The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform

Yang Wang - One of the best experts on this subject based on the ideXlab platform.

Jean-marc Rolain - One of the best experts on this subject based on the ideXlab platform.

  • In vitro Polymyxin activity against clinical multidrug-resistant fungi
    Antimicrobial Resistance & Infection Control, 2019
    Co-Authors: Hanane Yousfi, Jean-marc Rolain, Stéphane Ranque, Fadi Bittar
    Abstract:

    Background Although antifungals are available and usually used against fungal infections, multidrug-resistant (MDR) fungal pathogens are a growing problem for public health. Moreover, fungal infections have become more prevalent nowadays due to the increasing number of people living with immunodeficiency. Thus, previously rarely-isolated and/or unidentified fungal species including MDR yeast and moulds have emerged around the world. Recent works indicate that Polymyxin Antibiotics (Polymyxin B and colistin) have potential antifungal proprieties. Therefore, investigating the in vitro activity of these molecules against clinical multidrug-resistant yeast and moulds could be very useful. Methods In this study, a total of 11 MDR yeast and filamentous fungal strains commonly reported in clinical settings were tested against Polymyxin Antibiotics. These include strains belonging to the Candida , Cryptococcus and Rhodotorula yeast genera, along with others belonging to the Aspergillus , Fusarium , Scedosporium , Lichtheimia and Rhizopus mould genera. The fungicidal or fungistatic action of colistin against clinical yeast strains was determined by the time-kill study. Further, a checkerboard assay for its combination with antifungal agents, usually used in clinical practices (amphotericin B, itraconazole, voriconazole), was carried out against multi-drug resistant fungal strains. Results Polymyxin B and colistin exhibited an antifungal activity against all MDR fungal strains tested with MICs ranging from 16 to 128 μg/ml, except for the Aspergillus species. In addition, colistin has a fungicidal action against yeast species, with minimum fungicidal concentrations ranging from 2 to 4 times MICs. It induces damage to the MDR Candida albicans membrane. A synergistic activity of colistin-amphotericin B and colistin-itraconazole associations against Candida albicans and Lichtheimia corymbifera strains, respectively, and colistin-fluconazole association against Rhodotorula mucilaginosa, was demonstrated using a checkerboard microdilution assay. Conclusion colistin could be proposed, in clinical practice, in association with other antifungals, to treat life-threatening fungal infections caused by MDR yeasts or moulds.

  • In vitro Polymyxin activity against clinical multidrug-resistant fungi
    Antimicrobial Resistance and Infection Control, 2019
    Co-Authors: Hanane Yousfi, Jean-marc Rolain, Stéphane Ranque, Fadi Bittar
    Abstract:

    Background Although antifungals are available and usually used against fungal infections, multidrug-resistant (MDR) fungal pathogens are a growing problem for public health. Moreover, fungal infections have become more prevalent nowadays due to the increasing number of people living with immunodeficiency. Thus, previously rarely-isolated and/or unidentified fungal species including MDR yeast and moulds have emerged around the world. Recent works indicate that Polymyxin Antibiotics (Polymyxin B and colistin) have potential antifungal proprieties. Therefore, investigating the in vitro activity of these molecules against clinical multidrug-resistant yeast and moulds could be very useful.

  • Mechanisms of Polymyxin resistance: Acquired and intrinsic resistance in bacteria
    Frontiers in Microbiology, 2014
    Co-Authors: Abiola O. Olaitan, Serge Morand, Jean-marc Rolain
    Abstract:

    Polymyxins are polycationic antimicrobial peptides that are currently the last-resort Antibiotics for the treatment of multidrug-resistant, Gram-negative bacterial infections. The reintroduction of Polymyxins for antimicrobial therapy has been followed by an increase in reports of resistance among Gram-negative bacteria. Some bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, develop resistance to Polymyxins in a process referred to as acquired resistance, whereas other bacteria, such as Proteus spp., Serratia spp., and Burkholderia spp., are naturally resistant to these drugs. Reports of Polymyxin resistance in clinical isolates have recently increased, including acquired and intrinsically resistant pathogens. This increase is considered a serious issue, prompting concern due to the low number of currently available effective Antibiotics. This review summarizes current knowledge concerning the different strategies bacteria employ to resist the activities of Polymyxins. Gram-negative bacteria employ several strategies to protect themselves from Polymyxin Antibiotics (Polymyxin B and colistin), including a variety of lipopolysaccharide (LPS) modifications, such as modifications of lipid A with phosphoethanolamine and 4-amino-4-deoxy-L-arabinose, in addition to the use of efflux pumps, the formation of capsules and overexpression of the outer membrane protein OprH, which are all effectively regulated at the molecular level. The increased understanding of these mechanisms is extremely vital and timely to facilitate studies of antimicrobial peptides and find new potential drugs targeting clinically relevant Gram-negative bacteria.

Xiaoming Wang - One of the best experts on this subject based on the ideXlab platform.

Fadi Bittar - One of the best experts on this subject based on the ideXlab platform.

  • In vitro Polymyxin activity against clinical multidrug-resistant fungi
    Antimicrobial Resistance and Infection Control, 2019
    Co-Authors: Hanane Yousfi, Jean-marc Rolain, Stéphane Ranque, Fadi Bittar
    Abstract:

    Background Although antifungals are available and usually used against fungal infections, multidrug-resistant (MDR) fungal pathogens are a growing problem for public health. Moreover, fungal infections have become more prevalent nowadays due to the increasing number of people living with immunodeficiency. Thus, previously rarely-isolated and/or unidentified fungal species including MDR yeast and moulds have emerged around the world. Recent works indicate that Polymyxin Antibiotics (Polymyxin B and colistin) have potential antifungal proprieties. Therefore, investigating the in vitro activity of these molecules against clinical multidrug-resistant yeast and moulds could be very useful.

  • In vitro Polymyxin activity against clinical multidrug-resistant fungi
    Antimicrobial Resistance & Infection Control, 2019
    Co-Authors: Hanane Yousfi, Jean-marc Rolain, Stéphane Ranque, Fadi Bittar
    Abstract:

    Background Although antifungals are available and usually used against fungal infections, multidrug-resistant (MDR) fungal pathogens are a growing problem for public health. Moreover, fungal infections have become more prevalent nowadays due to the increasing number of people living with immunodeficiency. Thus, previously rarely-isolated and/or unidentified fungal species including MDR yeast and moulds have emerged around the world. Recent works indicate that Polymyxin Antibiotics (Polymyxin B and colistin) have potential antifungal proprieties. Therefore, investigating the in vitro activity of these molecules against clinical multidrug-resistant yeast and moulds could be very useful. Methods In this study, a total of 11 MDR yeast and filamentous fungal strains commonly reported in clinical settings were tested against Polymyxin Antibiotics. These include strains belonging to the Candida , Cryptococcus and Rhodotorula yeast genera, along with others belonging to the Aspergillus , Fusarium , Scedosporium , Lichtheimia and Rhizopus mould genera. The fungicidal or fungistatic action of colistin against clinical yeast strains was determined by the time-kill study. Further, a checkerboard assay for its combination with antifungal agents, usually used in clinical practices (amphotericin B, itraconazole, voriconazole), was carried out against multi-drug resistant fungal strains. Results Polymyxin B and colistin exhibited an antifungal activity against all MDR fungal strains tested with MICs ranging from 16 to 128 μg/ml, except for the Aspergillus species. In addition, colistin has a fungicidal action against yeast species, with minimum fungicidal concentrations ranging from 2 to 4 times MICs. It induces damage to the MDR Candida albicans membrane. A synergistic activity of colistin-amphotericin B and colistin-itraconazole associations against Candida albicans and Lichtheimia corymbifera strains, respectively, and colistin-fluconazole association against Rhodotorula mucilaginosa, was demonstrated using a checkerboard microdilution assay. Conclusion colistin could be proposed, in clinical practice, in association with other antifungals, to treat life-threatening fungal infections caused by MDR yeasts or moulds.

Tony Velkov - One of the best experts on this subject based on the ideXlab platform.

  • Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae.
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Irene Galani, Ilias Karaiskos, Phillip J. Bergen, Heidi Yu, Jiping Wang, Ke Chen, Hasini Wickremasinghe, Jinxin Zhao, Tony Velkov
    Abstract:

    Resistance to Polymyxin Antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with Polymyxin-based combinations against multidrug-resistant (including Polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (Polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various Polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most Polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of Polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, Polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (Polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the Polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of Polymyxin-based combinations in patients.

  • discovery of novel Polymyxin like Antibiotics
    Advances in Experimental Medicine and Biology, 2019
    Co-Authors: Tony Velkov, Kade D Roberts
    Abstract:

    The antimicrobial lipopeptides Polymyxin B and colistin (Polymyxin E) are used as a ‘last-line’ therapy for infections caused by multidrug-resistant (MDR) Gram-negative pathogens. However, their effective use as antibiotic drugs in the clinical setting is still plagued by significant toxicity issues, in particular their potential for nephrotoxicity. Furthermore, resistance to the Polymyxins has begun to emerge in the clinic, which implies a total lack of Antibiotics for the treatment of life-threatening infections caused by the Gram-negative ‘superbugs’. This chapter details our current understanding of Polymyxin structure-activity relationships as well as recent pre-clinical and clinical drug development efforts aimed at generating new Polymyxin Antibiotics with improved safety and efficacy.

  • Curcumin Attenuates Colistin-Induced Neurotoxicity in N2a Cells via Anti-inflammatory Activity, Suppression of Oxidative Stress, and Apoptosis
    Molecular Neurobiology, 2016
    Co-Authors: Giuseppe D. Ciccotosto, Roberto Cappai, Shusheng Tang, Daowen Li, Xilong Xiao, Tony Velkov
    Abstract:

    Neurotoxicity is an unwanted side-effect seen in patients receiving therapy with the “last-line” Polymyxin Antibiotics. This is the first study to show that colistin-induced neurotoxicity in neuroblastoma-2a (N2a) cells gives rise to an inflammatory response involving the IL-1β/p-IκB-α/NF-κB pathway. Pretreatment with curcumin at 5, 10, and 20 μM for 2 h prior to colistin (200 μM) exposure for 24 h, produced an anti-inflammatory effect by significantly down-regulating the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2), phosphorylation of the inhibitor of nuclear factor-kappa B (NF-κB) (p-IκB)-α, and concomitantly NF-κB levels. Moreover, curcumin significantly decreased intracellular reactive oxygen species (ROS) production and increased the activities of the anti-ROS enzymes superoxide dismutase, catalase, and the intracellular levels of glutathione. Curcumin pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis. Overall, our findings demonstrate for the first time, a potential role for curcumin for treating Polymyxin-induced neurotoxicity through the modulation of NF-κB signaling and its potent anti-oxidative and anti-apoptotic effects.

  • Pharmacokinetics/pharmacodynamics of colistin and Polymyxin B: are we there yet?
    International Journal of Antimicrobial Agents, 2016
    Co-Authors: Thien B. Tran, Brian T Tsuji, Alan Forrest, Tony Velkov, Roger L. Nation, Phillip J. Bergen, Jian Li
    Abstract:

    Abstract The Polymyxin Antibiotics [colistin and Polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available Polymyxins have very different pharmacological properties, as colistin (Polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both Polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the ‘Bad Bugs, No Drugs’ era, Polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative ‘superbugs’. Rational approaches to the use of Polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.

  • Quantitation of Polymyxin–Lipopolysaccharide Interactions Using an Image-Based Fluorescent Probe
    Journal of Pharmaceutical Sciences, 2016
    Co-Authors: Mitchell P. Mcinerney, Tony Velkov, Kade D Roberts, Roger L. Nation, Jian Li, Philip E. Thompson, Joseph A. Nicolazzo
    Abstract:

    The frequency of Polymyxin-resistant pathogenic Gram-negative bacteria appearing in the clinic is increasing, and the consequences are largely mediated by modification of lipopolysaccharide (LPS) in the outer membrane. As Polymyxins exert their antibacterial effect by binding to LPS, understanding their mode of binding will prove highly valuable for new antibiotic discovery. In this study, we assess the potential of MIPS-9451, a fluorescent Polymyxin analogue designed for imaging studies, as a fluorescent reporter molecule, titrating it against 17 different Gram-negative species and/or strains of LPS. MIPS-9451 bound to the various species and/or strains of LPS with a dissociation constant ranging between 0.14 ± 0.01 μM (Escherichia coli) and 0.90 ± 0.42 μM (Porphyromonas gingivalis; mean ± standard error). Furthermore, we assessed the applicability of MIPS-9451 to rank affinities of Polymyxin B to different LPS species in a displacement assay which yielded inhibition constants of 6.2 μM ± 33%, 7.2 μM ± 30%, and 0.95 μM ± 13% for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella enterica, respectively (mean ± coefficient of variation). The results from this study are concordant with those observed with similarly structured Polymyxin probes, confirming the potential of MIPS-9451 for quantitation of Polymyxin-LPS affinities in discovery programs of novel Polymyxin Antibiotics.