Podophyllum resin, also known as podophyllin, is an antimitotic and caustic agent.100, 117, 118
Podophyllum resin is used topically for the treatment of external genital and perianal exophytic warts (condylomata acuminata) caused by human papillomavirus (HPV).100, 101, 102, 103, 104, 105, 106, 107, 112 The drug also is recommended for the treatment of urethral HPV warts†101 , but is not recommended for the treatment of vaginal, cervical, anal, or rectal HPV warts.101 Podophyllum resin should not be used to treat subclinical genital HPV infection (without exophytic warts).101 Podophyllum resin has been used topically for the treatment of verruca vulgaris† (common warts).109
Human Papillomavirus Infections
External Genital and Perianal HPV Warts
Podophyllum resin is used topically for the treatment of external genital and perianal HPV warts.100, 101, 102, 103, 104, 105, 106, 107, 112
Regimens recommended by the US Centers for Disease Control and Prevention (CDC) and others for the treatment of external genital and perianal exophytic human papillomavirus (HPV) warts are topical therapies for self-administration (imiquimod 5%, podofilox 0.5%), topical therapies that must be administered by a health-care provider (podophyllum resin 10-25%, trichloroacetic acid [TCA] 80-90%, bichloroacetic acid [BCA] 80-90%), or surgical techniques (cryotherapy, electrosurgery, surgical excision).101, 111, 112, 116 Alternative regimens include intralesional interferon alfa or laser surgery.101 The CDC and others recommend that selection of a therapy for the treatment of exophytic warts be guided by the preference of the patient, available resources, experience of the health-care provider, factors relating to the warts (e.g., size, number, morphology, anatomic site involved), and factors related to the therapy (e.g., cost, convenience, adverse effects).101, 111, 112 There is some evidence that warts located on moist surfaces and/or in intertriginous areas appear to respond better to topical treatments (e.g., imiquimod, podofilox, podophyllum resin, TCA) than warts on drier surfaces; however, there is no clear evidence that any one therapy is superior to any other available therapy and no single treatment is ideal for all patients or all warts.101, 114 Overly aggressive treatment should be avoided and the risks versus benefits of the therapy selected should be evaluated throughout treatment; therapy should be changed if the desired response is not obtained.101, 113, 114
The primary goal of treatment of exophytic genital and perianal HPV warts is the destruction or clearance of visible, symptomatic warts.101, 110, 111, 112 Most patients have fewer than 10 genital warts with a total wart area of 0.5-1 cm2, and treatment with recommended regimens generally can induce wart-free periods.101 Without treatment, exophytic genital and perianal HPV warts may spontaneously regress, remain unchanged, or increase in size or number becoming painful and a source of psychological trauma.101, 110, 111, 112, 114 No currently available therapy for exophytic genital and perianal warts, including podophyllum resin, has been shown to eradicate HPV (i.e., produce a virologic cure) or affect the natural history of HPV infection.101, 110, 112, 114 In addition, while there is some evidence that exophytic warts play a role in transmission of HPV to sexual partners, it is unclear whether treating these warts has any effect on transmission of the virus.101, 110, 111, 112, 113, 114, 116 Existing data indicate that currently available treatment regimens may reduce, but probably do not eradicate, infectivity.101 It is unclear whether reduction in viral DNA following treatment impacts future transmission of the virus.101 HPV apparently may establish one or more sites of latent infection following primary infection with the virus.110, 112, 113, 114 Despite the use of therapies that effectively result in the destruction or clearance of exophytic HPV warts, latent or subclinical HPV infection can persist and recurrence of visible warts commonly occurs.110, 111, 112, 113, 114
Exophytic genital and perianal warts generally are caused by HPV types 6101, 110, 116 or 11.101, 110, 116 Other HPV types (e.g., types 16, 18, 31, 33, 35)101 sometimes are present in the anogenital region, may be present in visible warts, and have been strongly associated with vaginal, anal, and cervical intraepithelial dysplasia and squamous cell carcinoma.101, 110, 116 Individuals with visible genital warts often are infected simultaneously with multiple HPV types.101 Because genital warts caused by HPV have a characteristic appearance, biopsy to confirm the diagnosis generally is necessary only if the diagnosis is uncertain, warts do not respond to standard therapies, the disease worsens during therapy, the patient is immunocompromised, and/or warts are pigmented, indurated, fixed, and ulcerated.101 Tests for detecting HPV DNA are widely available, but the clinical usefulness of these tests in the routine diagnosis or management of visible genital or perianal warts has not been determined.101
If visible genital and perianal warts have cleared after treatment, patients should be cautioned to watch for recurrences and that such recurrences occur most frequently during the first 3 months.101 Because external genital warts can be difficult to identify, a follow-up examination 3 months after treatment may be beneficial.101 Earlier follow-up visits may benefit certain patients by providing the opportunity for the clinician to document the absence of warts, monitor for and treat complications of therapy, and provide the patient additional education and counseling.101 Examination of sexual partners is not necessary for the management of genital HPV warts because no data indicate that reinfection plays a role in recurrences and, in the absence of curative therapy, treatment to reduce transmission is not realistic.101 However, sexual partners of patients with genital HPV warts may benefit from examination to assess the presence of HPV warts or other sexually transmitted diseases and also may benefit from counseling about the implications of having a partner who has HPV warts.101 Women with genital HPV warts should be advised to undergo regular Papanicolaou (Pap) tests as recommended for women without genital warts.101
In published clinical studies evaluating use of podophyllum resin 25% solution for the treatment of external genital and perianal warts in men and women, topical application of the solution by a health professional once weekly for 3-7 weeks resulted in clearance of warts in 32-79% of patients; the recurrence rate reported in these studies was 21-65%.102, 112, 114, 116 Mucosal warts are more likely to respond to topical podophyllum resin than highly keratinized warts on relatively dry areas, including the penile shaft, scrotum, and labia majora.112
Although not commercially available, podophyllum resin 0.5-2% solutions† have been prepared extemporaneously for self-administration by the patient in the treatment of external exophytic genital and perianal HPV warts.103, 106 These podophyllum resin 0.5-2% solutions may be better tolerated and associated with a decreased risk of systemic effects compared with podophyllum resin 10-25% solutions; however, controlled studies evaluating safety and efficacy of these solutions have not been performed and the fact that the concentration and stability of these extemporaneous solutions cannot be assured should be considered.103, 104 In addition, there presumably is no need for extemporaneous preparation of podophyllum resin 0.5-2% solutions for self-administration since topical preparations containing a standardized amount (0.5%) of purified podofilox (the major biologically active lignan contained in podophyllum resin) are commercially available for self-administration and have been shown to be safe and effective for the topical treatment of external genital and perianal warts.104, 116 (See Podofilox 84:28.)
For the treatment of external genital HPV warts in adults and adolescents with human immunodeficiency virus (HIV) infection, the CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) generally recommend a patient-applied topical therapy (imiquimod 5%, podofilox 0.5%) for uncomplicated lesions and a topical therapy administered by a health-care provider (podophyllum resin 10-25%, TCA, BCA) or a surgical technique (cryotherapy, electrosurgery, surgical excision) for complex or multicentric lesions or those that are inaccessible to patient-applied treatments.120 Although topical agents (podofilox 0.5%, imiquimod 5%, podophyllum resin, TCA 80-90%) are recommended as alternatives for the treatment of HPV warts in HIV-infected children†, the CDC, NIH, and IDSA state that topical therapy often is ineffective in these patients and use of a surgical technique (cryotherapy, electrosurgery) may be preferred.121
Urethral, Vaginal, Cervical, Anal, and Oral HPV Warts
For the treatment of urethral meatus HPV warts†, the CDC recommends use of cryotherapy or topical application of a 10-25% solution of podophyllum resin in compound tincture of benzoin.101
For the treatment of intravaginal HPV warts, the CDC recommends use of cryotherapy or topical application of a 80-90% solution of TCA or BCA.101 Because of potential systemic absorption and systemic toxicity (see Cautions), some experts caution against vaginal application of podophyllum resin and the drug is not included in current CDC recommendations for treatment of intravaginal warts.101 In addition, use of a cryoprobe in the vagina is not recommended because of the risk for vaginal perforation and fistula formation.101 If 80-90% TCA or BCA solution is used for the treatment of vaginal HPV warts, a small amount of the solution should be applied to the warts and allowed to dry, at which time a white frosting develops.101 If an excess amount of acid is applied, the treated areas should be powdered with talc or sodium bicarbonate powder or a liquid soap preparation can be used to remove unreacted acid.101 TCA or BCA treatment can be repeated weekly if necessary.101
The CDC recommends that treatment of exophytic cervical warts be managed in consultation with an expert and that the presence of high-grade squamous intraepithelial lesions (SIL) must be excluded before exophytic cervical warts are treated.101
For the treatment of intra-anal warts, the CDC recommends use of cryotherapy, topical application of a 80-90% solution of TCA or BCA, or surgical removal.101 Management of warts on rectal mucosa should be referred to an expert.101
Podophyllum resin is applied topically.100
The drug usually is applied in the form of a 10-25% solution in compound benzoin tincture; the CDC, at least one manufacturer, and other experts recommend that these solutions only be applied by a health-care provider and not dispensed to the patient.100, 101, 109 Solutions containing lower concentrations of podophyllum resin (i.e., 0.5-2% ethanolic solutions) have been prepared extemporaneously for self-administration by patients†;103, 106 however, safety and efficacy of these solutions have not been established.103, 104
Prior to application of podophyllum resin solution, the affected area should be thoroughly cleansed.100 The solution should then be applied sparingly to lesions, avoiding contact with normal tissue, and allowed to air dry.100, 101 The skin adjacent to the area being treated may be protected by applying petrolatum or flexible collodion prior to application of the drug. Use of large amounts of the drug should be avoided, since systemic toxicity may occur.
Immediately after the prescribed period of treatment (usually 1-4 hours), the dried drug should be thoroughly removed from the area of application using alcohol or soap and water.100 Care must be taken to ensure that all of the drug has been removed.100 To determine the patient's sensitivity to the drug, the manufacturer of Podocon-25® recommends that the drug be removed within 30-40 minutes after the initial application; for subsequent application, the drug should be removed after the minimum time period required to produce the desired result (usually 1-4 hours).100 Warts generally become blanched within a few hours after application of the drug and become necrotic within 24-48 hours. After about 72 hours, the lesions begin to slough and gradually disappear without scarring.
Human Papillomavirus Infections
External Genital and Perianal HPV Warts
For the topical treatment of external genital and perianal exophytic warts caused by human papillomavirus (HPV), a 10-25% solution of podophyllum resin in compound tincture of benzoin usually is used.100, 101 To minimize the potential for systemic absorption and systemic adverse effects, the CDC and other experts recommend that each treatment session be limited to less than 10 cm2 and that less than 0.5 mL of the solution be used during each treatment session.101 Alternatively, some clinicians recommend that lower concentrations of the drug (e.g., a 5% solution) be used for the treatment of large (i.e., larger than 10-20 cm2) genital and perianal warts. Podophyllum resin applied to genital and perianal warts should be thoroughly washed off the treatment area after the prescribed period of treatment (usually 1-4 hours).100 Topical podophyllum resin can be applied once weekly for up to 3-6 weeks.101, 120, 121
Patients should be cautioned to watch for recurrences, especially during the first 3 months.101 A follow-up examination 3 months after completion of treatment may be beneficial since identification of external genital warts may be difficult.101
If podophyllum resin is used for the topical treatment of urethral meatus HPV warts†, a 10-25% solution of the drug in compound tincture of benzoin should be applied and may be repeated once weekly.101 Care should be taken to ensure that the treatment area has dried completely before making contact with surrounding normal mucosa.101
For the topical treatment of verruca vulgaris† (common warts), a 5% solution of podophyllum resin has been used. One manufacturer has recommended that the treatment area be covered with a nonporous, slightly elastic tape for up to 24 hours. The wart is then removed with the tape or by curettage after the tape has been removed; the area can be treated with a mild topical anti-infective agent until completely healed.
Podophyllum resin is a powerful caustic and severe irritant.100 Topical application of podophyllum resin has been associated with adverse local reactions and potentially serious adverse systemic effects, including GI, hematologic, and CNS effects.100, 101, 108, 109 At least one fatality has been reported as the result of systemic toxicity following cutaneous application of podophyllum resin for the treatment of extensive areas of exophytic warts caused by human papillomavirus (HPV).109 Therefore, podophyllum resin should only be used under close medical supervision and care should be taken to ensure that the drug is not applied to normal skin or mucous membranes, is not applied to extensive areas or in excessive amounts, and is removed from the treatment area within the prescribed period of time (usually 1-4 hours).100, 101, 108, 109 (See Dosage and Administration.)
Topical application of podophyllum resin has resulted in local reactions including erythema, tenderness, pruritus, burning, pain, and swelling.104, 112 Irritation of adjacent skin, local erosion, ulceration, and scarring may occur.116
Potentially serious adverse systemic effects have been reported with topical application of podophyllum resin.100, 101, 109, 112 The risk of systemic toxicity may be increased if podophyllum resin is applied to friable, bleeding, or recently biopsied skin, or if the drug is inadvertently applied to normal skin and mucous membranes surrounding a wart being treated.109
Initial manifestations of systemic toxicity of podophyllum resin have included dizziness, lethargy, nausea, vomiting, abdominal pain, and diarrhea (sometimes severe and protracted).108, 109
Adverse CNS effects have occurred occasionally and such effects may be delayed in onset and prolonged in duration. Cerebral toxicity manifested by altered sensorium ranging from mild confusion to coma may occur. Cerebral effects may persist for 7-10 days during which time EEG may show generalized slowing. Other initial, adverse nervous system effects include visual and auditory hallucinations, paranoid delusions, acute psychotic reaction, disorientation, mental confusion, and delirium. Ataxia, hypotonia, and areflexia also occur and generally improve more slowly than effects on sensorium. Delayed nervous system toxicity of podophyllum resin involves the peripheral nervous system. Sensorimotor polyneuropathy, when it occurs, appears about 2 weeks after application of the drug, may progressively worsen for up to 3 months, and may persist for up to 9 months or longer. Electrodiagnostic determinations (i.e., nerve conduction studies and electromyelography) indicate an axonal neuropathy. Signs and symptoms of peripheral neuropathy, including autonomic neuropathy, include paralytic ileus, urinary retention, sinus tachycardia, symptomatic orthostatic hypotension, paresthesias of the extremities, absent ankle reflexes, stocking-and-glove sensory loss, weakness of the extremities, and decreased response to painful stimuli. Other adverse nervous system effects include stupor, increased CSF protein, hyperventilation, decreased respiration and apnea, agitation, lethargy, and seizures.
Adverse hematologic effects (e.g., leukopenia, thrombocytopenia) have occurred following topical application of podophyllum resin,100, 108, 109 especially when the drug was applied to extensive areas.108, 109 Renal failure and hepatotoxicity (increased serum concentrations of LDH, AST [SGOT], and alkaline phosphatase) also have been reported following topical application of podophyllum resin.
Precautions and Contraindications
Podophyllum resin is contraindicated in patients with diabetes mellitus or poor circulation, in patients receiving corticosteroids, and in women who are pregnant or breast-feeding.100
Because of the potential for serious adverse systemic effects following topical application, podophyllum resin should only be used under close medical supervision and should be applied by a health-care provider.100, 101, 109 In addition, the drug should be applied only to affected areas (not normal skin or mucous membranes) and recommendations regarding the extent and duration of topical application of the drug should be followed.100, 101, 109 The drug should be removed from the treatment area within the prescribed period of time (usually 1-4 hours).100 (See Dosage and Administration.)
Podophyllum resin should not be applied to bleeding warts, moles, birthmarks, or unusual warts with hair growing from them.100 In addition, some clinicians recommend that the drug not be applied to friable or bleeding sites or to warts that have been recently biopsied since systemic absorption of the drug may be facilitated.109 Podophyllum resin is intended for external use only, and contact with eyes should be avoided.100 If contact occurs, the affected eye(s) should be washed with large amounts of warm water and a clinician and regional poison control center (800-222-1222) consulted.100
The fact that immunosuppressed individuals, including those with human immunodeficiency virus (HIV) infection, may have less of a response to treatment of genital and perianal warts than immunocompetent individuals101, 120, 121 and may have more frequent recurrences after treatment should be considered.101 In addition, biopsy to confirm a diagnosis of HPV warts may be required more frequently in immunosuppressed individuals since squamous cell carcinomas arising in or resembling genital warts may occur more frequently in these individuals.101
Topical podophyllum resin is not a cure, and patients should be informed that new warts may develop during or after therapy with the drug.101 The effect of topical podophyllum resin on transmission of HPV is unknown.101
Podophyllum resin is contraindicated during pregnancy.100, 101
Use of topical podophyllum resin during pregnancy has been associated with complications including birth defects, fetal death, and stillbirth.100 Intrauterine death has occurred following topical application of podophyllum resin to vulval warts during the 32nd week of pregnancy. Following topical application of the drug during the 23rd, 24th, 25th, 28th, and 29th weeks of pregnancy in one woman, minor fetal anomalies including preauricular skin tags and a simian crease on the left hand occurred. Following oral administration during pregnancy of a preparation containing podophyllum, possible adverse fetal effects of the drug have included skin tags on the ear and cheek, polyneuritis, limb malformations, and septal heart defects.
It is not known whether topically applied podophyllum resin is distributed into human milk.100 The drug is contraindicated in women who are breast-feeding.100
Podophyllum resin is an antimitotic and caustic agent;100, 117, 118 the drug also has cathartic effects.109, 117 The exact mechanism(s) of action of podophyllum resin in the topical treatment of exophytic warts caused by human papillomavirus (HPV) has not been elucidated but may be related to the antimitotic effects of podofilox (podophyllotoxin), the major biologically active lignan contained in the resin.117 Podofilox has antimitotic activity and arrests mitosis in metaphase in a manner similar to colchicine.117 Podofilox reversibly binds to tubulin, the protein subunit of the spindle microtubules, at a site that is the same as or overlaps the colchicine binding site thereby preventing polymerization of tubulin into microtubules.117 (See Pharmacology in Podofilox 84:36.)
Podophyllum resin, also known as podophyllin, is an antimitotic and caustic agent.100, 117, 118 Podophyllum resin is prepared from podophyllum obtained from various plant families including Podophyllaceae, Coniferae, and Berberidaceae.117 The principal natural sources of podophyllum are the rhizomes and roots of Podophyllum peltatum (known as American mandrake, May apple, Duck's foot, Indian apple) or a related Indian species, P. hexandrum (previously known as P. emodi ).117, 118, 119 Podophyllum resin is the powdered mixture of resins extracted from podophyllum by percolation with alcohol and subsequent precipitation from the concentrated percolate upon addition to acidified water.119 The major biologically active lignan contained in podophyllum resin is podofilox (also known as podophyllotoxin);117, 118 however, podophyllum resin is a crude mixture containing a nonstandardized amount of podofilox with other lignans (e.g., α-peltatin, β-peltatin) and various known and unknown caustic and cytotoxic materials.117 The concentration of podofilox in podophyllum resin varies depending on the specific source of podophyllum.100, 101, 116, 117
Podophyllum resin occurs as an amorphous powder varying in color from light brown to greenish yellow or brownish gray; the resin has a characteristic odor and is highly irritating to eyes and mucous membranes.118 Podophyllum resin is soluble in alcohol with a slight opalescence.118
Commercially available Podocon-25® contains 25% podophyllum resin in benzoin tincture and is prepared exclusively from the American plant species which generally contains a lower concentration of podofilox than the Indian plant species.100
Podophyllum resin darkens when exposed to temperatures greater than 25°C or when exposed to light.118 Podophyllum resin and the commercially available 25% solution of podophyllum resin in benzoin tincture should be stored in tight, light-resistant containers.100, 119 The commercially available 25% topical solution in benzoin tincture should be stored at 15-30°C.100
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder* | |||
Topical | Solution | 25% | Podocon-25® (in compound benzoin tincture) | Paddock |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. Paddock Laboratories. Podocon-25® (25% podophyllin in benzoin tincture) prescribing information. Minneapolis. MN; 2005 Aug.
101. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. MMWR Recomm Rep . 2006; 55(RR-11):1-94. [Fulltext MMWR]
102. Stone KM, Becker TM, Hadgu A et al. Treatment of external genital warts: a randomised clinical trial comparing podophyllin, cryotherapy, and electrodisiccation. Genitourin Med . 1990; 66:16-9. [PubMed 2179111][PubMedCentral]
103. White DJ, Billingham C, Chapman S et al. Podophyllin 0.5% or 2.0% v podophyllotoxin 0.5% for the self treatment of penile warts: a double blind randomised study. Genitourin Med . 1997; 73:184-7. [PubMed 9306898][PubMedCentral]
104. Edwards A, Atma-Rm A, Thin RN. Podophyllotoxin 0.5% v podophyllin 20% to treat penile warts. Genitourin Med . 1988; 64:263-5. [PubMed 3169757][PubMedCentral]
105. Lassus A. Comparison of podophyllotoxin and podophyllin in treatment of genital warts. Lancet . 1987; 1:512-3.
106. Maiti H, Haye KR. Topical podophyllin for genital warts. Lancet . 1987; 1:795- 6.
107. Jensen SL. Comparison of podophyllin application with simple surgical excision in clearance and recurrence of perianal condylomata acuminata. Lancet . 1985; 2:1146-7. [PubMed 2865614]
108. Stoehr GP, Peterson AL, Taylor WJ. Systemic complications of local podophyllin therapy. Ann Intern Med . 1978; 89:362-3. [PubMed 686551]
109. Slater GE, Rumack BH, Peterson RG. Podophyllin poisoning: systemic toxicity following cutaneous application. Obstet Gynecol . 1978; 52:94-5. [PubMed 683634]
110. Phelps WC, Alexander KA. Antiviral therapy for human papillomaviruses: rationale and prospects. Ann Intern Med . 1995; 123:368-382. [PubMed 7625626]
111. Drake LA, Ceilley RI, Cornelison RL et al. Guidelines of care for warts: human papillomavirus. J Am Acad Dermatol . 1995; 32:98-103. [PubMed 7822522]
112. Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med . 1997; 102:28-37. [PubMed 9217660]
113. Beutner KR. Bridging the gap. Arch Dermatol . 1990; 126:1432-34. [PubMed 2173496]
114. Stone KM. Human papillomavirus infection and genital warts: update on epidemiology and treatment. Clin Infect Dis . 1995; 20(Suppl 1):S91-7. [PubMed 7540876]
115. Syrjanen KJ. Epidemiology of human papillomavirus (HPV) infections and their associations with genital squamous cell cancer. APMIS . 1989; 97:957-70. [PubMed 2556164]
116. Baker GE, Tyring SK. Therapeutic approaches to papillomavirus infections. Dermatol Clin . 1997; 15:331-40. [PubMed 9098642]
117. Sackett DL. Podophyllotoxin, steganacin and combretastatin: natural products that bind at the colchicine site of tubulin. Pharmacol Ther . 1993; 59:163-228. [PubMed 8278462]
118. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 30th ed. London: The Pharmaceutical Press; 1993:765-6.
119. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995: 1238-9.
120. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep . 2004; 53(RR-15):1-112.
121. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep . 2004; 53(RR-14):1-92.