Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-Resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety.

Cefiderocol (Fetroja®) is a siderophore cephalosporin and has demonstrated potent activity against extended-spectrum beta-lactamases producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii, Burkholderia cepacia, and Klebsiella pneumoniae. However, cefiderocol has limited activity against Gram-positive bacteria and anaerobes like Bacterodies fragilis. In the APEKS-cUTI study, 183 (73%) of 252 patients in the cefiderocol group versus 65 (55%) of 119 patients in the imipenem-cilastatin group achieved the composite outcome of clinical and microbiological eradication of Gram-negative bacteria (treatment difference of 18.58%; 95% CI 8.23-28.92, p = 0.0004) in complicated urinary tract infections (cUTIs). Cefiderocol was non-inferior to imipenem-cilastatin in cUTIs caused by Gram-negative bacteria such as E. coli, K. pneumoniae, P. aeruginosa, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, and Citrobacter freundii. Cefiderocol required dose adjustment in patients with renal impairment and percentage of time that free drug concentrations above the minimum inhibitory concentration (%fT > MIC) best correlated with clinical outcomes. The most common adverse events with cefiderocol were gastrointestinal symptoms such as diarrhea, constipation, nausea, vomiting, or upper abdominal pain. Two phase III clinical trials, the CREDIBLE-CR study and the APEKS-NP study, investigated the efficacy and safety of cefiderocol for the treatment of pneumonia or cUTI, and both studies showed higher all-cause mortality associated with cefiderocol. Therefore, the use of cefiderocol should be limited only to the treatment of cUTIs from Gram-negative bacteria, especially in patients who have limited or no alternative treatment options.

Leave it to Lefamulin: A Pleuromutilin Treatment Option in Community-Acquired Bacterial Pneumonia.

Lefamulin (BC-3781) is the first systemic pleuromutilin antibiotic found to be safe and effective in the treatment of community-acquired bacterial pneumonia (CABP) in humans. This novel antibiotic was developed to combat the increasing incidence of bacterial resistance to current therapies. As the first semisynthetic pleuromutilin for systemic use in humans, lefamulin has demonstrated efficacy against the most common bacteria responsible for CABP, including strains exhibiting resistance to macrolides, fluoroquinolones, tetracyclines, vancomycin, and beta-lactams. In vitro studies have demonstrated efficacy against Staphylococcus aureus, beta-hemolytic and viridans group streptococci, coagulase-negative staphylococci, Enterococcus faecium, Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophilia, and Moraxella catarrhalis at MIC values lower than those of currently available therapies. Two phase III trials (LEAP-1 and LEAP-2) have demonstrated similar findings, meeting non-inferiority criteria for CABP with a minimal side-effect profile. Pharmacokinetic and pharmacodynamic evaluations have shown sufficient drug levels in plasma, subcutaneous adipose tissue, skeletal muscle, and epithelial lining fluid, warranting further investigation for other clinical uses. Lefamulin was approved by the United States Food and Drug Administration (FDA) on 19 August 2019 for the treatment of CABP.

Eravacycline, a newly approved fluorocycline.

Complicated intra-abdominal infections (cIAIs) are commonly associated with multimicroorganisms and treatment choices are becoming narrower due to developing resistance, especially in the gram-negative Enterobacteriaceae species. Eravacycline is a newly developed, fully synthetic tetracycline derivative that has shown potent broad-spectrum activity against a wide variety of microorganisms, including those such as extended spectrum ß-lactamase producing Enterobacteriaceae and Acinetobacter. Eravacycline has shown activity against many gram-positive organisms such as methicillin-resistant S. aureus and vancomycin resistant Enterococcus faecalis and Enterococcus faecium (VRE), gram-negative organisms such as Escherichia coli, and anaerobic species of microorganisms such as Bacteroides. This fluorocycline has been compared to ertapenem and meropenem for the treatment of complicated intra-abdominal infections and levofloxacin for the treatment of complicated urinary tract infections. Eravacycline was shown to be noninferior to ertapenem but did not meet noninferiority criteria in comparison to levofloxacin. Oral and IV formulations on eravacycline were tested in clinical trials, but at this time, only the IV formulation is FDA approved. Eravacycline has been noted to have a half-life of 20 h with protein binding around 80%; AUC over minimum inhibitory concentration (MIC) has also been shown to be eravacycline's best predictor of efficacy. Of note, eravacycline does not require any renal dose adjustments, as the majority of its clearance is by nonrenal pathways.

Oral administration of red ginseng powder fermented with probiotic alleviates the severity of dextran-sulfate sodium-induced colitis in a mouse model.

Red ginseng is a well-known alternative medicine with anti-inflammatory activity. It exerts pharmacological effects through the transformation of saponin into metabolites by intestinal microbiota. Given that intestinal microflora vary among individuals, the pharmacological effects of red ginseng likely vary among individuals. In order to produce homogeneously effective red ginseng, we prepared probiotic-fermented red ginseng and evaluated its activity using a dextran sulfate sodium (DSS)-induced colitis model in mice. Initial analysis of intestinal damage indicated that the administration of probiotic-fermented red ginseng significantly decreased the severity of colitis, compared with the control and the activity was higher than that induced by oral administration of ginseng powder or probiotics only. Subsequent analysis of the levels of serum IL-6 and TNF-α, inflammatory biomarkers that are increased at the initiation stage of colitis, were significantly decreased in probiotic-fermented red ginseng-treated groups in comparison to the control group. The levels of inflammatory cytokines and mRNAs for inflammatory factors in colorectal tissues were also significantly decreased in probiotic-fermented red ginseng-treated groups. Collectively, oral administration of probiotic-fermented red ginseng reduced the severity of colitis in a mouse model, suggesting that it can be used as a uniformly effective red ginseng product.

Red ginseng powder fermented with probiotics exerts antidiabetic effects in the streptozotocin-induced mouse diabetes model.

CONTEXT: Red ginseng (heat-processed Panax ginseng) is a well-known alternative medicine with pharmacological antidiabetic activity. It exerts pharmacological effects through the transformation of saponin into metabolites by the intestinal microbiota. Given that intestinal conditions and intestinal microflora vary among individuals, the pharmacological effects of orally administered red ginseng likely may vary among individuals. OBJECTIVE: To overcome this variation and produce homogeneously effective red ginseng, we evaluated the antidiabetic effects of probiotic-fermented red ginseng in a mouse model. MATERIALS AND METHODS: The antidiabetic efficacy of orally administered probiotic-fermented red ginseng was assessed in ICR mice after induction of diabetes using streptozotocin (170 mg/kg body weight). Samples were given orally for 8 weeks, and indicators involved in diabetic disorders such as body weight change, water intake, blood glucose, glucose tolerance and various biochemical parameters were determined. RESULTS: Oral administration of probiotic-fermented red ginseng significantly decreased the level of blood glucose of about 62.5% in the fasting state and induced a significant increase in glucose tolerance of about 10.2% compared to the control diabetic mice. Additionally, various indicators of diabetes and biochemical data (e.g., blood glycosylated haemoglobin level, serum concentrations of insulin, and α-amylase activity) showed a significant improvement in the diabetic conditions of the mice treated with probiotic-fermented red ginseng in comparison with those of control diabetic mice. DISCUSSION AND CONCLUSION: Our results demonstrate the antidiabetic effects of probiotic-fermented red ginseng in the streptozotocin-induced mouse diabetes model and suggest that probiotic-fermented red ginseng may be a uniformly effective red ginseng product.

In vivo evidence of the immunomodulatory activity of orally administered Aloe vera gel.

The gels of Aloe species contain immunomodulatory components such as aloctin A and acemannan. Most studies on these gels were performed in in vitro cell culture systems. Although several studies examined their immunomodulatory activity in vivo, the route of administration was intraperitoneal or intramuscular. Here, we evaluated the in vivo immunomodulatory activity of processed Aloe vera gel (PAG) in mice. Oral administration of PAG significantly reduced the growth of C. albicans in the spleen and kidney following intravenous injection of C. albicans in normal mice. PAG administration also reduced the growth of C. albicans in streptozotocin-induced diabetic mice. PAG administration did not increase ovalbumin (OVA)-specific cytotoxic T lymphocyte (CTL) generation in normal mice, but did increase it in high-fat-diet induced diabetic mice. These findings provide the first clear evidence for the immunomodulatory activity of orally administered Aloe vera gel.

Hypoglycemic and hypolipidemic effects of processed Aloe vera gel in a mouse model of non-insulin-dependent diabetes mellitus.

The effects of processed Aloe vera gel (PAG) on the course of established diet-induced non-insulin-dependent diabetes mellitus (NIDDM) were studied in C57BL/6J mice. NIDDM was induced in C57BL/6J mice by feeding them a high-fat diet. Mice exhibiting diet-induced obesity (DIO) with blood glucose levels above 180mg/dl were selected to examine the antidiabetic effects of PAG. Oral administration of PAG for 8 weeks reduced circulating blood glucose concentrations to a normal level in these DIO mice. In addition, the administration of PAG significantly decreased plasma insulin. The antidiabetic effects of PAG were also confirmed by intraperitoneal glucose tolerance testing. PAG appeared to lower blood glucose levels by decreasing insulin resistance. The administration of PAG also lowered triacylglyceride levels in liver and plasma. Histological examinations of periepididymal fat pad showed that PAG reduced the average size of adipocytes. These results demonstrate that the oral administration of PAG prevents the progression of NIDDM-related symptoms in high-fat diet-fed mice, and suggest that PAG could be useful for treating NIDDM.

Synergistic activation of monocytes by polysaccharides isolated from Salicornia herbacea and interferon-gamma.

The hot water extract of Salicornia herbacea, SHE, has recently been shown to have strong immunomodulatory activity. In the present study, we purified the polysaccharides, termed SHP, from SHE preparation and examined their immunomodulatory activity alone and in combination with interferon (IFN)-gamma. The combination of SHP and IFN-gamma synergistically inhibited the growth of the mouse monocytic cell line, RAW 264.7, inducing further differentiation to strongly adherent macrophages. The differentiation-inducing activity of SHP alone and in combination with IFN-gamma was confirmed by changes in the expression of differentiation antigens such as CD11b, CD18 and CD24. In addition, the combination of SHP and IFN-gamma synergistically activated RAW cells to produce cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta, and nitric oxide (NO). The synergistic activity of SHP was more prominent when SHP concentration was low. Increased production of TNF-alpha, IL-1 beta and NO was correlated with an increased level of their respective transcripts. These results confirm that Salicornia herbacea contains immunomodulatory polysaccharides that activate monocytes synergistically with small doses of IFN-gamma.