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.     

微量液基稀释法测定化合物特苄康唑的体外抗真菌活性

参照美国国家临床试验标准化委员会提出的标准,以氟康唑,酮康唑和布替萘芬为对照,用微量液基稀释药敏试验方法,测定特苄康唑对１２种临床常见真菌的最低抑菌浓度。结果除烟曲霉外,特苄康唑对其他１１和睦具菌的ＭＩＣ８０均４ｍｇ／Ｌ以下,其体外抗直菌活性明显于氟康唑,尤其对酵母的抗菌活性是氟康唑的８－２５６倍,与酮康唑作用相当。     

The therapeutic effects of itraconazole, a new triazole antifungal agent, for experimental fungal infections]

The therapeutic efficacy of itraconazole (ITZ), and oral triazole antifungal agent, was studied using several experimental fungal infections in animals. The following results were obtained: 1. ED50 values of ITZ and ketoconazole (KCZ) in a murine model of systemic candidiasis produced by intravenous challenge of Candida albicans alls were 32.9 mg/kg and 224 mg/kg, respectively. ITZ suppressed the proliferation of Candida experimentally colonized in the GI-tract of mice and/or a secondary dissemination induced by prednisolone. 2. An oral dose of 40 mg/kg/day ITZ administered for experimental pulmonary cryptococcosis in mice inhibited the fungal proliferation in the lung and the dissemination to the brain. 3. ED50 values of ITZ and KCZ for experimental systemic Aspergillus infection in mice were 103.6 mg/kg and 882 mg/kg, respectively. 4. ITZ suppressed the development of local symptoms in guinea pigs with experimental dermatophytosis. Culture studies performed on cutaneous tissues from infected sites on day-19 postinfection revealed that ITZ treatment lowered the culture-positive rate to a greater extent than KCZ-treatment. 5. Plasma concentrations of ITZ after a single dose of 100 mg/kg in mice were determined using the bioassay method: Cmax was 11 micrograms/ml and T 1/2 was 24 hours. 6. These results show that oral ITZ is highly effective in the treatment of deep-seated and superficial fungal infections produced in experimental animals.     

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 and in vivo activities of HQQ-3, a new triazole antifungal agent

The activity of HQQ-3, a new triazole antifungal agent, was evaluated and compared with those of fluconazole, ketoconazole and terbinafine in vitro and with fluconazole in vivo. HQQ-3 exhibited potent in vitro activity against clinically important fungi. The activity of HQQ-3 against Candida spp. was superior to those of fluconazole and terbinafine and comparable or superior to that of ketoconazole. HQQ-3 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC80s range, 4 to >64 microg/ml). Against Cryptococcus neoformans and filamentous fungi, the activity of HQQ-3 was superior to that of fluconazole. HQQ-3 also exhibited potent in vivo activity against murine systemic infections caused by C. albicns and C. krusei. The 50% effective doses against these infections were 0.12 to 1.9 mg/kg of body weight. These result suggest that HQQ-3 may be useful in the treatment of candidiasis.     

In vitro antifungal activity of amorolfine, a new morpholine antimycotic agent

In vitro antifungal activities of amorolfine (MT-861), a newly developed morpholine antimycotic agent, against a wide range of pathogenic fungal strains were investigated using an agar-dilution method with an imidazole antifungal agent, clotrimazole (CTZ), as the reference drug. The results showed that MT-861 had a broad antifungal spectrum, and was active against all of the pathogenic fungi tested except nonpigmented filamentous fungi such as aspergilli and penicillia. Dermatophytes and Malassezia furfur was the most highly susceptible to MT-861. Antifungal activities of MT-861 against most strains of these fungi as well as those against most strains of dimorphic fungi were higher than those of CTZ. By contrast, MT-861 showed lower activities against pathogenic yeasts such as Candida albicans than CTZ. Several assay conditions, such as inoculum size of fungi, incubation time, media pH and compositions including serum supplementation, affected MT-861 activities against C. albicans and, to lesser extents, those against Trichophyton mentagrophytes. MIC values of MT-861 against C. albicans and other Candida spp., were the lowest on casitone agar. MT-861 exerted fungicidal actions toward susceptible fungi such as T. mentagrophytes and Sporothrix schenckii at relatively low concentrations, and these activities were increased when the time of incubation was extended beyond 24 hours after inoculation of testing organisms. Susceptibilities of any strains of C. albicans and C. glabrata to MT-861 were not reduced by as many as 15 successive transfers in MT-861 containing media.     

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 a novel lipopeptide antifungal agent, FK463, against various fungal pathogens

The antifungal activities of FK463 against various pathogenic fungi were tested by standard broth microdilution methods, and compared with the activities of five currently available antifungal agents; viz., fluconazole (FLCZ), itraconazole, miconazole, amphotericin B and flucytosine. Fourteen clinical isolates of Candida albicans categorized as FLCZ susceptible, FLCZ susceptible-dose dependent and FLCZ resistant were similarly susceptible to FK463 with geometric (GM) MIC values of 0.010, 0.011 and 0.015 microg/ml, respectively. All of 17 clinical isolates of Aspergillus fumigatus were inhibited by FK463 at 0.0078 microg/ml or lower concentrations. The antifungal activity of FK463 against a wider range of medically important yeasts and filamentous fungi were studied using stock fungal strains. While Cryptococcus, Trichosporon, Fusarium, Pseudallescheria and Alternaria species or zygomycetes were scarcely or not inhibited by 16 microg/ml of FK463, two Candida species (C. albicans, C. glabrata), as well as all species of Aspergillus, Paecilomyces and Penicillium, were highly susceptible with GM-MICs of < or = 0.008 microg/ml. The other fungal species including several non-albicans Candida were less susceptible with GM-MICs ranging between 0.016 and 2 microg/ml. MICs of the reference drugs were within the range thus previously reported. These results suggest that FK463 be of use in the treatment of serious fungal infections.     

In vitro activity of new artemisinin derivatives against Plasmodium falciparum clinical isolates from Gabon

Nowadays, artemisinins are the mainstay of malaria treatment, but initial indications of resistance against clinically used derivatives are present. In this study, ten new artemisinin derivatives were tested in vitro against Plasmodium falciparum laboratory strains as well as clinical isolates from Gabon. All derivatives were highly active, with 50% inhibitory concentrations (IC(50) values) <13 nM in the clinical isolates. The activity of one fluoro-containing derivative did not correlate with that of the parent compound, suggesting a different activity profile. New artemisinin derivatives with different activity profiles are of special interest as they represent an important class of candidates for pre-clinical testing in clinical parasite isolates adapted to currently used artemisinins, since derivatisation is one possible strategy to prolong the clinical usefulness of this important class of antimalarials.     

Ciclopiroxolamine: in vitro antifungal activity against clinical yeast isolates

The in vitro susceptibility of 225 clinical isolates of yeasts to ciclopiroxolamine (CPO) was compared with that of clotrimazole, econazole, ketoconazole, miconazole, tioconazole, fluconazole, itraconazole and nystatin using a standardized agar diffusion method (NeoSensitabs). Two hundred and eight strains of yeasts comprising 16 species of Candida and 22 strains belonging to other yeast genera were tested. One strain (0.4%) was resistant, four strains (1.8%) of intermediate susceptibility and 220 strains (97.3%) susceptible to CPO. More strains were susceptible to CPO than to the other antifungals studied. Susceptibility patterns of antifungal agents were not linked to species. The in vitro antifungal susceptibility profile of CPO was better than topical azole derivatives or fluconazole and itraconazole against a wide variety of clinically important yeasts.     

In vitro antifungal activity of ZJ-522, a new triazole restructured from fluconazole and butenafine, against clinically important fungi in comparison with fluconazole and butenafine

The antifungal activity of ZJ-522, a new triazole antifungal agent restructured from fluconazole and butenafine, was compared to that of fluconazole and butenafine against 43 strains of fungi representing 13 fungal species. MICs were determined by using the National Committee for Clinical Laboratory Standards (NCCLS)-recommended broth microdilution method for yeasts, which was modified for filamentous fungi. ZJ-522 was about 50-fold and 2 to 16-fold more potent than fluconazole against yeasts and filamentous fungi respectively, but it was less active than butenafine against filamentous fungi, although butenafine was inactive against most yeasts. Thus, the fashion of ZJ-522 antifungal activity more similar to that of fluconazole than that of butenafine indicates that ZJ-522 should be an inhibitor of lanosterol 14alpha-demethylase but not of squalene epoxidase, and should be a candidate for clinical development.     

In vitro activity of protoanemonin, an antifungal agent

Protoanemonin, the lactone of gamma-hydroxy-vinylacrylic acid, isolated from Pulsatilla alpina has in vitro activity against fungi. The MIC is 15 micrograms/ml and RNA inhibition seems to be the first target of the drug. The LD50 of protoanemonin in male Swiss albino mice was 190 mg/kg.     

In vitro activity of fluconazole, a novel bistriazole antifungal agent

Fluconazole is a novel triazole antifungal agent with excellent activities against a broad range of medically important fungi. The in vitro antifungal activities of fluconazole especially against Candida albicans were examined and the results summarized as follows: 1. Fluconazole was proved to exhibit the highest antifungal activity in synthetic amino-acid medium, fungal (SAAMF), well buffered in a physiologically neutral range. 2. In a exposed time-killing test performed using SAAMF (pH 7.4), the growth inhibition by fluconazole was enhanced in proportion to an increase of fluconazole concentration and 99% inhibition was observed at a concentration of 1 microgram/ml though further increases of concentration up to 80 micrograms/ml failed to demonstrate complete inhibition. 3. Activities of fluconazole against medically important various yeasts were determined by a broth dilution method in SAAMF using the viable counts technique. Among 9 species tested, C. albicans and Candida kefyr were the most sensitive to fluconazole with a IC99 range from 0.20 microgram/ml to 0.39 microgram/ml. On the contrary, Candida glabrata, Cryptococcus neoformans and Trichosporon cutaneum were the least sensitive with a IC99 range from 3.13 micrograms/ml to 12.5 micrograms/ml. 4. Growth inhibition activities of fluconazole against 4 species of Aspergillus were measured on the basis of mycelial protein content. IC50 and IC90 of fluconazole against Aspergillus fumigatus were distributed in the range of 23.9-43.5 micrograms/ml and 50- greater than 100 micrograms/ml, respectively. 5. The anti-Candida activity of fluconazole was little affected by serum concentrations. Fluconazole at a concentration of 0.20 microgram/ml inhibited significantly the mycelial-phase growth and germ tube elongation of C. albicans in a medium supplemented with serum. 6. The germ tube formation and elongation of C. albicans cells engulfed by murine peritoneal exudative cells were significantly affected in a medium containing 1 microgram fluconazole per ml.     

In vitro interactions of antifungal agents against clinical isolates of Fusarium spp

The in vitro activities of amphotericin B (AMB), itraconazole (ITC), voriconazole (VCZ) and terbinafine (TBF) alone and in the combinations AMB+VCZ, TBF+ITC and TBF+VCZ were evaluated against 29 clinical isolates of Fusarium spp. (15 Fusarium solani, 7 Fusarium oxysporum, 2 Fusarium decemcellulare, 2 Fusarium dimerum and 3 other Fusarium spp.). Minimum inhibitory concentrations were determined using the method of the Clinical and Laboratory Standards Institute and the interaction activity was calculated using the fractional inhibitory concentration index. The four antifungal drugs tested alone showed very limited activity against most of the isolates. In contrast, the combination TBF+VCZ showed synergy for 21 isolates. The combination AMB+VCZ showed synergism for only five strains. No interaction or antagonism was observed among the remaining strains. TBF+ITC showed no interaction for 18 strains. The in vitro antifungal activity of the drugs alone and in combination varied for different species. These results corroborate previous in vitro studies in which the combination TBF+VCZ showed synergy against Fusarium spp., although further studies are needed to elucidate its potential usefulness for therapy.     

帕珠沙星对临床分离致病菌的体外抗菌活性研究

目的评价帕珠沙星的体外抗菌活性。方法采用琼脂二倍稀释法，测定帕珠沙星与左氧氟沙星对342株临床分离菌株的最低抑菌浓度（MIC）。结果帕珠沙星对革兰阴性菌和革兰阳性菌的MIC90分别为0．06～4和1～16μg／ml。对大肠埃希菌、阴沟肠杆菌、变形菌、铜绿假单胞菌、不动杆菌和链球菌的MIC90为0．06～4μg／ml，是左氧氟沙星的1／2～1／8;对肺炎克雷伯菌、金葡菌和表葡菌与左氧氟沙星抗菌作用相当，MIC90分别为0．5、1、1μg／ml；对流感嗜血杆菌、黏膜炎莫拉菌和粪肠球菌的MIC90为0．5、1、16μg／ml，高于左氧氟沙星（0．25、0．5、8μg／ml）。结论帕珠沙星对革兰阴性菌和革兰阳性菌均具有广谱的抗菌作用，对革兰阴性菌的抗菌活性优于革兰阳性菌。     

In vitro activity of piperacillin/tazobactam against isolates from patients enrolled in clinical trials

The in vitro activity of piperacillin alone or titrated with a constant concentration of 4 mug/ml tazobactam was evaluated against 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical trial studies in North America. Tazobactam increased susceptibility rates of piperacillin for Enterobacteriaceae from 81% to 96%, Staphylococcus (methicillin susceptible) spp. from 6% to 100%, Bacteroides fragilis group from 79% to >99% and Haemophilus from 85% to 98%. The excellent activity of piperacillin against Pseudomonas, Streptococcus and Enterococcus was maintained in the presence of tazobactam. Overall piperacillin/tazobactam had better activity than ticarcillin/clavulanic acid, ceftazidime, and in general equaled the activity of imipenem. The excellent in vitro, extended-spectrum activity of piperacillin/tazobactam suggests its utility for various infections.     

In vitro bactericidal activities of new oral penem, faropenem against the various clinical isolates]

The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of faropenem (FRPM) more compared with those of various oral beta-lactams against 15 isolates each of 6 species of microorganism. FRPM possessed potent in vitro antibacterial activity against both aerobic and anaerobic Gram-positive bacteria tested. FRPM showed the same activity as new oral cephems such as cefdinir, cefditoren and cefcapene against all Gram-negative bacteria, but K. pneumoniae strains were less susceptible. The MBC of FRPM against S. pneumoniae and the other strains tested equal and were within 1 dilution the MIC of that, respectively. These results suggest that FRPM has excellent in vitro bactericidal activity against clinical isolates and is a clinically useful for the chemotherapy of bacterial infections.     

In vitro activity of faropenem against beta-lactamase producing clinical isolates

Each 20 strains of beta-lactamase producing methicillin susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Bacteroides fragilis group were used as the test strains. Drug susceptibility of these strains to faropenem (FRPM), cefdinir, cefditoren, cefcapene, cefteram, cefaclor, and ampicillin was determined by an agar dilution method according to the NCCLS guideline M100-S9. beta-Lactamase activity of the test strains was determined by a spectrophotometric method. In the present study, FRPM was highly active against beta-lactamase-producing strains, and no close correlation was found between the MICs of FRPM for the test strains and their beta-lactamase activities. These results suggest that FRPM has potential in successful application for the treatment of infectious diseases with various types of bacterial pathogens including beta-lactamase producing strains.     

In vitro activity of doripenem against Acinetobacter baumannii clinical isolates

Doripenem is a carbapenem with activity against Gram-positive and Gram-negative pathogens. This study evaluated the in vitro activity of doripenem against a collection of 87 Acinetobacter baumannii clinical isolates, showing that the activity of doripenem was superior to imipenem and meropenem for strains carrying the bla(OXA-58) gene. A. baumannii clinical isolates expressing the bla(OXA-24) gene were resistant to doripenem, imipenem and meropenem. However, in clinical isolates expressing the bla(OXA-58) gene, the percentage of isolates with a doripenem minimum inhibitory concentration >8microg/mL was much lower than that of imipenem and meropenem. This study shows that the activity of doripenem was superior to imipenem and meropenem for strains carrying the bla(OXA-58) gene.     

In vitro activity of novel rifamycins against gram-positive clinical isolates

We describe novel rifamycins that have improved activity, compared with rifampin, against clinical isolates of staphylococci and streptococci, with MIC(90)s of 0.008 and 0.0005 microg/ml, respectively. This enhanced antibacterial activity, along with their potential lack of drug-drug interactions, are considerations that suggest the potential of these novel rifamycins in combination therapy to treat serious Gram-positive infections.