. vaginalis should be performed because of
media, and urethral or urine sediment specimens can be inoculated.25 the high prevalence of T. vaginalis infection among men with nongono-
However, studies have shown that NAAT is superior to a wet mount coccal, nonchlamydial urethritis and coinfection with these organisms. If
preparation or culture to detect T. vaginalis in male patients.10,26,28,29,47–49 there has been laboratory validation, testing of urethral or urine speci-
Although the TMA test is approved only in the United States for female mens with NAAT is preferred.2 If T. vaginalis is diagnosed, metronidazole
specimens, it may be used in laboratories that have conducted validation or tinidazole is prescribed (see Chapter 274). Current CDC guidelines
procedures on male specimens.2,46,50 T. vaginalis PCR is not commercially recommend presumptive treatment with metronidazole or tinidazole in

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION G  Genitourinary Tract Infections

TABLE 51.3  Recommended Treatment of Urethritis in Postpubertal Children and Adolescents


Gram Stain Suggested Treatment
RESULTS AVAILABLE
Increased Neutrophils Gram-Negative
Intracellular Diplococci
Present Presenta Treat for gonococcal and chlamydial urethritis.
For Neisseria gonorrhoeae: for postpubertal children >45 kg and adolescents, ceftriaxone
(250 mg IM once) or cefixime (400 mg PO once) and azithromycin (1 g PO once)
For Chlamydia trachomatis: for postpubertal children ≥8 years and adolescents, azithromycin (1 g
PO once) or doxycycline (100 mg bid PO for 7 days)
Present Absent Treat for nongonococcal urethritis. Azithromycin (1 g PO once) or doxycycline (for 7 days) or
ofloxacin (300 mg PO bid for 7 days) or levofloxacin (500 mg PO once daily for 7 days) or
erythromycin base (500 mg PO qid for 7 days) or erythromycin ethylsuccinate (800 mg PO qid
for 7 days)
Absent Absent Defer treatment until microbiologic results are available, or if patient is high risk by history and
follow-up cannot be ensured, treat for gonococcal and chlamydial urethritis
RESULTS NOT AVAILABLE
Urethral discharge — Treat for gonococcal and chlamydial urethritis
No urethral discharge — Defer treatment until microbiologic results are available, or if patient is high risk and follow-up
cannot be ensured, treat for gonococcal and chlamydial urethritis
RECURRENT OR PERSISTENT URETHRITIS
— — Azithromycin (1 g PO once) if not used for initial episode; for failure, moxifloxacin (400 mg PO qd
for 7 days) to cover Mycoplasma genitalium; metronidazole (2 g PO once) or tinidazole (2 g PO
once) to cover Trichomonas vaginalis
a
Gram stains are considered inadequate to evaluate prepubertal children for N. gonorrhoeae.
IM, intramuscularly; IV, intravenously; PO, orally.
Data from Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(RR- 3):1–137.

cases of persistent urethritis in areas of high prevalence for men who have pathogenesis, and management are substantially different for the two age
sex with women.2 U. urealyticum can be difficult to eradicate, and resis- groups.7 Vaginitis and vulvitis are a continuum in young children,
tance to tetracyclines has been demonstrated.1,51 Patients who do not whereas they are distinct clinical entities in adolescents.
respond to therapy should be referred to a urologist.
Female patients with findings suggesting bacterial cystitis can be
treated presumptively for UTI. However, if urethritis is suspected, a single
Vulvovaginitis in Prepubertal Girls
dose of azithromycin (1 g) or a 7-day course of doxycycline (100 mg
twice per day) is indicated pending results of urine culture and STI
Etiologic Agents and Epidemiology
testing.2 If symptoms of dysuria due to vulvovaginitis are found, treat- Prepubertal girls can have specific or nonspecific vaginal infections.7
ment should be directed at the cause. Although the CDC’s 2015 STD Several factors predispose young girls to vulvovaginal irritation, includ-
treatment guidelines do not specifically discuss persistent urethritis in ing proximity of the vagina to the rectum, poor hygienic practices, lack
females, treatment of M. genitalium should be considered when other of protective labial fat pads and pubic hair, and lack of an estrogen effect
causes have been ruled out, and ideally, testing for this organism should on vaginal mucosa.7,62 Prepubertal girls are more likely than postpubertal
be done.35 girls to experience vulvar irritation and trauma from soaps, bubble baths,
and clothing.7 The lack of estrogen effect in prepubertal girls promotes
Complications an environment with a neutral pH, predisposing to overgrowth with a
variety of potential pathogens.6,62 Vaginal microbial infections that are
Complications of urethritis include disseminated gonococcal infection not STIs usually are caused by respiratory tract and enteric pathogens.
(0.5% to 3%) and reactive arthritis syndrome (i.e., Reiter syndrome). In T. vaginalis is rare in prepubertal children because lack of estrogen
male patients, epididymitis (1% to 2%) and, rarely, prostatitis and bala- makes the vagina resistant to this infection.7 Isolation of Gardnerella
noposthitis also occur.1,16 Female patients with N. gonorrhoeae, C. tracho- vaginalis in prepubertal vaginitis is not diagnostic of bacterial vaginosis
matis, and M. genitalium infection also are at risk for PID and (BV) but has been reported in prepubertal girls after sexual assault.7
infertility.7,16,36,59 M. genitalium has been associated with preterm birth Candida vulvovaginitis is not common in prepubertal girls unless there
and spontaneous abortion.2,59 In male and female patients, STIs associ- are other risk factors, such as antibiotic use, diabetes mellitus, immuno-
ated with urethritis increase susceptibility to infection with, viral shed- suppression, or use of diapers; 3% to 4% of prepubertal girls have
ding, and transmission of HIV.2,60,61 Candida spp. as part of normal vaginal flora.7,62
Although prepubertal vulvovaginitis is not often sexually transmitted,
Prevention sexual abuse must be considered if pathogens such as C. trachomatis, N.
gonorrhoeae, T. vaginalis, human papillomavirus (HPV), or HSV are
Correct and consistent use of condoms is the most effective means of identified.7,62 Attributing HPV to sexual abuse rather than vertical trans-
preventing and reducing transmission of the STIs associated with mission or inoculation from caregivers and autoinoculation is challeng-
urethritis. ing because of the lack of studies in this age group regarding incubation,
latency to clinical presentation, and cutoff ages for vertical transmis-
VULVOVAGINITIS sion.62 Similar to the cervical epithelium of postpubertal girls, the
cuboidal vaginal epithelium of prepubertal girls is susceptible to N.
Vulvovaginitis (i.e., inflammation of the vagina or vulva) is a common gonorrhoeae and C. trachomatis.6 Other causes of vulvovaginitis include
gynecologic problem in prepubertal and adolescent girls. The cause, foreign body, vulvar skin disorders, and allergic reactions (Box 51.1).

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Urethritis, Vulvovaginitis, and Cervicitis 51
BOX 51.1  Etiologic Factors in Prepubertal Vulvovaginitis BOX 51.2  Testing Vaginal Discharge or Aspirate Specimens From
Prepubertal Girls With Vulvovaginitis
NONSPECIFIC CAUSES
Contact or Allergic Reactions (Common) Gram stain for bacteria and white blood cellsa
Culture for aerobic and anaerobic bacteria
• Bubble-bath preparations
Culture for Neisseria gonorrhoeae and Chlamydia trachomatisb
• Shampoos, soaps
Wet mount to detect clue cellsc or trichomonadsd
• Laundry detergents
Potassium hydroxide preparation to detect fungal elementsd and
• Clothing (e.g., nylon undergarments)
note odor
Physical Factors (Common) Scotch tape specimen from perianal area in early morning if
pinworms are suspected
• Foreign body
• Sand (e.g., sandbox) a
Gram stain should not be used to diagnose or exclude N. gonorrhoeae in prepubertal
• Poor hygiene (e.g., wet diapers) children.
b
Nonculture tests usually are not recommended in cases of abuse due to the risk of false-
SPECIFIC MICROBIOLOGIC CAUSES positive results, but nucleic acid amplification testing (NAAT) of vaginal or urine specimens
may be an acceptable alternative particularly in other circumstances.
Not STI Related c
Clue cells are stippled epithelial cells whose borders are obscured by adherent bacteria.
• Shigella spp. d
Culture also can be performed for Trichomonas vaginalis and yeast. NAAT for Trichomonas
• Yersinia enterocolitica vaginalis has not been adequately studied in prepubertal children.
• Enteric bacilli
• Staphylococcus aureus
• Group A Streptococcus
• Haemophilus influenzae otoscope head is used. Examination with the patient under anesthesia
• Enterobius vermicularis may be necessary in some cases.
• Moraxella catarrhalis
• Streptococcus pneumoniae
• Neisseria meningitidis
Laboratory Findings and Diagnosis
• Candida spp. Samples of a vaginal discharge are obtained (Box 51.2) using a sterile,
saline-moistened swab for potassium hydroxide (KOH) preparation,
Possibly STI Related (Less Common) Gram stain, and culture.62 A vaginal wash using nonbacteriostatic saline
• Neisseria gonorrhoeae or vaginal aspiration using an eyedropper are alternative methods of
• Chlamydia trachomatis specimen collection.7,62 However, the latter specimens may not be as
• Trichomonas vaginalis sensitive for identification of C. trachomatis if few epithelial cells are
• Herpes simplex virus collected, which are necessary because the organism is an obligate intra-
cellular pathogen. Culture confirmation of N. gonorrhoeae and C. tracho-
Vulvar Skin Disorders matis is the most admissible legal evidence for cases of suspected sexual
• Eczema abuse.
• Psoriasis
NAAT for vaginal or urine specimens may be an alternative to culture
for testing of vaginal secretions in girls.2 T. vaginalis can be detected
STI, sexually transmitted infection. in vaginal wash specimens or by culture.7,53 If Enterobius infestation
is suspected, the parent is instructed to examine the perianal region
at night for the small, white pinworms, and a Scotch tape swab or
paddle specimen is collected from the perianal area immediately on
the child’s awakening. Samples for culture for yeast should be consid-
Clinical Manifestations, Differential Diagnosis, and ered if itching persists or the history suggests risk factors for candidal
Clinical Approach infection.7,62

The clinical features of vulvovaginitis in children include vaginal dis-


charge, vulvar irritation, pruritus, dysuria, bleeding, genital inflamma-
Treatment
tion, and foul smell.7,62 When associated with a foreign body, the discharge The mainstay of treatment for nonspecific vulvovaginitis is education,
can be profuse, foul smelling, and blood tinged.7 Parents often are attention to personal hygiene, and avoidance of agents such as bubble
unaware that the child has inserted something into the vagina. In Entero- baths and tight nylon undergarments that provoke the problem.62 Sitz
bius vermicularis–associated vulvovaginitis, recurrent symptoms and baths in warm water without soap may be helpful. Vitamin A and D
vulvar or anal pruritus are common. Discharge can be bloody in cases of ointment or petroleum jelly can protect the vulva, and a short course of
vulvovaginitis caused by Shigella spp. or Streptococcus pyogenes infec- 1% hydrocortisone cream can alleviate acute exacerbations of irritant
tion.6,7,62 Bleeding also should raise concern about trauma. Diffusely vulvitis.7,62 In severe cases, an estrogen cream may be applied for several
hyperemic vulvar mucosa suggests streptococcal vulvovaginitis. Discharge weeks to ameliorate symptoms.7,62 If a foreign body is detected, removal
associated with gonococcal infection is commonly green and purulent, usually resolves the problem.
whereas discharge is less common with chlamydial infection. Treatment of vulvovaginitis due to specific pathogens is initiated on
All prepubertal children with vulvovaginitis require a careful history the basis of the Gram stain, wet mount preparation, culture, or NAAT
and physical examination. Vaginitis due to S. pyogenes can occur after a results. Recommended treatments for N. gonorrhoeae are ceftriaxone
pharyngeal or skin infection in the patient or family members. Finding alone for patients who weigh 45 kg or less and ceftriaxone along with
a sibling with an STI raises concern about sexual abuse by someone azithromycin for those who weigh more than 45 kg. For C. trachomatis,
associated with the family.7,62 Gynecologic examination includes abdomi- erythromycin is given to patients who weigh less than 45 kg, azithromycin
nal inspection and palpation. In a gentle and supportive manner, inspec- for those younger than 8 years of age and who weigh 45 kg or more, and
tion of the perineal skin, vulva, and perirectal and genital areas is azithromycin or doxycycline for older girls. For Candida, an antifungal
performed to detect excoriation, erythema, ulcers, or structural abnor- agent, such as clotrimazole, is used, or oral fluconazole is used if topical
malities. Visualization of the vagina and cervix without instrumentation therapy is not effective. Treatment for S. pyogenes is penicillin or amoxi-
usually is possible with the patient in the knee-chest position.7 This cillin. Other antimicrobial agents are chosen on the basis of vaginal bacte-
facilitates detection of a foreign body, especially if a magnifying lens or rial culture results.2,7,62

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION G  Genitourinary Tract Infections

Complications in the urethra of male sex partners of women diagnosed with BV but did
not find this organism in male controls.64 Sexual activity, multiple sexual
The follow-up of children with vulvovaginitis depends on the cause. partners, receptive oral sex, and vaginal insertion of sex toys that were
Fortunately, gonococcal and chlamydial vulvovaginitis rarely are associ- not cleaned are associated with BV, whereas the use of condoms appears
ated with upper tract disease, and impairment of fertility is unlikely if to be protective.64,73,74,77–80 Treatment of sex partners does not appear to
the infection is treated adequately.7 For recurrences due to S. pyogenes, prevent recurrence.64 However, a systematic review of randomized, con-
pharyngeal colonization in the patient and carriage in family members trolled trials of male partner treatment for BV criticized these studies for
are considered.62 having methodologic flaws.81
Up to one third of women experience recurrent episodes of BV within
Vaginitis in Pubertal Girls 3 months of treatment.66 In one study, factors associated with recurrence
over a 12-month period included a history of BV and having a female
Etiologic Agents and Epidemiology sex partner or a regular sex partner.82 Recurrence may be related to
reinfection from an infected partner or to failure to re-establish lactoba-
Under the influence of estrogen at puberty, the vaginal epithelium shifts cilli dominance with persistence of pathogenic bacteria.63,67,72 Some
from cuboidal to a glycogen-containing stratified squamous epithelium, investigators have postulated that the recurrence of BV is related to
and there is an associated increased growth of lactobacilli that produce persistence of a biofilm containing G. vaginalis and other organisms that
lactic acid and hydrogen peroxide.6,7,63 This results in a decrease in vaginal adheres to the epithelial cells and provides protection from systemic and
fluid pH from a prepubertal level of about 7.0 to about 4.0. Changes in topical antibiotics.72,83–85
the epithelium, colonizing flora, and pH render the vaginal environment Candidiasis.  Vulvovaginal candidiasis has an estimated lifetime inci-
relatively resistant to infection caused by C. trachomatis and N. gonor- dence of up to 75%.86 Candidal colonization of the vagina usually origi-
rhoeae. In adolescents, these two organisms cause cervicitis rather than nates from the gastrointestinal tract, and sexual transmission is not an
vulvovaginitis. important mode of acquisition.2,63,86 As many as 30% of healthy asymp-
Leukorrhea, the normal white mucous vaginal discharge that repre- tomatic women are colonized with yeast, and Candida albicans is the
sents the effect of estrogen on the vaginal mucosa in adolescents, must organism found in most uncomplicated cases.63,66 Risk factors include
be distinguished from pathologic discharge. Saline wet mount examina- pregnancy, poorly controlled diabetes, immunosuppression, receptive
tion of vaginal secretions reveals sheets of epithelial cells without inflam- oral sex, use of estrogen, and use of various contraceptives, including
matory cells, yeast, clue cells, or trichomonads. Leukorrhea sometimes is intrauterine devices, diaphragms, vaginal rings, and possibly spermi-
considered excessive by patients, and they need reassurance.7,63 cides.63,65,66,86 Antibiotic use is mentioned frequently, but it is not a major
The major causes of vaginitis in adolescents are BV, candidiasis, and cause of infection in most women. Rather, colonization by species of
T. vaginalis infection. BV has replaced the term nonspecific vaginitis Candida may place a subpopulation of women at higher risk for symp-
because the condition usually is not inflammatory but arises from a tomatic infection.66,86–88 For approximately one half of girls and women,
change in the vaginal flora.7,64 Less common causes of vaginitis in ado- no risk factors are identified.63,66
lescents include ulceration and infection associated with tampons, cervi- Most women experience uncomplicated vulvovaginal candidiasis, with
cal caps, vaginal contraceptive ring, and other foreign bodies; chemical infrequent mild to moderate episodes caused by C. albicans.86 However,
agents such as those found in douches and spermicides; and toxin- 10% to 20% of women have complicated vulvovaginal candidiasis that is
producing Staphylococcus aureus.6,7,65 more severe, recurrent, or caused by other Candida species. These women
Bacterial Vaginosis.  BV is the most common cause of vaginitis in are more likely to have underlying medical risk factors such as diabetes
postpubertal women, affecting approximately one third of women.63,66–68 or immunocompromise.2,86 Approximately 5% of women have recurrent
BV represents a disruption in the normal vaginal flora, with a decrease disease (i.e., ≥4 episodes in a 12-month period), which is more likely to
in lactobacilli and overgrowth of a variety of primarily anaerobic organ- be associated with C. glabrata and other non-albicans Candida
isms. BV-associated organisms include G. vaginalis, genital mycoplasmas species.2,66,86,89 Most women with recurrent vulvovaginal candidiasis do
(M. hominis), U. urealyticum, Bacteroides, Prevotella, Porphyromonas, not have diabetes mellitus or immunosuppression, but these conditions
Peptostreptococcus, Fusobacterium, and Mobiluncus species.63,64,69–71 increase the risk. It is postulated that some patients may have a genetic
Although many patients with BV have moderate to heavy concentrations predisposition to recurrent vulvovaginal candidiasis, suppression of local
of vaginal Gardnerella species, detection of this organism is not diagnostic immunity due to virulence factors produced by the Candida species, or
because vaginal colonization is common in patients without BV and not an alteration in local innate response leading to an aggressive inflamma-
specific for the diagnosis.63,64,71 tory leukocytic response to yeast colonization.63,66,86,90,91
New technologies employing amplification of ribosomal RNA are Trichomonas vaginalis.  T. vaginalis is the third most common cause of
being used to characterize bacterial species that are not identified by infectious vaginitis and has a worldwide distribution, with prevalence in
culture 64,70–72 They include three clostridial bacteria, Leptotrichia and community-based studies ranging from 2% to 46% of women.10,63 It is
Megasphaera species, and Eggerthella-like bacteria.70–72 In one study, the most prevalent curable STI worldwide, with most cases found in
detection of these noncultivatable bacteria had excellent sensitivity and women.27 In the United States, an estimated 3.7 million people are
specificity for diagnosing BV compared with standard diagnostic infected.37
criteria.71 Studies using PCR testing of urine or vaginal swabs from girls and
In a multivariate analysis of NHANES data from 2001 through 2004, women between the ages of 14 and 26 years have shown T. vaginalis
risk factors for BV included a higher number of lifetime sex partners, prevalence rates of approximately 2% to 3%, which was higher than the
douching, low educational achievement, and being non-Hispanic black.68 rate for gonorrhea among the same people.52 Certain populations may
BV has also been associated with poverty, smoking, having a female have a higher prevalence, including 26% of symptomatic and 7% of
sex partner, high body mass index, and previous pregnancy.68,73,74 The asymptomatic women at STI clinics, up to 18% of patients at adolescent
prevalence of BV among women attending STI clinics is higher (30% clinics, 10% of women in college health programs, and up to 47% of
to 37%) than among college students (4% to 15%)7 and the prevalence incarcerated women.2,10,52 Other risk factors include being African Ameri-
of BV in a nationally representative sample of 14-19 year old women can, smoking, using alcohol and drugs, having multiple partners, and
was 18.5%.68 adolescents having an older sexual partner.2,10 T. vaginalis facilitates
BV is more common among adolescents and young adults who are transmission and acquisition of HIV and commonly is associated with
sexually active and have multiple sexual partners. However, designating other STIs.
BV as an STI has been controversial because some studies have found BV
in sexually inexperienced females.64,66,68,75,76 One study of women entering Clinical Manifestations and Differential Diagnosis
the military found that 19% of subjects denying a history of vaginal
intercourse met criteria for BV compared with 28% who had been active Clinical presentations that help differentiate BV from candidal vulvovagi-
sexually.75 Another study questioned the accuracy of sexual histories nitis and trichomonal vaginitis are shown in Table 51.4. In the sexually
having failed to find BV in truly sexually inexperienced college students.77 active adolescent, cervicitis also must be excluded because it can occur as
Studies have shown a concordance between the presence of G. vaginalis a coinfection or as the sole cause of the vaginal discharge.92

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Urethritis, Vulvovaginitis, and Cervicitis 51
TABLE 51.4  Characteristics and Recommendations for Treatment of Vaginitis in Adolescents
Bacterial Vaginosis Candidal Vaginitis Trichomonal Vaginitis
SYMPTOMS
Odor of vaginal discharge Malodorous Usually not malodorous May be malodorous
Vulvar itch Sometimes Yes or discomfort Yes
Dysuria Sometimes Yes Yes
Dyspareunia Sometimes Yes Yes
Other symptoms No Symptoms often exacerbated No
before menses
SIGNS
Appearance of vaginal Thin, homogeneous, white, clings to vaginal wall, Thick, curd-like Heavy, grey or yellow-green, frothy
discharge ± frothy
Other signs No Vulvar and vaginal erythema, vulvar Vulvar and vaginal erythema
edema
LABORATORY FINDINGS
pH >4.5 <4.5 >4.5
KOH preparation Fishy, amine odor when mixed with 10% KOH Hyphae or pseudohyphae Occasionally positive whiff test
(positive whiff test)
Saline preparation Clue cells, few neutrophils Neutrophils and epithelial cells in Motile trichomonads, neutrophils
equal numbers
Gram stain Few gram-positive bacilli; abundant mixed flora Hyphae or pseudohyphae or Trichomonads visualized rarely
blastospores
Culture Not useful Can be useful if KOH negative Culture more sensitive than wet mount
TREATMENT
Oral Topical intravaginala Oral
Metronidazole (500 mg bid for 7 days) or Butoconazole cream Metronidazole (2 g for 1 dose or
clindamycin (300 mg bid for 7 days) or Clotrimazole cream 500 mg bid for 7 days) or tinidazole
tinidazole (2 g qd for 2 days) or tinidazole (1 g Miconazole cream or vaginal (2 g in a single dose)
qd for 5 days) suppository
Topical intravaginal Terconazole cream or vagina
Clindamycin cream 2% (one full applicator suppository
amount per vagina at bedtime for 7 days) or Tioconazole ointment
clindamycin ovules (100 mg per vagina at Oral
bedtime for 3 days) Fluconazole (150 mg once)
Metronidazole 0.75% gel (one full applicator
amount per vagina qd for 5 days)
a
Intravaginal therapies are available in 1- to 14-day regimens.
KOH, potassium hydroxide.

Symptomatic BV manifests with a thin, white-grey, homogeneous stippled epithelial cells whose borders are obscured by adherent bacteria
vaginal discharge that adheres to the vaginal walls and has a fishy odor.64,66 (see Fig. 51.1).64 Diagnostic accuracy increases with use of the Amsel
Women with symptomatic candidal infection commonly complain of criteria.25 Alternative tests include the use of Gram stain to group bacteria
vaginal pruritus and burning, dysuria, and dyspareunia. Discharge into morphologic types (i.e., Nugent scoring). Amsel criteria and Nugent
can be thick and white with a cottage cheese appearance or can be scores show good correlation.2,93
watery and homogeneous. Discharge usually is not malodorous, and Alternative testing includes nonmicroscopic point-of-care testing.
in many cases, women do not notice a change in vaginal discharge.66,86 Some tests detect the metabolic products of BV-related organisms such
Patients with symptomatic trichomoniasis often have pruritus and a as sialidase and prolineaminopeptidase.2,64 A DNA probe for G. vaginalis
malodorous, frothy, yellow or greenish discharge and can have dysuria, ribosomal RNA is available but is not useful if rapid results are needed.
abdominal pain, vulvar erythema and edema, and bloody vaginal This test is most helpful as a supplemental marker to detect high con-
discharge. Cervicitis can occur, with punctuate hemorrhages (i.e., straw- centrations of G. vaginalis.22,93
berry cervix) and friability. Asymptomatic T. vaginalis infection occurs Routine aerobic and anaerobic vaginal cultures are not helpful, and
commonly.10 molecular diagnostic techniques are primarily a research tool.2,67 BV
usually does not produce an inflammatory response, and the finding of
Laboratory Findings and Diagnosis WBCs on a vaginal smear indicates concurrent vaginitis or cervicitis due
to another cause.92,93
Laboratory features that help distinguish BV from candidal vulvovaginitis Candida species.  Candida vaginitis is diagnosed by demonstrating
and trichomonal vaginitis are shown in Table 51.4. budding, hyphae, pseudohyphae, or blastospores on microscopic exami-
Bacterial Vaginosis.  The diagnosis of BV is commonly established in nation of a saline or 10% KOH preparation.2,63 This technique has a
the clinical setting by the finding of three or more of the following Amsel sensitivity of about 50% because organisms such as C. glabrata, which
criteria: (1) thin, homogeneous vaginal discharge; (2) vaginal pH >4.5; does not form hyphae or pseudohyphae, are easily missed on microscopy.2
(3) characteristic fishy or amine odor released when 10% KOH is added If the KOH preparation is negative, culture can confirm the diagnosis in
to the vaginal fluid specimen (i.e., positive whiff test); and (4) 20% or symptomatic people.67,86 Culture may be particularly helpful for patients
more of epithelial cells having the appearance of clue cells, which are with ongoing nonspecific symptoms in whom BV and trichomoniasis

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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION G  Genitourinary Tract Infections

have been excluded.86 In cases of complicated vulvovaginal candidiasis, Candidiasis.  Topical therapy with azoles, such as clotrimazole, tercon-
culture is important in identifying the species of the organism because azole, miconazole, butoconazole, and tioconazole, is effective for vulvo-
therapy may be different or longer.63,94 Culture can also demonstrate vaginal candidiasis in 1- to 7-day regimens. Many of these topical
eradication of the organism, and for patients with persistent symptoms, formulations are available over the counter. Single-dose fluconazole
an alternative cause should be investigated.63,94 It is useful to measure (150 mg) therapy has efficacy that is comparable to topical therapy.2,63,66,102
vaginal pH because the vaginal pH remains low (<4.5) in vaginal candi- Symptomatic relief and negative fungal cultures are achieved in up to
diasis, unlike BV or trichomoniasis.86 90% of patients with uncomplicated vulvovaginal candidiasis. Sexual
Trichomonas vaginalis.  Diagnosis of trichomoniasis can be made by partners usually do not require therapy unless they have candidal
visualizing the motile protozoa on a wet mount preparation; however, balanitis.2
the test result is negative in 30% to 50% of cases.2,67 Culture using Recurrent or chronic candidal vulvovaginitis merits investigation for
Diamond media or the InPouch T. vaginalis culture system is more sensi- predisposing conditions, which includes obtaining cultures to confirm
tive.2,25,67 Culture can be performed on vaginal specimens, including the diagnosis and identify the pathogen.63 These infections may require
patient self-collected specimens. a longer duration of topical (7 to 14 days) or oral therapy including
Conventional and liquid Papanicolaou (Pap) tests are not considered nonfluconazole imidazole drugs.2,66,67,86 Topical boric acid in the form of
diagnostic because of high false-positive and false-negative rates.2,95 A suppositories (600 mg in a gelatin capsule) and topical flucytosine have
DNA probe test has a sensitivity of 63% and specificity of 99% compared been useful in patients with non-albicans Candida species and imidazole-
with culture and TMA. It usually is best performed in the laboratory resistant species. Alternative therapies are useful, especially in cases of
rather than the office setting because the test is moderately complex and non-albicans Candida species.66,86,94 When using fluconazole, patients
requires about 45 minutes to complete.2 with recurrent vulvovaginal candidiasis can be treated initially with a
One point-of-care test that uses an immunochromatographic capillary single dose every 3 days for a total of three doses, followed by 100 mg,
flow assay with monoclonal antibodies takes 10 minutes to complete and 150 mg, or 200 mg once each week for 6 months.2 For women who
has 82% to 95% sensitivity and 97% to 100% specificity.2 PCR has excel- cannot take fluconazole, repeated topical imidazole therapy has been
lent sensitivity and specificity (85% to 100%) but is not available com- effective.2,66,67
mercially.10 TMA has 95% to 100% sensitivity and 95% to 100% specificity Suppressive therapy usually is continued for 6 months, but recurrence
and is approved for endocervical, urine, and vaginal swab specimens in is common after therapy is discontinued because organisms are sup-
women.2,47,48 NAAT using SDA is approved for use with female endocervi- pressed rather than eradicated. Prophylaxis can be reinstituted.2,63,86
cal, vaginal, and urine specimens.2 Fluconazole resistance and clinical failure is uncommon but increasing,
Because urine or vaginal specimens collected without use of a specu- and although not usually warranted, in patients with breakthrough
lum can be used to detect trichomoniasis, vulvovaginal candidiasis, N. Candida infection, susceptibility testing may be helpful.2,103 Only topical
gonorrhoeae, and C. trachomatis, it is possible to avoid the more invasive azole medications are recommended in pregnancy.2
speculum examination to determine the cause of vaginitis in Trichomonas vaginalis.  Systemic therapy with oral metronidazole or
adolescents. tinidazole is indicated for treatment of trichomoniasis.2 Metronidazole
has an 84% to 98% cure rate with a 7-day course (500 mg twice daily)
Management or a large single dose (2 g taken orally). Most recurrent infections are
from reinfection, and although uncommon, metronidazole resistance has
Bacterial Vaginosis.  Metronidazole administered orally for 7 days is been reported in approximately 4% to 10% of cases.2,49,67,69 Topical
the recommended therapy for women with symptomatic BV,2 and it is therapy with metronidazole gel is not effective because the gel does not
preferred over single-dose therapy because of superior efficacy.2,25,64,69 penetrate the urethral and perivaginal glands adequately.2,10,49
Alternative regimens with intravaginal metronidazole or clindamycin, Single-dose tinidazole (2 g taken orally) has a 92% to 100% cure rate
which are outlined in Table 51.4, have fewer gastrointestinal side effects and reports of 1% resistance.2 Studies show tinidazole to be equivalent
and cure rates similar to those for oral metronidazole at 1 month or superior to single-dose metronidazole for cure and symptom resolu-
after treatment.2,25,67,69 Clindamycin cream should not be used when tion.2 One study found a 92% cure rate using a combination of oral and
condoms are used because the oil base weakens the latex.2 Alternate vaginal tinidazole in patients unresponsive to metronidazole.104 Tinida-
therapeutic regimens have included the use of tinidazole, which has zole appears to be better tolerated than metronidazole and has fewer
fewer side effects than metronidazole but is more expensive, and oral gastrointestinal tract and central nervous system side effects.
clindamycin.2,66,96 Sexual partners should be evaluated for STIs and treated for tricho-
A Cochrane review found insufficient evidence to recommend for or moniasis. For treatment failures, susceptibility testing is recommended
against probiotics. The 2015 STD treatment guidelines do not recom- for metronidazole and tinidazole.2,49 Women with HIV infections should
mend this therapy or currently available lactobacillus formulations as be treated with metronidazole for 7 days rather than single-dose therapy
adjunctive or replacement therapy to restore normal vaginal flora.2,97 because the latter is less effective in these patients due to concurrent BV,
There are no current standard recommendations for treatment of impaired immunity, and concurrent antiretroviral therapy, which may
recurrent BV infection, which occurs within 3 months in approximately impact clearance and reduce the efficacy of metronidazole.2,105 There are
one third of women.69 Treatment may only suppress biofilm-embedded no contraindications to using metronidazole during pregnancy, but
infection and allow organisms to evade host defense responses. Recur- tinidazole should not be used because of concerns about moderate
rences may be due to relapse rather than reinfection.67,69,85 A large, mul- adverse risks.2
ticenter study demonstrated the 70% efficacy of twice-weekly maintenance
therapy using metronidazole vaginal gel, but it only suppressed BV in
many subjects and led to vaginal candidiasis as a complication.98,99 One
Complications
uncontrolled study showed promising results with nitroimidazole and Bacterial Vaginosis.  BV has been associated with chorioamnionitis,
boric acid used to disrupt the biofilm and allow penetration of the postpartum endometritis, posthysterectomy vaginal cuff cellulitis, post­
antibiotic.100 Other regimens that have been evaluated include oral abortion PID, premature rupture of membranes, preterm labor and
nitroimidazole and intravaginal boric acid followed by suppressive delivery, low birth weight, spontaneous abortion, and intra-amniotic
metronidazole gel and a combination of monthly oral metronidazole and infection.25,64,76,106 The risk of preterm delivery is restricted to a small
fluconazole.100,101 The latter regimen was associated with decreased BV subset of women; risk may be related to the genetic host response to
episodes and increased colonization with normal flora. inflammation and cytokine production.25,64,76 Vaginal microorganisms
Long-term treatment with vaginal metronidazole is well tolerated, can ascend to the upper tract, causing infection and inflammation in the
unlike oral treatment, which can be associated with neutropenia or decidua, chorioamnion, or amniotic fluid.64
peripheral neuropathy. Prolonged treatment with clindamycin increases Data are conflicting about whether the treatment of pregnant women
the risk of C. difficile colitis.69 Resistance to metronidazole and clindamy- for BV prevents complications.2,25,64,76,107–110 Two systematic reviews found
cin has been seen in cases of recurrent BV.68 The 2015 STDs treatment little evidence that screening and treating all pregnant women prevents
guidelines do not recommend treating asymptomatic nonpregnant preterm birth.108,109 The evidence for screening asymptomatic women at
women.2 low risk for preterm delivery were poor, and evidence for women at high

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Urethritis, Vulvovaginitis, and Cervicitis 51
risk for preterm delivery were conflicting. The 2015 STD treatment a pathologic or infectious process. The ectropion usually is not friable,
guidelines state that the evidence is insufficient to recommend screening and edema or friability suggests infection.6
of asymptomatic pregnant women at low or high risk for preterm deliv-
ery, but they do recommend treatment for all symptomatic pregnant
women using any oral or vaginal regimen.2
Ectocervicitis
BV has been associated with an elevated risk of acquiring T. vaginalis, Ectocervicitis represents infection of the stratified squamous epithelium
N. gonorrhoeae, C. trachomatis, and HSV-2.2,109,111 Studies also have of the ectocervix. Ectocervicitis can occur in conjunction with trichomo-
shown an association between BV and cervicitis and PID, but a causal nal vaginitis and HSV infection. HSV causes ectocervicitis and
relationship remains unproved.64,66 Organisms associated with BV have endocervicitis.6
been found in the upper genital tracts of women with PID. Studies using
endometrial biopsies have found an association between BV and endo-
metritis, which may be silent clinically or manifest as intermenstrual or
Endocervicitis
increased bleeding.64 Etiologic Agents and Epidemiology
Women with BV are more likely to have PID, and women with PID
are more likely to have BV.25,64,76 Treatment of BV has been associated Endocervicitis represents infection of the endocervical columnar epithe-
with decreased PID in women undergoing abortion and decreased lium and can produce mucopurulent cervicitis. Common pathogens that
postoperative cuff cellulitis.64,76 Intravaginal treatment of BV has been cause endocervicitis are N. gonorrhoeae, C. trachomatis, M. genitalium,
associated with improved rates of resolution of cervicitis.64 However, the and HSV.6,116–119 Multiple studies have demonstrated an association
relationship between BV and PID for women not undergoing abortion between M. genitalium and mucopurulent cervicitis.16,33,36,59,116–118,120–123
or uterine instrumentation is not clear.25,76,112 There is no current recom- There also is a possible association with BV because cervicitis is more
mendation for treatment of nonpregnant, asymptomatic women as a likely to resolve when patients also are treated for BV.25,116–118,120 Theories
standard clinical practice.2,64 about this relationship include proinflammatory vaginal cytokines in
Trichomonas vaginalis.  Trichomoniasis has been associated with pre- patients with BV and the glycosidases and proteinases produced by
mature rupture of membranes, preterm delivery, and low-birth-weight BV-associated organisms that may degrade cervicovaginal mucus.116,117
infants,.2,25,113 T. vaginalis has also been associated with an increased risk The prevalence of cervicitis varies from 22% to 41% depending on the
of PID in women who are HIV positive.2,113 Although treatment of T. definition used, which is inconsistent among the various studies in the
vaginalis during pregnancy does not appear to reduce complications, the literature.116 A randomized, multicenter study that ruled out C. tracho-
2015 CDC STD treatment guidelines recommend that all symptomatic matis, N. gonorrhoeae, T. vaginalis, and M. genitalium by NAAT found
pregnant women should be tested and considered for treatment at any that 61% of subjects had mucopurulent cervicitis of unknown origin.124
stage of pregnancy.2,107,114 Although a single dose of metronidazole has Clinically apparent cervicitis is not caused solely by sexually transmit-
been demonstrated to be safe at all stages of pregnancy, more studies are ted agents. Other entities include tuberculosis, noninfectious causes such
needed regarding use of tinidazole, and current recommendations rec- as sarcoidosis and Behçet disease, and local insults due to chemical
ommend avoiding use in pregnancy.2 douches, spermicides, and foreign bodies.116–119
Human Immunodeficiency Virus.  BV and T. vaginalis enhance acquisi-
tion of HIV and transmission to a partner.2,25,29,64,76,105,115 Vulvovaginal Clinical Manifestations and Differential Diagnosis
candidiasis has been associated with increased HIV seroconversion in
HIV-negative women and higher levels of cervicovaginal HIV shedding Endocervicitis often is overlooked and underdiagnosed because signs and
in HIV-positive women. Treatment of T. vaginalis reduces HIV viral symptoms can be mild or absent. PID is one consequence of untreated
shedding in vaginal secretions.105 However, no studies have demonstrated mucopurulent cervicitis.6 Sexually active adolescents with vaginal dis-
similar effects on viral shedding in subjects with BV or vulvovaginal charge, lower abdominal pain, abnormal vaginal bleeding, or deep dys-
candidiasis.2,25 pareunia should be evaluated for endocervicitis.6 Evaluation also is
indicated if a sexual partner has an STI.
Vulvitis in Adolescents Cervical abnormalities associated with endocervicitis range from
subtle changes to a yellow endocervical discharge and an edematous,
Inflammation of the vulva in adolescents most commonly is caused by erythematous, and easily friable appearance to the cervix.6 There is no
HSV and yeasts (see Table 51.4). HSV often causes painful genital ulcers, consensus definition for mucopurulent cervicitis, which makes evalua-
along with vulvar inflammation and inguinal lymphadenopathy (see tion of the research literature difficult.116,117 Definitions include inflam-
Chapter 50).7 Occasionally, inflammation can be associated with T. vagi- mation of the endocervix with possible edema, yellow-green endocervical
nalis infection. discharge, increased numbers of neutrophils on microscopic examina-
tion of cervical secretions, and inducible endocervical bleeding.
Prevention The 2015 CDC STD treatment guidelines outline the two major
diagnostic criteria as purulent or mucopurulent endocervical discharge
Correct and consistent use of condoms is the most effective means of and sustained endocervical bleeding.2 Mucopurulence is characterized by
preventing and reducing transmission of the STIs associated with a yellow or green color on a cotton-tipped applicator obtained from the
vulvovaginitis. endocervix. The number of neutrophils considered significant varies in
different studies from at least 30 cells per 400× magnified microscopic
CERVICITIS field to more than 10 cells per 1000× magnified microscopic field.
Although the use of a 30-cell cut point provides greater specificity, detec-
Cervicitis is inflammation of the endocervix or ectocervix. Both are tion of yellow endocervical mucopus is more accurate than the number
common problems among adolescents, but neither is common in prepu- of WBCs.2,6,117–119
bertal girls. Under the influence of estrogens after puberty, the vaginal
epithelium and ectocervix become cornified and relatively resistant to
infection with a number of pathogens, including N. gonorrhoeae and C.
Laboratory Findings and Diagnosis
trachomatis.7 In contrast, the endocervix continues to be lined with Specific microbiologic diagnosis informs appropriate treatment. Patients
columnar epithelium and remains susceptible to infection with these should be tested for N. gonorrhoeae, C. trachomatis, T. vaginalis, and BV.
organisms. In adolescents and adult women, these organisms usually Gram-negative intracellular diplococci are seen on Gram stain in about
cause endocervicitis in the absence of vaginitis. one half of cases of gonococcal endocervicitis.6 Given the poor sensitivity
A normal developmental finding in adolescents is the ectropion, an of the Gram stain and the possibility of infection in the absence of any
erythematous area surrounding the os at the junction between columnar abnormality, evaluation for gonococcal endocervicitis must include
and stratified squamous epithelium. During adolescence, the ectropion NAAT.2 Inflammatory changes can be even less remarkable with endo-
recedes as the result of squamous metaplasia. Although some adolescents cervicitis caused by C. trachomatis. NAAT is recommended in all cases of
with a large ectropion may have significant vaginal discharge, this is not suspected C. trachomatis infection.2 A saline wet mount preparation can

365
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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION G  Genitourinary Tract Infections

at lower risk for STIs, treatment can await the results of diagnostic
TABLE 51.5  Treatment of Cervicitis in Adolescents testing.2
Results Suggested Treatment More data are needed about the treatment of M. genitalium cervicitis.
The antibiotics directed at treating N. gonorrhoeae and C. trachomatis are
Mucopurulent or purulent Treat for Chlamydia trachomatis or
endocervical discharge and/ Neisseria gonorrhoeae with positive
not adequate to treat cervicitis caused by other organisms, and the
or sustained easily induced test results or consider presumptive
standard treatment regimen for PID with cefoxitin and doxycycline is
endocervical bleeding treatment for C. trachomatis and N. ineffective for women with M. genitalium associated with PID.120,125,126
gonorrhoeae if prevalence is high in Testing for M. genitalium is recommended for women with persistent
patient population or community cervicitis or persistent PID for whom re-exposure to an infected partner
(e.g., known contact, new and/or or nonadherence has been ruled out.2,35,116 If the initial treatment did not
multiple sex partners, age ≤25, include azithromycin, the antibiotic should be given. According to CDC
unprotected sex) and testing not guidelines, moxifloxacin can be given based on having positive M. geni-
possible and/or follow-up cannot be talium test results.2 Other investigators have suggested considering this
ensured; if at low risk for STIs, treatment for recurrent or persistent cervicitis when testing is not avail-
treatment can be deferred pending able,35 but some have questioned the treatment of cervicitis of unknown
microbial results origin because the clinical cure described is not related to antibiotic
Trichomonas seen on wet Treat with oral metronidazole or therapy.127
mount or identified on rapid tinidazole The need to consider M. genitalium in the adolescent population was
test, culture, NAAT demonstrated in several studies. One showed a cumulative rate over a
27-month period among 14- to 17-year-old girls to be 14%, which was
Bacterial vaginosis diagnosed Treat with oral metronidazole or
concordant with their male partners.128 Another study of girls and women
tinidazole or intravaginal
metronidazole or clindamycin
14 to 21 years old found a rate of 22%.129
Follow-up after completion of therapy is recommended for adoles-
Clinical presentation suggesting Consider oral acyclovir or famciclovir or cents with persistent symptoms.2 The management of mucopurulent
herpes simplex virus valacyclovir cervicitis also requires evaluation and treatment of all sexual partners for
infection STIs, and it provides an opportunity to reinforce STI prevention
Persistent or recurrent cervicitis Rule out re-exposure or treatment failure measures.2
for N. gonorrhoeae and C.
trachomatis or other identified STIs
and exclude BV. Testing for
Complications
Mycoplasma genitalium in settings Complications of untreated mucopurulent cervicitis include PID and the
with validated assays can be possible long-term sequelae of ectopic pregnancy and infertility. The
conducted. Moxifloxacin can be used relationship between N. gonorrhoeae or C. trachomatis and PID is well
if NAAT results are positive and initial established, and there is increasing evidence that M. genitalium also is
treatment with azithromycin (1 g PO
associated with PID.6,59,118,130–132 Cervicitis also increases the risk of trans-
once) failed. CDC recommends
mission and acquisition of HIV infection. Viral shedding of HIV decreases
deferring therapy until further
with effective treatment for cervicitis.2,6,118
microbial results are availablea
BV, bacterial vaginosis; CDC, Centers for Disease Control and Prevention; NAAT, nucleic acid
amplification test, STIs, sexually transmitted infections. Prevention
a
Data from Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, Consistent use of condoms can reduce transmission of STI pathogens
2015. MMWR Recomm Rep 2015;64(RR-3):1–137. associated with cervicitis.

All references are available online at www.expertconsult.com.

be used to diagnose T. vaginalis and to help establish the diagnosis of


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PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION G  Genitourinary Tract Infections

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