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Article ; Online: Commercial Methods for Antifungal Susceptibility Testing of Saprophytic Molds: Can They Be Used to Detect Resistance?

Paranos, Paschalis / Espinel-Ingroff, Ana / Meletiadis, Joseph

2024 Volume 10, Issue 3

Abstract: Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological cutoff values (ECVs) have been defined in order to detect non-wild-type (NWT) isolates ... ...

Abstract	Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological cutoff values (ECVs) have been defined in order to detect non-wild-type (NWT) isolates harboring resistance mechanisms. We reviewed the literature in order to find studies where commercial methods were used to evaluate for in vitro susceptibility of filamentous fungi and assess their ability to detect NWT isolates according to the available ECVs. Data were found for the gradient concentration strips Etest and MIC Test Strips (MTS), broth microdilution Sensititre YeastOne (SYO), Micronaut-AM and the agar dilution VIPcheck assays. Applying itraconazole, voriconazole and posaconazole Etest ECVs for
Language	English
Publishing date	2024-03-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2784229-0
ISSN	2309-608X ; 2309-608X
ISSN (online)	2309-608X
ISSN	2309-608X
DOI	10.3390/jof10030214
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Thesis: Antifungal susceptibility testing and drug interaction modeling in moulds

Meletiadis, Joseph

2002

Author's details	door Joseph Meletiadis
Language	English ; Greek
Size	130 S. : Ill., graph. Darst.
Publishing country	Netherlands
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Nijmegen, Univ., Diss., 2002
Note	Zsfassung in griech. Sprache
HBZ-ID	HT013507971
ISBN	90-9015970-3 ; 978-90-9015970-6
Database	Catalogue ZB MED Medicine, Health

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Shelf mark	Loan status	Location
2003 E 366	order for loan	Magazin

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Article ; Online: A new PK/PD target for assessing efficacy of micafungin against Candida parapsilosis.

Beredaki, Maria-Ioanna / Pournaras, Spyros / Meletiadis, Joseph

The Journal of antimicrobial chemotherapy

2023 Volume 79, Issue 1, Page(s) 157–165

Abstract: Background: Pharmacokinetic/pharmacodynamic (PK/PD) targets of echinocandins failed to support current clinical breakpoints of Candida parapsilosis as the PTA is low for susceptible isolates despite the good clinical efficacy of echinocandins against ... ...

Abstract	Background: Pharmacokinetic/pharmacodynamic (PK/PD) targets of echinocandins failed to support current clinical breakpoints of Candida parapsilosis as the PTA is low for susceptible isolates despite the good clinical efficacy of echinocandins against these infections. We therefore investigated the effect of micafungin against C. parapsilosis using an in vitro PK/PD in the presence of 10% human serum. Methods: Three susceptible (MIC = 0.5-2 mg/L) and one resistant (MIC > 8 mg/L) C. parapsilosis sensu stricto isolates were tested at two different inocula (104 and 103 cfu/mL) simulating micafungin human exposures in RPMI and in RPMI + 10% pooled human serum. The exposure-effect relationship tAUC0-24/MIC was described and different PK/PD targets were determined in order to calculate the PTA for the standard 100 mg IV q24h dose. Results: A maximal effect was found at fCmax ≥ 4 mg/L in RPMI and tCmax ≥ 64 mg/L (fCmax = 0.08 mg/L) in the presence of serum for which in vitro PK/PD targets were 50 times lower. Stasis in the presence of serum was found at 272-240 tAUC0-24/MIC, close to the clinical PK/PD target (285 tAUC/MIC), validating the in vitro model. However, the PTA was low for susceptible isolates with EUCAST/CLSI MICs ≤ 2 mg/L. Among the different PK/PD targets investigated, the PK/PD target 28 tAUC/MIC associated with 10% of maximal effect with the low inoculum resulted in PTAs ≥ 95% for susceptible isolates with EUCAST/CLSI MICs ≤ 2 mg/L. Conclusions: A new PK/PD target was found for micafungin and C. parapsilosis that supports the current clinical breakpoint. This target could be used for assessing echinocandin efficacy against C. parapsilosis.
MeSH term(s)	Humans ; Micafungin/pharmacology ; Candida parapsilosis ; Antifungal Agents/pharmacology ; Antifungal Agents/therapeutic use ; Lipopeptides/pharmacology ; Candida ; Echinocandins/pharmacology ; Mitomycin/pharmacology ; Microbial Sensitivity Tests
Chemical Substances	Micafungin (R10H71BSWG) ; Antifungal Agents ; Lipopeptides ; Echinocandins ; Mitomycin (50SG953SK6)
Language	English
Publishing date	2023-10-30
Publishing country	England
Document type	Journal Article
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkad360
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Article ; Online: Development of an agar-based screening method for terbinafine, itraconazole, and amorolfine susceptibility testing of

Siopi, Maria / Efstathiou, Ioanna / Arendrup, Maiken C / Meletiadis, Joseph

Journal of clinical microbiology

2023 Volume 62, Issue 1, Page(s) e0130823

Abstract: Resistance in dermatophytes is an emerging global public health issue. We, therefore, developed an agar-based method for ... ...

Abstract	Resistance in dermatophytes is an emerging global public health issue. We, therefore, developed an agar-based method for screening
MeSH term(s)	Humans ; Terbinafine/pharmacology ; Itraconazole/pharmacology ; Trichophyton/genetics ; Antifungal Agents/pharmacology ; Agar ; Microbial Sensitivity Tests ; Squalene Monooxygenase/genetics ; Drug Resistance, Fungal/genetics ; Arthrodermataceae/genetics ; Morpholines
Chemical Substances	Terbinafine (G7RIW8S0XP) ; Itraconazole (304NUG5GF4) ; Antifungal Agents ; Agar (9002-18-0) ; amorolfine (AB0BHP2FH0) ; Squalene Monooxygenase (EC 1.14.14.17) ; Morpholines
Language	English
Publishing date	2023-12-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	390499-4
ISSN	1098-660X ; 0095-1137
ISSN (online)	1098-660X
ISSN	0095-1137
DOI	10.1128/jcm.01308-23
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Article ; Online: Defining Optimal Doses of Liposomal Amphotericin B Against Candida auris: Data From an In Vitro Pharmacokinetic/Pharmacodynamic Model.

Beredaki, Maria-Ioanna / Sanidopoulos, Ioannis / Pournaras, Spyros / Meletiadis, Joseph

The Journal of infectious diseases

2023 Volume 229, Issue 2, Page(s) 599–607

Abstract: Background: Candida auris isolates exhibit elevated amphotericin B (AMB) minimum inhibitory concentrations (MICs). As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in ... ...

Abstract	Background: Candida auris isolates exhibit elevated amphotericin B (AMB) minimum inhibitory concentrations (MICs). As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) dilution model. Methods: Four C. auris isolates with Clinical and Laboratory Standards Institute (CLSI) AMB MICs = 0.5-2 mg/L were tested in an in vitro PK/PD model simulating L-AMB pharmacokinetics. The in vitro model was validated using a Candida albicans isolate tested in animals. The peak concentration (Cmax)/MIC versus log10 colony-forming units (CFU)/mL reduction from the initial inoculum was analyzed with the sigmoidal model with variable slope (Emax model). Monte Carlo analysis was performed for the standard (3 mg/kg) and higher (5 mg/kg) L-AMB doses. Results: The in vitro PK/PD relationship Cmax/MIC versus log10 CFU/mL reduction followed a sigmoidal pattern (R2 = 0.91 for C. albicans, R2 = 0.86 for C. auris). The Cmax/MIC associated with stasis was 2.1 for C. albicans and 9 for C. auris. The probability of target attainment was >95% with 3 mg/kg for wild-type C. albicans isolates with MIC ≤2 mg/L and C. auris isolates with MIC ≤1 mg/L whereas 5 mg/kg L-AMB is needed for C. auris isolates with MIC 2 mg/L. Conclusions: L-AMB was 4-fold less active against C. auris than C. albicans. Candida auris isolates with CLSI MIC 2 mg/L would require a higher L-AMB dose.
MeSH term(s)	Animals ; Amphotericin B/pharmacology ; Antifungal Agents/pharmacokinetics ; Candida auris ; Candida ; Candida albicans ; Microbial Sensitivity Tests
Chemical Substances	liposomal amphotericin B ; Amphotericin B (7XU7A7DROE) ; Antifungal Agents
Language	English
Publishing date	2023-12-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad583
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Zs.MO 445: Show issues

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Article ; Online: Development of an in vitro pharmacokinetic/pharmacodynamic model in the presence of serum for studying micafungin activity against Candida albicans: a need for revision of CLSI susceptibility breakpoints.

Beredaki, Maria-Ioanna / Arendrup, Maiken C / Andes, David / Meletiadis, Joseph

The Journal of antimicrobial chemotherapy

2023 Volume 78, Issue 6, Page(s) 1386–1394

Abstract: Background: The CLSI breakpoint for micafungin and Candida albicans is 0.25 mg/L, higher than the CLSI epidemiological cut-off value (0.03 mg/L) whereas the EUCAST values are identical (0.016 mg/L). We developed a novel in vitro dialysis-diffusion ... ...

Abstract	Background: The CLSI breakpoint for micafungin and Candida albicans is 0.25 mg/L, higher than the CLSI epidemiological cut-off value (0.03 mg/L) whereas the EUCAST values are identical (0.016 mg/L). We developed a novel in vitro dialysis-diffusion pharmacokinetic/pharmacodynamic (PK/PD) model, confirmed correlation to in vivo outcome and studied micafungin pharmacodynamics against Canida albicans. Methods: Four C. albicans isolates, including a weak (F641L) and a strong (R647G) fks1 mutants, were studied using a 104 cfu/mL inoculum and RPMI medium with and without 10% pooled human serum. The exposure-effect relationship fAUC0-24/MIC was described for CLSI and EUCAST methodology. Monte Carlo simulation analysis included standard (100 mg i.v.) and higher (150-300 mg) doses q24h to determine the corresponding probability of target attainment (PTA). Results: The in vitro PK/PD targets for stasis/1-log kill were 36/57 fAUC0-24/MIC in absence and 2.8/9.2 fAUC0-24/MIC in the presence of serum, and similar for wild-type and fks mutant isolates. The PTAs for both PK/PD targets were high (>95%) for EUCAST susceptible isolates but not for CLSI susceptible non-wild-type isolates (CLSI MICs 0.06-0.25 mg/L). 300 mg q24h was needed to attain PK/PD targets for non-wild-type isolates with CLSI MICs 0.06-0.125 mg/L and EUCAST MICs 0.03-0.06 mg/L. Conclusion: The in vitro 1-log kill effect corresponded to stasis in animal model and mycological response in patients with invasive candidiasis, thereby validating the model for studying pharmacodynamics of echinocandins in vitro. EUCAST breakpoints were well supported by our findings but our data questions whether the current CLSI breakpoint, which is higher than the epidemiological cut-off values, is appropriate.
MeSH term(s)	Animals ; Humans ; Micafungin/pharmacology ; Candida albicans ; Antifungal Agents/pharmacology ; Antifungal Agents/therapeutic use ; Candida ; Echinocandins/pharmacology ; Candidiasis, Invasive/drug therapy ; Microbial Sensitivity Tests
Chemical Substances	Micafungin (R10H71BSWG) ; Antifungal Agents ; Echinocandins
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkad096
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Zs.A 1197: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 124: Show issues

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Article ; Online: Optimization of the EUCAST reference broth microdilution method for echinocandin susceptibility testing of Aspergillus fumigatus.

Siopi, Maria / Georgiou, Panagiota-Christina / Pournaras, Spyros / Meletiadis, Joseph

The Journal of antimicrobial chemotherapy

2023 Volume 78, Issue 12, Page(s) 2830–2839

Abstract: Background: Because of the high inoculum (105 cfu/mL) used in the EUCAST susceptibility testing of Aspergillus spp., determination of the minimal effective concentration (MEC) of echinocandins is challenging as the morphological differences are subtle.!# ...

Abstract	Background: Because of the high inoculum (105 cfu/mL) used in the EUCAST susceptibility testing of Aspergillus spp., determination of the minimal effective concentration (MEC) of echinocandins is challenging as the morphological differences are subtle. Methods: The MECs of 10 WT and 4 non-WT Aspergillus fumigatus isolates were determined with the EUCAST E.Def 9.4. Plates were inoculated with increasing inocula (102-105 cfu/mL) and after 24 and 48 h of incubation, MECs were determined macroscopically (magnifying mirror) and microscopically (inverted microscope) by two observers, spectrophotometrically (OD at 405 nm) and colorimetrically (absorbance at 450/630 nm after 2 h incubation with 400 mg/L XTT/6.25 μM menadione). The interobserver (between observers)/intermethod (compared with the microscopic method) essential agreement (EA, ±1 2-fold dilution) and categorical agreement (CA) were determined for each inoculum. Results: Echinocandin-induced microscopic hyphal alterations or macroscopic changes in turbidity were subtle with a 105 cfu/mL inoculum compared with the lower inocula of 103 and 102 cfu/mL, where more distinct changes in turbidity and formation of characteristic rosettes were obvious at the MEC after 48 h. A 105 cfu/mL inoculum resulted in wider MEC distributions (3-6 dilutions) and lower interobserver EA (69%), macroscopic-microscopic EA (26%) and CA (71%) compared with a 103 cfu/mL inoculum (2-3 dilutions, 100%, 100% and 100%, respectively). Spectrophotometric readings using a 103 cfu/mL inoculum showed good EA (57-93%) and excellent CA (86%-100%), while the XTT assay demonstrated excellent EA (93%) and CA (100%). Conclusions: A 48 h incubation using a 103 cfu/mL inoculum improved echinocandin MEC determination for A. fumigatus with the EUCAST method, while the colorimetric assay could allow automation.
MeSH term(s)	Echinocandins/pharmacology ; Aspergillus fumigatus ; Antifungal Agents/pharmacology ; Aspergillus ; Spectrophotometry ; Microbial Sensitivity Tests
Chemical Substances	Echinocandins ; Antifungal Agents
Language	English
Publishing date	2023-10-06
Publishing country	England
Document type	Journal Article
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkad306
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Zs.A 1197: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 124: Show issues

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Article: Assessing Clinical Potential of Old Antibiotics against Severe Infections by Multi-Drug-Resistant Gram-Negative Bacteria Using In Silico Modelling.

Paranos, Paschalis / Vourli, Sophia / Pournaras, Spyros / Meletiadis, Joseph

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 12

Abstract: In the light of increasing antimicrobial resistance among gram-negative bacteria and the lack of new more potent antimicrobial agents, new strategies have been explored. Old antibiotics, such as colistin, temocillin, fosfomycin, mecillinam, ... ...

Abstract	In the light of increasing antimicrobial resistance among gram-negative bacteria and the lack of new more potent antimicrobial agents, new strategies have been explored. Old antibiotics, such as colistin, temocillin, fosfomycin, mecillinam, nitrofurantoin, minocycline, and chloramphenicol, have attracted the attention since they often exhibit in vitro activity against multi-drug-resistant (MDR) gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The current review provides a summary of the in vitro activity, pharmacokinetics and PK/PD characteristics of old antibiotics. In silico modelling was then performed using Monte Carlo simulation in order to combine all preclinical data with human pharmacokinetics and determine the probability of target (1-log kill in thigh/lung infection animal models) attainment (PTA) of different dosing regimens. The potential of clinical efficacy of a drug against severe infections by MDR gram-negative bacteria was considered when PTA was >95% at the epidemiological cutoff values of corresponding species. In vitro potent activity against MDR gram-negative pathogens has been shown for colistin, polymyxin B, temocillin (against E. coli and K. pneumoniae), fosfomycin (against E. coli), mecillinam (against E. coli), minocycline (against E. coli, K. pneumoniae, A. baumannii), and chloramphenicol (against E. coli) with ECOFF or MIC90 ≤ 16 mg/L. When preclinical PK/PD targets were combined with human pharmacokinetics, Monte Carlo analysis showed that among the old antibiotics analyzed, there is clinical potential for polymyxin B against E. coli, K. pneumoniae, and A. baumannii; for temocillin against K. pneumoniae and E. coli; for fosfomycin against E. coli and K. pneumoniae; and for mecillinam against E. coli. Clinical studies are needed to verify the potential of those antibiotics to effectively treat infections by multi-drug resistant gram-negative bacteria.
Language	English
Publishing date	2022-11-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15121501
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Article ; Online: Early phenotypic detection of fluconazole- and anidulafungin-resistant Candida glabrata isolates.

Georgiou, Panagiota-Christina / Arendrup, Maiken Cavling / Meletiadis, Joseph

The Journal of antimicrobial chemotherapy

2022 Volume 77, Issue 6, Page(s) 1655–1661

Abstract: Background: Increased fluconazole and echinocandin resistance in Candida glabrata requires prompt detection in routine settings. A phenotypic test based on the EUCAST E.DEF 7.3.2 protocol was developed for the detection of fluconazole- and anidulafungin- ...

Abstract	Background: Increased fluconazole and echinocandin resistance in Candida glabrata requires prompt detection in routine settings. A phenotypic test based on the EUCAST E.DEF 7.3.2 protocol was developed for the detection of fluconazole- and anidulafungin-resistant isolates utilizing the colorimetric dye XTT. Methods: Thirty-one clinical C. glabrata isolates, 11 anidulafungin resistant and 14 fluconazole resistant, were tested. After optimization studies, 0.5-2.5 × 105 cfu/mL of each isolate in RPMI 1640 + 2% d-glucose medium containing 100 mg/L XTT + 0.78 μΜ menadione and 0.06 mg/L anidulafungin (S breakpoint) or 16 mg/L fluconazole (I breakpoint) in 96-well flat-bottom microtitration plates were incubated at 37°C for 18 h; we also included drug-free wells. XTT absorbance was measured at 450 nm every 15 min. Differences between the drug-free and the drug-treated wells were assessed using Student's t-test at different timepoints. ROC curves were used in order to identify the best timepoint and cut-off. Results: The XTT absorbance differences between fluconazole-containing and drug-free wells were significantly lower for the resistant isolates compared with susceptible increased exposure isolates (0.08 ± 0.05 versus 0.25 ± 0.06, respectively, P = 0.005) at 7.5 h, with a difference of <0.157 corresponding to 100% sensitivity and 94% specificity for detection of resistance. The XTT absorbance differences between anidulafungin-containing and drug-free wells were significantly lower for the resistant isolates compared with susceptible isolates (0.08 ± 0.07 versus 0.200 ± 0.03, respectively, P < 0.001) at 5 h, with a difference of <0.145 corresponding to 91% sensitivity and 100% specificity, irrespective of underlying mutations. Conclusions: A simple, cheap and fast phenotypic test was developed for detection of fluconazole- and anidulafungin-resistant C. glabrata isolates.
MeSH term(s)	Anidulafungin/pharmacology ; Antifungal Agents/pharmacology ; Candida glabrata ; Drug Resistance, Fungal/genetics ; Echinocandins/pharmacology ; Fluconazole/pharmacology ; Humans ; Microbial Sensitivity Tests
Chemical Substances	Antifungal Agents ; Echinocandins ; Fluconazole (8VZV102JFY) ; Anidulafungin (9HLM53094I)
Language	English
Publishing date	2022-04-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkac075
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Article ; Online: Evaluation of the Vitek 2 system for antifungal susceptibility testing of

Siopi, Maria / Pachoulis, Ioannis / Leventaki, Sevasti / Spruijtenburg, Bram / Meis, Jacques F / Pournaras, Spyros / Vrioni, Georgia / Tsakris, Athanasios / Meletiadis, Joseph

Journal of clinical microbiology

2024 Volume 62, Issue 4, Page(s) e0152823

Abstract: Although the Vitek 2 system is broadly used for antifungal susceptibility testing ... ...

Abstract	Although the Vitek 2 system is broadly used for antifungal susceptibility testing of
MeSH term(s)	Humans ; Fluconazole/pharmacology ; Amphotericin B/pharmacology ; Antifungal Agents/pharmacology ; Candida auris ; Micafungin ; Caspofungin ; Microbial Sensitivity Tests ; Echinocandins/pharmacology
Chemical Substances	Fluconazole (8VZV102JFY) ; Amphotericin B (7XU7A7DROE) ; Antifungal Agents ; Micafungin (R10H71BSWG) ; Caspofungin (F0XDI6ZL63) ; Echinocandins
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	390499-4
ISSN	1098-660X ; 0095-1137
ISSN (online)	1098-660X
ISSN	0095-1137
DOI	10.1128/jcm.01528-23
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