Prosthetic joint infection (PJI) after total shoulder arthroplasty (TSA) is a devastating complication. Cephalosporins are considered the standard of care for antibiotic prophylaxis during TSA procedures; however reported β-lactam allergies may result in the use of less effective alternatives which are associated with higher infection and complication rates. The aim of this study is to evaluate the relationship between reported β-lactam allergies, antibiotic choice, and revision rates in TSA. A retrospective chart review was conducted on all TSA procedures performed at a single institution between January 2015 and January 2025. Information was collected regarding reported allergies to antibiotics including allergy severity and specific reactions. Additionally, all antibiotics administered during the procedures, intraoperative reactions to administered antibiotics, surgical complications, and subsequent revision procedures were collected. Revision procedures were categorized as septic or aseptic based on preoperative diagnosis. Perioperative antibiotics and patient allergies were categorized into penicillins, cephalosporins, clindamycin, vancomycin and other. Data from 4,232 TSAs were collected. 23% of patients had a reported antibiotic allergy and 15% had a β-lactam allergy. Cephalosporins were administered in 94% of all TSAs, but use declined with increasing β-lactam allergy severity, dropping from 90% in mild cases to 44% in severe cases, with corresponding increases in clindamycin and vancomycin use. Higher allergy severity was strongly associated with reduced cephalosporin use and increased alternative antibiotic use (OR = 0.40, p<.001). Notably, cephalosporins were given to patients labeled as having anaphylactic reactions to penicillins or cephalosporins with no adverse events reported. Overall, intraoperative cephalosporin prophylaxis was significantly associated with decreased all-cause revision odds (OR = 0.47, p<.001) and the presence of a β-lactam allergy was associated with increased likelihood requiring a revision procedure for a presumed septic etiology. The severity of reported β-lactam allergies strongly influences perioperative antibiotic selection despite evidence that most reported allergies are unreliable, unnecessarily increasing patient risk for PJI. Lack of cephalosporin prophylaxis was associated with increased revision rates, underscoring the clinical and economic value of appropriate antibiotic use. Given the high prevalence of mislabeled β-lactam allergies, established delabeling strategies using allergy testing or test-dosing in the operating room may offer a safe and effective means to increase first-line antibiotic use and improve stewardship. Level III, Retrospective Cohort Comparison, Prognosis Study.
Colonizing antibiotic resistant bacteria often exists within functionally structured microbial communities, where occurrence is influenced by dependencies essential to stability and function. Considering these interactions could improve understanding of factors influencing diversity of colonizing resistant bacteria within human community settings. Using a framework that considered biotic interactions, we reexamined factors associated with assemblage of colonizing antibiotic resistant Escherichia coli strains in a densely populated urban informal settlement. We identified antibiotic selection, colonization legacy, positive feedbacks and dispersal as key assembly processes. Antibiotics and colonization legacy exerted strain-specific effects while dispersal factors influenced all strains rather uniformly. Specifically, areas frequently exposed to bactericidal antibiotics were dominated by locally established resistant strains, whereas areas frequently exposed to bacteriostatic antibiotics had increased presence of less-established strains. Assemblage configuration was influenced by relative abundance of strains initially present in and around the disturbed areas. Hygiene practices reinforced local strains consistently while weather variables had variable effects: high monthly average minimum temperatures increased abundance of nearly all strains, whereas increases in monthly average maximum temperature, humidity, and rainfall uniformly decreased strain abundance. Overall, we show that survival selection, driven by selective forces, and dispersal selection, shaped by colonization potential, jointly influenced strains recruitment and assembly, suggesting antibiotics and priority effects as factors contributing to resistant E. coli assemblages in this setting. Together these findings underscore need for context-specific antibiotic stewardship and hygiene interventions.
Breath analysis offers a promising, non-invasive approach for early disease detection in livestock, particularly for bovine respiratory disease (BRD). However, the widespread use of antibiotics in veterinary practice raises concerns about their potential to confound breath-based diagnostics. In this study, we analysed breath samples from 65 calves to evaluate the diagnostic performance of volatile organic compounds (VOCs) as biomarkers of BRD. We identified several candidate ions, including formaldehyde and acetone/propanal, that showed significant elevation at the onset of disease and a modest detection capability (AUC = 0.53-0.77). However, the strongest discrimination between diseased and controls occurred after antibiotic administration, suggesting a confounding pharmacological influence. To isolate this effect, a secondary trial was conducted in which healthy calves were treated with oxytetracycline dihydrate (Alamycin® LA 300). This revealed rapid and transient changes in the breath volatilome, with significant increases in dimethyl sulphide and (C₅H₁₀O)H+ within 1 hour, and other VOCs, including formaldehyde and acetone/propanal within 24 hours of treatment. These findings demonstrate that antibiotics can substantially alter breath VOC profiles, potentially mimicking or masking disease signals. We conclude that breath-based diagnosis of BRD holds promise but must account for treatment history to avoid misclassification. Moreover, the reproducible and time-resolved nature of the VOC response suggests that breath analysis could also be developed as a tool for monitoring antimicrobial exposure and optimising therapeutic dosing in livestock.
Natural products remain a major source of antibiotics, but discovery efforts have traditionally treated biosynthetic gene clusters as sources of individual bioactive molecules1-5. Increasing evidence has suggested that microorganisms can instead encode coordinated multi-metabolite systems, yet the genetic architectures and biological logic of such systems remain poorly understood6-12. Here we show that Streptomyces spp. encode a highly conserved biosynthetic megacluster that produces four structurally distinct natural product families-stravidins, acidomycin, dapamycins, and 2-methyl-7-keto-8-aminopelargonic acid (α-Me-KAPA)-alongside the biotin-binding protein streptavidin. These components converge on bacterial biotin metabolism through complementary mechanisms, including enzyme inhibition, prodrug activation, cofactor mimicry and biotin sequestration. The encoded metabolites are co-produced and act synergistically across Gram-negative and mycobacterial species, with stravidin S2 and α-Me-KAPA showing enhanced efficacy in combination in a mouse model of multidrug-resistant Escherichia coli infection. This megacluster reveals a genetically encoded chemical arsenal that functions as a naturally evolved combination therapy against a conserved metabolic pathway. More broadly, our findings suggest that higher-order biosynthetic architectures may represent an overlooked reservoir of antibiotic mechanisms and support a shift from discovering isolated natural products to reconstructing native synergistic systems.
Antibiotics and antibiotic resistance genes (ARGs) in coastal urban waters pose increasing environmental and public health risks due to their persistence and their role in accelerating antimicrobial resistance (AMR), yet their dynamics remain difficult to predict under data-scarce conditions. This study developed an integrated multi-model framework that combines a process-based hydrological model, a modified LOADEST model, multiple machine learning approaches, and Shapley additive explanations (SHAP) for interpretability to predict antibiotics and AMR indicators (mainly ARGs) in three coastal zones of Singapore. Using readily available hydrometeorological datasets and limited routine water quality variables, the framework achieved robust performance, with the Long Short-Term Memory (LSTM) model performing best among the machine learning models. The LSTM-based integrated framework showed good predictive performance for low-censored antibiotics, as exemplified by clarithromycin (CLAR; NSE = 0.62 ± 0.13), and most AMR indicators across the three coastal zones (average NSE = 0.67 ± 0.10), whereas predictive performance decreased for highly censored antibiotics due to the limited information available for learning temporal variability. SHAP feature analysis showed that routine water quality variables and flow dominated model predictions, while meteorological factors were less influential, and SHAP temporal patterns further indicated that antibiotic responses to environmental drivers occurred on timescales comparable to catchment-to-coastal hydrological transport times, whereas ARGs consistently exhibited longer lagged responses across all regions. Incorporating predicted CLAR as an input feature in the macrolide-associated ARG model identified a positive association between CLAR and ARG only in the region with relatively high CLAR concentrations, and SHAP-derived interaction strengths showed that CLAR interacted most strongly with routine water quality variables, followed by hydrological factors, with weak interactions observed for meteorological variables. Overall, the proposed framework provides a practical and transferable hybrid modelling approach for predicting antibiotic and ARG dynamics in data-limited coastal environments.
Acute otitis media is among the most common childhood infections and a major source of antibiotic use. Evidence from randomized trials shows that around 80% of cases resolve spontaneously, with antibiotics offering only modest symptomatic benefit and causing frequent adverse effects. Watchful waiting-with accurate diagnosis, effective analgesia, and clear safety-netting-achieves equivalent outcomes to immediate treatment in most children. Antibiotics remain essential for infants aged under 6 months, bilateral or suppurative disease, and high-risk groups. Aligning practice with evidence supports safer, more rational care and helps mitigate antimicrobial resistance.
The use of antibiotics to promote growth and prevent disease in livestock and poultry animals has raised concerns about antimicrobial resistance and its consequences for public health. Increasing pressure on the livestock and poultry industries demands improved productivity, reduced economic losses, and the assurance of food safety for human consumption. Plant bioactive compounds (PBCs) have emerged as safe and sustainable alternatives to antibiotics that promote the growth, support animal health and improve productivity without compromising food safety. PBCs represent a diverse group of secondary metabolites-including phenolics, terpenoids, polysaccharides, and organosulfur compounds-that exhibit a wide range of biological activities relevant to livestock and poultry nutrition and health. Recent studies have shown that supplementing animals with PBCs as feed additives, either as crude extracts or individual compounds, improves growth performance, nutrient utilization, and modulates gut microbiota, while also exerting antioxidant, anti-inflammatory, antimicrobial, and immunoregulatory effects, thereby enhancing overall resilience of animals. The multifunctional properties of PBCs, and the reduced risk of resistance development position them as promising candidates for next-generation feed additives for livestock and poultry production. However, challenges remain regarding optimal concentration, variability in bioavailability, stability during feed processing, and the standardization of active components. Here, we discuss the major PBCs and their potential as functional feed additives to improve livestock and poultry production. We further highlight research gaps and outline future prospects required to advance their adoption in sustainable animal production.
The diagnosis of acute community-acquired bacterial urinary tract infections (UTIs) in adult men presently recognizes four key clinical entities: cystitis, prostatitis, pyelonephritis, and epididymo-orchitis, each with distinct diagnostic criteria. Bacteriuria of clinically undetermined significance, defined as documented bacteriuria with non-specific systemic symptoms (e.g., confusion, functional decline, or isolated fever) but no localized UTI signs, is common in elderly patients and requires evaluation with sepsis risk scores so as to avoid unnecessary antibiotics. Urinary colonization, frequent in older men, does not warrant treatment unless prior to urological procedures. Cystitis is diagnosed by local symptoms (dysuria, urgency, suprapubic pain), absence of fever, and positive urine culture, ruling out prostatitis or pyelonephritis. Acute prostatitis is identified by cystitis symptoms plus fever or sepsis, with imaging reserved for complications. Acute pyelonephritis is diagnosed by fever or sepsis, flank pain (spontaneous or on percussion), and positive urine culture; cystitis symptoms may be absent. Urine culture (thresholds: ≥103 CFU/mL for bacteriuria, leukocyturia >30 × 103/mL) remains the gold standard, while urine dipstick testing is not recommended due to low predictive value. Routine blood tests (inflammatory markers, PSA, or blood cultures) are unnecessary in outpatient management, even for febrile UTIs, unless acute kidney injury or complications are suspected. Pyelonephritis requires imaging (urgent in cases of sepsis or obstruction) to assess for uropathy, and epididymo-orchitis mandates STI screening.
Bronchiectasis is a chronic respiratory disease characterised by irreversible bronchial dilatation, persistent airway inflammation and recurrent infections. Symptoms, particularly cough, sputum production and dyspnoea, are the most immediate and patient-relevant expression of the disease, linking clinical presentation, airway biology and outcomes. While asthma and COPD management algorithms already integrate symptom burden into therapeutic decision-making, bronchiectasis care has historically relied on exacerbation history to guide preventive interventions. Over the past decade, an expanding body of evidence has demonstrated that daily symptoms mirror current infection and inflammation, profoundly impact quality of life, and predict future exacerbations. Comparative analyses across chronic lung diseases further highlight the central role of symptom monitoring in defining disease activity and risk. The updated European Respiratory Society guidelines translate this evidence into clinical practice, marking a paradigm shift from an exacerbation-driven to a symptom-centred and treatable-traits model. This review synthesises clinical, biological and therapeutic insights linking symptoms to bronchiectasis pathophysiology, disease activity and treatment response. We discuss how airway clearance, mucoactive therapy, antibiotics, pulmonary rehabilitation and targeted anti-inflammatory strategies, including dipeptidyl peptidase-1 inhibition, can address specific symptom profiles. We also mention the role of comorbidities and psychosocial management, establishing symptoms as the cornerstone of a holistic, multidimensional care approach. Recognising symptoms as both biomarkers of activity and therapeutic targets represents a major step toward precision medicine in bronchiectasis, aligning clinical management with patient experience and the biological drivers of disease.
Acinetobacter baumannii is a multidrug-resistant pathogen known for its robust biofilm formation, leading to persistent infections and treatment failure. Traditional antibiotics often struggle to penetrate these biofilms. Cinnamaldehyde, a plant-derived antimicrobial compound, holds potential as an antibiofilm agent. This study investigates its effects on biofilm formation, EPS production, cell surface properties, oxidative stress response, and gene expression in A. baumannii. This study evaluated the antibiofilm activity of cinnamaldehyde using A. baumannii. Biofilm formation was quantified via crystal violet assay, while structural alterations were visualised using light microscopy, SEM, and CLSM. EPS production and cell surface hydrophobicity were evaluated using phenol-sulfuric acid and MATH assays. Catalase activity was assessed through H₂O₂ sensitivity, and qRT-PCR analysed gene expression. Cytotoxicity was evaluated using the MTT assay on mouse fibroblast cells. Cinnamaldehyde significantly inhibited biofilm formation, with 86.67% reduction at 0.007% (v/v), without affecting planktonic growth. Microscopy revealed disrupted biofilm architecture and reduced microcolony formation. SEM showed reduced EPS and altered cell morphology. EPS quantification confirmed a 33.06% reduction. Cell surface hydrophobicity decreased from 86.76% to 21.93%, impairing bacterial adhesion. H₂O₂ sensitivity increased, indicating reduced catalase activity. Gene expression analysis showed downregulation of bfmR, ompA, csuA/B, and katE. Cinnamaldehyde showed minimal cytotoxicity in mouse fibroblast cells. Cinnamaldehyde effectively inhibits A. baumannii biofilms through structural disruption, EPS reduction, altered surface hydrophobicity, oxidative stress sensitization, and gene suppression. Its non-toxic nature and broad mechanisms highlight its potential as a plant-based antibiofilm agent for controlling resistant infections.
Under low concentrations of antibiotics causing DNA damage, Escherichia coli bacteria can trigger stochastically a stress response known as the SOS response. While the expression of this stress response can make individual cells transiently able to overcome antibiotic treatment, it can also delay cell division, thus impacting the whole population's ability to grow and survive. In order to study the trade-offs that emerge from this phenomenon, we propose a bi-type age-structured population model that captures the phenotypic plasticity observed in the stress response. Individuals can belong to two types: either a fast-dividing but prone to death "vulnerable" type, or a slow-dividing but "tolerant" type. We study the survival probability of the population issued from a single cell as well as the population growth rate in constant and periodic environments. We show that the sensitivity of these two different notions of fitness with respect to the parameters describing the phenotypic plasticity differs between the stochastic approach (survival probability) and the deterministic approach (population growth rate). Moreover, under a more realistic configuration of periodic stress, our results indicate that maximal population growth can only be achieved through fine-tuning simultaneously both the induction of the stress response and the repair efficiency of the damage caused by the antibiotic.
Algal-derived extracellular organic matter (EOM) is an important photosensitizer to trigger antibiotics photodegradation in sunlit waters. However, ubiquitous metal ions may substantially alter this process, and the underlying mechanisms remain insufficiently understood. In this study, we systematically investigated the effects of representative metal ions (Fe3+, Cu2+, Cr3+, Zn2+, Mn2+) on the EOM-sensitized photodegradation of sulfamethoxazole (SMX). All tested metal ions inhibited SMX photodegradation to different extents, following the order: Fe3+ ≈ Cu2+ > Cr3+ > Zn2+ ≈ Mn2+. The inhibition strength was strongly correlated with the conditional stability constants (log KSC) of metal-EOM complexes, indicating that metal-EOM complexation dominantely governs the suppression of EOM photosensitization. Fluorescence excitation-emission matrix analysis and triplet-state probe experiments showed that metal binding markedly reduced the formation of excited triplet-state EOM (3EOM*), the key reactive oxygen species (ROS) responsible for SMX transformation. Electron spin resonance analysis further revealed that the production of secondary ROS derived from 3EOM* was also suppressed after complexation. To gain molecular-level insight, representative EOM model compounds were examined using time-dependent density functional theory. The calculations showed that complexation induced ligand-to-metal charge transfer (LMCT) excitation pathways, which provided a plausible electronic mechanism for the competitive dissipation of excitation energy and the observed suppression of triplet-state formation. These findings identify that metal-EOM complexation as an important yet previously underappreciated factor controlling antibiotic photodegradation in aquatic waters, and highlight its relevance for improving predictions of contaminant persistence under environmentally realistic conditions.
This study aimed to explore the culturable bacterial community in healthy volunteers, with a focus on the staphylococcal population. First, 120 bacterial isolates were collected from conjunctival swabs of 49 healthy volunteers (aged 18 to 77 years). Isolates were characterized by phenotypic analyses, and 68 of them were confirmed as staphylococci by MALDI-TOF/MS and a multiplex PCR assay. The Staphylococcus strains (n = 68) were tested for resistance to the most relevant clinical antibiotics. Clonal relationships among isolates were evaluated by pulsed-field gel electrophoresis (PFGE), and the presence of mecA and mecC, as well as pvl genes, was investigated. Staphylococcus aureus (74%) was the major identified species, followed by Staphylococcus epidermidis (19%) and Staphylococcus xylosus (7%). A high incidence of resistance was detected against gentamicin (64%), erythromycin (62%), and penicillin (51%). Moreover, 33 isolates (48%) exhibited multidrug-resistant phenotypes, and the two S. epidermidis strains harbouring the mec genes exhibited the highest resistance. A marked heterogeneity among isolates, mostly for S. aureus and S. epidermidis, was revealed, clustering them into 20 and 4 genotypes, respectively. The prevalence of the same clones, isolated from different volunteers, across the three species, and the different phenotypic resistance patterns within the same PFGE type, was observed. These findings corroborate that staphylococci constitute a significant component of the ocular microbiota in healthy individuals; however, their exhibited antimicrobial resistance profiles are of concern.
Damaged skin barriers create a vulnerable interface for pathogen colonization, and subsequent pathogen invasion significantly delays tissue repair. Hydrogel dressings have been widely applied in clinical wound management as an effective treatment modality. However, prolonged reliance on antibiotics can induce allergic reactions and exacerbate the risk of drug resistance. Therefore, the development of natural hydrogel dressings that are biocompatible, mechanically robust, and antibiotic-free remains a critical technological challenge. In this study, OHA/PVA/HCMC@NaHCO3 composite hydrogels were prepared using oxidized hyaluronic acid (OHA), hydrazine-containing carboxymethylcellulose (HCMC), polyvinyl alcohol (PVA), and sodium bicarbonate (NaHCO3) as the primary components. The high aldehyde content of OHA chemically crosslinked with hydrazine-containing HCMC formed acylhydrazine bonds, while physical crosslinking with PVA and NaHCO3 formed hydrogen bonds. The incorporation of PVA enhanced the mechanical strength of the hydrogel without compromising its high liquid absorption capacity. NaHCO3 imparts notable antibacterial and antioxidant properties to the composite hydrogel. These effects act synergistically with HA, promoting wound healing while preserving HA's intrinsic skin repair functionality. It exhibited potent antibacterial activity against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. In vitro analyses confirmed good biocompatibility and the ability to promote fibroblast proliferation and migration. In a rat full-thickness skin wound model, the OHA/PVA/HCMC@NaHCO3 hydrogel significantly accelerated wound closure, promoted epidermal regeneration, reduced inflammation, and enhanced collagen deposition and tissue remodeling. The drug-free, readily prepared OHA/PVA/HCMC@NaHCO3 composite hydrogels demonstrate promising potential for clinical application in the treatment of infected wounds.
Despite the progress made in the treatment of periprosthetic joint infections, identifying the causative pathogen remains a challenge. Optimal antibiotic therapy requires a confirmed diagnosis, which relies on two positive cultures for the same microorganism. Even though both can produce consistent results, there is little data on the combination of sonication fluid culture (SFC) with standard fluid and tissue cultures for the microbiology diagnosis. We hypothesized that this combination could increase the number of confirmed microbiology diagnoses. This was retrospective, descriptive, single-centre study of consecutive patients who underwent a complete change of their hip or knee prosthesis between January 2019 and September 2021 due to a suspected infection. We expected that at least 5% of patients would have the infectious role of a micro-organism confirmed with sonication. The effect of prior antibiotic therapy was analysed on a subset of patients. The analysis involved 223 patients with PJI diagnosis, 73 of whom had received antibiotics. The rate of confirmed microbiology diagnosis confirmed by one single positive sample culture plus SFC was 13.5% [9.6-18.6]. The rate was not significantly different in patients who had received antibiotic therapy (p = 0.960). According to our results, sonication could improve the rate of confirmed microbiology diagnosis of a PJI in our study, both in patients who previously received antibiotic therapy and in patients who had not yet been treated. This could make it a useful supplement to periprosthetic sampling in current practice.
Non-typhoidal Salmonella (NTS) bloodstream infections complicate Plasmodium falciparum (Pf) malaria infections in children under-five, but bacterial co-infections are often missed due to absence of microbiological diagnosis. We compared signs/symptoms and outcome of NTS bloodstream infection, severe Pf malaria and NTS-Pf malaria co-infections. In an area with high, stable Pf malaria transmission (Kongo Central, DR Congo), children (>28 days- <5 years) admitted to hospital with severe febrile illness were enrolled during 18 months (NCT04473768/NCT04850677). Data (in-hospital and 1-month post-discharge) were prospectively collected. NTS bloodstream infections and severe Pf malaria were diagnosed in 12% (331/2682) and 52% (1389/2682) of enrolled children, respectively. NTS-Pf co-infections occurred in 10% (264/2682) of enrolled children, i.e., Pf malaria co-infected 80% (264/330) of NTS bloodstream infections and NTS co-infected 6% (78/1389) of severe Pf malaria. In children with recent Pf malaria (i.e., HRP2-antigen persistence with negative microscopy), NTS occurred in 32% (173/545), making recent malaria a major risk factor for NTS (OR=5.85, p < 0.001). Compared to severe Pf malaria, age under-two (OR=2.19), > 3 days of fever (OR=3.28) and acute malnutrition (OR=2.20-3.48) were risk factors for NTS (p < 0.001) and NTS cases more often had hypoglycemia, grunting, hepato-/splenomegaly, jaundice or altered consciousness, but overall clinical presentation was not discriminative. In-hospital NTS case fatality was high (24% versus 3% in severe Pf malaria), occurred within 2 days of admission in 64% of deaths, and was preceded by general danger/sepsis signs. NTS cases had slower fever resolution, more frequent in-hospital fever recurrence, longer hospital stays, and more post-discharge deaths (n = 4) than severe Pf malaria cases. NTS and Pf malaria frequently co-infected children under-five. Severe Pf malaria and NTS bloodstream infections could not be distinguished clinically, but fatality rates were higher in NTS. Low thresholds for empirical NTS antibiotics and early danger sign recognition triggering sepsis care might improve outcome.
Aquaculture faces severe threats from bacterial disease outbreaks, creating an urgent need for safe, and sustainable alternatives to synthetic antibiotics and harmful chemicals. Alstonia scholaris (L.) R. Br. (Apocynaceae), widely recognized in traditional medicine for its therapeutic potential, has received limited attention in aquaculture. This study evaluated the antimicrobial potency of A. scholaris leaf extracts against key fish pathogens. The ethanolic extract showed promising broad-spectrum antibacterial potency and further bioassay-guided fractionation of it targeting Pseudomonas fluorescens led to putative identification of oleanolic acid as the principal bioactive constituent. The isolated compound exhibited broad-spectrum antibacterial activities against P. fluorescens, Streptococcus agalactiae, and Streptococcus iniae. Safety evaluation using zebrafish embryos demonstrated that the ethanolic extract caused no mortality at or below 125 µg/mL and was found non-teratogenic, while, the isolated compound exhibited no embryotoxicity up to 300 µg/mL concentration. This study reports the first identification of oleanolic acid from the ethanolic extract of A. scholaris leaves using bioassay-guided fractionation targeting P. fluorescens. These findings highlight the potential of the A. scholaris leaves ethanolic extract and its isolated active compound as safe, effective, and sustainable antimicrobial alternatives for bacterial disease management in aquaculture.
We report a man in his 90s who was referred to our pleural clinic with a left-sided moderate large pleural effusion. Despite the absence of systemic inflammatory features and normal serum inflammatory markers, pleural fluid microbiology was diagnostic of empyema. Initially, the patient was treated with a short course of antibiotics, as the clinical impression of the multidisciplinary team was that the presentation did not align with typical systemic inflammatory features of empyema. However, recurrence of the effusion after drainage led to further bacterial growth from repeat samples, ultimately clarifying the diagnosis. This illustrates how an attenuated systemic inflammatory response, consistent with immunosenescence, can complicate the diagnosis and management of pleural infection in elderly patients.
Amphiphilic aminoglycosides offer a promising approach to combat antibiotic resistant Gram-negative bacteria. Here, a series of neamine-based amphiphiles bearing alkyl chains of varying lengths (C4-C16) was synthesized via a concise route through selective modification at the 6'-amino position of neamine. Antibacterial evaluation revealed a chain length-dependent activity, with the C14- and C15-alkyl neamine amphiphiles exhibiting the most potent antibacterial activity against ESKAPE pathogens. The C15 derivative displayed superior activity compared to neamine and synergized with multiple clinical antibiotics against P. aeruginosa. Mechanistic studies indicated that this synergy results from enhanced outer membrane permeability, and cytotoxicity assays confirmed low toxicity at therapeutically relevant concentrations.
The widespread use and abuse of antibiotics have led to an increase in antibiotic resistance, and new methods and approaches are needed to combat bacterial infections. One promising alternative is to intervene early stage in the infection process. Adhesion is a prerequisite for bacteria to colonize on the cell surface. Various pathogenic Escherichia coli strains utilize carbohydrate-specific lectins to bind to specific glycoconjugate receptors on host cells for cell adhesion. The most important and best-studied bacterial lectins are FimH and PapG. Therefore, blocking the adhesion of bacteria to cells mediated by FimH and PapG through high-affinity carbohydrate antagonists is an extremely attractive therapeutic target. This paper systematically reviews the research progress of FimH and PapG inhibitors over the past two decades. For FimH-targeted mannoside antagonists, we elaborate the effects of glycosidic linkage types, aromatic substituent modification, conformational rigidification and multivalent structural design on binding affinity, metabolic stability and in vivo performance. Meanwhile, we outline the research framework of high-affinity PapG inhibitors based on galactose scaffolds. Classical optimization strategies, including terminal aromatic group modification, selective hydroxyl substitution and hydrophobic moiety incorporation, can effectively improve the binding affinity and isoform selectivity of PapG ligands. In addition, multivalent modification acts as a universally effective strategy for both FimH and PapG inhibitors. Furthermore, we prospect the rational design directions of anti-adhesive agents in the future, providing systematic theoretical reference and practical guidance for the subsequent structural optimization, pharmacological evaluation and clinical translation of FimH and PapG inhibitors.