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Query: UNIPROT:Q29983 (MIC)
 21,138 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amphotericin B (AMB) is considered the gold standard in the treatment of serious systemic mycoses in spite of its nephrotoxicity and adverse effects. Association with lipids enables larger doses of AMB to be given with a longer t((1/2)) and C(max), without the toxic effects at lower concentrations. Liposome-encapsulated AMB shows a lower affinity for mammalian cells and improves V(d), thus decreasing toxicity. Amphotericin B lipid complex (ABLC) is an AMB formulation associated with a biodegradable phospholipid matrix (5% molar) from which the drug is released by cell phospholipases. ABLC is recommended for serious mycoses refractory to conventional antifungal therapy or when AMB is contraindicated. We compared the in vitro antifungal activity of ABLC, AMB and fluconazole (FLZ) against 328 strains of clinically significant opportunistic fungi using a microdilution method (NCCLS, M-27A). 64.9% of the yeasts were inhibited by MIC of ABLC </= AMB resulting in a similar or slightly superior efficacy compared to AMB when tested against Candida albicans, C. glabrata, C. guilliermondii, C. parapsilosis and C. tropicalis. Effectiveness against C. krusei was lower for ABLC (5.99 microg/ml for ABLC, 1.58 microg/ml for AMB). However, for Aspergillus fumigatus, the activities of AMB and ABLC were 1.62 and 2.46 microg/ml, respectively; A. niger 0.72 microg/ml, 0.76 microg/ml (ABLC and AMB, respectively); A. clavatus, A. candidus, A. tenuissima, A. corymbifera and Exophiala jeanselmei, Scedosporium spp. and Miceliophtora spp. showed a low susceptibility to both AMB formulations. ABLC is a useful alternative to AMB or FLZ for the treatment of severe fungal infections, due to the broad spectrum of antifungal actions observed in this study.
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PMID:Comparative in vitro antifungal activity of amphotericin B lipid complex, amphotericin B and fluconazole. 1085 29

This study evaluated the in vitro pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans. MICs were determined for three clinical isolates according to NCCLS guidelines (M27). Time-kill studies were performed using antifungal concentrations of 0.25-32 x MIC and inocula of 10(3) and 10(5) CFU/ml. At predetermined time points over 72 hours, samples of each inoculum/drug combination were withdrawn and plated using a spiral plater. Colony counts were determined after incubation at 35 degrees C for 48 hours. Area under the kill curves (AUKCs) were plotted versus the AUC/MIC ratios. Inoculum effect was evaluated by calculating an estimated AUKC for the low inoculum then comparing it to the measured low inoculum using the unpaired Student's t-test. The MICs of fluconazole and itraconazole for isolate 97-1199, 97-1061, and 97-585 were 2, 4, 32 microg/ml and 0.03, 0.06, 0. 5 microg/ml, respectively. For amphotericin B, the MIC was 0. 25 microg/ml for each isolate. The triazoles demonstrated fungistatic activity against each isolate at both inocula with the exception of itraconazole against C. neoformans 97-585. Maximal suppression was noted at concentrations 8-16 x MIC correlating with an AUC/MIC of 192 for both inocula. Conversely, amphotericin B was fungicidal and displayed concentration-dependent activity against each isolate at both inocula. Maximal killing was observed at concentrations >4 x MIC for the low inoculum and >8 x MIC for the high inoculum for each isolate. No statistically significant differences were detected between the measured and estimated AUKCs for each antifungal agent. In conclusion, our results suggest that the triazoles were most effective against C. neoformans when concentrations were maintained at 8-16 x MIC. Amphotericin B, on the other hand, was concentration-dependent; thus, greater activity was exerted at higher concentrations.
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PMID:A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology. 1103 39

Voriconazole is a promising azole effective against a variety of fungi, including yeasts. In this study, we tested in vitro activities of voriconazole, fluconazole, itraconazole and amphotericin B against some ATCC and reference strains and 250 clinical yeast isolates. We also evaluated the effect of time of reading on MIC results. Voriconazole was the most active agent against Candida and Trichosporon isolates, including the putatively fluconazole-resistant C. krusei (MIC(90) 0.25 microg/ml) and C. glabrata (MIC(90) 0.5 microg/ml). Amphotericin B MICs were scattered in a considerably narrow range in both RPMI 1640 and Antibiotic Medium 3. MICs at 24 hours and 48 hours were similar in general for all antifungals tested. The highest percentage of strains that showed 24-hour and 48-hour MICs within +/-1-log(2) dilution was observed for amphotericin B tested in RPMI (99%), and the lowest for amphotericin B tested in Antibiotic Medium 3 (80%). In conclusion, voriconazole is very effective against a wide spectrum of Candida species and 24-hour readings could substitute 48-hour MIC evaluation.
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PMID:Susceptibility testing of voriconazole, fluconazole, itraconazole and amphotericin B against yeast isolates in a Turkish University Hospital and effect of time of reading. 1103 41

We performed a prospective study to compare the Etest and the microdilution method (NCCLS guidelines) for determining the MICs of fluconazole, itraconazole, flucytosine and amphotericin B for 35 strains of Cryptococcus neoformans. For the microdilution method (MDM) RPMI 1640 medium with 2% glucose was used for fluconazole, itraconazole and flucytosine, and Antibiotic Medium 3 for amphotericin B. For the Etest, RPMI 1640 medium with 2% glucose and solidified with 1.5% agar was used for the four antifungal agents. Amphotericin B was also tested on Antibiotic Medium 3 solidified with 1.5% agar. Fluconazole and flucytosine MICs by the Etest showed good correlation with the broth MDM (81.1 and 89.2% agreement within two dilutions, respectively). With the tested population of itraconazole- and amphotericin B-susceptible isolates, the MIC agreement for itraconazole was 54%; amphotericin B showed the lowest agreement (8.1% on Antibiotic Medium 3 and 13.5% on RPMI).
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PMID:Comparison of the Etest and microdilution method for antifungal susceptibility testing of Cryptococcus neoformans to four antifungal agents. 1110 21

Both intrinsic and acquired resistance to amphotericin B have been documented for Candida lusitaniae. Amphotericin B remains the drug of choice for many critical fungal infections, and the detection of resistance is essential to monitor treatment effectively. The limitations of the National Committee for Clinical Laboratory Standards (NCCLS) reference methodology for detection of amphotericin B resistance are well documented, and several alternative methods have been proposed. Etest assays with RPMI and antibiotic medium 3 (AM3) agar were compared to the NCCLS M27-A broth macrodilution method using AM3 for amphotericin B resistance testing with 49 clinical isolates of C. lusitaniae. The panel included nine isolates with known or presumed resistance to amphotericin B on the basis of in vivo and/or in vitro data. The distribution of amphotericin B MICs by Etest with RPMI ranged from 0. 032 to 16 microg/ml and was bimodal. All of the putatively resistant isolates were inhibited by amphotericin B at >/=0.38 microg/ml and could be categorized as resistant using this breakpoint. Etest with AM3 yielded a broader amphotericin B MIC range (0.047 to 32 microg/ml), and there were six putatively resistant isolates for which MICs were >1 microg/ml. The separation of putatively susceptible and resistant isolates was less obvious. Broth macrodilution with AM3 generated a unimodal distribution of MICs (ranging from 0.032 to 2 microg/ml) and failed to discriminate most of the putatively resistant isolates at both 24 and 48 h. Etest using RPMI and, to a lesser extent, using AM3 provided better discrimination between amphotericin B-resistant and -susceptible isolates of C. lusitaniae.
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PMID:Improved detection of amphotericin B-resistant isolates of Candida lusitaniae by Etest. 1113 95

In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 10(6) CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h. Increasing doses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R(2)] = 90 to 93%; AUC/MIC ratio, R(2) = 49 to 69%; T > MIC, R(2) = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses. Given the narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.
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PMID:Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. 1118 81

The increase in the use of antifungal agents for prophylaxis and therapy has led to the development of antifungal drug resistance. Drug combinations may prevent or delay resistance development. The aim of the present study was to investigate whether naturally and designed cationic antifungal peptides act synergistically with commonly used antimycotics. No enhanced activity was found upon addition of dhvar4, a designed analogue of the human salivary peptide histatin 5, or PGLa to fluconazole or 5-flucytosine, respectively. In contrast, strong synergism of amphotericin B with the peptides was found against several Aspergillus, Candida, and Cryptococcus strains, and against an amphotericin B-resistant C. albicans laboratory mutant in the standardised broth microdilution assays according to the NCCLS standard method M27-T. Amphotericin B showed synergism with dhvar5, another designed analogue of histatin 5, and with magainin 2 against all seven tested strains. Combinations of amphotericin B with histatin 5, dhvar4, and PGLa showed synergism against four of the seven strains. The growth inhibitory activity of amphotericin B was enhanced by sub-MIC concentrations of peptide, but its haemolytic activity remained unaffected, suggesting that its cytotoxicity to host cells was not increased and that peptides may be suitable candidates for combination therapy.
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PMID:Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity. 1120 68

The in vitro activity of terbinafine alone and in combination with other antifungal agents was tested against isolates of Aspergillus fumigatus, A. flavus and A. niger. Testing was performed in a modified National Committee for Clinical Laboratory Standards (NCCLS) macrodilution broth assay, and interactions were examined using a checkerboard design. Terbinafine was highly active against Aspergillus isolates (minimum inhibitory concentration [MIC] 0.01 to 2 microg ml(-1)) with a primary fungicidal action (minimum fungicidal concentration [MFC] 0.02 to 4 microg ml(-1)). Amphotericin B was also highly active and cidal as expected (MIC 1 microg ml(-1), MFC 1 to 4 microg ml(-1)). The triazoles itraconazole and voriconazole were highly active but showed a variable degree of cidal activity against the different strains, voriconazole having the more potent cidal activity. Fluconazole had no significant activity (MIC > 128 microg ml(-1)). Drug combinations were tested in the A. fumigatus and A. niger strains. Terbinafine and amphotericin showed an additive to synergistic interaction depending on the isolate. Combinations of terbinafine with itraconazole or voriconazole displayed a potent synergistic interaction and fungicidal activity against all isolates. Surprisingly, fluconazole also potentiated the activity of terbinafine in an additive to synergistic fashion, despite its lack of activity alone. The results suggest potential clinical application of terbinafine in aspergillosis, either alone or in combination with amphotericin or triazoles.
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PMID:Synergistic interaction of terbinafine with triazoles or amphotericin B against Aspergillus species. 1127 Apr 14

Three methods were compared for the susceptibility testing of yeast isolates to fluconazole and amphotericin B: two fagar diffusion methods (Etest and a tablet diffusion test) and the National Committee for Clinical Laboratory Standards (NCCLS) broth microdilution method. Given as MIC(50)s (range), fluconazole endpoints were: for the 24 h broth microdilution test, 0.25 mg/L (0.06-32 mg/L); for the Etest, 0.38 mg/L (0.064-24 mg/L); and for the NCCLS broth microdilution test, 2 mg/L (0.06->or=64 mg/L). With breakpoints of <3 mg/L for susceptible and >16 mg/L for resistant, the Etest and the 24 h microdilution test classified the isolates in agreement with the classification obtained by the NCCLS method. Results obtained by Etest were in closer NCCLS method than those obtained with the tablet test. Amphotericin B endpoints were lower for the 24 h microdilution and Etests than MICs obtained by the NCCLS broth microdilution method. Reproducibility was high for all tests; however, disadvantages of both diffusion tests were microcolonies in the inhibition zone and dependence on stringent standardization of inoculum.
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PMID:Comparison of Etest and a tablet diffusion test with the NCCLS broth microdilution method for fluconazole and amphotericin B susceptibility testing of Candida isolates. 1132 61

The in vitro activity of flucytosine (5FC) against 1,140 clinical isolates of Candida spp. and Cryptococcus neoformans was evaluated and compared with the activity of amphotericin B, fluconazole and itraconazole. Overall, 87.72% (1,000/1,140) of yeasts were susceptible to 5FC. This agent showed less potent in vitro activity against Candida glabrata, Candida krusei, Candida guilliermondii and Cryptococcus neoformans (MIC90s, 8-16 microg/ml) and intermediate activity or resistance to 6.5% of Candida albicans, 5.1% of Candida tropicalis and 0.8% of Candida parapsilosis strains. Amphotericin B showed potent activity against isolates with an MIC of 5FC > or = 8 microg/ml. A total of 112 of 140 strains that were SFC-intermediate or -resistant showed decreased susceptibility to azoles (P < 0.01).
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PMID:Flucytosine primary resistance in Candida species and Cryptococcus neoformans. 1139 20


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