Evaluation of the post-antibiotic effect in vivo for the combination of a β-lactam antibiotic and a β-lactamase inhibitor: ceftazidime-avibactam in neutropenic mouse thigh and lung infections

2021 ◽  
pp. 1-9
Author(s):  
Johanna Berkhout ◽  
Maria J. Melchers ◽  
Anita C. van Mil ◽  
Claudia M. Lagarde ◽  
Wright W. Nichols ◽  
...  
Keyword(s):  
Antibiotic Effect ◽  
Lactam Antibiotic ◽  
Lung Infections ◽  
Post Antibiotic Effect ◽  
Lactamase Inhibitor

scholarly journals Bioprospecting the antimicrobial, antibiofilm and antiproliferative activity of Symplocos racemosa Roxb. Bark phytoconstituents along with their biosafety evaluation and detection of antimicrobial components by GC-MS

2020 ◽  
Author(s):  
Henna Sood ◽  
Yashwant Kumar ◽  
Vipan Kumar Gupta ◽  
Daljit Singh Arora
Keyword(s):  
Mtt Assay ◽  
Inhibitory Concentration ◽  
Drug Resistant ◽  
Acute Oral Toxicity ◽  
Oral Toxicity ◽  
Swiss Albino Mice ◽  
Antibiotic Effect ◽  
Post Antibiotic Effect ◽  
Symplocos Racemosa

Abstract Background: The increased occurrence of the antibiotic resistance has added up to the misery of mankind. There is an immediate need to search alternatives and Symplocos racemosa is one such potent medicinal plant . The aim of the study was to explore various activities of its phytoconstituents, confirm their biosafety and identify the active components.Methods: The ethylacetate extract and the major group of phytoconstituents were tested for minimal inhibitory concentration, viable cell count studies, Post antibiotic effect, activity against 34 multi-drug resistant microorganisms, anti-biofilm and anti proliferative potential. The biosafety was evaluated by Ames and MTT assay. In vivo safety of flavonoids was determined by acute oral toxicity test using Swiss albino mice. The antimicrobial components in flavonoids were also identified by using TLC and GC-MS analysis.Results: Ethyl acetate was the best organic extractant. The phytochemical analyses revealed the presence of flavonoids, cardiac glycosides, saponins, tannins, triterpenes and Phytosterols. Flavonoids exhibited the highest antimicrobial potential whereas tannins, triterpenes and phytosterols were completely inactive. Their Minimum Inhibitory Concentration ranged from 0.5-10 mg/ml; exhibited a bactericidal mode of action and a prolonged post antibiotic effect. The phytoconstituents displayed a significant antibiofilm potential by inhibiting the initial cell attachment, disrupting the pre-formed biofilms and reducing the metabolic activity of biofilms. The phytoconstituents were significantly active against the drug-resistant strains of E.coli , MRSA and Salmonella spp. Flavonoids showed significant cytotoxic effect against the RD, L20B and Hep2 cell lines (IC 50 361-494 µg/ml). All the test extracts were biosafe as depicted by the Ames test, MTT assay. Also, flavonoids did not induce any abnormality in biochemical parameters and Organs’ histopathology of the Swiss albino mice during the in vivo acute oral toxicity studies. The flavonoids were resolve into 4 bands (S1-S4) using TLC, where S3 was the most active and its GC-MS analysis revealed the presence of Bicyclo [2.2.1]heptan-2-one,1,7,7-trimethyl-, (1S)- at an RT of 11.14 as the major compound.Conclusions: These findings suggest that Symplocos racemosa bark could be a potential source of antimicrobial metabolites, which could substantially contribute to the arsenal of existing natural drugs for combating the antimicrobial resistance.

Model-Based Dose-Exposure-Response Assessment for Lead and Backup Spectinamide in a Mouse Model of Tuberculosis

2020 ◽  
Author(s):  
◽  
Santosh Wagh ◽  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Exposure Response ◽  
Antibiotic Effect ◽  
Post Antibiotic Effect

Despite decades of research, tuberculosis remains the oldest pathogen-based disease that is the leading cause of death from a single infectious agent. Among many anti-tubercular therapies under investigation, the semisynthetic compounds spectinamides are a promising novel class of anti-tuberculosis agents. One such lead candidate, spectinamide 1810, and backup spectinamide 1599 have demonstrated excellent efficacy, safety, and drug-like properties in various in vitro and in vivo assessments. The dose-ranging and dose fractionation studies were designed to characterize the dose-exposure-response relationship for lead and backup spectinamide in a mouse model of Mycobacterium tuberculosis infection. In this current study, we used 26 and 23 combinations of dose level and dosing frequency for the lead and backup spectinamide, respectively. The dedicated pharmacokinetic studies with a collection of series of blood samples were conducted in healthy animals. Population pharmacokinetic analysis was performed using non-linear mixed effect modeling to estimate pharmacokinetic parameters in healthy animals. The Bayesian principles were applied for reliable pharmacokinetic estimation in infected animals by using informed priors obtained from healthy animals. The individual pharmacokinetic parameters were obtained for infected animals through post-hoc estimation and subsequently used for pharmacokinetic/-pharmacodynamic (PK/PD) indices and mechanism-based PK/PD modeling. The obtained data on spectinamides’ plasma concentrations and counts of colony-forming units were analyzed using a PK/PD approach as well as classical anti-infective PK/PD indices. The population pharmacokinetic analysis results suggest that there is no difference in the pharmacokinetic parameters of lead and backup spectinamide in infected animals as compared to healthy animals. The PK/PD index analysis showed that the efficacy of spectinamide 1810 is largely driven by concentration (Cmax/MIC) and exposure (AUC/MIC) rather than a threshold minimum inhibitory level (T>MIC). Although similar results were obtained for spectinamide 1599 in previously performed in vitro experiments, in the present in vivo studies, spectinamide 1599 did not demonstrate the expected correlation between efficacy and PK/PD indices. Therefore, we could not identify major drivers for the efficacy of this compound. Additionally, a novel mechanism-based PK/PD model with consideration to post-antibiotic effect could adequately describe the exposure-response relationship for lead and backup spectinamide. This supports the idea that the in vitro observed post-antibiotic effect of these spectinamides can translate to the in vivo situation, as well. Altogether we suggest, the obtained results and pharmacometric model for the exposure-response relationship of lead and backup spectinamides provide a rational basis for dose selection for future efficacy studies of these compounds against Mycobacterium tuberculosis in mice and other animal species.

scholarly journals Marine Peptide-N6NH2 and Its Derivative-GUON6NH2 Have Potent Antimicrobial Activity Against Intracellular Edwardsiella tarda in vitro and in vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Huihui Han ◽  
Da Teng ◽  
Ruoyu Mao ◽  
Ya Hao ◽  
Na Yang ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Edwardsiella Tarda ◽  
Microtubule Polymerization ◽  
Antibiotic Effect ◽  
Intracellular Activities ◽  
Marine Peptide ◽  
Derivatives Of ◽  
Post Antibiotic Effect

Edwardsiella tarda is a facultative intracellular pathogen in humans and animals. There is no effective way except vaccine candidates to eradicate intracellular E. tarda. In this study, four derivatives of marine peptide-N6NH2 were designed by an introduction of unnatural residues or substitution of natural ones, and their intracellular activities against E. tarda were evaluated in macrophages and in mice, respectively. The minimum inhibitory concentration (MIC) value of N6NH2 and GUON6NH2 against E. tarda was 8 μg/mL. GUON6NH2 showed higher stability to trypsin, lower toxicity (<1%) and longer post-antibiotic effect (PAE) than N6NH2 and other derivatives. Antibacterial mechanism results showed that GUON6NH2 could bind to LPS and destroyed outer/inner cell membranes of E. tarda, superior to N6NH2 and norfloxacin. Both N6NH2 and GUON6NH2 were internalized into macrophages mainly via lipid rafts, micropinocytosis, and microtubule polymerization, respectively, and distributed in the cytoplasm. The intracellular inhibition rate of GUON6NH2 against E. tarda was 97.05–100%, higher than that in case of N6NH2 (96.82–100%). In the E. tarda-induced peritonitis mouse model, after treatment with of 1 μmol/kg N6NH2 and GUON6NH2, intracellular bacterial numbers were reduced by 1.54- and 1.97-Log10 CFU, respectively, higher than norfloxacin (0.35-Log10 CFU). These results suggest that GUON6NH2 may be an excellent candidate for novel antimicrobial agents to treat infectious diseases caused by intracellular E. tarda.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

scholarly journals Aerosol-based antimicrobial photoinactivation in the lungs: an action spectrum study

2021 ◽  
Author(s):  
Chiara Treghini ◽  
Alfonso Dell’Accio ◽  
Franco Fusi ◽  
Giovanni Romano
Keyword(s):  
Light Source ◽  
A Priori ◽  
Action Spectrum ◽  
Multidrug Resistant ◽  
Theoretical Modelling ◽  
Resistant Bacteria ◽  
Lung Infections ◽  
Killing Action ◽  
Definition Of

AbstractChronic lung infections are among the most diffused human infections, being often associated with multidrug-resistant bacteria. In this framework, the European project “Light4Lungs” aims at synthesizing and testing an inhalable light source to control lung infections by antimicrobial photoinactivation (aPDI), addressing endogenous photosensitizers only (porphyrins) in the representative case of S. aureus and P. aeruginosa. In the search for the best emission characteristics for the aerosolized light source, this work defines and calculates the photo-killing action spectrum for lung aPDI in the exemplary case of cystic fibrosis. This was obtained by applying a semi-theoretical modelling with Monte Carlo simulations, according to previously published methodology related to stomach infections and applied to the infected trachea, bronchi, bronchioles and alveoli. In each of these regions, the two low and high oxygen concentration cases were considered to account for the variability of in vivo conditions, together with the presence of endogenous porphyrins and other relevant absorbers/diffusers inside the illuminated biofilm/mucous layer. Furthermore, an a priori method to obtain the “best illumination wavelengths” was defined, starting from maximizing porphyrin and light absorption at any depth. The obtained action spectrum is peaked at 394 nm and mostly follows porphyrin extinction coefficient behavior. This is confirmed by the results from the best illumination wavelengths, which reinforces the robustness of our approach. These results can offer important indications for the synthesis of the aerosolized light source and definition of its most effective emission spectrum, suggesting a flexible platform to be considered in further applications.

scholarly journals South Africa’s Best BARK Medicines Prescribed at the Johannesburg Muthi Markets for Skin, Gut, and Lung Infections: MIC’s and Brine Shrimp Lethality

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 681
Author(s):  
Gugulethu P. Khumalo ◽  
Nicholas J. Sadgrove ◽  
Sandy F. Van Vuuren ◽  
Ben-Erik Van Wyk
Keyword(s):  
South Africa ◽  
Brine Shrimp ◽  
Bark Extract ◽  
Respiratory Pathogens ◽  
Medicinal Uses ◽  
Brine Shrimp Lethality ◽  
Sclerocarya Birrea ◽  
Lung Infections ◽  
Tract Infections

Indigenous trade of medicinal plants in South Africa is a multi-million-rand industry and is still highly relevant in terms of primary health care. The purpose of this study was to identify today’s most traded medicinal barks, traditionally and contemporaneously used for dermatological, gastrointestinal, and respiratory tract infections; then, to investigate the antimicrobial activity and toxicity of the respective extracts and interpret outcomes in light of pharmacokinetics. Thirty-one popularly traded medicinal barks were purchased from the Faraday and Kwa Mai-Mai markets in Johannesburg, South Africa. Information on the medicinal uses of bark-based medicines in modern commerce was recorded from randomly selected traders. The minimum inhibitory concentration (MIC) method was used for antimicrobial screening, and brine shrimp lethality was used to determine toxicity. New medicinal uses were recorded for 14 bark species. Plants demonstrating some broad-spectrum activities against tested bacteria include Elaeodendron transvaalense, Erythrina lysistemon, Garcinia livingstonei, Pterocelastrus rostratus, Rapanea melanophloeos, Schotia brachypetala, Sclerocarya birrea, and Ziziphus mucronata. The lowest MIC value of 0.004 mg/mL was observed against Staphylococcus epidermidis for a dichloromethane bark extract of E. lysistemon. The tested medicinal barks were shown to be non-toxic against the Artemia nauplii (brine shrimp) bioassay, except for a methanol extract from Trichilia emetica (69.52% mortality). Bacterial inhibition of bark extracts with minimal associated toxicity is consistent with the safety and valuable use of medicinal barks for local muthi market customers. Antimicrobial outcomes against skin and gastrointestinal pathogens are feasible because mere contact-inhibition is required in vivo; however, MIC values against respiratory pathogens require further explaining from a pharmacokinetics or pharmacodynamics perspective, particularly for ingested rather than smoked therapies.

scholarly journals Characterization of Host Responses duringPseudomonas aeruginosaAcute Infection in the Lungs and Blood and after Treatment with the Synthetic Immunomodulatory Peptide IDR-1002

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Kelli Wuerth ◽  
Amy H. Y. Lee ◽  
Reza Falsafi ◽  
Erin E. Gill ◽  
Robert E. W. Hancock
Keyword(s):  
Gene Expression ◽  
Bacterial Resistance ◽  
Lymphocyte Activation ◽  
Lavage Fluid ◽  
Innate Immune ◽  
Microbial Infection ◽  
Content Type ◽  
Innate Defense ◽  
Lung Infections

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis.P. aeruginosalung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multidrug resistance are becoming more prevalent. Here, we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acuteP. aeruginosalung infectionin vivo. IDR-1002 significantly reduced the bacterial burden in bronchoalveolar lavage fluid (BALF), as well as MCP-1 in BALF and serum, KC in serum, and interleukin 6 (IL-6) in BALF. Transcriptome sequencing (RNA-Seq) was conducted on lungs and whole blood, and the effects ofP. aeruginosa, IDR-1002, and the combination ofP. aeruginosaand IDR-1002 were evaluated. Differential gene expression analysis showed thatP. aeruginosaincreased multiple inflammatory and innate immune pathways, as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results showed that IDR-1002 was effective in treatingP. aeruginosaacute lung infections and associated inflammation.

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