MICs Of Itraconazole Research Articles

Antifungal Susceptibilities of Clinical Isolates of Candida Species, Cryptococcus neoformans , and Aspergillus Species from Taiwan: Surveillance of Multicenter Antimicrobial Resistance in Taiwan Program Data from 2003

The susceptibilities of nonduplicate isolates to six antifungal agents were determined for 391 blood isolates of seven Candida species, 70 clinical isolates (from blood or cerebrospinal fluid) of Cryptococcus neoformans, and 96 clinical isolates of four Aspergillus species, which were collected in seven different hospitals in Taiwan (as part of the 2003 program of the study group Surveillance of Multicenter Antimicrobial Resistance in Taiwan). All isolates of Candida species other than C. glabrata and C. krusei were susceptible to fluconazole. Among the 59 C. glabrata isolates, 16 (27%) were not susceptible to fluconazole, and all were dose-dependently susceptible or resistant to itraconazole. For three (5.1%) C. glabrata isolates, voriconazole MICs were 2 to 4 microg/ml, and for all other Candida species isolates, voriconazole MICs were </=0.5 microg/ml. The proportions of isolates for which amphotericin B MICs were >/=2 microg/ml were 100% (3 isolates) for C. krusei, 11% (23 of 207 isolates) for Candida albicans, 3.0% (2 of 67 isolates) for Candida tropicalis, 20% (12 of 59 isolates) for C. glabrata, and 0% for both Candida parapsilosis and Candida lusitaniae. For three (4%) Cryptococcus neoformans isolates, fluconazole MICs were >/=16 microg/ml, and two (3%) isolates were not inhibited by 1 mug of amphotericin B/ml. For four (4.2%) of the Aspergillus isolates, itraconazole MICs were 8 microg/ml. Aspergillus flavus was less susceptible to amphotericin B, with the MICs at which 50% (1 microg/ml) and 90% (2 microg/ml) nsrsid417869\delrsid7301351 of isolates were inhibited being twofold greater than those for Aspergillus fumigatus and Aspergillus niger. All Aspergillus isolates were inhibited by </=1 microg of voriconazole/ml, including isolates with increased resistance to amphotericin B and itraconazole. This study revealed the emergence in Taiwan of decreased susceptibilities of Candida species to amphotericin B and of C. neoformans to fluconazole and amphotericin B. Voriconazole was the most potent agent against the fungal isolates tested, including fluconazole- and amphotericin B-nonsusceptible strains.

Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma

To monitor changes in itraconazole susceptibility of isolates from a patient undergoing treatment for pulmonary Aspergillus infection and relate these changes to genotypic/phenotypic alterations. Six Aspergillus fumigatus isolates were serially recovered from the patient. Itraconazole MICs were determined by Etest and NCCLS methodology. Growth characteristics and phenotype were monitored. Molecular analysis included random amplified polymorphic DNA (RAPD) assay and sequencing of the cyp51A gene. The MIC of itraconazole against the first isolate before treatment was 0.25 mg/L; the MIC against the second isolate, recovered after 6 months of itraconazole therapy, was >16 mg/L; and that against the third isolate, obtained 2 months after discontinuation of the therapy, was 0.5 mg/L. The MIC against the last three isolates, acquired after restoration of itraconazole therapy for 4-7 months, was >16 mg/L. The six isolates shared identical band patterns of RAPD assay using four primers and the same sequence in intertranscribed spacers (ITS). Therefore, the six isolates were likely to be the same strain of A. fumigatus, and mutations involving itraconazole resistance possibly occurred in these isolates after prolonged itraconazole therapy. Sequencing of the cyp51A gene in the coding region revealed a mutation of M220I in cytochrome P450 sterol 14-alpha-demethylase in the second resistant isolate and a mutation of G54R in the last three resistant isolates. Expression changes of some pump genes, such as MDR3, may also, in part, be related to the resistance to itraconazole. We conclude that resistance of A. fumigatus to itraconazole occurred in a patient treated with the drug, and the resistance may result from mutations in the cyp51A gene-the gene encoding the target enzyme for itraconazole.

Initial results from a longitudinal international surveillance programme for anidulafungin (2003)

This longitudinal study evaluated the in vitro activity of anidulafungin against 880 clinical yeast isolates and 68 mould isolates from 64 medical centres in North America, Latin America and Europe. MICs of anidulafungin, amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole and voriconazole were determined using reference method (M27-A2) guidelines. The M38-A reference method was used for the filamentous fungi, including determination of minimum effective concentrations (MECs) of anidulafungin. Anidulafungin was more active when compared with fluconazole and itraconazole for Candida albicans (MIC(90), 0.06 mg/L), Candida tropicalis (MIC(90), 0.06 mg/L), Candida glabrata (MIC(90), 0.12 mg/L), Candida krusei (MIC(90), 0.06 mg/L) and Candida lusitaniae (MIC(90), 1 mg/L) as well as the less-often encountered yeast species. Anidulafungin was less active against Candida parapsilosis, Candida guilliermondii and Candida famata (MIC(50), 1-2 mg/L). Anidulafungin also exhibited excellent activity against all Aspergillus spp. (MEC(90), < or =0.03 mg/L). Anidulafungin was also evaluated comparing two end point reading criteria and two incubation intervals. Data indicate that longer incubation periods do not significantly influence overall MIC ranges. These international surveillance results for anidulafungin confirm the activity observed in studies of smaller numbers of isolates.

In vitro susceptibilities of isolates of Sporothrix schenckii to itraconazole and terbinafine.

Thirty isolates of the yeast form of Sporothrix schenckii were evaluated for in vitro susceptibility to itraconazole and terbinafine by the recommended NCCLS modified technique (M27-A2). The MICs of itraconazole obtained oscillated between 0.062 and 4.0 microg/ml, and those of terbinafine oscillated between 0.007 and 0.50 microg/ml; therefore, terbinafine showed greater in vitro activity.

In vitro activities of three licensed antifungal agents against spanish clinical isolates of Aspergillus spp.

The aim of the present study was to identify retrospectively trends in the species distributions and the susceptibility patterns of Aspergillus species causing fungal infections in Spanish medical centers from 2000 to 2002. The susceptibilities of 338 isolates to amphotericin B, itraconazole, and voriconazole were tested. Aspergillus fumigatus was the most common species (54.7%), followed by Aspergillus terreus (14.8%) and Aspergillus flavus (13.9%). Non-A. fumigatus species were encountered in 45.3% of the samples studied. The majority of Aspergillus isolates were obtained from respiratory tract specimens, followed by ear and skin samples. The geometric mean (GM) MIC of amphotericin B was 0.56 micro g/ml, and the amphotericin B MIC was >2 micro g/ml for 16 isolates (4.7%). Nine of them were A. terreus. The GM MIC of itraconazole was 0.37, and the itraconazole MIC was >4 micro g/ml for 12 (3.5%) isolates. The voriconazole MICs were also high for 8 of the 12 strains for which itraconazole MICs were high (voriconazole MIC range, 2 to 8 micro g/ml).

Identification of genes differentially expressed in association with reduced azole susceptibility in Saccharomyces cerevisiae.

An isolate of S. cerevisiae with reduced susceptibility to fluconazole and itraconazole was developed in the laboratory and used to identify genes that are differentially expressed in association with this phenotype. S. cerevisiae strain ATCC 9763 was passaged in increasing concentrations of itraconazole. Itraconazole and fluconazole MICs for the initial isolate (9763S) were 2 and 16 mg/L and for the final isolate (9763I) were 16 and > or =64 mg/L, respectively. Duplicate sets of total RNA from 9763S and 9763I were isolated and hybridized to Affymetrix S98 yeast arrays. To validate results, six differentially expressed genes were further examined by RT-PCR. Of the nearly 6400 open reading frames represented on the array, a total of 116 genes (1.8%) were found to be differentially expressed. Cell wall maintenance genes TIR4 and CCW12, sterol metabolism gene UPC2, small molecule transport genes AUS1 and YHK8, and stress response gene CUP1-1 were expressed at a level at least 2.5-fold higher than the expression level found in 9763S. Eleven energy generation genes, ionic homeostasis genes FRE1, FRE2 and FRE4, and sterol metabolism genes ERG8 and ERG13 were expressed at least 2.5-fold lower than the expression level found in 9763S. Several genes found to be differentially expressed in this study have been shown previously to be differentially expressed in the fungal response to azole treatment. In addition, the potential role of AUS1 and/or YHK8 as mediators of drug efflux is intriguing and warrants further study.

Histone Deacetylase Inhibitors Enhance Candida albicans Sensitivity to Azoles and Related Antifungals: Correlation with Reduction in CDR and ERG Upregulation

Histone acetylation and deacetylation play important roles in eukaryotic gene regulation. Several histone deacetylase (HDA) inhibitors have been characterized, including trichostatin A (TSA), apicidin, and sodium butyrate. We tested their effects on Candida albicans in vitro growth, heat sensitivity, and germ tube formation; minimal effects were observed. However, there was a dramatic effect of TSA on C. albicans sensitivity to the azoles fluconazole, itraconazole, and miconazole. Similar effects were observed with other HDA inhibitors and with the antifungals terbinafine and fenpropimorph, which target, as do azoles, enzymes in the ergosterol biosynthetic pathway. In contrast, HDA inhibitors had minimal effect on the activities of amphotericin B, flucytosine, and echinocandin, which have unrelated targets. Specifically, addition of 3 micro g of TSA/ml lowered the itraconazole MIC for five susceptible C. albicans isolates an average of 2.7-fold at 24 h, but this increased to >200-fold at 48 h. Thus, the primary effect of TSA was a reduction in azole trailing. TSA also enhanced itraconazole activity against Candida parapsilosis and Candida tropicalis but had no effect with four less related yeast species. To examine the molecular basis for these effects, we studied expression of ERG genes (encoding azole and terbinafine targets) and CDR/MDR1 genes (encoding multidrug transporters) in C. albicans cells treated with fluconazole or terbinafine with or without TSA. Both antifungals induced to various levels the expression of ERG1, ERG11, CDR1, and CDR2; addition of TSA reduced this upregulation 50 to 100%. This most likely explains the inhibition of azole and terbinafine trailing by TSA and, more generally, provides evidence that trailing is mediated by upregulation of target enzymes and multidrug transporters.

Detection of human P-glycoprotein-like molecule in azole-resistant Candida albicans from HIV+ patients.

Azole resistance in Candida albicans may be due to several mechanisms. It has been demonstrated that C. albicans possesses sequences with a high degree of homology with the human MDR-1 gene coding for P-glycoprotein (P-gp), belonging to the ATP-binding cassette transporter (ABC) superfamily and responsible for the multidrug resistance (MDR) in tumor cells. On this basis, the expression and intracellular localization of human P-gp-like molecule in C. albicans strains showing different sensitivity to fluconazole were investigated by flow cytometry and immunoelectron microscopy. Post-embedding immunolabeling revealed that monoclonal antibody (mAb) MM4.17, which recognizes an external epitope of human P-gp, reacted with both fluconazole-sensitive (3153 and CO 23-1) and fluconazole-resistant (AIDS 68 and CO 23-2, isolated from AIDS patient and in vitro drug-selected, respectively) strains of C. albicans. However, the resistant strains displayed a number of MM4.17-reactive epitopes much higher than the drug-sensitive ones. The C. krusei ATCC 6458 strain, whose resistance is not mediated by the presence of ABC transporters, was not reactive at all with mAb MM4.17. The specificity of the immunolabeling was confirmed by a competitive inhibition assay performed by using phage clone particles capable of mimicking the MM4.17-reactive epitope. The flow cytometric analysis confirmed a higher level of intracytoplasmic P-gp expression in azole-resistant strains of C. albicans. Both cyclosporin A and verapamil, which are well-known MDR inhibitors, strongly reduced the MICs for fluconazole and itraconazole of the tested azole-resistant AIDS 68 strain, while they did not influence the MICs of either the sensitive 3153 strain of C. albicans or the ATCC 6458 strain of C. krusei. Overall, our data suggest the existence of a P-gp-like drug efflux pump in C. albicans that may participate in the mechanisms of azole-resistance of this fungus.

In vivo activity of posaconazole against Mucor spp. in an immunosuppressed-mouse model.

The in vivo activities of posaconazole, itraconazole, and amphotericin B in neutropenic mice with zygomycosis were compared. The in vitro MICs of posaconazole and itraconazole for the strains of Mucor spp. used in this study ranged from 0.125 to 8 microg/ml and 0.25 to 8 microg/ml, respectively. The in vitro MIC range for amphotericin B is 0.125 to 0.25 microg/ml. At twice-daily doses of >or=15 mg/kg of body weight, posaconazole prolonged the survival of the mice and reduced tissue burden.

Comparison of NCCLS microdilution method and Etest in antifungal susceptibility testing of clinical Trichosporon asahii isolates

We investigated the in vitro activity of amphotericin B, fluconazole, and itraconazole against clinical Trichosporon asahii isolates ( n = 43) by NCCLS M27A reference microdilution method and explored the correlation between Etest and NCCLS reference method. Microdilution MIC ranges following 48 h of incubation were 1–8, 0.25–16, and 0.06–4 μg/ml for amphotericin B, fluconazole, and itraconazole, respectively. The corresponding Etest MIC ranges were determined as 0.125- > 8, 0.25- > 64, and 0.03–8 μg/ml. Of interest, Etest tended to produce lower amphotericin B MICs and widen the MIC range compared to microdilution. The influence of Etest on fluconazole and itraconazole MICs was in contrary with that observed for amphotericin B. Etest MICs of fluconazole and itraconazole tended to be higher than microdilution MICs. The wider range of amphotericin B MICs obtained by using Etest methodology may facilitate discrimination of isolates with reduced susceptibility to amphotericin B. However, clinical significance of these findings remain yet unknown and determination of MIC breakpoint values is required.

In vitro and in vivo activities of posaconazole against Coccidioides immitis.

Posaconazole (SCH 56592) was tested against 25 strains of Coccidioides immitis to determine their in vitro susceptibilities. The geometric mean 48-h MIC of posaconazole (POSA) was 0.5 microg/ml, the MIC range was 0.25 to 1 microg/ml, and the MIC at which 50% of the isolates tested are inhibited (MIC50) and the MIC90 were 0.5 and 1 microg/ml, respectively. The geometric mean 48-h MIC of itraconazole (ITRA) was 0.23 microg/ml, the MIC range was 0.125 to 0.5 microg/ml, and the MIC50 and MIC90 were both 0.25 microg/ml. Two strains of C. immitis were selected for in vivo studies on the basis of the POSA 48-h MICs for the isolates. POSA orally administered at 0.01, 0.1, 0.5, 1, 5, and 10 mg/kg of body weight/day was compared with ITRA administered at 10 and 30 mg/kg three times a day. The spleens and livers of mice that died or survived to day 50 were removed to measure the fungal burdens. Mice had >or=90% survival when they were treated with >or=0.5 mg of POSA per kg or 30 mg of ITRA per kg. Cultures of whole spleens and livers from mice treated with 10 mg of POSA per kg showed >or=70% sterilization. No sterilization of whole spleens and livers from mice treated with ITRA was seen. POSA displayed potent in vivo activity against the two strains of C. immitis tested.

Azole cross-resistance in Aspergillus fumigatus.

We susceptibility tested 17 clinical isolates of Aspergillus fumigatus, for most of which MICs of itraconazole were elevated (MIC at which 50% of the isolates tested are inhibited, 16 microg/ml), against itraconazole, posaconazole, ravuconazole, and voriconazole. Posaconazole was the most active against itraconazole-susceptible isolates. A complex pattern of cross-resistance and hypersusceptibility was seen with voriconazole and ravuconazole, suggesting marked differences in activity and mechanisms of resistance.

Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998.

The antifungal drug susceptibilities of two collections of Cryptococcus 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 (MIC(50)s), and the MIC(90)s 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 (>or=2 microg/ml) for 2 isolates, and the MICs of flucytosine were elevated (>or=32 microg/ml) for 14 isolates. Among the azoles, the fluconazole MIC was elevated (>or=64 microg/ml) for 8 isolates and the itraconazole MIC (>or=1 microg/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.

Treatment of Absidia corymbifera infection in mice with amphotericin B and itraconazole

The activities of amphotericin B and itraconazole were studied in a temporarily neutropenic murine model of disseminated Absidia corymbifera infection, caused by two different strains. Amphotericin B MICs were 0.25 mg/L for both strains and itraconazole MICs were 1 and 2 mg/L. Amphotericin B was effective in vivo with both isolates. Itraconazole was less effective.

Resistance to itraconazole in Aspergillus nidulans and Aspergillus fumigatus is conferred by extra copies of the A. nidulans P-450 14alpha-demethylase gene, pdmA.

Triazoles selectively inhibit the cytochrome P-450-dependent C-14 lanosterol alpha-demethylase (P-450 14 alpha DM), a key enzyme in ergosterol biosynthesis in fungi. To investigate mechanisms of triazole resistance in a mould, we used Aspergillus nidulans, a genetically amenable model fungus closely related to more pathogenic members of the genus. We selected for genes that would give resistance to itraconazole following transformation with a high copy genomic library of A. nidulans. In all the resistant colonies that we isolated, resistance was conferred by extra copies of the A. nidulans P-450 14 alpha DM gene, pdmA. We determined that in A. nidulans, extra copies of pdmA increase the MIC for itraconazole 36 times over wild-type controls. Similarly, transformation of an Aspergillus fumigatus strain with pITZR1 resulted in increased resistance to itraconazole. Our results indicate that triazole resistance in clinical isolates of moulds may result from amplification or overexpression of the P-450 14 alpha DM and demonstrate the utility of A. nidulans as a promising model fungus for the analysis of drug resistance and susceptibility in the pathogenic fungus A. fumigatus.

Sputum itraconazole concentrations in cystic fibrosis patients.

Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients with allergic bronchopulmonary aspergillosis. There was a high interindividual variability in sputum itraconazole concentration and sputum/serum drug concentration ratio. Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range.

Comparison of the Etest and microdilution method for antifungal susceptibility testing of Cryptococcus neoformans to four antifungal agents

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).

A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology

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 0.25-32xMIC 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°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, 32μg/ml and 0.03, 0.06, 0.5μg/ml, respectively. For amphotericin B, the MIC was 0.25μg/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 8-16xMIC 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 >4xMIC for the low inoculum and >8xMIC 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 8-16xMIC. Amphotericin B, on the other hand, was concentration-dependent; thus, greater activity was exerted at higher concentrations.

Pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Candida albicans☆

The objective of this study was to evaluate the pharmacodynamic activity of fluconazole, itraconazole, and amphotericin B against Candida albicans. Susceptibilities were determined according to the NCCLS guidelines (M27). Time-kill studies were performed using antifungal concentrations of 0.25–32 × MIC. Samples were withdrawn at predetermined timepoints, then plated using a spiral plater. Colony counts were determined after incubation at 35°C for 24 h. The AUKC 0–48 was plotted against the concentration/MIC ratio. Candida isolates (95-2672, 96-15, and 95-2542) were classified as susceptible, susceptible-dose dependent, and resistant to fluconazole and itraconazole (MIC = 0.25 and 0.03 μg/mL, 32 and 0.5 μg/mL, 64 and 1 μg/mL; respectively). All three isolates were susceptible to amphotericin B (MIC = 0.13 μg/mL). Fluconazole inhibited the growth of the susceptible and S-DD isolates and was ineffective at all concentrations against the resistant isolate. Itraconazole, on the other hand, inhibited growth of the susceptible isolate, but was ineffective for the S-DD and resistant isolates. Maximal effectiveness was noted at the concentration 8 × MIC and 2 × MIC for fluconazole and itraconazole, respectively. Amphotericin B demonstrated concentration-dependent antifungal activity. The times necessary for the colony counts to fall below the limit of quantification were inversely related to increasing concentrations of amphotericin B. The maximal effect for amphotericin B was recorded at 2 × MIC. In summary, the triazoles inhibit growth of susceptible C. albicans; however, careful consideration should be given to the MIC for S-DD isolates because itraconazole may not be active if the MIC is reported in the higher susceptible-dose dependency range. In reference to amphotericin B, optimal activity may be achieved by maximizing the peak drug concentration/MIC ratio.

In-vivo itraconazole resistance of Aspergillus fumigatus in systemic murine aspergillosis. EBGA Network. European research group on Biotypes and Genotypes of Aspergillus fumigatus.

An animal model of disseminated aspergillosis was used to test the in-vivo activity of itraconazole against four isolates of Aspergillus fumigatus. Two reference isolates of A. fumigatus known to be resistant to itraconazole in vitro and in vivo were used as control isolates, and two new isolates were tested under the same conditions. For each isolate MICs for itraconazole and amphotericin B were determined by an NCCLS-based method. Mice infected intravenously were treated either with itraconazole 100 mg/ kg/day or amphotericin B 4.5 mg/kg/day for 10 days. Amphotericin B showed good in-vivo activity against all four isolates. For one strain, which had a low in-vitro MIC for itraconazole, in-vivo therapy with itraconazole prolonged the survival of mice and reduced fungal burdens in organs compared with untreated controls. In mice infected with a strain with a high MIC of >16 mg/L, itraconazole neither prolonged survival nor reduced fungal load in organs compared with controls. It is concluded that there is a relationship between MIC and treatment outcome in mice for A. fumigatus infection.