Oral Antifungal Agents Research Articles

Review on dermatomycosis: pathogenesis and treatment

Dermatophytes, a group of keratinophilic fungi thriving on the keratin substrate are the etio-logical agents responsible for causing cutaneous infections. Dermatophytosis is currently treated with the commercially available topical and oral antifungal agents in spite of the existing side effects. Treatment of these cutaneous infections with secondary metabolites produced by marine microorganisms is considered as a novel approach. For many years these organisms have been explored with the view of developing antibacterial, antifungal, antiviral, anti- cancer and antiparasitic drugs. Exploring the unexplored aspect of actinobacteria for developing antidermatophytic drugs is a novel attempt which needs further investigation.

Aspergillus fumigatus Scleritis Associated with Monoclonal Gammopathy of Undetermined Significance

A 68-year-old woman presented with pain in her left eye. Necrosis with calcium plaques was observed on the medial part of the sclera. Aspergillus fumigatus was isolated from the culture of the necrotic area. On systemic work-up including serum and urine electrophoresis studies, the serum monoclonal protein of immunoglobulin G was detected. The patient was diagnosed with monoclonal gammopathy of undetermined significance and fungal scleritis. Despite intensive treatment with topical and oral antifungal agents, scleral inflammation and ulceration progressed, and scleral perforation and endophthalmitis developed. Debridement, antifungal irrigation, and tectonic scleral grafting were performed. The patient underwent a combined pars plana vitrectomy with an intravitreal injection of an antifungal agent. However, scleral and intraocular inflammation progressed, and the eye was enucleated. Aspergillus fumigatus was isolated from the cultures of the eviscerated materials. Giemsa staining of the excised sclera showed numerous fungal hyphae.

Monthly Itraconazole Versus Classic Homeopathy for the Treatment of Recurrent Vulvovaginal Candidiasis

When used to treat acute infections of vulvovaginal candidiasis as well as maintenance therapy to prevent recurrence, oral or topical antifungal agents of the azole group lower the incidence of and cure most of the infections. Cessation of maintenance treatment, however, results in recurrent vulvovaginal candidiasis (RVVC) within 6 months in about 50% of women. Classic homeopathy (CH) is a widely used controversial alternative treatment for RVVC, but there is little objective data demonstrating its effectiveness. Two previous studies reported that oral and intravaginal administration of Lactobacillus acidophilus in women with RVVC was associated with some subjective and objective improvements. This prospective, single center, randomized trial was a 12-month study that compared the effectiveness of monthly cycle-dependent itraconazole with and without lactobacilli and CH in reducing the frequency of clinical episodes of RVVC in 150 women with prior episodes. Patients positive for Candida albicans were randomly assigned to receive either itraconazole/lactobacilli (group 1), itraconazole monotherapy (group 2), or CH alone (group 3). Induction therapy for an acute infection for both group 1 and 2 patients consisted of single-day doses of itraconazole 200 mg b.i.d. This dose was continued during 6 months of maintenance therapy in groups 1 and 2; additionally, group 1 patients were given a suppository containing lactobacilli intravaginally. The women in groups 1 and 2 received no further treatment. Group 3 patients were treated using a single homeopathic remedy during the entire 12 months. Patients' RVVC related-complaints and their level of satisfaction with therapy was evaluated using a visual analogue scale. The absence of vulvovaginal candidiasis in vaginal culture was achieved significantly earlier among women in groups 1 and 2 than those in group 3 (log-rank test; P < 0.0001). Following induction therapy before the start of the maintenance regimen, 40 of 47 women (85%) in group 1 and 44 of 49 women (89.8%) in group 2 were free of Candida detectable in culture. Women in group 3 had a recurrence of the infection significantly earlier than women in the both groups 1 and 2 (log-rank test; P = 0.002). At 12 months, 78% (18/23) of the women in group 1, 76%, (19/25) of those in group 2, and 39% (9/29) of those in group 3 were free of Candida in culture. The level of discomfort from RVVC and dissatisfaction with therapy was significantly higher among women in group 3 than those in groups 1 and 2 (P < 0.001). These findings are consistent with other earlier studies showing that itraconazole is more effective for treatment of RVVC than classic homeopathy. There was no added benefit with lactobacilli.

Posaconazole

Posaconazole is a novel second-generation Triazole oral antifungal agent. It is highly effective in the prophylaxis of invasive fungal infections in immunocompromised patients. It is used as a first-line agent as well as for salvage therapy in invasive fungal infections including aspergillosis, oropharyngeal and esophageal candidiasis. It has a good adverse effect profile. With the rising incidence of invasive fungal infections due to the HIV pandemic and medical advancements in transplantation and cancer therapy, these features make posaconazole a valuable addition in the family of antifungal agents.

Annular Lupus Vulgaris Mimicking Tinea Cruris

Cutaneous tuberculosis is an infrequent form of extrapulmonary tuberculosis. It is often clinically and histopathologically confused with various cutaneous disorders. A 36-year-old man attended our clinic with slowly progressive, asymptomatic, annular skin lesions on both the thighs and buttocks for 10 years. He consulted with many physicians and was improperly treated with an oral antifungal agent for several months under the diagnosis of tinea cruris, but no resolution of his condition was observed. A diagnosis of lupus vulgaris was made based on the histopathologic examination and the polymerase chain reaction assay. Anti-tuberculosis therapy was administered and the lesions started to regress.

Successful Nonoperative Management of Gastrointestinal Mucormycosis: Novel Therapy for Invasive Disease

Invasive opportunistic fungal infections caused by agents of Mucorales that involve the gastrointestinal tract are uncommon but aggressive. These ubiquitous fungal spores typically are inhaled and can germinate in immunocompromised hosts. Standard therapy for invasive mucormycosis includes parenteral amphotericin B (AMB) in combination with radical debridement of infected tissues. Early diagnosis and treatment are of paramount importance. Unfortunately, long-term survival is poor owing to the prohibitive morbidity and mortality rates associated with the medical and surgical therapies. Posaconazole is a novel, extended-spectrum triazole oral antifungal agent with documented success in the treatment of patients with invasive mucormycosis. Case report and literature review. A 50-year-old man presented with invasive mucormycosis of the lower esophagus, stomach, and liver, resulting in gastrointestinal hemorrhage. The infection did not respond to AMB but was treated successfully with a combination of posaconazole and liposomal AMB (LAMB) without surgical debridement. To our knowledge, this is the first reported case of extensive gastric and intrahepatic mucormycosis that responded to combination posaconazole and LAMB without surgical debridement. This approach may be an alternative to surgery in patients who are precluded from extensive surgical intervention.

Efficacy of Fluconazole for the Treatment of Onychomycosis

To evaluate the efficacy of fluconazole for the treatment of onychomycosis. Searches of MEDLINE (1966-May 2009) and International Pharmaceutical Abstracts (1970-May 2009) were performed. Key search terms included fluconazole and onychomycosis. In addition, reference citations from identified publications were reviewed. All articles in English identified from the data sources were evaluated. All studies evaluating oral fluconazole for the treatment of onychomycosis were included in the review. Seven studies evaluating fluconazole treatment for onychomycosis were identified. One study used daily dosing and the rest used once-weekly dosing. Treatment doses ranged from 100 mg to 450 mg weekly and 150 mg daily, and durations ranged from 12 weeks to 12 months. Most of the studies evaluated the efficacy of fluconazole in patients with toenail onychomycosis due to dermatophyte infection. Fluconazole was superior to placebo, with mycologic eradication rates ranging from 36% to 100% in placebo-controlled studies. In one of the comparative studies, the mycologic cure rate was lower with fluconazole (31.2%) compared with terbinafine (75%) and itraconazole (61.1%). Common adverse events reported with fluconazole use were headache, gastrointestinal pain, and diarrhea. Fluconazole is less effective than terbinafine and itraconazole in the treatment of onychomycosis. However, fluconazole may be preferred in patients unable to tolerate other oral antifungal agents due to the dosing regimen, adverse effect profile, and drug interactions.

Physicochemical characterization of terbinafine-cyclodextrin complexes in solution and in the solid state

Terbinafine (TB) is an allylamine derivative used as oral and topical antifungal agent. The physicochemical properties of the complexes between TB and different cyclodextrins (CDs): α-CD, β-CD, hydroxypropylβ-CD, methylβ-CD and γ-CD, have been studied in pH 12 aqueous solutions at 25 °C and in the solid state. Different phase solubility profiles of TB in the presence of CDs have been obtained: AL type for TB with hydroxypropylβ-CD and γ-CD, AP type for the complexes with methylβ-CD and α-CD, while a BS profile was found for TB-β-CD. The apparent stability constants of the complexes were calculated at 25 °C from the phase solubility diagrams. The higher increase of TB solubility, up to 200-fold, together with the higher value of the stability constant were found for the complex with methylβ-CD. Solid systems of 1:1 drug:CD molar ratio were prepared and characterised using X-ray diffraction patterns, thermal analysis and FTIR spectroscopy. The coevaporation method can be considered the best method in preparing these solid complexes. The complexes of TB with natural CDs, except with α-CD, were crystalline, whereas the methyl and hydroxypropyl derivatives gave rise to amorphous phases. Dissolution rate studies have been performed with TB-β-CD and TB-HPβ-CD complexes, showing a positive influence of complexation on the drug dissolution.

Antifungal treatment and chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is an inflammatory disease with a multifactorial etiology. Antifungal therapy is not routinely used to treat it. However, evidence implicating fungi in some forms of CRS recently has been published. Controversy exists as to whether fungi identified in sinonasal cultures are always pathogenic. Immunologic evidence supporting the role of fungi in the pathogenesis of CRS is also debated. Topical antifungal therapy is more widely used than oral therapy, with amphotericin B irrigation being the most common. Although some studies show benefit from this irrigation, others refute the efficacy. Although oral antifungal agents are used uncommonly, itraconazole is the most commonly used drug. The efficacy of oral itraconazole in CRS has never been assessed in a clinical trial. Given the current evidence, the use of antifungals to treat CRS is controversial and has limited indications.

PHARMACOLOGY AND THERAPEUTICS: Onychomycosis in Children: Prevalence and Management

: Onychomycosis in children is often accompanied by tinea pedis and a family history of onychomycosis. The prevalence of onychomycosis in children is substantially lower than that of adults; therefore it is important to confirm the clinical diagnosis. The most common presentation of onychomycosis is the distal and lateral subungual type. The organism most commonly isolated in North America is Trichophyton rubrum. Oral antifungal therapy is required, especially when the onychomycosis is of moderate to severe intensity, with nail matrix involvement. The new oral antifungal agents itraconazole, terbinafine, and fluconazole are being increasingly used for the treatment of onychomycosis. Review of the literature suggests that these agents are effective and safe in managing onychomycosis in children. The short duration of therapy required with these drugs should help improve compliance. The data suggest that the new oral antifungal agents have a role in the treatment of onychomycosis in children. Further experience will help us better position these drugs when evaluating the management of onychomycosis in children.

Voriconazole-Induced Phototoxicity Masquerading as Chronic Graft-versus-Host Disease of the Skin in Allogeneic Hematopoietic Cell Transplant Recipients

Systemic fungal infections pose a significant risk to patients following allogeneic hematopoietic cell transplantation (alloHCT). Voriconazole (Vfend ®, Pfizer) is an oral second-generation triazole antifungal agent that offers a broad spectrum of coverage against fungal species and is frequently utilized in the post-HCT setting. Herein, we describe 5 patients who were initially believed to be experiencing a flare of cutaneous chronic graft-versus-host disease (cGVHD), but who were actually exhibiting phototoxicity caused by voriconazole. A high index of suspicion for this adverse reaction in the post-alloHCT setting will prevent misdiagnosis and avoid inappropriate therapy for cGVHD.

Posaconazole: A new oral antifungal agent with an expanded spectrum of activity

The pharmacology, pharmacokinetics, pharmacodynamics, spectrum of activity and resistance, clinical utility, adverse effects, dosage and administration, and recommended monitoring of posaconazole are reviewed. Posaconazole is a member of the azole class of antifungals recently approved for the prophylaxis and treatment of invasive fungal infections. Posaconazole has a large volume of distribution and distributes well into tissues. Posaconazole-induced fungal killing is optimal when peak drug concentrations achieved are 2-10 times the organism's minimum inhibitory concentration. Posaconazole demonstrates fungistatic activity against most species of Candida, Cryptococcus, and Trichosporon. In a direct comparison, posaconazole appeared 2-4 times more active than itraconazole against most pathogenic yeast species. Posaconazole also showed activity against Candida and Aspergillus isolates resistant to the other azoles and amphotericin B. Posaconazole has superior activity to the other azoles against Zygomycetes isolates. It has demonstrated activity equal or superior to other antifungal agents against almost all varieties of yeast and mold. The most common treatment-related adverse events associated with posaconazole are nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and abnormal liver function test values. Significant drug interactions include cimetidine, rifabutin, and phenytoin, for which concomitant use should be avoided, as well as cyclosporine, tacrolimus, and midazolam, for which dosage reductions are recommended. Posaconazole is an oral anti-fungal agent with a broader spectrum of activity and better clinical efficacy than other available antifungals. It is less nephrotoxic than the polyenes and probably less likely to be involved in drug-drug interactions than the mold-active azoles.

In vitropharmacodynamic characteristics of griseofulvin against dermatophyte isolates ofTrichophyton tonsuransfrom tinea capitis patients

Tinea capitis is the most commonly observed fungal infection in childhood and is primarily caused by the dermatophyte species Trichophyton tonsurans, Microsporum canis, and Trichophyton violaceum. In North America and the United Kingdom T. tonsurans is responsible for more than 90% of cases. Griseofulvin has been the treatment of choice for tinea capitis for more than 40 years and is the sole oral antifungal agent approved by the FDA for the management of tinea capitis. Some researchers have expressed concern about the possibility of emerging resistance in tinea capitis isolates, especially when there is clinical failure to treatment. A total of 151 isolates of T. tonsurans (142), M. canis (7), and T. violaceum (2) collected from tinea capitis patients were evaluated for their susceptibility to griseofulvin using the CLSI M38-A method. MIC ranges and geometric means in parenthesis were observed for T. tonsurans 0.125-16 microg/ml (1.1 microg/ml), M. canis 0.25-2 microg/ml (0.61 microg/ml), and T. violaceum 2-4 microg/ml (2.82 microg/ml), respectively. In a time kill assay with T. tonsurans UAMH 9334, 50% and 90% reduction was observed in the number of colony forming units with >2x MIC after 6 h and 12 h of exposure to the griseofulvin, respectively. Of 142 T. tonsurans isolates studied, only three could grow on SDA containing 4 times to their griseofulvin MIC, representing resistance frequencies of 1.3 x 10(-6), 6.9 x 10(-7), and 9.7 x 10(-7). Furthermore a two-fold increase in MIC was observed in isolates collected at two time intervals in only one of eight patients. Interestingly, these isolates did not show the same increase in their in vitro resistance as exhibited by the three isolated mentioned above. In light of this data, we could not confirm any correlation between increased MIC and therapy failure.

Griseofulvin, an oral antifungal agent, suppresses hepatitis C virus replication in vitro

Hepatitis C virus (HCV), which infects an estimated 170 million people worldwide, is a major cause of chronic liver disease. The current standard therapy for chronic hepatitis C is based on pegylated interferon (IFN)alpha in combination with ribavirin. However, the success rate remains at approximately 50%. Therefore, alternative agents are needed for the treatment of HCV infection. Using an HCV-1b subgenomic replicon cell culture system (Huh7/Rep-Feo), we found that griseofulvin, an oral antifungal agent, suppressed HCV-RNA replication and protein expression in a dose-dependent manner. We also found that griseofulvin suppressed the replication of infectious HCV JFH-1. A combination of IFNalpha and griseofulvin exhibited a synergistic inhibitory effect in Huh7/Rep-Feo cells. We found that griseofulvin blocked the cell cycle at the G(2)/M phase in the HCV subgenomic replicon cells, but did not inhibit HCV internal ribosome entry site-dependent translation. Our results suggest that griseofulvin may represent a new approach to the development of a novel therapy for HCV infection.

The mold conundrum in chronic rhinosinusitis: Where do we stand today?

Chronic rhinosinusitis (CRS) is an inflammatory disorder affecting the nose and paranasal sinuses. Although bacteria have long been implicated as pathogens in most forms of CRS, fungi may be responsible for some forms. Several recent studies demonstrated that, under optimal conditions, fungi can be identified in the nose and paranasal sinuses of nearly every individual (including all CRS patients). An aberrant immune response to these ubiquitous fungi has been suggested to explain the development of CRS in some individuals. Several mechanisms requiring additional research, including adequate controls, have been proposed and are reviewed in this article. Although preliminary trials suggested that CRS signs and symptoms improve upon treatment with topical and oral antifungal agents, several double-blind, placebo-controlled trials demonstrated the contrary. In the absence of convincing immunologic data and evidence of clinical improvement upon therapy with antifungal agents, the case against fungi remains unproven.

Use of a Sustained Release Preparation of Clotrimazole to Treat Dermatophytosis in a Siamang (Hylobates syndactylus)

In November 2004, an adult male siamang (Hylobates syndactylus) from The Tisch Family Zoological Gardens-Jerusalem Biblical Zoo (Israel) presented with skin lesions on various body parts. Lesions consisted of alopecia and dry, crusty areas of hyperkeratosis. A diagnosis of dermatophytosis due to Microsporum canis was determined by fungal culture of skin scraping taken from the edge of several lesions. Treatment with various oral and topical antifungal agents such as griseofluvin, itraconozole, and lufenuron resulted in the resolution of most lesions and a decrease in size of the single remaining lesion, which continued to be culture positive for M. canis. The animal was anesthetized and an experimental sustained-release clotrimazole varnish was painted directly on the lesion. Initially there was no change in the lesion, and 2 months later a slightly altered formula was applied under anesthesia. One month later, the lesion began to reduce in size; 3 months after the start of treatment, although 2 years after the onset of clinical signs, the lesion resolved. Minimizing the number of treatments is always an advantage when dealing with exotic animals or zoological collections.

Pramiconazole, a novel oral antifungal agent, effectively treats pityriasis versicolor: Results of a dose-finding clinical study

Pramiconazole, a novel oral antifungal agent, effectively treats pityriasis versicolor: Results of a dose-finding clinical study

Treatment of onychomycosis: An update

Fungal infections of skin are one of the most common infections in human beings. The areas which are likely to get infected include the scalp, the hands and the feet. Dermatophytes, yeasts and moulds are the three major fungi responsible for skin infections. Earlier oral antifungal agents were used for treatment of fungal infection in finger and toe nails. The disadvantages of oral antifungal agents are toxicity and longer treatment period. Now medicated nail lacquers have been developed for the treatment of fungal infections i.e. onychomycosis, which has less toxicity and shorter treatment period.

Successful Treatment of Toenail Onychomycosis With Photodynamic Therapy

Although recent progresses in oral antifungal agents have made it possible to treat onychomycosis effectively, these drugs can have considerable adverse liver or kidney effects and medication interactions in special populations such as children, the elderly, and patients with underlying systemic diseases. We describe 2 patients with toenail onychomycosis who were sucessfully treated with photodynamic therapy (PDT).

Granular parakeratosis of multiple intertriginous areas

A 60-year-old woman presented with a 4-year history of a recurrent reddish-brown macular eruption mainly involving the submammary and inguinal flexures and with transient involvement of the axillae. The eruption usually flared during winter and would settle spontaneously within a few months. At presentation, it had persisted longer than usual into the warmer weather and varied in clinical appearance over the time of observation, at times showing psoriasiform features and hyperkeratosis. Biopsy revealed features typical of granular parakeratosis. It was unresponsive to multiple topical and oral antifungal agents, oral antibiotic therapy, topical corticosteroids and emollients, but eventually resolved with a combination of 1% hydrocortisone cream and 1% clotrimazole cream to which the patient added a commercial topical vitamin E preparation.