Candidiasis is caused by fungi of the Candida species that encompasses infections ranging from non-life-threatening mucocutaneous disorders to invasive diseases involving any organ system. Candida species represents a common human commensal on the skin and mucous membranes. Such colonisation does not otherwise cause infection in healthy persons unless the host defense mechanisms are impaired. Cell-mediated immunity, especially by Type 1 T helper cells is considered to be the predominant host defense mechanism against candidiasis in HIV-infected patients. Deficiencies in other components of innate and humoral immunity in the immune system, may also play a role in increasing the risk of invasive candidiasis in HIV/AIDS.
The incidence of mucosal candidiasis has declined since the introduction of antiretroviral therapy in the 1990s. However, oral candidiasis is still commonly seen in HIV-infected patients. The reported frequency of oral candidiasis in HIV-infected adults ranged from 5.8 to 98.3%. The carriage rate of oral yeasts in HIV-infected males in Hong Kong was reported to be 54.8%, with Candida albicans representing most of all yeasts isolated from the oral cavity. With increasing antifungal use, non-albicans species with different antimicrobial susceptibilities has become more commonly found. For example, C. glabrata and C. krusei are associated with reduced susceptibility to the commonly used azoles.
Clinical manifestations and diagnosis
Most of the infections associated with Candida in HIV patients are confined to the mucosal surfaces. Systemic candidiasis and candidaemia are not commonly seen. This section describes the clinical presentations and diagnosis of oropharyngeal, oesophageal, vulvovaginal candidiasis and candidaemia.
There are four distinct clinical types of oral candidiasis in HIV infection, namely pseudomembranous candidiasis (commonly known as “thrush”), erythematous candidiasis, angular cheilitis, hyperplastic candidiasis. The pseudomembranous and erythematous forms are most commonly seen in AIDS.
- Pseudomembranous candidiasis presents as a semi-adherent, whitish yellow, soft and creamy or sometimes confluent membranes caused by overgrowth of fungal hyphae mixed with desquamated epithelium and inflammatory cells. It can occur anywhere on the oral mucosa including the tongue, hard palate, soft palate and buccal mucosa. The lesions have an erythematous base after removal by scraping. Patients usually present with sore mouth or pain with swallowing.
- Erythematous candidiasis presents as a red, flat, subtle lesion most frequently affecting the hard or soft palates, buccal mucosa, and the dorsum of the tongue.
- Angular cheilitis, also known as angular stomatitis or perleche, is an erythematous fissuring at one or both angles of the mouth, with or without ulceration.
- The least commonly seen hyperplastic candidiasis is due to hyperkeratosis and appears as white and hyperplastic areas, which cannot be removed by scraping.
For oesophageal candidiasis, patients are usually symptomatic with dysphagia and odynophagia. Chest pain may also be present. Severe symptoms can lead to difficulty in swallowing. In oesophageal candidiasis, the epithelial lining is coated by a pseudomembrane consisting of yeasts, epithelia cells, leukocytes and necrotic debris. Oesophageal candidiasis is an AIDS-defining illness (ADI).
The diagnosis of oral candidiasis is usually based on typical clinical features; and rarely a confirmation by potassium hydroxide slide preparation of a scraping may be needed. Culture is usually not necessary unless improvement is not seen with appropriate antifungal therapy. The differential diagnosis of oropharyngeal candidiasis includes oral hairy leukoplakia, Kaposi’s sarcoma (KS) and rarely, lymphoma.
A therapeutic trial with fluconazole for patients with presumptive diagnosis of oesophageal candidiasis without endoscopic confirmation is a reasonable approach. In cases where empirical antifungal therapy does not improve symptoms then an endoscopic examination is warranted to rule out other differential diagnoses such as infections caused by cytomegalovirus or herpes simplex.
Vulvovaginal candidiasis is a common clinical condition in women even in the absence of HIV infection. Patients generally present with itching, vaginal discharge, vaginal erythema with adherent whitish discharge, dyspareunia, dysuria, and erythema and swelling of the labia and vulva. A diagnosis can be confirmed by wet mount preparation with the use of saline and 10% potassium hydroxide to demonstrate the presence of yeast or hyphae. A fungal culture should only be obtained if a patient fails to respond to appropriate antifungal therapy to determine if resistance is present.
Disseminated candidiasis or candidaemia is rarely seen in HIV infection. It is most often a hospital-acquired infection in patients with advanced immunosuppression. Involvement of the eyes (endophthalmitis), central nervous system (meningitis, encephalitis), and heart (endocarditis) are well described but again rare in HIV infection. Diagnosis of these infections are usually by positive culture from blood or sterile sites together with compatible clinical features.
Treatment of candidiasis
Both local and systemic antifungal agents are used for the treatment of candidiasis. In recent years, a number of newer antifungal agents have become available as alternatives in the treatment of candidiasis including non-albicans species. The four major categories of antifungal therapy are the polyenes, the triazoles, the echinocandins, and flucytosine. The following discussion regarding antifungal therapy is focused on agents available for clinical use in Hong Kong.
The polyene group includes the commonly used amphotericin B deoxycholate (AmB-d), lipid formulation amphotericin B (LFAmB) and nystatin. Amphotericin B has been the mainstay of antifungal therapy for decades but its use in Candida infections is limited by its toxicities and the presence of better alternatives from the triazole group. Nephrotoxicity is the commonest serious adverse effect associated with amphotericin B therapy, resulting in acute renal failure in up to 50% of AmB-d recipients. LFAmB is considerably more expensive and less readily available, but it is less nephrotoxic compared to AmB-d. LFAmB has not been shown to be superior to AmB-d otherwise in the treatment of candidiasis.
The triazole group includes fluconazole, itraconazole, voriconazole, and posaconazole. They inhibit ergosterol synthesis resulting in the disruption of fungal cell membrane. All compounds demonstrate similar activity against most Candida species except C. glabrata and C. krusei, which they are less active against. A loading dose is generally required for azoles if rapid action is required. Fluconazole is well tolerated and effective in many forms of candidiasis. It is readily absorbed with very good oral bioavailability resulting in concentrations equal to ~90% of those achieved by intravenous administration. Its absorption is not affected by food consumption and gastric acidity. Dose adjustment is required in renal impairment, and as a CYP450 inhibitor fluconazole may interact with antiretroviral drugs.
Itraconazole is generally reserved for patients with mucosal candidiasis as it may be useful in fluconazole-refractory disease since azole cross-resistance is not universal. However, blood concentrations vary widely in patients receiving itraconazole. Serum concentrations are about 30% higher when the solution is used compared to the capsule form. Itraconazole capsule is still an acceptable option if the solution form is not available. It is noted that administration of the capsule formulation with food increases absorption, whereas the oral solution is better absorbed on an empty stomach. Itraconazole has a similar side effect profile as fluconazole but drug interactions are more frequent. Voriconazole is effective for both mucosal and invasive candidiasis. In many aspects it is comparable to fluconazole but is more expensive and has more drug-drug interactions (DDI) and side effects. Its use in candidiasis has been for infections with C. krusei and fluconazole-resistant C. glabrata. Voriconazole has significant interactions with efavirenz (EFV), ritonavir, and rifampicin. Posaconazole is not commonly used for the primary therapy of candidiasis.
The echinocandin group is a new class of antifungal agents which includes caspofungin, anidulafungin, and micafungin. The minimum inhibitory concentration (MIC) of the echinocandins is low for a broad spectrum of Candida species, including the often azole-resistant C. glabrata and C. krusei. C. parapsilosis may be less susceptible to the echinocandins based on the demonstration of lower in vitro susceptibility compared to other Candida species. The three available echinocandins are considered to be of similar efficacy and proven to be useful in the treatment of esophageal and invasive candidiasis. While echinocandins have fewer adverse effects, their use may be limited by their intravenous route of administration, costs and availability.
Flucytosine demonstrates broad antifungal activity against most Candida species, with the exception of C. krusei. It is usually given in combination with amphotericin B in the treatment of invasive diseases such as Candida endocarditis or meningitis.
Of the above-mentioned antifungal agents, itraconazole and voriconazole are known to have variable serum concentrations in clinical use, especially in the presence of interacting drugs, resulting in both subtherapeutic and toxic levels. If available, therapeutic drug monitoring (TDM) may be useful in situations when the two antifungals are used for prolonged duration, and especially when potential DDI are anticipated. Antifungal susceptibility testing might be useful to guide the management of candidiasis when there is suspicion of drug resistance and/or failure to respond to initial antifungal therapy. In Hong Kong, antifungal susceptibility testing is currently not routinely performed and is available in only a few laboratories, while TDM for antifungals are not routinely available.
Management of specific conditions [Algorithm 19]
Oropharyngeal and oesophageal candidiasis
For oropharyngeal candidiasis, most patients respond initially to topical therapy. One of the reasons may be the uncommon practice of azole prophylaxis, and therefore a lower chance for the emergence of azole-resistant strains. For mild disease, clotrimazole troches, 10mg 5 times daily, OR miconazole 50 mg mucoadhesive buccal tablet applied to the mucosal surface over the canine fossa once daily for 7-14 days, are recommended. For moderate to severe disease, oral fluconazole 100-200mg daily for 7-14 days is recommended. For fluconazole-refractory disease, itraconazole solution 200mg daily can be tried initially as most patients respond to this therapy. Alternatives include voriconazole 200mg twice daily, posaconazole 400mg daily, AmB-d 0.3mg/kg or one of the echinocandins but these are rarely required. Chronic suppressive therapy is usually not necessary as recurrent infections typically occur in patients with ongoing immunosuppression without effective antiretroviral therapy. If suppressive therapy is required, fluconazole 100mg 3 times weekly is recommended. Continuous suppressive therapy is more effective than intermittent therapy for reducing the relapse rate, but there is a higher chance for drug resistance to develop.
For oesophageal candidiasis, oral fluconazole 200-400mg daily for 14-21 days is recommended. For patients who cannot tolerate oral therapy, intravenous fluconazole 400mg daily, AmB-d 0.3-0.7mg/kg daily or an echinocandin could be used instead. For fluconazole-refractory disease, alternatives are the same as for oropharyngeal candidiasis with the use of itraconazole, voriconazole, posaconazole, echinocandin or AmB-d 0.3-0.7mg/kg daily but for a longer duration of 14-21 days. Fluconazole 100-200mg 3 times weekly is recommended if chronic suppressive therapy of recurrent disease is required.
Treatment is the same as for HIV-negative patients as identical response rates are anticipated. Topical antifungal agents (vaginal tablets with clotrimazole, isoconazole or nystatin) are effective for uncomplicated vulvovaginal candidiasis. Alternatively, oral fluconazole 150mg as a single dose is also very effective. In complicated cases topical therapy can be administered intravaginally daily for more than 7 days or oral therapy with two to three 150mg doses of fluconazole every 72 hours. For recurrent disease, prolonged therapy with oral fluconazole followed by long-term prophylaxis at 150mg once per week may be required.
In conjunction with definitive antifungal therapy, removal of a causative intravascular catheter and evaluation for metastatic disease (ophthalmologic evaluation, echocardiography) should be pursued in candidaemia. Echinocandin is recommended as the initial therapy for candidaemia. Transition to fluconazole can be considered when the patient is clinically stable and when isolates show susceptibility to fluconazole (e.g. C. albicans). The recommended duration of therapy for candidaemia without obvious metastatic complications is 2 weeks after documented clearance of Candida from the bloodstream and resolution of symptoms attributable to candidaemia.
Issues of special interest
The incidence and prevalence of opportunistic infections including candidiasis has declined over the years ever since the availability of combination antiretroviral therapy. It is not surprising as antiretroviral therapy is able to effectively restore immunity against invasive candidiasis. The presence of oropharyngeal candidiasis, oesophageal candidiasis and candidaemia indicates progressive immune deficiency and should prompt the institution of antiretroviral therapy after confirmation of a low CD4 count. Other issues relating to candidiasis in HIV/AIDS are discussed below.
Isolation of Candida in respiratory specimens
A positive culture from respiratory secretions is frequently used as an indication to initiate antifungal therapy in febrile patients who have no other evidence of invasive disease. In fact, Candida pneumonia and lung abscess are rare in HIV infected patients and reported cases are usually terminal manifestations of disseminated infection. On the contrary, colonisation of the airway with Candida species and/or contamination of the respiratory secretions with oropharyngeal materials are extremely common. It must be noted that the growth of Candida from respiratory secretions rarely indicates invasive candidiasis and should not be the sole basis for starting antifungal therapy.
Drug interactions with antifungals
Antifungals commonly used in the treatment of candidiasis include fluconazole, itraconazole, voriconazole and the echinocandins. Concomitant use of these drugs together with commonly used antiretroviral therapy should be cautioned because of frequent DDI. Itraconazole and voriconazole in particular have the most frequent interactions noted. Amphotericin B and flucytosine are so far the safest compounds in terms of DDI. In the management of candidiasis, it would be prudent to check for any potential DDI before institution of antifungal therapy, followed by the avoidance of certain combinations and/or adjustment of dosages accordingly. With the advent of integrase inhibitors (INSTI) this is less of a concern compared to when only non-nucleoside reverse-transcriptase inhibitors (NNRTI) and protease inhibitors (PI) are available as the third drug in combination antiretroviral therapy.
Algorithm 19. Management of candidiasis in HIV infected patients
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