HERPES SIMPLEX VIRUS/ANTIBIOTIC RESISTANCE
From the 41st Annual Advances and Controversies in Clinical Pediatrics, presented by the Department of Pediatrics,
University of California, San Francisco, School of Medicine
Betsy C. Herold, MD, New York, NY
Educational Objectives
| The goal of this program is to improve current management of infectious disease, specifically, neonatal herpes
simplex virus (HSV) infections, and more broadly through judicious use of antibiotics. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Detail the epidemiology of neonatal HSV infections.
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| 2. Evaluate patients for suspected neonatal HSV infection.
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| 3. Prevent adverse neurologic sequelae of neonatal HSV infection.
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| 4. Describe emerging patterns of antimicrobial resistance.
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| 5. Utilize strategies to reduce antibiotic resistance.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgments
Dr. Herold was recorded at the 41st annual Advances and Controversies in Clinical Pediatrics, presented May 29-31,
2008, by the Department of Pediatrics, University of California, San Francisco, School of Medicine. The Audio-Digest
Foundation thanks Dr. Herold and UCSF School of Medicine for their cooperation in the production of this program.
| NEONATAL HERPES SIMPLEX VIRUS INFECTION
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| Case 1: 3-wk-old infant presented to emergency department (ED) with 1-day history of fever; infant irritable but easily
consolable; temperature 38.7°C; slight tachycardia; no focal problem or rash on examination; laboratory studies—
white blood cell (WBC) count elevated at 21,000/µL (70% polymorphonuclear neutrophils [PMN]); cerebrospinal fluid
(CSF) marginal (25 red blood cells [RBCs]/mL; 10 WBCs/mL [50% PMN; 50% lymphocytes]); protein elevated (124
mg/dL); alanine aminotransferase (ALT) 67 U/L; recommended therapy—hospitalize and 1) administer ampicillin,
ceftriaxone, and acyclovir, or 2) vancomycin, ceftriaxone, and acyclovir; vancomycin covers Listeria and reasonable
choice if cultures not available; elevated protein suggests meningitis
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| Do all febrile neonates need acyclovir? no, but consider possibility of herpes simplex virus (HSV) infection (presentation
variable); only 50% of children present with fever if central nervous system (CNS) disease or disseminated disease
present; ≈50% of infants with CNS disease have seizures (usually nonfocal; <25% of those with disseminated
disease); WBC count may not be elevated; in disseminated disease, elevated transaminases red flag for HSV infection;
unexplained tachypnea unusual presentation of HSV infection; blood in CSF not indicative of HSV in neonate (cortical
hemorrhage more common in older children)
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| Epidemiology: 85% of perinatal HSV infections occur during passage through birth canal (15% of cases acquired after
birth, due to exposure to nongenital lesions); HSV-2 infection predominates; maternal acquisition of HSV during pregnancy
associated with high risk for transmission (child most protected if mother already has HSV-2 antibodies)
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| Spectrum of neonatal HSV: continuum (no distinct categories)
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| Skin, eye, mucous membrane (SEM) disease: if only SEM disease present, mortality zero; skin lesions typically appear at
1- to 2-wk of age at sites of trauma; with maternal history of HSV infection, fetal scalp electrodes contraindicated; if
mother has history of herpes lesion near time of delivery, do not perform, eg, circumcision (wait until child clear of exposure);
rate of neurologic sequelae ≈5%; laboratory studies—direct fluorescent antibody (DFA) staining; sensitivity
>80% to >95% (few false positives); obtain viral and bacterial cultures
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| Disseminated disease: presents in first 5 to 10 days after birth; mimics sepsis (patients look sick); signs and symptoms include
fever, hepatomegaly, disseminated intravascular coagulation (DIC), and tachypnea; obtain viral cultures from sites
other than blood; CNS involvement may be present (order polymerase chain reaction [PCR] test of CSF); with treatment,
mortality ≈50% (rate of sequelae ≈40%); evaluation to define extent of disease—consider liver function tests (typically,
bacterial infection not associated with liver involvement); thrombocytopenia and DIC common; abdominal films;
chest x-ray (to detect infiltrates); computed tomography (CT), electroencephalography (EEG); if HSV infection
suspected—empiric administration of acyclovir recommended
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| CNS disease: onset 2 to 3 wk after birth; symptoms nonspecific, but may include focal seizures; ≈50% of patients develop
skin lesions; lumbar puncture (LP) has low specificity (use PCR); EEG diffusely abnormal (in older child, findings
localized to temporal lobes); early CT and magnetic resonance imaging (MRI) typically normal (cortical
hemorrhage late finding); viral encephalitis associated with enterovirus infection (less commonly, adenovirus); mortality
15% (sequelae 54%; empiric therapy recommended)
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| General approach to diagnosis: serologies have no role in diagnosis of neonatal HSV because of maternal antibody
and possibility that source postnatal; culture specimens can be combined (site not key); PCR of CSF; Kimberlin 2001—
cultures of skin and eye (particularly conjunctiva) best yield; negative PCR does not exclude possibility of neonatal HSV
CNS disease (do not discontinue acyclovir based on single PCR [repeat LP and culture])
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| PCR results from CSF of neonate (Kimberlin 1996): 24% of children with documented SEM disease had positive
PCR; first PCR negative in 25% of children with CNS disease demonstrated by MRI and EEG; HSV DNA detected
in 25% of children previously categorized as having SEM disease (suggests disease continuum); 6 of 8 negative samples
collected >5 days after initiation of acyclovir; clinical application of PCR findings—13 children given vidarabine and
6 given acyclovir (all had positive PCR at 10 days); 18 of 19 died or suffered moderate to severe neurologic impairment
within first year); 3 in 11 with negative PCR also had neurologic impairment; caveat—vidarabine no longer used because
of renal toxicity; current recommendations—persistence of positive PCR associated with poor outcome; obtain
CSF for PCR near end of course; if PCR still positive, continue acyclovir for 1 wk and repeat test (if positive, continue
acyclovir)
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| Safety and efficacy of high-dose intravenous (IV) acyclovir (Kimberlin, National Institute of Allergy
and Infectious Diseases Collaborative Antiviral Study Group, 2001): current duration of therapy 21 days;
infants given acyclovir 45 or 60 mg/kg per day for 14 to 21 days; ≈25% of subjects positive for HSV-1 (68% for HSV-2);
high mortality in CNS group (at 20 mg/kg per dose, mortality improved); morbidity—with improved therapy (higher
dose, longer duration), all children with SEM disease normal at 12 mo of age; CNS disease (no improvement); disseminated
disease (modest change); dose-related side effects—renal toxicity not common; only 2 in 72 children had elevated
creatinine levels at 60 mg/kg per day; however, neutropenia common; should we apply this regimen to HSV
encephalitis beyond neonatal period? without good studies, answer yes (use 21-day regimen)
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| Recurrent disease: skin recurrences likely (almost all patients have ≥1 recurrence in first 6 mo of life); direct correlation
between frequency of recurrences of SEM disease and adverse neurologic sequelae; if <3 recurrences within first 6
mo, child almost always normal (if ≥3 recurrences, only 70%-80% of patients neurologically normal)
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| Suppressive acyclovir therapy after neonatal HSV infection (Kimberlin 1996): after last dose of IV acyclovir,
oral acyclovir initiated at 300 mg/m2 per dose, bid or tid, for 6 mo; 18 in 26 children met enrollment criteria (16 in
18 treated tid); study conducted before valacyclovir available; safety—12 in 26 participants developed neutropenia (of
those, 4 had absolute neutrophil count [ANC] <500/µl); neutropenia developed in ≈50% of patients; oral acyclovir therapy
tid reduced recurrences, compared to historical controls; however, authors concluded that data insufficient to recommend
routine utilization of suppressive therapy after acute management of neonatal HSV infection
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| Risk for maternal transmission: risk greater with primary disease than recurrent disease; presence of maternal antibody
protective; prolonged duration of rupture of membranes increases risk; mucocutaneous barriers (if lesion present,
risk increased; avoid scalp electrodes); cesarean delivery reduces risk if performed ≤4 hr after rupture of membrane in
mother with active lesions
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| Valacyclovir prophylaxis (Andrews 2006): HSV-2-positive women given 500 mg oral valacyclovir bid starting 36
wk before delivery; control group given placebo; clinical recurrences reduced with suppressive therapy; shedding of
HSV within 7 days of delivery similar between groups
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| Other interventions: rapid HSV PCR testing of maternal secretions at delivery; if positive, cesarean delivery recommended;
testing cost-effective; more data needed
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| HSV vaccine (GlaxoSmithKline): currently in phase 3 trials; vaccine prevented genital herpes in ≈75% of patients;
vaccine 40% effective in preventing HSV-2; no efficacy against HSV-1 acquisition; no efficacy in preventing infection if
patient HSV-1-positive or male; bottom line—vaccine protected HSV-naive female patients from infection
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| JUDICIOUS USE OF ANTIBIOTICS
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| Clinical scenario A: 5-yr-old child presented to ED with 2-day history of fever and cough; child moderately ill, tachycardic,
and tachypneic; temperature elevated; pulse oximetry decreased to 97%, and breath sounds decreased on right side;
WBC count 22,000/µL with 70% PMNs; on chest x-ray, lobar infiltrates and effusion; initial management—plan to admit
patient; obtain lateral or decubitus films and prepare for diagnostic thoracentesis, chest tube, or video-assisted thoracic surgery
(VATS); simple lobar pneumonia—empiric administration of high-dose IV ampicillin treatment of choice for presumed
bacterial pneumonia in children >3 mo of age; Streptococcus pneumoniae most likely bacterial pathogen in this
scenario; despite increases in minimum inhibitory concentration (MIC), penicillin treatment failures in nonmeningeal disease
rare; ampicillin recommended unless staphylococcal infection suspected; consider third-generation cephalosporin if patient
septic or at high risk (eg, immunocompromised); if pneumatoceles or effusions present—add coverage for routine
Staphylococcus aureus and community-acquired methicillin-resistant S aureus (MRSA); 30% to 40% of pneumococci resistant
to macrolides (exception pneumonia due to Mycoplasma); add macrolides to regimen in high-risk populations (eg,
patients with sickle cell disease)
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| Aminopenicillins: mechanism of action—aminopenicillins bind to penicillin-binding proteins; as resistance mechanism,
bacteria produce β-lactamase; spectrum of coverage—Haemophilus influenzae, Escherichia coli, Klebsiella; S
pneumoniae has different mechanism of resistance (amoxicillin-clavulanate [Augmentin], ampicillin plus sulbactam
[Unasyn], or other β-lactamase inhibitor not helpful)
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| Resistance of S pneumoniae to antibiotics: organism resistant to every family and class of antibiotics; rate of resistance
to erythromycin 30% (penicillin, 25%); however, group A streptococci 100% susceptible to penicillin; macrolides—
increased resistance correlates with increased prescriptions (avoid macrolides); S pneumoniae most common cause of
acute sinusitis and also most common cause of otitis media (high-dose amoxicillin first-line therapy); for nontypeable H influenzae
or Moraxella catarrhalis, third-generation cephalosporin or modified penicillin that has β-lactamase inhibitor
makes sense; look for inducible resistance to clindamycin
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| Prevention and control of resistance: use least broad-spectrum antibiotic that targets pathogen suspected; use appropriate
dose and duration (smaller doses encourage resistance); vaccinating patients helps limit need for antibiotics and
development of antibiotic resistance
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| Clinical scenario B: 4-yr-old patient with history of diffuse abdominal pain lasting 2 to 3 days; child awake all night
with severe pain; pain improved, but temperature 39°C; child looks toxic in ED; abdomen diffusely tender with decreased
bowel sounds; WBC count 25,000/µL; ultrasonography (US) consistent with perforated appendicitis and peritonitis; patient
admitted; IV antibiotics started and surgical consult obtained; recommended initial therapy—1) ampicillin, gentamicin,
and metronidazole (eg, Flagyl), or 2) ampicillin and sulbactam (Unasyn; if child toxic, add aminoglycoside);
other options—piperacillin-tazobactam (Zosyn) or ticarcillin-clavulanate (Timentin) acceptable, but added coverage for
Pseudomonas usually not necessary in perforated appendicitis; cefoxitin is modified second-generation cephalosporin
(good coverage for Bacteroides fragilis; no enterococcal coverage)
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| Cephalosporins: mechanism of action mostly penicillin-binding proteins; with increasing generations, loss in gram-positive
coverage, but gain in gram-negative coverage; all cephalosporins inactive against Listeria and enterococci
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| Aminoglycosides: advantages of once-daily dosing—higher peak drug concentrations; prolonged postantibiotic effect;
reduced likelihood of induced resistance; less toxicity
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| Clinical scenario C: 3-yr-old patient presents to ED with 2- to 3-day history of leg pain and limp, and 1-day history of
fever; pinpoint pain over lower left femur; WBC normal; C-reactive protein (CRP) 10.0 mg/L; aspiration of bone at site
of pain sent for Gram stain and culture; Gram stain shows gram-positive cocci in clusters; recommended initial
management—1) nafcillin or cefazolin, or 2) clindamycin, depending on local prevalence of MRSA and clindamycin
resistance; in this case, nafcillin prescribed; bone scan confirms diagnosis of osteomyelitis (S aureus identified as pathogen);
patient afebrile; laboratory report—organism resistant to nafcillin, first-generation cephalosporins, and macrolides,
but susceptible to clindamycin, vancomycin, and trimethoprim-sulfamethoxazole (TMP-SMZ, eg, Bactrim);
issue whether to continue or change course of therapy
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| Clindamycin for osteomyelitis: oral formulation 100% bioavailable, but tastes bad; bone penetration excellent;
works by blocking protein synthesis; excellent activity against gram-positive cocci (not effective against enterococci); increased
resistance from B fragilis and group A streptococci; inducible resistance revealed by positive double-disk diffusion
test (D-test); toxicity—risk for Clostridium difficile colitis overrated (problem more common in adults)
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| Vancomycin: prudent use—treatment of serious infections resistant to β-lactamase antibiotics; serious infections in patients
allergic to penicillin; empiric treatment for neutropenic fever, but only if line infection suspected or patient at high
risk for Streptococcus viridans infection (look for mucositis); prophylaxis for, eg, subacute bacterial endocarditis; surgical
prophylaxis for prosthetic materials in patient or institution with high rate of hospital-acquired MRSA; inappropriate
use—single blood culture positive for coagulase-negative Staphylococcus or Corynebacterium if subsequent cultures
negative and contamination likely; continued empiric therapy when laboratory tests do not support it; primary treatment
for antibiotic-associated colitis; prophylaxis for dialysis or central lines; selective decontamination of bowel; eradication
of MRSA colonization
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| Emergence of community-acquired MRSA in pediatric population (Herold 1998): prevalence of community-acquired
MRSA without identified risk at University of Chicago Children’s Hospital increased from 10 in 100,000 admissions
(1988-1990) to 259 in 10,000 admissions (1993-1995)
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| Mechanism of methicillin resistance: MEC A gene contains sequence of DNA that encodes novel penicillin-binding protein;
hospital-acquired and community-acquired infections associated with separate strains of S aureus (USA 100 and
USA 300, respectively)
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| Treatment options
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| Oral therapy: clindamycin (depending on level of resistance to clindamycin in particular community); TMP-SMZ; for
more serious disease, consider adding rifampin (synergy shown); minocycline (if child old enough); linezolid
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| Systemic therapy: clindamycin, vancomycin, linezolid; daptomycin—excellent activity against MRSA; highly bactericidal;
does not penetrate lung well (not recommended for empyema and pneumonia); potential for thrombocytopenia
with prolonged use
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| Strategies to reduce antibiotic resistance: appropriate antibiotic selection—susceptibility of suspected pathogen
key; consider combination therapy; use optimal dose and route of administration; de-escalation—start empiric therapy
to cover most likely pathogens; once specific pathogen identified, de-escalate by narrowing spectrum of coverage;
restricted antimicrobial use—hospital formularies very helpful and should be used
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Suggested Reading
Andrews WW et al: Valacyclovir therapy to reduce recurrent genital herpes in pregnant women. Am J Obstet Gynecol
194:774, 2006; Elbers JM et al: A 12-year prospective study of childhood herpes simplex encephalitis: is there a
broader spectrum of disease? Pediatrics 119:e399, 2007; Herold BC et al: Community-acquired methicillin-resistant
Staphylococcus aureus in children with no identified predisposing risk. JAMA 279:623, 1998; Kimberlin D et al: Administration
of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and
mouth: results of a phase I/II trial. Pediatr Infect Dis J 15:247, 1996; Kimberlin DW et al: Application of the polymerase
chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. National Institute of Allergy
and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 174:1162, 1996; Kimberlin DW et al:
Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 108:223, 2001; Kimberlin
DW et al: Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections.
Pediatrics 108:230, 2001; Xu F et al: Trends in herpes simplex virus type 1 and type 2 seroprevalence in the
United States. JAMA 296:964, 2006.
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