Therapeutic efficacy of miconazole on deep-seated fungal infections in the respiratory tract system

We evaluated the therapeutic efficacy of miconazole (MCZ, Florid-F inj.), a new antifungal agent for parenteral use, in deep-seated fungal infections of respiratory tract system. A daily dose of 400-1,800 mg of MCZ was given intravenously for 12-38 days (mean: 23.4 days) to 7 patients: 2 patients with pulmonary aspergillosis, 1 patient with bronchial aspergillosis, 1 patient with pulmonary candidiasis and 3 patients with candidemia. One additional patient with pulmonary aspergillosis received three instillations of 20 mg of MCZ into the thoracic cavity. The clinical effects were excellent in 1, good in 4 and poor in 3 patients. The efficacy rate was 100% in 5 cases with respiratory fungal infections but 3 cases with candidemia did not respond well to the treatment. Four strains each of Aspergillus sp. and Candida sp. were identified as causative organisms. Seven of the 8 strains were eradicated by administration of MCZ. Side effects observed were irritation and heat in a leg in 1 patient, hyperlipoidemia in 2 patients and eosinophilia in 1 patient. The adverse reactions disappeared after the completion of the therapy. From the above results, we conclude that MCZ is one of the most useful antifungal agents for parenteral use as a first choice on deep-seated fungal infections in the respiratory tract.     

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.     

Laboratory and clinical study of intravenous miconazole

Laboratory and clinical study was carried out on miconazole (MCZ), a new synthetic imidazole. The antifungal activity of MCZ was studied and expressed as MICs for clinical isolates. The drug proved to have the highest activity against Cryptococcus neoformans, with MICs of no more than 0.16 micrograms/ml for all isolates of this species. MICs of Torulopsis glabrata were 0.08-5 micrograms/ml for all isolates and those of Candida albicans and Candida tropicalis were 5-20 micrograms/ml for more than 90% of the isolates. Most of other strains were less than 10 micrograms/ml. When 3 healthy adult men were administered each with 200 mg of MCZ by intravenous drip infusion for 1.25 hours, the mean serum MCZ concentration was 1.39 micrograms/ml at the end of the infusion, then decreased rapidly to 0.49 microgram/ml in following 30 minutes, and then decreased gradually to 0.17 microgram/ml 6 hours later. The mean cumulative urinary excretion rate of the drug was as low as 3.0% at this stage. A total of 25 patients with ages of 30-78 years, comprising 17 men and 8 women, were treated with 200-1,800 mg of MCZ daily for 3-93 days. The clinical effectiveness was ascertained in 19 cases among the patients; 9 cases with candidiasis, 3 with cryptococcosis and 7 with aspergillosis. Clinical responses were excellent in 2, good in 9 and poor in 8 cases, and its efficacy rates was 58%. The efficacy rate of the combination therapy with other antifungal agents was 60% in comparison with 57% of MCZ alone. Adverse reactions to the drug such as nausea, vomiting and anorexia were observed in 3 cases (12%). Abnormal changes in laboratory parameters were also observed: 3 patients with elevations of GOT and GPT, and another with eosinophilia.     

In vitro antifungal activity of itraconazole, a new triazole antifungal agent, against clinical isolates from patients with systemic mycoses]

The in vitro antifungal activity of itraconazole (ITZ), a new oral triazole antifungal agent, against clinical isolates from patients with systemic mycoses were compared with those of existing systemic antifungals, viz. ketoconazole (KCZ), miconazole or amphotericin B. The studies were performed with 65 isolates of pathogenic yeasts and 13 isolates of Aspergillus spp. using the agar dilution method on casitone agar. ITZ showed the most potent antifungal activities against isolates of pathogenic yeasts including several Candida spp. (Candida parapsilosis, Candida krusei, Candida guilliermondii), Cryptococcus neoformans, Trichosporon cutaneum (MIC less than or equal to 0.08 micrograms/ml) and Aspergillus spp. including Aspergillus fumigatus (MIC less than or equal to 5 micrograms/ml). On the other hand, activities of ITZ against isolates of other Candida spp. such as Candida albicans and Candida glabrata were lower than those of KCZ and other reference drugs. Some isolates of C. albicans and C. tropicalis were not completely inhibited by ITZ even at concentrations above 10 micrograms/ml on casitone agar. However, in the micro-broth dilution method using synthetic amino acid medium, fungal as the test medium, ITZ completely inhibited the growth of all these isolates at drug concentrations of less than or equal to 0.20 micrograms/ml.     

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.     

Antifungal activity and clinical efficacy of micafungin sodium (Funguard)

Micafungin sodium (MCFG) is a new lipopeptide antifungal agent of the echinocandin class. MCFG inhibits 1,3-beta-glucan synthesis in C. albicans and A. fumigatus in a non-competitive manner and has antifungal activity against both Aspergillus and Candida species. In neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis, the efficacy of MCFG was superior to that of fluconazole and itroconazole, but comparable to that of amphotericin B. The efficacy and safety of MCFG were investigated in 70 patients with deep-seated mycosis caused by Candida and Aspergillus species. The overall clinical response rates were 57.1% in aspergillosis and 78.6% in candidiasis. The incidence of adverse events related to micafungin was 17.9 %, and there was no dose-related occurrence of any adverse events. The results from this study indicated that micafungin was effective against aspergillosis and candidiasis, with no tolerability problems.     

Miconazole, a pharmacological barrier to skin fungal infections

INTRODUCTION: Miconazole (MCZ) is a time-honored antifungal of the imidazole class. MCZ exerts a multipronged effect on fungi. It inhibits the cytochrome P450 complex, including the 14α-demethylase enzyme required for ergosterol biosynthesis, in fungal cell membranes. In addition, intracellular accumulation of toxic methylated sterols occurs and the synthesis of triglycerides and phospholipids is altered. Disturbances in oxidative and peroxidative enzyme activities lead to an intracellular toxic concentration of hydrogen peroxide. As a result, intracellular organelle destruction then leads to cell necrosis. Farnesol synthesis stimulated in Candida spp. prevents the yeast-to-mycelium formation. MCZ is further active against Gram-positive bacteria. AREAS COVERED: This review aims at revisiting the MCZ antifungal activity in dermatomycoses. EXPERT OPINION: MCZ's wide spectrum of activity appears noteworthy. The full pharmacological profile of MCZ indicates its fungistatic profile through its effect on ergosterol biosynthesis. In addition, it exhibits a fungicidal effect against a number of fungal species, due to hydrogen peroxide accumulation. MCZ is characterized by high safety, efficacy and versatility, and a unique, multifaceted nature of activity in the treatment of dermatomycoses.     

In vitro synergism between nyasol, an active compound isolated from Anemarrhena asphodeloides, and azole agents against Candida albicans

The antifungal activity of nyasol (NYS) alone or with various antifungal agents was measured in vitro against Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. NYS is a compound recently purified from a medicinal plant, Anemarrhena asphodeloides. Among 12 agents, miconazole (MCZ), ketoconazole (KCZ), clotrimazole (CTZ), and cerulenin showed marked synergistic effects against C. albicans. The fractional inhibition concentration (FIC) indices against 4 strains of C. albicans were 0.067-0.31 for MCZ plus NYS, 0.078-0.31 for KCZ plus NYS, and 0.098-0.13 for CTZ plus NYS. These values indicate the possibility of using NYS as an adjuvant to azole agents in the chemotherapy of candidiasis.     

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.     

Epidemiology of Candida albicans infections and role of non-Candida-albicans yeasts

Infections of the skin and the mucous membranes due to Candida species may occur either in immuncompromised or in non-immuncompromised patients. This is in contrast to systemic candidiasis (e.g. candidemia) which is only seen in severely immunocompromised patients. Bloodstream infections caused by Candida species are increasingly recognized in critical ill adult and pediatric individuals, with significant associated morbidity and mortality. Candida albicans is the single most common fungal species causing nosocomial infections. However, non-Candida albicans spp., including fluconazole-less-susceptible Candida glabrata, have become more common pathogens. In some patient populations such as hematological (neutropenic) patients Non-C. albicans species are detected much more frequently as compared to non-neutropenic patients in the intensive care. Non-C. albicans species are more likely to occur in patients, who receive or have received antifungal therapy with azoles (e.g. fluconazole). In this review the current epidemiological trends in mucosal and invasive candidiasis are discussed with regard to the role of non-Candida albicans species as the causative agent in immunocompromised patients.     

Micafungin sodium (FK-463)

FK-463 (micafungin) represents the latest development candidate in a novel chemical class of echinocandin lipopeptide antifungal compounds. This agent has potent in vitro and experimental in vivo activity against a variety of pathogenic Candida species (yeasts) and Aspergillus fumigatus (filamentous fungus). This compound has favorable pharmacokinetics and a unique mode of action that makes it active against fungal isolates resistant to established antifungal agents, particularly the triazole agent fluconazole. Single- and multiple-dose phase I studies in normal human volunteers and phase II clinical trials in patients have been completed, with the compound being generally well tolerated and efficacious against infections caused by Candida and Aspergillus species. Published information on the in vitro and experimental in vivo activity, experimental and human pharmacokinetics, and clinical trial data of this new antifungal, echinocandin-like lipopeptide are summarized in this monograph.     

Clinical effect of miconazole gel against upper digestive tract mycosis

A total of 43 patients, comprising 41 patients with oral candidiasis and 2 with esophageal candidiasis, were treated with miconazole (MCZ) gel to assess its efficacy and safety in treating upper digestive tract mycosis. The efficacy of the drug was evaluable in 33 of them, consisting of 32 patients with oral candidiasis and 1 with esophageal candidiasis. The clinical efficacy rate of the drug against oral candidiasis was 87.5% (28/32 patients), and the clinical response was good in the 1 evaluable patient with esophageal candidiasis. The safety of the drug was assessed in 40 patients. In 3 (7.5%) of them, nausea occurred as an adverse event, but was not particularly serious in any of them. No abnormal laboratory test values caused by the drug were observed. The results suggested that MCZ gel would be a very useful drug in treating oral and esophageal candidiasis.     

人类免疫缺陷病毒相关性口腔念珠菌的药物敏感性分析

目的探讨HIV/AIDS病人口腔念珠菌对常用抗真菌药物的敏感性。方法采用微量液基稀释法,测定念珠菌对氟康唑、酮康唑、氟胞嘧啶和两性霉素B共4种常用抗真菌药物的敏感性(MIC值)。结果60株HIV相关性念珠菌对上述4种药物敏感性的几何均数分别为0.871、0.050、0.179和0.329 mg·L~(-1);耐药率分别为2%、5%、3%和5%;白色念珠菌和非白色念珠菌对氟康唑和两性霉素B的耐药率差异均具有显著性;有1株光滑念株菌对氟康唑、酮康唑和两性霉素B同时耐药。结论上述4种临床常用抗真菌药物可选作HIV/AIDS病人口腔念珠菌病的治疗,但应注意某些菌株的耐药和交叉耐药现象,尤其是非白色念珠菌。     

In vitro antifungal activity of itraconazole: a comparative study with ketoconazole]

In vitro antifungal activities of itraconazole (ITZ), a new oral triazole antifungal agent, were studied against a wide range of medically important fungi including 16 genera, 37 species and 51 strains stocked in this center. The test was carried out using the agar dilution method on Sabouraud dextrose agar. ITZ showed equal or superior antifungal activities to ketoconazole against most strains of pathogenic yeasts, dimorphic fungi, non-pigmented hypomycetes, dermatophytes and dematiacious fungi. Although some strains of Candida albicans and Candida tropicalis were not completely inhibited by ITZ at concentrations up to 80 micrograms/ml, partial growth inhibitions were observed even at drug concentrations as low as 0.04 microgram/ml. The antifungal activity of ITZ against C. albicans was markedly influenced by medium composition, medium pH, inoculum size and incubation time.     

In vitro antifungal activities of amorolfine against fresh isolates from patients with cutaneous mycosis

In vitro antifungal activities of amorolfine (MT-861), a new morpholine antifungal agent, were examined using an agar-dilution method, in comparison with those of 2 other antifungal agents, clotrimazole (CTZ) and bifonazole (BFZ), against 182 clinical isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, and Epidermophyton floccosum, which had been freshly isolated from a total of 182 cutaneous mycotic patients with various types of dermatophytes or cutaneous candidiasis. Antifungal activities of the 3 drugs against T. rubrum were in the order of MT-861 greater than CTZ greater than BFZ, with the lowest average MIC values (0.0070 micrograms/ml) obtained with MT-861. The average MIC value of MT-861 for clinical isolates from patients with pedis was roughly 2.3-fold higher than that for those from patients with tinea corporis. Out of 3 drugs tested MT-861 exhibited the most potent activities against clinical isolates of T. mentagrophytes, M. canis, and E. floccosum with average MIC values of 0.0267, 0.0079, and 0.0018 micrograms/ml, respectively. MIC values of MT-861 against isolates of Candida albicans ranged from 0.01 to 10 micrograms/ml, and the average value (0.1762 micrograms/ml) was the lowest of the 3 drugs.     

In vitro antifungal activity of N,N-phenyl-1,2,3,4-thiatriazole-5-yl-2,4-beta-resorcylcarbothioamide

The aim of this study was the determination of the antifungal activity of N,N-phenyl-1,2,3,4-thiatriazol-5-yl-2,4-beta-resorcylcarbothioamide (PTR) against Candida albicans, non-albicans Candida species, dermatophytes and moulds and of its influence on the enzymatic activity of C. albicans strains. The reference strains C. albicans ATCC 10231, 200 of C. albicans strains, 7 of non-albicans C. species, 12 dermatophyte strains and 20 mould strains were isolated from different patients. The mean minimum inhibitory concentration (MIC) of PTR against C. albicans strains isolated from patients was 19.6 mg/l, for reference C. albicans ATCC 10,231 it was 12.5 mg/l on Sabouraud's medium (SB). The mean MIC of isolates from patients was 16.9 mg/l, and reference strains 6.25 mg/l on YNB medium, respectively. The MIC of PTR against 7 non-albicans C. species was 27.7 mg/l on SB and 15.6 mg/l on YNB, respectively. The mean MIC of PTR against C. albicans strains isolated from patients was 14.9 mg/l, C. albicans ATCC 10,231 6.25 mg/l and non-Candida species strains 14 mg/l on RPMI medium. The MICs of PTR against dermatophytes ranged from 3 to 25 mg/l. The MICs of PTR against moulds were 25 mg/l and 100 mg/l, respectively. PTR inhibited the enzymatic activity of selected hydrolases of C. albicans and non-Candida species strains. PTR exerts a potent antifungal activity against the yeast-like fungi strains, moulds and dermatophytes. This new compound inhibited the enzymatic activity of selected hydrolases.     

In vitro activity of inexpensive topical alternatives against Candida spp. isolated from the oral cavity of HIV-infected patients

The use of inexpensive topical alternatives, e.g. oil of melaleuca (tea tree oil (TTO)), chlorhexidine (CHX), povidone iodine (PI) and gentian violet (GV), to treat oral candidiasis in human immunodeficiency virus (HIV)-infected patients has been proposed in resource-poor countries. However, pre-clinical studies comparing the antifungal activity of these agents are lacking. This study compared the minimal inhibitory concentrations (MICs) of TTO, GV, PI, CHX and fluconazole (FLZ) against 91 clinical Candida strains using Clinical and Laboratory Standard Institute (CLSI) methodology. Isolates were obtained from the oral cavity of acquired immune deficiency syndrome (AIDS) patients. Among the topical agents examined, GV showed the most potent activity against all Candida isolates tested (MIC range, MIC for 50% of the organisms (MIC(50)) and MIC for 90% of the organisms (MIC(90)) of 0.03-0.25 microg/mL, 0.06 microg/mL and 0.1 2microg/mL, respectively). CHX was 64 times less active than GV (MIC range, MIC(50) and MIC(90) of 0.5-16 microg/mL, 4 microg/mL and 8 microg/mL, respectively). The lowest antifungal activity was seen for PI (MIC(90)=0.25%). Moreover, GV, unlike the other topical agents tested, was fungicidal (minimum fungicidal concentration=1 microg/mL) against Candida albicans isolates (n=83). In addition, GV showed activity against FLZ-resistant C. albicans (n=3). The combination of GV and FLZ was not antagonistic and there was no interaction between the two compounds. GV possesses potent antifungal activity against FLZ-susceptible and -resistant Candida strains and is not antagonistic when used in combination with FLZ. In vivo evaluation is warranted.     

Clinical study of miconazole on deep-seated fungal infections]

An investigation was made on the efficacy and the safety of miconazole (MCZ) in the treatment of deep seated mycosis. The drug was administered through intravenous drip infusion at dose levels of 800 to 2,000 mg/day to 21 cases of confirmed mycosis for which causative organisms was identified and to 32 cases to which other antibiotics considered to be appropriate had been administered at febrile stages but had failed to take effect, hence mycoses were strongly suspected. The overall clinical efficacy rate was 84.3% (43/51). Treatments were "remarkably effective" in 6 cases, "effective" in 37, "not effective" in 8 and "indeterminable" in 2. The efficacy rates were 100% (21/21) in the confirmed mycosis cases and 73.3% (22/30) in the suspected mycosis cases. The mycological efficacies in the cases for which causative strains were identified were: disappeared in 14 (66.7%), decreased in 4 (19%), unchanged in 2 (9.5%) and unknown in 1 (4.8%), thus the overall disappearance ratio was 70% (14/20). Chest X-ray showed the disappearance of shadow in 1 patient and improvements in 14 of 23 patients examined. Adverse reactions were observed in 5 of the 53 cases (9.4%). From these results, MCZ may be considered as a highly useful drug not only in the treatment of deep mycosis but also in cases for which mycosis is strongly suspected.     

In vitro antifungal activity of itraconazole, a new triazole antifungal agent, against clinical isolates from patients with dermatomycoses]

In vitro antifungal activities of itraconazole (ITZ), a triazole antifungal agent, against clinical isolates obtained from patients with superficial and subcutaneous mycoses were examined using the agar dilution method on casitone agar. The clinical isolates tested were 7 species and 263 isolates including Trichophyton mentagrophytes (104 isolates), Trichophyton rubrum (103 isolates), Microsporum canis (3 isolates), Epidermophyton floccosum (2 isolates), Candida albicans (32 isolates), Malassezia furfur (7 isolates) and Sporothrix schenckii (12 isolates). The results are summarized as follows: 1. MIC values of ITZ for the isolates of dermatophytes and M. furfur distributed in a range of less than 0.0012-5 micrograms/ml indicating that ITZ had greater in vitro activities. These in vitro activities of ITZ were greater than those of clotrimazole or bifonazole. 2. C. albicans isolates were divided into 2 groups in terms of ITZ-susceptibilities, a high susceptibility group and low-susceptibility group with MIC values of 0.02-0.08 micrograms/ml and greater than 10 micrograms/ml, respectively. 3. The in vitro activities of ITZ against S. schenckii isolates with a geometric mean MIC of 0.119 micrograms/ml were greater than those of ketoconazole, miconazole or amphotericin B used as reference drugs.     

The role of caspofungin and the echinocandins in the antifungal armamentarium

The echinocandins are a recently-developed class of antifungal agents that interfere with fungal cell wall synthesis through the inhibition of glucan synthesis. Although several intravenous preparations are in various stages of development, caspofungin is the only currently approved agent and no oral echinocandin derivatives are presently available. Caspofungin is approved for the treatment of invasive aspergillosis in patients who are refractory to, or intolerant of, other antifungal therapies. This agent has activity against most Candida species, and in a prospective randomized trial, was as effective as, and better tolerated than amphotericin B in the treatment of candidal esophagitis. Activity against the cyst form of Pneumocystis carinii has also been demonstrated. Caspofungin is administered in a daily intravenous dose, and is well tolerated. Concomitant use of this agent with cyclosporine is presently not recommended. Other echinocandin derivatives presently in phase II/III clinical development include micafungin and anidulafungin.