Low Selectivity Indices of Ivermectin and Macrocyclic Lactones on SARS-CoV-2 Replication In Vitro

Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant human pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin, like the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin, reduced SARS-CoV-2 replication in vitro (EC50 of 2–5 μM). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells, suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index of <10. Thus, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index.

In vitro activity of cefepime-taniborbactam against carbapenemase producing Enterobacterales and Pseudomonas aeruginosa isolates recovered in Spain

Novel β-lactam-β-lactamase inhibitor combinations currently approved for clinical use are poorly active against metallo-β-lactamase (MBL)-producing strains. We evaluated the in vitro activity of cefepime-taniborbactam (FTB, formerly cefepime/VNRX-5133) and comparator agents against carbapenemase-producing Enterobacterales (n=247) and carbapenem-resistant Pseudomonas spp. (n=170) clinical isolates prospectively collected from different clinical origin in patients admitted to 8 Spanish hospitals. FTB was the most active agent in both Enterobacterales (97.6% MIC FTB ≤8/4 mg/L) and Pseudomonas populations (67.1% MIC FTB ≤8/4 mg/L). MIC FTB was >8 mg/L in 6/247 (2.4%) Enterobacterales isolates (3 KPC- Klebsiella pneumoniae , 1 VIM- Enterobacter cloacae , 1 IMP- E. cloacae and 1 NDM- Escherichia coli ) and in 56/170 (32.9%) Pseudomonas spp., 19 of them carbapenemase producers (15 VIM, 2 GES, 1 GES+VIM, 1 GES+KPC). Against the Enterobacterales isolates with meropenem MIC>2 mg/L (138/247), FTB was the most active agent against both serine-β-lactamases (107/138) and MBL producers (31/138) (97.2% and 93.5% MIC FTB ≤8/4 mg/L, respectively) whereas the activity of comparators was reduced, particularly against the MBL producers (ceftazidime-avibactam, 94.4% and 12.9%; meropenem-vaborbactam, 85.0% and 64.5%; imipenem-relebactam, 76.6% and 9.7%; ceftolozane-tazobactam, 1.9% and 0%; piperacillin-tazobactam, 0% and 0%, respectively). Among the meropenem-resistant Pseudomonas spp. isolates (163/170, MIC>2 mg/L), activity of FTB against serine-β-lactamase (35/163) and MBL producers (43/163) was 88.6% and 65.1%, respectively, whereas the susceptibility of comparators was: ceftazidime-avibactam, 88.5% and 16.0%; meropenem-vaborbactam, 8.5% and 7.0%; imipenem-relebactam, 2.9% and 2.3%; ceftolozane-tazobactam, 0% and 2.3%; and piperacillin-tazobactam, 0% and 0%, respectively. Microbiological results suggest FTB as a potential therapeutic option in patients infected with carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas isolates, including MBL producers.

New Method for Obtaining a Bioactive Essence Extracted from Iberian Ham Fat Rich in MUFA and Antioxidants

Iberian ham is one of the most representative Spanish products and presents an excellent nutritional and sensory quality. Iberian ham trimming fat is considered a by-product and to give a new use to this remaining part could represent a healthy and innovative option for obtaining sustainable foods. The purpose of this work was to obtain a new bioactive ingredient from Iberian ham trimming fat with the highest amount of antioxidants and monounsaturated fatty acids (MUFA), using a new non-invasive solvent-free method. To obtain the essence, two different extraction procedures were carried out. After fatty acid characterization, degree of acidity, peroxide index and a basic sensory analysis were performed. Antioxidant in vitro activity and total phenolic compounds (TPC) were also determined. This new ingredient showed a better sensory profile than raw ham fat, a lower degree of acidity, a higher content of MUFAs, and also showed a higher antioxidant capacity and an increase in phenolic compounds compared to the raw material. This bioactive essence could be used as a food, a cosmetic or a nutraceutical ingredient to prevent certain diseases related to oxidative stress and could also contribute to the maintenance of the circular economy.

Tigecycline: Role in the Management of cIAI and cSSTI in the Indian Context

The current millennium has witnessed an increased antimicrobial resistance which poses a mammoth challenge for public health management. This has resulted in an increase in morbidity and mortality, resulting in an increase in financial burden to the patients. A recent analysis from 10 hospitals in India reported that mortality rate increases by 1.57 times in patients suffering from multidrug resistance (MDR) bacterial infections as compared to patients infected with similar but susceptible infections. Due to the emergence of MDR and extensively drug-resistant (XDR) bacteria, most of the broad-spectrum antibiotics have been rendered ineffective. The mortality rate with Gram-negative strains is higher than with Gram-positive strains. Tigecycline is the first in class glycylcycline antibiotic with an expanded broad-spectrum activity. Tigecycline enters bacterial cells through energy-dependent pathways or via passive diffusion, to reversibly bind to the 30S ribosomal subunit. It has potent in vitro activity against Gram-negative carbapenemase producers, except Pseudomonas aeruginosa and Proteus spp. It also has good in vitro activity against Carbapenem-resistant Klebsiella pneumoniae strains. Hence, it is considered as a therapeutic option in XDR isolates. Recent meta-analyses have shown tigecycline to be as effective as its comparators with reducing mortality rates. Due to increased resistance reported in carbapenem-resistant isolates in Indian health-care settings, a colistin/polymyxin B-based combination therapy as a treatment option is being sought. A lower mortality rate has been reported with colistin-based combination therapy in Carbapenem-resistant Enterobacteriaceae-associated infections. Combinations with tigecycline, Fosfomycin, and chloramphenicol have shown to improve treatment outcomes. Tigecycline can be a good alternative in MDR and XDR complicated intra-abdominal and complicated skin and soft tissue infections. Appropriately designed clinical trials in Indian health-care setups will reinforce clinician’s confidence in using tigecycline in complex clinical situations.

Anti-SARS-CoV-2 human antibodies retaining neutralizing activity against SARS-CoV-2 B.1.1.529 (omicron)

SARS-CoV-2 B.1.1.529, designated omicron, was recently identified as a new variant of concern by WHO and is rapidly replacing SARS-CoV-2 delta as the most dominant variant in many countries. Unfortunately, because of the high number of mutations present in the spike of SARS-CoV-2 omicron, most monoclonal antibodies (mAbs) currently approved for treatment of COVID-19 lose their in vitro neutralizing activity against this variant. We recently described a panel of human anti-SARS-CoV-2 mAbs that potently neutralize SARS-CoV-2 Wuhan, D614G and variants alpha, beta, gamma and delta. In this work, we evaluated our mAb panel for potential in vitro activity against SARS-CoV-2 delta and omicron. Three mAbs from our panel retain neutralizing activity against both delta and omicron, with mAb 3B8 still resulting in complete neutralization at a concentration as low as 0.02 ug/ml for both variants. Overall, our data indicate that mAb 3B8 may have the potential to become a game-changer in the fight against the continuously evolving SARS-CoV-2.

In Vitro Activity of Gepotidacin Against Gram-negative and Gram-positive Anaerobes

Gepotidacin (formerly GSK2140944) is a first in class triazaacenaphthylene antibacterial currently in Phase III clinical trials. When tested against Gram-negative ( n =333) and Gram-positive ( n =225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates (MIC 90 ) at concentrations of 4 and 2 μg/ml, respectively. Given gepotidacin’s in vitro activity against the anaerobic isolates tested, further study is warranted to better understand gepotidacin’s utility in the treatment of infections caused by clinically relevant anaerobic organisms.

In Vitro Synergism of Azithromycin Combination with Antibiotics against OXA-48-Producing Klebsiella pneumoniae Clinical Isolates

Carbapenem-resistant Klebsiella pneumoniae has globally emerged as an urgent threat leading to the limitation for treatment. K. pneumoniae carrying blaOXA-48, which plays a broad magnitude of carbapenem susceptibility, is widely concerned. This study aimed to characterize related carbapenem resistance mechanisms and forage for new antibiotic combinations to combat blaOXA-48-carrying K. pneumoniae. Among nine isolates, there were two major clones and a singleton identified by ERIC-PCR. Most isolates were resistant to ertapenem (MIC range: 2–>256 mg/L), but two isolates were susceptible to imipenem and meropenem (MIC range: 0.5–1 mg/L). All blaOXA-48-carrying plasmids conferred carbapenem resistance in Escherichia coli transformants. Two ertapenem-susceptible isolates carried both outer membrane proteins (OMPs), OmpK35 and OmpK36. Lack of at least an OMP was present in imipenem-resistant isolates. We evaluated the in vitro activity of an overlooked antibiotic, azithromycin, in combination with other antibiotics. Remarkably, azithromycin exhibited synergism with colistin and fosfomycin by 88.89% and 77.78%, respectively. Bacterial regrowth occurred after exposure to colistin or azithromycin alone. Interestingly, most isolates were killed, reaching synergism by this combination. In conclusion, the combination of azithromycin and colistin may be an alternative strategy in dealing with blaOXA-48-carrying K. pneumoniae infection during a recent shortage of newly effective antibiotic development.