THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE MIKE LEWIS Prim Dent J. 2014;3(4):59-64
Candidal infection ABSTRACT In comparison to the range of antibiotics used in medicine, the spectrum of antifungal and antiviral drugs used in primary dental care is relatively limited. In practical terms, there are only three antifungal agents and two antiviral agents that have a role. This paper will describe the clinical presentation of orofacial candidal and viral infections and the use of antimicrobial drugs in their management.
Candida are fungi that are frequently encountered in the mouths of healthy individuals and are considered to be components of the normal oral microflora. The reported incidence of oral candidal carriage is 35–55% in healthy individuals, depending on the population group studied.1 Although the presence of Candida does not normally cause any clinical signs or symptoms, circumstances may develop that permit proliferation of Candida and subsequent obvious opportunistic infection. A range of predisposing factors is recognised (Table 1) and as such, candidosis has been termed ‘the disease of the diseased’.2 Candidal infection is not a single entity and it is generally accepted that there are four distinct primary forms of oral candisosis (pseudomembranous, acute erythematous, chronic erythematous and chronic hyperplastic), according to their clinical signs and symptoms.3,4
Antifungal agents The classification of antifungal drugs is based on the target of their activity and may be divided into polyenes, which were developed in the 1950s, and azoles, which came into use in the 1970s and 1980s. The use of specific antifungal drugs is influenced by the form of candidal infection and patient factors, in particular interactions with concomitant medication.
treat oral candidosis. These agents have a broad spectrum of activity but unfortunately are poorly absorbed within the gut and their clinical use is limited to topical delivery. Both these agents may be administered as a suspension or lozenge/pastille but they are difficult to use and taste unpleasant. More recently, pharmaceutical companies have discontinued most formulations of polyene antifungals, probably in part due to their limited therapeutic effect, poor patient compliance and development of alternative antifungal drugs that can be delivered systemically. The only polyene preparation still in dental use is nystatin oral suspension. The second generation of antifungal agents comprised the azoles, which inhibit the biosynthesis of ergosterol in the fungal cell membrane. Azole
TA B L E 1
PREDISPOSING FACTORS FOR ORAL CANDIDOSIS Local factor • Denture-wearing • Steroid inhaler use • Reduced salivary flow • Carbohydrate-rich diet Systemic factor
Polyene antifungals, the first fungicidal drugs, act due to their interaction with the ergosterol component within the fungal cell membrane that causes loss of cytoplasmic content. Two polyene antifungals, namely amphotericin and nystatin, have historically been used to
AUTHOR
Mike Lewis PhD, BDS, FRCPath, FDS Professor of Oral Medicine, Cardiff University
VOL 3 NO 4 NOVEMBER 2014
• Extremes of age • Endocrine disorders (diabetes) • Immunosuppression • Broad-spectrum antibiotics • Nutritional deficiencies
KEY WORDS Orofacial Infection, Antifungal Agent, Antiviral Agent, Primary Dental Care
59
THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE
TA B L E 2
ANTIFUNGAL AGENTS Format
Comments
Oral suspension 100,000 units/ml
Suspension is use as mouthrinse for five minutes then swallowed
Polyene Nystatin Azole Fluconazole
Capsule 50mg or Suspension 50mg/5ml
Interaction with warfarin and statins Do not prescribe for longer than 14 days
Miconazole
Oromucosal gel 24mg/ml
Interaction with warfarin and statins Sugar-free preparations are available Discontinue 48 hours after signs and symptoms have resolved
Miconazole
Cream 2%
Interaction with warfarin and statins Continue treatment for 10 days following resolution of signs and symptoms
Miconazole
Miconazole 2% and hydrocortisone 1% cream
Interaction with warfarin and statins Maximum of seven days treatment
Miconazole
Miconazole 2% and hydrocortisone 1% ointment
Interaction with warfarin and statins Maximum of seven days treatment
antifungals have a fungistatic rather than fungicidal activity against Candida and, consequently, it is important to simultaneously address underlying host conditions during azole therapy to provide the best chance of disease resolution. The azole agents that have been used most frequently to treat oral candidosis are miconazole and fluconazole. Like the polyenes, miconazole is not absorbed from the gut and its use in primary dental care is limited to topically applied formats, either alone or in a combination with hydrocortisone. The major benefit of fluconazole is that it can be given systemically via the mouth and is well
Figure 1: Pseudomembranous candidosis
60
absorbed from the gut. Fluconazole is especially effective because it is secreted in saliva and the salivary levels are almost equal to those achieved in the blood.
Pseudomembranous candidosis Pseudomembranous candidosis is characterised by the presence of white plaque-like lesions on the oral mucosa, which can be wiped off to reveal an erythematous mucosa. Although pseudomembranes can occur on any mucosal surface, the soft palate (Figure 1) and buccal sulcus are affected most frequently. Pseudomembranous candidosis is often described as ‘oral thrush’. Identification and elimination of any underlying host-related factors frequently leads to resolution of the condition. In primary care, pseudomembranous candidosis is most likely to be due to corticosteroid inhaler use, particularly in young adults as part of the management of asthma. Patients with a corticosteroid inhaler should be advised to rinse their mouth with water or brush their teeth immediately after using the inhaler. Fluconazole is the antifungal of choice, in the form of a 50mg capsule taken
P R I M A R Y D E N TA L J O U R N A L
Figure 2: Chronic hyperplastic candidosis
Figure 3: Chronic erythematous candidosis
Figure 4: Angular cheilitis
once daily for 7–14 days. Fluconazole does have some interactions with warfarin and statins (Table 2). Nystatin oral suspension, 1ml (100,000 units/ml) after food, four times daily for seven days, can be used if an azole is contraindicated.
are generally asymptomatic and if left untreated, approximately 5–10% of cases undergo malignant change, hence its status as a potentially malignant condition.6 Unlike other forms of oral candidosis, CHC is characterised by candidal hyphal invasion of the oral epithelium. The condition can occur at any site on the oral mucosa, but is most frequently seen as bilateral white patches in the buccal commissure regions of the mouth (Figure 2). Systemic fluconazole for 14 days is the regimen of choice because topical therapy is ineffective. The patient must stop smoking because the lesion will recur if this predisposing factor is not eliminated. Patients with CHC should be referred for specialist assessment.
Management is based on improving appliance hygiene by placement in dilute sodium hypochlorite (if acrylic contains no metal components) or chlorhexidine 0.2% mouthwash (if metal components are present) while sleeping. The application of miconazole oromucosal gel, in the form of a pea-sized amount spread over the fitting surface of the appliance before insertion, four times daily is also helpful.
Acute erythematous candidosis Acute erythematous candidosis is characterised by occurrence of uncomfortable erythematous patches on the oral mucosa, typically on the dorsum of the tongue. The condition is most frequently associated with receipt of a broad-spectrum antibiotic, particularly if there is also steroid inhaler use. Cessation of antibiotic treatment generally results in spontaneous resolution of the condition. The relationship between antibiotic therapy and this form of oral candidosis has resulted in the use of its alternative name of ‘antibiotic sore mouth’.5 Fluconazole, in the form of a 50mg capsule taken once daily for 7–14 days, is the antifungal regimen of choice. Alternatively, a pea-sized amount of miconazole oromucosal gel (24mg/ml) can be applied to the affected mucosa four times daily after food. Nystatin should be prescribed if the use of an azole is contraindicated.
Chronic hyperplastic candidosis Chronic hyperplastic candidosis (CHC) is a relatively rare form of oral candidosis with highest prevalence occurring in middle-aged men who smoke. The lesions
Chronic erythematous candidosis Chronic erythematous candidosis (also known as denture stomatitis or ‘Candidaassociated denture stomatitis’) is by far the most frequent form of oral candidosis. As its name suggests, this infection presents as erythema of the mucosa beneath the fitting surface of a partial or complete denture (Figure 3). Up to 65% of denture wearers have clinical signs of this infection, although the majority of sufferers are unaware of the infection. The condition can develop under any acrylic denture or intraoral appliance, but is almost invariably seen on the palate rather than on the mandibular mucosa. Wearing of an appliance while asleep or a poor fitting appliance are both recognised predisposing factors.
VOL 3 NO 4 NOVEMBER 2014
Other secondary forms of oral candidosis In addition to the four primary forms of oral candidosis, other Candida-associated lesions are recognised and these include angular cheilitis and median rhomboid glossitis. Angular cheilitis Angular cheilitis characteristically presents as erythematous lesions at the corners of the mouth (Figure 4). The condition is frequently associated with other forms of oral candidosis. Although Candida can be recovered from the lesional sites, the exact role of this organism in the infection is difficult to ascertain because bacterial species, in particular Staphylococcus aureus, are also frequently present. Treatment is based on the elimination of the intraoral primary candidal infection as described above. Topical application of miconazole cream or ointment to the angles twice daily should be prescribed. Median rhomboid glossitis Median rhomboid glossitis presents as a symmetrical diamond-shaped area in the midline of the dorsum of the tongue. The
61
THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE
Figure 5: Primary herpetic gingivostomatitis condition is chronic and represents atrophy of the filiform papillae. Candida are frequently isolated from the affected mucosa and the condition responds to fluconazole therapy, both of which support the role of candida in this condition.
Additional considerations In view of the fact that all forms of oral candidosis represent opportunistic infections as a result of an underlying host predisposing factor (Table 1), the use of antifungal therapy must be seen as an adjunct to main focus of management, which is the identification and elimination of any underlying predisposing factor. Haematological investigations to exclude iron deficiency or pernicious anaemia are indicated if initial management fails to produce clinical improvement. Undiagnosed or poorly controlled diabetes is a recognised predisposing factor to oral candidosis and therefore assessment of blood glucose is also required.
Viral infections A number of viruses can produce orofacial clinical signs and symptoms.
62
Essentially, there are three groups of viruses that are of importance in primary dental care; namely the herpes group, human papilloma viruses (HPV) and Coxsackie viruses. Of the eight viruses in the herpes group only herpes simplex virus type 1 (HSV-1), which causes primary herpetic gingivostomatitis and recurrent herpes labialis (cold sore), and varicella zoster virus (VZV), which causes shingles, are of direct relevance to primary dental care.7,8 Some types of HPV are associated with orofacial warts or papilloma (HPV 2 and 4) and oropharyngeal squamous cell carcinoma (HPV 16 and 18). Coxscakie viruses are associated with hand, foot and mouth disease and herpangina. The role of antiviral agents in primary dental care is limited to the use of aciclovir and penciclovir for acute or recurrent herpetic infections. No antiviral agents are prescribed for orofacial lesions caused by HPV or Coxsackie viruses.
Antiviral agents Historically the development of safe antiviral drugs has been difficult and the range of agents remains relatively small. However, the development of aciclovir in the 1970s represented the start of a new era of antiviral therapy and was recognised in part in 1988 by the award of the Nobel Prize in Medicine. Aciclovir, when converted in virally infected cells by kinases into aciclovir triphosphate, inhibits HSV DNA polymerases to prevent further viral replication. It has some activity against most types of herpes group viruses but is highly specific for HSV-1 and HSV-2, with significant activity against VZV. It must be emphasised that this antiviral drug and its close relative penciclovir only prevent replication of the virus and do not eradicate infection. Both drugs need to be prescribed as early as possible for optimum clinical impact. In addition, the drugs need to be taken or applied frequently due to their short half-life in cells.
P R I M A R Y D E N TA L J O U R N A L
Primary herpes simplex infection HSV-1 is responsible for almost all cases of primary herpetic gingivostomatitis, although HSV-2, which is associated with genital infection, has occasionally been encountered. Herpes viruses are endemic and 40% of children in the UK have antibody to HSV-1, which is evidence of having had primary infection, by the age of 12 years. Primary infection usually occurs during childhood and the mild symptoms of oral discomfort with raised temperature are often misdiagnosed as an episode of ‘teething’. On rare occasions, infection can cause widespread oral ulceration, blood-crusted lips (Figure 5) and pyrexia. Diagnosis of primary HSV infection can usually be made from the characteristic clinical signs and symptoms. In practice there is no requirement for microbiological confirmation of the condition although a rapid molecular-based diagnostic test is available in specialist settings. Treatment of primary herpetic stomatitis depends on the severity and stage of symptoms at the time of presentation. Management should be based on ensuring adequate fluid intake to avoid dehydration, systemic analgesics, such as paracetamol, to reduce pyrexia and an antimicrobial mouthwash, such as chlorhexidine, to control plaque deposits.
Figure 6: Herpes labialis Aciclovir, as a 200mg tablet or oral suspension (200mg/ml) taken five times daily, should be prescribed for patients with extensive mucosal involvement who present within first 48 hours of symptoms (Table 3). Treatment should be continued until resolution of signs and symptoms. The use of an antiviral is not justified in either patients with minimal symptoms or those who present at a late stage. Characteristically, symptoms of primary HSV infection persist for 10–14 days, after which time there is full recovery.
Secondary herpes simplex infection Approximately 30% of patients who have had a primary herpetic gingivostomatitis will subsequently suffer from secondary infection in the form of recurrent herpes labialis due to reactivation of latent virus in the tissues. The most frequently affected site is the lips, although any part of the face may be involved (Figure 6). Herpes labialis follows a typical cycle of prodrome tingling, blister, erosion and finally crusting before complete healing within 7–10 days. Aciclovir 5% cream
TA B L E 3
ANTIVIRAL AGENTS Format
Comments
Aciclovir
Tablet 200mg or suspension 200mg/5ml
Sugar-free suspension available
Aciclovir
Tablet 800mg
Shingles treatment pack
Aciclovir
Cream 5%
Penciclovir
Cream 1%
VOL 3 NO 4 NOVEMBER 2014
Not licensed for use in children under 12 years
63
THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE
or penciclovir 1% cream can be used topically for treatment of recurrent herpes labialis. It was originally thought that the topical application of aciclovir (five times daily) or penciclovir (every two hours) was only effective if used in the early prodrome and blister stages of an outbreak. However, it has been shown that both of these agents will reduce the time to healing even if applied at ulcer stage.9 A prophylactic approach involving aciclovir 200mg three times daily over a period of three months may be used in patients who suffer frequent and severe recurrences of herpes labialis. Rarely, reactivation of latent herpes viruses can cause areas of intraoral ulceration, usually affecting the attached gingivae or hard palate. Intraoral lesions often go unrecognised clinically, but appear to run a similar course to those occurring on the lip and the use of systemic aciclovir has a role in their treatment.
Shingles (herpes zoster) Shingles occurs as a result of reactivation of the varicella zoster virus in adult patients and has a tendency to affect sensory nerves. If the maxillary or mandibular
REFERENCES 1
2
3
4
64
Williams DW, Lewis MA. Isolation and identification of candida from the oral cavity. Oral Dis. 2000;6:3-11. Samaranayake LP, MacFarlane TW. Oral Candidosis. London: Wright; 1990. Ellepola AN, Samaranayake LP. Antimycotic agents in oral candidosis: an overview: 1. Clinical variants. Dent Update. 2000;27:111-6. Ellepola AN, Samaranayake LP. Antimycotic agents in oral
5
6
7
division of the trigeminal nerve is involved, the patient may experience toothache-like pain for several days prior to the appearance of the characteristic mucosal and cutaneous lesions. At an early stage of infection, therefore, the patient may well present in a primary dental care setting. If clinical examination fails to reveal any dental pathology, a diagnosis of shingles should be considered. The presence of unilateral ulceration or skin lesions limited to the area supplied by one division of the trigeminal nerve strongly suggests a diagnosis of shingles. Underlying systemic disease should always be considered as a possible initiating factor in shingles. Treatment is based on the relief of pain with analgesics and systemic antiviral therapy. Aciclovir has been found to be effective in the treatment of shingles, because VZV has similar replication pathways to that of HSV. However, owing to the reduced activity of the drug against VZV, the therapeutic dose needs to be increased from that used to treat herpes simplex infection. Therefore, a regimen of 800mg five times daily is advised. Two other antiviral agents, valaciclovir, a valine ester of aciclovir with improved oral absorption and increased intra-cellular
candidosis: an overview: 2. Treatment of oral candidosis. Dent Update. 2000;27:165-70. Soysa NS, Samaranayake LP, Ellepola AN. Antimicrobials as a contributory factor in oral candidosis—a brief overview. Oral Dis. 2008;14:138-43. Sitheeque MA, Samaranayake LP. Chronic hyperplastic candidosis/candidiasis (candidal leukoplakia). Crit Rev Oral Biol Med. 2003;14:253-67. Stoopler ET. Oral herpetic infections (HSV 1-8). Dent Clin
half-life, and famciclovir, a derivative and prodrug form of penciclovir, are also licensed for the treatment of orofacial herpetic conditions. Both drugs have a similar mode of action to aciclovir but have a potential advantage of better patient compliance because they are taken less frequently. At present, the use of these antiviral agents is limited to specialist care.
Summary Antifungal agents and antiviral agents have an important role to play in the treatment of fungal and herpes virus infections. Appropriate use of these drugs can greatly improve patient management. As with the prescribing of any medication to a patient, some basic principles such as patient age, medical history, other medication and hypersensitivity must be considered prior to making a final decision on the most appropriate drug regimen. Advice on prescribing of antifungal and antiviral agents is available in the British National Formulary,10 Antimicrobial Prescribing for General Dental Practitioners11 and Drug Prescribing for Dentistry.12 Every dental practice should have copies of these publications at hand for reference.
North Am. 2005;49:15-29. Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: overview on relevant clinicopathological features. J Oral Pathol Med. 2008;37:10721. 9 Raborn GW, Martel AY, Lassonde M, Lewis MAO, Boon R, Spruance SL. Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials. J Am Dent Assoc. 2002;133:303-9. 10 Joint Formulary Committee. British National Formulary.
8
BNF 68. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain; 2014. 11 Palmer NOA, Longman L, Randall C, Pankhurst CL. Antimicrobial Prescribing for General Dental Practitioners. London: FGDP(UK); 2012. 12 Scottish Dental Clinical Effectiveness Programme (SCDEP). Drug Prescribing for Dentistry. Dental Clinical Guidance. 2nd ed. Dundee; SDCEP; 2011.
P R I M A R Y D E N TA L J O U R N A L
Candidal infection ABSTRACT In comparison to the range of antibiotics used in medicine, the spectrum of antifungal and antiviral drugs used in primary dental care is relatively limited. In practical terms, there are only three antifungal agents and two antiviral agents that have a role. This paper will describe the clinical presentation of orofacial candidal and viral infections and the use of antimicrobial drugs in their management.
Candida are fungi that are frequently encountered in the mouths of healthy individuals and are considered to be components of the normal oral microflora. The reported incidence of oral candidal carriage is 35–55% in healthy individuals, depending on the population group studied.1 Although the presence of Candida does not normally cause any clinical signs or symptoms, circumstances may develop that permit proliferation of Candida and subsequent obvious opportunistic infection. A range of predisposing factors is recognised (Table 1) and as such, candidosis has been termed ‘the disease of the diseased’.2 Candidal infection is not a single entity and it is generally accepted that there are four distinct primary forms of oral candisosis (pseudomembranous, acute erythematous, chronic erythematous and chronic hyperplastic), according to their clinical signs and symptoms.3,4
Antifungal agents The classification of antifungal drugs is based on the target of their activity and may be divided into polyenes, which were developed in the 1950s, and azoles, which came into use in the 1970s and 1980s. The use of specific antifungal drugs is influenced by the form of candidal infection and patient factors, in particular interactions with concomitant medication.
treat oral candidosis. These agents have a broad spectrum of activity but unfortunately are poorly absorbed within the gut and their clinical use is limited to topical delivery. Both these agents may be administered as a suspension or lozenge/pastille but they are difficult to use and taste unpleasant. More recently, pharmaceutical companies have discontinued most formulations of polyene antifungals, probably in part due to their limited therapeutic effect, poor patient compliance and development of alternative antifungal drugs that can be delivered systemically. The only polyene preparation still in dental use is nystatin oral suspension. The second generation of antifungal agents comprised the azoles, which inhibit the biosynthesis of ergosterol in the fungal cell membrane. Azole
TA B L E 1
PREDISPOSING FACTORS FOR ORAL CANDIDOSIS Local factor • Denture-wearing • Steroid inhaler use • Reduced salivary flow • Carbohydrate-rich diet Systemic factor
Polyene antifungals, the first fungicidal drugs, act due to their interaction with the ergosterol component within the fungal cell membrane that causes loss of cytoplasmic content. Two polyene antifungals, namely amphotericin and nystatin, have historically been used to
AUTHOR
Mike Lewis PhD, BDS, FRCPath, FDS Professor of Oral Medicine, Cardiff University
VOL 3 NO 4 NOVEMBER 2014
• Extremes of age • Endocrine disorders (diabetes) • Immunosuppression • Broad-spectrum antibiotics • Nutritional deficiencies
KEY WORDS Orofacial Infection, Antifungal Agent, Antiviral Agent, Primary Dental Care
59
THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE
TA B L E 2
ANTIFUNGAL AGENTS Format
Comments
Oral suspension 100,000 units/ml
Suspension is use as mouthrinse for five minutes then swallowed
Polyene Nystatin Azole Fluconazole
Capsule 50mg or Suspension 50mg/5ml
Interaction with warfarin and statins Do not prescribe for longer than 14 days
Miconazole
Oromucosal gel 24mg/ml
Interaction with warfarin and statins Sugar-free preparations are available Discontinue 48 hours after signs and symptoms have resolved
Miconazole
Cream 2%
Interaction with warfarin and statins Continue treatment for 10 days following resolution of signs and symptoms
Miconazole
Miconazole 2% and hydrocortisone 1% cream
Interaction with warfarin and statins Maximum of seven days treatment
Miconazole
Miconazole 2% and hydrocortisone 1% ointment
Interaction with warfarin and statins Maximum of seven days treatment
antifungals have a fungistatic rather than fungicidal activity against Candida and, consequently, it is important to simultaneously address underlying host conditions during azole therapy to provide the best chance of disease resolution. The azole agents that have been used most frequently to treat oral candidosis are miconazole and fluconazole. Like the polyenes, miconazole is not absorbed from the gut and its use in primary dental care is limited to topically applied formats, either alone or in a combination with hydrocortisone. The major benefit of fluconazole is that it can be given systemically via the mouth and is well
Figure 1: Pseudomembranous candidosis
60
absorbed from the gut. Fluconazole is especially effective because it is secreted in saliva and the salivary levels are almost equal to those achieved in the blood.
Pseudomembranous candidosis Pseudomembranous candidosis is characterised by the presence of white plaque-like lesions on the oral mucosa, which can be wiped off to reveal an erythematous mucosa. Although pseudomembranes can occur on any mucosal surface, the soft palate (Figure 1) and buccal sulcus are affected most frequently. Pseudomembranous candidosis is often described as ‘oral thrush’. Identification and elimination of any underlying host-related factors frequently leads to resolution of the condition. In primary care, pseudomembranous candidosis is most likely to be due to corticosteroid inhaler use, particularly in young adults as part of the management of asthma. Patients with a corticosteroid inhaler should be advised to rinse their mouth with water or brush their teeth immediately after using the inhaler. Fluconazole is the antifungal of choice, in the form of a 50mg capsule taken
P R I M A R Y D E N TA L J O U R N A L
Figure 2: Chronic hyperplastic candidosis
Figure 3: Chronic erythematous candidosis
Figure 4: Angular cheilitis
once daily for 7–14 days. Fluconazole does have some interactions with warfarin and statins (Table 2). Nystatin oral suspension, 1ml (100,000 units/ml) after food, four times daily for seven days, can be used if an azole is contraindicated.
are generally asymptomatic and if left untreated, approximately 5–10% of cases undergo malignant change, hence its status as a potentially malignant condition.6 Unlike other forms of oral candidosis, CHC is characterised by candidal hyphal invasion of the oral epithelium. The condition can occur at any site on the oral mucosa, but is most frequently seen as bilateral white patches in the buccal commissure regions of the mouth (Figure 2). Systemic fluconazole for 14 days is the regimen of choice because topical therapy is ineffective. The patient must stop smoking because the lesion will recur if this predisposing factor is not eliminated. Patients with CHC should be referred for specialist assessment.
Management is based on improving appliance hygiene by placement in dilute sodium hypochlorite (if acrylic contains no metal components) or chlorhexidine 0.2% mouthwash (if metal components are present) while sleeping. The application of miconazole oromucosal gel, in the form of a pea-sized amount spread over the fitting surface of the appliance before insertion, four times daily is also helpful.
Acute erythematous candidosis Acute erythematous candidosis is characterised by occurrence of uncomfortable erythematous patches on the oral mucosa, typically on the dorsum of the tongue. The condition is most frequently associated with receipt of a broad-spectrum antibiotic, particularly if there is also steroid inhaler use. Cessation of antibiotic treatment generally results in spontaneous resolution of the condition. The relationship between antibiotic therapy and this form of oral candidosis has resulted in the use of its alternative name of ‘antibiotic sore mouth’.5 Fluconazole, in the form of a 50mg capsule taken once daily for 7–14 days, is the antifungal regimen of choice. Alternatively, a pea-sized amount of miconazole oromucosal gel (24mg/ml) can be applied to the affected mucosa four times daily after food. Nystatin should be prescribed if the use of an azole is contraindicated.
Chronic hyperplastic candidosis Chronic hyperplastic candidosis (CHC) is a relatively rare form of oral candidosis with highest prevalence occurring in middle-aged men who smoke. The lesions
Chronic erythematous candidosis Chronic erythematous candidosis (also known as denture stomatitis or ‘Candidaassociated denture stomatitis’) is by far the most frequent form of oral candidosis. As its name suggests, this infection presents as erythema of the mucosa beneath the fitting surface of a partial or complete denture (Figure 3). Up to 65% of denture wearers have clinical signs of this infection, although the majority of sufferers are unaware of the infection. The condition can develop under any acrylic denture or intraoral appliance, but is almost invariably seen on the palate rather than on the mandibular mucosa. Wearing of an appliance while asleep or a poor fitting appliance are both recognised predisposing factors.
VOL 3 NO 4 NOVEMBER 2014
Other secondary forms of oral candidosis In addition to the four primary forms of oral candidosis, other Candida-associated lesions are recognised and these include angular cheilitis and median rhomboid glossitis. Angular cheilitis Angular cheilitis characteristically presents as erythematous lesions at the corners of the mouth (Figure 4). The condition is frequently associated with other forms of oral candidosis. Although Candida can be recovered from the lesional sites, the exact role of this organism in the infection is difficult to ascertain because bacterial species, in particular Staphylococcus aureus, are also frequently present. Treatment is based on the elimination of the intraoral primary candidal infection as described above. Topical application of miconazole cream or ointment to the angles twice daily should be prescribed. Median rhomboid glossitis Median rhomboid glossitis presents as a symmetrical diamond-shaped area in the midline of the dorsum of the tongue. The
61
THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE
Figure 5: Primary herpetic gingivostomatitis condition is chronic and represents atrophy of the filiform papillae. Candida are frequently isolated from the affected mucosa and the condition responds to fluconazole therapy, both of which support the role of candida in this condition.
Additional considerations In view of the fact that all forms of oral candidosis represent opportunistic infections as a result of an underlying host predisposing factor (Table 1), the use of antifungal therapy must be seen as an adjunct to main focus of management, which is the identification and elimination of any underlying predisposing factor. Haematological investigations to exclude iron deficiency or pernicious anaemia are indicated if initial management fails to produce clinical improvement. Undiagnosed or poorly controlled diabetes is a recognised predisposing factor to oral candidosis and therefore assessment of blood glucose is also required.
Viral infections A number of viruses can produce orofacial clinical signs and symptoms.
62
Essentially, there are three groups of viruses that are of importance in primary dental care; namely the herpes group, human papilloma viruses (HPV) and Coxsackie viruses. Of the eight viruses in the herpes group only herpes simplex virus type 1 (HSV-1), which causes primary herpetic gingivostomatitis and recurrent herpes labialis (cold sore), and varicella zoster virus (VZV), which causes shingles, are of direct relevance to primary dental care.7,8 Some types of HPV are associated with orofacial warts or papilloma (HPV 2 and 4) and oropharyngeal squamous cell carcinoma (HPV 16 and 18). Coxscakie viruses are associated with hand, foot and mouth disease and herpangina. The role of antiviral agents in primary dental care is limited to the use of aciclovir and penciclovir for acute or recurrent herpetic infections. No antiviral agents are prescribed for orofacial lesions caused by HPV or Coxsackie viruses.
Antiviral agents Historically the development of safe antiviral drugs has been difficult and the range of agents remains relatively small. However, the development of aciclovir in the 1970s represented the start of a new era of antiviral therapy and was recognised in part in 1988 by the award of the Nobel Prize in Medicine. Aciclovir, when converted in virally infected cells by kinases into aciclovir triphosphate, inhibits HSV DNA polymerases to prevent further viral replication. It has some activity against most types of herpes group viruses but is highly specific for HSV-1 and HSV-2, with significant activity against VZV. It must be emphasised that this antiviral drug and its close relative penciclovir only prevent replication of the virus and do not eradicate infection. Both drugs need to be prescribed as early as possible for optimum clinical impact. In addition, the drugs need to be taken or applied frequently due to their short half-life in cells.
P R I M A R Y D E N TA L J O U R N A L
Primary herpes simplex infection HSV-1 is responsible for almost all cases of primary herpetic gingivostomatitis, although HSV-2, which is associated with genital infection, has occasionally been encountered. Herpes viruses are endemic and 40% of children in the UK have antibody to HSV-1, which is evidence of having had primary infection, by the age of 12 years. Primary infection usually occurs during childhood and the mild symptoms of oral discomfort with raised temperature are often misdiagnosed as an episode of ‘teething’. On rare occasions, infection can cause widespread oral ulceration, blood-crusted lips (Figure 5) and pyrexia. Diagnosis of primary HSV infection can usually be made from the characteristic clinical signs and symptoms. In practice there is no requirement for microbiological confirmation of the condition although a rapid molecular-based diagnostic test is available in specialist settings. Treatment of primary herpetic stomatitis depends on the severity and stage of symptoms at the time of presentation. Management should be based on ensuring adequate fluid intake to avoid dehydration, systemic analgesics, such as paracetamol, to reduce pyrexia and an antimicrobial mouthwash, such as chlorhexidine, to control plaque deposits.
Figure 6: Herpes labialis Aciclovir, as a 200mg tablet or oral suspension (200mg/ml) taken five times daily, should be prescribed for patients with extensive mucosal involvement who present within first 48 hours of symptoms (Table 3). Treatment should be continued until resolution of signs and symptoms. The use of an antiviral is not justified in either patients with minimal symptoms or those who present at a late stage. Characteristically, symptoms of primary HSV infection persist for 10–14 days, after which time there is full recovery.
Secondary herpes simplex infection Approximately 30% of patients who have had a primary herpetic gingivostomatitis will subsequently suffer from secondary infection in the form of recurrent herpes labialis due to reactivation of latent virus in the tissues. The most frequently affected site is the lips, although any part of the face may be involved (Figure 6). Herpes labialis follows a typical cycle of prodrome tingling, blister, erosion and finally crusting before complete healing within 7–10 days. Aciclovir 5% cream
TA B L E 3
ANTIVIRAL AGENTS Format
Comments
Aciclovir
Tablet 200mg or suspension 200mg/5ml
Sugar-free suspension available
Aciclovir
Tablet 800mg
Shingles treatment pack
Aciclovir
Cream 5%
Penciclovir
Cream 1%
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Not licensed for use in children under 12 years
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THE ROLE OF ANTIFUNGAL AND ANTIVIRAL AGENTS IN PRIMARY DENTAL CARE
or penciclovir 1% cream can be used topically for treatment of recurrent herpes labialis. It was originally thought that the topical application of aciclovir (five times daily) or penciclovir (every two hours) was only effective if used in the early prodrome and blister stages of an outbreak. However, it has been shown that both of these agents will reduce the time to healing even if applied at ulcer stage.9 A prophylactic approach involving aciclovir 200mg three times daily over a period of three months may be used in patients who suffer frequent and severe recurrences of herpes labialis. Rarely, reactivation of latent herpes viruses can cause areas of intraoral ulceration, usually affecting the attached gingivae or hard palate. Intraoral lesions often go unrecognised clinically, but appear to run a similar course to those occurring on the lip and the use of systemic aciclovir has a role in their treatment.
Shingles (herpes zoster) Shingles occurs as a result of reactivation of the varicella zoster virus in adult patients and has a tendency to affect sensory nerves. If the maxillary or mandibular
REFERENCES 1
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Williams DW, Lewis MA. Isolation and identification of candida from the oral cavity. Oral Dis. 2000;6:3-11. Samaranayake LP, MacFarlane TW. Oral Candidosis. London: Wright; 1990. Ellepola AN, Samaranayake LP. Antimycotic agents in oral candidosis: an overview: 1. Clinical variants. Dent Update. 2000;27:111-6. Ellepola AN, Samaranayake LP. Antimycotic agents in oral
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division of the trigeminal nerve is involved, the patient may experience toothache-like pain for several days prior to the appearance of the characteristic mucosal and cutaneous lesions. At an early stage of infection, therefore, the patient may well present in a primary dental care setting. If clinical examination fails to reveal any dental pathology, a diagnosis of shingles should be considered. The presence of unilateral ulceration or skin lesions limited to the area supplied by one division of the trigeminal nerve strongly suggests a diagnosis of shingles. Underlying systemic disease should always be considered as a possible initiating factor in shingles. Treatment is based on the relief of pain with analgesics and systemic antiviral therapy. Aciclovir has been found to be effective in the treatment of shingles, because VZV has similar replication pathways to that of HSV. However, owing to the reduced activity of the drug against VZV, the therapeutic dose needs to be increased from that used to treat herpes simplex infection. Therefore, a regimen of 800mg five times daily is advised. Two other antiviral agents, valaciclovir, a valine ester of aciclovir with improved oral absorption and increased intra-cellular
candidosis: an overview: 2. Treatment of oral candidosis. Dent Update. 2000;27:165-70. Soysa NS, Samaranayake LP, Ellepola AN. Antimicrobials as a contributory factor in oral candidosis—a brief overview. Oral Dis. 2008;14:138-43. Sitheeque MA, Samaranayake LP. Chronic hyperplastic candidosis/candidiasis (candidal leukoplakia). Crit Rev Oral Biol Med. 2003;14:253-67. Stoopler ET. Oral herpetic infections (HSV 1-8). Dent Clin
half-life, and famciclovir, a derivative and prodrug form of penciclovir, are also licensed for the treatment of orofacial herpetic conditions. Both drugs have a similar mode of action to aciclovir but have a potential advantage of better patient compliance because they are taken less frequently. At present, the use of these antiviral agents is limited to specialist care.
Summary Antifungal agents and antiviral agents have an important role to play in the treatment of fungal and herpes virus infections. Appropriate use of these drugs can greatly improve patient management. As with the prescribing of any medication to a patient, some basic principles such as patient age, medical history, other medication and hypersensitivity must be considered prior to making a final decision on the most appropriate drug regimen. Advice on prescribing of antifungal and antiviral agents is available in the British National Formulary,10 Antimicrobial Prescribing for General Dental Practitioners11 and Drug Prescribing for Dentistry.12 Every dental practice should have copies of these publications at hand for reference.
North Am. 2005;49:15-29. Arduino PG, Porter SR. Herpes Simplex Virus Type 1 infection: overview on relevant clinicopathological features. J Oral Pathol Med. 2008;37:10721. 9 Raborn GW, Martel AY, Lassonde M, Lewis MAO, Boon R, Spruance SL. Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials. J Am Dent Assoc. 2002;133:303-9. 10 Joint Formulary Committee. British National Formulary.
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BNF 68. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain; 2014. 11 Palmer NOA, Longman L, Randall C, Pankhurst CL. Antimicrobial Prescribing for General Dental Practitioners. London: FGDP(UK); 2012. 12 Scottish Dental Clinical Effectiveness Programme (SCDEP). Drug Prescribing for Dentistry. Dental Clinical Guidance. 2nd ed. Dundee; SDCEP; 2011.
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