TOPICS IN INFECTION
| HERPES SIMPLEX VIRUS INFECTION —Kim S. Erlich, MD, Assistant Clinical Professor of Medicine, University of
California, San Francisco, School of Medicine
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| Herpes simplex virus (HSV): HSV-1—primary cause of orolabial herpes (fever blister or cold sore); widely prevalent in
humans; estimated two thirds of population in United States infected; increased prevalence in crowded living conditions;
HSV-2—cause of ≈85% of genital herpes; HSV-1 and HSV-2 can cause oral herpes, genital herpes, or both; prevalence
steadily increasing; increased risk with increased sexual activity, increased number of sexual partners, and other sexually
transmitted diseases (STDs); genital lesions may serve as portal of entry for HIV; suppressing virus to prevent lesions from
occurring may lessen chance of acquiring HIV; herpesvirus structure—double-stranded DNA virus; nucleoprotein core
surrounded by outer protein capsid consisting of 162 identical capsomers; tegument protein surrounds capsid; outer lipoprotein
envelope makes virus susceptible to deactivation; glycoprotein G only glycoprotein unique to HSV-1 and HSV-2
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| Genital herpes: most prevalent STD in United States; estimated 1 million new cases annually; estimated 50 million infected
persons in United States; frequent recurrences likely caused by HSV-2; recurrences less frequent if infection
caused by HSV-1; signs and symptoms variable; asymptomatic shedding likely occurs intermittently in all infected individuals;
person infectious to sexual partners during that time; prevalence of STDs in United States—herpes, 45 to 60
million people; human papilloma virus (HPV), ≈20 million; Chlamydia, 3 million; hepatitis B, 1.25 million; HIV, estimated
1 million; steady increase in genital herpes caused by HSV-2 in last 30 yr; many people asymptomatic and unaware
they are infected
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| First episode of genital herpes: clinical features—can be atypical; usually more severe than recurrent episode; tender
vesicles, shallow ulcerations, local pain and itching, dysuria, urethral discharge, cervicitis/vaginal discharge, and tender
inguinal adenopathy (helps differentiate herpes from other causes of genital ulcer disease); systemic symptoms
(fever, headache, myalgias, and stiff neck in about one third of patients); clinical course—incubation period 2 to 12
days; vesicles turn into pustules; vesicular fluid highly contagious; by 1 wk, vesicles unroof, leaving moist ulcerations;
virus live as long as lesions moist; by 12 to 14 days (if untreated), ulcers dry up; at this stage, viral culture negative; lesions
heal without scarring
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| Pathogenesis of HSV infection: virus penetrates skin; centripetal migration to nerve ganglion where latency established;
virus incorporates into DNA of ganglionic cells; replication occurs locally; blisters and ulcers develop; viral shedding
occurs; virus remains latent in nerve root ganglion even with no visible signs; virus may reactivate spontaneously or
exogenously; with reactivation, virus travels back along nerve fibers to mucous membrane or epithelial surface, causing
recurrent lesions, ulcerations, and shedding; viral shedding can occur without symptoms; occasionally, virus reactivates
along different nerve fiber, producing symptoms in different area
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| Recurrent genital herpes: milder clinical illness, less extensive distribution, local symptoms only, frequency variable;
prodrome may be present (antiviral therapy can be initiated; may prevent outbreak); typically, lesions heal more quickly
than with first episode; many people psychologically burdened; psychologic counseling and support groups helpful in
dealing with depression and physical complaints
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| Neonatal HSV infection: more benign form limited to skin, eyes, and mucous membranes; more serious form involves
central nervous system (CNS); morbidity and mortality high; 2000 to 5000 cases in United States annually; risk for neonatal
HSV higher in women with first episode of HSV infection during pregnancy (particularly third trimester); initial infection
during pregnancy may be due to asymptomatic shedding in partner; less risk with recurrent disease (likely due to presence of
antibody that crosses placenta and protects baby); prevention—identify women at risk; counsel discordant couple to avoid
unprotected sex during pregnancy; antivirals given during late pregnancy reduce HSV outbreaks, viral shedding at delivery,
number of symptomatic outbreaks, and cesarean section rate; American College of Obstetricians and Gynecologists
(ACOG)—“acyclovir in pregnancy is acceptable and should be considered for HSV-positive women ≥36 weeks gestation”
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| Asymptomatic shedding: defined as isolation of virus in absence of symptomatic visible or typical lesions; symptoms
may be minimal or atypical; occurs in all patients; asymptomatic shedding frequent at time of initial infection; begins to
slow down over time; instrumental in transmission; for discordant couple, risk for transmission to uninfected partner 10% to
15% per year; data looking at HSV shedding in symptomatic and asymptomatic patients for >3-mo period showed at least 1
day of shedding in 68% of asymptomatic patients and 61% of symptomatic patients; data also show that of 144 discordant
couples, transmission of virus to uninfected partner occurred in 14 (9.7%)
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| Risk reduction: discuss risk for transmission during outbreaks and during asymptomatic shedding; condoms not 100% effective
due to behavioral and anatomic issues; suppressive antiviral therapy reduces symptomatic outbreaks and asymptomatic
shedding in infected patients; immunocompromised host—usually recurrent infection; may be atypical in
appearance (large area of involvement, prolonged virus shedding); high index of suspicion with mucous membrane or cutaneous
lesions; perirectal lesions common (may look like sacral decubitus)
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| Diagnosis: viral culture or direct antigen detection (direct fluorescent antibody test) recommended; cytology—Tzanck
preparation or cervical Papanicolaou (Pap) testing should not be used for diagnosis; antibody detection—commercially
available blood tests reliable and inexpensive; serology—older techniques (immunofluorescence testing, neutralization
assays) unreliable; IgM assays not useful for diagnosis; glycoprotein G-based type-specific serologic assays gold standard;
HerpeSelect (done by enzyme-liked immunosorbent assay [ELISA] or Immunoblot technique) highly sensitive and
specific, particularly for HSV-2
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| Antivirals: activated in infected cells by viral thymidine kinase; converted into triphosphate drug; safe and effective; acyclovir
has 10% to 30% bioavailability; higher bioavailability with valacyclovir and famciclovir allows for less frequent
dosing; excreted through kidneys (reduce dosage in patients with renal dysfunction); data looking at valacyclovir showed
faster healing of lesions and shorter duration of pain and viral shedding with 500-mg or 1000-mg formulation; treatment
guidelines for first episode of genital herpes—acyclovir 400 mg tid or 200 mg 5 times daily; valacyclovir 1000 mg
bid; famciclovir 250 mg tid; for recurrence—acyclovir 400 mg tid, valacyclovir 500 mg bid, or famciclovir 125 mg bid;
data show valacyclovir 500 mg bid for 3 days equivalent to 5-day regimen; famciclovir 1 g bid superior to placebo
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| Suppressive therapy: shown to prevent symptomatic recurrences; recommended regimen—acyclovir 400 mg bid,
famciclovir 250 mg bid, or valacyclovir 500 mg daily with <10 outbreaks per year or 1 g daily with >10 outbreaks per
year; asymptomatic shedding—data show reduced in women on acyclovir compared to those on placebo (0.3% vs
6.9%); suppressive therapy to prevent transmission—data show over 8-mo period, symptomatic infection increased in
placebo couples compared to those receiving valacyclovir (2.2% vs 0.5%); valacyclovir approved and indicated for preventing
transmission to uninfected partner; data also show best prevention of transmission achieved with condoms used
in conjunction with valacyclovir; for discordant couple, suppressive antiviral therapy should be recommended for partner
with HSV-2 to reduce rate of transmission; data show acyclovir and valacyclovir equally effective in suppression of
shedding
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| Other treatment considerations: topical therapies—not recommended; acyclovir ointment poorly absorbed; ineffective
in normal host; superior to placebo in compromised host; penciclovir (Denavir) superior to placebo for herpes labialis (not
evaluated for genital herpes); docosanol (Abreva) superior to placebo for oral herpes (not evaluated for genital herpes); L-
lysine not shown effective; alternative therapies—none recommended; vaccine—ongoing trial; 75% efficacy in women
with no previous HSV-1 infection; no effect in men; HerpeVac trial actively recruiting seronegative women; condoms—
important to counsel patients about use of condoms to prevent herpes and other STDs; important to talk to adolescent patients
about risk for STDs
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| SERIOUS PELVIC INFECTIONS —David E. Soper, MD, Professor and Vice Chairman for Clinical Affairs and Director,
Division of Benign Gynecology, Department of Obstetrics and Gynecology, Medical University of South Carolina,
Charleston
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| Five W’s of postoperative fever: wind—atelectasis not cause of fever; “wind” of early postoperative period associated
with release of cytokines; pneumonia can cause fever, but is later presentation; water—urinary tract infection (UTI)
most common cause; wound—abdominal incision, operative site, and drain sites; walking—deep venous thrombosis
(DVT) cause of low-grade fever, but most often related to intravenous (IV) catheter-related phlebitis; assess IV site and
discontinue if sign of infection present; wonder drugs—associated with drug fever
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| Postoperative fever: Fanning showed that although postoperative fever frequently evaluated by blood culture, urine culture,
and chest x-ray, evaluation rarely yields positive results; focused approach to evaluating postoperative fever recommended
rather than “shotgun” approach; febrile morbidity best defined by 2 temperature readings >101°F at any time in postoperative
period; fever work-up guided by patient’s signs and symptoms; UTI most common etiology of fever after hysterectomy; cuff
cellulitis and/or abscess uncommon but important cause of postoperative fever (diagnosis usually made after hospital discharge)
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| Cuff infection: incidence—<1% to 5%; risk factors—younger age, longer duration of surgery, lack of antibiotic prophylaxis,
clinic patient, preoperative vaginitis (bacterial vaginosis, Trichomonas vaginitis); antimicrobial prophylaxis
decreases risk substantially; antimicrobial prophylaxis—numerous studies support benefit; administer within 1 hr of
making incision; hospital should have protocol; should be administered by anesthesiologist preoperatively; single dose as
effective as multiple doses; administer second dose if duration of surgery >2 times half-life of antibiotic or with excessive
blood loss; indicated for vaginal and abdominal hysterectomy; antibiotic regimens—cefazolin most often used; cefoxitin
and cefotetan; metronidazole (500 mg or 1-g single IV dose) recommended for penicillin-allergic patients; tinidazole
(administer 4 to 12 hr before surgery [long half-life]); diagnosis—febrile morbidity, more pain and tenderness than expected,
localized peritoneal irritation, and bowel dysfunction; more on antibiotic regimens—broad-spectrum antibiotics,
especially first-generation cephalosporins, recommended; amoxicillin and potassium clavulanate (Augmentin) 500
mg tid option for postoperative pelvic cellulitis treated in outpatient setting; agents that cover aerobic organisms, ie, trimethoprim-sulfamethoxazole
(Septra), ciprofloxacin (Cipro), levofloxacin (Levaquin) or cephalexin (Keflex) combined
with metronidazole (covers anaerobic organisms) almost as effective as parenteral therapy
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| Pelvic abscess: vaginal cuff abscess—accounts for ≈60% of abscesses after hysterectomy; presents with persistent fever,
sensation of fullness, normal bowel function, and presence of mass on examination; adnexal abscess—tubo-ovarian
abscess; presents with new-onset fever, abdominopelvic pain, and pelvic mass; more refractory to therapy; more
likely to require drainage or surgery; therapeutic approach—establish diagnosis; transvaginal ultrasonography (US)
helpful; initiate broad-spectrum antibiotic therapy and reassess patient after 48 hr; look for lysis of fever, decreasing abdominopelvic
pain, normalization of white blood cell (WBC) count, and return of bowel function; if no response, ensure
adequate antibiotic coverage and rule out cuff or adnexal abscess; suspect abdominal incision; techniques for
drainage—transvaginal US-guided aspiration and computed tomography (CT)-guided transgluteal percutaneous drainage
recommended; other options include colpotomy, laparoscopic drainage, and laparotomy; transgluteal percutaneous
and transvaginal US-guided aspiration recommended; data show surgery abated 96% of time with placement of catheters
into abscess by interventional radiologist; free floating fluid on US suggests rupture of abscess and need for laparotomy
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| Necrotizing fasciitis: infection of superficial fascia; Colles’ fascia in vulva contiguous with Scarpa’s fascia in anterior
abdominal wall; vulvar abscesses or necrotizing fasciitis can track up over mons and into thigh; predisposing
conditions—diabetes, atherosclerosis, and steroid therapy; clinical presentation—begins as simple infection of subcutaneous
tissue; extends along superficial fascial planes; thrombosis of small vessels; destruction of superficial nerves;
signs—woody induration, particularly on vulva and thighs (hallmark sign), edema, erythema, drainage, and crepitant
subcutaneous tissue; skin changes occur late (do not wait to see before initiating therapy); laboratory—anemia from
hemolysis, leukocytosis, and hypocalcemia; x-ray may or may not show soft tissue gas; treatment—broad-spectrum antibiotics
and surgical debridement; operate early (do not waste time with frozen-section biopsy); resect all necrotic tissue;
“dig a ditch, not a tunnel”; many patients require care in intensive care unit
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| Systemic inflammatory response syndrome (SIRS): defined as temperature >38°C or <36°C; heart rate >90 bpm;
tachypnea significant negative sign; WBC >120,000/mm3 or <4,000/mm3 with >10% bands; infectious and noninfectious
causes; evaluation—careful history and physical examination; observe whether patient looks well; observe direction of
WBCs; obtain arterial blood gases and basic metabolic panel; look for metabolic acidosis (sign of generalized sepsis); act
aggressively
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| Clostridium sordellii-associated toxic shock syndrome (CATS): from 2003 to 2005, 4 deaths occurred in women
after medical abortions; patients received common “off-label” regimen of oral mifepristone and intravaginal misoprostol;
clinical features—sudden onset of weakness, nausea and vomiting, progressive refractory hypotension, local and spreading
edema; laboratory—hemoconcentration; no presence of Staphylococcus aureus or Streptococcus pyogenes; appendiceal
abscess-associated toxic shock reported with C sordellii; superantigen starts irreversible cytokine cascade
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Educational Objectives
The goal of this program is to educate the listener about the diagnosis and treatment of herpes simplex virus (HSV) and the
diagnosis and treatment of postoperative pelvic infections. After hearing and assimilating this program, the clinician will be
better able to:
 | 1. Summarize the prevalence and pathogenesis of HSV.
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| 2. Diagnose and treat patients with initial and recurrent episodes of HSV infection.
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| 3. Counsel patients about asymptomatic shedding and how to take appropriate measures to minimize those risks.
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| 4. Employ a focused approach to diagnosing postoperative fever.
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| 5. Diagnose and treat pelvic abscesses and necrotizing fasciitis.
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Resources for Patients with Herpes
National Herpes Hotline: (916)361-8488
American Herpes Foundation: (201)342-441, www.herpes-foundation.org
American Social Health Association: www.ashastd.org
www.herpesdate.com
Discussed on This Program
Acyclovir (acycloguanosine) [Zovirax]
Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600, Augmentin XR]
Cefazolin sodium [Ancef, Zolicef]
Cefotaxime sodium [Claforan]
Cefotetan disodium [Cefotan]
Cefoxitin sodium [Mefoxin]
Cephalexin [Biocef, Keflex]
Cephalexin HCl monohydrate [Keftab]
Cephalothin sodium [Keflin]
Ciprofloxacin [Ciloxan, Cipro, Cipro I.V., Cipro XR, Proquin XR]
Docosanol (Abreva)
Famciclovir [Famvir]
Levofloxacin [Levaquin, Quixin]
Metronidazole [Flagyl, Flagyl 375, Flagyl ER, Flagyl IV, Flagyl IV RTU, Metric 21, MetroCream, MetroGel, MetroGel-
Vaginal, MetroLotion, Noritate, Protostat]
Penciclovir [Denavir]
Tinidazole [Tindamax]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, Bactrim DS, Bactrim IV, Bactrim Pediatric,
Cotrim, Cotrim D.S., Cotrim Pediatric, Septra, Septra DS, Septra IV, Sulfatrim]
Valacyclovir HCl [Valtrex]
Suggested Reading
ACOG practice bulletin: Clinical management guidelines for obstetrician-gynecologists, number 57, November 2004.
Gynecologic herpes simplex virus infections. Obstet Gynecol 104(5 Pt 1:1111, 2004; Centers for Disease Control
and Prevention (CDC): Clostridium sordellii toxic shock syndrome after medical abortion with mifepristone and intravaginal
misoprostol—United States and Canada, 2001-2205. MMWR Morb Mortal Wkly Rep 54(29):724, 2005; Fanning
J et al: Frequency and yield of postoperative fever evaluation. Infect Dis Obstet Gynecol 6(6):252, 1998; Larsen JW
et al: Guidelines for the diagnosis, treatment and prevention of postoperative infections. Infect Dis Obstet Gynecol
11(1):65, 2003; Kamat AA et al: Wound infection in gynecologic surgery. Infect Dis Obstet Gynecol 8(5-6):230, 2000;
Spruance SL et al: A large-scale, placebo-controlled, dose-ranging trial of oral valacyclovir for episodic treatment of
recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med 156(15):1729, 1996; Triolo O et al: Amoxycillin/clavulanate
prophylaxis in gynecologic surgery. Int J Gynaecol Obstet 85(1):59, 2004; Wald A et al: Reactivation
of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 342:844, 2000; Zane
SB et al: Deaths from Clostridium sordellii after medical abortion. N Engl J Med 354(15):1645, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Erlich was recorded at the 27th Annual Advances in Infectious Diseases, sponsored by the University of California,
San Francisco, School of Medicine, held on April 26-28, 2006 in San Francisco, CA. Dr. Soper was recorded at
the 37th Annual Ob/Gyn Spring Symposium sponsored by the Medical University of South Carolina, held on March
27-29, 2006 in Charleston, SC. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
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