Oral candidiasis: causes, types and treatment

pharmaceutical-journal.com/cpd-and-learning/oral-candidiasis-causes-types-and-treatment/20208483.article

The Pharmaceutical Journal3 NOV 2020By Stephen Hughes, Oliver

Troise

Pharmacists and pharmacy teams should be able to recognise oral

thrush, a common yeast infection, and provide appropriate
treatment advice to resolve infections.

Source: Shutterstock.com

Pseudomembranous candidiasis is characterised by an extensive white ‘cottage cheese-like’ film, found on

buccal mucosa, tongue, periodontal tissues and oropharynx.

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Oral candidiasis is an opportunistic infection of the oral cavity often caused by the
overgrowth of Candida, a yeast-like fungus commonly found in the gastrointestinal
tract of humans, as normal skin flora and in mucous membranes[1]. Candida
albicans (C. albicans) accounts for around 80% of infections and can colonise the
cavity, either alone or in combination with non-albican species, including Candida
glabrata and Candida tropicalis[1],[2]. The typical colonisation rate of C. albicans varies
with age. In neonates it is 45%; in healthy children 45–65%; in healthy adults 30–45%;
in denture wearers 50–65%; in patients living in acute or long-term facilities, such as
nursing or residential homes, 65–88%; and in immunocompromised patients, such as
those with HIV and/or undergoing chemotherapy for acute leukaemia, it is 95% and
90% respectively[1],[3]. It is unclear why the carriage rate varies with age.
With increased availability and prescribing of broad-spectrum antibacterials (e.g.
penicillins, fluoroquinolones, macrolides) and immunosuppressive agents (e.g.
corticosteroids, azathioprine, methotrexate), and with increased immunosuppressive
comorbidities, including diabetes, cancer and AIDS, there has been an increase in the
number of reported cases of opportunistic oral Candida infections [3]. While not life-
threatening for most patients, it can cause significant patient discomfort and, in elderly
or hospitalised patients, can result in significant morbidity owing to impaired
nutrition[3].
However, in severely immunosuppressed patients, invasive and life-threatening
systemic Candida infection may develop. A tertiary care hospital reported that, of their
patients suffering from Candida bloodstream infection, 45% received
immunosuppressive therapy[4].
More than half a million prescriptions for oral Candida infections are issued each year
in England by GPs[5].
This article aims to aid pharmacists in the diagnosis and management of patients
suffering from oral candidiasis. It provides assistance in recognising patients at risk of
mucosal fungal infections, and the pharmacological and non-pharmacological options
to prevent occurrence and treat the infection.

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 Figure 1: an example of mild pseudomembranous candidiasis (white areas)
Source: Science Photo Library

Classification
There are several classifications of oral candidiasis, and their similarities and
differences are outlined below[1],[2].
Pseudomembranous candidiasis is the most common type and is characterised by
an extensive white ‘cottage cheese-like’ film, found on the buccal mucosa, tongue,
periodontal tissues and oropharynx [1],[3]. The plaque can usually be scraped off to
expose an underlying erythematous mucosa[2]. If thrush is associated with the use of
corticosteroid inhalers, rinsing the mouth with water (or cleaning a child’s teeth if not
able to rinse and spit) immediately after using the inhaler may avoid the problem.
Patients should be counselled on good dental hygiene on initiation of corticosteroid
inhalers[6]. See Box for preventative strategies for oral candidiasis[7].

Acute atrophic candidiasis is associated with a burning sensation in the mouth or

on the tongue, and often referred to as ‘antibiotic sore mouth’, because of its association
with prolonged use of broad-spectrum antibiotics[1]. The tongue may be bright red and
painful. Although this type of candidiasis is less common, diagnosis may be difficult,
but should be considered in the differential diagnosis of a sore tongue, especially in a
frail, older patient with dentures who has received antibiotic therapy or who is on
inhaled steroids. Other conditions that may be confused with acute atrophic candidiasis
include mucositis, denture stomatitis, erythema migrans, thermal burns, erythroplakia
and anaemia[3].

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Chronic presentations of oral candidiasis can occur, often with chronic inflammation
associated with denture usage[3].
Angular chelitis is defined as fissuring, scaling and erythema of the corners of the
mouth. It may be associated with Candida infection, but can be co-infected with
staphylococcus or streptococcusbacteria, which can complicate treatment and lead to
other oral bacterial infections[2].

Box: Prevention of oral candidiasis infection

If some of the predisposing factors listed in Table 1 apply, there are several practical
considerations patients can take to reduce the risk of infection.

Rinsing mouth out after eating, taking medication or using a corticosteroid

inhaler;
Good oral hygiene, brushing teeth twice per day;
Going for regular dental check-ups (even if patients do not have any teeth).

For denture wearers:

Properly cleaning dentures;

Brushing gums with a soft toothbrush;
Removing dentures each night;
Ensuring dentures fit properly and are not too loose.

For infants:

Sterilising dummies regularly and bottles after each use;

If using corticosteroid inhalers, rinsing the mouth with water or cleaning a
child’s teeth (if not able to rinse and spit) immediately after using the inhaler.

Source: NHS[7]

Risk factors
Local and systemic factors of the host can predispose patients to becoming infected with
a Candida species. The specifics of these are discussed below, and summarised in Table
1.
Local factors

Reduced salivary production can predispose patients to oral candidiasis, as salivary

constituents inhibit the overgrowth of Candida. Therefore, conditions reducing the
amount and characteristics of saliva secretions may lead to a Candida overgrowth[3].
Dental prostheses, such as dentures or fillings, can create a favourable environment for
the Candida organisms to latch[3]. Topical or inhaled corticosteroids temporarily
suppress the oral immune system and cause alterations in the oral flora, leading to an
overgrowth of Candida[3].
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Unbalanced dietary intake of sugars, carbohydrates and dairy products can promote
Candida growth by making the oral cavity more acidic and consequently favouring the
Candida organisms[8].

Systemic factors
Extremes of age may predispose individuals to candidiasis owing to immature or
weakened immunity, along with the variations in the Candida carriage rates[3].

Malnutrition, particularly in iron but also in other nutrients such as essential fatty
acids, folic acid, vitamins A and B6, magnesium, selenium and zinc, is often associated
with increased risk of oral candidiasis. Iron deficiency diminishes the fungistatic action
of transferrin and other iron-dependent enzymes used in suppressing fungal
overgrowth in the oral cavity,[8].

Prolonged use of broad-spectrum antibiotics (e.g. co-amoxiclav), or

immunosuppressants (e.g. azathioprine), alters the local oral flora by killing off bacteria
and suppressing the immune system. This results in a favourable environment for
Candida to grow[8].
Oral and invasive candidiasis is more frequently reported in patients with endocrine
dysfunctions, such as diabetes and Cushing’s syndrome; in immunodeficiency
conditions such as AIDS; and in patients receiving chemotherapy and radiotherapy for
the treatment of cancers. This is owing to the reasons previously outlined; these
morbidities impair the host defence mechanisms, leading to an overgrowth in the oral
flora[3].

Local factors Systemic factors

• Impaired local defense mechanisms • Impaired systemic defense

mechanisms

• Reduced saliva production • Immunodeficiency (e.g. AIDS)

• Smoking • Immunosuppressive medications

(e.g azathioprine)

• Atrophic oral mucosa • Endocrine disorders (e.g.

diabetes)

• Mucosal diseases (e.g. oral lichen planus) • Malnutrition

• Topical medications (e.g. corticosteriods) • Cancers

• Decreased blood supply (e.g. caused by • Some congenital conditions

radiotherapy or vasculitis)

• Poor oral hygiene • Broad-spectrum antibiotic therapy

• Dental prostheses or dentures

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 Local factors Systemic factors

• Altered or immature oral flora

Table 1: Factors predisposing for oral candidiasis

Diagnosis
Recognition of the associated lesions, such as the white plaque seen in the Figure, via an
oral or oesophageal examination (i.e. examining the back of the throat) should provide a
diagnosis of the more common forms of oral candidiasis (e.g. pseudomembranous
candidiasis). Diagnosis can, however, be confirmed microscopically via a mucosal
smear or biopsy as a Candida overgrowth, and should be considered for refractory
disease or the alternative presentations of the condition[1],[2],[3]. A positive microbiology
result for Candida alone does not indicate a necessity for treatment as patients are
routinely colonised, as aforementioned[2]. Oral candidiasis is uncommon in healthy
adults and may be the first presentation of an undiagnosed risk factor.

Treatment

Topical

Traditionally, topical antifungals are the preferred treatment for oral candidiasis.
Locally administered antifungals offer the advantage of reduced systemic exposure,
which results in fewer adverse drug reactions or interactions. The British National
Formulary (BNF) lists two options: nystatin and miconazole [10] . However, the four-
times-per-day administration makes patient adherence for the requisite 7–14 days
challenging. Reiterating the importance of this regular administration to patients for
preventing infection can help improve compliance.

Nystatin is the most commonly used topical treatment of oral candidiasis in the UK,
with little systemic exposure expected[11],[12]. The nystatin oral suspension is rapidly
cleared from the oral tract and concentrations fall quickly to subtherapeutic levels.
Therefore, the resultant short contact time with the oral mucosa can contribute to
reduced efficacy[11],[12]. For this reason, nystatin should generally be avoided in severe
infection or in immunocompromised patients[13].

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Miconazole, an imidazole, can be used for local application in the mouth. It remains a
useful and effective treatment for all types of oral candidiasis and has a broad spectrum
of activity against many species of Candida, including C. albicans [11]. A recent
systematic review showed that miconazole therapy is superior to nystatin for oral
candidiasis and is associated with a decrease in treated infection relapses[14]. However,
concomitant use of miconazole oral gel and warfarin can result in life-threatening
international normalised ratio (INR) derangement owing to the gel being absorbed
through the oral mucosa or the gastrointestinal tract when swallowed [15],[16]. Co-
administration of these medicines is contraindicated and should be avoided, as outlined
by the Medicines and Healthcare products Regulatory Agency. Patients should be
advised to use alternative topical therapies, such as nystatin. However, if the oral
candidiasis is refractory to nystatin, then the patient should receive systemic therapy
with a triazole, with close monitoring of their INR, and should be informed of the
increased risk of bleeding with this therapy.
Topical fluconazole, although traditionally unused within UK clinical practice, has been
reported for the treatment of oral candidiasis, although this usage is an off-label
application of oral fluconazole suspension. Owing to its good adhesion to the surface of
the oral mucosa and a once-daily administration, fluconazole 50mg/5mL oral solution
mouthwash is an option for uncomplicated oral candidiasis[12]. A small, randomised
control trial (n=34) reported that fluconazole oral suspension was superior to nystatin
at treating oral candidiasis in infants[17]. It was found that nystatin adhered poorly to
the oral mucosa, resulting in shorter time in the oral cavity and a faster ingestion of the
suspension, therefore having a lower efficiency compared with fluconazole. Another
small, open-label study (n=19) looked at using fluconazole suspension (2mg/mL three
times per day) as a rinse and spit regimen, obtaining 94% cure rates[18].

Systemic treatment

Reserved for more invasive infections, patients with concurrent immunodeficiency or

where compliance with topical therapies is challenging, systemic treatment options
include oral fluconazole first-line, with itraconazole generally reserved for refractory
infection (see Table 2)[10] .
Fluconazole remains the first-line systemic antifungal for oral candidiasis
treatment[10],[19]. Fluconazole has a broad range of activity against Candida spp, is well
tolerated orally, and has a relatively high oral bioavailability[11],[12]. The majority of the
evidence for oral fluconazole in adults is with 100–200mg once per day for 7–14
days[3],[11],[19],[20],[21]. Little published evidence exists for the use of lower systemic doses
(50mg/day) for pseudomembranous Candida infection advised in the UK. However,
this controversy is generally considered moot, as the 50mg/day dose has become
established clinical practice. In initial and simple presentations of oral candidiasis, this
dose is likely sufficient; higher doses are often reserved for the more resistant strains of
Candida.

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A correlation between the pathogen minimum inhibitory concentration (MIC) and
fluconazole exposure (area under the curve) predicts clinical efficacy in the treatment of
mucosal candidiasis. Optimum efficacy is seen with a total daily dose (TDD)/MIC ratio
of greater than 100 for patients treated for oral candidiasis with concurrent HIV
infection[22]. Lower TDD/MIC ratios (>50) are acceptable in immunocompetent hosts
and elicit an acceptable clinical response[22]. The lab-based breakpoint for identifying
fluconazole-sensitive C. albicans is 2mg/L; with the majority of isolates it is 1mg/L or
less[23]. Dosing of 50mg/day is acceptable for most immunocompetent patients with C.
albicans infection. Higher doses (100mg/day or more) are advised in
immunocompromised patients or if non-albican species are identified. Bespoke dosing
(TDD = 100 x MIC value) can also be considered in high MIC pathogen infections.
C. albicans fluconazole-resistant pathogens remain fortunately uncommon in clinical
practice[24]. The impact of low-dosed fluconazole, particularly when prolonged for
Candida prophylaxis in immunocompromised hosts, on antifungal resistance is less
clear. Trends in resistance patterns are challenging owing to low numbers of patients
tested and heterogeneity of clinical presentation. Low-dose fluconazole (50mg/day) in
treatment or prophylaxis may have a role in selecting out non-albican species where
MIC values to fluconazole are typically higher. Further study is required in this area, but
oropharyngeal infection associated with non-albican Candida should be suspected in
refractory infection where first line fluconazole is unsuccessful. A swab of the oral
mucosa should be considered to aid diagnostics in identifying Candida species, and
whether this pathogen is fluconazole resistant. This will help determine if either higher
doses of fluconazole are required or an alternate agent is needed (e.g. itraconazole).

Drug Route Dose

Nystatin Topical (i.e. 1mL (100 ,000  units) four times per day for at least 7
oral days, and continued for 48 hours after lesions have
suspension) resolved[25]

Miconazole Topical (i.e. 2.5 mL four times per day times for at least 7 days
oral gel) and continued until after lesions have healed or
symptoms have cleared[26]

Fluconazole Topical (i.e. 50 mg daily given for 7–14 days in oropharyngeal
oral candidiasis (maximum 14 days, except in
suspension) severely immunocompromised patients). An
and systemic increased dose of 100 mg daily is advised for
(i.e. enteral) “unusually difficult infections”[27]

Itraconazole Systemic 100–200 mg twice daily for 2 weeks (continue for

(i.e. enteral) another 2 weeks if no response) [28]

Table 2. Licensed therapies for the treatment of oral Candida infection

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There are some discrepancies with BNF treatment strategies and that of other
international recommendations for oral candidiasis management. For example, the
Infectious Diseases Society of America (IDSA) provides comprehensive guidance on the
management of oral candidiasis that differs on dosing advice provided by the BNF[19].
Most notably, dosing of nystatin oral solution and systemic fluconazole differ, with
higher dosing advised in the IDSA guidance[10],[19].

Treatment of oesophageal candidiasis

If oesophageal infection is suspected, systemic antifungal therapy is advised. While
topical therapies are advised in the BNF, the efficacy of these therapies is less clear, and
should generally be avoided in systemically unwell patients. Oral fluconazole, 200–
400mg (3–6mg/kg) once daily, for 14–21 days, is recommended[27]. In refractory
disease, itraconazole solution (100–200mg twice daily) or voriconazole (200mg twice
daily), for 14–21 days, is recommended. In patients unable to take or tolerate oral
therapy, parenteral therapy should be considered, such as intravenous fluconazole
(400mg once daily); or an echinocandin, such as caspofungin (70mg loading dose
followed by 50mg once daily for 14–21 days) or anidulafungin (200 mg loading dose
followed by 100 mg once daily for 14–21 days)[29],[30].

Prophylaxis in high-risk patients

Providing prophylactic treatment with antifungal agents reduces the incidence of oral
candidiasis in cancer patients undergoing treatment, with fluconazole found to be more
effective than topical polyenes[1]. Prophylaxis on either a daily or weekly basis with
antifungals reduces the incidence of oral candidiasis in patients receiving chemotherapy
and radiotherapy, or in HIV patients, with the reductions being most marked in those
with low CD4 counts and recurrent oral candidiasis. Antiseptic mouthwashes alone may
be effective prophylaxis in immunocompromised hosts and will prevent azole-resistant
Candida emerging [1],[31].

Best practice recommendations

Oral candidiasis is commonly encountered in primary and secondary care, especially
in patients of extremes of ages or with concurrent immunosuppressive status. As
such it is important to consider the following:
Increasing broad-spectrum antibiotic and immunosuppressive therapies are
resulting in an increased incidence of oral Candida infections;
Oral infection requires early effective treatment and is essential to minimise
complications and patient discomfort;
In immunocompetent hosts, topical treatments are available over the counter
and provide a valuable option in non-severe infections;

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 Systemic treatment is often required for more severe infections or in
immunocompromised individuals;
Optimising dosing and treatment choices remains a key strategy for improving
patient outcomes in the presence of increasing antifungal resistance;
Pharmacists should aim to advise patients on how to prevent occurrence, but
also ensure antifungal treatment is optimised.

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Citation: The Pharmaceutical Journal, Vol 305, No 7943, online | DOI:

10.1211/PJ.2020.20208483

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