Search Results (575)

Background and Objectives: Cancer patients are particularly susceptible to infections caused by multidrug-resistant Gram-negative bacteria (MDR GNB) due to chemotherapy- or radiation therapy-induced immunosuppression. Colistin is often prescribed as a last-resort agent for MDR GNB infection, but its clinical benefit in oncology patients remains unclear. This study aims to evaluate the mortality risk associated with colistin versus non-colistin regimens in cancer patient with MDR GNB infections, stratified by resistance profiles, infection sites, and concomitant medication use. Materials and Methods: A retrospective cohort study was conducted in adult cancer patients with MDR GNB infections that are resistant to at least three antibiotic classes and identified from at least two anatomical sites at a tertiary care hospital in Korea. Propensity score-matched in a 1:3 ratio either to the colistin group or non-colistin group and multivariate Cox hazard regression analyses were used to evaluate mortality in cancer patients with MDR GNB infections, primarily Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Results: A total of 85 patients (29 patients in the colistin and 56 patients in the non-colistin group) were included in the analysis. Overall, colistin use did not show a statistically significant mortality benefit compared to non-colistin regimens (hazard ratio (HR) 0.93, 95% CI 0.47–1.87). However, the subgroup analysis revealed that colistin had a potential association with significantly lower mortality in pneumonia patients with aminoglycoside-resistant infections (HR 0.04, 95% CI 0.002–0.69). Concomitant use of antipsychotics and benzodiazepines in selected resistance profiles also correlated with improved outcomes. In contrast, a potential association was found between concomitant macrolide use and increased mortality in patients with fluoroquinolone- or penicillin-resistant profiles. Conclusions: Colistin may offer survival benefits in selected high-risk cancer patients with MDR GNB pneumonia. Treatment outcomes are influenced by resistance profiles, infection sites, and concomitant medications, indicating the significant importance of individualized antimicrobial therapy and antimicrobial stewardship in oncology patients. Full article

Infections with multidrug-resistant (MDR) organisms remain a significant cause of morbidity and mortality among liver transplant recipients, despite advances in surgical techniques and immunosuppressive therapy. This prospective observational study aimed to evaluate the impact of targeted perioperative antibiotic prophylaxis against MDR Gram-negative bacteria on postoperative infections and mortality in liver transplant recipients. Seventy-nine adult patients who underwent liver transplantation and were admitted to the ICU for more than 24 h postoperatively were included. Demographics, disease severity scores, comorbidities, and lengths of ICU and hospital stay were recorded. Colonization with carbapenem-resistant Gram-negative bacteria was assessed via preoperative and postoperative cultures from the blood, urine, rectum, and tracheal secretions. Patients were divided into two groups: those with MDR colonization or infection who received targeted prophylaxis and controls who received standard prophylaxis. Infectious complications (30.4%) occurred significantly less frequently than non-infectious ones (62.0%, p = 0.005). The most common infections were bacteremia (22.7%), pneumonia (17.7%), and surgical site infections (2.5%), with most events occurring within 15 days post-transplant. MDR pathogens isolated included Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Although overall complication and mortality rates at 30 days and 3 months did not differ significantly between groups, the targeted prophylaxis group had fewer infectious complications (22.8% vs. 68.5%, p = 0.008), particularly bacteremia (p = 0.007). Infection-related mortality was also significantly reduced in this group (p = 0.039). These findings suggest that identification of MDR colonization and administration of targeted perioperative antibiotics may reduce septic complications in liver transplant patients. Further prospective studies are warranted to confirm benefits on outcomes and resource utilization. Full article

This study evaluated the antimicrobial efficacy of cefiderocol and various forms of silver (ionic and nanoparticulate) as potential components of wound-dressing reagents against both reference and multidrug-resistant (MDR) Gram-negative bacteria. The anticipated synergistic effect between cefiderocol and nanosilver was not consistently observed; in fact, for reference strains, the combination was less effective than cefiderocol alone. However, in MDR and cefiderocol-resistant A. baumannii strains, combining both agents enhanced antibacterial efficacy. Notably, the effectiveness of silver did not increase with concentration, and low or medium nanosilver concentrations were often more effective. Mechanistically, high concentrations of silver may antagonize cefiderocol’s action by inhibiting bacterial surface proteins involved in siderophore-mediated uptake. Generalized linear modeling confirmed that the strain type, silver form, concentration, and their interactions significantly influenced inhibition zones. These findings highlight the importance of agent selection, concentration, and formulation in designing effective antimicrobial wound dressings. They also suggest that further research is needed to optimize such combination therapies for clinical use. Full article

Background: Klebsiella variicola is a Gram-negative, capsulated, nonmotile, facultative anaerobic rod. It is one of the species belonging to the K. pneumoniae complex. The objective of this study was to gain insights into the antimicrobial resistance and virulence of K. variicola strains isolated from clinical samples from oncologic patients. Methods: Strain identification was performed using a mass spectrometry method. Whole genome sequencing was conducted for all analyzed strains. Antimicrobial susceptibility was determined using an automated method. The presence of antimicrobial resistance mechanisms and genes encoding extended-spectrum beta-lactamases (ESBL) was assessed using the double-disc synergy test and genotypic methods. Results: All isolates were identified as K. variicola using mass spectrometry and whole genome sequencing (WGS). All isolates were ESBL-positive, and two of them harbored the bla_CTX-M-15 gene. In our study, the bla_LEN-17 gene was detected in all strains. Genome sequence analysis of the K. variicola isolates revealed the presence of virulence factor genes, including entAB, fepC, ompA, ykgK, and yagWXYZ. Two different plasmids, IncFIB(K) and IncFII, were identified in all of the analyzed K. variicola strains. The detected virulence factors suggest the ability of the bacteria to survive in the environment and infect host cells. All isolates demonstrated in vitro susceptibility to carbapenems. Conclusions: Further studies are needed to confirm whether multidrug-resistant K. variicola strains represent an important pathogen in infections among oncologic patients. Full article

Determining the optimal duration of antibiotic therapy for infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) is a critical challenge in clinical medicine, balancing therapeutic efficacy against the risks of adverse effects and antimicrobial resistance. This narrative review synthesises current evidence and guidelines regarding antibiotic duration for MDR-GNB infections, emphasising bloodstream infections (BSI), hospital-acquired and ventilator-associated pneumonia (HAP/VAP), complicated urinary tract infections (cUTIs), and intra-abdominal infections (IAIs). Despite robust evidence supporting shorter courses (3–7 days) in uncomplicated infections caused by more susceptible pathogens, data guiding optimal therapy duration for MDR-GNB remain limited, particularly concerning carbapenem-resistant Enterobacterales (CRE), difficult-to-treat Pseudomonas aeruginosa (DTR-Pa), and carbapenem-resistant Acinetobacter baumannii (CRAB). Current guidelines from major societies, including IDSA and ESCMID, provide explicit antimicrobial selection advice but notably lack detailed recommendations on the duration of therapy. Existing studies demonstrate non-inferiority of shorter versus longer antibiotic courses in specific clinical contexts but frequently exclude critically ill patients or those infected with non-fermenting MDR pathogens. Individualised duration decisions must integrate clinical response, patient immunologic status, infection severity, source control adequacy, and pharmacologic considerations. Significant knowledge gaps persist, underscoring the urgent need for targeted research, particularly randomised controlled trials assessing optimal antibiotic duration for the most challenging MDR-GNB infections. Clinicians must navigate considerable uncertainty, relying on nuanced judgement and close monitoring to achieve successful outcomes while advancing antimicrobial stewardship goals. Full article

The increasing circulation of multi-drug-resistant pathogens, coupled with the sluggish development of new antibiotics, is weakening our capacity to combat human infections, resulting in elevated death tolls. To address this worldwide crisis, antimicrobial peptides (AMPs) are viewed as promising substitutes or adjuvants for combating bacterial infections caused by multidrug-resistant organisms. Here, the antimicrobial activity and structural characterization of a novel 13-amino acid cationic peptide named RKW (RKWILKWLRTWKK-NH2), designed based on known AMPs sequences and the identification of a key tryptophan-rich structural motif, were described. RKW displayed a broad-spectrum and potent antimicrobial and antibiofilm activity against Gram-positive and Gram-negative pathogens, including ESKAPE bacteria and fungi with minimal inhibitory concentrations (MBC) ranging from 5 µM to 20 μM. Structural results by fluorescence and Circular Dichroism (CD) spectroscopy revealed that the peptide was folded into a regular α-helical conformation in a membrane-like environment, remaining stable in a wide range of pH and temperature for at least 48 h of incubation. Furthermore, RKW showed low toxicity in vitro against mammalian fibroblast cells, indicating its potential as a promising candidate for the development of new antimicrobial or antiseptic strategies. Full article

The war between humans and bacteria started centuries ago. With the advent of antibiotics, there was a temporary ceasefire in this war, but the scenario soon started becoming worse with the emergence of drug-resistant strains within years of the deployment of antibiotics in the market. With the surge in the misuse of antibiotics, there was a drastic increase in the number of multidrug-resistant (MDR) and extensively drug-resistant bacterial strains, even to antibiotics like Methicillin and vancomycin, aggravating the healthcare scenario. The threat of MDR ESKAPE pathogens is particularly high in nosocomial infections, where biofilms formed by bacteria create a protective barrier that makes them highly resistant to antibiotics, complicating the treatment efforts. Scientists are looking at natural and sustainable solutions, as several studies have projected deaths contributed by drug-resistant bacteria to go beyond 50 million by 2050. Many plant-derived metabolites have shown excellent antibacterial and antibiofilm properties that can be tapped for combating superbugs. The present review explores the current status of various studies on antibacterial plant metabolites like alkaloids and flavonoids and their mechanisms in disrupting biofilms and killing bacteria by way of inhibiting key survival strategies of bacteria like motility, quorum-sensing, reactive oxygen species production, and adhesion. These mechanisms were found to be varied in Gram-positive, Gram-negative, and acid-fast bacteria like Mycobacterium tuberculosis, which will be discussed in detail. The successful tapping of the benefits of such plant-derived chemicals in combination with evolving techniques of nanotechnology and targeted drug delivery can go a long way in achieving the goal of One Health, which advocates the unity of multiple practices for the optimal health of people, animals, and the environment. Full article

Background: Canine pyoderma and otitis externa are prevalent bacterial skin infections in veterinary practice, frequently complicated by the emergence of multidrug-resistant (MDR) pathogens. Objectives: To investigate the frequency, antimicrobial resistance (AMR) profiles, and frequency of MDR bacterial isolates from dogs with pyoderma or otitis externa in Hong Kong. Methods: A retrospective study of bacterial isolates from 215 clinical samples collected from dogs presenting with pyoderma (n = 63) or otitis externa (n = 152) at veterinary clinics across Hong Kong between 2018 and 2022. Bacterial isolates were identified and subjected to antimicrobial susceptibility testing against 13 antimicrobial classes. Results: Staphylococcus spp., particularly S. pseudintermedius, were the most commonly isolated species, followed by Pseudomonas spp. and Proteus spp. High resistance rates were observed for orbifloxacin (61.3% in pyoderma; 76.7% in otitis externa), doxycycline (59.3%; 69.2%), clindamycin (62%; 68.9%), and enrofloxacin (50%; 55.5%). Most isolates were sensitive to ofloxacin, ticarcillin–clavulanate, tobramycin, ciprofloxacin, cefpodoxime, cefuroxime, and cefixime. MDR was detected in 67.5% of pyoderma and 66.8% of otitis externa isolates. Gram-negative bacteria exhibited significantly higher MDR rates than Gram-positive isolates. The multiple antibiotic resistance (MAR) index averaged 0.41 for pyoderma and 0.52 for otitis externa isolates. We found no significant associations between MDR and non-modifiable risk factors (i.e., age, sex, breed, and reproductive status). Conclusions: These findings highlight the critical need for prudent antimicrobial use and continuous surveillance of AMR trends in companion animals. A higher focus should be placed on topical antiseptic therapy, with oral antibiotics used only in exceptional cases and after susceptibility testing. From a One Health perspective, the potential transmission of MDR bacteria between companion animals and humans underscores the importance of a coordinated approach to antimicrobial stewardship across both veterinary and human medicine. Full article

Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: The favorable structural features from previous series were kept while the influence of the N-Boc-piperazinyl substituent per se, as well as its ring position and its replacement by various heteroaromatic rings, was evaluated. Thus, this paper describes the preparation of the MMV030666-derived 4′-(piperazin-1-yl)benzanilides for the first time, exhibiting broad-spectrum activity not only against plasmodia but also various bacterial strains. Results: A series of insightful structure–activity relationships were determined. Furthermore, pharmacokinetic and physicochemical parameters of the new compounds were determined experimentally or in silico. Drug-likeliness according to Lipinski’s rules was calculated as well. Conclusions: A diarylthioether derivative of the lead compound was promisingly active against P. falciparum and exhibited broad-spectrum antibacterial activity against Gram-positive as well as Gram-negative bacteria. It is considered for testing against multi-resistant bacterial strains and in vivo studies. Full article

Biofilm-associated infections caused by Gram-negative bacteria, especially multidrug-resistant strains, frequently occur in intensive care units and represent a major therapeutic challenge. The economic burden of biofilm-associated infections is considerable, making the search for new treatment approaches a focal point for policymakers and scientific funding bodies. Biofilm formation is regulated by quorum sensing (QS), a population density-dependent communication mechanism between cells mediated by small diffusible signaling molecules. QS modulates various intracellular processes, and some features of QS are common to all Gram-negative bacteria. While there are differences in the QS regulatory networks of different Gram-negative bacterial species, a common feature of most Gram-negative bacteria is the ability of N-acylhomoserine lactones (AHL) as inducers to diffuse across the bacterial membrane and interact with receptors located either in the cytoplasm or on the inner membrane. Targeting QS by inhibiting the synthesis, transport, or perception of signaling molecules using small molecules, quorum quenching enzymes, antibodies, combinatorial therapies, or nanoparticles is a promising strategy to combat virulence. In-depth knowledge of biofilm biology, antibiotic susceptibility, and penetration mechanisms, as well as a deep understanding of anti-QS agents, will contribute to the development of antimicrobial therapies to combat biofilm infections. Advancing antimicrobial therapies against biofilm infections requires a deep understanding of biofilm biology, antibiotic susceptibility, penetration mechanisms, and anti-QS strategies. This can be achieved through in vivo and clinical studies, supported by state-of-the-art tools such as machine learning and artificial intelligence. Full article

Background: The global rise of multidrug-resistant Gram-negative bacteria, particularly non-fermenting species and carbapenemase-producing Enterobacteriaceae, poses a significant challenge to hospital infection control. Methods: In this study, a total of 89 Acinetobacter spp. isolates, 14 Pseudomonas aeruginosa, and 14 carbapenem-resistant Enterobacteriaceae isolates were collected from patients in a tertiary hospital. Whole-genome sequencing and antimicrobial susceptibility testing were conducted. Resistance mechanisms and evolutionary relationships were analyzed using phylogenetic analysis and genetic context mapping. Results: Among the non-fermenting isolates, A. baumannii exhibited high resistance to carbapenems, clustering into distinct clonal groups enriched with genes associated with biofilm formation and virulence genes. P. aeruginosa isolates harbored fewer resistance genes but carried notable mutations in the efflux pump systems and the oprD gene. In Enterobacteriaceae, four bla_NDM alleles were identified within a conservative structural sequence, while bla_KPC-2 was located in a non-Tn4401 structure flanked by IS481- and IS1182-like insertion sequences. Phylogenetic analysis revealed that bla_NDM-positive E. coli strains were closely related to susceptible lineages, indicating horizontal gene transfer. Conversely, K. pneumoniae isolates harboring bla_KPC-2 formed a tight clonal cluster, suggesting clonal expansion. Conclusions: The study reveals distinct transmission patterns between resistance genes: horizontal dissemination of bla_NDM and clonal expansion of bla_KPC-2 in K. pneumoniae. These findings emphasize the need for resistance-gene-specific genomic surveillance and infection control strategies to prevent further nosocomial dissemination. Full article

Background/Objectives: Antibiotic resistance is a significant and escalating challenge that limits available therapeutic options. This issue is further exacerbated by the decreasing number of new antibiotics being developed. Our study aims to describe the epidemiology and pattern of antibiotic resistance in Gram-negative infections isolated from a cohort of hospitalized patients and to analyze the distribution of infections within the hospital setting. Methods: A retrospective study was conducted on all patients admitted to Vito Fazzi Hospital in Lecce, Italy, who required an infectious disease consultation due to the isolation of Gram-negative bacteria from 1 January 2018 to 31 December 2022. Results: During the study period, 402 isolates obtained from 382 patients (240 men and 142 women) with infections caused by Gram-negative bacteria were identified. Among these isolated, 226 exhibited multidrug resistance, defined as resistance to at least one antimicrobial agent from three or more different classes. In 2018, the percentage of multidrug-resistant isolates peaked at 87.6%, before decreasing to the lowest level (66.2%) in 2021. Overall, of the 402 isolates, 154 (38.3%) displayed resistance to carbapenems, while 73 (18.1%) were resistant to extended-spectrum beta-lactamases (ESBLs). Among the resistant microorganisms, Klebsiella pneumoniae showed the highest resistance to carbapenems, accounting for 85.2% of all resistant strains. Escherichia coli exhibited the greatest resistance to ESBLs, with a rate of 86.7%. Among carbapenem-resistant K. pneumoniae isolates, the following resistance rates were observed: KPC-1 at 98.2%, IMP-1 at 0.9%, VIM-1 at 0.9%, and NDM-1 at 0.9%. Conclusions: Patients with infections caused by multidrug-resistant bacteria have limited treatment options and are therefore at an increased risk of death, complications, and longer hospital stays. Rapid diagnostic techniques and antimicrobial stewardship programs—especially for ESBLs and carbapenemases—can significantly shorten the time needed to identify the infection and initiate appropriate antimicrobial therapy compared to traditional methods. Additionally, enhancing surveillance of antimicrobial resistance within populations is crucial to address this emerging public health challenge. Full article

Neonatal sepsis is a major cause of morbidity and mortality in neonates. A particular concern is the increasing prevalence of antibiotic-resistant strains among neonatal intensive care units (NICUs). Two novel beta-lactam/beta-lactamase inhibitors have recently been approved for use in neonates with multidrug-resistant infections: ceftazidime/avibactam and ceftolozane/tazobactam. These agents demonstrate efficacy against a range of multidrug-resistant gram-negative pathogens, including extended-spectrum beta-lactamases (ESBL)-producing and carbapenem-resistant Enterobacterales, as well as multidrug-resistant Pseudomonas aeruginosa. This narrative review aims to summarize the current knowledge concerning the utilization of ceftazidime/avibactam and ceftolozane/tazobactam in the NICU. According to the existing literature, both agents have been shown to be highly effective with a favorable safety profile in the neonatal population. Full article

Background/Objectives: The increasing prevalence of multidrug-resistant bacteria presents a major global health challenge, prompting a search for innovative antimicrobial strategies. This study aimed to develop and evaluate a novel nanobiostructure combining alumina nanoparticles (NPs) with the antimicrobial peptide lunatin-1 (Lun-1), forming peptide-functionalized nanofilaments. The main objective was to investigate how the site of peptide functionalization (C-terminal vs. N-terminal) affects membrane interactions and antibacterial activity. Methods: NP–peptide conjugates were synthesized via covalent bonding between lun-1 and alumina NP and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), zeta potential analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR), and solid-state ¹³C NMR. Antibacterial activities were assessed against different Gram-positive and Gram-negative strains. Biophysical analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and solid-state ²H NMR, were employed to evaluate peptide–membrane interactions in the presence of membrane-mimetic vesicles composed of POPC:POPG (3:1) and DMPC:DMPG (3:1). Results: Characterization confirmed the successful formation of NP–peptide nanofilaments. Functionalization at the N-terminal significantly influenced both antibacterial activity and peptide conformation compared to C-terminal attachment. Biophysical data demonstrated stronger membrane interaction and greater membrane disruption when lun-1 was conjugated at the N-terminal. Conclusions: The site of peptide conjugation plays a crucial role in modulating the biological and biophysical properties of NP–lunatin-1 conjugates. C-terminal attachment of lunatin-1 retains both membrane interaction and antibacterial efficacy, making it a promising strategy for the design of peptide-based nanotherapeutics targeting resistant pathogens. Full article

Vancomycin, a cornerstone antibiotic against severe Gram-positive infections, is increasingly challenged by resistance in Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin Enterococcus spp. (VRE), necessitating the development of novel therapeutic strategies. This review examines how structural modifications to vancomycin can enhance its antibacterial activity and explores the critical role of computational approaches in designing the next generation of analogs. By analyzing the existing literature, we highlight how strategic alterations, such as the introduction of lipophilic side chains, substitutions on the sugar moieties, and modifications to the aglycone core, have yielded derivatives with improved antibacterial potency. Notably, certain analogs (e.g., Vanc-83, Dipi-Van-Zn) have demonstrated expanded activity against Gram-negative bacteria and exhibited enhanced pharmacokinetic profiles, including prolonged half-lives and improved tissue penetration, crucial for effective treatment. Semisynthetic glycopeptides like telavancin, dalbavancin, and oritavancin exemplify successful translation of structural modifications, offering sustained plasma concentrations and simplified dosing regimens that improve patient compliance. Complementing these experimental efforts, computational methods, including molecular docking and molecular dynamics simulations, provide valuable insights into drug–target interactions, guiding the rational design of more effective analogs. Furthermore, physiologically based pharmacokinetic modeling aids in predicting the in vivo behavior and optimizing the pharmacokinetic properties of these novel compounds. This review highlights a critical path forward in the fight against multidrug-resistant infections. By meticulously examining the previously carried out structural refinement of vancomycin, guided by computational predictions and validated through rigorous experimental testing, we underscore its immense potential. Full article