Fluconazole MIC and the Fluconazole Dose/MIC Ratio Correlate with Therapeutic Response among Patients with Candidemia

ABSTRACT We tested 32 Candida isolates recovered in the early 1990s from the bloodstreams of patients with candidemia for in vitro susceptibility to fluconazole and determined if MIC and/or the daily dose of fluconazole/MIC ratio correlated with the response to therapy. This is a unique data set since 87.5% (28/32) of patients were treated with fluconazole doses now considered to be inadequate (≤200 mg), which contributed to high therapeutic failure rates (53% [17/32]). The geometric mean MIC and dose/MIC ratio for isolates associated with therapeutic failure (11.55 μg/ml and 14.3, respectively) differed significantly from values associated with therapeutic success (0.95 μg/ml and 219.36 [P = 0.0009 and 0.0004, respectively]). The therapeutic success rates among patients infected with susceptible (MIC ≤ 8 μg/ml), susceptible-dose dependent (S-DD) (MIC = 16 or 32 μg/ml), and resistant (MIC ≥ 64 μg/ml) isolates were 67% (14/21), 20% (1/5), and 0% (0/6), respectively. A dose/MIC ratio >50 was associated with a success rate of 74% (14/19), compared to 8% (1/13) for a dose/MIC ratio ≤50 (P = 0.0003). Our data suggest that both fluconazole MIC and dose/MIC ratio correlate with the therapeutic response to fluconazole among patients with candidemia. In clinical practice, dose/MIC ratio might prove easier to interpret than breakpoint MICs, since it quantitates the effects of increasing fluconazole doses that are alluded to in the S-DD designation.

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Correlation between In Vitro Susceptibility Determined by E Test and Response to Therapy with Amphotericin B: Results from a Multicenter Prospective Study of Candidemia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1289 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1289-1290 ◽

Cited By ~ 52

Author(s):

Cornelius J. Clancy ◽

M. Hong Nguyen

Keyword(s):

Prospective Study ◽

Amphotericin B ◽

Therapeutic Failure ◽

Response To Therapy ◽

Therapeutic Success ◽

In Vitro Susceptibility ◽

Multicenter Prospective Study

ABSTRACT Ninety-nine Candida bloodstream isolates underwent testing for susceptibility to amphotericin B by the E test, and the results were correlated with patients’ responses to amphotericin B. The MICs for isolates that were associated with therapeutic failure were significantly higher than the MICs for those associated with therapeutic success. A MIC of ≥0.38 μg/ml identified isolates likely to be associated with therapeutic failure.

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In Vitro Comparative Efficacy of Voriconazole and Itraconazole against Fluconazole-Susceptible and -Resistant Cryptococcus neoformans Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.2.471 ◽

1998 ◽

Vol 42 (2) ◽

pp. 471-472 ◽

Cited By ~ 44

Author(s):

M. Hong Nguyen ◽

Christine Y. Yu

Keyword(s):

Cryptococcus Neoformans ◽

Susceptibility Testing ◽

Clinical Isolates ◽

Comparative Efficacy ◽

In Vitro Susceptibility ◽

In Vitro Susceptibility Testing ◽

Fluconazole Resistant ◽

Dose Dependent

ABSTRACT In vitro susceptibility testing for 50 clinical isolates of fluconazole-susceptible or -resistant Cryptococcus neoformans was performed with itraconazole and voriconazole. Voriconazole was more potent than itraconazole for fluconazole-susceptible isolates and as potent as itraconazole for fluconazole-susceptible dose-dependent isolates and for fluconazole-resistant isolates. For fluconazole-resistant isolates, the voriconazole and itraconazole MICs ranged from 1 to 2 μg/ml.

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688. In Vitro Activity of Eravacycline, a New Tetracycline Analog, and Comparators Against the Six Most Commonly Isolated Ribotypes of Clostridioides difficile

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.756 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S312-S313 ◽

Cited By ~ 2

Author(s):

Eugenie Basseres ◽

Julie Miranda ◽

Anne J Gonzales-Luna ◽

Travis J Carlson ◽

Tasnuva Rashid ◽

...

Keyword(s):

Geometric Mean ◽

Vitro Activity ◽

In Vitro Activity ◽

Large Collection ◽

In Vitro Susceptibility ◽

Clostridioides Difficile ◽

Clostridioides Difficile Infection ◽

Abdominal Infections ◽

Insight Into

Abstract Background Eravacycline is a novel, tetracycline class antibacterial indicated for the treatment of complicated intra-abdominal infections in adults. In clinical trials, patients given eravacycline had a low likelihood of developing Clostridioides difficile infection (CDI). We hypothesized this was likely due, in part, to the in vitro susceptibility of eravacycline to C. difficile. The purpose of this study was to test the in vitro susceptibility of eravacycline vs. comparators on contemporary clinical isolates representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin. Methods Two hundred and thirty-four isolates from our biobank were selected from the six most common ribotypes (F001, F002, F014-020, F027, F106, and F255). Minimum inhibitory concentrations (MIC) at 24 hours were measured according to CLSI guidelines for eravacycline, vancomycin, metronidazole and fidaxomicin. MICs results were tabulated and are presented as the geometric mean by ribotype. Results Geometric MIC results are shown in Table 1. Eravacycline was the most potent antimicrobial tested followed by fidaxomicin, metronidazole, and vancomycin. Results were consistent amongst all ribotypes, including isolates with reduced susceptibility to vancomycin and metronidazole. Conclusion Eravacycline displayed potent in vitro activity against a large collection of clinical C. difficile isolates. These data provide insight into why patients given eravacycline had a low likelihood of developing CDI and support further research to better understand the use of eravacycline to prevent or potentially treat patients with CDI. Disclosures All authors: No reported disclosures.

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In vitro toxicity assessment of respirable solid surface composite sawing particles

Toxicology and Industrial Health ◽

10.1177/0748233720921683 ◽

2020 ◽

Vol 36 (4) ◽

pp. 250-262

Author(s):

W Kyle Mandler ◽

Seungkoo Kang ◽

Mariana Farcas ◽

Chaolong Qi ◽

Sherri A Friend ◽

...

Keyword(s):

Solid Surface ◽

Geometric Mean ◽

Construction Materials ◽

Lavage Fluid ◽

Cell Culture Supernatant ◽

In Vitro Toxicity ◽

Dependent Manner ◽

Respirable Particles ◽

Dose Dependent

Solid surface composites (SSCs) are a class of popular construction materials composed of aluminum trihydrate and acrylic polymers. Previous investigations have demonstrated that sawing SSC releases substantial airborne dusts, with a number-based geometric mean diameter of 1.05 µm. We reported that in mice, aspiration exposure to airborne SSC dusts induced symptoms of pulmonary inflammation at 24-h postexposure: neutrophilic influx, alveolitis, and increased lactate dehydrogenase (LDH) and pro-inflammatory cytokine levels in lavage fluid. The particles appeared to be poorly cleared, with 81% remaining at 14-day postexposure. The objective of this study was to determine the toxicity specifically of respirable particles on a model of human alveolar macrophages (THP-1). The relative toxicities of subfractions (0.07, 0.66, 1.58, 5.0, and 13.42 µm diameter) of the airborne particles were also determined. THP-1 macrophages were exposed for 24 h to respirable particles from sawing SSC (0, 12.5, 25, 50, or 100 µg/ml) or size-specific fractions (100 µg/ml). Exposure to respirable SSC particles induced THP-1 macrophage toxicity in a dose-dependent manner. Viability was decreased by 15% and 19% after exposure to 50 and 100 µg/ml SSC, respectively, which correlated with increased cell culture supernatant LDH activity by 40% and 70% when compared to control. Reactive oxygen species (ROS) production and inflammatory cytokines were increased in a dose-dependent manner. A size-dependent cytotoxic effect was observed in the cells exposed to subfractions of SSC particles. SSC particles of 0.07, 0.66, and 1.58 µm diameter killed 36%, 17%, and 22% of cells, respectively. These results indicate a potential for cytotoxicity of respirable SSC particles and a relationship between particle size and toxicity, with the smallest fractions appearing to exhibit the greatest toxicity.

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Evaluation of Amphotericin B Interpretive Breakpoints for Candida Bloodstream Isolates by Correlation with Therapeutic Outcome

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.4.1287-1292.2006 ◽

2006 ◽

Vol 50 (4) ◽

pp. 1287-1292 ◽

Cited By ~ 86

Author(s):

Benjamin J. Park ◽

Beth A. Arthington-Skaggs ◽

Rana A. Hajjeh ◽

Naureen Iqbal ◽

Meral A. Ciblak ◽

...

Keyword(s):

Amphotericin B ◽

Susceptibility Testing ◽

Clinical Laboratory ◽

National Committee ◽

Restricted Range ◽

Broth Microdilution ◽

Therapeutic Success ◽

In Vitro Susceptibility ◽

In Vitro Susceptibility Testing

ABSTRACT One hundred seven Candida bloodstream isolates (51 C. albicans, 24 C. glabrata, 13 C. parapsilosis, 13 C. tropicalis, 2 C. dubliniensis, 2 C. krusei, and 2 C. lusitaniae strains) from patients treated with amphotericin B alone underwent in vitro susceptibility testing against amphotericin B using five different methods. Fifty-four isolates were from patients who failed treatment, defined as death 7 to 14 days after the incident candidemia episode, having persistent fever of ≥5 days' duration after the date of the incident candidemia, or the recurrence of fever after two consecutive afebrile days while on antifungal treatment. MICs were determined by using the Clinical Laboratory Standards Institute (formally National Committee for Clinical Laboratory Standards) broth microdilution procedure with two media and by using Etest. Minimum fungicidal concentrations (MFCs) were also measured in two media. Broth microdilution tests with RPMI 1640 medium generated a restricted range of MICs (0.125 to 1 μg/ml); the corresponding MFC values ranged from 0.5 to 4 μg/ml. Broth microdilution tests with antibiotic medium 3 produced a broader distribution of MIC and MFC results (0.015 to 0.25 μg/ml and 0.06 to 2 μg/ml, respectively). Etest produced the widest distribution of MICs (0.094 to 2 μg/ml). However, none of the test formats studied generated results that significantly correlated with therapeutic success or failure.

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In Vitro Susceptibility of Talaromyces Marneffei In Malaysia: Comparison of Yeast and Mycelial Phases

10.21203/rs.3.rs-1158654/v1 ◽

2021 ◽

Author(s):

Xue Ting Tan ◽

Nurliyana binti Mohd Shuhairi ◽

Stephanie Jane Ginsapu ◽

Surianti Binti Shukor ◽

Fairuz Binti Amran

Keyword(s):

Amphotericin B ◽

Geometric Mean ◽

Antifungal Susceptibility ◽

Etiologic Agent ◽

Mycelial Form ◽

In Vitro Susceptibility ◽

Terbinafine Hydrochloride ◽

Acquired Immunodeficiency ◽

Immunodeficiency Syndrome

Abstract Talaromyces marneffei is an etiologic agent of talaromycosis. It can cause serious complications and death in immunocompromised patients, particularly in acquired immunodeficiency syndrome (AIDS) patients. This infectious disease is endemic in Southeast Asia including Malaysia. To date, published reports on the antifungal susceptibility profile of T. marneffei is very limited. The objective of this study is to determine the minimum inhibitory concentration (MIC) of T. marneffei in yeast and mycelial phases in Malaysia. In the year 2020, 27 clinical strains of T. marneffei were received from various hospitals in Malaysia. The identification was carried out using microscopic, macroscopic and molecular methods. Following that, the susceptibility of each isolate in both yeast and mycelial form to thirteen common antifungals was performed according to the broth microdilution in Clinical & Laboratory Standards Institute (CLSI) M38 method. The antifungals tested were anidulafungin, micafungin sodium, caspofungin diacetate, 5-fluorocytosine, amphotericin B and terbinafine hydrochloride, posaconazole, voriconazole, itraconazole, ketoconazole, ravuconazole, clotrimazole and isavuconazole. The geometric mean of all antifungals other than anidulafungin, micafungin sodium, caspofungin diacetate and 5-fluorocytosine against T. marneffei mould (mycelial) were >2 μg/ml. However, the geometric mean of all antifungals against T. marneffei yeast was <2 μg/ml. Our in vitro data suggests promising activities of amphotericin B, terbinafine hydrochloride, posaconazole, voriconazole, itraconazole, ketoconazole, ravuconazole, clotrimazole and isavuconazole against yeast and mould phases of T. marneffei.

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Characterization and Quantitation of the Pharmacodynamics of Fluconazole in a Neutropenic Murine Disseminated Candidiasis Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.9.2116 ◽

1999 ◽

Vol 43 (9) ◽

pp. 2116-2120 ◽

Cited By ~ 149

Author(s):

D. Andes ◽

M. van Ogtrop

Keyword(s):

Time Course ◽

Infection Model ◽

Maximal Effect ◽

Time Curve ◽

In Vitro Susceptibility ◽

Disseminated Candidiasis ◽

Wide Range ◽

Dosing Intervals ◽

Dose Dependent

ABSTRACT We determined the pharmacodynamic parameter and the magnitude of that parameter that was predictive of the efficacy of fluconazole in the treatment of disseminated candidiasis. We used a neutropenic murine model of disseminated Candida albicans infection to characterize the time course of activity of fluconazole. Quantitation of colony counts in kidneys after 24 h of therapy with a wide range of doses and three dosing intervals was used to determine the dose required to achieve 50% of the maximal effect (ED50). The ED50 was similar for each of the dosing intervals studied, supporting the area under the concentration-time curve (AUC) MIC ratio as the parameter that predicts the efficacy of fluconazole. Similar studies were performed with C. albicans strains for which fluconazole MICs are in the susceptible-dose-dependent range (MICs, 16 to 32 mg/liter). We found that the magnitude of the AUC/MIC ratio required to reach the ED50 was similar for all three organisms studied, ranging from 12 to 25. When the pharmacokinetics of fluconazole in humans are considered, these AUC/MIC ratios would support in vitro susceptibility breakpoints of 8 mg/liter for dosages of 200 mg/day and susceptibility breakpoints of 16 to 32 mg/liter for dosages of 400 to 800 mg/day.

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Use of in vitro susceptibility and pathogen prevalence data to model the expected clinical success rates of tigecycline and other commonly used antimicrobials for empirical treatment of complicated skin and skin-structure infections

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2007.07.020 ◽

2007 ◽

Vol 30 (6) ◽

pp. 514-520 ◽

Cited By ~ 10

Author(s):

Helio S. Sader ◽

Rajiv Mallick ◽

Andreas Kuznik ◽

Thomas R. Fritsche ◽

Ronald N. Jones

Keyword(s):

Clinical Success ◽

Empirical Treatment ◽

Success Rates ◽

In Vitro Susceptibility ◽

Prevalence Data ◽

Skin Structure ◽

Complicated Skin ◽

Pathogen Prevalence

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Impact of gonadotropins on oocyte maturation, fertilisation and developmental competence in vitro

Reproduction Fertility and Development ◽

10.1071/rd13024 ◽

2014 ◽

Vol 26 (5) ◽

pp. 752 ◽

Cited By ~ 5

Author(s):

Xuemei Wang ◽

Tony Tsai ◽

Jie Qiao ◽

Zhan Zhang ◽

Huai L. Feng

Keyword(s):

Oocyte Maturation ◽

Early Embryo ◽

Developmental Competence ◽

Dependent Manner ◽

Success Rates ◽

Maturation In Vitro ◽

High Concentrations ◽

Development In Vitro ◽

Dose Dependent

The aim of the present study was to evaluate the dose-dependent effects of gonadotropins, either singly (Bravelle (B), Luveris (L), Menupur (M), Repronex (R), Gonal-F (G), Follism (F) and Norvarel (N)) or in combination (Menupur + Bravelle; Repronext + Bravelle; and Bravelle + Norvarel), on rates of oocyte maturation, fertilisation and early embryo development in vitro in an animal model. Bovine cumulus–oocyte complexes (COCs) were purchased commercially and cultured in TCM-199 with 10% fetal bovine serum supplemented with varying concentrations of gonadotropin (0, 5, 10, 20, 40 IU or United States Pharmacopoeia (USP) mL–1) for 24 and 48 h according to current IVF clinical stimulation protocols. All gonadotropins enhanced oocyte maturation in vitro in a dose-dependent manner. Individually, Gonal-F (Merck KGaA, Darmstadt, Germany), Follism (Merck Co, Whitehouse Station, NJ, USA) and Repronext (Ferring, Parsippany, NJ, USA) promoted oocyte maturation; in combination, they effectively enhanced COC expansion and increased the maturation competence of MII oocytes. However, high concentrations of gonadotropins may result in maturation arrest. Specific combinations of gonadotropins may change the rate of early embryonic development (8–16-cells) and morula–blastocyst formation. These data provide support for the responsiveness of bovine oocytes to gonadotropins in vitro and the need to consider variations in the relative concentrations and ratio of combinations (FSH/LH or human chorionic gonadotropin) for optimisation of oocyte developmental competence. The results of the present study could be applied to therapeutic clinical stimulation protocols and help improve IVF success rates.

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