Candidiasis

Epidemiology and Microbiology

Candida infection in AIDS is almost exclusively mucosal; systemic invasion is a rare and late event.
Oropharyngeal candidiasis occurs in approximately three-quarters of all HIV-infected patients. In a third of
these individuals the infection tends to be recurrent and progressively more severe as immunodeficiency
advances. Esophageal involvement is reported in 20% to 40% of all AIDS patients; again, predominantly in
patients with advanced disease and severe depletion of CD4+ cells. It is important to recognize, as with other
opportunistic infections since the advent of HAART, the incidence of new Candida infections has decreased
by as much as 60% to 80%[1].
Key Point:
Candida infections are the most common fungal infections in AIDS; they are almost
always confined to mucosal surfaces.

Vulvo-vaginal candidiasis occurs in approximately 30% to 40% of HIV-infected women. Although HIV
infection is often cited as a risk factor for vulvo-vaginal infection, it is unclear whether vaginal candidiasis is in
fact more common in women with HIV infection when other important risk factors for vaginal infection, such
as sexual activity, and racial and ethnic background, are considered. However, it is apparent that
concomitant HIV infection influences the severity and persistence of vulvo-vaginal Candida infection.

Candida albicans is the primary causative agent of mucosal candidiasis in HIV-positive patients. It is
associated with virtually all initial episodes and approximately 75 to 90% of recurrent infections. Recently, a
related strain, C dubliniensis, has been implicated in many cases of HIV-associated infection [2]. This becomes
relevant since it appears that this strain is more likely to acquire resistance to azole antifungals, especially
fluconazole[3]. Recurrent disease is caused by the same strain of Candida in approximately half of cases; the
remaining 50% of cases are caused by new strains of C albicans or new species[4]. Other species, notably
Torulopsis glabrata and Candida parapsilosis, tend to cause infection in patients with very advanced disease
with extensive prior exposure to antifungal agents (especially the azoles). Most patients are colonized readily
with Candida which appears as part of the mouth flora in greater than 80% of HIV-positive patients [5]. The
actual defects in local immunity that predispose for progression from colonization to disease are not well
characterized. It is logical to assume that some deficiency in T cell immunity is important, as disease is
clearly more common and more severe as the CD4+ cell count falls. Additional defects in local oral clearance
mechanisms (eg, epithelial barriers, salivary flow, lysozyme and lactoferrin release) have been described in
HIV-positive patients and may be relevant to candidiasis [6]. In addition, nonspecific factors such as dental
hygiene, smoking and the use of antibacterials for prophylaxis are all recognized risk factors for oral
candidiasis and may increase the risk for specific patients.

Clinical Features

Most patients are symptomatic and may complain of some oral discomfort. Clinical manifestations include
pseudomembranous, erythematous (or atrophic), hypertrophic and angular cheilitis.
 The characteristic appearance of pseudomembranous candidiasis (also known as thrush) is a
creamy white exudative plaque (cottage-cheese-like) on the palate, tonsils, or buccal mucosa that
can be removed with a tongue depressor, with bleeding.

Figure 1. Pseudomembraneous candidiasis

  Erythematous candidiasis appears as flat, red atrophic plaques also on the mucosal surfaces.

Figure 2. Atrophic (erythematous) candidiasis

 The hypertrophic form often involves the lower surface of the tongue or the palate and buccal
mucosa and is characterized by a non-scrapable raised plaque (very similar to oral hairy
leukoplakia).

Figure 3. Hypertrophic candidiasis

 Angular cheilitis is associated with red, fissured, crusting lesions (which may ulcerate) at the corner
of the mouth. These lesions often cause pain, burning or difficulty opening the mouth.

Fungal cultures are rarely required for diagnosis; indeed, cultures can cause confusion, since many patients
are colonized with Candida. However, a scraping of a lesion will show characteristic spherical budding yeasts
and pseudohyphae when examined using potassium hydroxide (KOH) wet mount or gram stain.
 Figure 4. Candida albicans (microscopy)

Most patients with vaginal candidiasis present with vaginal itching, burning or pain and vaginal discharge.
Examination of the vaginal cavity reveals thrush, identical to that seen in the oropharynx.

Patients with esophageal candidiasis develop pseudomembranes, erosions and ulcers on the esophagus.
These individuals typically experience dysphagia. The combination of oral candidiasis and esophageal
symptoms is both specific and sensitive in predicting esophageal involvement. Patients who present in this
manner can be treated empirically with antifungal therapy. Endoscopy is usually reserved to evaluate for the
presence of other diagnoses such as herpetic or cytomegalovirus esophagitis, idiopathic ulceration, or
resistant candidiasis in those patients who fail to respond [7].

Key Point:
Patients with symptoms attributable to Candida esophagitis can usually be treated
with empiric antifungal therapy.

Treatment

A number of options, both local and systemic, are available for the treatment of oral candidiasis. (Table 1).
Initially, most patients respond well clinically to most forms of antifungal therapy, although mycologic
responses are less common. However, nystatin appears to be less effective than other treatments [8]. Many
noncomparative studies have clearly established the effectiveness of treatment of oropharyngeal candidiasis
in patients with AIDS. Clinical responses with the resolution of symptoms and signs occur in 90% to 100% of
patients generally within 7 days of initiating treatment. Mycologic responses are not usually as high and
Candida can still be cultured from the oral cavity in many patients.

Table 1: Therapeutic Options for Oral or Esophageal Candidiasis

Agent Formulation Dosage1

Nystatin Oral suspension 400-600,000 units (4-6 mL) 4 times daily
Pastille 1-2 pastilles 4 times daily
Clotrimazole Troche 10 mg (1 troche) 5 times daily
Ketoconazole Tablet 200 mg daily
400-600 mg daily2
Fluconazole Tablet 50-100 mg daily
Oral suspension 200-400 mg daily2
Itraconazole Capsule 200 mg daily
Oral suspension 100 mg (10 mL) twice daily
Amphotericin B IV infusion 0.3-0.5 mg/kg per day
Oral suspension 100 mg (1mL) 3-4 times daily
Pastilles (available in Europe, but not in the US)
1
Dosage is the usual dose for the typical patient. The average duration of therapy is 7-14 days. Individual
patients may require higher doses or more prolonged treatment.
2
Esophageal disease

Several studies have also been conducted comparing topical and systemic therapy. The clinical response
rates are generally similar with all therapeutic regimens, although signs and symptoms of disease tend to
respond more rapidly with systemic therapy. Patients treated with topical agents are less likely to have
mycologic clearance at the end of the treatment [9]. Similarly, most studies comparing systemic treatments
demonstrate results to be similar in clinical effectiveness. Response rates of 75% to 100% are generally
reported. The relapse rates with systemic therapies also appear to be equivalent. From a practical
standpoint, in patients with advanced disease, fluconazole and itraconazole may be preferable to
ketoconazole. The absorption of ketoconazole is dependent on gastric acidity, and achlorhydria can be
a problem in patients with advanced AIDS. Ketoconazole can be given with Coca-Colaý, which is
effective in providing acidic conditions in the stomach and enhancing the absorption ofketoconazole.
Itraconazole should be taken with food. The oral suspensionof itraconazole is associated with more
favorable clinical responses.

Key Point:
Both topical and systemic antifungal therapy are usually successful in mucosal
candidiasis, although symptoms tend to respond more rapidly to systemic agents.

Initial episodes of vulvo-vaginal candidiasis are managed readily with topical therapy and a large number of
agents are available[10]. In general, short courses of topical clotrimazole, miconazole or butoconazole (either
creams or suppositories) are very effective and systemic therapy is rarely needed for uncomplicated cases.
Fluconazole, given as a single dose of 150 mg, is a popular alternative.

Treatment of esophageal candidiasis requires systemic antifungal therapy. A multicenter, double-blind,

randomized study comparing fluconazole 100 mg daily and ketoconazole 200 mg daily, demonstrated a
clear-cut superiority of fluconazole in treatment of this disease [11]. Eighty-one percent of patients randomized
to fluconazole experienced resolution of symptoms, compared with 66% of patients assigned to ketoconazole
therapy. Endoscopic responses were also significantly more frequent in the fluconazole-treated patients.
More recent trials comparing fluconazole and itraconazole have found these agents to be equivalent in
activity for the treatment of Candida esophagitis[12]. Oral azole treatment may be ineffective in advanced
disease. In this circumstance, systemic amphotericin B, 20-30 mg/day for 7-14 days may be necessary.

Relapses of any form of mucosal candidiasis are common and at least one-third of patients develop recurrent
mucosal candidiasis. One approach to clinical management is to treat each episode as it occurs. However, in
many patients, recurrent symptomatic disease may be sufficiently severe to warrant consideration of chronic
suppression. Fluconazole, 100-200 mg/day, has proven very successful for the suppression recurrent
oropharyngeal disease and prevention of esophagitis [13]. A dose of 100 mg/weekly can prevent vaginal
candidiasis[14]. The major risk of this treatment approach is the possibility of developing azole-resistant
disease[15].

Key Point:
Fluconazole-resistant candidiasis is a feature of very advanced HIV infection,
occurring in patients with extensive prior exposure to fluconazole.

Prior to the use of HAART, approximately 5% to 7% of patients with advanced HIV disease developed
candidiasis that was refractory to standard fluconazole therapy. The prevalence appears to be much less
common since the introduction of HAART, although no formal data are available. The major risk factors for
the development of resistance include advanced HIV disease (CD4+ counts less than 50 cells/mm 3 and often
less than 10 cells/mm3) and extensive prior exposure to fluconazole[16,17]. Isolates are more likely to be species
other than C. albicans and tend also to be resistant in vitro, with MICs >/= 64 mcg/mL to fluconazole, in many
circumstances. Isolates with a more intermediate susceptibility have also been described [18]. The clinical
expression of disease is identical to that observed in patients with sensitive infection, but the disease tends to
be more progressive and symptomatic due to the lack of effective therapy. Thus, esophagitis is common.
Therapy for resistant Candida infection is unsatisfactory (Table 2). Improving immune function (eg, with more
potent antiretroviral therapy, if available) is often most beneficial [19]. Higher doses of fluconazole (up to 800
mg) may be effective in patients with infection caused by organisms with intermediate susceptibility; a
reasonable initial strategy may be to increase the dosage of fluconazole in patients with apparent clinical
failure to standard dosages[20]. This increased dosage is usually not effective for truly resistant strains, unless
there is a question of drug interactions or patient adherence leading to reduced serum levels. The
cyclodextrin oral suspension formulation of itraconazole has been reported to be effective in approximately
60% of cases; however, the benefit is short-lived if some form of chronic maintenance therapy is not
prescribed[21]. Amphotericin oral suspension is also effective in approximately 40% of patients; however, many
patients require parenteral amphotericin B for symptomatic control [22].

Table 2: Therapeutic options for candidiasis unresponsive to fluconazole

Agent Comment
Higher doses of fluconazole (800 May be effective for patients with Candida infections caused by
mg) organisms whose susceptibility in vitro is "intermediate" rather than
resistant
Itraconazole oral suspension Effective in approximately 50% of cases; need maintenance therapy;
breakthroughs occur
Amphotericin B oral suspension Optimal dosage unclear; need more than current labeling information
Amphotericin B parenterally 0.3 mg/kg for about 7-10 days is usually effective; but relapses off
therapy are common
Flucytosine No formal studies but may have a role as maintenance alone or
combined with fluconazole or intermittent amphotericin
Maximal antiretroviral therapy Anecdotal experience suggests many patients improve dramatically with
the introduction of more effective antiretrovirals
Case History (continued)
Symptoms and signs resolved after treatment with clotrimazole troches, and the patient
remained well for nine months. She then experienced another episode of oropharyngeal
candidiasis that again responded well to topical antifungal therapy. Her CD4+ count at
that time had declined to 94 cells/mm3. Three months later, the patient presents to the
emergency room complaining of an eight day history of fever including a five day history
of frontal headache gradually increasing in intensity. Examination reveals several small
papulo-pustular lesions on her trunk and arms that the patient had not previously noticed.
Her temperature is 39ýC. There is no neck stiffness. Neurological examination is
nonfocal, although she appears to be somewhat lethargic. A lumbar puncture reveals 18
white cells (all lymphocytes), protein 51, glucose 18. CSF cryptococcal antigen is 1:2048.
The opening pressure is 55 cms/H20. Culture was subsequently positive for C
neoformans. Her CD4+ count is 37 cells/mm3.