Fluconazole

Fluconazole is a novel triazole antifungal drug chiefly used in the treatment of opportunistic mycoses in immuno-compromised patients, particularly those with the acquired immuno-deficiency syndrome (AIDS). In comparison with other antifungal drugs, fluconazole has outstanding physical and pharmacokinetic properties, such as an excellent aqueous solubility allowing a parenteral formulation, high bioavailability by the oral route, even distribution throughout the tissues, including the central nervous system and the cerebro-spinal fluid, a long half-life (permitting once daily administration), and low binding to plasma proteins. It is excreted mainly as unchanged drug in the urine. Fluconazole is a broad-spectrum antifungal agent, especially effective againstCandida spp.,Cryptococcus neoformans and dermatophytes. Its antifungal efficacy was mainly proved by testing in animal models, since there is no relationship betweenin vitro andin vivo activities. It possesses a low toxicity and it is well-tolerated. Fluconazole is currently marketed for the treatment of oropharyngeal candidiasis in immuno-compromised patients and of atrophic oral candidiasis. Its place in the treatment of opportunistic mycoses in human immuno-deficiency virus-positive patients, in particular cryptococcal meningitis, is still under investigation but is promising.     

Fluconazole: a new antifungal agent

The chemistry, activity, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and administration of fluconazole are reviewed. Fluconazole is a triazole antifungal agent labeled for use in the treatment of oropharyngeal and esophageal candidiasis and cryptococcal meningitis. Like the imidazoles, fluconazole inhibits the C-14 demethylation of lanosterol, but it has little or no effect on mammalian cytochrome P-450 enzymes. Fluconazole's activity in vitro does not reflect its effectiveness in vivo. Pharmacokinetic characteristics include water solubility and excellent bioavailability, low protein binding, extensive tissue distribution, and penetration into the cerebrospinal fluid. Fluconazole is eliminated primarily by the kidneys; dosage adjustments are necessary in patients with renal insufficiency. Studies have shown fluconazole to be effective in patients with cryptococcal meningitis and candidiasis, but the superiority of fluconazole over such agents as amphotericin B, ketoconazole, clotrimazole, and itraconazole remains to be proved. Fluconazole has shown varying degrees of success in the treatment of other systemic mycoses. The adverse effects of fluconazole are relatively infrequent and are primarily gastrointestinal. Tolbutamide, warfarin, rifampin, cyclosporine, and phenytoin interact with fluconazole. The drug is available in both oral and intravenous formulations. Fluconazole is a broad-spectrum antifungal drug that appears to be similar in efficacy to other antifungals in the treatment of some systemic mycoses. More studies must be completed before fluconazole can be recommended as a first-line antifungal therapy.     

Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses

Fluconazole is a bis-triazole antifungal drug with novel pharmacokinetic properties (metabolic stability, relatively high water solubility) which contribute to its therapeutic activity. Clinical experience is limited to a relatively small number of mycoses and, as might be expected at this early stage of development, optimal dosage and duration of treatment for some serious mycoses is not yet established. Further study to evaluate higher dosages and to establish the efficacy of fluconazole relative to more established antifungal agents is required. In patients with oropharyngeal or oesophageal candidiasis, fluconazole produces rapid relief and eradicates the yeast in 50 to 90% of patients. Relapse of oral infection is common in chronically immunocompromised patients regardless of the antifungal used, and adequate primary therapy plus long term prophylaxis appears necessary in patients with AIDS. A single oral dose of fluconazole was comparable to standard topical azole therapy in women with acute vaginal candidiasis. Preliminary reports of success against deep-seated candidiasis are encouraging; moreover, experience in noncomparative clinical trials suggests that fluconazole 200 to 400mg once daily resolves infection in the majority of seriously ill patients. Clinical improvement has been reported in a few cases of pulmonary Aspergillus infection but the overall efficacy of conventional dosages of fluconazole in this mycosis has not been as impressive. Early experience in coccidioidosis, predominantly meningitis, suggests a beneficial clinical effect with oral fluconazole in this difficult to treat mycosis but relapse remains a problem. Fluconazole is a promising treatment of cryptococcal meningitis. The rate of clinical resolution and eradication of Cryptococcus neoformans from cerebrospinal fluid has been similar between fluconazole and amphotericin B treatment groups in comparative trials. Comparative trials of maintenance therapy indicate a similar low rate of relapse among patients given oral fluconazole once daily and intravenous amphotericin B once weekly. However, these results are preliminary and further study is required. Fluconazole has been well tolerated to date but wider clinical experience is needed, especially with regard to the rate occurrence of hepatotoxicity and exfoliative skin reactions. The promising clinical response of patients with various forms of candidiasis or cryptococcosis--together with convenient administration regimens--recommends fluconazole as a useful addition to currently available systemic antifungal therapies, in particular for the treatment of mycoses in patients with AIDS.     

Fluconazole (Diflucan): a review

Fluconazole is a triazole antifungal agent available for oral or intravenous use in the treatment of a number of localized and disseminated mycoses. Animal models have shown in vivo activity against infections caused by Candida spp. and Crytococcus neoformans. Fluconazole is also active in animal infections caused by Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and dermatophytes. Fluconazole acts by inhibiting synthesis of ergosterol, an essential sterol in fungal cell membranes. The drug is water-soluble, rapidly absorbed after oral dosing, and penetrates well into body fluids and tissues, including cerebrospinal fluid. It is excreted largely unchanged in urine and has an elimination half-life of approximately 30 h, allowing once-daily dosing. Extensive clinical trials document clinical efficacy in candidiasis - including oropharyngeal, esophageal, and disseminated forms - as well as in acute or suppressive therapy of cryptoccal meningitis. Other potential indications studied include prophylaxis of fungal infection in immunocompromised cancer patients, treatment of coccidioidal meningitis, and single-dose therapy of vaginal candidiasis. Fluconazole is generally well tolerated and infrequently associated with serious adverse effects or laboratory test abnormalities.     

Found in translation: integrated approaches to drug development

Anidulafungin is the most recently approved compound of the echinocandin antifungal class. Its mode of action is the noncompetitive inhibition of β–(1,3)-D-glucan synthesis. Potent fungicidal activity has been demonstrated against many Candida spp., including non-albicansCandida spp. and fluconazole-resistant strains, as well as fungistatic activity against Aspergillus spp. Owing to low oral bioavailability, it can only be administered intravenously. Anidulafungin is not metabolized by the liver and renal clearance is negligible, thus rendering dosage adjustments in patients with impaired hepatic or renal function unnecessary. Due to lack of interference with the cytochrome P450 pathway, it displays minimal drug–drug interaction. Anidulafungin has been approved by the US FDA for the treatment of esophageal and invasive candidiasis after clinical trials demonstrated its noninferiority to fluconazole. In September 2007, anidulafungin gained EMEA approval for the treatment of invasive candidiasis in adult non-neutropenic patients. For those with invasive or noninvasive candidiasis with resistance or intolerance to fluconazole in particular, as well as those requiring antifungal medication, that anidulafungin does not interact with concomitant medication means it may be regarded as a safe and efficacious treatment option. Promising results from animal models and experience with the other echinocandins indicate several potential lines of investigation: invasive aspergillosis, prophylaxis and treatment of transplant patients, and empirical treatment in patients with febrile neutropenia. Significant differences in clinical efficacy or safety favoring anidulafungin over the other echinocandins are yet to be discovered.     

Terbinafine: a pharmacological and clinical review

Terbinafine (TRB) is an allylamine antifungal agent that has been available for more than a decade. It is now used for the treatment of dermatophytic infections and onychomycosis. Despite several studies having demonstrated the efficacy of terbinafine against nondermatophytic infections including azole-resistant candidiasis, invasive aspergillosis, disseminated fusariosis and scedosporiosis, the role of TRB in the management of these infections remains greatly underappreciated. A brief review of pharmacodynamic, pharmacokinetic, in vitro and in vivo data and published case reports provides insight into the use of terbinafine as a potential adjunct in combination with azoles, polyenes or echinocandins in the management of severe drug-resistant or refractory mycoses. Despite the lack of intrinsic fungicidal activity against several nondermatophytes, when used in combination, particularly with azoles, TRB has demonstrated good antifungal efficacy that could be exploited in clinical practice. As comprehensive human clinical studies are not feasible with the rare occurence of these mycoses, experiments using animal models are essential to evaluate the in vivo efficacy of drug combinations. In summary, terbinafine has established itself as a drug of choice for dermatophytic infections; it must be considered in combination with other antifungal agents for the management of nondermatophytic refractory or resistant yeast/mold infections as well.     

Itraconazole: pharmacology, clinical experience and future development

Itraconazole is an orally active, broad-spectrum, triazole antifungal agent which has a higher affinity for fungal cytochrome P-450 than ketoconazole but a low affinity for mammalian cytochrome P-450. Itraconazole has a broader spectrum of activity than other azole antifungals and shows interesting pharmacokinetic features in terms of its tissue distribution. These properties have resulted in reduced treatment times for a number of diseases such as vaginal candidiasis, as well as effective oral treatment of several deep mycoses, including aspergillosis and candidiasis. Currently itraconazole is registered in 42 countries for the treatment of systemic fungal infections. Further development is concentrating on antifungal prophylaxis as well as on an oral solution and an intravenous formulation.     

Pharmacotherapy approaches to antifungal prophylaxis

Introduction: Invasive fungal infection (IFI) is a serious problem due to difficulties in early diagnosis and high mortality. Different approaches are adopted for the treatment and management of IFI, including prophylactic, empiric, preemptive and directed strategies.

Areas covered: This paper reviews the type of pharmacotherapy used for antifungal prophylaxis in infants with extremely low birth weights, pediatric patients with cardiac disease, preterm neonates, pediatric oncology patients, adult cancer patients with neutropenia, adult patients with hematologic malignancy, hematopoietic stem-cell transplantation recipients, organ transplant recipients, HIV-infected patients, immunosuppressed patients treated with moderate or high doses of corticosteroids, and patients with invasive fusariosis, candidemia, invasive candidiasis, systemic mycoses and immunocompromised patients.

Expert opinion: Azole drugs are the drugs most often used in cost-effective antifungal prophylaxis of patients with conditions such as immunodeficiency and cancer, which render them highly susceptible to IFI. Fluconazole is the most outstanding example. However, there are many azoles with different pharmacological characteristics that the physician can choose from. Echinocandins have favorable characteristics that make them useful for treating Candida infections. Antibodies, or their engineered derivatives directed against cell-wall polysaccharides and glycopeptides, and some protein epitopes of Candida albicans, appear to be a promising novel approach for prophylaxis against Candida infection and deserve further in-depth investigations.     

Options for the Management of Mucosal Candidiasis in Patients with AIDS and HIV Infection

Oropharyngeal candidiasis may be the first manifestation of human immunodeficiency viral (HIV) infection, and more than 90% of patients with the acquired immunodeficiency syndrome (AIDS) develop the disease. Although numerous antifungal agents are available, azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole), have largely replaced older topical antifungals (gentian violet, nystatin) in the management of the disease in these patients. A concern in these patients is clinical relapse, which appears to be dependent on degree of immunosuppression and is more common with clotrimazole and ketoconazole than with fluconazole or itraconazole. Candida esophagitis is also of concern, since it occurs in more than 10% of patients with AIDS. Fluconazole is an integral part of management. A cyclodextrin oral solution formulation of itraconazole has similar clinical response rates as fluconazole and is an effective alternative. In patients with fluconazole-resistant mucocutaneous candidiasis, treatment options include itraconazole and amphotericin B oral suspension and parenteral preparation.     

Terbinafine. An update of its use in superficial mycoses.

Terbinafine is an allylamine antifungal agent which has fungicidal activity against a wide variety of dermatophytes, moulds and certain dimorphic fungi, and fungistatic activity against Candida albicans. Oral terbinafine 250 mg/day is effective in the treatment of superficial dermatophyte infections such as onychomycosis, tinea pedis and tinea corporis/cruris, generally achieving mycological cure in > 80% of patients. The drug is also effective in children with tinea capitis when administered orally in the dosage range 62.5 to 250 mg/day for 4 weeks. Comparative data indicate that oral terbinafine is more effective than continuous or intermittent intraconazole in dermatophyte onychomycosis, and is as effective as itraconazole 400 mg/day in tinea pedis. The drug has shown greater efficacy than griseofulvin in dermatophyte onychomycosis, tinea pedis and tinea corporis/cruris, and comparable efficacy in children with tinea capitis. Additionally, oral terbinafine is more effective than ketoconazole 200 mg/day in tinea corporis/cruris. Topical terbinafine 1% formulations are effective when applied once or twice daily for up to 2 weeks, achieving mycological cure in > 80% of patients with tinea pedis, tinea corporis/cruris, cutaneous candidiasis and pityriasis versicolor. Its formulations are at least as effective as miconazole 2% cream and naftifine 1% gel in tinea pedis, and more effective than clotrimazole 1% cream, bifonazole 1% cream and oxiconazole 1% lotion. Mycological cure rates achieved with terbinafine generally improve after treatment cessation, reflecting the drug's fungicidal mechanism of action and its residual effect in tissue. Terbinafine is well tolerated after oral or topical administration and has a relatively low potential for drug interactions. Pharmacoeconomic data support the use of terbinafine in dermatophyte infections of the skin or nails. CONCLUSIONS: Evidence suggests that oral terbinafine is the treatment of choice for dermatophyte onychomycosis, as it achieves high rates of mycological and clinical cure, is generally well tolerated and has a relatively low potential for drug interactions. It must also be considered a first-line treatment option, along with itraconazole, in cutaneous mycoses which warrant systemic treatment; topical terbinafine is a treatment of choice in less extensive mycoses. The use of terbinafine in non-dermatophyte or mixed infections has not been fully defined.     

Clinical evaluation of fluconazole in patients with mycotic infection

Fluconazole, a triazole antifungal agent newly developed by Pfizer Inc.. was given orally to 4 patients with deep mycosis. Fluconazole was markedly effective against septicemia due to Candida and oral candidiasis accompanied with lingual ulcer in spite of seriousness of these underlying disease. In 2 patients with aspergilloma, eradication or contraction of fungus ball was observed and the drug was judged to be effective. In vitro MICs of fluconazole against clinically isolated Aspergillus spp. were much higher than its serum levels leaving a large discrepancy between in vitro activity and clinical efficacy. Although the dosage was 100-300 mg daily for 8 days to 6 months, neither adverse reactions nor laboratory parameter abnormalities were observed. The above results suggest that fluconazole is a useful agent in the treatment of fungal infections.     

Experience of fluconazole in pediatric patients

Fluconazole is a triazole agent and possesses a potent antifungal activity against fungi such as Candida, Cryptococcus and Aspergillus. Fluconazole is well absorbed following oral administration and shows bioavailability almost comparable to that attained in intravenous administration. The serum half-life is as long as about 30 hours and distributed widely into organs and tissues. Because of these it is expected to exhibit good clinical efficacy in the deep-seated mycosis. We evaluated the efficacy of fluconazole given orally to 3 pediatric patients with deep mycosis and also with aim of evaluating its prophylactic effect, gave fluconazole to 4 patients who had high risks of mycotic infections. Pathogenic fungi isolated from the 3 patients with mycosis were all Candida albicans and diagnoses made were Candida pneumonia, oral candidiasis and gastrointestinal candidiasis. Clinical efficacies were judged to be good in all of the 3 patients and C. albicans were found eradicated following the treatment. In the 4 patients to whom fluconazole was given prophylactically, no mycosis developed. Fluconazole was well tolerated and no incidence of side effects or clinical laboratory parameter abnormalities were seen any of the patients involved in the study.     

Clinical study of fluconazole on deep-seated fungal infections

Fluconazole is a novel antifungal agent, available in oral and intravenous forms, which was developed by Pfizer Central Research. It is characterized by its long serum half-life (approximately 30 hours) to allow once-a-day dosing and favorable safety profile. Fluconazole was administered orally or intravenously to 166 patients with deep-seated mycosis and it was possible to evaluate clinical efficacies in 99 patients. Clinical cures were obtained in 41 (87.2%) out of 47 cases of candidiasis, in 10 (66.7%) out of 15 cases of cryptococcosis, in 17 (48.6%) out of 35 cases of aspergillosis and in 1 case each (100%) of mucormycosis and mycosis due to an unspecified yeast. Side effects were observed in 10 cases (rash 2, fever 2, abdominal discomfort 1, nausea 1, edema 1, edema/pleural effusion/oliguria 1, finger stiffness 1, hiccup 1) with incidence rate of 6.0%. Drug administrations were discontinued in 4 cases. In general, however, fluconazole was well tolerated. Abnormal changes in laboratory test values due to the drug were observed in 32 cases and incidence rate was 19.3%. These were, however, slight and temporary changes and most of them were in parameters of liver function. It is not clear if these changes were related to the fluconazole administration, because other drugs were concomitantly administered to these cases. These results indicate that fluconazole is an agent with very good potential for the treatment of the systemic deep-seated mycoses.     

A clinical evaluation of fluconazole in the treatment of deep mycosis

Fluconazole is a novel triazole antifungal agent developed by Pfizer Inc. and available in both oral and intravenous forms. It is characterized by a long serum half-life of 25 to 30 hours and good absorbability into tissues. In the present study, fluconazole was given to 12 patients with deep mycosis orally, intravenously or by local infusion. The patients included 4 cases of candidemia, 1 case each of candidemia and candiduria, candiduria, esophageal candidiasis, Candida hepatic abscess, pulmonary cryptococcosis and septicemia due to unspecified yeasts and 2 cases of pulmonary aspergillosis. Clinical efficacies of fluconazole against these infections were excellent in 2 cases, good in 8 and fair in 2. None of the patients reported any side effects. From the results of the study, fluconazole appears to be a useful and safe drug for the treatment of deep seated mycosis.     

抗真菌药物的应用与发展

真菌感染既可累及浅部组织,也可侵犯深部各器官,易复发。临床上抗真菌药物治疗真菌感染易出现不良反应。本文简要综述抗真菌药物的临床应用及未来发展方向。     

Amphotericin B-Loaded Poly(lactic-co-glycolic acid) Nanofibers: An Alternative Therapy Scheme for Local Treatment of Vulvovaginal Candidiasis

Vulvovaginal candidiasis is an inflammation localized in the vulvovaginal area. It is mostly caused by Candida albicans. Its treatment is based on the systemic and local administration of antifungal drugs. However, this conventional therapy can fail owing to the resistance of the Candida species and noncompliance of patients. Amphotericin B-loaded poly(lactic-co-glycolic acid) nanofibers are single-use, antifungal, controlled drug delivery systems, and represent an alternative therapeutic scheme for the local treatment of vulvovaginal candidiasis. Nanofibers were characterized by analytical techniques and with an in vitro drug delivery study. In vitro and in vivo fungicidal activity of amphotericin B released from nanofibers was evaluated using the agar diffusion method and an experimental murine model of vulvovaginal candidiasis, respectively. Analytical techniques showed that amphotericin B was physically mixed in the polymeric nanofibers. Nanofibers controlled the delivery of therapeutic doses of amphotericin B for 8 consecutive days, providing effective in vitro antifungal activity and eliminated the in vivo vaginal fungal burden after 3 days of treatment and with only one local application. Amphotericin B-loaded poly(lactic-co-glycolic acid) nanofibers could be potentially applied as an alternative strategy for the local treatment of vulvovaginal candidiasis without inducing fungal resistance, yet ensuring patient compliance.     

New antifungal agents for the treatment of candidaemia

Suspected or proven invasive candidiasis is an important indication for antifungal drugs and a leading cause of death. Prompt initiation of effective therapy has a marked effect on survival, but the indiscriminate application of different risk-factor-based prediction models is massively increasing the number of patients treated unnecessarily. Fluconazole resistance levels are <5% in most European centres and the use of low doses is still common. Candins are fungicidal, have efficacy against device-related infections, have few interactions and are well tolerated. Accordingly, the use of newer, more expensive drugs must be carefully balanced in each case. Campaigns directed towards stewardship in antifungal drug use must take into consideration the choice of the drug, the dose and route of administration, and the length of therapy. Early microbiological information and medical education may contribute to better use of these important drugs. We review the characteristics of the new antifungals used for the treatment of candidaemia.     

药物联用抑制白念珠菌生长的研究进展

白念珠菌是念珠菌属最常见的种类之一,是临床上重要的侵袭性念珠菌感染来源。由于传统抗真菌药物的广泛使用,临床已经分离出很多耐药白念珠菌,导致部分传统药物在临床治疗效果明显下降。同时,一些化合物自身的毒性限制了其临床应用。在这种背景下,联合疗法由于发挥了各种药物或手段的协同作用,有可能改进单独用药的不足,具有抑制白念珠菌生长的巨大潜力。     

光滑念珠菌耐药机制的研究进展

随着念珠菌病患者中感染光滑念珠菌的比例逐年增加,光滑念珠菌已成为除白念珠菌、热带念珠菌外较为常见的致病念珠菌之一。抗光滑念珠菌的药物种类有限,随之而来的耐药问题日益严重,为临床治疗带来困难。本文综述了光滑念珠菌对唑类、棘白菌素类及多烯类药物的耐药机制。     

Pharmacotherapy approaches to antifungal prophylaxis

INTRODUCTION: Invasive fungal infection (IFI) is a serious problem due to difficulties in early diagnosis and high mortality. Different approaches are adopted for the treatment and management of IFI, including prophylactic, empiric, preemptive and directed strategies. AREAS COVERED: This paper reviews the type of pharmacotherapy used for antifungal prophylaxis in infants with extremely low birth weights, pediatric patients with cardiac disease, preterm neonates, pediatric oncology patients, adult cancer patients with neutropenia, adult patients with hematologic malignancy, hematopoietic stem-cell transplantation recipients, organ transplant recipients, HIV-infected patients, immunosuppressed patients treated with moderate or high doses of corticosteroids, and patients with invasive fusariosis, candidemia, invasive candidiasis, systemic mycoses and immunocompromised patients. EXPERT OPINION: Azole drugs are the drugs most often used in cost-effective antifungal prophylaxis of patients with conditions such as immunodeficiency and cancer, which render them highly susceptible to IFI. Fluconazole is the most outstanding example. However, there are many azoles with different pharmacological characteristics that the physician can choose from. Echinocandins have favorable characteristics that make them useful for treating Candida infections. Antibodies, or their engineered derivatives directed against cell-wall polysaccharides and glycopeptides, and some protein epitopes of Candida albicans, appear to be a promising novel approach for prophylaxis against Candida infection and deserve further in-depth investigations.