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Although intra-articular vancomycin powder (VP) is sometimes applied before the closure of the incision to prevent periprosthetic joint infection (PJI) after joint replacement, the dosage, efficacy, and safety remain controversial. This study aimed to explore the dosage, efficacy, and safety of intra-articular VP in the prophylaxis of infection after total knee arthroplasty (TKA) in a rat model. Sixty male rats were randomly divided into five groups after receiving TKA control (no antibiotics); systemic vancomycin (SV) (intraperitoneal injection, 88 mg/kg of body weight, equal to 1 g in a patient weighing 70 kg); and VP0.5, VP1.0, and VP2.0 (44 mg/kg, 88 mg/kg and 176 mg/kg, respectively; intra-articular). All animals were inoculated in the knee with methicillin-resistant S. aureus (MRSA). General status, serum biomarkers, radiology, microbiological assay, and histopathological tests were assessed within 14 days postoperation. Compared with the control and SV groups, bacterial counts, knee width, tissue inflammation, and osteolysis were reduced in the VP0.5, VP1.0, and VP2.0 groups, without notable body weight loss and incision complications. Among all the VP groups, VP1.0 and VP2.0 groups presented superior outcomes with regard to knee width and tissue inflammation than the VP0.5 group. Microbial culture indicated that no MRSA survived in the knee of VP1.0 and VP2.0 groups, while bacteria growth was observed in the VP0.5 group. No obvious changes in the structure and functional biomarkers of liver and kidney were observed in either the SV or VP groups. Therefore, intra-articular vancomycin powder at a dosage from 88 mg/kg to 176 mg/kg may be effective and safe in preventing PJI induced by methicillin-resistant S. aureus in the rat TKA model.Oritavancin displayed potent and stable activity (MIC90 range of 0.06 to 0.5 mg/L) over a 10-year period (2010 to 2019) against Gram-positive pathogens that cause bloodstream infections (BSI), including methicillin-resistant Staphylococcus aureus (MRSA) and resistant subsets of Enterococcus spp. Daptomycin and linezolid were also active against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus (VRE). Only oritavancin and linezolid remained active against Enterococcus faecium isolates displaying an elevated daptomycin MIC (i.e., 2 to 4 mg/L). Proportions of methicillin-resistant S. aureus and vancomycin-resistant Enterococcus within the respective S. aureus and enterococcal populations decreased over this period.In this first-in-human study, PLG0206, a novel engineered cationic antimicrobial peptide, was evaluated for safety, tolerability, and pharmacokinetics (PK) when intravenously (i.v.) administered as a single dose to healthy subjects. Six cohorts of 8 subjects each received escalating single i.v. infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1 to 4 h. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 h postinfusion. Safety and tolerability were assessed throughout the study. The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment-emergent adverse events (TEAE) related to PLG0206 was low, and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion-related reactions, which were mitigated with increasing infusion time and volume. There were no severe adverse events (SAEs), life-threatening events, or deaths throughout the study. i.v. PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t1/2) ranged from 7.37 to 19.97 h. Following a single i.v. infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of i.v. PLG0206 as an antimicrobial agent.Multidrug-resistant (MDR) Pseudomonas aeruginosa presents a serious threat to public health due to its widespread resistance to numerous antibiotics. P. aeruginosa commonly causes nosocomial infections including urinary tract infections (UTI) which have become increasingly difficult to treat. The lack of effective therapeutic agents has renewed interest in fosfomycin, an old drug discovered in the 1960s and approved prior to the rigorous standards now required for drug approval. Fosfomycin has a unique structure and mechanism of action, making it a favorable therapeutic alternative for MDR pathogens that are resistant to other classes of antibiotics. The absence of susceptibility breakpoints for fosfomycin against P. aeruginosa limits its clinical use and interpretation due to extrapolation of breakpoints established for Escherichia coli or Enterobacterales without supporting evidence. Furthermore, fosfomycin use and efficacy for treatment of P. aeruginosa are also limited by both inherent and acquired resistance mechanisms. This narrative review provides an update on currently identified mechanisms of resistance to fosfomycin, with a focus on those mediated by P. aeruginosa such as peptidoglycan recycling enzymes, chromosomal Fos enzymes, and transporter mutation. Additional fosfomycin resistance mechanisms exhibited by Enterobacterales, including mutations in transporters and associated regulators, plasmid-mediated Fos enzymes, kinases, and murA modification, are also summarized and contrasted. These data highlight that different fosfomycin resistance mechanisms may be associated with elevated MIC values in P. aeruginosa compared to Enterobacterales, emphasizing that extrapolation of E. coli breakpoints to P. aeruginosa should be avoided.Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). see more Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.We report in vitro susceptibility data from five consecutive annual SIDERO-WT surveillance studies (2014 to 2019) for cefiderocol and comparators tested against Gram-negative clinical isolates from North America and Europe. CLSI broth microdilution was used to determine MICs for Enterobacterales (n = 31,896), Pseudomonas aeruginosa (n = 7,700), Acinetobacter baumannii complex (n = 5,225), Stenotrophomonas maltophilia (n = 2,030), and Burkholderia cepacia complex (n = 425). MICs were interpreted by CLSI-approved clinical breakpoints (February 2021). Cefiderocol inhibited 99.8, 96.7, 91.6, and 97.7% of all Enterobacterales, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 μg/mL (susceptible breakpoint). Cefiderocol inhibited 99.9, 99.8, 100, and 99.8% of all P. aeruginosa, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 μg/mL (susceptible terobacterales (99.8% susceptible), P. aeruginosa (99.9%), A. baumannii (96.0%), and S. maltophilia (98.6%) collected in North America and Europe from 2014 to 2019 were highly susceptible to cefiderocol.The failure of antibiotic therapy in respiratory tract infections in cystic fibrosis is partly due to the high tolerance observed in Pseudomonas aeruginosa biofilms. This tolerance is mediated by changes in bacterial metabolism linked to growth in biofilms, opening up potential avenues for novel treatment approaches based on modulating metabolism. The goal of the present study was to identify carbon sources that increase the inhibiting and/or eradicating activity of tobramycin, ciprofloxacin, and ceftazidime against P. aeruginosa PAO1 biofilms grown in a synthetic cystic fibrosis sputum medium (SCFM2) and to elucidate their mode of action. After screening 69 carbon sources, several combinations of antibiotics + carbon sources that showed markedly higher anti-biofilm activity than antibiotics alone were identified. d,l-malic acid and sodium acetate could potentiate both biofilm inhibiting and eradicating activity of ciprofloxacin and ceftazidime, respectively, while citric acid could only potentiate biofilm inhibitory activity of tobramycin. The mechanisms underlying the increased biofilm eradicating activity of combinations ciprofloxacin/d,l-malic acid and ceftazidime/sodium acetate are similar but not identical. Potentiation of ceftazidime activity by sodium acetate was linked to increased metabolic activity, a functional TCA cycle, increased ROS production, and high intracellular pH, whereas the latter was not required for d,l-malic acid potentiation of ciprofloxacin. Finally, our results indicate that the potentiation of antibiotic activity by carbon sources is strain dependent.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the need for broad-spectrum antivirals against coronaviruses (CoVs). Here, pheophorbide a (Pba) was identified as a highly active antiviral molecule against human CoV-229E after bioguided fractionation of plant extracts. The antiviral activity of Pba was subsequently shown for SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV), and its mechanism of action was further assessed, showing that Pba is an inhibitor of coronavirus entry by directly targeting the viral particle. Interestingly, the antiviral activity of Pba depends on light exposure, and Pba was shown to inhibit virus-cell fusion by stiffening the viral membrane, as demonstrated by cryoelectron microscopy. Moreover, Pba was shown to be broadly active against several other enveloped viruses and reduced SARS-CoV-2 and MERS-CoV replication in primary human bronchial epithelial cells. Pba is the first described natural antiviral against SARS-CoV-2 with direct photosensitive virucidal activity that holds potential for COVID-19 therapy or disinfection of SARS-CoV-2-contaminated surfaces.