In vitro activity of the new triazole BMS-207147 against Aspergillus species in comparison with itraconazole and amphotericin B

The in vitro activity of BMS-207147 against 80 clinical isolates of Aspergillus was compared with that of itraconazole and amphotericin B, using a validated microtiter method. Geometric mean MICs (in microg/ml) were as follows: 1.71 for BMS-207147, 0.67 for itraconazole, and 0.63 for amphotericin B. The range of concentrations of each drug was 0.125 to >16 microg/ml. Aspergillus fumigatus was significantly more susceptible to BMS-207147 (P < 0. 05) than A. terreus and A. flavus. No BMS-207147-resistant A. fumigatus isolates were identified, though eight itraconazole-resistant (MIC, >8 microg/ml) isolates were. BMS-207147 is active against Aspergillus spp. at slightly high concentrations compared with itraconazole and amphotericin B.     

E test法检测3种抗真菌药物对128株酵母菌的体外活性

目的调查我院酵母菌对氟康唑等3种抗菌药的敏感性，指导临床用药。方法使用Etest法测定3种抗真菌药对128株酵母菌的MIC。结果两性霉素B对128株酵母菌的抗菌活性最强(敏感率94．5％，MIC50和MIC90分别为0．25和1mg／L)，其次为氟康唑和伊曲康唑(前者敏感率92．2％，MIC50和MIC90为2和8mg／L；后者为64．1％．MIC50和MIC90为0．064和0．75mg／L)；71株白念珠菌对两性霉素B、氟康唑和伊曲康唑的敏感率分别为100％、98．5％和91．6％；30株热带念珠菌对氟康唑、两性霉素B和伊曲康唑的敏感率分别为96．7％、86．7％和19．9％；12株光滑念珠菌对两性霉素B、氟康唑和伊曲康唑的敏感率分别为100％、74．9％和33．3％。结论我院自念珠菌对3种抗真菌药高度敏感，非白念念珠菌对3种抗真菌药表现不同程度耐药，应加强对非白念念珠菌耐药性的监控。     

In vitro activity of antifungal agents against yeast species

The antimicrobial activity of 8 antifungal agents have been compared in vitro against 151 strains of yeast fungi and 2 of Geotrichum candidum. The drugs were the classical nystatin and amphotericin-B, 5-flucytosine, and 5 imidazoles, clotrimazole, econazole, ketoconazole, miconazole, and tioconazole. An agar dilution technique with incubation at 37 degrees C was used. By this procedure, econazole was the most active agent per weight basis among those suitable for topical therapy. Tioconazole had a wide spectrum and high activity. Ketoconazole had an antimicrobial activity which makes it an interesting agent considering its applicability in systemic therapy. The activity of 5-flucytosine surpasses that of other systemically applicable agents.     

In vitro activities of ravuconazole (BMS-207147) against 541 clinical isolates of Cryptococcus neoformans

The in vitro activities of the new triazole, ravuconazole (BMS-207147), were compared to those of fluconazole and itraconazole against 541 clinical isolates of Cryptococcus neoformans. Isolates were obtained from cerebrospinal fluid (396), blood (116), and miscellaneous clinical specimens (29). Overall, ravuconazole (MIC at which 90% of the isolates are inhibited [MIC(90)], 0.25 microg/ml) was more active than either itraconazole (MIC(90), 0.5 microg/ml) or fluconazole (MIC(90), 8 microg/ml). Among the isolates inhibited by > or =16 microg of fluconazole/ml, 90.2% were inhibited by < or =1 microg of ravuconazole/ml. On the basis of our findings and the favorable pharmacokinetic properties of ravuconazole, we suggest that ravuconazole may be useful for the treatment of infectious diseases due to C. neoformans and that further clinical studies to confirm these promising in vitro results are warranted.     

Patterns of in vitro activity of itraconazole and imidazole antifungal agents against Candida albicans with decreased susceptibility to fluconazole from Spain.

Two groups of recent clinical isolates of Candida albicans consisting of 101 isolates for which fluconazole MICs were < or = 0.5 microgram/ml (n = 50) and > or = 4.0 micrograms/ml (n = 51), respectively, were compared for their susceptibilities to fluconazole, clotrimazole, miconazole, ketoconazole, and itraconazole. Susceptibility tests were performed by a photometer-read broth microdilution method with an improved RPMI 1640 medium supplemented with 18 g of glucose per liter (RPMI-2% glucose; J. L. Rodríguez-Tudela and J. V. Martínez-Suárez, Antimicrob. Agents Chemother. 38:45-48, 1994). Preparation of drugs, basal medium, and inocula was done by the recommendations of the National Committee for Clinical Laboratory Standards. The MIC endpoint was calculated objectively from the turbidimetric data read at 24 h as the lowest drug concentration at which growth was just equal to or less than 20% of that in the positive control well (MIC 80%). In vitro susceptibility testing separated azole-susceptible strains from the strains with decreased susceptibilities to azoles if wide ranges of concentrations (20 doubling dilutions) were used for ketoconazole, miconazole, and clotrimazole. By comparison with isolates for which fluconazole MICs were < or = 0.5 microgram/ml, those isolates for which fluconazole MICs were > or = 4.0 micrograms/ml were in general less susceptible to other azole drugs, but different patterns of decreased susceptibility were found, including uniform increases in the MICs of all azole derivatives, higher MICs of several azoles but not others, and elevated MICs of fluconazole only. On the other hand, decreased susceptibility to any other azole drug was never found among strains for which MICs of fluconazole were lower.     

In vitro antifungal activity of BMS-181184 against systemic isolates of Candida,Cryptococcus, and Blastomyces species

BMS-181184 is a water-soluble derivative of the pradimicin group of antifungal compounds. We determined the in vitro activities of BMS-181184 and comparator agents amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 184 systemic fungal isolates collected at the Health Sciences Centre in Winnipeg, Canada, between 1987 and 1995. BMS-181184 demonstrated MICs of between 1 and 8 μg/mL for all Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida lusitaniae, and Cryptococcus neoformans isolates tested. BMS-181184 was less active against Candida parapsilosis (MIC₉₀ = 16 μg/mL) and Blastomyces dermatitidis (MIC₉₀ = 32 μg/mL). Isolates of Candida species with fluconazole MICs of ≥16 μg/mL and those with fluconazole MICs of ≤8 μg/mL demonstrated similar BMS-181184 sensitivities.     

In vitro activities of 10 antifungal drugs against 508 dermatophyte strains

We have tested 508 strains belonging to 24 species of dermatophytes against 10 antifungal drugs following mainly the NCCLS (M38-P) standard for filamentous fungi. However, several important factors, such as the temperature (28 versus 35 degrees C) and time of incubation (4 to 10 days versus 21 to 74 h), have been modified. The antifungals used were itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, terbinafine, amphotericin B, fluconazole, UR-9825, and G-1. In general, with the exception of fluconazole and G-1, all antifungals were shown to be highly effective.     

In vitro susceptibility of 245 yeast isolates to amphotericin B, 5-fluorocytosine, ketoconazole, fluconazole and itraconazole.

The in vitro activity of amphotericin B, 5-fluorocytosine, ketoconazole, fluconazole and itraconazole was tested against 245 yeast strains isolated from clinical specimens (68 Candida albicans, 74 Candida tropicalis, 43 Candida krusei, 28 Candida glabrata, 19 Candida parapsilosis, 8 Candida lusitaniae and 5 Candida guilliermondii). An agar dilution method was employed to carry out testing. Minimal inhibitory concentrations to restrain 90% of isolate growth (MIC90) ranged from 0.12 to 2 mg/l for amphotericin B and for 5-fluorocytosine, from 0.03 to 8 mg/l for ketoconazole, from 0.05 to 50 mg/l for itraconazole and from 0.1 to > 100 mg/l for fluconazole. Among the azole derivatives, the most active was ketoconazole, followed by itraconazole. Only 1 strain of C. albicans was resistant to amphotericin B (MIC > 4 mg/l). Both C. tropicalis and C. krusei responded poorly to fluconazole and the former to itraconazole as well. The species most susceptible to the antifungal agents tested was C. glabrata and the most resistant were C. tropicalis and C. krusei.     

In vitro interaction of terbinafine with itraconazole,fluconazole, amphotericin B and 5-flucytosine against Aspergillus spp

We investigated the in vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine, against Aspergillus spp. We tested three isolates of Aspergillus fumigatus (one resistant to itraconazole), and two each of Aspergillus flavus, Aspergillus niger and Aspergillus terreus. We employed a broth microdilution-based method derived from an in vivo validated method capable of detecting itraconazole resistance in A. fumigatus. We studied the effect on the MICs by calculation of the fractional inhibitory concentration (FIC) and fractional fungicidal concentration (FFC) (99.99% kill). Itraconazole and terbinafine were synergic or additive in all strains (FIC = 0.15-1.0). Fluconazole and terbinafine were synergic with A. fumigatus, A. terreus and A. flavus (FIC = 0.3-0.5) and indifferent with A. niger (FIC = 2) isolates. Amphotericin B and terbinafine were mostly indifferent or antagonistic (FIC = 1.0-4.02). Flucytosine and terbinafine were usually indifferent or antagonistic (FIC = 0.63-8.5). FFCs were generally in accord with FICs. The use of terbinafine in combination therapy for Aspergillus infections with azoles seems promising, whereas terbinafine and amphotericin B or flucytosine in combination were less effective.     

In vitro activity of sertaconazole against dermatophyte isolates with reduced fluconazole susceptibility

We have studied the in vitro antifungal activity of sertaconazole against 114 dermatophytes with low susceptibility to fluconazole following the National Committee for Clinical Laboratory Standards for filamentous fungi (M38-P). However, several important factors such as the temperature (28 vs. 35 degrees C) and time of incubation (4-10 days vs. 21-74 h), have been found to affect dermatophytes. Isolates were recently recovered from human samples. Sertaconazole was active against 114 isolates of 12 fungal dermatophyte species, showing an overall geometric mean of 0.41 microg/ml with a minimum inhibitory concentration (MIC) range of 0.01-2 microg/ml against these isolates with reduced fluconazole susceptibility. Differences between both antifungals were significant (p < 0.05). MIC(50) and MIC(90) of sertaconazole were of 0.5 and 1 microg/ml, respectively, while the MIC of fluconazole was >/=16 microg/ml. None of the isolates was resistant to sertaconazole during the study while for four isolates the MIC of fluconazole was >/=64 microg/ml. No evidence of cross-resistance between both antifungals was found.     

In vitro activity of antifungal drugs against Plasmodium falciparum field isolates

The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs necessitates a continuous effort to develop new antimalarial agents. We therefore aimed to assess the in vitro activity of the antifungal drugs clotrimazole, fluconazole, ketoconazole, itraconazole, voriconazole, flucytosine, amphotericin B, and caspofungin against field isolates of P. falciparum from Lambaréné, Gabon. Using the histidin-rich protein 2 (HRP-2) assay we determined the drug susceptibility (EC(50), EC(90)) of 16 field isolates obtained from outpatients attending the Albert Schweitzer Hospital in Lambaréné, Gabon. For fluconazole, itraconazole and caspofungin the in vitro growth inhibition of these drugs is reported for the first time. Our data indicate that clotrimazole, fluconazole, itraconazole and caspofungin show median EC(50) values of 3.1 μg/mL, 1.9 μg/mL, 1.1 μg/mL and 1.1 μg/mL respectively. Ketoconazole, voriconazole, flucytosine and amphotercin B showed no relevant growth inhibition within the range of drug concentrations used in this study.     

In vitro activity of systemic antifungal agents against Malassezia furfur.

The activity of four antifungal agents against 15 systemic (blood and vascular catheter) and 10 superficial (skin) Malassezia furfur isolates was evaluated. MIC ranges were similar for the two groups of organisms: amphotericin B, 0.3 to 2.5 micrograms/ml; flucytosine, greater than 100 micrograms/ml; miconazole, 0.4 to 1.5 micrograms/ml; and ketoconazole, 0.025 to 0.4 micrograms/ml.     

In vitro activities of terbinafine in combination with fluconazole and itraconazole against isolates of Candida albicans with reduced susceptibility to azoles.

A checkerboard microdilution method was applied to study the in vitro interaction of terbinafine with either fluconazole and itraconazole against 30 strains of Candida albicans. Synergy was observed in 40% of the terbinafine-fluconazole interactions and in 43% of the terbinafine-itraconazole interactions, while antagonism was not observed. Even when only additivity was achieved, the combinations still showed beneficial effects since at least twofold reductions in the MICs of both drugs were found in 100% of the terbinafine-fluconazole interactions and in 76% of the terbinafine-itraconazole interactions.     

In vitro antibacterial activity of fluoroquinolones against Porphyromonas gingivalis strains

OBJECTIVES: The objective of the study was to evaluate the in vitro activity of ciprofloxacin, gatifloxacin and moxifloxacin against 16 Porphyromonas gingivalis strains. METHODS: MICs of the quinolones were established by Etest and the agar dilution technique. Experiments focused on determination of the spontaneous mutation rate and the induction of resistant strains, using 0.25-fold MIC of antibiotic. Fragments of gyrA and gyrB as well as of parC were sequenced. RESULTS: Moxifloxacin and gatifloxacin had very low MIC values. Subinhibitory concentrations of the fluoroquinolones rapidly induced mutations. The spontaneous mutation rate was strain- and quinolone-dependent; the lowest rate was encountered after moxifloxacin. The predicted serum concentrations of the quinolones were bactericidal to wild-type strains, but 100 mg/L of each tested quinolone was insufficient to kill a mutant exhibiting moderate resistance. Often the mutants exhibited high resistance to >/=32 mg/L. All these mutants bore a Ser-83-->Phe substitution in GyrA. CONCLUSIONS: DNA gyrase is the primary target of fluoroquinolones in P. gingivalis. In terms of the achievable level in the gingival fluid and the MICs, moxifloxacin might prevent the development of resistance and may be an alternative in the antibiotic treatment of P. gingivalis-associated periodontitis.     

In vitro comparison of terbinafine and itraconazole against Penicillium marneffei

We evaluated terbinafine and itraconazole against 30 isolates of Penicillium marneffei using a modification of the National Committee for Clinical Laboratory Standards broth macrodilution MIC testing protocol for yeasts. The minimal fungicidal concentration (MFC) was determined by plating 100 microl from each MIC drug dilution having no growth onto Sabouraud glucose agar incubated at 30 degrees C. The MFC was the dilution at which growth was absent at 72 h of incubation. The MICs, in micrograms per milliliter, were as follows: terbinafine, 0.03 to 1.0 (geometric mean titer, 0.09); itraconazole, 0.03 to 0.5 (geometric mean titer, 0.04). The MFCs, in micrograms per milliliter, were as follows: terbinafine, 0.03 to 8 (geometric mean titer, 2.60); itraconazole, 0.03 to 8 (geometric mean titer, 2. 45). Primary fungicidal activity (MFC within 2 dilutions of MIC) was observed with terbinafine in eight isolates and with itraconazole in four isolates. The data indicate that terbinafine is active against P. marneffei in vitro and may have a previously unrealized role in the management of infections caused by this fungus.     

In vitro activities of the new antifungal triazole SCH 56592 against common and emerging yeast pathogens

A broth microdilution method performed in accordance with the National Committee for Clinical Laboratory Standards guidelines was used to compare the in vitro activity of the new antifungal triazole SCH 56592 (SCH) to that of fluconazole (FLC), itraconazole (ITC), and ketoconazole (KETO) against 257 clinical yeast isolates. They included 220 isolates belonging to 12 different species of Candida, 15 isolates each of Cryptococcus neoformans and Saccharomyces cerevisiae, and seven isolates of Rhodotorula rubra. The MICs of SCH at which 50% (MIC(50)) and 90% (MIC(90)) of the isolates were inhibited were 0.06 and 2.0 microg/ml, respectively. In general, SCH was considerably more active than FLC (MIC(50) and MIC(90) of 1.0 and 64 microg/ml, respectively) and slightly more active than either ITC (MIC(50) and MIC(90) of 0.25 and 2.0 microg/ml, respectively) and KETO (MIC(50) and MIC(90) of 0.125 and 4.0 microg/ml, respectively). Our in vitro data suggest that SCH has significant potential for clinical development.     

In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes

In vitro antifungal susceptibility testing results of a new antifungal triazole, posaconazole (POS), were compared to results with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), and fluconazole (FLC) against clinical agents of zygomycosis. The MICs of POS at which 50% and 90% of the isolates were inhibited were 0.25 and 4 microg/ml, respectively. POS was significantly more active than VRC and FLC and slightly more active than ITC. The results suggest that POS has significant potential for clinical development against the zygomycetes.     

In vitro susceptibility study of BMS-284756 against Legionella species.

Legionella organisms are often associated with respiratory infections, and Legionella pneumonia results in significant mortality unless it is promptly and effectively treated. The present study was undertaken to compare the in vitro activity of BMS-284756 (T-3811ME), a novel des-F(6)-quinolone, against Legionella species versus the activity of other fluoroquinolones (levofloxacin, moxifloxacin, and ciprofloxacin) and of the macrolides erythromycin, clarithromycin, and azithromycin. The most potent agents tested against Legionella pneumophila serogroup 1, the largest group tested, were BMS-284756, moxifloxacin, and levofloxacin (MIC(90) = 0.016 mg/L). The MIC(90) range for BMS-284756 was 0.008-0.03 mg/L against the total panel of L pneumophila serogroups 1-9 and 12, with the lowest MIC(90) observed for serogroup 7 and the highest for serogroup 2. BMS-284756 was one of the most potent agents tested against isolates of L micdadei, L longbeachae, and other Legionella species (MIC(90) range: 0.008-0.06 mg/L). These results and the high intrinsic activity of BMS-284756 against other respiratory pathogens support its use as empiric monotherapy for a wide range of respiratory infections.     

In vitro antifungal and fungicidal spectra of a new pradimicin derivative, BMS-181184.

A new pradimicin derivative, BMS-181184, was compared with amphotericin B and fluconazole against 249 strains from 35 fungal species to determine its antifungal spectrum. Antifungal testing was performed by the broth macrodilution reference method recommended by the National Committee for Clinical Laboratory Standards (document M27-P, 1992). BMS-181184 MICs for 97% of the 167 strains of Candida spp., Cryptococcus neoformans, Torulopsis glabrata, and Rhodotorula spp. tested were < or = 8 micrograms/ml, with a majority of MICs being 2 to 8 micrograms/ml. Similarly, for Aspergillus fumigatus and 89% of the 26 dermatophytes tested BMS-181184 MICs were < or = 8 micrograms/ml. BMS-181184 was fungicidal for the yeasts, dermatophytes, and most strains of A. fumigatus, although the reduction in cell counts was less for A. fumigatus than for the yeasts. BMS-181184 was active against Sporothrix schenckii, dematiaceous fungi, and some members of the non-Aspergillus hyaline hyphomycetes. BMS-181184, however, was not fungicidal against members of the family Dematiaceae. BMS-181184 lacked activity or had poorer activity (MICs, > or = 16 micrograms/ml) against Aspergillus niger, Aspergillus flavus, Malassezia furfur, Fusarium spp., Pseudallescheria boydii, Alternaria spp., Curvularia spp., Exserohilum mcginnisii, and the zygomycetes than against yeasts. The activity of BMS-181184 was minimally (twofold or less) affected by changes in testing conditions (pH, inoculum size, temperature, the presence of serum), testing methods (agar versus broth macrodilution), or test media (RPMI 1640, yeast morphology agar, high resolution test medium). Overall, our results indicate that BMS-181184 has a broad antifungal spectrum and that it is fungicidal to yeasts and, to a lesser extent, to filamentous fungi.