scholarly journals In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against Candida auris

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 355
Author(s):  
Unai Caballero ◽  
Sarah Kim ◽  
Elena Eraso ◽  
Guillermo Quindós ◽  
Valvanera Vozmediano ◽  
...  
Keyword(s):  
Interaction Model ◽  
Antifungal Drugs ◽  
Health Concern ◽  
Candida Auris ◽  
Fungistatic Activity ◽  
Drug Concentrations ◽  
Low Concentrations ◽  
Wide Range ◽  
Time Kill

Candida auris is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against C. auris. Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole–echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of C. auris infections.

scholarly journals In Vitro Interaction and Killing-Kinetics of Amphotericin B Combined with Anidulafungin or Caspofungin against Candida auris

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1333
Author(s):  
Unai Caballero ◽  
Elena Eraso ◽  
Guillermo Quindós ◽  
Nerea Jauregizar
Keyword(s):  
Amphotericin B ◽  
Antifungal Drugs ◽  
Candida Auris ◽  
Dose Requirement ◽  
Fungistatic Activity ◽  
Invasive Infections ◽  
Kill Curve ◽  
Time Kill ◽  
In Vitro Interaction

Treatment of invasive infections caused by Candida auris is challenging due to the limited therapeutic options. The combination of antifungal drugs may be an interesting and feasible approach to be investigated. The aim of this study was to examine the in vitro activity of amphotericin B in combination with anidulafungin or caspofungin against C. auris. In vitro static time–kill curve experiments were conducted for 48 h with different combinations of amphotericin B with anidulafungin or caspofungin against six blood isolates of C. auris. The antifungal activity of 0.5 mg/L of amphotericin B was limited against the six isolates of C. auris. Similarly, echinocandins alone had a negligible effect, even at the highest tested concentrations. By contrast, 1 mg/L of amphotericin B showed fungistatic activity. Synergy was rapidly achieved (8 h) with 0.5 mg/L of amphotericin B plus 2 mg/L of anidulafungin or caspofungin. These combinations lead to a sustained fungistatic effect, and the fungicidal endpoint was reached against some C. auris isolates. Additionally, ≥0.5 mg/L of either of the two echinocandins with 1 mg/L of amphotericin B resulted in fungicidal effect against all C. auris isolates. In conclusion, combinations of amphotericin B with anidulafungin or caspofungin provided greater killing with a lower dose requirement for amphotericin B compared to monotherapy, with synergistic and/or fungicidal outcomes.

scholarly journals Assessment of Candida auris Response to Antifungal Drugs Using Time–Kill Assays and an Animal Model

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S73-S73 ◽  
Author(s):  
Ronen Ben-Ami ◽  
Liat Ashkenazi ◽  
Judith Berman ◽  
Nuphar Korolker ◽  
Anna Novikov
Keyword(s):  
Amphotericin B ◽  
Fungicidal Activity ◽  
Antifungal Drugs ◽  
Rank Test ◽  
Infection Model ◽  
Candida Auris ◽  
Fungistatic Activity ◽  
Kill Curve ◽  
Time Kill

Abstract Background Candida auris is an emerging nosocomial pathogen that is resistant to Fluconazole and variably susceptible to other systemic drug classes. Treatment with echinocandins has been recommended based on MICs in the susceptible range, but supporting in vivo data is lacking. Methods We tested the MIC of C. auris strains (n = 12) to fluconazole, voriconazole, posaconazole. anidulafungin, amphotericin B and flucytosine. Representative C. auris strains from Israel and South Africa, and a reference C. albicans strain were analysed using time–kill curve assays. Fungicidal activity was defined as reduction of ≥3 log from baseline CFU/ml. Response to caspofungin treatment was assessed in BALB/c mice immunosuppressed with cyclophosphamide and inoculated with 7 × 107C. auris cells by tail vein injection. Mice were treated from day +1 to day +7 with caspofungin (IP) at doses of 1 or 5 mg/kg and compared with sham-treated controls. Survival was assessed daily. Kaplan-Meier survival analyses were performed and treatment arms were compared using the log-rank test. Results Drug susceptibility results (MIC50 and MIC90) were: fluconazole, 64 and 128 mg/l; voriconazole, 0.5 and 24 mg/l; posaconazole, 0.5 and 27 mg/l; anidulafungin, 0.03 and 0.06 mg/l; amphotericin B, 2 and 8 mg/l; flucytosine, 0.3 and 1 mg/l. Time–kill curve analyses showed log reduction from baseline CFU concentration of −3.0 to −2.8 for fluconazole (MIC ×1), 5.6–6.1 for amphotericin B (MIC ×4) and −0.4 to −0.9 for caspofungin (MIC ×16), consistent with fungicidal activity of amphotericin B and weak fungistatic activity of caspofungin. In the mouse model, survival rate was similar with sham treatment (33%) and treatment with caspofungin 1 mg/kg/day (44%) and 5 mg/kg/day (22%), P = 0.7. Conclusion Despite generally low MIC, caspofungin has only mild fungistatic activity on C. auris and no effect on survival in a mouse infection model. Amphotericin B has fungicidal activity against C. auris. Disclosures All authors: No reported disclosures.

scholarly journals Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 381
Author(s):  
Lara Muñoz-Muñoz ◽  
Carolyn Shoen ◽  
Gaye Sweet ◽  
Asunción Vitoria ◽  
Tim J. Bull ◽  
...  
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Mycobacterium Ulcerans ◽  
Health Concern ◽  
Macrocyclic Lactones ◽  
Wide Range ◽  
Poor Treatment ◽  
Spectrum Activity ◽  
Time Kill ◽  
Broad Spectrum Activity

Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy.

scholarly journals The NDV-3A vaccine protects mice from multidrug resistantCandida aurisinfection

2018 ◽  
Author(s):  
Shakti Singh ◽  
Priya Uppuluri ◽  
Abdullah Alqarihi ◽  
Hana Elhassan ◽  
Samuel French ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Protective Efficacy ◽  
Antifungal Drugs ◽  
Surface Proteins ◽  
Health Concern ◽  
Drug Resistant ◽  
Candida Auris ◽  
N Terminus ◽  
Almost All

AbstractCandida aurisis an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host - a trait unique from otherCandidaspecies. Besides being associated globally with life-threatening disseminated infections,C. aurisalso poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins inC. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin ofC. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognizedC. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels ofC. auriscross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethalC. aurisdisseminated infection, compared to the control alum-vaccinated mice. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, againstC. auriscandidemia. Identification of Als3-like adhesins inC. aurismakes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against otherCandidaspecies and safety as well as efficacy in clinical trials. Considering thatC. auriscan be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.Author SummaryCandida aurishas emerged as a major health concern to hospitalized patients and nursing home subjects.C. aurisstrains display multidrug resistance to current antifungal therapy and cause lethal infections. We have determined thatC. aurisharbors homologs ofC. albicansAls cell surface proteins. TheC. albicansNDV-3A vaccine, harboring the N-terminus of Als3p formulated with alum, generates cross-reactive antibodies againstC. aurisclinical isolates and protects neutropenic mice from hematogenously disseminatedC. aurisinfection. Importantly, the NDV-3A vaccine displays an additive protective effect in neutropenic mice when combined with micafungin. Due to its proven safety and efficacy in humans againstC. albicansinfection, our studies support the expedited testing of the NDV-3A vaccine againstC. aurisin future clinical trials.

scholarly journals In vitro antimicrobial activity of the organic extract of Cladonia substellata Vainio and usnic acid against Staphylococcus spp. obtained from cats and dogs

2017 ◽  
Vol 37 (4) ◽  
pp. 368-378 ◽  
Author(s):  
Jusciêne B. Moura ◽  
Agueda C. de Vargas ◽  
Gisele V. Gouveia ◽  
João J. de S. Gouveia ◽  
Juracy C. Ramos-Júnior ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Biological Activities ◽  
Meca Gene ◽  
Usnic Acid ◽  
Organic Extract ◽  
In Vitro Antimicrobial Activity ◽  
Low Concentrations ◽  
Wide Range ◽  
Staphylococcus Spp

ABSTRACT: Cladonia substellata Vainio is a lichen found in different regions of the world, including the Northeast of Brazil. It contains several secondary metabolites with biological activity, including usnic acid, which has exhibited a wide range of biological activities. The aim of this study was to evaluate the in vitro antimicrobial activity of the organic extract of C. substellata and purified usnic acid. Initially, Staphylococcus spp., derived from samples of skin and ears of dogs and cats with suspected pyoderma and otitis, were isolated and analyzed. In antimicrobial susceptibility testing against Staphylococcus spp., 77% (105/136) of the isolates were resistant to the antimicrobials tested. In the assessment of biofilm production, 83% (113/136) were classified as producing biofilm. In genetic characterization, 32% (44/136) were positive for blaZ, no isolate (0/136) was positive for the mecA gene, and 2% (3/136) were positive for the icaD gene. The in vitro antimicrobial activity of the organic extract of C. substellata and purified usnic acid against Staphylococcus spp. ranged from 0.25mg/mL to 0.0019mg/mL, inhibiting bacterial growth at low concentrations. The substances were more effective against biofilm-producing bacteria (0.65mg/mL-0.42mg/mL) when compared to non-biofilm producing bacteria (2.52mg/mL-2.71mg/mL). Usnic acid and the organic extract of C. substellata can be effective in the treatment of pyoderma and otitis in dogs and cats caused by Staphylococcus spp.

Effects of polymethoxylated flavone metabolites on apoB100 secretion and MTP activity in Huh7.5 cells

2021 ◽  
Vol 18 ◽  
Author(s):  
Danielle R. Gonçalves ◽  
Thais B. Cesar ◽  
John A. Manthey ◽  
Paulo I. Costa
Keyword(s):  
Lipid Synthesis ◽  
Dependent Manner ◽  
Transfer Protein ◽  
Low Concentrations ◽  
Wide Range ◽  
Cell Assays ◽  
Polymethoxylated Flavones ◽  
High Concentrations

Background: Citrus polymethoxylated flavones (PMFs) reduce the synthesis of liver lipoproteins in animal and in vitro cell assays, but few studies have evaluated the direct effects of their metabolites on this highly regulated process. Objective: To investigate the effects of representative metabolites of PMF on the secretion of liver lipoproteins using the mammalian cell Huh7.5. Method: In this study, the influences of three PMFs and five previously isolated PMF metabolites on hepatic apoB-100 secretion and microsomal transfer protein (MTP) activity were evaluated. Tangeretin (TAN), nobiletin (NOB) and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), and their glucuronides (TAN-Gluc, NOB-Gluc and HMF-Gluc) and oxidatively demethylated metabolites (TAN-OH, NOB-OH, HMF-OH) were incubated with Huh7.5 cells to measure their inhibitory effects on lipid synthesis. Results: The results showed that TAN, HMF and TAN-OH reduced the secretion of apoB-100 in a dose-dependent manner, while NOB and the other tested metabolites showed no inhibition. MTP activity in the Huh7.5 cells was significantly reduced in the presence of low concentrations of TAN, and in high concentrations of NOB-OH. This study also showed that PMFs and PMF metabolites produced a wide range of effects on apoB-100 secretion and MTP activity. Conclusion: The results suggest that while PMFs and their metabolites control dyslipidemia in vivo, the inhibition of MTP activity cannot be the only pathway influenced by these compounds.

scholarly journals In vitro Insecticidal and Time-Kill Profile of Ethyl Acetate Extract of Marine Streptomyces sp. Isolated from Sundarbans, Bangladesh

2015 ◽  
Vol 17 (2) ◽  
pp. 151-156 ◽  
Author(s):  
Md Anwarul Haque ◽  
Ashish Kumar Sarker ◽  
Mohammad Sayful Islam ◽  
Md Ajijur Rahman ◽  
Md Akter Uzzaman Chouduri ◽  
...  
Keyword(s):  
Ethyl Acetate ◽  
Mangrove Forest ◽  
Bacterial Strains ◽  
Streptomyces Species ◽  
Streptomyces Sp ◽  
Cell Counts ◽  
Wide Range ◽  
Marine Streptomyces ◽  
Time Kill

The marine soil and sediment samples were collected from different locations of mangrove forest Sundarbans, Bangladesh the largest tidal halophytic mangrove forest in the world. A total of twenty nine Actinomycete strains (AIAH-1 to AIAH-29) were isolated by serial dilution method using isolation media. Among twenty nine strains, AIAH-10 was selected for further study due to its potent antibacterial activity against a wide range of pathogenic bacterial strains. On the basis of morphological, cultural and biochemical studies, the strain AIAH-10 was assigned to Streptomyces sp. The present study was designed to investigate the in vitro insecticidal and time-kill profile of ethyl acetate extracts of marine Streptomyces sp. A dose dependent mortality was observed against the larvae of Sitophilus oryzae. The larval mortality was recorded as 100% in the concentration of 80 mg/ml and higher concentrations, LC50 was found as 11.48 mg/ml. The minimum inhibitory concentration was recorded as 8 to 32 mg/ml against six different pathogenic bacterial strains. Average Log10 reductions in viable cell counts for the extracts ranged from 1.91 Log10 and 2.86 Log10 cfu/mL after 3 h interaction and 2.10 Log10 and 2.93 Log10 after 6 h interaction at MIC, 2 × MIC, 3 × MIC and 4 × MIC concentrations. This investigation reveals that the Streptomyces species isolated from Sundarbans, Bangladesh may be interesting source for the isolation of potent bioactive compounds. DOI: http://dx.doi.org/10.3329/bpj.v17i2.22332 Bangladesh Pharmaceutical Journal 17(2): 151-156, 2014

scholarly journals In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

1998 ◽  
Vol 42 (10) ◽  
pp. 2503-2510 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Wiley A. Schell ◽  
Christine C. Dykstra ◽  
Susan K. Jones ◽  
Richard R. Tidwell ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Candida Albicans ◽  
Fusarium Solani ◽  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Inhibitory Compounds ◽  
Wide Range ◽  
Fluconazole Resistant ◽  
Resistant Strains

ABSTRACT Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities againstCandida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active againstAspergillus fumigatus, Fusarium solani,Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.

scholarly journals Enhanced Resistance to Bacterial Infection in Protegrin-1 Transgenic Mice

2008 ◽  
Vol 52 (5) ◽  
pp. 1812-1819 ◽  
Author(s):  
Queenie C. K. Cheung ◽  
Patricia V. Turner ◽  
Cheng Song ◽  
De Wu ◽  
Hugh Y. Cai ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Bacterial Infection ◽  
Ectopic Expression ◽  
Farm Animals ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Cell Counts ◽  
Enhanced Resistance ◽  
Wide Range

ABSTRACT Antibiotic-resistant bacteria have become a public health concern. It was suggested that one source of resistant pathogens may be food-producing animals. Alternative approaches are therefore needed to enhance the resistance of farm animals to bacterial infection. Protegrin-1 (PG-1) is a neutrophil-derived antimicrobial peptide that possesses activity against a wide range of bacteria and enveloped viruses. Here we report on the production of transgenic mice that ectopically expressed PG-1 and compare their susceptibilities to Actinobacillus suis infection with those of their wild-type (WT) littermates. Of the 126 mice that were challenged with A. suis, 87% of the transgenic mice survived, whereas 31% of their WT littermates survived. The PG-1 transgenic mice had significantly lower bacterial loads in their lungs and reduced numbers of pulmonary pathological lesions. The antimicrobial function of PG-1 was confirmed in vitro by using fibroblast cells isolated from the transgenic mice but not the WT mice. Moreover, differential blood cell counts in bronchoalveolar lavage fluid indicated greater number of neutrophils in PG-1 transgenic mice than in their WT littermates after bacterial challenge. Our data suggest that the ectopic expression of PG-1 in mice confers enhanced resistance to bacterial infection, laying the foundation for the development of livestock with improved resistance to infection.

scholarly journals In VitroInteraction between Alginate Lyase and Amphotericin B against Aspergillus fumigatus Biofilm Determined by Different Methods

2012 ◽  
Vol 57 (3) ◽  
pp. 1275-1282 ◽  
Author(s):  
Francesca Bugli ◽  
Brunella Posteraro ◽  
Massimiliano Papi ◽  
Riccardo Torelli ◽  
Alessandro Maiorana ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Extracellular Polymeric Substances ◽  
Alginate Lyase ◽  
Antifungal Drugs ◽  
Antibiofilm Activity ◽  
Content Type ◽  
Time Kill

ABSTRACTAspergillus fumigatusbiofilms represent a problematic clinical entity, especially because of their recalcitrance to antifungal drugs, which poses a number of therapeutic implications for invasive aspergillosis, the most difficult-to-treatAspergillus-related disease. While the antibiofilm activities of amphotericin B (AMB) deoxycholate and its lipid formulations (e.g., liposomal AMB [LAMB]) are well documented, the effectiveness of these drugs in combination with nonantifungal agents is poorly understood. In the present study,in vitrointeractions between polyene antifungals (AMB and LAMB) and alginate lyase (AlgL), an enzyme degrading the polysaccharides produced as extracellular polymeric substances (EPSs) within the biofilm matrix, againstA. fumigatusbiofilms were evaluated by using the checkerboard microdilution and the time-kill assays. Furthermore, atomic force microscopy (AFM) was used to image and quantify the effects of AlgL-antifungal combinations on biofilm-growing hyphal cells. On the basis of fractional inhibitory concentration index values, synergy was found between both AMB formulations and AlgL, and this finding was also confirmed by the time-kill test. Finally, AFM analysis showed that whenA. fumigatusbiofilms were treated with AlgL or polyene alone, as well as with their combination, both a reduction of hyphal thicknesses and an increase of adhesive forces were observed compared to the findings for untreated controls, probably owing to the different action by the enzyme or the antifungal compounds. Interestingly, marked physical changes were noticed inA. fumigatusbiofilms exposed to the AlgL-antifungal combinations compared with the physical characteristics detected after exposure to the antifungals alone, indicating that AlgL may enhance the antibiofilm activity of both AMB and LAMB, perhaps by disrupting the hypha-embedding EPSs and thus facilitating the drugs to reach biofilm cells. Taken together, our results suggest that a combination of AlgL and a polyene antifungal may prove to be a new therapeutic strategy for invasive aspergillosis, while reinforcing the EPS as a valuable antibiofilm drug target.

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