Search Results (857)

Pulmonary hypertension complicating chronic obstructive pulmonary disease (COPD-PH) has a worse prognosis than airflow limitation alone but its pathogenesis is thought to be primarily due to alveolar hypoxia affecting pulmonary circulation. Two observations are not fully explained by this model. First, the majority of exacerbations of COPD are infectious and there is a stable frequent-exacerbator phenotype that is not fully accounted for by spirometric severity. Second, the airways of COPD are not sterile. They are home to a resident microbial community that changes as the disease progresses and the gut microbial community also undergoes disease-associated changes. This review examines whether microbial factors actively contribute to pulmonary vascular remodelling or merely reflect advanced disease. Three candidate exposures are considered: chronic airway colonisation, dysbiosis of the airway and gut communities and recurrent infectious exacerbation. We then examine the virulence mechanisms and host-recognition pathways of non-typeable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Pseudomonas aeruginosa, rhinovirus, influenza viruses, respiratory syncytial virus and SARS-CoV-2. We then trace the pathways linking microbial recognition to vascular injury: Toll-like receptor signalling and NF-κB activation; interleukin-6, tumour necrosis factor-α and interleukin-1β; endothelin-1 upregulation against nitric oxide depletion; reactive oxygen species and hypoxia-inducible factor signalling converging with hypoxic pulmonary vasoconstriction; and, along the gut–lung axis, lipopolysaccharide translocation, trimethylamine N-oxide and depletion of short-chain fatty acid-producing taxa. Therapeutically, there is evidence and a vascular rationale for interventions that decrease exacerbation frequency. Pulmonary vasodilators have a sound physiological rationale, although their clinical efficacy is frequently limited by worsening ventilation–perfusion mismatch. Current evidence supports biological plausibility rather than demonstrated causality: no direct longitudinal human study has established that microbial alterations or microbial exposure cause pulmonary vascular remodelling in COPD-PH. We identify study designs capable of directly testing this hypothesis. Full article

Antimicrobial resistance is now documented in a substantial proportion of laboratory-confirmed bacterial infections worldwide, and although the most extreme extensively drug-resistant (XDR) and pandrug-resistant (PDR) phenotypes are concentrated among Gram-negative bacilli, resistance in Gram-positive cocci continues to rise and remains a major determinant of outcomes in severe infection. This structured comprehensive narrative review, based on a documented search of PubMed/MEDLINE, Scopus and Web of Science to June 2026, is confined to the three Gram-positive cocci of greatest clinical importance—Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecium—and summarises current global and European surveillance data for this organisms, describes the principal molecular mechanisms responsible for resistance to β-lactams, glycopeptides, fluoroquinolones, oxazolidinones, lipopeptides, tetracyclines, folate-pathway inhibitors, macrolides–lincosamides–streptogramins and aminoglycosides, and reviews the therapeutic options and investigational agents that may extend the treatment repertoire against multidrug-resistant (MDR) Gram-positive cocci. Surveillance indicators for the three species are compared side by side, and the agents discussed are separated according to whether they are licensed, clinically evaluated but not widely licensed, or still preclinical. Its scope is deliberately narrower than that of pan-bacterial accounts of antimicrobial resistance: it concentrates on the determinants that routine molecular confirmation does not detect, on the divergent pathogen-specific trajectories visible in recent surveillance, and on the distinction between agents supported by randomised evidence and those still at the discovery stage. Our review is structured rather than systematic; the PRISMA 2020 flow diagram is used as a reporting template only, and no claim of PRISMA compliance is made. Full article

Antimicrobial resistance and the formation of biofilms in Gram-positive pathogens such as Streptococcus pneumoniae and Staphylococcus aureus are making the treatment of infections increasingly difficult. This study systematically evaluates the effect of gliotoxin (GT), an antimicrobial metabolite produced by Aspergillus fumigatus, on bacterial growth and biofilm formation, as well as its activity in combination with antibiotics. Three strains of S. pneumoniae and two strains of S. aureus (one methicillin-susceptible and one methicillin-resistant) were analysed. Planktonic growth was examined, and biofilm prevention assays were conducted by assessing biomass via crystal violet staining and viable cell counts. In addition, the combined effect of GT with cefotaxime and vancomycin was evaluated. GT inhibited planktonic growth and significantly reduced the biomass and viability of biofilms in a concentration-dependent manner. Moreover, its combination with conventional antibiotics (cefotaxime or vancomycin) showed strong synergy, drastically decreasing bacterial survival. These findings highlight the potent antibacterial and anti-biofilm activity of GT and its ability to enhance antibiotic efficacy, providing insight into fungal–bacterial interactions and suggesting potential therapeutic applications. Full article

Blood cultures are frequently obtained in hospitalized patients with COVID-19, although the diagnostic yield and clinical meaning of culture positivity vary markedly according to case mix, disease severity, and timing of sampling. Omicron-era data remain comparatively limited. We aimed to characterize blood-culture positivity, pathogen distribution, inflammatory correlates, antimicrobial exposure, and short-term outcomes in a homogeneous cohort hospitalized during the SARS-CoV-2 Omicron BA.5 wave. This retrospective observational study included 395 patients hospitalized with SARS-CoV-2 infection between 12 July and 25 September 2022. Patients were categorized as blood-culture positive when a named bacterial species was recorded and as culture negative when “No growth” was documented. Continuous variables were compared using the Mann–Whitney U test and categorical variables using Fisher’s exact or chi-square tests, as appropriate. A parsimonious multivariable logistic regression model was used to explore factors independently associated with blood-culture positivity. Blood cultures were positive in 89/395 patients (22.5%). Gram-positive organisms accounted for 52.8% of positive cultures and Gram-negative organisms for 47.2%. The most frequent isolates were Streptococcus pneumoniae (20.2% of positive cultures), Enterococcus faecalis (18.0%), Klebsiella pneumoniae (18.0%), Staphylococcus aureus (14.6%), Escherichia coli (14.6%), and Pseudomonas aeruginosa (14.6%). Compared with patients with no growth, those with positive cultures had higher admission leukocyte counts (median 13.42 vs. 11.22 × 10⁹/L; p < 0.001), C-reactive protein (116.15 vs. 105.50; p = 0.007), and interleukin-6 (17.24 vs. 9.39; p = 0.027). A documented sepsis diagnosis was more frequent in the culture-positive group (48.3% vs. 28.1%; OR 2.39, 95% CI 1.47–3.88; p < 0.001). Mortality was numerically higher with culture positivity (20.2% vs. 14.4%) but did not reach statistical significance (p = 0.188). In the adjusted model, higher leukocyte count remained independently associated with culture positivity (aOR 1.10 per 1 × 10⁹/L, 95% CI 1.05–1.15; p < 0.001), while vaccination status showed an inverse exploratory association (aOR 0.58, 95% CI 0.35–0.96; p = 0.033). The exploratory model AUC was 0.672 (bootstrap 95% CI 0.608–0.731); calibration was not assessed. Blood-culture positivity was common in this hospitalized BA.5 cohort and showed a nearly balanced Gram-positive/Gram-negative distribution. Leukocytosis and clinically documented sepsis were the clearest correlates of positivity, whereas mortality did not differ significantly. These findings support selective blood-culture use driven by bacterial infection signals and emphasize the need to connect antimicrobial decisions to microbiological evidence. Full article

Bacterial pneumonia in horses typically occurs secondary to predisposing factors that compromise defence mechanisms. This 10-year retrospective study evaluated bacterial pneumonia in 81 horses treated at the equine clinic of Freie Universität Berlin from January 2015 to December 2024. Horses infected with primary pathogens such as Rhodococcus equi or Streptococcus equi ssp. equi were not included in the study. The most common predisposing events were aspiration, mainly following oesophageal obstruction (37.0%), post-anaesthetic disease (27.2%), primary respiratory signs (24.7%), and other conditions (11.1%). Horses with aspiration were significantly older than the “other” groups. Tachypnoea, tachycardia, and fever were common but not universal. Bronchopneumonia was the most frequent diagnosis overall and predominated after aspiration, whereas pleuropneumonia was more common after general anaesthesia and in horses with primary respiratory signs. Bacteriological examinations were performed in 51 horses. Mixed infections were common, and Streptococcus equi ssp. zooepidemicus was frequently isolated. Resistant isolates were detected in most tested cases, and multidrug resistance was especially common in post-anaesthetic horses. Overall survival to discharge was 77.8% and did not differ significantly between predisposing events. However, initial lymphopenia, pleural effusion, and the need for thoracic drainage were associated with reduced survival. Anaerobic bacterial isolation, pulmonary abscessation, and diagnosis were associated with readmission because of respiratory signs. Most survivors had acceptable long-term outcomes, although recurrent respiratory signs were common. Full article

Background: Developing molecular tools for the diagnosis of bacterial meningitis is crucial for improving the diagnosis and initiation of prompt treatment of patients. This study aimed to evaluate the diagnostic performance of cerebrospinal fluid and serum multiplex PCR compared with conventional diagnostic methods for detecting bacterial pathogens among patients clinically suspected of bacterial meningitis. Methods: A cross-sectional study was conducted at Tikur Anbessa Specialized Hospital and Yekatit 12 Hospital Medical College from August 2023 to February 2024. A total of 202 patients who were suspected of having meningitis were included in the study. Conventional laboratory analysis, including Gram staining and bacterial culture from CSF, was performed. CSF and serum PCR for the detection of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus agalactiae, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, and Klebsiella pneumoniae were performed. The agreement between tests used to detect etiologic agents of bacterial meningitis was determined by McNemar’s Test and Cohen’s kappa statistic. Results: Of the 202 study participants, 109 (54.0%) were male, and 178 (88.1%) were pediatric, with the majority being infants (mean age: 1.45 ± 0.69 years). Poor feeding was the most common clinical presentation at 151/202 (74.8%), followed by high fever at 144/202 (71.3%), and loss of consciousness at 134/202 (66.3%). Among the 202 CSF samples, nine (4.5%) and 11 (5.4%) tested positive for culture and Gram stain, respectively. Bacterial DNA was detected in 54/202 (26.7%) of the CSF samples and 93/202 (46.0%) of the serum samples. E. coli was detected in 30/54 (55.5%) of CSF samples and 57/93 (61.2%) of serum samples, followed by S. pneumoniae, which was detected in 8/54 (14.8%) of CSF samples and 27/93 (29.0%) of serum samples. The overall agreement between CSF and serum PCR is 60.9% (123/202), with a positive percent agreement of 62.96% (34/54), and a negative percent agreement of 60.14% (89/148). McNemar’s test indicated a significant difference between the two tests (p < 0.0001), and Cohen’s kappa statistic showed slight agreement (κ = 0.188, 95% CI: 0.109–0.293). Conclusions: Bacterial DNA was detected more often in serum multiplex PCR than CSF PCR or culture, suggesting its potential role as a complementary diagnostic tool for epidemiological surveillance, particularly in resource-limited settings where lumbar puncture may not always be feasible. However, serum PCR should not replace CSF analysis for definitive diagnosis; rather, it can serve as a screening or surveillance tool, with positive results requiring clinical correlation and, where possible, CSF confirmation. A relatively small sample size, reliance on conventional PCR, absence of comparison with quantitative PCR, potential blood contamination, lack of sequencing, and lack of long-term outcome data limit the generalizability of our findings. Future investigations should include a large sample size in conjunction with confirmatory culture techniques to enhance the robustness and validity of the findings. Full article

Sortase A (SrtA) enzymes covalently anchor surface proteins to Gram-positive bacterial cell walls, promoting colonization and virulence. In Streptococcus pneumoniae, previous studies identified both a domain-swapped dimer and an active refolded monomer, but the active enzyme has not been characterized at the structural and residue-specific level. Here, we performed quantitative proteomic comparisons of wild-type and SrtA knockout strains that confirmed the loss of multiple LPxTG-containing virulence factors, including ZmpB, NanA, and IgA1 protease, consistent with an essential role for SrtA in surface protein anchoring. To enable mechanistic studies, we established a biochemical framework to produce monomeric Streptococcus pneumoniae SrtA by refolding and developed a gel-based assay using recombinant substrates to monitor catalytic activity. The refolded monomer, but not the swapped dimer, catalyzed cleavage and transpeptidation of a canonical LPxTG substrate in a metal-independent manner under the conditions examined. We further report high-resolution NMR backbone assignments for the active monomer and identify substrate-induced chemical shift perturbations that localize to the active site. Together, these findings provide an integrated proteomic, biochemical, and NMR characterization of monomeric, catalytically active Streptococcus pneumoniae SrtA and reveal residue-specific interactions with a canonical LPNTG recognition peptide. Full article

Background: Antimicrobial resistance (AMR) is among the most pressing challenges in modern infectious medicine, driving progressive failure of standard antibacterial therapy and rising mortality from infections caused by multidrug-resistant (MDR) pathogens. Antibiotic potentiation through adjuvant compounds capable of restoring the activity of existing drugs represents a promising strategy to overcome resistance without developing fundamentally new antibacterial molecules. This study aimed to evaluate the antibiotic-potentiating activity of a dextrin/polyvinyl alcohol/iodine complex (D/PVA/I-1), developed at the Scientific Center for Anti-Infectious Drugs JSC (Almaty, Kazakhstan), against clinically relevant MDR reference strains. Methods: Nine reference strains, Staphylococcus aureus (ATCC 33591, BAA-39), Escherichia coli (ATCC BAA-196, BAA-2523), Klebsiella pneumoniae (ATCC BAA-2524, 700603), Acinetobacter baumannii (ATCC BAA-1790), Streptococcus pneumoniae (ATCC BAA-660), and Haemophilus influenzae (ATCC 33930), and two clinical isolates, P. aeruginosa SCAID PHRX1-2019 and E. coli SCAID WND1-2021, were tested. Antibiotic-potentiating activity was assessed by checkerboard assay with calculation of the fractional inhibitory concentration index (FICI); bactericidal kinetics were evaluated by time-kill analysis. The effect of D/PVA/I-1 on cytoplasmic membrane permeability was investigated using a crystal violet uptake assay. Results: Of 45 D/PVA/I-1–antibiotic combinations tested across nine antibiotics, synergy (FICI ≤ 0.5) was demonstrated in 44.4% of cases, partial synergy in 48.9%, and additive effects in 6.7%; no antagonistic interactions were detected. The most pronounced potentiating effect occurred against Gram-positive pathogens, particularly MRSA strains (66.7% synergistic combinations). Time-kill analysis confirmed suppression of the regrowth phenotype characteristic of MDR strains under monotherapy and restoration of bactericidal activity against antibiotics to which strains exhibited intrinsic resistance. D/PVA/I-1 induced a dose- and time-dependent increase in membrane permeability in both Gram-positive and Gram-negative organisms. Conclusions: D/PVA/I-1 is an effective broad-spectrum antibiotic potentiator and represents a promising basis for combination therapy regimens against MDR infections. Full article

The mitigation measures adopted to reduce the spread of COVID-19 have not only impacted the transmission of respiratory infections but also other infectious diseases. In this study, we explored the effect of the pandemic on the epidemiology of Central Nervous System (CNS) infections by conducting a retrospective analysis of diagnostic data obtained from cerebrospinal fluids (CSFs) collected before, during, and after the pandemic from patients with acute-suspected neuro-infectious syndrome. The samples were analyzed using a meningitis/encephalitis molecular syndromic panel. A total of 4203 CSFs were split into three groups: pre-pandemic (August 2018–February 2020), pandemic (March 2020–March 2022) and post-pandemic (April 2022–March 2024). Each pathogen was statistically assessed individually, comparing one group vs. another. Results showed that viral pathogens were the most frequently detected across all groups; however, Streptococcus pneumoniae was the single most identified pathogen. Comparison of the pre-pandemic and pandemic groups by statistical analysis showed a significant reduction in neuro-infections caused by enterovirus, S. pneumoniae and N. meningitidis, while the other pathogens were not affected. In conclusion, a reduction in CNS infections caused by respiratory and close-contact-transmitted pathogens, including both viral and bacterial agents, was observed during the period when COVID-19 containment measures were in effect. Full article

Although most upper respiratory tract infections (URTIs) have a viral etiology, antibiotics are widely prescribed, thus contributing substantially to antimicrobial resistance. This study investigated the potential beneficial effects of a novel strain, Limosilactobacillus reuteri LMG P-27481, against major URT pathobionts (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae) with the aim of reducing or delaying antibiotic use. Antibacterial and immunomodulatory activities were evaluated using L. reuteri alone or combined with resveratrol, a natural compound with antiviral and anti-inflammatory properties. Both agents inhibited pathogen growth, while their combination showed additive antibacterial activity, particularly against Gram-negative bacteria. Antioxidant assays demonstrated significant antioxidant capacity for both agents, with enhanced effects in combination in NBT and ABTS assays but antagonistic in ORAC. Immune mediators (IL-6, IL-8, IL-1β, TNF-α, IL-25, IL-33, CCL17, CCL22) were assessed in epidermal, epithelial, and macrophage cell lines, together with epidermal integrity markers (Filaggrin, Loricrin, Involucrin) in a 3D reconstructed human skin model (EpiDermFT^TM). L. reuteri, resveratrol, and their combination exerted cell-specific effects in the different models, modulating cytokine expression and production, and barrier integrity. Our findings support the potential efficacy of oral L. reuteri LMG P-27481 plus resveratrol in URTIs. Full article

Early, rapid, and accurate detection is essential for clinical management and epidemiological control of acute respiratory infections caused by pathogens. Traditional testing methods such as microbial culture, serological testing, and PCR are restrictive in terms of operation and logistics and are therefore not easily used in point-of-care settings. The CRISPR/Cas system is an adaptive prokaryotic immune system composed of clustered regularly interspaced short palindromic repeats and their associated proteins, which has been used as a nucleic acid diagnostic platform with programmable sequence-specific target recognition and signal-amplifying collateral cleavage activity. Existing reviews have mostly focused on the classification of Cas enzymes or amplification strategies; in this review, a pathogen-centric approach was taken, covering viral pathogens (SARS-CoV-2, influenza virus, RSV, HAdV and VZV), bacterial pathogens (Mycobacterium tuberculosis, Streptococcus pneumoniae, Mycoplasma pneumoniae and Staphylococcus aureus) and fungal pathogens (Aspergillus fumigatus and Pneumocystis jirovecii). Key technological advances, such as isothermal amplification coupling, single-vessel integrated reaction designs, amplification-free digital detection, and electrochemical biosensor integration, are evaluated for Cas9-, Cas12-, and Cas13-based systems, with their mechanistic bases outlined. The current challenges that hinder clinical translation, such as sample matrix interference, multiple signal cross-talk, crRNA off-target effects, and the lack of large-scale validation studies, are critically assessed. At the same time, future pathways for portable, integrated, and inexpensive diagnostic platforms are suggested. Full article

Co-infection between influenza and Streptococcus pneumoniae is an important public health concern, since influenza can increase susceptibility to secondary bacterial invasion and enhance bacterial transmission. We develop and analyze a compartmental model of influenza–pneumococcal co-infection with eleven epidemiological compartments, incorporating imperfect vaccination, quarantine, and a three-stage pneumococcal progression from colonization to invasive disease. We establish the positivity and boundedness of solutions, determine the equilibria, and derive, via the next-generation matrix method, the sub-model reproduction numbers $R_0^I$ and $R_0^P$ together with the composite threshold $R_0=max\{R_0^I,R_0^P\}$. Each single infection undergoes a forward bifurcation: the disease-free equilibrium is locally asymptotically stable when the corresponding reproduction number is below unity, and a unique endemic equilibrium—globally asymptotically stable in the pneumococcal sub-model, established by a Goh–Volterra Lyapunov function—emerges above it. When both thresholds exceed unity, the two infections compete for the shared susceptible pool and undergo competitive exclusion: one infection persists while the other, together with the co-infected class, is eliminated. We show that the outcome is governed not by the disease-free reproduction numbers but by the invasion reproduction numbers evaluated at the single-infection boundary equilibria, so that even equal disease-free thresholds do not yield coexistence. Numerical simulations confirm the analytical results and quantify the effect of quarantine and vaccination, providing a framework for assessing control of interacting respiratory infections. Full article

Species of the genus Streptococcus constitute important pathogens in human and veterinary medicine, being responsible for a wide spectrum of infections ranging from mild illnesses to severe invasive pathologies. Although β-lactams continue to be effective against most species, the global increase in resistance to macrolides, lincosamides, tetracyclines, and, in some cases, reduced susceptibility to penicillin represents a growing challenge for antimicrobial therapy. This review synthesizes the clinical and epidemiological landscape of antimicrobial resistance in the main Streptococcus species, including Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus dysgalactiae, and other species of clinical and veterinary relevance, addressing their epidemiological profiles, molecular mechanisms of resistance, and virulence factors. The main genetic determinants involved in resistance are discussed, namely the erm, mef, and tet genes, as well as the impact of alterations in penicillin-binding proteins, horizontal gene transfer, and biofilm formation on the persistence of infections and decreased therapeutic efficacy. Simultaneously, the main virulence factors are analyzed, including polysaccharide capsules, adhesins, toxins, extracellular enzymes, and immune response evasion mechanisms that contribute to the colonization, dissemination, and severity of infections. The importance of epidemiological and genomic surveillance, particularly through whole-genome sequencing, in monitoring the spread of resistant clones and identifying determinants of resistance and virulence is also highlighted. Taken together, the data highlight the need to strengthen programs for the rational use of antimicrobials, to promote integrated surveillance strategies from a One Health perspective, and to deepen knowledge about the interaction between antimicrobial resistance and virulence, in order to improve strategies for the prevention, diagnosis, and treatment of infections caused by Streptococcus spp. Full article

Streptococcus pneumoniae is the major causative agent of community-acquired pneumonia, one of the main infectious diseases that causes inflammation in the alveoli and leads to significant morbidity and mortality across various age groups. Current treatments are challenged by multidrug-resistant strains of S. pneumoniae, which has led to the reemergence of pneumonia in recent years; therefore, it is pivotal to identify new drug targets. The enzyme chorismate synthase (CS), involved in the shikimate pathway of S. pneumoniae, aids in the synthesis of vital aromatic amino acids and other metabolites required for bacterial viability. The present study identifies natural compounds that can inhibit CS using an in silico approach, including pharmacophore modeling, virtual screening, molecular docking, ADME analysis, and molecular dynamics (MD) simulations. Our results suggest that the identified compounds can bind effectively to the active site of S. pneumoniae CS (SpCS), exhibiting affinities better than the known inhibitor 1-benzofuran-3-one and close to the enzyme’s natural substrate, 5-enolpyruvylshikimate-3-phosphate (EPSP). This study suggests lead natural compounds as promising candidates for further investigation as potential inhibitors for the treatment of pneumonia, offering a novel strategy to combat this resilient pathogen. Full article

Antimicrobial resistance (AMR) in respiratory infections represents a major global health challenge, compounded by biological barriers that limit the effectiveness of conventional antibiotics, including mucus hypersecretion, biofilm formation, and intracellular pathogen persistence. Nanotechnology has emerged as a promising platform for addressing these limitations through advanced drug-delivery strategies. This narrative review provides an integrated overview of nanocarrier systems—including lipid-based (e.g., liposomes, solid lipid nanoparticles), polymeric (e.g., PLGA, chitosan), and inorganic nanoparticles (e.g., silver, gold, zinc oxide)—with emphasis on their pharmaceutical design parameters for pulmonary delivery. Key mechanisms by which nanotechnology enhances antimicrobial efficacy include targeted and controlled drug delivery, improved penetration of mucus and biofilms via surface engineering, synergistic combination therapies, and intrinsic antimicrobial activity through mechanisms such as reactive oxygen species generation. Preclinical studies targeting major respiratory pathogens, including Pseudomonas aeruginosa, Mycobacterium tuberculosis, Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus, demonstrate enhanced biofilm disruption, intracellular drug delivery, and reductions in bacterial burden. However, important translational challenges remain, including long-term safety, manufacturing scalability, regulatory complexity, and the potential for microbial adaptation. Future directions focus on stimuli-responsive systems, inhalable formulations, and biomimetic platforms to improve targeting and therapeutic precision. Collectively, nanotechnology represents a delivery-oriented strategy with the potential to enhance existing antimicrobial therapies and support the development of more effective interventions against resistant respiratory infections. Full article