scholarly journals Why MIC matters? Microbiologists vs. clinicians

2013 ◽  
Vol 4 (1S) ◽  
pp. 39-43
Author(s):  
Corrado Girmenia
Keyword(s):  
Clinical Practice ◽  
Antifungal Agents ◽  
Fungal Species ◽  
Wild Type ◽  
Mechanisms Of Resistance ◽  
In Vitro Sensitivity ◽  
Sensitivity Tests ◽  
Type Population ◽  
European Standards

Several mechanisms of resistance may interfere with the patients’ healing from a fungal infection. However, in premature children fungi are generally susceptible to antifungal agents, except in case of vertical transmission from the mother. In vitro sensitivity tests have been recently harmonized between American and European standards, after years of unhomogeneity: to date, the interpretation of epidemiological cut-off of wild-type population and clinical cut-off are common, and are often updated. Sensitivity tests are difficult to perform, but luckily new commercial tests approvedby FDA are available. Sometimes, knowing the intrinsic sensitivities and resistances of every fungal species and subspecies may be enough in the clinical practice, since few resistances are acquired.

scholarly journals In vitro and in vivo resistance of Leishmania infantum to meglumine antimoniate: a study of 37 strains collected from patients with visceral leishmaniasis.

1997 ◽  
Vol 41 (4) ◽  
pp. 827-830 ◽  
Author(s):  
F Faraut-Gambarelli ◽  
R Piarroux ◽  
M Deniau ◽  
B Giusiano ◽  
P Marty ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Infantum ◽  
Strongly Correlated ◽  
Duration Of Treatment ◽  
In Vitro Sensitivity ◽  
Sensitivity Tests ◽  
Leishmania Parasites ◽  
Immunocompetent Patients

Primary and secondary unresponsiveness to meglumine has long been described in human visceral leishmaniasis. However, no studies have been performed to elucidate if these therapeutic failures were due to strain variability in meglumine sensitivity or were related to host factors. We have studied the in vitro sensitivity of 37 strains of Leishmania infantum isolated from 23 patients (11 human immunodeficiency virus-infected and 12 immunocompetent patients) with visceral leishmaniasis. Sensitivity tests were performed by infecting murine macrophages with Leishmania parasites and culturing them in medium containing different concentrations of meglumine. For each test we calculated a 50% effective dose (ED50) corresponding to the meglumine concentration at which 50% of the Leishmania parasites survived. In vitro results were strongly correlated to immediate clinical outcome. All strains requiring an ED50 of >70 microg/ml were related to therapeutic failures, whereas all strains requiring an ED50 of <40 microg/ml corresponded to an initial efficiency of meglumine. Among those patients who were initially improved, relapses occurred in all immunocompromised patients and in most immunocompetent patients who had a short duration of treatment (15 days). Finally, we found that in vitro sensitivity of strains decreased progressively in relapsing patients treated with meglumine. Consequently, the physician may be encouraged to alternate meglumine with other treatments such as amphotericin B or pentamidine, especially in the case of relapsing patients.

scholarly journals Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Wiley A. Schell ◽  
A. M. Jones ◽  
Katyna Borroto-Esoda ◽  
Barbara D. Alexander
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Candida Krusei ◽  
Wild Type ◽  
Content Type ◽  
Clinical Resistance ◽  
Excellent Activity ◽  
Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

scholarly journals Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nivea Pereira de Sa ◽  
Adam Taouil ◽  
Jinwoo Kim ◽  
Timothy Clement ◽  
Reece M. Hoffmann ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Rational Design ◽  
Antifungal Agents ◽  
Pathogenic Fungus ◽  
Pathogenic Fungi ◽  
Growth Defect ◽  
Wild Type ◽  
Secondary Infections ◽  
Heavy Burden

AbstractPathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus Cryptococcus neoformans (Cn) results in ergosterol 3β-D-glucoside accumulation, renders Cn non-pathogenic, and immunizes mice against secondary infections by wild-type Cn, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in Cn cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the Cn Δsgl1 mutant and prevents dissemination of wild-type Cn to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1’s substrate specificity and enable the rational design of antifungal agents targeting Sgl1.

scholarly journals Monitoring and Tracking Changes in Sensitivity to Azoxystrobin Fungicide in Alternaria solani in Wisconsin

Plant Disease ◽  
2008 ◽  
Vol 92 (4) ◽  
pp. 555-560 ◽  
Author(s):  
N. Rosenzweig ◽  
G. Olaya ◽  
Z. K. Atallah ◽  
S. Cleere ◽  
C. Stanger ◽  
...  
Keyword(s):  
Management Practices ◽  
Alternaria Solani ◽  
Wild Type ◽  
In Vitro Sensitivity ◽  
Commercial Potato ◽  
Repeated Applications ◽  
Polymerase Chain ◽  
Sensitivity Changes ◽  
Sensitivity Decrease

Azoxystrobin is a common fungicide used by farmers of Solanaceous crops against Alternaria solani, but there was growing concern about decreased sensitivity with repeated applications. In 2002 and 2003, monitoring of A. solani from commercial potato fields in Wisconsin indicated increased frequency and a statewide distribution of isolates with decreased in vitro sensitivity to azoxystrobin. Mean effective concentration in inhibiting spore germination by 50% values gathered in 2002 and 2003 were approximately 20-fold higher than baseline isolates of A. solani collected in 1998 from fields that had never been treated with azoxystrobin. This sensitivity decrease was correlated with site-specific mutations in the cytochrome b detected by quantitative real-time polymerase chain reaction. The F129L and the G143A substitution have been shown to cause a reduction in sensitivity or resistance, respectively, to quinone outside inhibitors. All of the recovered A. solani isolates collected in 2002 and 2003 were wild type at position 143. However, all three mutations responsible for the F129L substitution (TTA, CTC, and TTG) were detected in our samples. In addition, the frequency of this amino acid substitution in A. solani isolates was statistically different across sampling sites and years, indicating that sensitivity changes depended on specific disease management practices.

Expression of Ara-C Metabolizing Enzymes Mediates in Vitro Sensitivity to Ara-C in Primary AML Cells From Patients with Denovo AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3481-3481
Author(s):  
Ajay Abraham ◽  
Savitha Varatharajan ◽  
Ashok kumar Jayavelu ◽  
Shaji R Velayudhan ◽  
Rayaz Ahmed ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Candidate Genes ◽  
P Value ◽  
Mrna Levels ◽  
Wild Type ◽  
Mutation Status ◽  
Expression Levels ◽  
In Vitro Sensitivity ◽  
Mrna Expression Levels

Abstract Abstract 3481 Wide inter-individual variation in terms of treatment outcome and toxic side effects of treatment exist among patients with AML receiving chemotherapy with cytarabine (ara-C) and daunorubicin. The pre-requisite for the cytotoxic action of pro-drug Ara-C is the enzymatic conversion to its active tri-phosphorylated form ara-CTP. Many drug activating (Deoxycytidine kinase (dCK) and human Equilibrative Nucleoside Transporter 1 (hENT1) and deactivating (Cytidine deaminase (CDA), 5'nucleotidase (NT5C2) genes and ribonucleoside reductase (RRM1), which are involved in transport and biotransformation of cytarabine contribute to the variation in ara-C sensitivity in AML patients. FLT3-ITD and NPM1 mutations act as major poor and good prognostic markers respectively in cytogenetically normal AML. The effect of these mutations in ara-C metabolism remains to be elucidated. The present study aims to determine independent as well as the combined effect of ara-C metabolizing genes mRNA expression on in-vitro ara-C cytotoxicity and the role of FLT3-ITD and NPM mutations on mRNA expression of these genes. Diagnostic bone marrow sample (median blasts 65%; range 21 – 98%) from 98 adult patients with de novo AML (other than AML-M3) were included in this study. mRNA expression levels for each target gene relative to housekeeping gene GAPDH was analyzed using Taqman based gene expression assays. In vitro cytotoxicity was assessed using MTT cell viability assay and IC-50 was calculated. In vitro sensitivity or resistance was classified on the basis of the IC-50 values <6uM and >6uM ara-C respectively. FLT3 ITD and NPM mutation status at diagnosis were determined through PCR followed by Genescan analysis using genomic DNA samples. Type of NPM mutation was identified by sequencing. When ara-C IC-50 values were compared with the mRNA expression levels of these candidate genes, Ara-C sensitive samples (n= 30; IC-50 < 6uM) showed significantly higher mRNA expression of dCK and hENT1 compared to those with Ara-C resistance (n=51) IC50 >6uM (median 314 (61.56 – 1232) vs. 180 (31.87 – 749.2); p = 0.0004 and median 172.1 (44.12 – 657.6) vs. 96.19 (37.49 – 432.4), p= 0.0008 respectively. RRM1 and NT5C2 did not show any association with in vitro Ara-C cytotoxicity, while CDA showed a trend towards association with lower CDA expression in ara-C sensitive samples. Based on these findings we put forward Ara-C resistance index (RI). RI is calculated by the formula RI = ΔCT (dCK X ENT1)/ ΔCT CDA. (Smaller ΔCT value= higher mRNA expression). RI values were significantly higher in resistant (IC50 >6uM) compared to sensitive cells (median: 6.084; range 1.89–11.82) vs. 3.702 (1.89–9.80); p=<0.0001). This association should now be validated in an independent cohort. Effects of NPM and FLT3 mutation status on Ara-C metabolizing genes were then evaluated. No significant association was found between FLT3-ITD status and the mRNA expression of these candidate genes. Interestingly, dCK mRNA levels were significantly higher in samples with NPM mutation (n=39) compared to NPM wild type (n=59); median 272.3 (41.64–1232) vs. 188.6 (31.87–1030); p value= 0.01. When analysed separately, patients with NPM type A mutation (n=27) showed significantly higher dCK expression (median 347.4 (41.64–1232) vs. 188.6 (31.87–1030); p value= 0.003 compared to those with wild type NPM1. This first report showing an association between expression profiles of ara-C metabolizing genes and NPM mutation should form the basis for evaluating their clinical correlations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals C7-07: Presence of amphiregulin autocrine-loop predicts in vitro sensitivity of EGFR wild type NSCLC and HNSCC cell lines to gefitinib and cetuximab

2007 ◽  
Vol 2 (8) ◽  
pp. S382
Author(s):  
Kimio Yonesaka ◽  
Kreshnik Zejnullahu ◽  
Alison J. Homes ◽  
Bruce E. Johnson ◽  
Pasi A. Janne
Keyword(s):  
Cell Lines ◽  
Wild Type ◽  
Autocrine Loop ◽  
In Vitro Sensitivity ◽  
Hnscc Cell

SLIDE CULTURE OF TUBERCLE BACILLI: II. IN VITRO SENSITIVITY TESTING

1954 ◽  
Vol 1 (1) ◽  
pp. 30-35 ◽  
Author(s):  
R. W. Reed
Keyword(s):  
Sensitivity Testing ◽  
Simple Method ◽  
Slide Culture ◽  
In Vitro Sensitivity ◽  
Sensitivity Tests ◽  
Conventional Methods ◽  
Technical Simplicity ◽  
Tuberculostatic Agents

A technically simple method of testing the sensitivity of tubercle bacilli to tuberculostatic agents is described which gives accurate results directly from positive sputum in one or two weeks. Parallel slide and tube sensitivity tests against streptomycin and isoniazid on 136 specimens show 49% and 68% agreement respectively. The number of cultures within the sensitive range of each drug was almost identical. The advantages of slide sensitivity testing over conventional methods are technical simplicity and rapid results.

scholarly journals SUSCEPTIBILITY TEST FOR FUNGI: CLINICAL AND LABORATORIAL CORRELATIONS IN MEDICAL MYCOLOGY

2015 ◽  
Vol 57 (suppl 19) ◽  
pp. 57-64 ◽  
Author(s):  
Ana ALASTRUEY-IZQUIERDO ◽  
Marcia S.C. MELHEM ◽  
Lucas X. BONFIETTI ◽  
Juan L. RODRIGUEZ-TUDELA
Keyword(s):  
Susceptibility Testing ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Fungal Species ◽  
Medical Mycology ◽  
Candida Spp ◽  
Disease Epidemiology ◽  
Resistant Strains ◽  
European Standards

SUMMARYDuring recent decades, antifungal susceptibility testing has become standardized and nowadays has the same role of the antibacterial susceptibility testing in microbiology laboratories. American and European standards have been developed, as well as equivalent commercial systems which are more appropriate for clinical laboratories. The detection of resistant strains by means of these systems has allowed the study and understanding of the molecular basis and the mechanisms of resistance of fungal species to antifungal agents. In addition, many studies on the correlation of in vitro results with the outcome of patients have been performed, reaching the conclusion that infections caused by resistant strains have worse outcome than those caused by susceptible fungal isolates. These studies have allowed the development of interpretative breakpoints for Candida spp. and Aspergillus spp., the most frequent agents of fungal infections in the world. In summary, antifungal susceptibility tests have become essential tools to guide the treatment of fungal diseases, to know the local and global disease epidemiology, and to identify resistance to antifungals.

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