teaser
The emergence of azole resistance, the selection of resistant Candida species, poor patient compliance associated with oral gel treatments and the high cost of echinocandins necessitates the development of new antifungal agents to treat oral candidiasis
Michael A Petrou
PHD
Department of Medical Mycology
Hammersmith Hospital
Imperial College NHS Trust
London
UK
Candida is widely distributed throughout the human population and can be found in the oral cavity of 20 to 50% of adults, and can be a simple harmless commensal or an intermittent/opportunistic pathogen. There have been reports of infections by Candida involving every tissue in the human body;
however, the commonest manifestations are superficial infections of the mucous membranes of the oral cavity and the vagina as oral and vaginal thrush. Oral thrush was recognised as a human disease by Hippocrates who described two cases of oral aphthae (circa 460-377 BC).[1] Oropharyngeal and oesophageal
candidiasis has been associated with many underlying diseases.
Oropharyngeal candidiasis may be the first manifestation of HIV infection and can occur in up to 90% of HIV-infected patients during the course of the disease.[2]
Oesophageal candidiasis, which is characterised clinically as dysphagia and retrosternal pain, occurs as a progression of oropharyngeal candidiasis, can be present with or without oropharyngeal involvement and has been reported in approximately 10-15% of patients with AIDS.[3] Unlike oropharyngeal candidiasis, oesophageal candidiasis is associated with significant morbidity and is capable of producing incapacitating illness, wasting syndrome, ulcers and erosions that might act as the focus for dissemination and painful swallowing that leads to malnutrition in infected individuals.[4,5]
Oropharyngeal candidiasis has also been a severe problem in many immunocompromised patients, such as those individuals with underlying haematological malignancy, in those with congenital cell-mediated immune dysfunction, in patients undergoing radiotherapy or surgery for cancer, particularly laryngectomy and head and neck and following solid organ transplantation or prolonged antimicrobial therapy.[6-9]
Candida species
Candida albicans accounts for approximately 70-80% of oral isolates recovered from non-HIV-infected individuals, while C. glabrata and C. tropicalis account for approximately 5-8% each, and the other non-albicans Candida species are recovered only rarely.[10] C. albicans is the species most often implicated in oropharyngeal/oesophageal candidiasis, consistently accounting for 90% or more of baseline isolates.[5,11,12] Over the years
there has been a significant increase in the frequency of non-albicans Candida species, particularly in the HIV-infected individual and other groups of patients on prophylaxis. In our laboratory recovery of mixed species, particularly C. albicans with C. glabrata and C. krusei from the oral cavity of HIV patients, was a common occurrence, as was the recovery of only the latter two species after fluconazole treatment. In the 1980s, non-albicans Candida species accounted for 3-4% of oral isolates recovered from HIV-infected patients, while in the 1990s, 17% of isolates recovered from HIV patients were non-albicans Candida species, and this was a direct result of either prophylaxis or treatment with fluconazole.[13,14] A shift from fluconazole-sensitive C. albicans to fluconazole-resistant
C. glabrata has also been seen in our hospital in critically ill patients in ICU or post-transplant, particularly in renal and other patients who are usually given fluconazole prophylaxis.
Drug resistance
The emergence of azole resistance, particularly to fluconazole, and the selection of resistant species such as C. krusei and C. glabrata heightened the need for development of new antifungal agents with different targets or with better delivery to the site of infection, thus reducing the possibility of cross-resistance.
It is important to start appropriate treatment once diagnosis is confirmed, unfortunately, despite initially successfully treating oropharyngeal candidiasis in the absence of immune reconstitution, the majority of patients with AIDS will eventually develop a recurrence.[15] The obvious reason for clinical failures and recurrence is the formation of biofilms during infection and the inability of antifungal drugs to penetrate down to the core where the Candida cells are in a dormant state, thus never really eradicating the infection. After treatment these dormant cells will slowly reform the biofilms and reinfect the same areas. It is necessary, therefore, for antifungal drugs that can either penetrate to the core of the Candida mass, as seen in vitro
with echinocandins, or can adhere firmly to the cells rendering them incapable of regrowth. Dormant or non-growing cells, due to drug action in the oral cavity or the oesophagus, will be washed by saliva, food and drink or gradually shed, preventing reinfection.
Current treatment
Current treatment includes both topical and systemic drugs as shown in Table 1. Further to the topical polyene antifungal drugs amphotericin B, nystatin and topical azoles, several systemic antifungal agents have also been used for the treatment of oropharyngeal and oesophageal candidiasis. First was the orally bioavailable ketoconazole, followed by fluconazole, itraconazole, voriconazole and posaconazole, and the three
intravenously administered echinocandins caspofungin, anidulafungin and micafungin.
Polyene, clotrimazole and miconazole oral gel treatment, though relatively effective and inexpensive, is frequently problematic due to patient tolerance and compliance. Patients either refuse to take the drug or skip several doses resulting in clinical failure. The taste of these preparations, in particular the itraconazole
solution, is unpleasant and many patients refuse to take them (non-compliance).
All three echinocandins have been approved in the USA for the treatment of candida oesophagitis but only micafungin is licensed in the EU. All three have demonstrated excellent efficacy in clinical trials at different concentrations or using amphotericin B or fluconazole as comparators.[16] High relapse rates observed for the echinocandins and the very high costs involved when compared to fluconazole, as well as the fact that the echinocandins can only be administered intravenously, will limit their use to refractory cases or for patients where other agents cannot be used.
HIV-positive patients
As mentioned above, while topical agents may be used for oropharyngeal candidiasis, they have proved ineffective for oesophageal candidiasis. Numerous antifungal agents are available for the treatment of oropharyngeal candidiasis, however, several factors must be considered when choosing antifungal agents for patients with HIV or AIDS. One important factor is efficacy and another is drug interactions. In HIV-positive patients, antifungals are less efficacious than in
patients with cancer, time to antifungal response is also more prolonged, and the relapse rate is higher in patients with HIV than in other patient populations.[17,18] Therefore, certain predisposed HIV-positive patients will experience recurrent episodes of oropharyngeal candidiasis and subsequently receive numerous courses of antifungals during their lifetime. As their disease progresses, they experience shorter intervals between episodes of oropharyngeal candidiasis and oesophageal candidiasis and thus more antifungal exposure, which may lead to antifungal resistance or selection of resistant species and severe morbidity.[19] There is a need, therefore, for an agent (preferably topical) that will not interfere with the treatment for
the underlying disease and which is active against all known Candida species involved in oropharyngeal and oesophageal candidiasis. Miconazole is one such drug.
Miconazole
Miconazole is a white crystalline powder that is soluble only in solvents. It was discovered in 1969 by Godefroi et al.[20] and was the second imidazole derivative to be tested against fungal pathogens and used in clinical practice both topically and systemically to treat fungal infections. Miconazole in vitro inhibits the growth of most yeasts implicated in infection as
well as dermatophytes, which are the agents of most superficial mycoses. Very low concentrations of the drug are needed to inhibit the growth of most yeasts including C. glabrata and other Candida species with elevated minimum inhibitory concentrations (MICs) to fluconazole.[21]
It has been shown that at high concentration miconazole
affects the membrane permeability that can lead to the death of susceptible organisms and can also prevent formation of hyphae (Germ tubes) in C. albicans, which is considered to be the first step of tissue invasion by this organism.[22,23] It has been shown that miconazole causes oxidative damage and death of
fungal cells due to accumulation of drug-induced reactive oxygen species.[24,25]
In an attempt to respond to the non-compliance seen with the other topical drugs and to avoid unnecessary exposure to drug side effects, a new mucoadhesive tablet containing miconazole was tested in healthy volunteers.[26] Miconazole was used at 50mg and 100mg daily, and the mucoadhesive tablet has shown significantly longer duration and higher saliva concentrations of miconazole than has the oral gel. Saliva concentrations exceeded those required to inhibit the growth
of most Candida species and remain above the MIC levels for >7 hours. More importantly, the plasma concentrations of miconazole were undetectable, thus dispensing with the undesirable effects associated with systemically administered or orally bioavailable azoles.
A further phase III study tested the efficacy of the miconazole mucoadhesive tablet once daily which was compared to miconazole oral gel four times daily in 282 patients with head and neck cancer who were treated with radiation.[27] The mucoadhesive preparation was found to be slightly superior (p=0.13) to the oral gel, particularly in those patients with multiple lesions. A similar phase III study in patients with HIV is currently ongoing.
The miconazole mucoadhesive tablet is approved in Europe as Loramyc for topical treatment of oral candidiasis and it is recommended as the first line drug for the treatment of oral candidiasis in the 2007 HIV/AIDS treatment and care clinical protocols for the WHO European region and will be considered by the FDA once the data from the ongoing phase III trial are
ready.[28]
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