In vitro activity of the echinocandin antifungal agent LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus spp

LY303,366 (LY) is a novel derivative of the echinocandin class of antifungal agents. The in vitro activities of LY, itraconazole (ITZ), and amphotericin B (AMB) were assessed against 60 Aspergillus isolates, including 35 isolates of A. fumigatus, eight isolates of A. terreus, eight isolates of A. flavus, eight isolates of A. niger and one isolate of A. nidulans. Four A. fumigatus isolates were resistant to ITZ. Susceptibility testing for all drugs was performed with a broth microdilution procedure. LY was tested in two media: antibiotic medium 3 (AM3) and Casitone with 2% glucose (CAS) with an inoculum of 2 x 10(3) spores/ml. ITZ and AMB were tested in RPMI 1640 with 2% glucose with an inoculum of 1 x 10(6) spores/ml. All tests were incubated at 37 degrees C for 48 h. A novel end point was used to determine a minimal effective concentration (MEC) for LY, i. e., almost complete inhibition of growth save a few tiny spherical colonies attached to the microplate. MICs were measured for ITZ and AMB with a no-growth end point. Ranges and geometric mean (GM) MECs were from 0.0018 to >0.5 and 0.0039 mg/liter and from 0.0018 to >0.5 and 0.008 mg/liter for LY in AM3 and LY in CAS, respectively. Differences between species were apparent, with A. flavus being significantly less susceptible to LY than any other species tested with both media (P 16 and 0.7 mg/liter for ITZ and from 0.25 to 16 and 1.78 mg/liter for AMB. Minimal fungicidal concentrations (MFCs) were also determined for all drugs. GM MFCs were 0.018, 0.09, 19.76, and 12.64 mg/liter for LY in AM3, LY in CAS, ITZ, and AMB, respectively. LY in AM3 and LY in CAS were fungicidal for 86.7 and 68% of isolates, respectively (98% killing). In comparison, ITZ and AMB were fungicidal for 35 and 70% of isolates, respectively (99.99% killing). A reproducibility study was performed on 20% of the isolates. For 12 isolates retested, the MEC or MIC was the same or was within 1 dilution of the original value for 11, 11, 10, and 9 isolates for LY in AM3, LY in CAS, ITZ, and AMB, respectively. In conclusion, LY seems to be a promising antifungal agent with excellent in vitro activity against Aspergillus spp.     

In-vitro activities of amphotericin B, itraconazole and voriconazole against 150 clinical and environmental Aspergillus fumigatus isolates

The influence of CNS functional state and structural changes of neurons in spinal cord following local exposure to 38 or 76 Gy X-radiation. Morphological analysis show, that stimulation of peripheral nerves increase, but hypoxia or barbiturates decrease destruction of spinal neurons by radiation. Value destruction also depends of neurons volumes.     

Imipenem inhibits in vitro activity of amphotericin B directed against Aspergillus fumigatus

A decrease of the susceptibility of Aspergillus fumigatus strains to amphotericin B was found when tested in combination with high concentrations (128-2048 mg/l) of the antibacterial agent imipenem by checkerboard titration and agar diffusion assay. Only bacteriologically active imipenem showed the antagonism. The mechanism of action is unknown. However, imipenem and amphotericin B did not react directly, as shown by checkerboard titration with bacterial strains as well as by HPLC analysis. It is concluded that imipenem medication may influence the efficacy of amphotericin B treatment in aspergillosis.     

In vitro activity of voriconazole against yeasts, moulds and dermatophytes in comparison with fluconazole, amphotericin B and griseofulvin

Voriconazole (CAS 137234-62-9, UK-109,496), a new antifungal triazole derivative, was studied in vitro against 650 clinical isolates, representing yeasts, moulds and dermatophytes, and was compared with fluconazole (CAS 86386-73-4), amphotericin B (CAS 1397-89-3), and griseofulvin (CAS 126-07-8). The mean minimum inhibitory concentrations (MICs) of voriconazole were 0.06 microgram/ml against yeasts (n = 187), 0.74 microgram/ml against moulds (n = 260) and 0.10 microgram/ml against dermatophytes (n = 203). Data from these in vitro studies showed that voriconazole was more potent than fluconazole against most species studied, but particularly against the isolates of moulds and dermatophytes. Overall, voriconazole and amphotericin B indicated comparably good activity against yeasts and moulds. Voriconazole was highly potent against 13 Aspergillus species studied (mean MIC 0.35 microgram/ml) and also showed noteworthy activity (mean MICs 0.08-0.78 microgram/ml) against emerging and less common clinical isolates of opportunistic moulds such as of Alternaria spp., Cladosporium spp., Acremonium spp., Chrysosporium spp., and Fusarium spp. In addition, voriconazole was more active in vitro than griseofulvin against most dermatophytes tested. The in vitro results confirmed that voriconazole has indeed a broad antifungal spectrum and could also be effective against a wide range of fungal infections in patients.     

In vitro evaluation of voriconazole against clinical isolates of yeasts, moulds and dermatophytes in comparison with itraconazole, ketoconazole, amphotericin B and griseofulvin

The in vitro activity of voriconazole (UK-109, 496), a new antifungal triazole derivative, against 650 clinical isolates of yeasts, moulds and dermatophytes was compared with that of itraconazole, ketoconazole, amphotericin B and griseofulvin. The geometric means of the minimum inhibitory concentrations (MICs) of voriconazole were 0.05 microgram ml-1 against yeasts (n = 187), 0.58 microgram ml-1 against moulds (n = 260) and 0.08 microgram ml-1 against dermatophytes (n = 203). The overall activity of voriconazole against yeasts and moulds was good, being similar to that of itraconazole, ketoconazole and amphotericin B. Voriconazole was highly effective against Aspergillus fumigatus (mean MIC 0.23 microgram ml-1) and other Aspergillus species and showed noteworthy activity (mean MICs 0.08-0.78 microgram ml-1) against emerging and less common clinical isolates of opportunistic moulds, such as Alternaria spp., Cladosporium spp., Acremonium spp., Chrysosporium spp. and Fusarium spp. On the other hand, voriconazole was less active in vitro than the comparative agents studied against various species of zygomycetes, such as Mucor spp., Rhizopus spp. and Absidia spp. Voriconazole and the other two azoles, itraconazole and ketoconazole, were more active than griseofulvin in vitro against most dermatophytes tested.     

Susceptibility of Aspergillus strains from culture collections to amphotericin B and itraconazole

BACKGROUND: Over the last decade the benefits of occlusive dressings have been appreciated. These dressings allow the epithelium to resurface easier. The wound heals quicker. OBJECTIVE: To evaluate a new silicone sheeting for immediate post-op wound care. Our objective was to determine its benefit in the wound care management after laser skin resurfacing. METHOD: The silicone sheeting was applied immediately after laser resurfacing in 35 individuals. This temporary skin replacement was held in place with 4 x 4 gauzes and tube gauze netting. Although the tube netting and the 4 x 4 gauzes were changed daily the silicone sheeting remained in place for 4 or 5 days. Following this, applications of a petrolatum-based ointment were continued for another 5 days. At day 10 the skin care program was changed to a moisturizing sunscreen. Bleaching cream was added at day 15 in darker complexed individuals. RESULTS: The dressing accelerated wound healing. Pain and swelling were minimized under the sheeting. Histologic examinations demonstrated a more rapid reepithelialization at these treated sites. Other than technical problems, such as the riding up of the dressing over the jawline or retraction of the dressing off the lips or off the eyelids, there were no adverse sequelae. The wound healed rapidly and allowed the rapid progression to the application of a moisturizer-sunscreen or a skin-bleaching cream. Other than these technical problems there were no complications. No wound infections were noted. CONCLUSION: The use of silicone sheeting following skin resurfacing facilitated a rapid reepithelialization of treated areas. There was a remarkable reduction in erythema and edema accompanying the use of the dressing. The program made it possible for patients to return to work in 12-15 days.     

Potentiation of antifungal activity of amphotericin B by azithromycin against Aspergillus species

The potential role of azithromycin in combination with amphotericin B against 25 clinical isolates of Aspergillus was assessed. The MIC of amphotericin B was 1 microg/ml for 44% of the isolates, 0.5 microg/ml for 48%, and 0.25 microg/ml for 8%. All isolates were resistant to azithromycin. Synergism, defined as a > or = twofold reduction in the MIC of both drugs upon combination, was demonstrated between amphotericin B and azithromycin for all 25 isolates. To prove that azithromycin exerts its antifungal effect by inhibiting protein synthesis, we studied [35S]-methionine incorporation into protein in one Aspergillus isolate. Neither amphotericin B at 0.125 microg/ml (fourfold below its MIC) nor azithromycin at 16 microg/ml (> or = 16-fold below its MIC) had any effect on protein synthesis when tested alone. Upon combination, however, a 68% inhibition in protein synthesis was evident by the inhibition of [35S]-methionine incorporation.     

Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice

A murine model of intratracheally induced histoplasmosis was used to evaluate a new triazole antifungal agent, Schering (SCH) 56592, for treatment of histoplasmosis. MICs were determined for SCH 56592, amphotericin B, and itraconazole by testing yeast-phase isolates from 20 patients by a macrobroth dilution method. The MICs at which 90% of the isolates are inhibited were for 0.019 microgram/ml for SCH 56592, 0.5 microgram/ml for amphotericin B, and < or = 0.019 microgram/ml for itraconazole. Survival studies were done on groups of 10 B6C3F1 mice with a lethal inoculum of 10(5). All mice receiving 5, 1, or 0.25 mg of SCH 56592 per kg of body weight per day, 2.5 mg of amphotericin B per kg every other day (qod), or 75 mg of itraconazole per kg per day survived to day 29. Only 44% of mice receiving 5 mg of itraconazole/kg/day survived to day 29. Fungal burden studies done in similar groups of mice with a sublethal inoculum of 10(4) showed a reduction in CFUs and Histoplasma antigen levels in lung and spleen tissue in animals treated with 2 mg of amphotericin B/kg qod, 1 mg of SCH 56592/kg/day, and 75 mg of itraconazole/kg/day, but not in those treated with lower doses of the study drugs (0.2 mg of amphotericin B/kg qod, 0.1 mg of SCH 56592/kg/day, or 10 mg of itraconazole/kg/day). Serum drug concentrations were measured 3 and 24 h after the last dose in mice (groups of five to seven mice), each treated for 7 days with SCH 56592 (10 and 1 mg/kg/day) and itraconazole (75 and 10 mg/kg/day). Mean levels measured by bioassay were as follows: SCH 56592, 10 mg/kg/day (2.15 micrograms/ml at 3 h and 0.35 microgram/ml at 24 h); SCH 56592, 1 mg/kg/day (0.54 microgram/ml at 3 h and none detected at 24 h); itraconazole, 75 mg/kg/day (22.53 micrograms/ml at 3 h and none detected at 24 h); itraconazole, 10 mg/kg/day (1.33 micrograms/ml at 3 h and none detected at 24 h). Confirmatory results were obtained by high-pressure liquid chromatography assay. These studies show SCH 56592 to be a promising candidate for studies of treatment of histoplasmosis in humans.     

In vitro activity of the new ketolide HMR3647 in comparison with those of macrolides and pristinamycins against Enterococcus spp

Ninety-four erythromycin-susceptible and 107 erythromycin-resistant enterococcal strains (MIC of >/=512 microgram/ml) were inhibited by the ketolide HMR3647 at MICs of 相似文献   

In vitro testing of susceptibilities of filamentous ascomycetes to voriconazole, itraconazole, and amphotericin B, with consideration of phylogenetic implications

The in vitro susceptibilities of three hundred eighty-one isolates representing two classes, five orders, nine families, 30 genera, and 51 species of ascomycetous fungi to voriconazole, itraconazole, and amphotericin B were tested by using a modification of the National Committee for Clinical Laboratory Standards M27-A reference method. For those fungi of known phylogenetic relatedness, drug MICs were consistently low for isolates among all clades, except for members of the family Microascaceae. The highest MICs of all drugs tested were consistently for the Microascaceae, supporting the observation of fungal phylogeny and corresponding susceptibility to antifungal drugs. Itraconazole and voriconazole have a broad range of activity against phylogenetically similar agents of hyalohyphomycosis, phaeohyphomycosis, chromoblastomycosis, and mycetoma.     

In vitro efficacy and fungicidal activity of voriconazole against Aspergillus and Fusarium species

Twenty-nine Aspergillus isolates and 25 Fusarium isolates underwent in vitro antifungal susceptibility testing by a broth macrodilution procedure adapted from the National Committee for Clinical Laboratory Standards guidelines. The MIC50s of both voriconazole and amphotericin B were 0.5 microg/ml and 1 microg/ml against species of Aspergillus and Fusarium, respectively, while the MIC90s of both agents were 1 and 2 microg/ml. Voriconazole was more active in vitro than amphotericin B: the geometric mean MICs of voriconazole and amphotericin B against Aspergillus spp. were 0.36 microg/ml and 0.64 microg/ml, respectively. Voriconazole also demonstrated fungicidal activity against Aspergillus spp., with 86% (24/29) of isolates exhibiting minimum lethal concentrations of < or = 4 microg/ml.     

In vitro and in vivo antifungal activity of amphotericin B lipid complex: are phospholipases important?

BACKGROUND: Second primary malignancies are common after bilateral retinoblastoma; their estimated incidence has been as high as 51% 50 years after diagnosis. Fifteen patients who developed sebaceous gland carcinoma after radiation therapy have been reported in the literature, five of whom were treated for bilateral retinoblastoma. METHODS: The authors conducted a retrospective chart review of patients treated for bilateral retinoblastoma at Duke University Medical Center who later developed sebaceous gland carcinoma. RESULTS: This article reports two patients who developed sebaceous gland carcinoma after radiation therapy for bilateral retinoblastoma. CONCLUSIONS: Delay in diagnosis is often associated with sebaceous gland carcinoma. Because high mortality is observed with metastatic disease, the recognition of this association is important for anyone who follows patients with a history of bilateral retinoblastoma or prior cranial radiation therapy.     

In vitro activity of fluvastatin, a cholesterol-lowering agent, and synergy with flucanazole and itraconazole against Candida species and Cryptococcus neoformans

Fluvastatin, a cholesterol-lowering drug, exhibited minimal activity (MICs of 64 to >128 microg/ml) against Candida species and Cryptococcus neoformans. When fluvastatin was combined with fluconazole or itraconazole, both synergistic and additive effects were noted (fractional inhibitory concentration indices of < or = 0.156 to 0.625; fractional lethal concentration indices of < or = 0.156 to 0.75). This combined fungicidal activity was confirmed by time-versus-killing studies.     

Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis

The interactions of amphotericin B and itraconazole were studied in murine invasive candidiasis. Candida albicans-infected mice were treated for 10 consecutive days, 24 h after infection. Survival was monitored over 30 days and kidney cultures were done. Mice treated with amphotericin B (0.2 mg/kg/day intraperitoneally) or itraconazole (100 mg/kg/day by oral gavage in two divided doses/ day) had a 30-day survival of 20% or 40%. Concomitant administration of both drugs resulted in 100% mortality; 90% of mice treated with amphotericin B (1 mg/kg/day) survived. With the combination, 100% were dead by day 28 (P < or = .001 vs. amphotericin B). With sequential therapy (i.e., 5 days with one drug and then 5 days with the other), survival was inferior to that with amphotericin B alone but similar to that with itraconazole alone. Kidney culture results confirmed the antagonism of the combination compared with amphotericin B alone. In treatment of murine invasive candidiasis, the concomitant or sequential use of amphotericin B and itraconazole results in a negative interaction.     

In vitro comparative efficacy of voriconazole and itraconazole against fluconazole-susceptible and -resistant Cryptococcus neoformans isolates

In vitro susceptibility testing for 50 clinical isolates of fluconazole-susceptible or -resistant Cryptococcus neoformans was performed with itraconazole and voriconazole. Voriconazole was more potent than itraconazole for fluconazole-susceptible isolates and as potent as itraconazole for fluconazole-susceptible dose-dependent isolates and for fluconazole-resistant isolates. For fluconazole-resistant isolates, the voriconazole and itraconazole MICs ranged from 1 to 2 microg/ml.     

In vitro activities of two glycylcyclines against gram-positive bacteria

The glycylcyclines designated CL 329,998 and CL 331,002 are N,N-dimethylglycylamido derivatives of minocycline and 6-demethyl-6-deoxytetracycline, respectively. In vitro activities of these two antimicrobial agents were compared with those of tetracycline, minocycline, and seven other antimicrobial agents against 412 gram-positive organisms. Both new drugs were significantly more active than minocycline against methicillin-resistant Staphylococcus aureus (MICs for 90% of isolates tested, 0.25 and 0.5 microgram/ml versus 4 micrograms/ml). CL 329,998 inhibited all streptococci, lactobacilli, and Leuconostoc spp. at concentrations of < or = 0.5 microgram/ml, with CL 331,002 slightly less active against some species. All enterococci, including minocycline-resistant and multidrug-resistant isolates, were inhibited at < or = 0.5- and < or = 1.0-microgram/ml concentrations of the new drugs, respectively. Only bacteriostatic activity was evident by time-kill curves. The two glycylcyclines demonstrated activities in vitro that were superior to those of minocycline against several gram-positive bacterial species, and at relatively low concentrations, they inhibited isolates resistant to both tetracycline and minocycline.     

In vitro activities of antimicrobial agents against Candida species

A single surgeon's consecutive series of 50 arthroscopically repaired meniscal tears in 48 patients was retrospectively reviewed. None of these patients had concomitant ligament damage to the knee. The average follow-up period was 10 years, 9 months. Criteria for clinical success included 1) history of pain of grade 1 or less and absence of locking, catching, or giving way; 2) a physical examination demonstrating no significant effusion and a painless and negative jump sign; and 3) no subsequent surgical procedures on the repaired meniscus. Patient satisfaction was quite high, although clinical confirmation was possible in only 38 knees, indicating a clinical success rate of 76%. Bilateral standing radiographs were obtained on these 38 operated knees and were evaluated using Fairbank's classification. Evaluation of the radiographs revealed that 8% of the operated knees had minimal joint changes, as compared with 3% in the contralateral, nonoperated knee. This study demonstrates that arthroscopic meniscal repair in knees with isolated meniscal tears has the potential for a long-term successful clinical and radiographic outcome.     

Accumulation of amphotericin B in human macrophages enhances activity against Aspergillus fumigatus conidia: quantification of conidial kill at the single-cell level

Several cardiac serum markers such as cardiac myosin light chain, creatine kinase MB, and cardiac troponins have been shown to be elevated in patients with acute myocardial infarction. These markers are well utilized as clinical indicators for diagnosis and prognosis of myocardial necrosis. Recent studies have strongly indicated that cardiac structural protein troponin T and I are predictive of future cardiac events in patients with acute coronary syndromes including unstable angina pectoris. Immunoassays have also been developed to measure serum levels of cardiac troponins in recent years. These biochemical markers may be useful as a guide for intervention in the near future.     

In vitro activities of ampicillin-sulbactam and amoxicillin-clavulanic acid against Acinetobacter baumannii

In vitro susceptibility patterns of newer beta-lactamase-inhibiting antibiotics ampicillin-sulbactam (A/S) and amoxicillin-clavulanic acid (A/C) for 100 consecutive isolates of Acinetobacter baumannii obtained from various clinical samples were studied. The A/C MIC for 86% of the strains was more than 16/8 microgram/ml, whereas there was an A/S MIC of more than 16/8 microgram/ml for only 38% of the strains. This showed that A/S has significantly superior in vitro activity compared to A/C against A. baumannii, although, theoretically, both should have similar activities. The therapeutic superiority of A/S over A/C needs to be studied, or else the breakpoints for these agents in in vitro tests need to be redefined.     

In vitro activity of dirithromycin against Chlamydia trachomatis

Dirithromycin is a new macrolide antibiotic with an active metabolite, erythromycylamine. We evaluated the in vitro activities of both drugs against 16 isolates of Chlamydia trachomatis and compared them with that of doxycycline. In vitro susceptibility testing was performed with McCoy cell monolayers. The MIC was defined as the lowest concentration of antibiotic without inclusions. The MBC was defined as the lowest concentration of antibiotic yielding no inclusions after passage onto 24-h-old antibiotic-free McCoy cell monolayers. Dirithromycin and erythromycylamine appeared to be equally effective against these 16 strains of C. trachomatis (MIC for 90% of strains tested, 1 mg/ml; MBC for 90% of strains tested, 2 micrograms/ml). Both were less active than doxycycline (MIC for 90% of strains tested, 0.06 micrograms/ml; MBC for 90% of strains tested, 0.12 micrograms/ml). The combination of dirithromycin and erythromycylamine appeared to be additive.