Correlation of in vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1

Cameron, Miriam L.; Schell, Wiley A.; Bruch, Steve; Bartlett, John A.; Waskin, Hetty; Perfect, John R.

doi:10.1128/aac.37.11.2449

Cited by 152 publications

(92 citation statements)

References 22 publications

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“…A total of 1,295 patient-episode-isolate events in which patients were infected with Candida spp., received fluconazole therapy, and were characterized as treatment successes or failures at the end of therapy were included in 12 published clinical databases (Table 5). These studies included seven (692 patientepisode-isolate events) in which the infection was mucosal in nature and where the daily dose of fluconazole was typically 100 mg/day (6,14,15,37,80,84,88) and five (603 patientepisode-isolate events) in which invasive candidiasis (bloodstream, tissue, normally sterile-site infection) was treated with higher doses (usually 400 mg/day) of fluconazole (5,18,38,84,100). Although the clinical response was not stratified by species of Candida, the species distribution in these studies was typical for the two broad infection types: mucosal (80% C. albicans, 20% non-C. albicans) and invasive (40% C. albicans, 60% non-C. albicans).…”

Section: Clinical Correlation and Support Of Clsi Mic Breakpoints Formentioning

confidence: 99%

Interpretive Breakpoints for Fluconazole and Candida Revisited: a Blueprint for the Future of Antifungal Susceptibility Testing

2006

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SUMMARY Developing interpretive breakpoints for any given organism-drug combination requires integration of the MIC distribution, pharmacokinetic and pharmacodynamic parameters, and the relationship between in vitro activity and outcome from both in vivo and clinical studies. Previously, the Subcommittee for Antifungal Testing of the Clinical and Laboratory Standards Institute (CLSI [formerly National Committee for Clinical Laboratory Standards]) proposed MIC interpretive breakpoints for fluconazole and Candida spp. These breakpoints were considered to be somewhat weak, because the clinical data supporting them came largely from mucosal infections and there were very few infections involving strains with elevated fluconazole MICs. We readdress the issue of fluconazole breakpoints for Candida by using published clinical and microbiologic data to provide further validation of the breakpoints proposed by the CLSI in 1997. We also address interpretive breakpoints for agar disk diffusion testing of fluconazole. The MIC distribution for fluconazole was determined with a collection of 13,338 clinical isolates. The overall MIC at which 90% of the isolates were inhibited was 8 μg/ml: 91% were susceptible (S) at a MIC of ≤8 μg/ml and 3% were resistant (R) (MIC ≥ 64 μg/ml). Similar results were obtained for 2,190 isolates from randomized clinical trials. Analysis of available data for 1,295 patient-episode-isolate events (692 represented mucosal infections and 603 represented invasive infections) from 12 published clinical studies demonstrated an overall success rate of 77%, including 85% for those episodes in which the fluconazole MIC was ≤8 μg/ml, 67% for those episodes in which the MIC was 16 to 32 μg/ml, and 42% for those episodes with resistant (MIC ≥ 64 μg/ml) isolates. Pharmacodynamic analysis demonstrated a strong relationship between MIC, fluconazole dose, and outcome. A dose/MIC ratio of ∼25 was supportive of the following susceptibility breakpoints for fluconazole and Candida spp.: S, MIC ≤ 8 μg/ml; susceptible-dose dependent (SDD), MIC = 16 to 32 μg/ml; R, MIC ≥ 64 μg/ml. The corresponding disk test breakpoints are as follows: S, ≥19 mm; SDD, 15 to 18 mm; R, ≤14 mm.

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Section: Clinical Correlation and Support Of Clsi Mic Breakpoints Formentioning

confidence: 99%

Interpretive Breakpoints for Fluconazole and Candida Revisited: a Blueprint for the Future of Antifungal Susceptibility Testing

2006

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“…However, amphotericin B has a number of adverse side effects and fluconazole exhibits only fungistatic activity. Furthermore, mutants resistant to these drugs are emerging in Candida species and Cryptococcus neoformans (Cameron et al, 1993;Paugam et al, 1994;White et al, 1998). Therefore, it has become an important issue to develop new antifungal agents that are fungicidal, less toxic, and employ different mechanisms of action for use in combination drug therapies.…”

Section: Introductionmentioning

confidence: 99%

Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans

2006

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Fludioxonil is employed as an agricultural fungicide to control plant-pathogenic fungi such as Botrytis cinerea. Cryptococcus neoformans is a basidiomycetous human fungal pathogen that causes fatal disease in immunocompromised hosts. This paper demonstrates that three different signalling cascades regulate sensitivity of C. neoformans to fludioxonil. Fludioxonil inhibited growth of the serotype A sequence reference strain H99 but not that of the sequenced serotype D strain JEC21. In the drug-sensitive wild-type strain, fludioxonil exposure activated the Hog1 osmosensing pathway, and hog1D mutations conferred fludioxonil resistance. Fludioxonil treatment caused cell growth inhibition following cell swelling and cytokinesis defects in the sensitive wild-type but not in a hog1D mutant strain, suggesting that Hog1 activation results in morphological cellular defects. Fludioxonil exerted a fungistatic effect on the wild-type strain H99, but exhibited fungicidal activity against calcineurin mutant strains, indicating that the calcineurin pathway contributes to drug resistance in this fungus. Combination of fludioxonil and the calcineurin inhibitor FK506 synergistically inhibited C. neoformans growth. mpk1D MAPK mutant strains exhibited fludioxonil hypersensitivity, indicating that this pathway also contributes to drug resistance. These studies provide evidence that the broad-spectrum antifungal drug fludioxonil exerts its action via activation of the Hog1 MAPK pathway and provide insight into novel targets for synergistic antifungal drug combinations.

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“…The itraconazole MICs increased from 0.05 to 0.4 ,ug/ml in two patients and from 0.05 to >6.4 j±g/ml in the other two patients (total of 52 isolates tested over 2 years) (Fig. 2) The remaining patient, who has been described previously (20), differs in that he appeared to have acquired a strain for which the fluconazole MIC was 16 (1,3,4,8,11,15,(17)(18)(19)(20). In almost every instance, failure has occurred in patients who have been on fluconazole for long periods of time.…”

mentioning

confidence: 99%

“…Although candidiasis is usually amenable to therapy with local or systemic antifungal drugs,' failures of fluconazole therapy for mucocutaneous infections due to Candida albicans have been reported (1,3,4,8,11,15,(17)(18)(19)(20). Itraconazole has been shown to be efficacious for thrush (22) but has been used infrequently.…”

mentioning

confidence: 99%

Azole resistance in oropharyngeal Candida albicans strains isolated from patients infected with human immunodeficiency virus

Tiballi

Zarins

et al. 1994

Antimicrob Agents Chemother

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For 212 oropharyngeal isolates of Candida albicans, the fluconazole MICs for 50 and 90%6 of strains tested were 0.5 and 16 ,ug/ml, respectively, and those of itraconazole were 0.05 and 0.2 ,ug/ml, respectively. Of 16 isolates for which fluconazole MICs were >64 ,ug/ml, itraconazole MICs for 14 were <0.8 ,ug/ml and for 2 were >6.4 ,g/ml. Most fluconazole-resistant strains remained susceptible to itraconazole; whether itraconazole will prove effective for refractory thrush remains to be shown.Oropharyngeal candidiasis is the most common fungal infection in patients with AIDS (7). Although candidiasis is usually amenable to therapy with local or systemic antifungal drugs,' failures of fluconazole therapy for mucocutaneous infections due to Candida albicans have been reported (1,3,4,8,11,15,(17)(18)(19)(20). Itraconazole has been shown to be efficacious for thrush (22) but has been used infrequently. With increasing reports of failure of fluconazole therapy, we sought to determine the itraconazole susceptibilities of fluconazole-susceptible and -resistant C. albicans isolated from our patients infected with human immunodeficiency virus (HIV).C. albicans strains. A total of 212 isolates of C. albicans from 46 different patients were studied. These strains had been isolated over the course of 2 1/2 years (July 1991 to January 1994) from patients with HIV infection who were treated in the Infectious Dis'eases Clinic at the Ann Arbor Veterans Affairs Medical Center. Thirty-four patients had at least one episode of thrush, and 12 patients were colonized with C. albicans but did not have thrush. Some, but not all, of these patients had taken part in a previously reported study (20).Susceptibility testing. The proposed standard broth macrodilution method for antifungal susceptibility testing of fluconazole (National Committee for Clinical Laboratory Standards document M27-P) was used for in vitro susceptibility tests (16). Stock solutions were stored at -70°C after preparation in distilled water for fluconazole and in dimethylsulfoxide for itraconazole. Each day an assay was performed, a new vial of stock solution was thawed and diluted in distilled water.For fluconazole, final concentrations ranged from 0.06 to 64 ,ug/ml; for itraconazole, final concentrations ranged from 0.006 to 6.4 ,ug/ml. Turbidity in each tube was assessed by the criteria put forth by Espinel-Ingroff et al., in which the MIC was defined as the tube with .80% inhibition of growth (6, 16). For each set of susceptibility studies, three standard organisms (a C. krusei strain and two C. albicans strains) were included.For all 212 isolates, the fluconazole MIC for 50% of strains tested (MIC50) was 0.5 ,ug/ml and the MIC90 was 16 ,ug/ml; the itraconazole MIC50 was 0.05 jig/ml, and the MIC90 was 0.2 ,ug/ml. The fluconazole MICs for the majority of isolates (151) were c2 ,ug/ml; for these isolates, the itraconazole MIC50 and MIC90 were correspondingly low, at 0.05 and 0.1 ,ug/ml, respectively. For those 61 isolates for which fluconazole MICs ranged from 4 to ...

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Correlation of in vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1

Cited by 152 publications

References 22 publications

Interpretive Breakpoints for Fluconazole and Candida Revisited: a Blueprint for the Future of Antifungal Susceptibility Testing

Interpretive Breakpoints for Fluconazole and Candida Revisited: a Blueprint for the Future of Antifungal Susceptibility Testing

Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans

Azole resistance in oropharyngeal Candida albicans strains isolated from patients infected with human immunodeficiency virus

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