Search Results (3,531)

Lower respiratory tract infections caused by Pseudomonas aeruginosa are a global concern. Patients with chronic lung diseases such as cystic fibrosis and non-cystic fibrosis bronchiectasis often do not receive adequate antibiotic delivery through conventional routes. P. aeruginosa employs several mechanisms, including biofilm formation and efflux pumps to limit the accumulation of bactericidal drug concentrations. Direct drug delivery to the lung epithelial lining fluid can increase antibiotic concentration and reduce treatment failure rates. This review discusses current research and developments in inhaled antibiotic formulations for treating P. aeruginosa infections. Recent studies on particle engineering for the dry powder inhalers of antibiotics emphasized three fundamental principles of development: micro, nano, and nano-in-microparticles. Carrier-free microparticles showed potential for high-dose delivery but suffered from poor aerosolization, which could be improved through a drug–drug combination. Amino acids in a co-spray-dried system improved powders’ aerodynamics and reduced moisture sensitivity while incorporating the chitosan/poly(lactic-co-glycolic acid) (PLGA)-modified release of the drug. Nano-in-microsystems, embedding lipid carriers, showed improved antibiofilm activity and controlled release. We also highlight emerging biologics, including antibacterial proteins/peptides, vaccines, bacteriophages, and probiotics. Research on antibiotics and biologics for inhalation suggests excellent safety profiles and encouraging efficacy for some formulations, including antimicrobial peptides and bacteriophage formulations. Further research on novel molecules and synergistic biologic combinations, supported by comprehensive animal lung safety investigations, will be required in future developments. Full article

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has become one of the most serious problems confronting modern healthcare, particularly in intensive care units where patients are highly susceptible, procedures are frequent, and antibiotic exposure is often prolonged. In this review, carbapenem resistance in K. pneumoniae is presented not as a fixed feature of individual bacteria, but as a process that is constantly changing and closely interconnected. We bring together evidence showing how the spread of successful bacterial lineages, the exchange of resistance genes, and gradual genetic adjustment combine to drive both the rapid spread and the long-lasting presence of resistance. A major focus is placed on mobile genetic elements, including commonly encountered plasmid backbones, transposons, and insertion sequences that carry carbapenemase genes such as blaKPC, blaNDM, and blaOXA-48-like. These elements allow resistance genes to move easily between bacteria and across different biological environments. The human gut plays a particularly important role in this process. Its microbial community serves as a largely unseen reservoir where resistance genes can circulate and accumulate well before infection becomes clinically apparent, making prevention and control more difficult. This review also discusses the key biological factors that shape resistance levels, including carbapenemase production, changes in the bacterial cell membrane, and systems that expel antibiotics from the cell, and explains how these features work together. Advances in molecular testing have made it possible to identify resistance more quickly, supporting earlier clinical decisions and infection control measures. Even so, current tests remain limited by narrow targets and may miss low-level carriage, hidden genetic reservoirs, or newly emerging resistance patterns. Finally, we look ahead to approaches that move beyond detection alone, emphasizing the need for integrated surveillance, thoughtful antibiotic use, and coordinated system-wide strategies to lessen the impact of CRKP. Full article

Major reconstructive free-flap surgery often requires ICU admission, yet early signals associated with postoperative antibiotic escalation remain poorly characterized. We conducted a single-center retrospective cohort study of 119 consecutive postoperative ICU admissions after major free-flap reconstruction. Exposures were postoperative day-1 procalcitonin (PCT) and documented postoperative shock; the primary endpoint was clinician-initiated antibiotic escalation (“upgrade”), and secondary endpoints were documented microbiological positivity and ICU mechanical ventilation duration. Escalation occurred in 85/119 admissions (71.4%). Day-1 PCT was higher with escalation (median 0.25 vs. 0.135 ng/mL; p = 0.033), and shock was more frequent (59/85 [69.4%] vs. 13/34 [38.2%]; p = 0.003). Escalation was associated with longer ventilation (median 3515 vs. 2170 min; p < 0.001) and higher rates of any positive culture (54/85 [63.5%] vs. 8/34 [23.5%]; p < 0.001). In multivariable logistic regression adjusting for operative time and intraoperative IV volume, shock remained independently associated with escalation (adjusted OR 3.52, 95% CI 1.48–8.36; p = 0.004), whereas log-transformed PCT was not (p = 0.224). PCT showed modest apparent discrimination for escalation (AUC 0.63), improving to 0.71 when combined with shock. These findings should be interpreted as observational associations with escalation behavior, supporting prospective evaluation of physiology-plus-biomarker stewardship approaches. Full article

Background/Objectives: Infection prevention and control (IPC) programs combine pathogen-targeted measures (e.g., admission screening) with hospital-wide standard precautions (e.g., hand hygiene, HH). We assessed temporal associations between screening, HH, antimicrobial stewardship (AMS), and hospital-level outcomes in a tertiary paediatric hospital. Methods: This study was a retrospective hospital-wide ecological time-series at the Children’s Memorial Health Institute. Annual aggregate data: 2011–2024 for screening, colonisation, and healthcare-associated infections (HAIs) with alert pathogens; 2016–2024 for antibiotic consumption (ATC J01, systemic antibacterials). Process indicators: number of screening tests and alcohol-based hand rub (ABHR) consumption per 1000 patient-days (PD). Outcomes: colonisations/HAIs per 1000 PD and defined daily doses (DDD) per 1000 PD overall and by class. Trends used linear regression and Spearman’s rank correlation. Results: Screening intensity increased from 39 to 150/1000 PD (slope +8.3/year; R² = 0.90; p < 0.001). Detected colonisation rose (2.5 → peak 8.05/1000 PD in 2023; slope +0.39; R² = 0.81; p < 0.001), while multidrug-resistant-organism (MDRO)-attributable HAIs remained low/stable (0.27–0.62/1000 PD; slope −0.014; p = 0.023). ABHR consumption increased from 26.1 to 78.0 L/1000 PD in 2020 (p < 0.001) and partially normalised to 60.0 in 2024 (>2 × baseline). Overall ATC J01 showed no long-term linear trend (~278–356 DDD/1000 PD; +2.57/year; p = 0.46), but class mix shifted: carbapenems, fluoroquinolones, and amoxicillin–clavulanate decreased; third/fourth-generation cephalosporins, piperacillin/tazobactam, and glycopeptides increased. Conclusions: In this tertiary paediatric setting, expansion of risk-based admission screening and sustained implementation of horizontal IPC measures were accompanied by increased detection of colonisation with alert pathogens, while MDRO-attributable HAIs remained low and stable at the hospital level. Over the same period, AMS activity coincided with a redistribution in antibiotic class use without a clear long-term reduction in total antibiotic consumption. These hospital-level findings are descriptive and hypothesis-generating; causal inference is limited by the ecological study design, and the heterogeneous, multispecialty structure of a tertiary paediatric centre. Full article

Infectious endometritis is a primary cause of subfertility in mares. Many manuals and guidelines are available for administering intrauterine infusions of antibiotics and biofilm-disrupting solutions, detailing concentrations, vehicle solutions, and buffers. However, the stability of these combinations has not been documented. Therefore, our study investigated how factors such as storage temperature, concentration, buffer types, combinations of biofilm disruptors, and vehicle solutions affected pH stability over 24 h in uterine infusion preparations commonly used by veterinary theriogenologists to treat endometritis in mares. In experiment 1, amikacin, ampicillin, ceftiofur, ciprofloxacin, gentamicin, penicillin G potassium, penicillin G procaine, and ticarcillin clavulanate were diluted in saline and lactated Ringer’ s solution and stored at 5 ° C, 21 ° C, and 37 ° C for 24 h. Solutions were evaluated for pH and physical characteristics at 0, 1, 3, 6, and 24 h after storage. In experiment 2, 1- and 2-g doses of amikacin, ampicillin, and gentamicin were compared, evaluating the same volume at different concentrations and their stability over 24 h. Experiment 3 combined biofilm chelators (i.e., Tris-EDTA, hydrogen peroxide, and dimethyl sulfoxide) with antibiotic solutions and evaluated interactions among products. Experiment 4 compared the stability of each antibiotic diluted in saline and lactated Ringer’ s solution. Statistical analysis was performed using GraphPad Prism 9.3.0. Significance was set at p < 0.05. The results indicated that the stability of antibiotic solutions for uterine infusions in mares is significantly influenced by storage conditions and pH fluctuations. Solutions containing aminoglycosides showed an increase in pH over time, suggesting that buffering agents like sodium bicarbonate can enhance stability. In contrast, other antibiotics exhibited a decrease in pH, particularly at elevated temperatures, which may reduce their effectiveness. In conclusion, the pH stability of uterine infusions is affected by various storage conditions and vehicles, underscoring the importance of evaluating antibiotic treatments for quality control. While pH changes were observed, the potential impact on the overall stability or antimicrobial activity of the solutions requires further investigation. Full article

The irrational or excessive use of antibiotics causes the emergence of bacterial resistance, making antibiotics less effective or ineffective. As the number of resistant antibiotics increases, it is crucial to develop new strategies and innovative approaches to potentiate the efficacy of existing antibiotics. Prior to this, we discovered that some of the traditional antibiotics produce reactive oxygen species (ROS) under specific light exposure. In this paper, we report a multifunctional polymeric nanoparticle (F8IC NPs-PME) that combines targeted and photodynamic–photothermal therapy (PDT-PTT) in one device. The PME on the surface of F8IC enables the selective binding of F8IC NPs-PME to the surface of Gram-negative bacteria. In addition, PME and F8IC can generate ROS and photothermia under near-infrared light excitation, respectively. The results showed that the sterilization efficiency of F8IC NPs-PME at a concentration of 8 μg/mL was as high as 94.7% against kanamycin-resistant E. coli under 808 nm near-infrared light irradiation (0.8 W/cm², 10 min). This antimicrobial strategy can achieve efficient bacteria killing with a low dosage of antibiotics and opens up a new avenue for fighting bacterial resistance. Full article

Diet plays a central role in shaping the composition and metabolic activity of the oral microbiota, thereby influencing both oral and systemic health. Disturbances in this delicate host–microbe balance, triggered by dietary factors, smoking, poor oral hygiene, or antibiotic use, can lead to microbial dysbiosis and increase the risk of oral diseases such as periodontitis, as well as chronic systemic disorders including diabetes, cardiovascular disease, Alzheimer’s disease, and certain cancers. Among dietary contaminants, exposure to toxic heavy metals such as cadmium (Cd), lead (Pb), mercury (Hg), nickel (Ni), and arsenic (As) represents an underrecognized modifier of the oral microbial ecosystem. Even at low concentrations, these elements can disrupt microbial diversity, promote inflammation, and impair metabolic homeostasis. Saliva has recently emerged as a promising, non-invasive biofluid for monitoring nutritional status and early metabolic alterations induced by diet and environmental exposures. Salivary biomarkers, including metabolites, trace elements, and microbial signatures, offer potential for assessing the combined effects of diet, microbiota, and toxicant exposure. This review synthesizes current evidence on how diet influences the oral microbiota and modulates susceptibility to heavy metal toxicity. It also examines the potential of salivary biomarkers as integrative indicators of nutritional status and metabolic health, highlights methodological challenges limiting their validation, and outlines future research directions for developing saliva-based tools in personalized nutrition and precision health. Full article

The antibacterial activity of 18 phenolic compounds, including flavonoids and phenolic acids, against organisms of Escherichia coli, Klebsiella pneumoniae, and Proteus vulgaris that are resistant to several drugs was assessed in this study using the agar diffusion method. The strain’s strong resistance was confirmed by antibiotic susceptibility testing, which used fourteen drugs and only found inhibition zones for five of them. Out of the polyphenols, four compounds were effective against P. vulgaris, five against K. pneumoniae, and twelve against E. coli bacteria. The greatest inhibitory zone (18.75 ± 0.25 mm) against E. coli was shown by propyl gallate, an ester of gallic acid. Activity was significantly impacted by structural changes. Propyl substitution increased antibacterial activities across all strains, while methoxy substitution decreased them. The antibacterial effectiveness was reduced by the hydroxylation of flavonoids and the C3–C4 dihydroxylation of cinnamic acid. Propyl gallate primarily had antagonistic effects, while combination experiments demonstrated additive, synergistic, and antagonistic interactions. Propyl gallate (ΔG = −7.5 kcal/mol) exhibited substantial binding affinities with TEM-1 and NDM-1 β-lactamases via hydrogen and hydrophobic interactions, according to molecular docking. These results demonstrate propyl gallate as a viable antibacterial adjuvant option and validate the structure–activity relationship of phenolic compounds. Full article

This study reports the fabrication of chitosan/carboxymethyl cellulose (C/M) nanocomposites by electrolyte gelation–spray drying and the evaluation of their antibacterial performance as carriers for the antibiotic ampicillin. Chitosan (C), a cationic biopolymer derived from chitin, was combined with the anionic polysaccharide carboxymethyl cellulose (M) at different mass ratios to form stable nanocomposites via electrostatic interactions and then collected in a spray dryer. The resulting particles exhibited mean diameters ranging from 800 to 1500 nm and zeta potentials varying from +90 to −40 mV, depending on the C/M ratio. The optimal formulation (C/M = 2:1 ratio) achieved a high recovery yield (71.1%), lower PDI (0.52), and ampicillin encapsulation efficiency EE (82.4%). Fourier transform infrared spectroscopy (FTIR) confirmed the presence of hydrogen bonding and ionic interactions among C/M, and ampicillin within the nanocomposite matrix. The nanocomposites demonstrated controlled ampicillin release and pronounced antibacterial activity against Staphylococcus aureus, with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 3.2 µg/mL and 5.3 µg/mL, respectively, which were lower than those of free ampicillin. These results indicate that the chitosan/carboxymethyl cellulose nanocomposites are promising, eco-friendly carriers for antibiotic delivery and antibacterial applications. Full article

Perinatal antibiotic exposure poses a significant risk to maternal-offspring immune programming and infant gut microbiota development. This study investigated the time-specific effects of maternal cefoperazone sodium (CPZ) administration on IgG transfer and offspring gut microbiota in a murine model. Pregnant C57BL/6J mice were assigned to control (CON), gestational (G-CPZ), lactational (L-CPZ), and combined gestational/lactational (GL-CPZ) treatment groups. Results showed that all CPZ treatments significantly reduced IgG and its subtype levels in maternal serum, colostrum, and offspring serum (p < 0.05). Concurrently, mRNA expression of the neonatal Fc receptor (FcRn), critical for IgG transport, was downregulated in both maternal breast and offspring intestinal tissues (p < 0.05). Furthermore, 16S rRNA sequencing revealed that CPZ exposure altered offspring gut microbiota diversity and composition. Alpha diversity was reduced, particularly in the G-CPZ group, while beta diversity showed significant separation in L-CPZ and GL-CPZ groups (p < 0.05). Taxonomic shifts included decreased Bacteroidetes and Lactobacillus, and in the GL-CPZ group, a marked increase in Firmicutes and potential pathobionts like Enterococcus and Hungatella (p < 0.05). These findings demonstrate that perinatal antibiotic exposure, depending on its timing, impairs maternal-offspring IgG transfer via the FcRn pathway and induces distinct, persistent alterations in the offspring’s gut microbiota, which may have implications for neonatal immunity and long-term health. Full article

Objective: The aim of this study was to develop and evaluate non-antibiotic strategies against Helicobacter pylori by establishing a bovine immune milk platform and designing a synergistic multi-antigen immunogen to enhance humoral immune responses. Methods: Inactivated Helicobacter pylori (H. pylori) was used to immunize dairy cows, and the resulting immune milk was characterized for antibody specificity, acid stability, and target antigens via ELISA, Western blot, agglutination assays, and mass spectrometry. Key identified antigens (UreA, UreB, UreE, UreG, HypA, FlaA, and FlaB) were produced as recombinant proteins. Their immunogenicity was evaluated in a murine model, comparing single antigens with various protein combinations. Immune responses were assessed by antigen-specific IgG ELISA, bacterial agglutination titers, flow cytometry for T-cell activation, and histopathology for safety. Results: Immune milk contained high-titer, acid-stable IgG antibodies targeting multiple H. pylori virulence factors. In mice, while single proteins induced specific IgG, a multi-antigen cocktail (FlaA + FlaB + HypA + UreA + UreB + UreE + UreG) elicited significantly higher serum agglutination titers (~7 × 10³) than single antigens or inactivated whole-cell vaccine, alongside robust CD4⁺ T-cell activation. No formulations showed any hepatorenal or splenic toxicity. Conclusion: Bovine immune milk is a viable platform for acid-stable antibody delivery. A rationally designed multi-antigen cocktail synergistically enhances functional humoral immunity in vivo, providing a promising foundation for developing antibody-based or subunit vaccine strategies against H. pylori. Full article

Background: Cefepime/enmetazobactam (FEP/META) is a novel fixed-dose β-lactam/β-lactamase inhibitor combination. The objective was to study the physicochemical stability of the approved daily dose in polypropylene syringes and elastomeric devices over a 24 or 72 h period to understand the feasibility of using FEP/META in prolonged infusions and its use for outpatient parenteral antibiotic therapy (OPAT). Methods: Solutions of FEP/META were prepared in 0.9% NaCl or 5% dextrose (D5W) and stored in syringes (6 g/1.5 g/48 mL) or silicone and polyisoprene elastomeric devices (EDs) at 6 g/1.5 g/120 mL and 6 g/1.5 g/240 mL: syringes were tested at 22–25 °C over a 24 h period, polyisoprene EDs at 2–8 °C over 72 h period, and silicone and polyisoprene EDs at 32 °C over a 24 h period. The solution was considered stable if it retained more than 90% of its initial concentration (Ci), no pH variation (±1 unit), no significant visual change, and with compliant subvisual examination. Liquid Chromatography–Electrospray Ionization–Quadrupole Time-of-Flight–Mass Spectrometry was utilized to identify intermediate degradation products. Results: At the daily dose, FEP/META retained >90% of its Ci up to 12 h in 0.9% NaCl and 24 h in D5W when stored in syringes. In silicone ED, stability was enhanced up to 24 h in D5W at all concentrations. The solution was chemically stable for 24 h when stored in polyisoprene ED in 0.9% NaCl at 2–8 °C. Conclusions: FEP/META combination showed prolonged stability with physicochemical integrity up to 12–24 h in all containers and conditions. It appears to be stable for prolonged infusions and for OPAT. Full article

Accurately identifying drug off-targets is essential for reducing toxicity and improving the success rate of pharmaceutical discovery pipelines. However, current deep learning approaches often struggle to fuse chemical structure, protein biology, and multi-target context. Here, we introduce HDPC-LGT (Hybrid Dual-Prompt Cross-Attention Ligand–Protein Graph Transformer), a framework designed to predict ligand binding across sixteen human translation-related proteins clinically associated with antibiotic toxicity. HDPC-LGT combines graph-based chemical reasoning with protein language model embeddings and structural priors to capture biologically meaningful ligand–protein interactions. The model was trained on 216,482 experimentally validated ligand–protein pairs from the Chemical Database of Bioactive Molecules (ChEMBL) and the Protein–Ligand Binding Database (BindingDB) and evaluated using scaffold-level, protein-level, and combined holdout strategies. HDPC-LGT achieves a macro receiver operating characteristic–area under the curve (macro ROC–AUC) of 0.996 and a micro F1-score (micro F1) of 0.989, outperforming Deep Drug–Target Affinity Model (DeepDTA), Graph-based Drug–Target Affinity Model (GraphDTA), Molecule–Protein Interaction Transformer (MolTrans), Cross-Attention Transformer for Drug–Target Interaction (CAT–DTI), and Heterogeneous Graph Transformer for Drug–Target Affinity (HGT–DTA) by 3–7%. External validation using the Papyrus universal bioactivity resource (Papyrus), the Protein Data Bank binding subset (PDBbind), and the benchmark Yamanishi dataset confirms strong generalisation to unseen chemotypes and proteins. HDPC-LGT also provides biologically interpretable outputs: cross-attention maps, Integrated Gradients (IG), and Gradient-weighted Class Activation Mapping (Grad-CAM) highlight catalytic residues in aminoacyl-tRNA synthetases (aaRSs), ribosomal tunnel regions, and pharmacophoric interaction patterns, aligning with known biochemical mechanisms. By integrating multimodal biochemical information with deep learning, HDPC-LGT offers a practical tool for off-target toxicity prediction, structure-based lead optimisation, and polypharmacology research, with potential applications in antibiotic development, safety profiling, and rational compound redesign. Full article

Biofilms formed by Staphylococcus aureus on medical devices and tissue surfaces are a major contributor to persistent infections due to their resistance to antibiotics. Hydrodynamic forces in physiological and device-associated environments significantly influence biofilm development, yet the dynamics of detachment and regrowth under flow remain poorly quantified. In this study, biofilm surface coverage was measured in microfluidic flow assays across combinations of shear rates and nutrient concentrations. A computational workflow was used to segment biofilm trajectories into three kinetic phases—growth, exodus, and regrowth—based on surface coverage dynamics. Each phase was modeled using parametric functions, and fitted parameters were interpolated across experimental conditions to reconstruct biofilm lifecycles throughout the flow–nutrient conditions. The analysis revealed that intermediate shear rates triggered early detachment events while suppressing subsequent regrowth, whereas lower and higher shear regimes favored biofilm persistence. The resulting model enables quantitative comparison of condition-specific biofilm behaviors and identifies key thresholds in mechanical and nutritional inputs that modulate biofilm stability. These findings establish a phase-resolved framework for studying S. aureus biofilms under hydrodynamic stress and support future development of targeted strategies to control biofilm progression in clinical and engineered systems. Full article

Background: The current rise in multidrug-resistant pathogens highlights the urgent need for the discovery of novel antibacterial agents with potential clinical applications. A considerable proportion of these developed resistances may be attributable to the intrinsic response of bacteria to antibiotic-induced stress conditions in the environment. Consequently, the identification and characterization of genetic alterations in physiological processes in response to antibiotics represent promising strategies for the discovery and characterization of naturally produced novel antibacterial agents. This study investigated the antimicrobial activity of an antimicrobial active isolate Actinomadura coerulea derived from a meerkat fecal sample. Methods: The production of secondary metabolites that potentially compromise bacterial cell wall integrity was confirmed by the induction of promoter activity in whole-cell biosensors in which an antibiotic-inducible promoter was fused to the luciferase cassette. During plate-based biosensor assays, we identified naturally resistant Bacillus subtilis colonies growing in the zone of inhibition around A. coerulea colonies. After these successive rounds of selection, highly resistant spontaneous B. subtilis mutants had evolved that were subjected to whole-genome sequencing. Results: Non-silent mutations were identified in pssA, which encodes a phosphatidylserine synthase; mdtR, as a gene for the repressor of multidrug resistance proteins, and yhbD, whose function is still unknown. A new cinnamycin-like molecule, coerumycin, was discovered based on the physiological role of PssA and comprehensive genomic analysis of A. coerulea. Additional experiments with cell extracts containing coerumycin as well as the cinnamycin-like compound duramycin confirmed that the interaction between coerumycin and the bacterial cell envelope is inhibited by a loss-of-function mutation in pssA. Conclusion: Our approach demonstrates that combining the exploration of niche habitats for actinomycetes with whole-cell biosensor screening and characterization of natural resistance development provides a promising strategy for identifying novel antibiotics. Full article