Multidrug-resistant Infections Research Articles

Negatively charged nanodiscs for the reduction of toxicity and enhanced efficacy of polymyxin B against Acinetobacter baumannii sepsis

The treatment of sepsis caused by multidrug-resistant (MDR) Gram-negative bacterial infections remains challenging. With these pathogens exhibiting resistance to carbapenems and new generation cephalosporins, the traditional antibiotic polymyxin B (PMB) has reemerged as a critical treatment option. However, its severe neurotoxicity and nephrotoxicity greatly limit the clinical application. Therefore, we designed negatively charged high-density lipoprotein (HDL) mimicking nanodiscs as a PMB delivery system, which can simultaneously reduce toxicity and enhance drug efficacy. The negative charge prevented the PMB release in physiological conditions and binding to cell membranes, significantly reducing toxicity in mammalian cells and mice. Notably, nanodisc-PMB exhibits superior efficacy than free PMB in sepsis induced by carbapenem-resistant Acinetobacter baumannii (CRAB) strains. Nanodisc-PMB shows promise as a treatment for carbapenem-resistant Gram-negative bacterial sepsis, especially caused by Acinetobacter baumannii, and the nanodiscs could be repurposed for other toxic antibiotics as an innovative delivery system. Statement of significanceMultidrug-resistant Gram-negative bacteria, notably carbapenem-resistant Acinetobacter baumannii, currently pose a substantial challenge due to the scarcity of effective treatments, rendering Polymyxins a last-resort antibiotic option. However, their therapeutic application is significantly limited by severe neurotoxic and nephrotoxic side effects. Prevailing polymyxin delivery systems focus on either reducing toxicity or enhancing bioavailability yet fail to simultaneously achieve both. In this scenario, we have developed a distinctive HDL-mimicking nanodisc for polymyxin B, which not only significantly reduces toxicity but also improves efficacy against Gram-negative bacteria, especially in sepsis caused by CRAB. This research offers an innovative drug delivery system for polymyxin B. Such advancement could notably improve the therapeutic landscape and make a significant contribution to the arsenal against these notorious pathogens.

Burden and Management of Multi-Drug Resistant Organism Infections in Solid Organ Transplant Recipients Across the World: A Narrative Review.

Solid organ transplant (SOT) recipients are particularly susceptible to infections caused by multidrug-resistant organisms (MDRO) and are often the first to be affected by an emerging resistant pathogen. Unfortunately, their prevalence and impact on morbidity and mortality according to the type of graft is not systematically reported from high-as well as from low and middle-income countries (HIC and LMIC). Thus, epidemiology on MDRO in SOT recipients could be subjected to reporting bias. In addition, screening practices and diagnostic resources may vary between countries, as well as the availability of new drugs. In this review, we aimed to depict the burden of main Gram-negative MDRO in SOT patients across HIC and LMIC and to provide an overview of current diagnostic and therapeutic resources.

Emerging 2D Nanomaterials-Integrated Hydrogels: Advancements in Designing Theragenerative Materials for Bone Regeneration and Disease Therapy.

This review highlights recent advancements in the synthesis, processing, properties, and applications of 2D-material integrated hydrogels, with a focus on their performance in bone-related applications. Various synthesis methods and types of 2D nanomaterials, including graphene, graphene oxide, transition metal dichalcogenides, black phosphorus, and MXene are discussed, along with strategies for their incorporation into hydrogel matrices. These composite hydrogels exhibit tunable mechanical properties, high surface area, strong near-infrared (NIR) photon absorption and controlled release capabilities, making them suitable for a range of regeneration and therapeutic applications. In cancer therapy, 2D-material-based hydrogels show promise for photothermal and photodynamic therapies, and drug delivery (chemotherapy). The photothermal properties of these materials enable selective tumor ablation upon NIR irradiation, while their high drug-loading capacity facilitates targeted and controlled release of chemotherapeutic agents. Additionally, 2D-materials -infused hydrogels exhibit potent antibacterial activity, making them effective against multidrug-resistant infections and disruption of biofilm generated on implant surface. Moreover, their synergistic therapy approach combines multiple treatment modalities such as photothermal, chemo, and immunotherapy to enhance therapeutic outcomes. In bio-imaging, these materials serve as versatile contrast agents and imaging probes, enabling their real-time monitoring during tumor imaging. Furthermore, in bone regeneration, most 2D-materials incorporated hydrogels promote osteogenesis and tissue regeneration, offering potential solutions for bone defects repair. Overall, the integration of 2D materials into hydrogels presents a promising platform for developing multifunctional theragenerative biomaterials.

Injectable exosome-loaded quaternized chitosan/oxidized sodium alginate hydrogel with self-healing, bioadhesive, and antibacterial properties for treating combined radiation-wound injury

The management of combined radiation-wound injury (CRWI) is a major clinical challenge owing to the delayed and prolonged wound-healing process. Moreover, the mechanisms underlying the healing of CRWI are complex, and chronic wounds can increase vulnerability to multidrug-resistant bacterial infections, vascular disease, and other adverse conditions. Although exosomes from iPSC-derived mesenchymal stem cells (iMSCs) can promote injury repair, the feasibility of encapsulating them within polysaccharide-based hydrogels to treat CRWI remains to be explored. Here, iMSC-derived exosomes were encapsulated within an injectable hydrogel (HACC/OSA) consisting of quaternized chitosan (HACC) and oxidized sodium alginate (OSA). The HACC/OSA hydrogel exhibited good self-healing properties, excellent injectability, and good biocompatibility. In mouse models of CRWI, the HACC/OSA hydrogel could form a protective barrier covering the wound. Due to the presence of quaternary ammonium salts, the hydrogel could provide long-term antimicrobial protection to the wound, which was favorable for wound healing. In addition, the hydrogel could also promote CRWI repair by stabilizing exosome release. The exosome-loaded hydrogel (HACC/OSA@Exos) significantly inhibited bacterial growth and promoted the repair of CRWI, as indicated by enhanced wound healing efficiency, rapid re-epithelialization, favorable collagen deposition, and abundant angiogenesis at the wound site. Together, the in vivo and in vitro results indicated that the exosome-loaded polysaccharide-based hydrogel (HACC/OSA@Exos) can promote the healing of CRWI and potentially serve as a valuable clinical agent for CRWI management.

ITS 100 - Reducing Multi-drug Resistant Organism Infection Status Burden in a Pediatric Urologic Patient Population

ITS 100 - Reducing Multi-drug Resistant Organism Infection Status Burden in a Pediatric Urologic Patient Population

Isolation and characterizations of bacteriophages to treat multi-drug resistant bacterial infections

Isolation and characterizations of bacteriophages to treat multi-drug resistant bacterial infections

Cinnamaldehyde targets SarA to enhance β-lactam antibiotic activity against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a current global public health problem due to its increasing resistance to the most recent antibiotic therapies. One critical approach is to develop ways to revitalize existing antibiotics. Here, we show that the phytogenic compound cinnamaldehyde (CIN) and β-lactam antibiotic combinations can functionally synergize and resensitize clinical MRSA isolates to β-lactam therapy and inhibit MRSA biofilm formation. Mechanistic studies indicated that the CIN potentiation effect on β-lactams was primarily the result of inhibition of the mecA expression by targeting the staphylococcal accessory regulator sarA. CIN alone or in combination with β-lactams decreased sarA gene expression and increased SarA protein phosphorylation that impaired SarA binding to the mecA promoter element and downregulated virulence genes such as those encoding biofilm, α-hemolysin, and adhesin. Perturbation of SarA-mecA binding thus interfered with PBP2a biosynthesis and this decreased MRSA resistance to β-lactams. Furthermore, CIN fully restored the anti-MRSA activities of β-lactam antibiotics in vivo in murine models of bacteremia and biofilm infections. Together, our results indicated that CIN acts as a β-lactam adjuvant and can be applied as an alternative therapy to combat multidrug-resistant MRSA infections.

The antimicrobial susceptibility patterns of diabetic foot ulcers in the South African public healthcare sector.

Diabetic foot syndrome is defined as the presence of a diabetic foot ulcer (DFU) associated with neuropathy, peripheral artery disease and infection. While the use of antimicrobials in the treatment of DFU infection remains a mainstay, the choice of antimicrobial remains problematic owing to the presence of multidrug-resistant polymicrobial infections. In the South African public healthcare sector, the treatment of DFUs is based on the Standard Treatment Guidelines (STGs) and the Essential Drug List. These guidelines are developed using evidence-based medicine and are based on global susceptibility patterns rather than local susceptibility data, and may not provide the most appropriate treatment options. To determine the antimicrobial susceptibility patterns of DFUs isolated from patients visiting selected Gauteng provincial public hospitals in order to determine a clinically effective treatment protocol for the management of these infections. Sample swabs were taken from 51 DFUs using the Levine method. Each sample swab was spread onto blood agar plates, and thereafter individual pathogens were isolated. The antimicrobial susceptibility patterns of all isolated pathogens were determined using zone of inhibition measurements. Pathogens were grouped according to macromorphological characteristics as well as susceptibility patterns, and a representative isolate from each group was then identified. A total of 51 DFU ulcer swabs from 45 patients were included in the study. From the sample swabs, a total of 445 pathogens were isolated. The most effective antimicrobial was found to be gentamicin, followed by ciprofloxacin. Amoxicillin/clavulanic acid, the first-line treatment according to the STGs, was found to be ineffective for many of the isolated pathogens. The most commonly isolated pathogens were Proteus mirabilis, Enterococcus faecalis and Pseudomonas aeruginosa. These findings demonstrate the urgent need to reassess the STGs and base treatment plans on local epidemiological data. This study provides valuable data on common causative pathogens in DFU infections, as well as the resistance patterns of these pathogens, forming a baseline on which to base future DFU treatment plans.

Condensation methodology for quantification of Polymyxin B fluorimetrically: application to pharmaceutical formulations and greenness assessment

The appearance of multidrug-resistant Gram-negative bacterial infections, along with the lack of newly discovered antibiotics, resulted in the return to old antimicrobial medications like Polymyxins. As a result, the suggested technique aims to develop a fast, environmentally friendly, and sensitive fluorimetric method for quantifying Polymyxin B. The investigated approach depends on generating a highly fluorescent derivative by a condensation pathway between the studied drug and ninhydrin in the presence of phenylacetaldehyde and then estimated spectrofluorimetrically. After the reaction conditions were well optimized, the fluorescent product was estimated at emission wavelength (λem) = 475.5 nm (following excitation at a wavelength (λex) = 386 nm. The developed calibration plot displayed rectilinear throughout the following range (0.2-3 µg mL− 1), and the calculated limit of detection and quantification were 0.062 µg mL− 1 and 0.187 µg mL− 1, respectively. As a consequence, the drug’s ophthalmic and intravenous pharmaceutical forms were both successfully quantified with an excellent degree of recovery. Finally, the methodology’s greenness was assessed utilizing Analytical Eco-Scale scores.

Black-Pigmented Marine Pseudomonas aeruginosa Exhibiting Anti-Bacterial Activity against Multidrug-Resistant (MDR) Wound Infection Bacteria

The urgency of multidrug-resistant (MDR) bacterial infections in wounds is a significant concern due to the high prevalence of MDR in healthcare settings. Black pigmented marine bacteria, strain PS1C, were isolated from marine sediment on Awur Beach Jepara, Central Java, Indonesia, and cultured in the laboratory. The aim of this research includes molecular identification of strain PS1C, extracting black pigment from strain PS1C, isolation of MDR bacteria from wounds, and evaluating the antibacterial activity of black pigment from strain PS1C against MDR bacteria isolates of wound infections. We examined the 16S rRNA gene sequences strain PS1C to identify the species. Then, the black pigment from PS1C was extracted using methanol: acetone (7:3) solvent. Antibacterial activity was evaluated against MDR bacteria from wounds with the microdilution method. A black-pigmented bacterium was isolated and identified as Pseudomonas aeruginosa PS1C. We found that the black pigment from P. aeruginosa PS1C can be developed as an antibacterial agent against the MDR bacterial isolate of wounds with MIC and MBC values of 6.25-12.5 mg/ml and 6.25-25 mg/ml, respectively. In conclusion, the study's findings highlight the potential of the extract of black pigment from P. aeruginosa PS1C as an antibacterial agent against wound-causing MDR bacteria and reinforce previous research into P. aeruginosa can be isolated from marine sources. Additional in vivo investigations and the identification of the antibacterial activity's mode of action are required.

A retrospective study of the predictors of mortality among patients in intensive care units at North West-Bank hospitals in Palestine

ABSTRACT Objectives The intensive care unit (ICU) mortality rate remains high, especially in developing countries, regardless of the advances in critical management. There is a lack of studies about mortality causes in hospitals and particularly ICUs in Palestine. This study evaluated the demographic and clinical characteristics of critically ill patients and determined the predictors of mortality among patients in the ICU. Methods A retrospective study assessed all patients who stayed in the ICU for more than 24 h from January 2017 to January 2019. Data were collected from the patient’s files. Patient characteristics (background, clinical variables, and comorbidities) were recorded. Results The study included 227 eligible ICU patients. The cases’ mean age was 55.5 (SD ± 18.2) years. The overall ICU mortality rate was 31.7%. The following factors were associated with high adjusted mortality odds: admission from inside the hospital (adjusted odds ratio (aOR), 2.1, 95% CI: 1.1–3.9, p < 0.05), creatinine level ≥2 mg/dl on admission (aOR, 2.7, 95% CI: 1.3–5.8, p < 0.01), hematology malignancy patients (aOR, 3.4, 95% CI: 1.6–6.7, p = 0.001), immune-compromised (aOR, 2.5, 95% CI: 1.3–4.7, p < 0.01), septic shock (aOR, 27.1, 95% CI: 7.9–88.3, p < 0.001), hospital-acquired infections (aOR: 13.4, 95% CI: 4.1–57.1, p < 0.001), and patients with multiple-source infection (aOR: 16.3, 95% CI: 6.4–57.1, p < 0.001). Also, high SOFA and APACHE scores predicted morality (p < 0.001). Conclusion The mortality rate among ICU patients was high. It was higher among those admitted from the hospital wards, septic shock, hospital-acquired infection, multiple infection sources, and multi-drug resistance infections. Thus, strategies should be developed to enhance the ICU environment and provide sufficient resources to minimize the effects of these predictors.

Evaluation of stem-cell therapies in companion animal disease models: a concise review (2015-2023).

Companion animals in veterinary medicine develop multiple naturally occurring diseases analogous to human conditions. We previously reported a comprehensive review on the feasibility, safety, and biologic activity of using novel stem cell therapies to treat a variety of inflammatory conditions in dogs and cats (2008-2015) [Hoffman AM, Dow SW. Concise review: stem cell trials using companion animal disease models. Stem Cells. 2016;34(7):1709-1729. https://doi.org/10.1002/stem.2377]. The purpose of this review is to provide an updated summary of current studies in companion animal disease models that have evaluated stem cell therapeutics that are relevant to human disease. Here we have reviewed the literature from 2015 to 2023 for publications on stem cell therapies that have been evaluated in companion animals, including dogs, cats, and horses. The review excluded case reports or studies performed in experimentally induced models of disease, studies involving cancer, or studies in purpose-bred laboratory species such as rodents. We identified 45 manuscripts meeting these criteria, an increase from 19 that were described in the previous review [Hoffman AM, Dow SW. Concise review: stem cell trials using companion animal disease models. Stem Cells. 2016;34(7):1709-1729. https://doi.org/10.1002/stem.2377]. The majority of studies were performed in dogs (n = 28), with additional studies in horses (n = 9) and cats (n = 8). Disease models included those related to musculoskeletal disease (osteoarthritis and tendon/ligament injury), neurologic disease (canine cognitive dysfunction, intervertebral disc disease, spinal cord injury) gingival/dental disease (gingivostomatitis), dermatologic disease (atopic dermatitis), chronic multi-drug resistant infections, ophthalmic disease (keratoconjunctivitis sicca, eosinophilic keratitis, immune-mediated keratitis), cardiopulmonary disease (asthma, degenerative valve disease, dilated cardiomyopathy), gastrointestinal disease (inflammatory bowel disease, chronic enteropathy), and renal disease (chronic kidney disease). The majority of studies reported beneficial responses to stem cell treatment, with the exception of those related to more chronic processes such as spinal cord injury and chronic kidney disease. However, it should also be noted that 22 studies were open-label, baseline-controlled trials and only 12 studies were randomized and controlled, making overall study interpretation difficult. As noted in the previous review, improved regulatory oversight and consistency in manufacturing of stem cell therapies are needed. Enhanced understanding of the temporal course of disease processes using advanced-omics approaches may further inform mechanisms of action and help define appropriate timing of interventions. Future directions of stem-cell-based therapies could include use of stem-cell-derived extracellular vesicles, or cell conditioning approaches to direct cells to specific pathways that are tailored to individual disease processes and stages of illness.

Unlocking roles of cationic and aromatic residues in peptide amphiphiles in treating drug-resistant gram-positive pathogens

Multidrug resistance (MDR) is a rising threat to global health because the number of essential antibiotics used for treating MDR infections is increasingly compromised. In this work we report a group of new amphiphilic peptides (AMPs) derived from the well-studied G3 (G(IIKK)3I-NH2) to fight infections from Gram-positive bacteria including susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), focusing on membrane interactions. Time-dependent killing experiments revealed that substitutions of II by WW (GWK), II by FF (GFK) and KK by RR (GIR) resulted in improved bactericidal efficiencies compared to G3 (GIK) on both S. aureus and MRSA, with the order of GWK > GIR > GFK > GIK. Electronic microscopy imaging revealed structural disruptions of AMP binding to bacterial cell walls. Fluorescence assays including AMP binding to anionic lipoteichoic acids (LTA) in cell-free and cell systems indicated concentration and time-dependent membrane destabilization associated with bacterial killing. Furthermore, AMP’s binding to anionic plasma membrane via similar fluorescence assays revealed a different extent of membrane depolarization and leakage. These observations were supported by the penetration of AMPs into the LTA barrier and the subsequent structural compromise to the cytoplasmic membrane as revealed from SANS (small angle neutron scattering). Both experiments and molecular dynamics (MD) simulations revealed that GWK and GIR could make the membrane more rigid but less effective in diffusive efficiency than GIK and GFK through forming intramembrane peptide nanoaggregates associated with hydrophobic mismatch and formation of fluidic and rigid patches. The reported peptide-aggregate-induced phase-separation emerged as a crucial factor in accelerated membrane disintegration and fast bacterial killing. This work has demonstrated the importance of membrane interactions to the development of more effective AMPs and the relevance of the approaches as reported in assisting this area of research.

Risk factors and economic burden for community-acquired multidrug-resistant organism-associated urinary tract infections: A retrospective analysis.

The spread of multidrug-resistant organisms (MDROs) has resulted in a corresponding increase in the incidence of urinary tract infections (UTIs). The risk factors and hospitalization burden for community-acquired MDRO-associated UTIs are discussed herein. This retrospective study included 278 patients with community-based MDRO-associated UTIs from January 2020 to January 2022. The MDRO (n = 139) and non-MDRO groups (n = 139) were separated based on drug susceptibility results. Community-based MDRO-associated UTIs mainly occurred in the elderly and frail patients with a history of invasive urinary tract procedures. The MDRO group imposed a greater economic burden compared to the non-MDRO group. Independent risk factors for community-based MDRO-associated UTIs were as follows: white blood cell (WBC) count > 10.0 × 109/L (OR = 2.316, 95% CI = 1.316-3.252; P = .018); ≥3 kinds of urinary tract obstructive diseases (OR = 1.720, 95% CI = 1.004-2.947; P = .048); use of 3rd generation cephalosporins (OR = 2.316, 95% CI = 1.316-4.076; P = .004); and a history of invasive urologic procedures (OR = 2.652, 95% CI = 1.567-4.487; P < .001). Days of hospitalization, antibiotic use, and bladder catheter use were significantly greater in the MDRO group than the non-MDRO group (P < .05).

Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury.

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin knockout cells following comparable polymyxin B exposures. Compared with polymyxin B exposure alone, concomitant gelofusine significantly increased cell viability as well as reduced LDH release, polymyxin B uptake, mitochondrial superoxide, and apoptosis. Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. In conclusion, the mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury.NEW & NOTEWORTHY Gelofusine is a gelatinous saline solution with the potential to attenuate polymyxin-associated nephrotoxicity. We demonstrated that the mechanisms of gelofusine renal protection involve reducing polymyxin B uptake by proximal tubule cells, limiting subsequent oxidative stress and apoptosis activation. In addition, gelofusine was more effective at reducing cellular injury than a known antioxidant control, methionine, and a megalin knockout cell line, indicating that gelofusine likely has additional pharmacological properties besides only megalin inhibition.

Photochemical Strategies toward Precision Targeting against Multidrug-Resistant Bacterial Infections.

Infectious diseases pose a serious threat and a substantial economic burden on global human and public health security, especially with the frequent emergence of multidrug-resistant (MDR) bacteria in clinical settings. In response to this urgent need, various photobased anti-infectious therapies have been reported lately. This Review explores and discusses several photochemical targeted antibacterial therapeutic strategies for addressing bacterial infections regardless of their antibiotic susceptibility. In contrast to conventional photobased therapies, these approaches facilitate precise targeting of pathogenic bacteria and/or infectious microenvironments, effectively minimizing toxicity to mammalian cells and surrounding healthy tissues. The highlighted therapies include photodynamic therapy, photocatalytic therapy, photothermal therapy, endogenous pigments-based photobleaching therapy, and polyphenols-based photo-oxidation therapy. This comprehensive exploration aims to offer updated information to facilitate the development of effective, convenient, safe, and alternative strategies to counter the growing threat of MDR bacteria in the future.

Clove and Peppermint Essential Oils Effect on Pathogenic Gut Micro-Biota in Chronic Hepatic Disease Patients

Multidrug-resistant bacteria infections in cirrhotic patients are currently increasing and associated with greater morbidity and mortality. The aim of this study was to decrease complications and bacterial infections that probably occurred after a patient undergoes liver transplantation surgery in Egypt using natural edible nontoxic peppermint and clove essential oils. All patients undergo clinical, laboratory, and microbiological testing. The recorded results showed that administered minimum inhibitory concentration (MIC) of clove and peppermint essential oils significantly reduced the total colony forming unit (CFU) count of multidrug-resistant pathogenic bacteria isolated from patients with chronic hepatic disease. The gas chromatography-mass spectrometry (GC-MS) analysis of clove and peppermint oil revealed the presence of active constituents with antibacterial activities as indicated in previous reviews.

Genome analyses of colistin-resistant high-risk blaNDM-5 producing Klebsiella pneumoniae ST147 and Pseudomonas aeruginosa ST235 and ST357 in clinical settings

BackgroundColistin is a last-resort antibiotic used in extreme cases of multi-drug resistant (MDR) Gram-negative bacterial infections. Colistin resistance has increased in recent years and often goes undetected due to the inefficiency of predominantly used standard antibiotic susceptibility tests (AST). To address this challenge, we aimed to detect the prevalence of colistin resistance strains through both Vitek®2 and broth micro-dilution. We investigated 1748 blood, tracheal aspirate, and pleural fluid samples from the Intensive Care Unit (ICU), Neonatal Intensive Care Unit (NICU), and Tuberculosis and Respiratory Disease centre (TBRD) in an India hospital. Whole-genome sequencing (WGS) of extremely drug-resitant (XDR) and pan-drug resistant (PDR) strains revealed the resistance mechanisms through the Resistance Gene Identifier (RGI.v6.0.0) and Snippy.v4.6.0. Abricate.v1.0.1, PlasmidFinder.v2.1, MobileElementFinder.v1.0.3 etc. detected virulence factors, and mobile genetic elements associated to uncover the pathogenecity and the role of horizontal gene transfer (HGT).ResultsThis study reveals compelling insights into colistin resistance among global high-risk clinical isolates: Klebsiella pneumoniae ST147 (16/20), Pseudomonas aeruginosa ST235 (3/20), and ST357 (1/20). Vitek®2 found 6 colistin-resistant strains (minimum inhibitory concentrations, MIC = 4 μg/mL), while broth microdilution identified 48 (MIC = 32–128 μg/mL), adhering to CLSI guidelines. Despite the absence of mobile colistin resistance (mcr) genes, mechanisms underlying colistin resistance included mgrB deletion, phosphoethanolamine transferases arnT, eptB, ompA, and mutations in pmrB (T246A, R256G) and eptA (V50L, A135P, I138V, C27F) in K. pneumoniae. P. aeruginosa harbored phosphoethanolamine transferases basS/pmrb, basR, arnA, cprR, cprS, alongside pmrB (G362S), and parS (H398R) mutations. Both strains carried diverse clinically relevant antimicrobial resistance genes (ARGs), including plasmid-mediated blaNDM-5 (K. pneumoniae ST147) and chromosomally mediated blaNDM-1 (P. aeruginosa ST357).ConclusionThe global surge in MDR, XDR and PDR bacteria necessitates last-resort antibiotics such as colistin. However, escalating resistance, particularly to colistin, presents a critical challenge. Inefficient colistin resistance detection methods, including Vitek2, alongside limited surveillance resources, accentuate the need for improved strategies. Whole-genome sequencing revealed alarming colistin resistance among K. pneumoniae and P. aeruginosa in an Indian hospital. The identification of XDR and PDR strains underscores urgency for enhanced surveillance and infection control. SNP analysis elucidated resistance mechanisms, highlighting the complexity of combatting resistance.

Risk Factors for Therapeutic Failure and One-Year Mortality in Patients with Intramedullary Nail-Associated Infection after Trochanteric and Subtrochanteric Hip Fracture Repair.

Despite the implications of trochanteric and subtrochanteric intramedullary (IM) nail infection for patients with hip fracture, little is known about risk factors for therapeutic failure and mortality in this population. We performed a retrospective observational analysis including patients diagnosed with trochanteric and subtrochanteric IM nail infection at a Spanish academic hospital during a 10-year period, with a minimum follow-up of 22 months. Of 4044 trochanteric and subtrochanteric IM nail implants, we identified 35 cases of infection during the study period (0.87%), 17 of which were chronic infections. Patients with therapeutic failure (n = 10) presented a higher average Charlson Comorbidity Index (CCI) (5.40 vs. 4.21, p 0.015, CI 0.26-2.13) and higher rates of polymicrobial (OR 5.70, p 0.033, CI 1.14-28.33) and multidrug-resistant (OR 7.00, p 0.027, CI 1.24-39.57) infections. Upon multivariate analysis, polymicrobial infection and the presence of multidrug-resistant pathogens were identified as independent risk factors for therapeutic failure. Implant retention was associated with an increased risk of failure in chronic infection and was found to be an independent risk factor for overall one-year mortality in the multivariate analysis. Our study highlights the importance of broad-spectrum empirical antibiotics as initial treatment of trochanteric and subtrochanteric IM nail-associated infection while awaiting microbiological results. It also provides initial evidence for the importance of implant removal in chronic IM-nail infection.

A membrane-targeting magnolol derivative for the treatment of methicillin-resistant Staphylococcus aureus infections.

Multidrug-resistant bacterial infections are a major global health challenge, especially the emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) urgently require alternative treatment options. Our study has identified that a magnolol derivative 6i as a promising agent with significant antibacterial activity against S. aureus and clinical MRSA isolates (MIC = 2-8 μg/mL), showing high membrane selectivity. Unlike traditional antibiotics, 6i demonstrated rapid bactericidal efficiency and a lower propensity for inducing bacterial resistance. Compound 6i also could inhibit biofilm formation and eradicate bacteria within biofilms. Mechanistic studies further revealed that 6i could target bacterial cell membranes, disrupting the integrity of the cell membrane and leading to increased DNA leakage, resulting in potent antibacterial effects. Meanwhile, 6i also showed good plasma stability and excellent biosafety. Notably, 6i displayed good in vivo antibacterial activity in a mouse skin abscess model of MRSA-16 infection, which was comparable to the positive control vancomycin. These findings indicated that the magnolol derivative 6i possessed the potential to be a novel anti-MRSA infection agent.