Tetracycline Derivatives Research Articles

The impact of minocycline in inhibiting glial scar formation in rats with traumatic brain injury: A mini scoping review

Minocycline, a second-generation tetracycline derivative, is proven to inhibit glial scar formation in several neurological diseases. However, studies associating micocycline in traumatic brain injury (TBI) is very limited. This review aims to determine the role of minocycline in inhibiting glial scar or astrogliosis formation in TBI animal models. This scoping review includes original studies in PubMed, Science Direct, and Google Scholar databases published between 1 January 2012 to 31 December 2022, in full text, involving rodent research, and written in English. Two authors who followed the Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, conducted the assessment independently. Of 2687 studies, 13 studies are reviewed. Two studies describe the benefits of minocycline in inhibiting glial scar formation in TBI, while 11 studies show that minocycline inhibits glial scar formation in diseases other than TBI. An explanation of the signaling pathways and cells involved in the mechanism of glial scar inhibition by minocycline can be found in ten articles, of which four observe the role of microglial cells, four observe the role of astrocyte cells, and two do not explain the mechanism. Research on the impact of minocycline in inhibiting glial scar formation in rats with TBI is limited. The results of this review support early research on the role of minocycline in inhibiting glial scar or astrogliosis in TBI, and similar studies in several other CNS diseases support this. However, the mechanism of minocycline's inhibitory pathway to glial scarring remains unclear.

JAAD Game Changers: Two decades of using the combination of tetracycline derivatives and niacinamide as steroid-sparing agents in the management of pemphigus: Defining a niche for these low toxicity agents

JAAD Game Changers: Two decades of using the combination of tetracycline derivatives and niacinamide as steroid-sparing agents in the management of pemphigus: Defining a niche for these low toxicity agents

Antimicrobial activity of eravacycline and other comparative agents on aerobic and anaerobic bacterial pathogens in Taiwan: A clinical microbiological study

ObjectivesEravacycline, a new tetracycline derivative, exhibits broad-spectrum antimicrobial susceptibility. This study aimed to comprehensively investigate in vitro activities of eravacycline, tigecycline, and ertapenem against various Gram-positive, Gram-negative, and anaerobic bacteria. MethodsMinimum inhibitory concentrations (MICs) were determined using the broth microdilution method. The following bacterial species were collected: vancomycin-sensitive (VS) Enterococci species, vancomycin-resistant Enterococci species (VRE), Staphylococcus aureus, Streptococcus anginosus, Bacteroides species, Clostridioides difficile, Clostridium innocuum, Clostridium perfringens, Parabacteroides distasonis, and Stenotrophomonas maltophilia. ResultsWe found that eravacycline exhibited superior in vitro activity compared to tigecycline and ertapenem. Notably, it exhibited the lowest MIC90 for several bacterial species, including VS E. faecalis (0.12 µg/mL), VS E. faecium (0.12 µg/mL), and others. Besides, VRE was susceptible to eravacycline (MIC90:0.12 µg/mL) and tigecycline (MIC90:0.12 µg/mL), but was all resistant to ertapenem (MIC90 > 64 µg/mL). S. aureus was also susceptible to eravacycline (MIC90:0.5 µg/mL) as well as tigecycline (MIC90:1.0 µg/mL). Furthermore, S. anginosus showed higher susceptibility to eravacycline (MIC90:2.0 µg/mL) and tigecycline (MIC90:4.0 µg/mL), but lower to ertapenem (MIC90:32.0 µg/mL). Eravacycline and tigecycline also demonstrated good susceptibility to anaerobes, including Bacteroides species (susceptibility rate: 100%), P. distasonis (100%), C. difficile (94.1‒100%), C. innocuum (94.1‒96.1%), and C. perfringens (88.9‒96.3%). For S. maltophilia, both tigecycline and eravacycline showed an MIC90 of 2 µg/mL. A moderate-to-strong correlation (rho = 0.608–0.804, P < 0.001) was noted between the MIC values of eravacycline and tigecycline against various bacterial species. ConclusionsOur study highlights the potential of eravacycline as an effective treatment option for multidrug-resistant bacterial infections.

Abstract 5745: Electrosprayed minocycline and temozolomide-loaded PLGA microparticles for the treatment of glioblastoma

Abstract Glioblastoma multiforme (GBM), the most common and aggressive form of malignant brain tumor, leads to poor prognoses with high rates of reoccurrence and low survival rates, therefore, it is vital to explore alternative treatments for GBM. Minocycline, a commonly used antibiotic and tetracycline derivative, has proven anti-angiogenic effects and the ability to inhibit tumor growth, making it an effective GBM treatment. Temozolomide is an alkylating antineoplastic agent and the current first-choice chemotherapy agent for GBM. Poly(lactic-co-glycolic acid) (PLGA) is widely used as a biomaterial for drug delivery due to its inert properties, great biocompatibility and versatility and has been approved by the FDA. Therefore, the objective of this project is to fabricate electrosprayed minocycline- and temozolomide-loaded PLGA microparticles with optimal morphology, drug loading, loading efficiency, and drug release kinetics for the treatment of GBM. The microparticles were fabricated by electrospraying vertically with a 2ml/hr flow rate, 14kV voltage, 20 cm distance for minocycline and a 10ml/hr flow rate, 10kV voltage, 10 cm distance for temozolomide with both collected on a copper/glass plate. The parameters that were investigated were the chamber humidity, duration of spraying, and the addition of polyethylene glycol (PEG), a hydrophilic polymer. To determine the microparticles’ morphology, bright-field microscopy and scanning electron microscopy (SEM) were used. The absorbance measurements at 350 and 327 nm were used to determine drug loading, loading efficiency, and release kinetics for minocycline and temozolomide, respectively. Microparticles with low chamber humidity and duration of spraying were more spherical, less aggregated and easier to collect for both drugs. The addition of PEG to minocycline-loaded microparticles led to higher drug loading and loading efficiency (4.02% ± 0.34, 64.30% ± 5.47 vs. 3.23% ± 0.29, 49.40% ± 4.49) as the PEG helps the solubilization of minocycline. Using acetonitrile instead of dichloromethane as the solvent, increased drug loading and loading efficiency (4.72% ± 0.76, 70.77 ± 11.43 vs. 2.37% ± 0.27, 35.62% ± 4.09) for temozolomide-loaded microparticles as more temozolomide can be solubilized in acetonitrile. Drug release kinetics demonstrated a burst release of minocycline in the first hour (65.46%). To decrease the burst release, the microparticles can be incorporated into a scaffold or depot. Overall, electrospraying is a promising method to fabricate drug loaded PLGA microparticles with high drug loading, loading efficiency, and right morphology and we determined optimal parameters to successfully fabricate electrosprayed drug loaded PLGA microparticles in the micron size range with high drug loading and loading efficiency compared to the often-used emulsion solvent extraction/evaporation for microparticle fabrication. Citation Format: Alma Rodriguez, Jaqueline Quintanilla, Juan Amieva, Marco A. Arriaga, Sean Nievera, Ivan Davila, Karen S. Martirosyan, Sue Anne Chew. Electrosprayed minocycline and temozolomide-loaded PLGA microparticles for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5745.

Antimicrobial resistance landscape in a metropolitan city context using open drain wastewater-based metagenomic analysis

One Health concept recognizes the inextricable interactions of diverse ecosystems and their subsequent effect on human, animal and plant health. Antimicrobial resistance (AMR) is a major One Health concern and is predicted to cause catastrophes if appropriate measures are not implemented. To understand the AMR landscape in a south Indian metropolitan city, metagenomic analysis of open drains was performed. The data suggests that in January 2022, macrolide class of antibiotics contributed the highest resistance of 40.1% in the city, followed by aminoglycoside- 24.4%, tetracycline- 11.3% and lincosamide- 6.7%. The ‘mutations in the 23S rRNA gene conferring resistance to macrolide antibiotics’ were the major contributor of resistance with a prevalence of 39.7%, followed by ‘16s rRNA with mutation conferring resistance to aminoglycoside antibiotics’- 22.2%, ‘16S rRNA with mutation conferring resistance to tetracycline derivatives’- 9.2%, and ‘23S rRNA with mutation conferring resistance to lincosamide antibiotics’- 6.7%. The most prevalent antimicrobial resistance gene (ARG) ‘mutations in the 23S rRNA gene conferring resistance to macrolide antibiotics’ was present in multiple pathogens including Escherichia coli, Campylobacter jejuni, Acinetobacter baumannii, Streptococcus pneumoniae, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Klebsiella pneumoniae and Helicobacter pylori. Most of the geographical locations in the city showed a similar landscape for AMR. Considering human mobility and anthropogenic activities, such an AMR landscape could be common across other regions too. The data indicates that pathogens are evolving and acquiring antibiotic resistance genes to evade antibiotics of multiple major drug classes in diverse hosts. The outcomes of the study are relevant not only in understanding the resistance landscape at a broader level but are also important for identifying the resistant drug classes, the mechanisms of gaining resistance and for developing new drugs that target specific pathways. This kind of surveillance protocol can be extended to regions in other developing countries to assess and combat the problem of antimicrobial resistance.

Minocycline and Diacetyl Minocycline Eye Drops Reduce Ocular Neovascularization in Mice.

To evaluate the efficacy of minocycline and a novel, modified minocycline analogue that lacks antimicrobial action, diacetyl minocycline (DAM), on choroidal neovascularization (CNV) in mice of both sexes. CNV was induced via laser injury in female and male C57BL/6J mice. Minocycline, DAM, or saline was administered via topical eye drops twice a day for 2 weeks starting the day after laser injury. CNV volume was measured using immunohistochemistry labeling and confocal microscopy. Minocycline reduced lesion volume by 79% (P ≤ 0.0004) in female and male mice. DAM reduced lesion volume by 73% (P ≤ 0.001) in female and male mice. There was no significant difference in lesion volume between minocycline and DAM treatment groups or between female and male mice. Both minocycline and DAM eye drops significantly reduced laser-induced CNV lesion volume in female and male mice. While oral tetracyclines have been shown to mitigate pathologic neovascularization in both preclinical studies and clinical trials, the present data are the first to suggest that tetracycline derivatives may be effective to reduce pathologic CNV when administered via topical eye drops. However, the action is unrelated to antimicrobial action. Targeted delivery of these medications via eye drops may reduce the potential for systemic side effects. Topical administration of minocycline and/or DAM via eye drops may represent a novel therapeutic strategy for disorders involving pathologic CNV.

In vitro Antimicrobial Activity and Dose Optimization of Eravacycline and Other Tetracycline Derivatives Against Levofloxacin-Non-Susceptible and/or Trimethoprim-Sulfamethoxazole-Resistant Stenotrophomonas maltophilia.

To better guide clinical use, we determined the in vitro antimicrobial activity of the new drug eravacycline and other tetracycline derivatives against levofloxacin (LVFX)-non-susceptible and/or trimethoprim-sulfamethoxazole (TMP-SMZ)-resistant Stenotrophomonas maltophilia and evaluated their dosing regimens. Seventy-seven unique strains of S. maltophilia were isolated from sputa samples and airway aspirate samples that were either LVFX-non-susceptible and/or TMP-SMZ-resistant. Monte Carlo simulations were performed for different dosing regimens according to the population pharmacokinetic parameters of antibiotics in patients with respiratory tract infections at the minimum inhibitory concentration (MIC). Eravacycline had excellent in vitro antibacterial activity against LVFX-non-susceptible and/or TMP-SMZ-resistant S. maltophilia. Monte Carlo simulations showed that for LVFX-non-susceptible strains, the cumulative fraction of response (CFR) of minocycline at the conventional recommended dose of 100 mg q12 h was 90.90%; for TMP-SMZ-resistant strains, the CFR of minocycline at a high dose of 200 mg q12 h was only 91.64%. For strains resistant to both LVFX and TMP-SMZ, the CFR of minocycline at a high dose of 200 mg q12 h was 89.81%. In contrast, the CFR of tigecycline was less than 40%, even at a dose of 100 mg q12 h. For pneumonia, minocycline is better for S. maltophilia that is non-susceptible to LVFX; for TMP-SMZ-resistant strains and strains that are not susceptible to either LVFX or TMP-SMZ, the efficiency of eravacycline requires further evaluation. Eravacycline may be a better choice for extremely resistant S. maltophilia strains that are non-susceptible to LVFX, TMP-SMZ, and minocycline.

Minocycline improves autism-related behaviors by modulating microglia polarization in a mouse model of autism.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with few pharmacological treatments. Minocycline, a tetracycline derivative that inhibits microglial activation, has been well-identified with anti-inflammatory properties and neuroprotective effects. A growing body of research suggests that ASD is associated with neuroinflammation, abnormal neurotransmitter levels, and neurogenesis. Thus, we hypothesized that minocycline could improve autism-related behaviors by inhibiting microglia activation and altering neuroinflammation. To verify our hypothesis, we used a mouse model of autism, BTBR T+Itpr3tf/J (BTBR). As expected, minocycline administration rescued the sociability and repetitive, stereotyped behaviors of BTBR mice while having no effect in C57BL/6J mice. We also found that minocycline improved neurogenesis and inhibited microglia activation in the hippocampus of BTBR mice. In addition, minocycline treatment inhibited Erk1/2 phosphorylation in the hippocampus of BTBR mice. Our findings show that minocycline administration alleviates ASD-like behaviors in BTBR mice and improves neurogenesis, suggesting that minocycline supplementation might be a potential strategy for improving ASD symptoms.

The application of electrosprayed minocycline-loaded PLGA microparticles for the treatment of glioblastoma.

The survival of patients with glioblastoma multiforme (GBM), the most common and invasive form of malignant brain tumors, remains poor despite advances in current treatment methods including surgery, radiotherapy, and chemotherapy. Minocycline is a semi-synthetic tetracycline derivative that has been widely used as an antibiotic and more recently, it has been utilized as an antiangiogenic factor to inhibit tumorigenesis. The objective of this study was to investigate the utilization of electrospraying process to fabricate minocycline-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with high drug loading and loading efficiency and to evaluate their ability to induce cell toxicity in human glioblastoma (i.e., U87-MG) cells. The results from this study demonstrated that solvent mixture of dicholoromethane (DCM) and methanol is the optimal solvent combination for minocycline and larger amount of methanol (i.e., 70:30) resulted in a higher drug loading. All three solvent ratios of DCM:methanol tested produced microparticles that were both spherical and smooth, all in the micron size range. The electrosprayed microparticles were able to elicit a cytotoxic response in U87-MG glioblastoma cells at a lower concentration of drug compared to the free drug. This work provides proof of concept to the hypothesis that electrosprayed minocycline-loaded PLGA microparticles can be a promising agent for the treatment of GBM and could have potential application for cancer therapies.

Whole Genome Sequencing of an Extensively Drug-Resistant Raoultella planticola Isolate Containing blaKPC-2, blaNDM-1, and blaCTX-M-15.

Raoultella planticola harboring genes that confer resistance to antimicrobials, such as carbapenems, have been associated with severe infections in immunocompromised patients. In this study, we reported the first whole genome sequence of a Brazilian isolate of R. planticola and the genomic context of antibiotic resistance markers. By whole-genome sequencing (WGS) of a carbapenem-resistant R. planticola isolate, RpHUM1, we found 23 resistance-encoding genes belonging to 9 classes of antibiotics (aminoglycosides, β-lactams, fluoroquinolones, fosfomycin, macrolides, phenicols, sulfonamides, tetracycline, and diaminopyrimidine derivatives) and 3 plasmids (RpHUM1pEaer-4382s, RpHUM1_pFDAARGOS_440, and RpHUM1pRSF1010). This isolate coharbored the genes blaKPC-2, which is carried by the plasmid RpHUM1pEaer-4382s, and blaNDM-1 and blaCTX-M-15 all located in the accessory genome. In addition, these genes were associated with, at least, one mobile genetic element. This comprehensive knowledge is of great importance for implementation of control measures to prevent the rapid dissemination of this neglected microorganism and their genetic resistance background.

Nano therapy Spotlight: Arestin™ Minocycline Microspheres

Within the last ten years, recent advancements in nanotechnology and repurposed pharmaceutical development has led several successful therapeutics through clinical trials and subsequently onto the market. On the nanotechnology side, size, shape, charge, and formulation are all considered in improving the overall efficacy or delivery of the therapeutic. Nanoparticle therapies hit the market in the late 90’s when the FDA approved CosmoFer®, an iron sugar colloid that also saw use in the European market. While these early nano pharmaceuticals were primitive compared to today’s standards, these medications proved that a nanoparticulate therapeutic can and would be accepted by the FDA, albeit under much scrutiny. On the pharmaceutical side, older legend drugs that have been proved efficacious for many years are beginning to be repurposed for other uses. For example, Pfizer’s 2015 approval of Rapamune® (Rapamycin) is indicated for the treatment of Lymphangioleiomyomatosis (LAM) a rare lung disease infecting mostly women in early adulthood. The drug, however, was first approved in 1999 and was used in the prophylaxis of organ rejection as an immunosuppressant. Another indication for Rapamycin is in age related diseases; a 2006 paper published by Dr. Blagosklonny at the Roswell Park Comprehensive Cancer center showed that Rapamycin could inhibit certain pathways that are related to aging. Many other medications on the market such as monoclonal antibody therapies have also seen a rise in new implication discovery and there is much evidence to suggest other drugs will be researched in the future for other alternative treatments. Because of such developments, pharmaceutical companies have tapped into the nanoparticle development world to find novel therapies for diseases we once thought were unavoidable. This is shown by the sheer expected market growth of about two billion dollars from 2021-2026, and the fifteen different nanoparticle-based therapeutics that have already been FDA approved since in just the last three years. Although the nanoparticle technology scope may seem to hover over novel cancer therapies, autoimmune disorders, blood borne diseases and neurological disorders, many therapies have come about in some interesting fields of study. One such therapeutic is called Arestin®, a new dentistry medication for the treatment of severe periodontitis, better known as gum disease. Gum disease is caused by poor oral hygiene and is attributed to various bacterial infections within the gum-line and if left untreated it can cause soft tissue damage or jawbone degradation. Typically, an antibiotic mouthwash or ultrasonic dental cleaner can be used to treat minor periodontitis but, in severe cases where there is significant gum-line recession, a more direct therapeutic is needed to treat the infection directly at the source. Arestin® is a nanoparticle formulation containing minocycline HCl impregnated within a bio-reabsorable polymer that is delivered directly into the gum-line via a blunt tip syringe. Minocycline is a tried-and-true antibiotic with a rich history of over thirty years on the market as a second-generation tetracycline derivative. It is both a gram positive and gram negative [broad spectrum] antibiotic and is very well tolerated in patients making it an excellent candidate in late-stage gum disease intervention. Here, this review, discuss Arestin® and subsequently Minocycline Hydrochloride’s: history, mechanism of action, formulation/production, side effects and the future of reformulated nano pharmaceuticals that are continuing to move the market share up.

Influences of Jujube Witches' Broom (JWB) Phytoplasma Infection and Oxytetracycline Hydrochloride Treatment on the Gene Expression Profiling in Jujube.

Jujube witches' broom disease (JWB), caused by Candidatus Phytoplasma ziziphi, is the most destructive phytoplasma disease threatening the jujube industry. Tetracycline derivatives treatments have been validated to be capable of recovering jujube trees from phytoplasma infection. In this study, we reported that oxytetracycline hydrochloride (OTC-HCl) trunk injection treatment could recover more than 86% of mild JWB-diseased trees. In order to explore the underlying molecular mechanism, comparative transcriptomic analysis of healthy control (C group), JWB-diseased (D group) and OTC-HCl treated JWB-diseased (T group) jujube leaves was performed. In total, 755 differentially expressed genes (DEGs), including 488 in 'C vs. D', 345 in 'D vs. T' and 94 in 'C vs. T', were identified. Gene enrichment analysis revealed that these DEGs were mainly involved in DNA and RNA metabolisms, signaling, photosynthesis, plant hormone metabolism and transduction, primary and secondary metabolisms, their transportations, etc. Notably, most of the DEGs identified in 'C vs. D' displayed adverse change patterns in 'D vs. T', suggesting that the expression of these genes was restored after OTC-HCl treatment. Our study revealed the influences of JWB phytoplasma infection and OTC-HCl treatment on gene expression profiling in jujube and would be helpful for understanding the chemotherapy effects of OTC-HCl on JWB-diseased jujube.

Scope and Limitations of Exploiting the Ability of the Chemosensitizer NV716 to Enhance the Activity of Tetracycline Derivatives against Pseudomonas aeruginosa.

The spread of antibiotic resistance is an urgent threat to global health that requires new therapeutic approaches. Treatments for pathogenic Gram-negative bacteria are particularly challenging to identify due to the robust OM permeability barrier in these organisms. One strategy is to use antibiotic adjuvants, a class of drugs that have no significant antibacterial activity on their own but can act synergistically with certain antibiotics. Previous studies described the discovery and development of polyaminoisoprenyl molecules as antibiotic adjuvants with an OM effect. In particular, the compound NV716 has been shown to sensitize Pseudomonas aeruginosa to tetracycline antibiotics such as doxycycline. Here, we sought to explore the disruption of OM to sensitize P. aeruginosa to otherwise inactive antimicrobials using a series of tetracycline derivatives in the presence of NV716. We found that OM disruption expands the hydrophobicity threshold consistent with antibacterial activity to include hydrophobic molecules, thereby altering permeation rules in Gram-negative bacteria.

Stenotrophomonas maltophilia Infections: A Systematic Review and Meta-Analysis of Comparative Efficacy of Available Treatments, with Critical Assessment of Novel Therapeutic Options.

PubMed/MEDLINE and Embase were searched from inception to 30 November 2022. The primary outcome was all-cause mortality. Secondary outcomes included clinical failure, adverse events, and length of stay. A random effects meta-analysis was performed. This study was registered with PROSPERO (CRD42022321893). Twenty-four studies, all retrospective, were included. A significant difference in terms of overall mortality was observed when comparing as a monotherapy TMP/SMX versus FQs (odds ratio (OR) 1.46, 95% confidence interval (CI) 1.15-1.86, I2 = 33%; 11 studies, 2407 patients). The prediction interval (PI) did not touch the no effect line (1.06-1.93), but the results were not robust for the unmeasured confounding (E-value for point estimate of 1.71). When comparing TMP/SMX with TDs, the former showed an association with higher mortality but not significant and with a wide PI (OR 1.95, 95% CI 0.79-4.82, PI 0.01-685.99, I2 = 0%; 3 studies, 346 patients). Monotherapies in general exerted a protective effect against death opposed to the combination regimens but were not significant (OR 0.71, 95% CI 0.41-1.22, PI 0.16-3.08, I2 = 0%; 4 studies, 438 patients). Against SM infections, FQs and, possibly, TDs seem to be reasonable alternative choices to TMP/SMX. Data from clinical trials are urgently needed to better inform therapeutic choices in this setting by also taking into account newer agents.

Comparing novel antibiotics and carbapenems for complicated intra-abdominal infections: a systematic review and meta-analysis of randomized controlled trials

Carbapenem-sparing antibiotic is urgently needed for patients with complicated intra-abdominal infections (cIAIs). Even though several novel antibiotics - novel β-lactam-β-lactamase inhibitor combinations - ceftolozane-tazobactam and ceftazidime-avibactam, and novel tetracycline derivative - eravacycline have been developed for cIAIs, whether these antibiotics are comparable to carbapenem for cIAIs remain unclear. A comprehensive search was conducted on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov until October 1, 2022. Only RCTs that compared the clinical efficacy and safety of novel antibiotic against carbapenem for patients with cIAIs were included. Among 11 selected RCTs, no significant differences were observed in terms of clinical cure rate at test of cure between the study and the control group in the analysis of clinical evaluable population (93.6% vs 93.7%, risk ratio [RR], 1.00; 95% CI, 0.98-1.01; p = 0.84), microbiologically evaluable population (93.0% vs 94.5%; RR, 0.98; 95% CI, 0.96-1.00; p = 0.10), and modified intention-to-treat population (85.9% vs 87.7%; RR, 0.98; 95% CI, 0.95-1.01; p = 0.13). All these findings remain consistent across the subgroup analyses and sensitivity tests. Similarly, there were no significant differences in terms of microbiological eradication between the study and the control group (87.8% vs 89.7%; RR, 0.98; 95% CI, 0.96-1.01; p = 0.18). The risks of adverse events were similar between groups. The clinical efficacy, microbiological response, and safety of the novel antibiotics, including ceftazidime-avibactam, ceftolozane-tazobactam, and eravacycline are comparable to carbapenem in the treatment of patients with cIAI. These agents can be potential therapeutic options as carbapenem-sparing antibiotic for cIAIs.

Investigation of the Efficacy of Cinnamaldehyde, Cannabidiol and Eravacycline in a Malaria Model

In this study, it was aimed to investigate the antimalarial activity of cinnamaldehyde (CIN) and cannabidiol (CBD) which have shown various biological activities such as potent antimicrobial activity and eravacycline (ERA), a new generation tetracycline derivative, in an in vivo malaria model. The cytotoxic activities of the active substances were determined by the MTT method against L929 mouse fibroblasts and their antimalarial activity were determined by the four-day test in an in vivo mouse model. In this study, five groups were formed: the CIN group, the CBD group, the ERA group, the chloroquine group (CQ) and the untreated group (TAG). 2.5 x 107 parasites/mL of P.berghei-infected erythrocyte suspension was administered IP to all mice. The determined doses of active substances were given to the mice by oral gavage in accordance with the four-day test and the parasitemia status in the mice was controlled for 21 days with smear preparations made from the blood taken from the tail end of the mice. The IC50 values, which express the cytotoxic activity values of the active substances were determined as 27.55 μg/mL, 16.40 μM and 48.82 μg/mL for CIN, CBD and ERA, respectively. The mean parasitemia rate in untreated mice was 33% on day nine and all mice died on day 11. On the ninth day, when compared with the TAG group, no parasites were observed in the CIN group, while the average parasitemia was 0.08% in the CBD group and 17.8% in the ERA group. Compared to the mice in the TAG group, the life expectancy of the other groups was prolonged by eight days in the CIN group, 12 days in the CBD group and eight days in the ERA group. It has been determined that all three active subtances tested in this study suppressed the development of Plasmodium parasites in an in vivo mouse model and prolonged the life span of the mice. It is thought that the strong antimalarial activity of CIN and CBD shown in the study and the possible positive effect of ERA on the clinical course can be improved by combining them with the existing and potential antimalarial molecules.

Invitro susceptibility of common Enterobacterales to eravacycline in Taiwan.

New tetracycline derivatives exhibit broad-spectrum antimicrobial activities. This study aimed to assess the invitro activity of eravacycline against common Enterobacterales. Clinical Enterobacterales isolates were collected between 2017 and 2021. The minimum inhibitory concentration (MIC) was determined using a broth microdilution test. We identified Klebsiella pneumoniae (n=300), Escherichia coli (n=300), Klebsiella oxytoca (n=100), Enterobacter cloacae complex (n=100), Citrobacter freundii (n=100), and Proteus mirabilis (n=100). All P. mirabilis strains were resistant to eravacycline. Excluding P. mirabilis, the susceptibility rates to eravacycline, omadacycline, and tigecycline were 75.2%, 66.9%, and 73%, respectively. The MIC50 and MIC90 (mg/L) of eravacycline were 0.5 and 4 for K. pneumoniae, 0.5 and 1 for E. coli, 0.5 and 1 for K. oxytoca, 0.5 and 2 for E. cloacae complex, and 0.25 and 1 for C. freundii. In cefotaxime non-susceptible and meropenem susceptible Enterobacterales, excluding P. mirabilis, the susceptibility rates of eravacycline, omadacycline, and tigecycline were 69.7%, 57.1%, and 66.2%. We found decreased susceptibility rates of three new tetracycline derivatives against meropenem non-susceptible Enterobacterales (eravacycline: 47.1%, omadacycline: 39.4%, and tigecycline: 39.4%). Eravacycline showed a high susceptibility rate against cefotaxime non-susceptible and meropenem susceptible K. oxytoca (100%), C. freundii (93.2%), E. coli (85.9%), and meropenem non-susceptible E. coli (100%). This study provides the MIC and susceptibility rate of eravacycline for common Enterobacterales. Eravacycline could be a therapeutic choice for cefotaxime non-susceptible or meropenem non-susceptible Enterobacterales, especially K. oxytoca, C. freundii, and E. coli.

Design and screening of tetracycline antibiotics: an in-silico approach

A prominent class of broad-spectrum antibiotics known as tetracycline works by inhibiting the synthesis of proteins, which prevents the development of bacteria. Tetracycline resistance is typically attributed to one or more of the following causes: ribosomal binding site mutations, acquisition of mobile genetic elements carrying tetracycline-specific resistance genes, and/or chromosomal mutations that increase the expression of intrinsic resistance mechanisms. In this research, our objective is to virtually plan and conduct in-silico experiments to find tetracycline derivatives with inhibitory capability against tetracycline resistance protein. The tetracycline derivatives were screened using the Data Warrior, Discovery Studio, PyRx, and Swiss ADME web tools. Initially, 19 tetracycline derivatives were primarily screened for ADME and toxicity study followed by docking study. Among the tetracycline derivatives, C1, C11, C12, C14, C16, and C17 were found to be the potential drug-like molecules with binding energies of -8.9 kcal/mol, -8.4 kcal/mol, -8.5 kcal/mol, -7.7 kcal/mol, -7.7 kcal/mol, -8.6 kcal/mol respectively. In particular, C1 was predicted to have a better binding affinity towards the target protein than the others.

Minocycline alleviated scopolamine-induced amnesia by regulating antioxidant and cholinergic function

Background and aimMinocycline, a tetracycline derivative, has been found to exert neuroprotective properties. The current project aimed to assess the antioxidant status and cholinergic function in the amnesia induced by scopolamine. MethodsWe evaluated the passive avoidance performance, acetylcholine esterase (AChE) enzyme activity, and the oxidative stress indicators in the following groups: Normal control, scopolamine, and the treatment groups (the animals were given minocycline (10–30 mg/kg)). ResultsScopolamine (intraperitoneal) injection was associated with impairment of passive avoidance performance and neurotoxicity. Minocycline pronouncedly ameliorated scopolamine injury as presented by the increased latency time to darkness and stay time in lightness along with the decreased darkness entry. Moreover, minocycline decreased lipid peroxidation, while it elevated the levels of superoxide dismutase, AChE enzymes, and thiol groups in both the cortex and hippocampus. ConclusionOur data suggested that minocycline modulated the antioxidant status and AChE in the brains, which may contribute to its protective effects against scopolamine-induced amnesia.

655. Combination Eravacycline Therapy for Carbapenem-Resistant Acinetobacter baumannii Pneumonia

Abstract Background Acinetobacter baumannii typically causes infections in debilitated, hospitalized patients and is difficult to treat due to multiple virulence factors and the presence of intrinsic and acquired antibiotic resistance mechanisms leading to frequent isolation of multi-drug resistant (MDR) phenotypes. Due to problematic pharmacokinetics and/or dose-limiting toxicities of salvage agents, combination therapy with aminoglycosides, ampicillin/sulbactam, polymyxins, minocycline, or tigecycline, is often used. Eravacycline has demonstrated greater in-vitro potency against A. baumannii compared to other tetracycline derivatives making it potentially the more appealing option. However, its utility is hindered by a lack of data supporting pharmacodynamic targets and adequate dosing strategies for CRAB. The goal of this case series was to describe our experience with the use of combination eravacycline therapy for the treatment of CRAB pneumonia. Methods This case series included all patients ≥ 18 years of age, diagnosed with SARS-CoV-2, ≥ 1 sputum culture positive for CRAB and a clinical diagnosis of new bacterial pneumonia, who received at least one dose of eravacycline between April 1st and October 1st, 2020. The primary outcome was clinical resolution of CRAB pneumonia. Secondary outcomes evaluated microbiological resolution, need for extended durations of therapy, and frequency of re-starting CRAB therapy within 48 hours of completion. Results In total, 25 patients were included in this case series. The median duration of combination therapy was 10 days. Most patients (96%) received eravacycline + ampicillin/sulbactam, with 7 of those patients also receiving inhaled colistin (Table 2). In total, 17 (68%) patients achieved clinical resolution of CRAB pneumonia. Post-treatment sputum cultures were collected in 18 patients, of which 13 (72%) achieved microbiological resolution. One patient received &amp;gt; 14 days of therapy and no patients re-initiated therapy within 48 hours of eravacycline completion. Table 1:Baseline CharacteristicsTable 2:Study Outcomes Conclusion In this small case series, eravacycline showed favorable clinical outcomes in patients with CRAB pneumonia. In light of limited treatment options, this agent can be considered for CRAB pneumonia salvage therapy. Disclosures All Authors: No reported disclosures.