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Mico Nazo Le
Mico Nazo Le
10.2217/17460913.3.3.265 © 2008 Future Medicine Ltd ISSN 1746-0913 Future Microbiol. (2008) 3(3), 265–269 265
DRUG EVALUATION – Barasch & Griffin
against various fungal organisms. A recent article autoimmune disease treatments include cyto-
by Bii et al. reported that 80 clinical isolates of toxic and immune-modulating agents that affect
Cryptococcus neoformans showed greater in vitro the hematopoietic system. However, the largest
susceptibility to miconazole than to fluconazole recent increase in the immune compromised
or flucytocin [12]. A similar study that compared population can be attributed to the appearance
topical miconazole with econazole and nystatin and rapid spread of HIV and the immune
for efficacy against vaginal candidiasis also showed destruction this virus produces in infected indi-
the former two drugs to be effective and superior viduals. Despite current therapeutic advances,
to the nystatin [13]. Using a different in vitro test- HIV infection is not curable and continues to
ing method, Uchida et al. demonstrated that spread throughout the world. In this setting,
itraconazole and miconazole performed equally opportunistic fungal infections are common and
well but significantly better than fluconazole in so is resistance to available remedies [18]. Oral
killing both albicans and non-albicans Candida candidiasis is one of the most common oppor-
species [14]. tunistic infections in AIDS and its incidence
Less encouraging results were also published. increases with the viral load and decreased CD4
Paniagua et al. tested 80 C. albicans strains from cell counts [18]. While highly active antiviral
clinical sources and described 45% resistance to therapies have reduced its prevalence, candidiasis
miconazole but 100% susceptibility to ampho- remains the most common opportunistic oral
thericin B [15]. In a comparative study of Candida infection in HIV patients. This disease can have
isolates from the UK and Italy, Manfredi et al. high morbidity in immunosuppressed patients;
found significant differences in antifungal sus- thus, its prevention and treatment in HIV
ceptibility between isolates from the two geo- groups is an important goal [19].
graphic locations [16]. Susceptibility to all tested
azole compounds (including miconazole) was Oral candidiasis in HIV-infected patients
much lower in strains collected from the UK Oral candidiasis treatment in HIV-infected
than the strains from Italy. groups has been described in two systematic
The results of this latter study are consistent reviews of the literature [20,21]. Interestingly, nei-
with findings of increased microbial resistance ther of these articles mentioned miconazole.
patterns with increased use of antimicrobial Nevertheless, the articles presented current data
compounds. Development of resistance is typi- that suggest that systemic triazoles are superior
cally a multifactorial process that occurs after to topical nystatin for both clinical cure and
repeated exposure of the pathogen to a specific prevention of candidiasis. Similarly, both arti-
drug. However, resistant species can be trans- cles stated that increasing fungal resistance to
ferred through person-to-person contagion. triazoles in this patient population is worri-
Fungal resistance can occur through a variety of some. Both articles concluded that the evidence
mechanisms, including drug efflux (most com- base is generally weak and more research is
mon for azoles), alternative paths for sterol bio- required. One article that did address the effi-
synthesis, alterations in drug targets and cacy of miconazole in HIV-infected patients
reduction of concentration of the target enzyme. concluded that this drug was superior to nystatin
Yeasts, particularly the non-albicans Candida suspension for controlling oral and esophageal
species, are common offenders [17]. A number of candidiasis [22] No systemic treatments were
factors are involved in the continually increasing tested in this study.
development of microbial resistance, and their Another significant issue in the treatment of
nature and significance are beyond the scope of fungal diseases in the HIV-infected population is
this article. However, one factor in particular is the potential for drug interactions. Systemic
pertinent to the current discussion, as the inci- azoles affect the hepatic enzymes and, with
dence and morbidity of fungal infections is of them, the pharmacokinetics of other common
significance here: this factor is immune suppres- HIV medications. Topical antifungals are not
sion and the increased longevity of patients in absorbed, and thus they do not interact with
this population [17]. other medications [23]. However, due to the
flushing effect of saliva in the oral cavity, the nec-
The immune suppression connection essary drug concentration for therapeutic pur-
The current medical era is partly defined by a rel- poses is rarely achieved for adequate amounts of
atively high prevalence of immunocompromised time at this site. Thus, an even greater problem
patients. Organ transplantation, cancer and and the main cause of treatment failure with
topical agents is patient noncompliance. Most again that miconazole Lauriad was well toler-
topical antifungal agents require application to ated and as effective as the gel preparation used
the oral mucosa several times per day (four times four times per day. No other antifungals were
for miconazole and amphothericin B, five times included in this study. A similar Phase III study
for clotrimazole [24,25]) in order to achieve the in HIV-infected patients is currently ongoing.
necessary MIC for clinical cure. The taste of Miconazole Lauriad has been approved for
these topical preparations is another reason for topical use in oral candidiasis in Europe (includ-
noncompliance [24] Microbiological cure for oral ing the UK) and has a good chance of receiving
candidiasis is rarely achieved regardless of the FDA approval in the USA pending the results of
therapy [26]. the ongoing Phase III trial.
Because of these problems, prescribers often Another mucoadhesive miconazole-containing
forego topical treatment in favor of the more tablet has been developed and tested in an HIV-
comfortable, less complicated use of systemic infected population [30]. This randomized trial
azoles. Unfortunately, results of this practice compared a 10 mg once-daily miconazole tablet
included significant drug interactions and with 400 mg systemic ketoconazole also used
development of resistance, particularly to flucon- once daily. Clinical and microbiologic responses
azole [24,27]. In 1998, resistant Candida species were similar in the two groups but side effects
accounted for more than 5% of recurrences or were more common in ketoconazole patients.
oropharyngeal disease [24]. Thus, current treatment Although the noninferiority of the topical treat-
guidelines call for topical agents as the first line of ment was proven here, we note that the systemic
drugs for oral and/or pharyngeal candidiasis in treatment dosage was subtherapeutic, which may
HIV patients [23–26]. render these results invalid.
A formulation of miconazole in a 33% colla-
New miconazole formulations gen base has been tested in vitro and shown to
In an attempt to respond to the noncompliance have stronger antifungal effect than miconazole
problem, new topical antifungal formulations gel on Candida species [31]. We are not aware on
have been introduced and tested. Miconazole in any further developments of this miconazole
a 50 and 100 mg mucoadhesive tablet (micon- formulation. Last, a 0.25% miconazole
azole Lauriad®) formulated for extended release nitrate/zinc oxide ointment for diaper derma-
was initially tested in healthy volunteers [28]. titis complicated by candidiasis has shown sig-
Both concentrations were used once daily and nificant efficacy [32] and is currently the only
had significantly longer duration and higher prescription product for that purpose. This
saliva concentration than a commercially availa- preparation has not been tested for other forms
ble miconazole gel used three times per day. of fungal disease.
Importantly, the saliva concentration of micon-
azole after the administration of the Lauriad Conclusion
tablet exceeded the MIC for Candida species Fungal diseases continue to be highly prevalent
(1 ug/ml) for more than 7 h. Plasma drug and can have significant morbidity in immune
concentrations were undetectable and no signif- compromised populations. Unfortunately, the
icant adverse events were reported. This study growth of these populations is unlikely to abate
demonstrated that this new miconazole formu- soon, which will probably increase the need for
lation is capable of maintaining adequate drug antifungal medications, as well as the develop-
concentration for a prolonged period of time. ment of resistant organisms. In this setting, top-
The above report was followed by a Phase III ical formulations that overcome the limitations
study, which tested the efficacy of the new of bad taste and multiple daily applications have
miconazole formulation in 282 head and neck an important role in early treatment and control
cancer patients treated with radiation therapy of fungal overgrowth. Miconazole is a topical
[29]. Patients with clinical oral candidiasis were fungicidal medication that has multiple mecha-
assigned to either miconazole Lauriad 50 mg nisms of action. Despite its long presence on the
once daily or miconazole oral gel 500 mg four- market and common usage, relatively little fun-
times daily and examined for disease resolution gal resistance to this medication has been
after 7 and 14 days. The Lauriad preparation reported. New formulations of miconazole, such
was slightly superior (p = 0.13) to the gel, par- as the Lauriad compound, may provide a vital
ticularly in patients with multiple lesions alternative to systemic therapy in patients with
(p = 0.013). This noninferiority study showed limited disease.
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Oral Pathol. Oral Radiol. Endod. 92, administration via a bioadhesive slow release University of Alabama at Birmingham,
170–179 (2001). tablet and an oral gel to healthy male and SDB 111, 1530 3rd Avenue S
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management of oropharyngeal candidiasis 29. Bensadoun RJ, Daoud J, El Guedari B et al.: Fax: +1 205 975 0603;
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CD003940 (2006). tablets with miconazole 500-mg gel in the Postdoctoral fellow
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Evaluating diagnosis and treatment of oral and prospective, randomized, single-blind, University of Alabama at Birmingham,
esophageal candidiasis in Ugandan AIDS multicenter, comparative Phase III trial in SDB 111, 1530 3rd Avenue S
patients. Emerg. Infect. Dis. 5, 274–277 patients treated with radiotherapy for head Birmingham, AL 35294-0007, USA
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