Renal function tests, including BUN, SCr, and urine output, should be monitored in
R.F. To minimize the risk of acyclovir nephrotoxicity, R.F. should be well hydrated,
and each acyclovir dose should be infused for 1 hour. In addition, the IV infusion site
should be inspected for inflammation and pain, and R.F. should be asked about pain
Oral acyclovir therapy is inappropriate for R.F. On the basis of studies in adults,
the absorption of acyclovir after oral administration is variable, slow, and
incomplete. The relative bioavailability (F) of acyclovir is low (F = 0.15–0.30) and
decreases with increasing doses.
26 The mean peak plasma concentration has ranged
from only 0.83 to 1.61 mcg/mL after multiple acyclovir doses of 200 to 800 mg.
Thus, with only approximately 50% of acyclovir penetrating the blood–brain barrier,
the concentrations of acyclovir in the CSF may be inadequate for R.F. There is only
very limited information regarding the use of oral valacyclovir for therapy. A small
pharmacokinetic trial of oral valacyclovir in patients with HSV encephalitis found
that while therapeutic CSF concentrations of valacyclovir were achieved, CSF
concentrations dropped over time, likely because of resolution of inflammation of the
blood–brain barrier. Consequently, switching to oral therapy cannot be recommended
at this time and therapy with IV acyclovir should be continued to complete a 21-day
Adverse Effects of US Food and Drug Administration (FDA)–Indicated Drugs
9 Local irritation, phlebitis; increased SCr, BUN; nausea, vomiting; itching, rash; increased
liver transaminases; CNS toxicity; hematologic abnormalities
13 Nausea, dizziness (lightheadedness), insomnia (5%–10%); depression, anxiety, irritability,
hallucination, confusion, dry mouth; constipation, ataxia, headache, peripheral edema,
orthostatic hypotension (1%–5%); suicide ideation or attempt (<1%)
14 Nephrotoxicity; neutropenia; rash; headache; alopecia; anemia; abdominal pain; fever;
infection; ocular hypotonia; nausea, vomiting; asthenia; diarrhea
16 Fever, nausea, vomiting; renal dysfunction; anemia; diarrhea; headache; electrolyte
abnormalities; bone marrow suppression; seizure; anorexia; abdominal pain; mentalstatus
changes; paresthesia, peripheral neuropathy; cough, dyspnea; rash; first-degree AV block,
17 Increased SCr; anemia; neutropenia, pancytopenia, thrombocytopenia; abdominal pain,
anorexia; diarrhea; nausea, vomiting; retinal detachment, vitreous hemorrhage, cataracts,
corneal opacification; neuropathy; rash
18 Nausea, vomiting; diarrhea; abdominal pain; dizziness, vertigo, insomnia; self-injury and
19 Worsening of respiratory status, bacterial pneumonia, pneumothorax, apnea, ventilator
dependence; cardiac arrest, hypotension; rash; conjunctivitis
20 CNS (insomnia, dizziness, headache, nervousness, fatigue); GI (nausea, vomiting,
anorexia, dry mouth, abdominal pain) (1%–3%)
21 Burning or stinging on instillation (4.6%); palpebral edema (2.8%); keratopathy;
hypersensitivity reaction; stromal edema; hyperemia; increased intraocular pressure
22 Headache (14%); nausea (15%); vomiting (6%); dizziness (3%); abdominal pain (3%)
23 Neutropenia; thrombocytopenia; diarrhea; nausea, vomiting; abdominal pain; increased
SCr; insomnia; peripheral neuropathy; paresthesias; CNS (ataxia, dizziness, seizures,
psychosis, hallucinations, confusion, drowsiness); retinal detachment (during treatment of
CMV retinitis); hypersensitivity
24 Bronchospasm; decline in respiratory function, especially if underlying respiratory disease;
nasal or throat irritation or congestion; headache; cough; diarrhea; nausea, vomiting
electrocardiogram; GI, gastrointestinal; SCr, serum creatinine.
Most neonates acquire herpes from the infected genital secretions of the mother at
delivery, and most cases are caused by HSV-2 virus.
28 The incidence ranges from 1
in 3,000 to 5,000 deliveries per year in the United States. The infection can present
in one of three forms: localized to the skin, eye, and mouth (SEM) (45%);
encephalitis (30%); or disseminated disease (25%). The effects of neonatal herpes
can be devastating, and severe disabilities persist in many afflicted children.
currently available antivirals, the mortality has ranged from 4% in those with CNS
involvement to 29% in those with other disseminated disease.
infections may also be acquired after birth through contact with family members with
symptomatic or asymptomatic oral-labial HSV-1 infection or from nosocomial
transmission. When the virus is transmitted from the mother, clinical evidence of
infection in the neonate usually is present 5 to 17 days after birth. Although skin
vesicles are the hallmark of infection, at least one-third to one-half of neonates never
In 70% of patients, the disease may progress from isolated skin
lesions to involve other organs, including the lungs, liver, spleen, CNS, and eyes.
Diagnosis can be made by direct fluorescent antibody examination of epithelial
cells from the infant or the mother. Examination of the base of a vesicular lesion may
show giant cells and intranuclear inclusions, which are characteristic of HSV
infections. Serologic test results can support a diagnosis of neonatal herpes.
QUESTION 1: S.P., an 18-year-old pregnant woman, was admitted to labor and delivery with premature
trimester of pregnancy. Is R.P. at risk of developing herpes infection?
R.P. is at risk of acquiring herpes infection because the mother had genital herpes
during the first trimester and because he was delivered vaginally rather than by
30 The risk of a newborn acquiring the disease from an infected
mother with primary disease is about 35%; that from a mother who has reactivation
CASE 79-2, QUESTION 2: Ten days after birth, R.P. exhibited poor feeding patterns, irritability, and
respiratory distress. Three days later, skin lesions appeared. How should R.P. be treated?
R.P. is manifesting signs of HSV infection and should be treated with antiviral
therapy (Table 79-2). The drug of choice for neonatal herpes simplex virus infections
28,29 Vidarabine was the first antiviral agent used in the treatment of
neonatal HSV. Because of the drastic reduction in morbidity, it became the standard
of therapy to which other antiviral agents were compared. In clinical trials
comparing vidarabine with acyclovir, acyclovir was shown to be as effective as
vidarabine in infants with SEM involvement, encephalitis, and disseminated HSV
31 Although both agents were equally effective, acyclovir was safer and
easier to administer, making it the standard of care for neonatal HSV.
US Food and Drug Administration (FDA)–Indicated Drugs for Various Viral
Disease Drug Dosage (Age Group) Route Duration
Herpes encephalitis Acyclovir (Zovirax)
Neonatal herpes Acyclovir (Zovirax) Birth–3 months: 10–20 mg/kg
Acyclovir (Zovirax) >12 years: 5 mg/kg every 8
Acyclovir (Zovirax) >12 years: 10 mg/kg every 8
Acyclovir (Zovirax) >40 kg: 800 mg QID
5 mg/kg every 12 hours; then 5
mg/kg/day, 5 days a week maintenance
Cidofovir (Vistide) 5 mg/kg every week for 2
Foscarnet (Foscavir) 90 mg/kg every 12 hours; then
900 mg BID; 900 mg every day PO Induction for 21
>9 years: 100 mg BID PO 10 days (treatment),
>14 years: 100 mg BID PO 7 days (treatment,
1–13 years: 100 mg BID PO Up to 6 weeks for
24–40 kg: 60 mg BID PO 5 days (treatment)
24–40 kg: 60 mg every day PO 10 days
Zanamivir (Relenza) >7 years: 10 mg (2 inhalations)
Adolescent and adult: 10 mg (2
>5 years: 10 mg (2 inhalations)
Ribavirin (Virazole) 6 g in 300 mL for 12–18
aFDA-approved dose is 10 mg/kg. Although doses of 15–20 mg/kg have been used, safety has not been
BID, 2 times day; IV, intravenously; PO, orally; QID, 4 times a day.
CASE 79-2, QUESTION 3: What dosage of acyclovir should R.P. receive?
Although an IV dosage of 30 mg/kg given in three divided doses has been shown to
be effective in the treatment of neonatal herpes, the use of 60 mg/kg given in three
divided doses is superior in decreasing morbidity and mortality. The higher dose of
acyclovir is associated with a higher frequency of hematologic abnormalities,
9,32,33 The minimum duration of therapy should be 14 days for
neonates with only SEM involvement, whereas longer courses (e.g., 21 days) are
indicated in infants with CNS involvement or disseminated disease.
The role of prolonged oral suppressive therapy in newborns with SEM
involvement has been investigated.
34,35 Acyclovir, given orally (PO) at 300 mg/m2
per dose 3 times a day (TID), resulted in a reduction in the recurrences of lesions.
Half of these patients developed neutropenia. One patient had lesions resistant to
35 Because the long-term benefits cannot be fully attributed to the use of
suppressive acyclovir, suppressive therapy for patients with SEM involvement is not
Oral-Facial Herpes (Herpes Labialis)
Both primary and recurrent oral-facial HSV-1 infections can be asymptomatic.
Gingivostomatitis and pharyngitis are the most common clinical manifestations of a
first episode of HSV-1 infection, and recurrent herpes labialis is most commonly
caused by reactivated HSV infection. Clinical features include fever, malaise,
they are candidates for antiviral therapy.
Herpes labialis (cold sores) is the most common oral-facial HSV infection.
Clinical features include pain or paresthesia and erythematous or papular lesions
followed by vesiculation and swelling. These lesions usually crust and heal in a few
days. Viral cultures generally are positive within 2 to 3 days. Rapid diagnosis can be
made by visualizing viral particles in vesicular fluid with electron microscopy or
fluorescent antibody staining of cells from vesicles.
INDICATIONS FOR ANTIVIRAL TREATMENT
QUESTION 1: M.K., a 26-year-old man, experienced pain and erythematous skin lesions on his face and
of any other illness. Should he be treated with antiviral drugs?
Most patients with herpes labialis have a self-limiting benign course and the
lesions heal within 10 days. Antiviral drugs (e.g., acyclovir, valacyclovir,
famciclovir) are indicated only when the patient has a primary infection, an
underlying illness, or a compromised immune system that may lead to prolonged
M.K. should not receive antiviral therapy. However, acetaminophen or
nonsteroidal anti-inflammatory agents (NSAIDs) can be considered for symptomatic
relief. Although ice, ether, lysine, silver nitrate, and smallpox vaccine have been
used to treat cold sores, no data support their efficacy. Symptomatic treatment with
ice or popsicles may also be beneficial.
QUESTION 1: P.L., a 16-year-old boy diagnosed with acute lymphocytic leukemia 8 months ago, is now
the significance of these findings for P.L., who is about to undergo a bone marrow transplant?
Immunosuppressed patients have more frequent and severe mucocutaneous HSV
infections. Therefore, IV acyclovir should be considered to suppress the reactivation
of oral-facial HSV infections.
36,37 Oral therapy with famciclovir is approved for use
38 but efficacy in other immunocompromised patients is not
CASE 79-4, QUESTION 2: P.L. did not receive antiviral therapy. Two weeks later, he developed malaise
and painful oral-mucosal and skin lesions on his face. HSV was identified from the lesion by
immunofluorescence. What is the treatment of choice for P.L.?
Acyclovir should be administered IV at 5 mg/kg every 8 hours for 7 days
the lesions are healed, followed by oral acyclovir 200 mg TID for about 6 months.
In patients with marrow transplants and culture-proven recurrent mucocutaneous
herpes simplex, oral acyclovir (400 mg 5 times daily for 10 days) is significantly
more effective than placebo in reducing pain, virus shedding, new lesion formation,
39 Valacyclovir and famciclovir have also been used in the
QUESTION 1: N.B., a 43-year-old woman, experiences 8 to 10 cold sores a year. These are typically
immunocompetent patients with recurrent herpes labialis?
Topical agents approved by the US Food and Drug Administration (FDA) for the
treatment of recurrent herpes labialis in immunocompetent patients include acyclovir
5% cream (Zovirax), acyclovir 5% and hydrocortisone 1% cream (Xerese),
docosanol 10% cream (Abreva), and penciclovir 1% cream (Denavir). Clinical
trials demonstrate that each agent modestly decreases healing time of herpes lesions
when started at the first sign or symptom of a cold sore.
cream may be more effective than acyclovir cream, the benefit is small.
advantage of docosanol cream compared with the other agents is its availability
without a prescription. The topical agents must be applied within 1 hour of the first
sign or symptom of a cold sore and then every 2 hours for 4 days while awake.
Studies evaluating the use of oral antiviral agents have produced conflicting
results. In some studies, oral antiviral medications have shown to decrease the
duration of pain and healing time in immunocompetent patients. One study
demonstrated that oral acyclovir 200 mg 5 times daily for 5 days had no benefit.
However, 400 mg 5 times daily for 5 days started within 1 hour of the development
of a cold sore significantly decreased duration of pain and healing time in
2 g at the first signs of a cold sore followed by 2 g 12 hours later, and famciclovir
1,500 mg as a single dose showed similar clinical efficacy.
directly compared the efficacy of the different oral antiviral medications.
of dosing and cost should be considered when choosing a particular agent.
Daily suppressive therapy may be recommended in patients with six or more
recurrences per year, in patients with frequent infection who do not experience a
prodrome, or in patients with severe episodes. In immunocompetent patients with six
or more episodes of herpes labialis, oral acyclovir 400 mg twice a day (BID) for 4
months was more effective than placebo in decreasing the number of recurrences.
Oral valacyclovir, 500 mg once daily or 1,000 mg once daily, is efficacious in
decreasing the number of recurrences.
54 Controlled trials of famciclovir for chronic
suppressive therapy of herpes labialis have not been performed.
N.B. should be treated with either a topical antiviral medication or an oral
antiviral for the acute episode of herpes labialis. She should be instructed to start
treatment as soon as the first sign or symptom of the cold sore appears. If suppressive
therapy is desired, N.B. should be treated with oral acyclovir or valacyclovir.
The incidence of acyclovir-resistant herpes in patients with herpes labialis is greater
in immunocompromised patients compared with immunocompetent patients. Current
estimates of HSV resistance in the immunocompromised population are about 5%;
some populations, such as bone marrow transplant patients, have a resistance rate
IV foscarnet 40 mg/kg every 8 hours is more effective and less
toxic than IV vidarabine 15 mg/kg/day in patients with AIDS and mucocutaneous
herpetic lesions unresponsive to IV acyclovir.
57 More concerning, however, are the
reports of foscarnet-resistant HSV, particularly in the bone marrow transplant
58,59 Cidofovir has been used with moderate success in such cases. In
patients with recurrent acyclovir-resistant genital herpes, limited evidence suggests
that topical imiquimod 5% cream may be effective.
Chickenpox used to be a common childhood infection, but the incidence has
decreased by up to 84% in states with moderate use of the varicella-zoster virus
61 This vaccine is now considered a routine childhood
vaccine by the American Academy of Pediatrics. Unimmunized adolescents and
adults who have not had chickenpox should also be vaccinated. Before the vaccine
was available, approximately 4 million cases occurred per year in the United States:
90% of cases occurred in children and adolescents less than 15 years of age with the
majority of cases occurring between 1 and 4 years of age.
cases of chickenpox, complications and mortality have also declined.
population at risk for complications such as pneumonia and encephalitis, because of
VZV, include immunocompromised individuals and pregnant women. Children with
HIV are at an increased risk of mortality from VZV.
Chickenpox is a contagious disease; the average incubation period is 14 to 16
days. Children are considered contagious from 1 to 2 days before the onset of rash
until all vesicles have crusted (usually 4–6 days after the onset of rash).
After household exposure, more than 90% of susceptible individuals become
infected. Thus, a history of exposure is useful in making a diagnosis. A smear of cells
scraped from the lesions will show multinucleated giant cells. Viruses also can be
identified in vesicular lesions by electron microscopy, or antigen can be detected by
countercurrent immunoelectrophoresis. Chickenpox is a primary varicella-zoster
infection, whereas herpes zoster (shingles) is caused by reactivation of VZV.
revealed the following results:
BUN, 9 mg/dL (normal, 5–18 mg/dL; 1.8–6.4 mmol/L)
SCr, 0.2 mg/dL (normal, 0.5–0.8 mg/dL; 44–71 μmol/L)
Serum aspartate aminotransferase, 65 international units/L (normal, 0–34 units/L)
Serum alanine aminotransferase 122 international units/L (normal, 0–34 units/L)
/day) was instituted. Oral diphenhydramine was also prescribed for itching, but
A.V. required only two doses on the first hospital day.
New lesions were noted on the second day of acyclovir therapy, but by the third day no new lesions
Neonates, adults, immunocompromised hosts, patients with progressive varicella,
and those with extracutaneous complications, benefit from acyclovir therapy.
Acyclovir is effective in preventing dissemination of VZV infection, accelerating
cutaneous healing, decreasing fever and pain, and reducing mortality.
prolonged progressive course of varicella and demonstrated an extracutaneous
manifestation of varicella infection (e.g., ataxia with abnormal cerebellar signs).
Because of the concern of possible cerebellar involvement, the use of IV acyclovir
immunocompetent patients with chickenpox? Should C.J. or K.J. be treated with acyclovir?
Three studies in children (2–18 years of age) have shown that oral acyclovir 20
mg/kg (when initiated within 24 hours of disease onset) 4 times a day (QID) for 5 to
10 days accelerates healing and decreases the formation of new lesions, fever, and
itching. However, the benefit is modest (usually healing 1 day sooner than placebo)
and does not reduce the complications of varicella.
66 Thus, the American Academy of
Pediatrics does not consider routine use of acyclovir in healthy children justified,
and it is not indicated for C.J.
Adolescents and adults are more likely to develop complications (e.g., pneumonia,
encephalitis) than children. Others at higher risk for developing complications
include those with chronic cutaneous or pulmonary disease, patients receiving
chronic salicylate therapy, and patients receiving short, intermittent, or aerosolized
In these patients, acyclovir therapy may be warranted.
Acyclovir 800 mg PO QID for 5 days in adolescents and adults (initiated within 24
hours of disease onset) decreases the number of lesions and reduces time for healing,
fever, and itching. The effect of acyclovir on prevention of severe complications is
68–70 Thus, acyclovir therapy should be considered in those at increased risk
of severe chickenpox, e.g., those like K.J. who are older than 14 years or those with
chronic respiratory or skin disease.
71 There are no published clinical trials to support
the use of famciclovir and valacyclovir in the treatment of chickenpox. However,
valacyclovir or famciclovir may be preferred because of the need for less frequent
administration for adolescents and adults at risk for moderate-to-severe
CASE 79-7, QUESTION 2: What is the role of supportive treatment in C.J. and K.J.?
Cool baths and application of calamine or other topical antipruritic agents may
decrease itching. Fingernails should be trimmed to avoid scratching and secondary
bacterial infections. In severe cases, a systemic antipruritic and antihistamine
preparation may be useful because some degree of sedation may be desired. In C.J.
and K.J., aspirin should not be used because Reye syndrome has been associated
with the use of salicylates in chickenpox or flulike illness (see Chapter 102,
Herpes zoster infections are caused by the reactivation of dormant VZV in the
sensory neurons. Reactivation is believed to occur because of waning immunity. The
incidence of herpes zoster is higher in immunocompromised patients (e.g., those with
HIV or cancer or those receiving immunosuppressive medications), and the incidence
of zoster increases with age. It tends to be more severe in the elderly.
Acute herpes zoster infection is characterized by pain, which is described as a
deep aching or burning pain. It may be accompanied by excessive sensitivity to touch.
Many patients exhibit a rash that presents initially as erythematous patches and
progresses to vesicles that crust in 7 to 10 days. By 1 month, the rash is usually gone,
Postherpetic neuralgia (PHN) is the most common complication of acute herpes
zoster characterized by pain that continues for more than 1 month after the onset of the
rash. It is estimated that 10% to 70% of patients experience PHN, and its prevention
is important because PHN pain is difficult to treat.
The goal of pharmacotherapy in acute herpes zoster is to inhibit viral replication,
to reduce pain and duration of rash. Ultimately, by inhibiting the virus, nerve damage
can be prevented and the incidence and severity of PHN can be decreased.
Unfortunately, no therapy can prevent all cases of PHN.
The herpes zoster vaccine (Zostavax) significantly reduces the incidence of herpes
zoster and the associated resulting PHN (see Chapter 64, Vaccinations).
ANTIVIRAL THERAPY IN IMMUNOCOMPETENT PATIENTS
herpes zoster vaccine. A diagnosis of herpes zoster is made. What therapy should be initiated?
Acyclovir is the standard antiviral agent against which new VZV therapies are
compared. In immunocompetent patients, oral acyclovir 800 mg 5 times daily for 10
days is moderately beneficial in reducing acute pain during the first 28 days.
Acyclovir therapy should be initiated within 72 hours of the onset of the rash. The
benefit of acyclovir in reducing PHN and chronic pain is modest at best. Although a
number of trials showed no benefit from acyclovir in reducing PHN, a meta-analysis
of acyclovir treatment in herpes zoster concluded that acyclovir was effective, but
that 6.3 patients would need to be treated to prevent one patient from having PHN 6
months after the outbreak of VZV.
Famciclovir (Famvir) is approved for the treatment of acute herpes zoster
infection. Famciclovir is a prodrug and is rapidly absorbed and converted to the
active drug penciclovir in the intestine. The bioavailability of famciclovir is greater
than acyclovir, resulting in higher concentrations of active drug in the infected cells.
In addition, the intracellular half-life (10 hours) of penciclovir allows for less
74 Famciclovir 500 mg TID is as effective as acyclovir 800
mg 5 times a day in reducing the duration of acute pain and healing of the rash.
Although famciclovir does not decrease the incidence of PHN, it may reduce the
To overcome the poor oral bioavailability of acyclovir, valacyclovir (Valtrex), a
prodrug of acyclovir, was developed. Valacyclovir is rapidly and extensively
absorbed and converted to acyclovir after oral administration. Valacyclovir 1 g TID
is as effective as acyclovir 800 mg 5 times a day in terms of reducing rash
progression and time to rash healing, and valacyclovir is more effective than
acyclovir in relieving zoster-associated pain.
77 Valacyclovir is comparable to
famciclovir with respect to decreasing the duration of acute zoster-associated pain
E.O. should be started on either acyclovir, famciclovir, or valacyclovir.
times a day. Therapy should be initiated within 72 hours of the rash onset and
continued for 10 days; the duration of therapy for famciclovir and valacyclovir is 7
days. Although therapy may not prevent PHN, it may decrease the duration of pain.
Because these agents are renally eliminated, the dosage should be adjusted based on
E.O.’s reduced creatinine clearance (Table 79-3).
For acute illness, E.O. may require pain control with medications such as
nonsteroidal anti-inflammatory agents, opioids, or tramadol.
should be counseled to keep the area of the rash clean and dry and to avoid topical
antibiotics. If the rash worsens or fever develops, he should contact his health care
Clinical Pharmacokinetics of Antiviral Drugs
9,25,26,79–82 Adults 3.4–22.9 (based
dosage interval to12 and 24 hours
15,83,84 Adults 0.8–6.6 (based
dosage interval to12 and 24 hours
b 18.8 L/hour 6.0–10 Use 75 mg/day inpatients if ClCr
N/A N/A 0.63 L/hour/kg 3.2–7.8 Dosage
normal adult doseif >40 kg and
Adolescents N/A N/A N/A 0.32 L/hour/kg 8.1
20 20–48 L/hour 25–32 Because it
those with severerenal failure
dosage interval to12 and 24 hours
24,89,90 Adults 0.02–0.1 (based
aPharmacokinetic properties of active metabolite penciclovir.
bActive metabolite oseltamivir carboxylate.
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