scholarly journals Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro.

1997 ◽  
Vol 41 (2) ◽  
pp. 331-336 ◽  
Author(s):  
S P Franzot ◽  
A Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Susceptibility ◽  
National Committee ◽  
Tetrazolium Salt ◽  
Salt Reduction ◽  
Fluconazole Resistant ◽  
Subinhibitory Concentrations ◽  
Combination Regimens

Cryptococcus neoformans infections in patients with AIDS are often incurable, despite aggressive antifungal therapy. Combination regimens with additive or synergistic drugs could provide additional options for treating cryptococcal meningitis. We evaluated the efficacy of combination therapies using L-743,872, a pneumocandin antifungal drug, and amphotericin B or fluconazole against 18 strains of C. neoformans, including 11 C. neoformans var. neoformans, 3 C. neoformans var. gattii, and 4 fluconazole-resistant isolates. The combination of subinhibitory concentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C. neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Clinical and Laboratory Standards method), quantitative CFU, and tetrazolium salt reduction assays. Similarly, the addition of subinhibitory concentrations of L-743,872 to fluconazole enhanced fluconazole activity, but the effect was less dramatic than for the pneumocandin-amphotericin B combination. A marked synergism was observed in all combinations of amphotericin B and L-743, 872 (fractional inhibitory concentration index [FIC] of < or = 0.5). Fluconazole-resistant strains showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates. Combinations of pneumocandin with fluconazole revealed different activities for the various strains, including synergism (FIC < 1.0), additivity (FIC = 1.0), and autonomy (FIC between 1.0 and 2.0). Combination studies with fluconazole and L-743,872 showed additive and autonomous activities against fluconazole-resistant isolates. No antagonistic interactions (FIC < 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole. The results of this study suggest that L-743,872 can enhance the efficacy of fluconazole or amphotericin B in vitro and indicate a potential role for L-743,872 in combination therapy against C. neoformans.

scholarly journals Comparative Evaluation of FUNGITEST and Broth Microdilution Methods for Antifungal Drug Susceptibility Testing of Candida Species and Cryptococcus neoformans

1998 ◽  
Vol 36 (4) ◽  
pp. 926-930 ◽  
Author(s):  
Kate G. Davey ◽  
Ann D. Holmes ◽  
Elizabeth M. Johnson ◽  
Adrien Szekely ◽  
David W. Warnock
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Susceptibility Testing ◽  
Clinical Laboratory ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
National Committee ◽  
Broth Microdilution ◽  
Fluconazole Resistant

The FUNGITEST method (Sanofi Diagnostics Pasteur, Paris, France) is a microplate-based procedure for the breakpoint testing of six antifungal agents (amphotericin B, flucytosine, fluconazole, itraconazole, ketoconazole, and miconazole). We compared the FUNGITEST method with a broth microdilution test, performed according to National Committee for Clinical Laboratory Standards document M27-A guidelines, for determining the in vitro susceptibilities of 180 isolates ofCandida spp. (50 C. albicans, 50C. glabrata, 10 C. kefyr, 20C. krusei, 10 C. lusitaniae, 20C. parapsilosis, and 20 C. tropicalisisolates) and 20 isolates of Cryptococcus neoformans. Overall, there was 100% agreement between the methods for amphotericin B, 95% agreement for flucytosine, 84% agreement for miconazole, 83% agreement for itraconazole, 77% agreement for ketoconazole, and 76% agreement for fluconazole. The overall agreement between the methods exceeded 80% for all species tested with the exception ofC. glabrata (71% agreement). The poorest agreement between the results for individual agents was seen with C. glabrata (38% for fluconazole, 44% for ketoconazole, and 56% for itraconazole) and C. tropicalis (50% for miconazole). The FUNGITEST method misclassified as susceptible 2 of 12 (16.6%) fluconazole-resistant isolates, 2 of 10 (20%) itraconazole-resistant isolates, and 4 of 8 (50%) ketoconazole-resistant isolates of several Candida spp. Further development of the FUNGITEST procedure will be required before it can be recommended as an alternative method for the susceptibility testing of Candida spp. or C. neoformans.

Use of spectrophotometric reading for in vitro antifungal susceptibility testing ofAspergillusspp.

1999 ◽  
Vol 45 (10) ◽  
pp. 871-874 ◽  
Author(s):  
Eric Dannaoui ◽  
Florence Persat ◽  
Marie-France Monier ◽  
Elisabeth Borel ◽  
Marie-Antoinette Piens ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Susceptibility Testing ◽  
Clinical Laboratory ◽  
Antifungal Susceptibility ◽  
Reference Method ◽  
Antifungal Susceptibility Testing ◽  
Aspergillus Species ◽  
National Committee ◽  
Broth Microdilution Method

A comparative study of visual and spectrophotometric MIC endpoint determinations for antifungal susceptibility testing of Aspergillus species was performed. A broth microdilution method adapted from the National Committee for Clinical Laboratory Standards (NCCLS) was used for susceptibility testing of 180 clinical isolates of Aspergillus species against amphotericin B and itraconazole. MICs were determined visually and spectrophotometrically at 490 nm after 24, 48, and 72h of incubation, and MIC pairs were compared. The agreement between the two methods was 99% for amphotericin B and ranged from 95 to 98% for itraconazole. It is concluded that spectrophotometric MIC endpoint determination is a valuable alternative to the visual reference method for susceptibility testing of Aspergillus species.Key words: antifungal, susceptibility testing, Aspergillus, spectrophotometric reading.

scholarly journals Interactions between Triazoles and Amphotericin B against Cryptococcus neoformans

2000 ◽  
Vol 44 (9) ◽  
pp. 2435-2441 ◽  
Author(s):  
Francesco Barchiesi ◽  
Anna M. Schimizzi ◽  
Francesca Caselli ◽  
Andrea Novelli ◽  
Stefania Fallani ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Clinical Laboratory ◽  
Fungal Infections ◽  
National Committee ◽  
Positive Interaction ◽  
Pronounced Increase

ABSTRACT The interaction of amphotericin B (AmB) and azole antifungal agents in the treatment of fungal infections is still a controversial issue. A checkerboard titration broth microdilution-based method that adhered to the recommendations of the National Committee for Clinical Laboratory Standards was applied to study the in vitro interactions of AmB with fluconazole (FLC), itraconazole (ITC), and the new investigational triazole SCH 56592 (SCH) against 15 clinical isolates ofCryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of ≤0.50, was observed for 7% of the isolates in studies of the interactions of both FLC-AmB and ITC-AmB and for 33% of the isolates in studies of the SCH-AmB interactions; additivism (FICs, >0.50 to 1.0) was observed for 67, 73, and 53% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively; indifference (FICs, >1.0 to ≤2.0) was observed for 26, 20, and 14% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively. Antagonism (FIC >2.0) was not observed. When synergy was not achieved, there was still a decrease, although not as dramatic, in the MIC of one or both drugs when they were used in combination. To investigate the effects of FLC-AmB combination therapy in vivo, we established an experimental model of systemic cryptococcosis in BALB/c mice by intravenous injection of cells of C. neoformans 2337, a clinical isolate belonging to serotype D against which the combination of FLC and AmB yielded an additive interaction in vitro. Both survival and tissue burden studies showed that combination therapy was more effective than FLC alone and that combination therapy was at least as effective as AmB given as a single drug. On the other hand, when cells of C. neoformans 2337 were grown in FLC-containing medium, a pronounced increase in resistance to subsequent exposures to AmB was observed. In particular, killing experiments conducted with nonreplicating cells showed that preexposure to FLC abolished the fungicidal activity of the polyene. However, this apparent antagonism was not observed in vivo. Rather, when the two drugs were used sequentially for the treatment of systemic murine cryptococcosis, a reciprocal potentiation was often observed. Our study shows that (i) the combination of triazoles and AmB is significantly more active than either drug alone against C. neoformans in vitro and (ii) the concomitant or sequential use of FLC and AmB for the treatment of systemic murine cryptococcosis results in a positive interaction.

scholarly journals In Vitro Susceptibilities of Candida dubliniensisIsolates Tested against the New Triazole and Echinocandin Antifungal Agents

1999 ◽  
Vol 37 (3) ◽  
pp. 870-872 ◽  
Author(s):  
M. A. Pfaller ◽  
S. A. Messer ◽  
S. Gee ◽  
S. Joly ◽  
C. Pujol ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Clinical Laboratory ◽  
National Committee ◽  
Mucosal Disease ◽  
Fluconazole Resistant ◽  
Resistant Strains ◽  
Investigational Agents ◽  
Multidrug Resistance Transporters

Candida dubliniensis is a newly recognized fungal pathogen causing mucosal disease in AIDS patients. Although preliminary studies indicate that most strains of C. dubliniensis are susceptible to established antifungal agents, fluconazole-resistant strains have been detected. Furthermore, fluconazole-resistant strains are easily derived in vitro, and these strains exhibit increased expression of multidrug resistance transporters, especially MDR1. Because of the potential for the development of resistant strains of C. dubliniensis, it is prudent to explore the in vitro activities of several of the newer triazole and echinocandin antifungals against isolates of C. dubliniensis. In this study we tested 71 isolates of C. dubliniensis against the triazoles BMS-207147, Sch 56592, and voriconazole and a representative of the echinocandin class of antifungal agents, MK-0991. We compared the activities of these agents with those of the established antifungal agents fluconazole, itraconazole, amphotericin B, and 5-fluorocytosine (5FC) by using National Committee for Clinical Laboratory Standards microdilution reference methods. Our findings indicate that the vast majority of clinical isolates of C. dubliniensis are highly susceptible to both new and established antifungal agents. Strains with decreased susceptibilities to fluconazole remained susceptible to the investigational agents as well as to amphotericin B and 5FC. The increased potencies of the new triazole and echinocandin antifungal agents may provide effective therapeutic options for the treatment of infections due to C. dubliniensis.

scholarly journals Trends in Antifungal Drug Susceptibility of Cryptococcus neoformans Isolates in the United States: 1992 to 1994 and 1996 to 1998

2001 ◽  
Vol 45 (11) ◽  
pp. 3065-3069 ◽  
Author(s):  
Mary E. Brandt ◽  
Michael A. Pfaller ◽  
Rana A. Hajjeh ◽  
Richard J. Hamill ◽  
Peter G. Pappas ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Clinical Laboratory ◽  
The United States ◽  
Drug Susceptibility ◽  
Antifungal Drug ◽  
National Committee ◽  
Broth Microdilution Method

ABSTRACT The antifungal drug susceptibilities of two collections ofCryptococcus neoformans isolates obtained through active laboratory-based surveillance from 1992 to 1994 (368 isolates) and 1996 to 1998 (364 isolates) were determined. The MICs of fluconazole, itraconazole, and flucytosine were determined by the National Committee for Clinical Laboratory Standards broth microdilution method; amphotericin B MICs were determined by the E-test. Our results showed that the MIC ranges, the MICs at which 50% of isolates are inhibited (MIC50s), and the MIC90s of these four antifungal agents did not change from 1992 to 1998. In addition, very small numbers of isolates showed elevated MICs suggestive of in vitro resistance. The MICs of amphotericin B were elevated (≥2 μg/ml) for 2 isolates, and the MICs of flucytosine were elevated (≥32 μg/ml) for 14 isolates. Among the azoles, the fluconazole MIC was elevated (≥64 μg/ml) for 8 isolates and the itraconazole MIC (≥1 μg/ml) was elevated for 45 isolates. Analysis of 172 serial isolates from 71 patients showed little change in the fluconazole MIC over time. For isolates from 58 patients (82% of serial cases) there was either no change or a twofold change in the fluconazole MIC. In contrast, for isolates from seven patients (12% of serial cases) the increase in the MIC was at least fourfold. For isolates from another patient there was a 32-fold decrease in the fluconazole MIC over a 1-month period. We conclude that in vitro resistance to antifungal agents remains uncommon in C. neoformans and has not significantly changed with time during the past decade.

scholarly journals In Vitro and In Vivo Antifungal Activities of T-2307, a Novel Arylamidine

2008 ◽  
Vol 52 (4) ◽  
pp. 1318-1324 ◽  
Author(s):  
Junichi Mitsuyama ◽  
Nobuhiko Nomura ◽  
Kyoko Hashimoto ◽  
Eio Yamada ◽  
Hiroshi Nishikawa ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Activities ◽  
Spectrum Activity ◽  
Effective Doses ◽  
Fluconazole Resistant ◽  
Clinically Significant ◽  
Dose Dependent

ABSTRACT The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 μg/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 μg/ml), and Aspergillus species (MIC range, 0.0156 to 4 μg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg·kg−1·dose−1, respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.

scholarly journals In vitro susceptibilities of clinical and environmental isolates of Cryptococcus neoformans to five antifungal drugs.

1996 ◽  
Vol 40 (3) ◽  
pp. 822-824 ◽  
Author(s):  
S P Franzot ◽  
J S Hamdan
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Clinical Laboratory ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
National Committee ◽  
Environmental Isolates ◽  
Susceptibility Data

A total of 53 Cryptococcus neoformans strains, including clinical and environmental Brazilian isolates, were tested for their susceptibilities to amphotericin B, 5-flucytosine, ketoconazole, fluconazole, and itraconazole. The tests were performed according to the National Committee of Clinical Laboratory Standards recommendations (document M27-P). In general, there was a remarkable homogeneity of results for all strains, and comparable MICs were found for environmental and clinical isolates. This paper represents the first contribution in which susceptibility data for Brazilian C. neoformans isolates are provided.

scholarly journals Melanization of Cryptococcus neoformans and Histoplasma capsulatum Reduces Their Susceptibilities to Amphotericin B and Caspofungin

2002 ◽  
Vol 46 (11) ◽  
pp. 3394-3400 ◽  
Author(s):  
David van Duin ◽  
Arturo Casadevall ◽  
Joshua D. Nosanchuk
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Fungal Pathogens ◽  
Histoplasma Capsulatum ◽  
Clinical Laboratory ◽  
National Committee ◽  
Broth Macrodilution ◽  
Mammalian Infection

ABSTRACT The fungal pathogens Cryptococcus neoformans and Histoplasma capsulatum produce melanin-like pigments in the presence of l-dopa in vitro and during mammalian infection. We investigated whether melanization affected the susceptibilities of the fungi to amphotericin B, caspofungin, fluconazole, itraconazole, or flucytosine (5FC). Using the standard macrodilution MIC protocol (the M27A protocol) of the National Committee for Clinical Laboratory Standards for yeast, we found no difference in the susceptibilities of melanized and nonmelanized C. neoformans and H. capsulatum isolates. Killing assays demonstrated that melanization reduced the susceptibilities of both fungi to amphotericin B and caspofungin. Laccase-deficient C. neoformans cells grown with l-dopa were significantly more susceptible than congenic melanin-producing yeast to killing by amphotericin B or caspofungin. Preincubation of amphotericin B or caspofungin with melanins decreased their antifungal activities. Elemental analysis of melanins incubated with amphotericin B or caspofungin revealed an alteration in the C:N ratios of the melanins, which indicated binding of these drugs by the melanins. In contrast, incubation of fluconazole, itraconazole, or 5FC with melanins did not significantly affect the antifungal efficacies of the drugs or the chemical composition of the melanins. The results suggest a potential explanation for the inefficacy of caspofungin against C. neoformans in vivo, despite activity in vitro. Furthermore, the results indicate that fungal melanins protect C. neoformans and H. capsulatum from the activities of amphotericin B and caspofungin and that this protection is not demonstrable by standard broth macrodilution assays.

scholarly journals Metarrhizium anisopliae as a Cause of Sinusitis in Immunocompetent Hosts

1999 ◽  
Vol 37 (1) ◽  
pp. 195-198 ◽  
Author(s):  
Sanjay G. Revankar ◽  
Deanna A. Sutton ◽  
Stephen E. Sanche ◽  
Jyothi Rao ◽  
Marcus Zervos ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Susceptibility Testing ◽  
Chronic Sinusitis ◽  
Clinical Laboratory ◽  
Antifungal Susceptibility ◽  
National Committee ◽  
Insect Populations ◽  
Clinically Significant ◽  
Control Insect

Metarrhizium anisopliae is a common pathogen of insects and has even been used to control insect populations. It is rarely isolated from human or animal sources, but recently, there have been three reported cases of disease, two in humans and one in a cat. We present our experience with five isolates from human sources, including two that were the apparent causes of two cases of sinusitis in immunocompetent hosts. The first patient was a 36-year-old male with frontal and ethmoid sinusitis, and the second was a 79-year-old female with chronic sinusitis. Both patients underwent surgery, and pathology of the surgical specimens revealed branching hyphae. Cultures grew onlyMetarrhizium species. Neither patient received antifungal therapy, and both did well postoperatively. The other three isolates were cultured from bronchoalveolar lavage specimens but were not felt to be clinically significant. Antifungal susceptibility testing using the National Committee for Clinical Laboratory Standards macrobroth method revealed that all isolates were resistant to amphotericin B, 5-flucytosine, and fluconazole. Itraconazole and newer azole compounds were more active. Metarrhizium species may cause disease in humans, even those without evidence of immunosuppression, and are apparently highly resistant to amphotericin B in vitro.

scholarly journals Comparison of MIC Test Strip and Sensititre YeastOne with the CLSI and EUCAST Broth Microdilution Reference Methods for In Vitro Antifungal Susceptibility Testing of Cryptococcus neoformans

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Fatima Zohra Delma ◽  
Abdullah M. S. Al-Hatmi ◽  
Jochem B. Buil ◽  
Hein van der Lee ◽  
Marlou Tehupeiory-Kooreman ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Test Strip ◽  
Error Rates ◽  
Broth Microdilution ◽  
Content Type ◽  
In Vitro Antifungal Susceptibility

ABSTRACT We compared MIC test strip (MTS) and Sensititre YeastOne (SYO) methods with EUCAST and CLSI methods for amphotericin B, 5-fluocytosine, fluconazole, voriconazole, and isavuconazole against 106 Cryptococcus neoformans isolates. The overall essential agreement between the EUCAST and CLSI methods was >72% and >94% at ±1 and ±2 dilutions, respectively. The essential agreements between SYO and EUCAST/CLSI for amphotericin B, 5-flucytosine, fluconazole, and voriconazole were >89/>93% and between MTS and EUCAST/CLSI were >57/>75%. Very major error rates were low for amphotericin B and fluconazole (<3%) and a bit higher for the other drugs (<8%).

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