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The global crisis of antimicrobial resistance (AMR) necessitates the development of broad-spectrum antibacterial drugs effective against multi-drug resistant (MDR) pathogens. BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI) selectively inhibits bacterial DNA replication via inhibition of DNA gyrase and topoisomerase IV. BWC0977 exhibited a minimum inhibitory concentration (MIC 90 ) of 0.03–2 µg/mL against a global panel of MDR Gram-negative bacteria including Enterobacterales and non-fermenters, Gram-positive bacteria, anaerobes and biothreat pathogens. BWC0977 retains activity against isolates resistant to fluoroquinolones (FQs), carbapenems and colistin and demonstrates efficacy against multiple pathogens in two rodent species with significantly higher drug levels in the epithelial lining fluid of infected lungs. In healthy volunteers, single-ascending doses of BWC0977 administered intravenously ( https://clinicaltrials.gov/study/NCT05088421 ) was found to be safe, well tolerated (primary endpoint) and achieved dose-proportional exposures (secondary endpoint) consistent with modelled data from preclinical studies. Here, we show that BWC0977 has the potential to treat a range of critical-care infections including MDR bacterial pneumonias. In this work, the authors probe the efficacy of BWC0977, a bacterial topoisomerase inhibitor, in pre-clinical animal models, also demonstrating that BWC0977 is safe and well tolerated in healthy human volunteers, in a phase 1 trial.

The risk of bacteremia is considered low in children with acute bronchiolitis. However the rate of occult bacteremia in infants with RSV infection is not well established. The aim was to determine the actual rate and predictive factors of bacteremia in children admitted to hospital due to confirmed RSV acute respiratory illness (ARI), using both conventional culture and molecular techniques. A prospective multicenter study (GENDRES-network) was conducted between 2011-2013 in children under the age of two admitted to hospital because of an ARI. Among those RSV-positive, bacterial presence in blood was assessed using PCR for Meningococcus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, in addition to conventional cultures. 66 children with positive RSV respiratory illness were included. In 10.6% patients, bacterial presence was detected: H. influenzae (n = 4) and S. pneumoniae (n = 2). In those patients with bacteremia, there was a previous suspicion of bacterial superinfection and had received empirical antibiotic treatment 6 out of 7 (85.7%) patients. There were significant differences in terms of severity between children with positive bacterial PCR and those with negative results: PICU admission (100% vs. 50%, P-value = 0.015); respiratory support necessity (100% vs. 18.6%, P-value < 0.001); Wood-Downes score (mean = 8.7 vs. 4.8 points, P-value < 0.001); GENVIP scale (mean = 17 vs. 10.1, P-value < 0.001); and length of hospitalization (mean = 12.1 vs. 7.5 days, P-value = 0.007). Bacteremia is not frequent in infants hospitalized with RSV respiratory infection, however, it should be considered in the most severe cases.

Background. Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. Methods. We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged ⩾18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). Results. A total of 1867 patients were randomized and received ⩾1 dose of study medication. In the clinically evaluable population, at 7–14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, −2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, −1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, −0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. Conclusions. Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.

Summary Levofloxacin (Levaquin®) is a fluoroquinolone antibacterial that is the L-isomer of ofloxacin. A high-dose (750 mg) short-course (5 days) of once-daily levofloxacin is approved for use in the US in the treatment of community-acquired pneumonia (CAP), acute bacterial sinusitis (ABS), complicated urinary tract infections (UTI) and acute pyelonephritis (AP). The broad spectrum antibacterial profile of levofloxacin means that monotherapy is often a possibility in patients with CAP at times when other agents may require combination therapy, although levofloxacin can be used in combination therapy when necessary. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent bactericidal activity and may reduce the potential for resistance to emerge. In addition, this regimen lends itself to better compliance because of the shorter duration of treatment and the convenient once-daily administration schedule. Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation; importantly, patients can transition between the formulations, which results in more options in regards to the treatment regimen and the potential for patients with varying degrees of illness to be treated. Levofloxacin has good tissue penetration and an adequate concentration can be maintained in the urinary tract to treat uropathogens. Levofloxacin is generally well tolerated and has good efficacy in the treatment of patients with CAP, ABS, complicated UTI and AP. The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP, ABS and UTIs is well established, and the high-dose, short-course levofloxacin regimen has been shown to be noninferior to the 10-day regimen in CAP and ABS, and to have a similar tolerability profile. Similarly, the high-dose, short-course levofloxacin regimen is noninferior to ciprofloxacin in patients with complicated UTI or AP. Thus, levofloxacin is a valuable antimicrobial agent that has activity against a wide range of bacterial pathogens; however, its use should be considered carefully so that the potential for resistance selection can be minimized and its usefulness in severe infections and against a range of penicillin- and macrolide-resistant pathogens can be maintained. Pharmacodynamic Properties Levofloxacin is the synthetic L -isomer of the racemic quinolone ofloxacin. It interferes with critical processes in the bacterial cell, such as DNA replication, transcription, repair and recombination, by inhibiting type II topoisomerases. Levofloxacin is active against a broad range of Gram-positive, Gram-negative and atypical bacteria that may be causative pathogens in community-acquired and nosocomial infections. In general, levofloxacin shows good in vitro activity against clinically-relevant Gram-positive, -negative and atypical organisms. Levofloxacin is active against the Gram-positive penicillin-susceptible and -resistant strains of Streptococcus pneumoniae , the Gram-negative species Enterobacter cloacae and Proteus mirabilis , and the atypical organisms Chlamydophila pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae , with minimum concentrations required to inhibit the growth of 90% of strains (MIC90) of ≤2 mg/L. Levofloxacin is highly active against the Gram-negative species Haemophilus influenzae , H. parainfluenzae and Moraxella catarrhalis (MIC90 of ≤0.06 mg/L), including β-lactamase positive strains of H. influenzae and M. catarrhalis. The activity of levofloxacin against Gram-positive meticillin/oxacillin-susceptible Staphylococcus aureus is slightly reduced, with the MIC90 (≤4 mg/L) in the susceptible to intermediate range, and the activity of levofloxacin against the Gram-negative Escherichia coli (MIC90 ≤0.06 to >8 mg/L) and Pseudomonas aeruginosa (MIC90 0.5–64 mg/L) is variable. Rates of S. pneumoniae resistance to levofloxacin have remained ≤1% in surveillance programmes undertaken in the US, Canada and worldwide; in penicillin-resistant isolates of S. pneumoniae , the rate of resistance to levofloxacin was ≤2.7%. Recent data suggest that the rate of levofloxacin resistance in S. pneumoniae in the US has decreased between 2004 and 2006. Levofloxacin resistance has not been identified in H. influenzae or M. catarrhalis in surveillance studies conducted up to 2005, but it has been identified in E. coli, P. aeruginosa and S. aureus. As the activity of levofloxacin is concentration dependent, the most common predictor of microbiological and clinical efficacy is the area under the plasma concentration-time curve (AUC): MIC ratio. A ratio of >30 was used in some studies to predict in vivo activity, particularly against S. pneumoniae , but a higher ratio (>100) is suggested as being predictive of a bactericidal effect and thus reducing the potential of first-step mutations occurring. In simulated pharmacodynamic analyses of levofloxacin 750 mg, the probability of an AUC: MIC target of ≥30 being attained in the plasma was ≥97%. Pharmacokinetic Properties Following oral administration, levofloxacin is rapidly absorbed and maximum plasma concentrations are attained in 1–2 hours. The absolute bioavailability of levofloxacin is ≈99% and the oral solution or tablet formulations and intravenous formulation are bioequivalent. Plasma protein binding is low (≤38%). Levofloxacin is distributed throughout the body and the concentration in other tissues (e.g. epithelial lining fluid, alveolar cells or macrophages, paranasal sinuses mucosa and urine) can exceed that in the plasma 2–4 hours after administration. The pharmacokinetics of levofloxacin are not affected by age, gender, race, HIV status or the presence of a serious community-acquired bacterial infection. However, gastrointestinal absorption of the drug can be reduced by magnesium- or aluminium-containing antacids, metal cations, such as iron and vitamin preparations with zinc, as well as sucralfate. The concomitant use of levofloxacin with a range of other drugs has not resulted in any clinically significant effects in a small number of formal drug interaction studies. Clinically significant effects, such as symptomatic hyperglycaemia and hypoglycaemia, have been reported with levofloxacin, usually in patients with diabetes mellitus receiving concomitant hypoglycaemic agents/insulin. Postmarketing experience includes reports that levofloxacin enhances the effects of warfarin. Therapeutic Efficacy The efficacy of oral and/or intravenous levofloxacin 750 mg once daily for 5 days has been established in randomized, well designed trials in adults with CAP, ABS, complicated UTI or AP. Levofloxacin 750 mg once daily for 5 days was noninferior to levofloxacin 500 mg once daily for 10 days in the treatment of adults with CAP and ABS infections according to the primary endpoint of clinical response rate 7–14 days after the end of treatment. Clinical and microbiological response rates in the clinically evaluable population of patients with CAP were 92.4% versus 91.1% and 93.2% versus 92.4% in those receiving the 750 mg dosage regimen versus the 500 mg dosage regimen. In patients with ABS, the corresponding response rates were 91.4% versus 88.6% and 91.5% versus 89.4%, respectively. Levofloxacin 750 mg once daily for 5 days was noninferior to ciprofloxacin 400 mg or 500 mg twice daily for 10 days in the treatment of adults with complicated UTI or AP infections according to the primary endpoint of microbiological response (eradication) rate on day 15–22 of the study. The microbiological response rate in levofloxacin or ciprofloxacin recipients (all patients with complicated UTI or AP) in the co-primary endpoint populations was 79.8% versus 79.8% (modified intent-to-treat population) and 86% versus 89.2% (microbiologically evaluable population). Clinical response rates in the corresponding groups were 81.1% versus 80.1% and 86.4% versus 88.4%, respectively. Tolerability Levofloxacin is generally well tolerated in patients with respiratory or UTIs. In a pooled analysis of patients with respiratory infections, the most commonly reported treatment-emergent adverse events included nausea, headache, diarrhoea, insomnia, constipation, abdominal pain, dizziness, dyspepsia and vomiting; the incidence of drug-related adverse events was not significantly different between those receiving the levofloxacin 750 mg or 500 mg regimen. No clinically important adverse events that occurred were deemed to be drug related. Discontinuation of therapy because of drug-related adverse events occurred in <2% of patients with respiratory infections. The most common treatment-emergent adverse events in patients with complicated UTI or AP were similar to those observed in patients with respiratory infections.

Silver is considered as antibacterial agent with well-known mode of action and bacterial resistance against it is well described. The development of nanotechnology provided different methods for the modification of the chemical and physical structure of silver, which may increase its antibacterial potential. The physico-chemical properties of silver nanoparticles and their interaction with living cells differs substantially from those of silver ions. Moreover, the variety of the forms and characteristics of various silver nanoparticles are also responsible for differences in their antibacterial mode of action and probably bacterial mechanism of resistance. The paper discusses in details the aforementioned aspects of silver activity.

Antimicrobial resistance is a serious threat to global public health, but little is known about the effects of microbial control on the microbiota and its associated resistome. Here we compare the microbiota present on surfaces of clinical settings with other built environments. Using state-of-the-art metagenomics approaches and genome and plasmid reconstruction, we show that increased confinement and cleaning is associated with a loss of microbial diversity and a shift from Gram-positive bacteria, such as Actinobacteria and Firmicutes , to Gram-negative such as Proteobacteria . Moreover, the microbiome of highly maintained built environments has a different resistome when compared to other built environments, as well as a higher diversity in resistance genes. Our results highlight that the loss of microbial diversity correlates with an increase in resistance, and the need for implementing strategies to restore bacterial diversity in certain built environments. The environmental microbiota can have important implications for our well-being. Here, the authors describe the composition of microbiomes from diverse buildings, including samples from clinical environments, and show that cleaner environments are associated with a loss of microbial diversity and an increase in genes associated with antibiotic resistance.

Broad antibacterial spectrum, high oral bioavailability and excellent tissue penetration combined with safety and few, yet rare, unwanted effects, have made the quinolones class of antimicrobials one of the most used in inpatients and outpatients. Initially discovered during the search for improved chloroquine-derivative molecules with increased anti-malarial activity, today the quinolones, intended as antimicrobials, comprehend four generations that progressively have been extending antimicrobial spectrum and clinical use. The quinolone class of antimicrobials exerts its antimicrobial actions through inhibiting DNA gyrase and Topoisomerase IV that in turn inhibits synthesis of DNA and RNA. Good distribution through different tissues and organs to treat Gram-positive and Gram-negative bacteria have made quinolones a good choice to treat disease in both humans and animals. The extensive use of quinolones, in both human health and in the veterinary field, has induced a rise of resistance and menace with leaving the quinolones family ineffective to treat infections. This review revises the evolution of quinolones structures, biological activity, and the clinical importance of this evolving family. Next, updated information regarding the mechanism of antimicrobial activity is revised. The veterinary use of quinolones in animal productions is also considered for its environmental role in spreading resistance. Finally, considerations for the use of quinolones in human and veterinary medicine are discussed.

Peptidoglycan and almost all surface glycopolymers in bacteria are built in the cytoplasm on the lipid carrier undecaprenyl phosphate (UndP) 1 – 4 . These UndP-linked precursors are transported across the membrane and polymerized or directly transferred to surface polymers, lipids or proteins. UndP is then flipped to regenerate the pool of cytoplasmic-facing UndP. The identity of the flippase that catalyses transport has remained unknown. Here, using the antibiotic amphomycin that targets UndP 5 – 7 , we identified two broadly conserved protein families that affect UndP recycling. One (UptA) is a member of the DedA superfamily 8 ; the other (PopT) contains the domain DUF368. Genetic, cytological and syntenic analyses indicate that these proteins are UndP transporters. Notably, homologues from Gram-positive and Gram-negative bacteria promote UndP transport in Bacillus subtilis , indicating that recycling activity is broadly conserved among family members. Inhibitors of these flippases could potentiate the activity of antibiotics targeting the cell envelope. A study identifies two broadly conserved families of flippases that catalyse the transport of undecaprenyl phosphate in bacteria and could function to recycle dolichol phosphate in eukaryotes and archaea.

To optimize linezolid treatment regimens for Gram-positive bacterial infections based on pharmacokinetic/pharmacodynamic analysis. The minimum inhibitory concentration (MIC) distribution of 572 Gram-positive strains from patients with clinically confirmed infections was analyzed. Using the Monte Carlo simulation method, the cumulative fraction of response and probability of target attainment were determined for linezolid regimens of 600 mg q.12h and q.8h Linezolid dosage of 600 mg q.12h yielded >90% cumulative fraction of response and probability of target attainment for staphylococcal infections with an MIC of ≤1 mg/l, enterococcal infections with higher MIC values required 600 mg q.8h. Linezolid 600 mg q.12h is still the clinically recommended empirical dosage for Gram-positive bacterial infections. However, as bacterial MICs increase, 600 mg q.8h may be required to achieve better efficacy.

Noble metal-based nanomaterials have shown promise as potential enzyme mimetics, but the facet effect and underlying molecular mechanisms are largely unknown. Herein, with a combined experimental and theoretical approach, we unveil that palladium (Pd) nanocrystals exhibit facet-dependent oxidase and peroxidase-like activities that endow them with excellent antibacterial properties via generation of reactive oxygen species. The antibacterial efficiency of Pd nanocrystals against Gram-positive bacteria is consistent with the extent of their enzyme-like activity, that is {100}-faceted Pd cubes with higher activities kill bacteria more effectively than {111}-faceted Pd octahedrons. Surprisingly, a reverse trend of antibacterial activity is observed against Gram-negative bacteria, with Pd octahedrons displaying stronger penetration into bacterial membranes than Pd nanocubes, thereby exerting higher antibacterial activity than the latter. Our findings provide a deeper understanding of facet-dependent enzyme-like activities and might advance the development of noble metal-based nanomaterials with both enhanced and targeted antibacterial activities. Noble metal nanoparticles are potential antibacterial agents, perhaps owing to their enzyme-like activities. Here, the authors find that the exposed facets of palladium nanocrystals demonstrate their specific antibacterial behavior against both Gram-positive and Gram-negative bacteria.