scholarly journals The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model

EBioMedicine ◽  
2021 ◽  
Vol 72 ◽  
pp. 103595
Author(s):  
Rana Abdelnabi ◽  
Caroline S. Foo ◽  
Suzanne J.F. Kaptein ◽  
Xin Zhang ◽  
Thuc Nguyen Dan Do ◽  
...  
Keyword(s):  
Combined Treatment ◽  
Infection Model ◽  
Antiviral Efficacy

scholarly journals Topical Astodrimer Sodium, a Non-Toxic Polyanionic Dendrimer, Demonstrates Antiviral Activity in an Experimental Ocular Adenovirus Infection Model

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3419
Author(s):  
Eric G. Romanowski ◽  
Kathleen A. Yates ◽  
Jeremy R. A. Paull ◽  
Graham P. Heery ◽  
Robert M. Q. Shanks
Keyword(s):  
Antiviral Activity ◽  
Antiviral Therapy ◽  
Infection Model ◽  
Adenovirus Infection ◽  
Antiviral Efficacy ◽  
Ocular Infections ◽  
Further Development ◽  
Ocular Tolerability ◽  
Efficacy Studies ◽  
Viral Titers

There is no approved antiviral therapy for adenovirus (HAdV) ocular infections. Astodrimer sodium (SPL7013) is a polyanionic dendrimer with antiviral activity. The current study evaluated the ocular tolerability and anti-adenoviral efficacy of topical SPL7013 in rabbit ocular models. In a tolerability study, rabbits were treated with 3% SPL7013, vehicle, or 0.5% cidofovir. Their eyes were graded using the Draize scale. In antiviral efficacy studies, HAdV5 inoculated eyes were treated with 3% SPL7013, vehicle, or 0.5% cidofovir. Eyes were cultured for the virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14. Viral titers were determined. There were no differences in Draize scores between 3% SPL7013 and vehicle on any day. Cidofovir produced significantly higher Draize scores on day 12 than SPL7013 and vehicle. The 3% SPL7013 and 0.5% cidofovir significantly reduced daily viral titers and positive cultures per total compared with vehicle on several different days. The 3% SPL7013 and 0.5% cidofovir significantly reduced the duration of HAdV5 shedding compared to vehicle. The 3% SPL7013 demonstrated significantly more antiviral activity compared with vehicle in the Ad5/NZW rabbit ocular model. The 3% SPL7013 induced “minimal” to “practically non-irritating” Draize scores in the ocular tolerability study. Further development of astodrimer sodium as a topical antiviral therapy for adenoviral ocular infections is indicated.

scholarly journals Gentamicin Combined With Hypoionic Shock Rapidly Eradicates Aquaculture Bacteria in vitro and in vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Gao ◽  
Zhongyu Chen ◽  
Wei Yao ◽  
Daliang Li ◽  
Xinmiao Fu
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
Combined Treatment ◽  
Fish Farming ◽  
Edwardsiella Tarda ◽  
Small Scale ◽  
Infection Model ◽  
Dependent Manner ◽  
Aquatic Animals

Bacterial pathogens are a major cause of infectious diseases in aquatic animals. The abuse of antibiotics in the aquatic industry has led to the proliferation of antibiotic resistance. It is therefore essential to develop more effective and safer strategies to increase the efficacy and extend the life span of the antibiotics used in aquaculture. In this study, we show that six aquaculture bacterial pathogens (i.e., Aeromonas hydrophila, Vibrio alginolyticus, Edwardsiella tarda, Streptococcus iniae, Vibrio harveyi, and Vibrio fluvialis) in the stationary phase can be rapidly killed after immersion in gentamicin- or neomycin-containing, ion-free solutions for a few minutes. Such hypoionic shock treatment enhances the bacterial uptake of gentamicin in an ATP-dependent manner. Importantly, we demonstrate, as a proof of concept, that gentamicin under hypoionic shock conditions can effectively kill A. hydrophila in vivo in a skin infection model of zebrafish (Danio rerio), completely curing the infected fish. Given that pathogenic bacteria generally adhere to the skin surface and gills of aquatic animals, our strategy is of potential significance for bacterial infection control, especially for small-scale economic fish farming and ornamental fish farming. Further, the combined treatment can be completed within 5 min with a relatively small volume of solution, thus minimizing the amount of residual antibiotics in both animals and the environment.

scholarly journals A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 469 ◽  
Author(s):  
Sebastian Franck ◽  
Robin Michelet ◽  
Fiordiligie Casilag ◽  
Jean-Claude Sirard ◽  
Sebastian G. Wicha ◽  
...  
Keyword(s):  
Survival Data ◽  
Lipid A ◽  
Treatment Success ◽  
Combined Treatment ◽  
Pharmacokinetic Interaction ◽  
Infection Model ◽  
Event Analysis ◽  
Bacterial Reduction ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response relationship of amoxicillin with MPLA coadministration and establish a link to survival. Antibiotic serum concentrations, bacterial numbers in lung and spleen and survival data of mice being untreated or treated with amoxicillin (four dose levels), MPLA, or their combination were analyzed by nonlinear mixed-effects modelling and time-to-event analysis using NONMEM® to characterize these treatment regimens. On top of a pharmacokinetic interaction, regarding the pharmacodynamic effects the combined treatment was superior to both monotherapies: The amoxicillin efficacy at highest dose was increased by a bacterial reduction of 1.74 log10 CFU/lung after 36 h and survival was increased 1.35-fold to 90.3% after 14 days both compared to amoxicillin alone. The developed pharmacometric pharmacokinetic/pharmacodynamic disease-treatment-survival models provided quantitative insights into a novel treatment option against pneumonia revealing a pharmacokinetic interaction and enhanced activity of amoxicillin and the immune system stimulator MPLA in combination. Further development of this drug combination flanked with pharmacometrics towards the clinical setting seems promising.

scholarly journals Imidazo[1,2-a]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium InfectionIn Vivo

2016 ◽  
Vol 60 (8) ◽  
pp. 5018-5022 ◽  
Author(s):  
Garrett C. Moraski ◽  
Yong Cheng ◽  
Sanghyun Cho ◽  
Jeffrey W. Cramer ◽  
Alexander Godfrey ◽  
...  
Keyword(s):  
Treatment Regimen ◽  
Mycobacterium Avium ◽  
Antimicrobial Agents ◽  
Combined Treatment ◽  
Infection Model ◽  
Significant Activity ◽  
Content Type ◽  
New Class

ABSTRACTA panel of six imidazo[1,2-a]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity againstMycobacterium aviumstrains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouseM. aviuminfection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti-M. aviumactivity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active againstM. aviumand could potentially serve as an effective addition to a combined treatment regimen.

Emetine as an antiviral agent suppresses SARS-CoV-2 replication by inhibitinginteraction of viral mRNAwith eIF4E: An in vitro study

2020 ◽  
Author(s):  
Ram Kumar ◽  
Nitin Khandelwal ◽  
Yogesh Chander ◽  
Thachamvally Riyesh ◽  
Baldev R. Gulati ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protective Efficacy ◽  
In Vitro Study ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Infection Model ◽  
Target Cells ◽  
Lethal Challenge ◽  
Antiviral Efficacy

AbstractEmetine is a FDA-approved drug for the treatment of amebiasis. In the recent times we had also demonstrated the antiviral efficacy of emetine against some RNA and DNA viruses. Following emergence of the COVID-19, we further evaluated thein vitro antiviral activity of emetine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The therapeutic index of emetine was determined to be 10910.4, at a cytotoxic concentration 50 (CC50) of 1603.8 nM and effective concentration 50 (EC50) of 0.147 nM.Besides, we also demonstrated the protective efficacy of emetine against lethal challenge with infectious bronchitis virus (IBV; a chicken coronavirus) in the embryonated chicken egg infection model. Emetine treatment was shown to decrease viral RNA and protein synthesis without affecting other steps of viral life cycle such as attachment, entry and budding.In a chromatin immunoprecipitation (CHIP) assay, emetine was shown to disrupt the binding of SARS-CoV-2 RNA with eIF4E (eukaryotic translation initiation factor 4E, a cellular cap-binding protein required for initiation ofprotein translation). Further, SARS-CoV-2 was shown to exploit ERK/MNK1/eIF4E signalling pathwayfor its effective replication in the target cells. To conclude, emetine targets SARS-CoV-2 protein synthesis which is mediated via inhibiting the interaction of SARS-CoV-2 RNA with eIF4E. This is a novel mechanistic insight on the antiviral efficacy of emetine. In vitro antiviral efficacy against SARS-CoV-2 and its ability to protect chicken embryos against IBV suggests that emetine could be repurposed to treat COVID-19.

scholarly journals Quorum Sensing Inhibitors Increase the Susceptibility of Bacterial Biofilms to Antibiotics In Vitro and In Vivo

2011 ◽  
Vol 55 (6) ◽  
pp. 2655-2661 ◽  
Author(s):  
Gilles Brackman ◽  
Paul Cos ◽  
Louis Maes ◽  
Hans J. Nelis ◽  
Tom Coenye
Keyword(s):  
Quorum Sensing ◽  
Combined Treatment ◽  
Model Systems ◽  
Burkholderia Cenocepacia ◽  
Bacterial Biofilms ◽  
Infection Model ◽  
Content Type ◽  
Combined Use

ABSTRACTAlthough the exact role of quorum sensing (QS) in various stages of biofilm formation, maturation, and dispersal and in biofilm resistance is not entirely clear, the use of QS inhibitors (QSI) has been proposed as a potential antibiofilm strategy. We have investigated whether QSI enhance the susceptibility of bacterial biofilms to treatment with conventional antimicrobial agents. The QSI used in our study target the acyl-homoserine lactone-based QS system present inPseudomonas aeruginosaandBurkholderia cepaciacomplex organisms (baicalin hydrate, cinnamaldehyde) or the peptide-based system present inStaphylococcus aureus(hamamelitannin). The effect of tobramycin (P. aeruginosa,B. cepaciacomplex) and clindamycin or vancomycin (S. aureus), alone or in combination with QSI, was evaluated in variousin vitroandin vivobiofilm model systems, including two invertebrate models and one mouse pulmonary infection model.In vitrothe combined use of an antibiotic and a QSI generally resulted in increased killing compared to killing by an antibiotic alone, although reductions were strain and model dependent. A significantly higher fraction of infectedGalleria mellonellalarvae andCaenorhabditis eleganssurvived infection following combined treatment, compared to treatment with an antibiotic alone. Finally, the combined use of tobramycin and baicalin hydrate reduced the microbial load in the lungs of BALB/c mice infected withBurkholderia cenocepaciamore than tobramycin treatment alone. Our data suggest that QSI may increase the success of antibiotic treatment by increasing the susceptibility of bacterial biofilms and/or by increasing host survival following infection.

scholarly journals In Vitro Evaluation of Antimicrobial Peptide Tridecaptin M in Combination with Other Antibiotics against Multidrug Resistant Acinetobacter baumannii

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3255
Author(s):  
Manoj Jangra ◽  
Vrushali Raka ◽  
Hemraj Nandanwar
Keyword(s):  
Antimicrobial Peptide ◽  
Acinetobacter Baumannii ◽  
Ex Vivo ◽  
Combined Treatment ◽  
Antimicrobial Effect ◽  
Concomitant Administration ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Permeability Barrier

The rapid emergence of antimicrobial resistance in Acinetobacter baumannii coupled with the dried pipeline of novel treatments has driven the search for new therapeutic modalities. Gram-negative bacteria have an extra outer membrane that serves as a permeability barrier for various hydrophobic and/or large compounds. One of the popular approaches to tackle this penetration barrier is use of potentiators or adjuvants in combination with traditional antibiotics. This study reports the in vitro potential of an antimicrobial peptide tridecaptin M in combination with other antibiotics against different strains of A. baumannii. Tridecaptin M sensitized the bacteria to rifampicin, vancomycin, and ceftazidime. Further, we observed that a tridecaptin M and rifampicin combination killed the bacteria completely in 4 h in an ex vivo blood infection model and was superior to rifampicin monotherapy. The study also found that concomitant administration of both compounds is not necessary to achieve the antimicrobial effect. Bacteria pre-treated with tridecaptin M (for 2–4 h) followed by exposure to rifampicin showed similar killing as obtained for combined treatment. Additionally, this combination hampered the survival of persister development in comparison to rifampicin alone. These findings encourage the future investigation of this combination to treat severe infections caused by extremely drug-resistant A. baumannii.

scholarly journals Low-Temperature Gas Plasma Combined with Antibiotics for the Reduction of Methicillin-Resistant Staphylococcus aureus Biofilm Both In Vitro and In Vivo

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 828
Author(s):  
Li Guo ◽  
Lu Yang ◽  
Yu Qi ◽  
Gulimire Niyazi ◽  
Jianbao Zheng ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Low Temperature ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Healing Process ◽  
Combined Treatment ◽  
Infection Model ◽  
Wound Infections ◽  
Methicillin Resistant ◽  
Gas Plasma

Biofilm infections in wounds seriously delay the healing process, and methicillin-resistant Staphylococcus aureus is a major cause of wound infections. In addition to inactivating micro-organisms, low-temperature gas plasma can restore the sensitivity of pathogenic microbes to antibiotics. However, the combined treatment has not been applied to infectious diseases. In this study, low-temperature gas plasma treatment promoted the effects of different antibiotics on the reduction of S. aureus biofilms in vitro. Low-temperature gas plasma combined with rifampicin also effectively reduced the S. aureus cells in biofilms in the murine wound infection model. The blood and histochemical analysis demonstrated the biosafety of the combined treatment. Our findings demonstrated that low-temperature gas plasma combined with antibiotics is a promising therapeutic strategy for wound infections.

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