scholarly journals Biofilm Production and Antibiofilm Activity of Echinocandins and Liposomal Amphotericin B in Echinocandin-Resistant Yeast Species

2016 ◽  
Vol 60 (6) ◽  
pp. 3579-3586 ◽  
Author(s):  
Laura Judith Marcos-Zambrano ◽  
Marta Gómez-Perosanz ◽  
Pilar Escribano ◽  
Oscar Zaragoza ◽  
Emilio Bouza ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Metabolic Activity ◽  
Liposomal Amphotericin ◽  
Antifungal Susceptibility ◽  
Growth Control ◽  
Liposomal Amphotericin B ◽  
Antibiofilm Activity ◽  
Wild Type ◽  
Content Type ◽  
Type Strains

The echinocandins and liposomal amphotericin B are active against biofilm produced by echinocandin-susceptibleCandidastrains. However, few data have been reported on the production of biofilm by echinocandin-resistant isolates and their antifungal susceptibility. We studied the production of biofilm byfksmutantCandidastrains and intrinsically echinocandin-resistant non-Candidaisolates and the susceptibility of both entities to liposomal amphotericin B and echinocandins. We analyzed the production of biofilm by isolates from patients with fungemia (fksmutantCandida,n= 5; intrinsically echinocandin-resistant non-Candida,n= 12; andCandidawild type,n= 10). Biofilm formation was measured to classify strains according to biomass (crystal violet assay) and metabolic activity (XTT reduction assay). Preformed biofilms were tested against liposomal amphotericin B, caspofungin, micafungin, and anidulafungin. The sessile MIC was defined as the antifungal concentration yielding a 50% or 80% reduction in the metabolic activity of the biofilm compared to that of the growth control (SMIC50and SMIC80, respectively).fksmutantCandidaisolates formed biofilms in a fashion similar to that ofCandidawild-type strains. The echinocandins had the highest activity against biofilms formed by wild-typeCandidaisolates, followed byfksmutantCandidaisolates and non-Candidaisolates. Liposomal amphotericin B had the highest activity againstfksmutantCandidabiofilms. The formation of biofilm by echinocandin-resistant strains was similar to that of wild-type strains, although resistance to echinocandins remained high.

scholarly journals Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Saad J. Taj-Aldeen ◽  
Husam Salah ◽  
Winder B. Perez ◽  
Muna Almaslamani ◽  
Mary Motyl ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Hot Spot ◽  
Antifungal Susceptibility ◽  
Tertiary Hospital ◽  
Wild Type ◽  
Content Type ◽  
Cutoff Values ◽  
Echinocandin Resistance ◽  
Candida Infections ◽  
Type Strains

ABSTRACT A total of 301 Candida bloodstream isolates collected from 289 patients over 5 years at a tertiary hospital in Qatar were evaluated. Out of all Candida infections, 53% were diagnosed in patients admitted to the intensive care units. Steady increases in non-albicans Candida species were reported from 2009 to 2014 (30.2% for Candida albicans versus 69.8% for the other Candida species). Etest antifungal susceptibility testing was performed on all recovered clinical isolates to determine echinocandin (micafungin and anidulafungin) and amphotericin B susceptibilities and assess non-wild-type (non-WT) strains (strains for which MICs were above the epidemiological cutoff values). DNA sequence analysis was performed on all isolates to assess the presence of FKS mutations, which confer echinocandin resistance in Candida species. A total of 3.9% of isolates (12/301) among strains of C. albicans and C. orthopsilosis contained FKS hot spot mutations, including heterozygous mutations in FKS1. For C. tropicalis, the Etest appeared to overestimate strains non-WT for micafungin, anidulafungin, and amphotericin B, as 14%, 11%, and 35% of strains, respectively, had values above the epidemiological cutoff value. However, no FKS mutations were identified in this species. For all other species, micafungin best reported the echinocandin non-WT strains relative to the FKS genotype, as anidulafungin tended to overestimate non-wild-type strains. Besides C. tropicalis, few strains were classified as non-WT for amphotericin B.

scholarly journals In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Johan W. Mouton ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Treated Group ◽  
Liposomal Amphotericin B ◽  
Wild Type ◽  
Resistance Mutations ◽  
Content Type

ABSTRACT Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866–1871, 2013, https://doi.org/10.1128/AAC.02226-12 ). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR34/L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR34/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR34/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED50) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P > 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

scholarly journals Caspofungin at Catheter Lock Concentrations Eradicates Mature Biofilms of Candida lusitaniae and Candida guilliermondii

2014 ◽  
Vol 58 (8) ◽  
pp. 4953-4956 ◽  
Author(s):  
Maria Simitsopoulou ◽  
Daniela Kyrpitzi ◽  
Aristea Velegraki ◽  
Thomas J. Walsh ◽  
Emmanuel Roilides
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Candida Guilliermondii ◽  
Liposomal Amphotericin B ◽  
Antibiofilm Activity ◽  
Test Species ◽  
Content Type ◽  
Lock Therapy ◽  
Catheter Lock ◽  
Candida Lusitaniae

ABSTRACTThe antibiofilm activities of caspofungin, anidulafungin, micafungin, and liposomal amphotericin B were studied againstCandida lusitaniae,Candida guilliermondii, and aCandida albicanscontrol strain. While anidulafungin and micafungin (0.007 to 2,048 mg/liter) showed reduced activity against biofilms of both test species, caspofungin displayed concentration-dependent antibiofilm activity, reaching complete and persistent eradication at concentrations achievable during lock therapy (512 to 2,048 mg/liter,P< 0.05). Although liposomal amphotericin B strongly inhibited mature biofilms, it possessed lower antibiofilm activity than caspofungin (P< 0.05).

Qualitative and quantitative change of the tolerance to liposomal amphotericin B triggered by biofilm maturation in C. parapsilosis

2019 ◽  
Vol 58 (6) ◽  
pp. 827-834
Author(s):  
D Casagrande Pierantoni ◽  
L Roscini ◽  
L Corte ◽  
M Bernardo ◽  
M Bassetti ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Candida Parapsilosis ◽  
Opportunistic Pathogen ◽  
Hospital Environment ◽  
Liposomal Amphotericin B ◽  
Antibiofilm Activity ◽  
Planktonic Cells ◽  
Large Variability ◽  
Qualitative And Quantitative

Abstract Candida parapsilosis is an emerging opportunistic pathogen present in both clinical and natural environment, with a strong frequency of biofilm forming strains. While the drugs active against biofilm are rare, liposomal amphotericin B is credited with an antibiofilm activity in some opportunistic species of the genus Candida. Using freshly isolated strains from hospital environment, in this paper we could show the prevalence of biofilm forming vs. nonbiofilm forming strains. The former displayed a large variability in terms of biofilm biomass and metabolic activity. Liposomal amphotericin B minimum inhibitory concentration (MIC) of planktonic cells was below the breakpoint, whereas the sessile cells MIC (SMIC) was 1 or 2 orders of magnitude above the planktonic MIC. When the drug was applied to freshly attached cells, that is, biofilm in formation, the MIC (called SDMIC) was even below the MIC value. All resistance metrics (MIC, SMIC, and SDMIC) were quite variable although no correlation could be detected between them and the metrics used to quantify biofilm activity and biomass production. These findings demonstrate that young biofilm cells are even more susceptible than planktonic cells and that early treatments with this drug can be beneficial in cases of prosthesis implantation or especially when there is the necessity of a CVC reimplantation during a sepsis.

scholarly journals Investigation of the Efficacy of Micafungin in the Treatment of Histoplasmosis Using Two North American Strains of Histoplasma capsulatum

2011 ◽  
Vol 55 (9) ◽  
pp. 4447-4450 ◽  
Author(s):  
Chadi A. Hage ◽  
Patricia Connolly ◽  
Daniel Horan ◽  
Michelle Durkin ◽  
Melinda Smedema ◽  
...  
Keyword(s):  
Amphotericin B ◽  
North American ◽  
Liposomal Amphotericin ◽  
Histoplasma Capsulatum ◽  
Liposomal Amphotericin B ◽  
Content Type ◽  
Yeast Form

ABSTRACTMicafungin alone and combined with liposomal amphotericin B was evaluated against two strains ofHistoplasma capsulatum. Micafungin was activein vitroagainst the mold but not the yeast form but was ineffectivein vivo. Micafungin appears to be ineffective in treatment of histoplasmosis.

scholarly journals Efficacy of Liposomal Amphotericin B and Posaconazole in Intratracheal Models of Murine Mucormycosis

2013 ◽  
Vol 57 (7) ◽  
pp. 3340-3347 ◽  
Author(s):  
Guanpingsheng Luo ◽  
Teclegiorgis Gebremariam ◽  
Hongkyu Lee ◽  
Samuel W. French ◽  
Nathan P. Wiederhold ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Intratracheal Instillation ◽  
Cortisone Acetate ◽  
Liposomal Amphotericin B ◽  
Immunocompromised Patients ◽  
Content Type ◽  
Pulmonary Mucormycosis ◽  
Life Threatening

ABSTRACTMucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation ofMucoralesspores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate-treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates ofMucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threateningMucoralesinfections.

scholarly journals Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Katrien Van Bocxlaer ◽  
Amanda Fortes Francisco ◽  
Vanessa Yardley ◽  
Andy Harris ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Skin Inflammation ◽  
Skin Lesions ◽  
Disease Stage ◽  
Liposomal Amphotericin B ◽  
Local Skin ◽  
Content Type ◽  
Tissue Inflammation

ABSTRACTDisfiguring skin lesions caused by several species of theLeishmaniaparasite characterize cutaneous leishmaniasis (CL). Successful treatment of CL with intravenous (i.v.) liposomal amphotericin B (LAmB) relies on the presence of adequate antibiotic concentrations at the dermal site of infection within the inflamed skin. Here, we have investigated the impact of the local skin inflammation on the pharmacokinetics (PK) and efficacy of LAmB in two murine models of localized CL (Leishmania majorandLeishmania mexicana) at three different stages of disease (papule, initial nodule, and established nodule). Twenty-four hours after the administration of one 25 mg/kg of body weight LAmB (i.v.) dose to infected BALB/c mice (n= 5), drug accumulation in the skin was found to be dependent on the causative parasite species (L. major>L. mexicana) and the disease stage (papule > initial nodule > established nodule > healthy skin). Elevated tissue drug levels were associated with increased vascular permeability (Evans blue assay) and macrophage infiltration (histomorphometry) in the infected skin, two pathophysiological parameters linked to tissue inflammation. After identical treatment of CL in the two models with 5 × 25 mg/kg LAmB (i.v.), intralesional drug concentrations and reductions in lesion size and parasite load (quantitative PCR [qPCR]) were all ≥2-fold higher forL. majorthan forL. mexicana. In conclusion, drug penetration of LAmB into CL skin lesions could depend on the disease stage and the causativeLeishmaniaspecies due to the influence of local tissue inflammation.

scholarly journals In Vitro and In Vivo Exposure-Effect Relationship of Liposomal Amphotericin B against Aspergillus fumigatus

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Maria Siopi ◽  
Johan W. Mouton ◽  
Spyros Pournaras ◽  
Joseph Meletiadis
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Simulation Analysis ◽  
Maximal Activity ◽  
Liposomal Amphotericin B ◽  
Content Type ◽  
Exposure Effect

ABSTRACT In vitro pharmacokinetic/pharmacodynamic data of liposomal amphotericin B (L-AMB) were compared with animal data from neutropenic and nonneutropenic models of azole-susceptible and azole-resistant invasive aspergillosis. L-AMB was equally effective. The in vitro fCmax (maximum concentration of free drug)/MIC ratio associated with 50% of maximal activity was 0.31 (0.29 to 0.33), similar to that in neutropenic but not nonneutropenic mice (0.11 [0.06 to 0.20]). Simulation analysis indicated that standard L-AMB doses (1 to 3 mg/kg) are adequate for nonneutropenic patients, but higher doses (7.5 to 10 mg/kg) may be required for neutropenic patients for Aspergillus fumigatus isolates with MICs of 0.5 to 1 mg/liter.

scholarly journals Lichtheimia corymbifera Colonization Leading to Pulmonary Infection Can Be Prevented with Liposomal Amphotericin B in a New Murine Model

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Thomas Brunet ◽  
Kévin Brunet ◽  
Grégory Jouvion ◽  
Estelle Cateau ◽  
Sandrine Marchand ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
High Efficiency ◽  
Antifungal Drugs ◽  
Liposomal Amphotericin B ◽  
Content Type ◽  
Pulmonary Mucormycosis ◽  
Lung Colonization ◽  
Lichtheimia Corymbifera

ABSTRACT The incidence of pulmonary mucormycosis is constantly increasing, especially in hematological patients staying in high-efficiency particulate air-filtered rooms. Pulmonary inhalation of spores may occur outside the hospital, leading to invasive disease once patients received chemotherapies. We developed a new pulmonary mucormycosis mouse model mimicking the expected pathophysiology in human to study antifungal drugs. Naive mice were inoculated intratracheally with Lichtheimia corymbifera spores. After 3 days, mice received corticosteroids and cyclophosphamide and secondarily developed the disease, while only 5% of the initial inoculum was present in the lungs at day 3. Lung colonization with L. corymbifera spores in immunocompetent mice can last at least 44 days. Antifungal drug was administered the day of immunosuppression. Injection of a single 15 mg/kg of body weight dose of liposomal amphotericin B significantly improved survival and pulmonary fungal burden compared with controls, whereas 80 mg/kg oral posaconazole did not. These results show that a unique dose of liposomal amphotericin B offers a real potential decolonization treatment to prevent infection in our mouse model of L. corymbifera lung colonization followed by lung infection.

scholarly journals EUCAST Reference Testing of Rezafungin Susceptibility and Impact of Choice of Plastic Plates

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Karin Meinike Jørgensen ◽  
Rasmus Krøger Hare ◽  
Manuel Cuenca-Estrella ◽  
Oscar Zaragoza
Keyword(s):  
Antifungal Susceptibility ◽  
Reference Method ◽  
Wild Type ◽  
Phase 3 ◽  
Content Type ◽  
Microtiter Plates ◽  
The Difference ◽  
Long Acting ◽  
Interlaboratory Reproducibility ◽  
Type Strains

ABSTRACT Rezafungin is a new long-acting echinocandin currently in phase 3 development. Epidemiological cutoff values are necessary for breakpoint setting but have not been established due to unexplained interlaboratory MIC variations observed in a prior multicenter study. Here we investigated if the choice of microtiter plates affected the variability when anidulafungin was included as a comparator. Testing by the EUCAST E.Def 7.3.1 reference method using tissue and cell culture-treated polystyrene plates (TC plates) and untreated polystyrene plates (UT plates) from four manufacturers was performed. Six control strains (Candida albicans, n = 3; C. krusei, n = 2; C. parapsilosis, n = 1) were tested (520 MICs). Subsequently, 5 or 6 wild-type isolates and 4 or 5 fks mutants of C. albicans, C. glabrata, C. krusei, C. parapsilosis (wild type only), and C. tropicalis were tested (930 MICs). For each strain-plate combination, ≥98% of the repetitive MICs were within 3 dilutions. The rezafungin modal MICs for the collated C. albicans control strain distributions were 0.016 mg/liter across TC plates but 0.03 mg/liter across UT plates, whereas they were 0.004 mg/liter and 0.016 mg/liter, respectively, for anidulafungin. The difference was most pronounced with Falcon plates and was not observed for C. krusei and C. parapsilosis. Eleven rezafungin MICs for mutants overlapped with the MICs for wild-type isolates (TC plates, n = 4; UT plates, n = 7). For anidulafungin, five overlaps (all UT plates) were observed. Most overlaps (rezafungin, n = 5; anidulafungin, n = 3) were caused by fks mutants of C. tropicalis (Fks1, F650F/L) and C. glabrata (Fks2. D666Y; rezafungin, n = 2; anidulafungin, n = 1). Interlaboratory variation was low. The use of TC plates resulted in lower MICs, particularly for C. albicans and Falcon plates, ad this was more often the case for anidulafungin than for rezafungin. Adoption of TC plates for EUCAST antifungal susceptibility testing would improve interlaboratory reproducibility and the separation of non-wild-type and wild-type strains.

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