Professional Documents
Culture Documents
PERIODONTOLOGY 2000
ISSN 0906-6713
Antifungal chemotherapy
Several Candida species, most notably Candida albicans, cause the most common oral and oropharyngeal fungal infections. Estimates range from 40% to
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fungal infections include cryptococcal (supercial ulcers, nodules or granulomas), histoplasmosis (ulcerative nodules) and blastomycosis (mucosal ulcerations) (55). These latter infections are uncommon in immunocompetent patients and are better treated by an infectious disease physician (26). The chemotherapy for oral candidiasis is listed in Table 1. Management is primarily via topical administration of polyenes (nystatin) and various imidazole azoles (clotrimazole, miconazole and ketoconazole) and the newer triazoles (uconazole and itraconazole) (3, 26, 38, 55). Fungal infections are typical rebound infections that tend to be symptomatically suppressed by chemotherapy, only to recur when the therapy is withdrawn. A long duration of treatment is commonly necessary (2 weeks or longer), which is unfortunately a factor in the increasing mycotic resistance to chemotherapy. The least expensive treatment is topical nystatin, miconazole, clotrimazole and ketoconazole cream, while amphotericin cream is moderate in cost and oral ketoconazole, itraconazole and uconazole are the most expensive (55).
Table 1. Drugs and adult dosagesa for oral fungal infections (16, 21, 26, 38, 55, 77))
Topical Nystatin (MycostatinA and NilstatA) Oral suspension: 100,000 units/ml; 5, 60, 480 ml; 5 ml swished for 2 minutes 25 times per day Oral troches: 200,000 units/troche; dissolve in mouth four times per day Clotrimazole (MycelexA): 10-mg troches; one ve times per day Amphotericin B (FungizoneA) Oral suspension: 100 mg/ml; swish and swallow one mg four times per day ` Lotion, creme, ointment: 3%; apply 24 times per day Itraconazole (SporanoxA): oral solution 10 mg/ml; 150 ml; 10 mg swished and swallowed two times per day Systemic oral Ketoconazole (NizoralC): 200 mg tabs; 200400 mg per day Fluconazole (DiucanA): 50, 100, 150, 200 mg tabs; 200 mg on day one; 100 mg per day thereafter Itraconazole (SporanoxA): 100 mg caps; 200 mg per day 5-Flucytosine (AncobonA): 250 and 500 mg caps; 50150 mg per kg per day in divided doses at 6-hour intervals; used only in conjunction with amphotericin B, uconazole or itraconazole
a
Denture stomatitis
Denture stomatitis is characterized by an erythematous lesion under full or partial dentures. The prevalence rate is 1167%, and the cause may be either traumatic, allergic or infectious (39). Denture hygiene consists of soaking in chlorhexidine, bleach, chlorine dioxide or alkaline-buffered glutaraldehyde (39); a soaking of non-metallic dentures with a 1% sodium hypochlorite solution for 15 minutes with a subsequent rinse for at least 2 minutes under running water has been recommended (63). Dentures can also be soaked in a nystatin suspension or the affected area treated with various antifungal preparations: 1) nystatin (MycostatinA or NilstatA) oral suspension of 100,000 units/ml at 25 ml four times daily for 2 minutes and then swallowed, 2) nystatin ointment (15-gram tube) applied to the inner surface of the denture and affected oral area after each meal, 3) nystatin topical powder applied as a thin layer under the denture after meals and after cleaning the denture and 4) ketoconazole (NizoralA) 2% cream (15-gram tube) applied daily to the affected area at bedtime (39, 63).
with the latter divided into the imidazoles and the triazoles (Table 1). Other miscellaneous antifungal agents include 5-ucytosine (AncobonA), ternabine (LamisilA), butenane (MentaxA), ciclopirox (LoproxA), tolnafate (TinactinA), haloprogin (HalotexA), naftine (NaftinA) and undecylenate (DesenexA). Many of the miscellaneous agents are used in the management of dermatophytic fungal infections (ringworm and athletes foot).
Polyenes
Amphotericin B (FungizoneA) For over 30 years, amphotericin B has remained the standard parenteral therapy for most fungal infections with only limited fungal resistance development. It is the agent of choice for Histoplasma capsulatum, Coccidioides immitis, systemic candidiasis, Blastomyces dermatitidis, Cryptococcus neoformans, Aspergillus fumigatus, mucormycosis and sporotrichosis. Its mechanism of action is to insert itself into the fungal cytoplasmic membrane, bind to its sterol components and increase membrane permeability by producing membrane pores which allow the loss of potassium ions and other intracellular constituents (77). Serious adverse drug reactions include impaired renal function, respiratory and car-
Antifungal agents
Two general classes of drugs useful in mycotic infections are currently available: polyenes and azoles
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diac arrest, hypoglycemia, hypokalemia, bone marrow depression, paresthesia, hearing loss, neuropathy, psychosis, hepatic dysfunction and jaundice (16). Reduced toxicity and improved pharmacokinetics have been achieved with liposomal, colloidal and lipid formulations of amphotericin B. It may be synergistic with the azoles (79). The combination of amphotericin B with antineoplastic agents, corticosteroids, zidovudine, cyclosporin and nephrotoxic agents may result in increased adverse drug reactions (16). Hypokalemia may cause severe digitalis or skeletal muscle relaxant toxicity and electrolyte disturbances with diuretics. Amphotericin B is a US Food and Drug Administration (FDA) Pregnancy C category drug. Amphotericin B is primarily intended for use in patients with progressive and potentially fatal fungal infections and is not indicated for noninvasive mycotic infections: oral thrush, vaginal or esophageal candidiasis in patients with a normal neutrophil count.
Ketoconazole (NizoralA) Ketoconazole is now a second-line drug for most fungal infections, as the newer azoles have better pharmacokinetics and produce less hormonal imbalance, fewer drug interactions, less gastrointestinal and liver toxicity with a broader spectrum of action, particularly against Aspergillus. The beta elimination half-life is 9 hours, and the drug is 9599% protein bound (77). Ketoconazole may still be employed for oral, pharyngeal and esophageal Candida infections and coccidioidomycosis, paracoccidioidomycosis, histoplasmosis and chromomycosis (16). Adverse drug reactions seen with ketoconazole include anorexia, nausea and vomiting (1743%), impotence and reduced libido (521%), gynecomastia in males and menstrual irregularities in females (16%), alopecia (8%), hepatotoxicity or hepatitis (1 in 10,000 to 1 in 50,000 users), skin rash (410%) and systemic anaphylaxis (16, 82). Ketoconazole serum levels are decreased by antacids, H2 blockers, omeprazole, sucralfate, isoniazid and rifampin. Ketoconazole may decrease the blood levels or efcacy of the oral contraceptives, protease inhibitors and theophylline and may increase the blood levels and therapeutic or toxic effects of warfarin, corticosteroids, cyclosporine, zolpidem, tacrolimus, nisoldipine and benzodiazepines (16). Women taking oral contraceptives should be advised to use an additional method of contraception. Ketoconazole is an FDA Pregnancy C drug. Fluconazole (DiucanA) Fluconazole possesses signicantly superior pharmacokinetics compared with ketoconazole with greater than 90% bioavailability, similar pharmacokinetics orally or intravenously and good central nervous system penetration, with only 1112% of the drug protein bound (77, 82). Peak oral plasma levels occur in 12 hours in a fasting patient, and steadystate blood levels occur in 510 days given orally (16, 77, 82). The terminal (beta) plasma half life is 2050 hours (average 30 hours) due to its wide volume of distribution, and the elimination half-life rises to 59 98 hours with renal function impairment since 80% of the drug is excreted unchanged (16, 77, 82). Serious hepatotoxicity with uconazole is rare, but if the azoles are used for longer than 2 weeks, liver function tests should be performed (26). Patients who do not respond to antifungal therapy should be evaluated for their immunocompetence (26). Minor adverse effects include gastrointestinal distress
Nystatin (MycostatinA and NilstatA) Nystatin has been the standard for oral topical antifungal therapy for decades and remains therapeutic as resistance is limited. Nystatin is not absorbed orally and probably acts similarly to amphotericin B by binding to sterols in the rigid fungal cell membrane to alter membrane permeability and allow outward leakage of vital intracellular components. Nystatin is essentially nontoxic and nonallergenic with only large oral doses for intestinal candidiasis associated with nausea, vomiting, diarrhea and gastrointestinal pain (16). No teratogenic effects have been detected (16).
Azoles
The era of orally effective antifungal therapy began in 1981 with the introduction of ketoconazole, which was largely supplanted in 1990 and 1992 by uconazole and itraconazole, respectively, due to the poor pharmacokinetics of ketoconazole (very limited bioavailability, no intravenous preparation and no central nervous system penetration) (77). The azoles inhibit C-14 alpha demethylation of lanosterol in fungi by binding to cytochrome P450 enzymes, thereby decreasing the ergosterol synthesis necessary for fungal cytoplasmic membrane synthesis (77). Synthesis of mammalian testosterone and cortisol is also reduced (77).
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(14%), headache (12%), reversible alopecia (10 20%), transient increase in liver enzymes and rash; anaphylaxis and exfoliative dermatitis are rare (16, 77, 82). Fluconazole is an FDA Pregnancy C drug; it is not recommended in nursing mothers, as it is excreted in breast milk and should be avoided during pregnancy if possible (42, 82). Fluconazole increases the blood levels or pharmaceutical and toxic effects of cyclosporine, phenytoin, theophylline, sulfonylureas (glyburide, glipizide and tolbutamide), warfarin and zidovudine, tricyclic antidepressants, alfentanil, zolpidem, corticosteroids, nisoldipine, tacrolimus, losartan, buspirone and the benzodiazepines (16). Fluconazole may or may not alter the blood levels of the oral contraceptives, and the blood levels of uconazole may be increased by hydrochlorothiazide and decreased by cimetidine and rifampin (16). Itraconazole (SporanoxA) Itraconazole is associated with less adverse effects than other azoles and has greater afnity for the fungal CP 450 system, giving it greater efcacy against human pathogenic fungi, especially Aspergillus (42). Its elimination half-life is 1922 hours, and it is 99% protein bound (77). Its range of adverse effects is similar to those of ketoconazole and uconazole but less in incidence, and hepatotoxicity is rare (16, 42, 77). It is a FDA Pregnancy Class C drug. Itraconazole is contraindicated in people taking cisapride, as serious ventricular cardiac arrhythmia (torsade de pointes) may occur (16). Proton pump inhibitors and H2 antagonists decrease the blood levels of itraconazole and its combination with calciumchannel blockers may result in peripheral edema
(82). Itraconazole increases the blood levels of the same drugs as uconazole, with the addition of ritonavir, HMG-CoA reductase inhibitors (statins) and felodipine (16). A reduction in itraconazole effects may occur when combined with didanosine, phenytoin and rifampin (16). Table 2 lists the drugs of choice for various fungal infections and also alternative or second-line drugs (16, 77, 81, 82).
Miscellaneous agents
Flucytosine (AncobonA) or 5-uocytosine is indicated for the treatment of Candida and cryptococcal infections but is rarely used alone due to rapid resistance development. Flucytosine is combined with amphotericin B or the azoles. It is a uorine analogue of cytosine and is metabolized in the fungal cell to 5-uorouracil and then to 5-uorodeoxyuridylic acid, which inhibits thymidylate synthetase (77). Its adverse effects are similar to amphotericin B, allowing for synergistic toxic effects and it is an FDA Pregnancy Class C drug.
Table 2. Systemic drugs of choice for mycotic infections and alternate agents (16, 77, 81, 82)
Primary Oropharyngeal candidiasis Aspergillosis Blastomycosis Coccidioides Cryptococcus Histoplasmosis Mucormycosis Paracoccidioides Pseudallescheria Sporotrichosis Zygomycosis Fluconazole Amphotericin B Itraconazole or amphotericin B Fluconazole or amphotericin B Amphotericin B with or without uconazole Itraconazole or amphotericin B Amphotericin B Itraconazole or amphotericin B Ketoconazole or itraconazole Itraconazole or amphotericin B Amphotericin B Secondary (alternate) Ketoconazole, itraconazole Itraconazole Ketoconazole Ketoconazole, itraconazole Fluconazole or itraconazole Ketoconazole None None None Potassium iodide, uconazole, ketoconazole None
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all nosocomial infections with a potential 57% mortality if the fungi invade the blood (candidemia) (83). Approximately 52% of all Candida nosocomial bloodstream infections are due to C. albicans, 20% to Candida glabrata and 11% to Candida tropicalis (83). Aspergillosis is the second most common nosocomial fungal infection (83). Antifungal resistance in HIV/AIDS patients is increasing alarmingly (25, 76, 84), with up to 33% of these patients having azoleresistant C. albicans in the oral cavity (44, 47, 53, 62). The prolonged use of the azoles in both the treatment and prophylaxis of Candida infections has contributed signicantly to both azole and amphotericin B resistance in fungi (25, 27, 76). Three resistance mechanisms exist for Candida: 1) overexpression of multidrug efux MFS and ATPbinding cassette transporters, 2) overproduction of the target receptor and 3) mutations in the CYP51A1 genes that then alter the afnity of the drugs for their fungal targets (50). C. albicans resistance to the azoles is primarily via two mechanisms: 1) a decrease in afnity for the azole target enzyme P450-dependent sterol C14 alpha demethylase (CYP51A1) via mutations in the ERG 11 gene (41) and 2) energy-dependent drug efux from the fungal cell (1). The active efux of the azoles from Candida depends on the MFS and ATP-binding cassette superfamilies of efux proteins (24). A third mechanism may exist whereby the ergosterol in the fungal membrane is replaced by methylfecosterol to reduce receptor binding (24). Resistance to polyene antifungals is rare and occurs primarily in immunocompromised individuals via altered or reduced ergosterol in the Candida cytoplasmic membrane that reduces the binding of amphotericin B to its receptor (24, 76). Resistance in 5-uorocytosine occurs due to reduced cellular uptake and enzymatic conversion to its active metabolite (24). Many factors contribute to antifungal drug resistance (persistence or progression of an infection despite appropriate antimicrobial therapy): intrinsic susceptibility or resistance of the organism, host defenses, site of the infection (catheters, dentures, biolms and prosthetic devices), patient compliance with drug regimens, drug pharmacokinetics, infection severity and unnecessary use, prophylaxis and duration of therapy (84). Strategies to reduce mycotic drug resistance include: 1) use of high doses for as short a time as possible (as with all antimicrobial agents), 2) avoidance of azole prophylaxis for oral or vaginal candidiasis, 3) use of combination agents if proven effective by clinical trials and 4) development
Antiviral chemotherapy
There are eight distinct members (herpesviruses) of the Herpesviridae family subdivided into three groups: alpha, beta and gamma. The alpha-herpesviruses are herpes simplex virus 1 (HSV-1, herpes labialis), herpes simplex virus 2 (herpes genitalis) and human herpesvirus 3 (HHV-3, herpes zoster virus or varicella zoster virus). The beta-herpesviruses are human hespesvirus 5 (cytomegalovirus), human herpesvirus 6 and human herpesvirus 7. The gammaherpesviruses are human herpesvirus 4 (EpsteinBarr virus) and human herpesvirus 8 (10, 29). The term herpes (creep, crawl, serpentine) originated with Hippocrates description of the characteristic neural tract lesions of herpes zoster. Personto-person transfer was demonstrated in 1893 (86). Unique features of the herpesviruses are their ability to produce recurrent infections in the presence of human immunity and to remain latent in nerve tissue until reactivation (86). The neurotropic her-
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pesviruses include HSV-1, HSV-2 and varicella zoster virus, and the lymphotropic herpesviruses are Epstein-Barr virus, cytomegalovirus and HHV-6, HHV-7 and HHV-8 (9). The herpes virus is a large double-stranded DNA molecule with four components: 1) an electrondense core with viral DNA, 2) a capsid of 162 capsomeres, 3) an amorphous layer of protein (tegument) surrounding the capsid and 4) an envelope that surrounds the capsid-tegument structure consisting of at least ten glycosylated or non-glycosylated viral proteins, lipids and polyamines (86). To be infectious, the virus must attach to a host cell receptor, fuse its envelope with the plasma membrane and allow the de-enveloped capsid to be transported into the cell nucleus (45, 86). Then alpha, beta and gamma genes of the virus encode for thymidine kinase, DNA polymerase, the alpha-trans-inducing factor that switches on the viral replication cascade, virion host-shut-off protein, glycoproteins and capsid proteins that allow for viral synthesis (45, 86). Herpesviruses have two unique properties: the capacity to invade and replicate in the central nervous system and to establish neurotropic latent infections (86). HSV-1, HSV-2 and varicella zoster virus are transported by retrograde movement to the nuclei of sensory ganglia where they can remain in a quiescent state for the entire life of the individual. However, if the virus is reactivated by some currently unknown mechanism, it then moves down the nerve ber(s) and enters the skin or mucosa to produce discrete or extensive eruptions along the distribution of the nerve (86). Herpes labialis is the eruption at the terminus of the fth cranial nerve.
10 days) may be indicated for immunocompromised patients but the drug must be started very early in the course of the disease (72). Both immunoglobulin G (IgG) and IgM antibodies are formed in response to HSV-1 in 24 weeks and persist for life (86). Recurrent orolabial herpes commonly begins with a prodrome of pain, tingling and itching for about 6 hours followed by a characteristic three to ve vesicular eruptions at the vermillion border of the lip (herpes labialis) (86). Within 4896 hours, the lesions progress to pustules and ulcers, with healing at 8 10 days (86). Recurrent HSV-1 infections of the skin resemble varicella zoster virus infections; HSV-1 and HSV-2 infections may occur at the tip of a nger (herpetic whitlow), become disseminated in wrestlers (herpes gladitorium), involve the eye (herpetic keratoconjunctivitis), act as a causative agent for erythema multiformae (9) and produce fatal encephalitis (86). It is estimated that 3040% of those infected with HSV-1 have recurrences (72). The differential diagnosis of recurrent HSV-1 infection should include herpangina, candidiasis, Epstein-Barr virus, Stevens Johnson syndrome, and recurrent aphthous stomatitis (86). Transmission of HSV-1 may occur via skin, cloth, saliva, gloves, dental charts and other fomites. Viral shedding occurs 4.7% to 9% of the time in asymptomatic infected people and may increase to 90% in those with active disease (67). HSV-1 is transmitted to the genital area far more often than HSV-2 to the oral cavity (67). The treatment of oral HSV-1 infections by systemic antiviral agents is generally discouraged (34), except for serious systemic disease in immunocompromised individuals, where acyclovir (400 mg 2 times/day) may be the drug of choice (72). Topical therapy with penciclovir cream may be marginally effective with a reduction in symptoms by 1 day (86). Acyclovir at 200 mg ve times per day may reduce the number of labial lesions at days 57 in skiers (86). Systemic therapeutic or prophylactic antiviral chemotherapy may be considered for people with more than six recurrences per year, a history of erythema multiformae, common exposure to sun or stress and those undergoing surgery on the trigeminal ganglia for neuralgia (75). Oral prophylaxis with acyclovir at 4001000 mg/day may decrease the frequency of HSV-1 recurrences by 5078% (74). Antiviral chemotherapy for HSV-1 should essentially be reserved for serious mucocutaneous or disseminated HSV infection in immunocompromised hosts and not employed for annoying but nonlifethreatening infections. Resistance to the azole antiviral agents is increasing and is of serious concern.
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Children with neonatal skin, eye or mouth herpes (HSV-2) sensitive to acyclovir demonstrate 9098% normalcy at age 2 years, with encephalitis at 4350% normalcy at age 2 and with disseminated herpes at 5762% normalcy at age 2 years (34, 86). These numbers might not be as high if the maternal HSV-2 were rendered resistant to acyclovir through indiscriminate use.
greater than 50 partners (85). In males, the odds of acquiring genital herpes is close to zero with one partner, 20% with 210 partners, 35% with 1150 partners and 70% with more than 50 partners (85). There is an 80% chance of infection in one contact with an actively infected partner (85). Asymptomatic shedding occurs in approximately 12% of people with primary HSV-1, 18% with primary HSV-2 and 23% with recurrent HSV-2 (85). Approximately 20% of all people with HSV-2 are truly asymptomatic, while 60% may have signs and symptoms that remain unrecognized by the patient and physician (5). About 85% of all females and virtually all males have at least one recurrence within the rst year after the primary infection, and many individuals average 45 episodes per year (5, 8). Individuals with a severe primary infection (lasting longer than 35 days) have a doubled recurrence rate (8), and males have at least a 20% greater recurrence rate than females (8). The recurrence rate is 1.9 per 100 days in females and 2.7 per 100 days in males (5, 8), with the virus shed for 16% of days (5, 46) making it impossible to accurately determine when viral shedding does not occur. Acyclovir, famciclovir and valacyclovir all decrease the symptomatic recurrence rate of genital herpes (5, 17). The dosage of acyclovir for initial HSV-2 is 200 mg every 4 hours (5 times per day) for 10 days (16). For recurrent herpes genitalis, the dose of valacyclovir is 500 mg twice daily for 5 days and for famciclovir is 125 mg twice daily for 5 days (16). Chronic suppression with acyclovir is dosed at 400 mg twice daily, 200 mg three times daily or 200 mg ve times daily for 12 months followed by re-evaluation (17).
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Herpes zoster can occur in anyone with a history of varicella, and its incidence increases with age: 1.3 4.8 per 1000 people below age 50 years, 5 per 1000 age 5059 years and 10 per 1000 age 80 years (35). After a varicella infection, the virus proceeds to sensory nerve endings and eventually to dorsal root ganglia, where it may remain latent for many years (35). When reactivated by thermal, inammatory, radiation or mechanical trauma in the 20% of individuals where it does not remain dormant (9), it is transported down the sensory nerve to be released into the skin (35). The zona zoster is the grape-like cluster of vesicular eruptions restricted to the unilateral geographic distribution of a single sensory nerve (9). Herpes zoster of the maxillary branch of the trigeminal nerve is distributed on the facial skin from the lower eyelid to upper lip and the mandibular branch from the ear to the midline and intraorally to the tongue, lip mucosa and mandibular gingiva (21). Shingles is derived from the Latin for belt to describe girdle-like lesions around the waist (9). Herpes zoster without a rash is zoster sine herpetica (9). The burning, aching and lancinating pain of postherpetic neuralgia may persist for days, weeks or indenitely (35). The longer the neuralgia lasts, the more refractory it is to treatment (35). Standard therapy for acute herpes zoster in nonimmunocompromised adults is acyclovir at 800 mg orally ve times per day, famciclovir at 500 mg three times a day or valacyclovir at 1 gram orally three times per day for 7 days (16, 35). In immunocompromised patients, intravenous acyclovir is indicated at 10 mg/kg three times daily, and valacyclovir is not indicated (35). The inhibitory concentration of acyclovir for herpes zoster virus must reach 13 mg per ml of blood (ten times higher than for herpes simplex viruses). Orally acyclovir at 800 mg ve times per day reaches 11.5 mg/ml (49). Antiviral therapy for herpes zoster virus should be considered for all older than age 50 and all persons with ophthalmic herpes zoster virus, peripheral motor neuropathy, herpes zoster virus affecting cervical dermatomes and immunocompromised patients (4, 51, 56). Oral and parenteral antivirals will reduce herpes zoster pain, promote healing, reduce complications and increase social activity (4, 51, 56).
ally manifested in adolescents and young adults as fever, pharyngitis and swollen posterior cervical lymph nodes (653). Other common signs and symptoms include anorexia, myalgia, arthralgia, splenomegaly, hepatomegaly and jaundice (2, 78). Severe, protracted or complicated infectious mononucleosis may be manifested as meningoencephalitis, myocarditis, pneumonia, bone marrow depression, hepatic necrosis and splenic rupture (2, 78). The Epstein-Barr virus has a strong tropism for B lymphocytes and epithelial cells (2, 78) ensuring an unlimited potential for viral survival (78). Approximately 85% of infectious mononucleosis is caused by Epstein-Barr virus and 15% by cytomegalovirus (65). The incubation period for infectious mononucleosis is 57 weeks, and the disease is transmitted by salivary exchange with the salivary gland ductal epithelium cells serving as a reservoir for the virus (65). Diseases associated with persistent Epstein-Barr virus expression include Burkitts lymphoma, nasopharyngeal carcinoma and X-linked lymphoproliferative immune deciency; Hodgkins, T-cell and central nervous system lymphomas; post-transplant lymphoproliferative disease; leiomyosarcoma and leiomyoma and oral hairy leukoplakia (2, 65, 78). Generally no antiviral drug treatment is indicated for infectious mononucleosis or oral hairy leukoplakia, as most cases resolve spontaneously but acyclovir (800 mg ve times per day) along with corticosteroids has been proposed for serious infectious mononucleosis with upper respiratory obstruction (2).
Cytomegalovirus
Cytomegalovirus (HHV-5) is the most pathogenic of the herpesviruses for the immunocompromised host (6), and acute oral infection is manifested as gingivitis and oral ulcers (19). The seroprevalence of cytomegalovirus ranges from 4050% of the general population to 100% in those with HIV (31). Cytomegalovirus is commonly latent in most HIV patients but is commonly reactivated when the CD4 count falls to 50100/ml (13). Exacerbation of cytomegalovirus may then result in esophageal ulcers, fever, malaise, pancytopenia, encephalitis, pneumonitis and, most commonly, retinitis (2040% of AIDS patients) (13). Cytomegalovirus-induced retinitis is sight-threatening and is aggressively treated intravenously with ganciclovir with or without foscarnet and occasionally orally with ganciclovir (13). Solid organ transplant patients are also prone to either a new or reactivated cytomegalovirus infection and may be man-
Epstein-Barr virus
Epstein-Barr virus (HHV-4) is responsible for infectious mononucleosis (benign lymphoproliferative syndrome), which is often asymptomatic but classic-
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aged with oral acyclovir, valacyclovir or ganciclovir prophylaxis (43). Most cytomegalovirus infections in immunocompetent people are asymptomatic with mild inuenza-like symptoms (19, 31). In otherwise healthy children, cytomegalovirus rarely produces clinical illness, but in older children may result in hepatitis, pneumonitis and mononucleosis-like symptoms (15% of cases) (18). Intrauterine cytomegalovirus infection is rare (0.5% of newborns), but 510% of these infections result in severe developmental and teratogenic damage: low birth weight, cataracts, cerebral calcication, macrocephaly and hydrocephaly (18). Oral cytomegalovirus infection occurs primarily but not exclusively in HIV-positive individuals and is manifested by large erythematous ulcers particularly in the palate but also on the lip, gingiva, tongue and oral mucosa (19, 40). Severe gingivitis and gingival hyperplastic overgrowth may also occur (19, 40). Cytomegalovirus is shed in the saliva, urine, tears, sputum, semen and blood, with breastfeeding an important route of transmission in the newborn (32). Severe oral cytomegalovirus infection must be managed with ganciclovir, as acyclovir is not effective (18).
chronic fatigue syndrome, Guillain-Barre syndrome, facial paralysis, Epstein-Barr virusnegative Burkitts lymphoma, Hodgkins lymphoma, Sjogrens syn drome, multiple sclerosis, sarcoidosis and systemic lupus erythematosus, but there is little or no evidence to substantiate such claims (10, 15). Human herpes virus 6 is now subclassied as HHV-6A and HHV-6B, with HHV-6A being the pathogenic form (10). The role of antiviral therapy for HHV-6 is under investigation, but the virus appears relatively resistant to acyclovir and sensitive to ganciclovir and famciclovir (15).
Human herpesvirus 7
HHV-7 is another lymphotropic virus with a reservoir in T lymphocytes, replication in salivary glands and transmission via salivary exchange (2, 48). It was discovered in 1990 (30), resides in CD4 lymphocytes and infects virtually all persons by age 5 years. HHV-7 is less pathogenic than cytomegalovirus or HHV-6 in immunocompromised patients but is involved in graft rejection and may be another cause of roseola (30).
Human herpesvirus 8
HHV-8, which was discovered in 1994 (11), is related to Epstein-Barr virus and is found in saliva, semen and blood mononuclear cells (34). It is also known as Kaposis sarcomaassociated herpesvirus (34). HHV-8 is very common in the saliva of persons with AIDS and Kaposis sarcoma but is rare or absent in healthy controls (34). In the San Francisco Mens Health Study, HHV-8 latencyassociated nuclear antigen (anti-LANA) seroprevalence was 37.6% in homosexual males and 0% in non-homosexual males (52). HHV-8 can also be transmitted from renal graft donors to recipients, as seropositivity increases from 6.4% of graft recipients before transplantation to 17.7% 1 year later (52). This makes HHV-8 a member of a long list of transplant-transmitted microbial agents: human herpesviruses, Candida, cryptococcus, tuberculosis, toxoplasma and saprophytic bacteria (61). HHV-8 is associated with three lymphoproliferative neoplastic diseases: Kaposis sarcoma, primary effusion lymphoma and multicentric Castlemans disease (66).
Human herpesvirus-6
Human B-lymphotrophic virus was isolated in 1986 as a distinct herpesvirus and is now designated HHV-6 (44). The closest DNA homology is between HHV-6, cytomegalovirus and HHV-7 (15). This viral infection is primarily manifested in children as roseola infantum (exanthum subitum, sixth disease) with a rapid onset of fever of 35 days in duration, an erythematous rose-pink maculopapular rash and otitis after the body temperature normalizes (10, 15). Up to 90% of children older than age 2 years are seropositive for HHV-6, and the virus is responsible for 25% of hospital visits between ages 612 months (15). The virus is primarily transmitted via saliva and replicates in lymphocytes, macrophages, endothelial and epithelial cells (44) and is the most ubiquitous of all human herpesviruses. IgG antibodies to HHV6 persist for life in 95% of adults (15). Primary infection in adults is rare but serious, as it manifests as an infectious mononucleosislike fever, lymphadenopathy, hepatitis, encephalitis, febrile seizures and bulging fontanels (15, 44). Most adult HHV-6 infection is seen in adults with HIV or solid organ or bone marrow transplants (15). Claims have been made that HHV-6 is associated with or causes
Enteroviruses
Enteroviruses, particularly coxsackieviruses, are responsible for four oropharyngeal lesions: 1) herpan-
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gina, 2) hand, foot and mouth disease, 3) lymphonodular pharyngitis and 4) ulcerative pharyngitis (21). All four diseases are manifested by fever, lymphadenopathy, diarrhea and oropharyngeal vesicular lesions that differ according to location: herpangina (soft palate and fauces of the throat), hand, foot and mouth disease (buccal mucosa, soft palate, skin of hands and feet distal to the elbows and knees), lymphonodular pharyngitis (orange papules on the soft palate) and ulcerative pharyngitis (aphthae-like ulcers of the buccal mucosa, lips and soft palate) (21). Hand, foot and mouth disease (enterovirus 71) has been responsible for the deaths of 55 children in Taiwan due to central nervous system infection (70). An outbreak has also occurred recently in Australia (54). The treatment of oral enterovirus infections is palliative with acetaminophen (paracetamol) and topical solutions (BenadrylA and KaopectateA). An experimental drug, pleconaril, that prevents picornaviruses (enteroviruses and rhinoviruses) from attaching to cellular receptors and releasing RNA into the cell has been efcacious in the management of life-threatening central nervous system enterovirus infections (64).
multiple crops of small painful ulcers (up to 100 at a time) usually 23 mm in diameter that may fuse into large painful ulcers (87). All forms of recurrent aphthous stomatitis are conned to nonkeratinized tissue: mucosa, mouth oor, ventral surface of the tongue, soft palate and tonsillar fauces (87). Both major and minor recurrent aphthous stomatitis begin at ages 1019 years and the herpetiform type at ages 2029 years (68). The immunopathogenesis of recurrent aphthous stomatitis consists of a mononuclear inltrate in the pre-ulcer phase with large granular T4 lymphocytes, then T8 supressor cells with some polymorphonuclear cells and human leukocyte antigens class I and II appearing in basal epithelial cells (68). Natural killer cells and acute-phase reactants (C9, C-reactive protein) are increased (68). Immune-mediated destruction of the epithelium may be the nal common pathway (87). Serum immunoglobin levels are normal (68) and autoimmunity is not operant (87). Individuals with recurrent aphthous stomatitis are genetically predisposed (68, 87). Additional predisposing factors for recurrent aphthous stomatitis include fever, trauma, food allergy, folate, iron and B12 deciency; Crohns disease, Behcets disease, cyclic neutropenia, HIV infection, IgA deciency and the FAPA syndrome (fever, aphthae, pharyngitis and adenitis) (68, 87). Most cases are idiopathic (68, 87). Physiological or psychological stress has often been proposed as a contributing factor, but this relationship has been questioned (58). Certain foods have been implicated as triggers for recurrent aphthous stomatitis: cows milk, gluten, chocolate, nuts, cinnamon, spices, preservatives as well as drugs (nonsteroidal anti-inammatory agents) (72). Systemic disease as a predisposing factor should be addressed. The management of recurrent aphthous stomatitis is essentially palliative to reduce pain and restore oral function (Table 3). The mainstay of therapy is topical corticosteroids, with local analgesics as a secondary recourse. Topical tetracycline may be effective (28), but low-dose systemic thalidomide may be ineffective (82). It is questionable whether systemic corticosteroids or immunosuppressants (azathioprine) have a satisfactory riskbenet ratio for use in recurrent aphthous stomatitis. Amlexanox A (Aphthasol ) has been formulated specically for the topical treatment of recurrent aphthous ulcers and may act by reducing the formation or release of inammatory cell mediators (histamine, leukotrienes and neutrophils) at recurrent aphthous ulcer sites. Adverse reactions associated with amlexanox
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Table 3. Suggested therapies for recurrent aphthous stomatitis (16, 68, 71, 72)
Topical therapies Corticosteroids Betamethasone diproprionate (DiprosoneA): 0.05% ointment; 15, 45 grams Betamethasone valerate (ValisoneA): 0.1% ointment; 15, 45 grams Clobetasol (TemovateA): 0.05% ointment; 15, 30, 45 grams Dexamethasone (DecadronA): 0.1% cream; 15, 30 grams Fluocinonide (LidexA): 0.05% ointment and cream; 15, 30, 45 grams Triamcinolone (KenalogA): 0.05%, 0.1%; ointment and cream Antimicrobial agents Chlorhexidine (PeridexA): 0.12% Tetracycline: 250 mg in 5 ml of sterile water; apply to lesion four times per day Analgesics Amlexanox (AphthasolA): 5% paste Diphenhydramine (BenadrylA): 12.5 mg per 5-ml elixir in alcohol; 118 ml Lidocaine (XylocaineA): 5% ointment, 50 grams; 2% viscous, 50 and 100 ml Lidocaine and diphenhydramine in 50% elixer with SucralfateA, KaopectateA and MaaloxA Specic drug regimens (72) Amlexanox (AphthasolA): 5% oral paste, 5-g tube; apply thin coat to ulcer after meals and at bedtime Dexamethasone (DecadronA): 0.5 mg per 5-ml elixir, 100 ml: rinse one teaspoonful (5 ml) for 3 minutes four times per day and expectorate until lesions resolve; do not swallow Fluocinonide (LidexA): 0.05% cream; 30-g tube: apply thin coat to ulcer after meals and at bedtime; do not use longer than 2 weeks
vate free virions, 3) be effective topically for mucocutaneous lesions, 4) allow for complete healing of affected cells, 5) be associated with a low incidence of adverse drug reactions, 6) have a specic afnity for the causative virus and 7) have a limited tendency to induce viral drug resistance (33). The search for antiviral agents with even a few of these properties has been difcult and generally unrewarding; potential new agents with different approaches are discussed below. Acyclovir (ZoviraxA) Acyclovir is an analogue of 2-deoxyguanosine and is metabolized to its active form, acyclovir triphosphate, by thymidine kinase in HSV-1, HSV-2 and varicella zoster virus and by phosphokinase in cytomegalovirus (7). It inhibits the synthesis of viral DNA by competing with 2-deoxyguanosine triphosphate as a substrate for viral DNA polymerase. When acyclovir and not 2-deoxyguanosine is introduced into the replication viral DNA, the chain synthesis is terminated (7). Selective toxicity is extant, as acyclovir triphosphate has 3050 times greater afnity for HSV-1 DNA polymerase than human DNA polymerase (7). Acyclovir is slowly and incompletely absorbed orally, with a peak blood concentration at 1.5 to 2 hours (16). Food does not affect its absorption, but its bioavailability is only 1530% (16). It is a FDA Pregnancy C drug and is excreted in breast milk. Minor adverse effects include anorexia, edema, leg pain, headache (0.62.2%), skin rash (0.31.7%), nausea and vomiting (2.74.8%) and diarrhea (0.3 2.4%) (16). Severe lethargy and drowziness may occur when acyclovir is combined with zidovudine (16). Probenecid increases the blood levels of acyclovir. It is formulated in 200-, 400- and 800-mg tablets. Acyclovir is active against HSV-1, HSV-2, varicella zoster virus, Epstein-Barr virus and cytomegalovirus (16). Its approved uses are for initial and recurrent genital herpes, herpes zoster and chicken pox (10). It unlabeled uses include cytomegalovirus and HSV infections following bone marrow or renal transplantation, disseminated primary eczema herpeticum, HSV-associated erythema multiforme, herpes labialis, varicella pneumonia, herpes zoster virus encephalitis, infectious mononucleosis, herpetic whitlow and ocular herpes (16). The dosage of acyclovir for initial genital herpes is 200 mg every 4 hours (ve times per day) for 10 days; for chronic suppressive therapy for recurrent genital
Antiviral agents
There are three groups of antiviral agents:1) those that inactivate intact viruses (virucides), 2) those that inhibit viral replication (antivirals) and 3) those that augment or modify host responses (immunomodulators) (34). The virucides include ether, chloroform, ultraviolet light and lasers. All antiviral agents target viral nucleic acid synthesis to inhibit ongoing viral replication; the virus may then resume replication when the drug is terminated (34). Antivirals may reduce attachment of the virus to the host cell wall, prevent uncoating of the viral genome, reduce the assembly of progeny virions or inhibit virus-directed macromolecular synthesis (34). The host response is vital to recovery from the virus and is moderated by cytotoxic T lymphocytes (34). The ideal antiviral agent should: 1) produce an immediate termination of viral replication, 2) inacti-
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herpes it is 400 mg twice daily, 200 mg three times per day or 200 mg ve times per day for up to 12 months with re-evaluation; for herpes zoster it is 800 mg ve times per day for 710 days (16). The minimum inhibitory concentration for acyclovir against HSV-1 is 0.020.9 mg/ml, 0.4 mg/ml against HSV-2, 2.6 mg/ml for varicella zoster virus and 4757 mg/ml for cytomegalovirus (7, 34). Two hundred milligrams of acyclovir produces a blood level of 0.40.8 mg/ml and 800 mg produces a blood level of 1.6 mg/ml (34). Valacyclovir (Valtrex ) Valacyclovir is a prodrug for acyclovir, as it is almost completely metabolized to acyclovir by a rst-pass effect. Its advantage is much better bioavailability (35 times greater) than acyclovir (16). It is supplied in 500-mg tablets. Valacyclovir is approved for the treatment of herpes zoster and recurrent genital herpes (10). The dose for herpes zoster virus is 1 g three times per day for 7 days and for recurrent HSV-2 is 500 mg twice daily for 5 days (16). It is classied as an FDA Pregnancy B drug. Valacyclovir is not indicated for immunocompromised patients, as thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome have occurred in such patients. Penciclovir (DenavirA) Penciclovir is only approved as a topical 1% cream for the treatment of recurrent herpes labialis (72). Famciclovir (FamvirA) Famciclovir is metabolized to penciclovir with a bioavailability of 77% and has an FDA Pregnancy B classication. It is approved for use in acute herpes zoster and recurrent genital herpes. It is prepared in 125-, 250- and 500-mg tablets. The dose for herpes zoster is 500 mg every 8 hours for 7 days and, for recurrent genital herpes, 125 mg twice daily for 5 days. Signicant adverse drug reactions include headache (23%), paresthesia (2.6%), diarrhea and vomiting (16). Blood levels of famciclovir are increased by cimetidine, probenecid and theophylline, and famciclovir increases the blood levels of digoxin (16). Cidofovir (VistideA) Cidofovir is used parenterally for the management of cytomegalovirus retinitis.
A
Foscarnet (FoscavirA) Foscarnet is employed parenterally for the treatment of cytomegalovirus retinitis and herpes simplex virus in immunocompromised patients with acyclovir-resistant strains. Chemically it is trisodium phosphoformate and complexes with viral DNA to prevent cleavage of pyrophosphate from nucleoside triphosphate, thereby blocking DNA template extension (7). Ganciclovir (CytoveneA) Ganciclovir has an added hydroxymethyl group at the 3 position of an acyclovir side chain that allows it to slow viral DNA chain elongation but prevents it from functioning as a DNA chain terminator as is acyclovir (7). However the inhibitory concentration of ganciclovir against cytomegalovirus is 1050 times less than against HSV, making it the drug of choice against cytomegalovirus (7, 34). It is also very active against HHV-6. Ganciclovir is indicated for the treatment and prevention of cytomegalovirus-induced retinitis and in immunocompromised patients for the management of cytomegalovirus-associated hepatitis, pneumonitis and gastroenteritis (16). It may also be used for prophylaxis in AIDS patients and in solid organ transplants (43). It is an FDA Pregnancy C drug and has very poor bioavailability (59%). It is prepared in 250- and 500-mg capsules and as a powder for injection. Minor adverse drug reactions include diarrhea, nausea, anorexia and vomiting, with more serious effects of headache, confusion and coma; fever, chills and abdominal pain. The major difculty with ganciclovir is its association with serious bone marrow toxicity of thrombocytopenia and neutropenia (1540%) of patients (34). Approximately onethird of patients may discontinue the drug due to central nervous system or bone marrow toxicity (34). Ganciclovir increases the likelihood of toxicity with cytotoxic drugs, seizures with imipenem and cilastatin and renal toxicity with cyclosporine and amphotericin B (16).
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proaches: 1) non-antiviral palliative, 2) antiviral topical and 3) antiviral systemic. Non-antiviral palliative Table 4 lists various preparations empirically employed to reduce the pain associated with herpes simplex infections. Topical steroids may spread the viral infection (63). Patients must be warned to avoid self-inoculation by touching the herpetic lesions and then the eye, genitalia or other body parts to spread the disease (63). Topical oral antiviral agents Many topical therapies have been employed in an attempt to reduce pain and shorten healing time with mixed and mostly unsatisfactory results: ether, glutaraldehyde, povidone-iodine, ascorbic acid, alpha- and beta-interferon, iododioxiuridine and ara-
bosine (33, 72). Topical antiviral agents are generally discouraged for active primary and secondary herpes infections, but 1% topical penciclovir cream has recently been approved for recurrent herpes infections (72). Systemic oral antiviral agents Severe primary herpetic gingivostomatitis or recurrent herpes labialis may be treated with oral acyclovir at doses of 200400 mg (Table 4) (33, 63, 72), while varicella zoster may respond to acyclovir (800 mg ve times per day), famciclovir (500 mg three times per day) or valacyclovir (1000 mg three times per day) for 7 days (9, 63).
Table 4. Palliative and antiviral therapy for adult herpes simplex virus (9, 16, 63, 72)
Palliative for pain Lidocaine (XylocaineA): 2%: apply for 2 minutes; do not gargle or swallow Dyclonine (DycloneA): 0.5%, 1%: apply for 2 minutes; do not gargle or swallow Diphenhydramine syrup (BenalinA) or diphenhydramine elixer (BenadrylA): 12.5 mg per 5 ml: rinse with one teaspoon every 2 hours; do not swallow Diphenhydramine with magnesium hydroxide or aluminum hydroxide: equal parts (50% mixture of each): rinse with two teaspoonfuls (10 ml) for 2 minutes and expectorate Sucralfate suspension: rinse with 2 teaspoonfuls (10 ml) 2 minutes prior to meals and at bedtime and expectorate PreSun 15A: lip gel (15 ounces) or sunscreen lotion (4 ounces): apply to susceptible area/lips 1 hour before sun exposure and every hour thereafter Oral topical antiviral ointment Acyclovir (ZoviraxA): topical ointment 5%: apply to area every 2 hours during waking hours beginning with rst symptoms Penciclovir (DenavirA): 1% cream: apply every 2 hours during waking hours for 4 days; begin if possible during prodromal symptoms Oral systemic antivirals Primary herpetic gingivostomatitis Acyclovir (ZoviraxA): 200-mg capsules; .50: one capsule ve times per day until gone Severe recurrent herpes labialis for those at risk from sun exposure Acyclovir (ZoviraxA): 400-mg caps; .14: two capsules per day until gone starting the day before sun exposure Varicella zoster Acyclovir (ZoviraxA): 800 mg ve times per day for 7 days Famciclovir (FamvirA): 500 mg three times per day for 7 days Valacyclovir (ValtrexA): 1000 mg three times per day for 7 days
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sistance to acyclovir is via gene mutations encoding DNA polymerase or the thymidine kinase responsible for the phosphorylation of acyclovir to its active form (43). Cross-resistance occurs with penciclovir and ganciclovir (43). Resistance in cytomegalovirus includes mutations in the UL97 region of the viral genome leading to impaired phosphorylation of ganciclovir to its active form or point mutations in DNA polymerase (20). A single point mutation is region V of cytomegalovirus DNA polymerase (deletion of codons 981982) can confer instantaneous multiple resistance to ganciclovir, cidofovir and foscarnet (12). Resistance to foscarnet and cidofovir results from mutations in DNA polymerase that prevent enzyme binding of the drugs (20), while resistance to amantadine is via an altered amino acid in M2 protein (7).
of drug resistance and its promotion by prolonged, repetitive and frivolous use must always be foremost in the clinicians mind.
References
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Summary
Fungal and viral infections are difcult to treat, since fungal infections commonly rebound after suppression by the antifungal agent and current antiviral drugs are only virustatic, allowing the virus to reassert its pathogenicity if not eliminated by the host defenses. In addition, fungal infections commonly are associated with signicant biolms, retarding drug penetration, and the uid nature of the oral cavity does not promote drugfungus contact for long periods of time. Both mycotic and viral pathogens are developing sophisticated methods to elude the toxic effects of drugs intended to eliminate their existence. The drug therapy of oral fungal and viral infections is therefore limited but occasionally successful (more with fungal than viral infections) and is often relegated to palliative care. The specter
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