Multidrug-resistant Pathogens Research Articles

Murepavadin Enhances the Killing Efficacy of Ciprofloxacin against Pseudomonas aeruginosa by Inhibiting Drug Efflux.

Pseudomonas aeruginosa is a multidrug-resistant Gram-negative pathogen and one of the leading causes of ventilator-associated pneumonia and infections in patients with chronic obstructive pulmonary disease and cystic fibrosis. Murepavadin is a peptidomimetic that specifically targets outer-membrane lipopolysaccharide transport protein LptD of P. aeruginosa. In this study, we find that murepavadin enhances the bactericidal efficacy of ciprofloxacin. We further demonstrate that murepavadin increases intracellular accumulation of ciprofloxacin by suppressing drug efflux. In addition, the murepavadin-ciprofloxacin combination exhibits a synergistic bactericidal effect in an acute murine pneumonia model. In conclusion, our results identify an effective drug combination for the treatment of P. aeruginosa infections.

Green synthesis of trimetallic CuO/Ag/ZnO nanocomposite using Ziziphus spina-christi plant extract: characterization, statistically experimental designs, and antimicrobial assessment

In this study, Ziziphus spina christi leaves was used to synthesize a trimetallic CuO/Ag/ZnO nanocomposite by a simple and green method. Many characterizations e.g. FTIR, UV–vis DRS, SEM–EDX, TEM, XRD, zeta-size analysis, and DLS, were used to confirm green-synthesized trimetallic CuO/Ag/ZnO nanocomposite. The green, synthesized trimetallic CuO/Ag/ZnO nanocomposite exhibited a spherical dot-like structure, with an average particle size of around 7.11 ± 0.67 nm and a zeta potential of 21.5 mV. An extremely homogeneous distribution of signals, including O (79.25%), Cu (13.78%), Zn (4.42%), and Ag (2.55%), is evident on the surface of green-synthetic nanocomposite, according to EDX data. To the best of our knowledge, this is the first study to effectively use an industrially produced green trimetallic CuO/Ag/ZnO nanocomposite as a potent antimicrobial agent by employing different statistically experimental designs. The highest yield of green synthetic trimetallic CuO/Ag/ZnO nanocomposite was (1.65 mg/mL), which was enhanced by 1.85 and 5.7 times; respectively, by using the Taguchi approach in comparison to the Plackett–Burman strategy and basal condition. A variety of assays techniques were utilized to evaluate the antimicrobial capabilities of the green-synthesized trimetallic CuO/Ag/ZnO nanocomposite at a 200 µg/mL concentration against multidrug-resistant human pathogens. After a 36-h period, the tested 200 µg/mL of the green-synthetic trimetallic CuO/Ag/ZnO nanocomposite effectively reduced the planktonic viable counts of the studied bacteria, Escherichia coli and Staphylococcus aureus, which showed the highest percentage of biofilm reduction (98.06 ± 0.93 and 97.47 ± 0.65%; respectively).

Recreational hot springs as environmental reservoir of potential multidrug-resistant pathogens

Recreational hot springs as environmental reservoir of potential multidrug-resistant pathogens

Antifungal Activity of Disalt of Epipyrone A from Epicoccum nigrum Likely via Disrupted Fatty Acid Elongation and Sphingolipid Biosynthesis.

Multidrug-resistant fungal pathogens and antifungal drug toxicity have challenged our current ability to fight fungal infections. Therefore, there is a strong global demand for novel antifungal molecules with the distinct mode of action and specificity to service the medical and agricultural sectors. Polyenes are a class of antifungal drugs with the broadest spectrum of activity among the current antifungal drugs. Epipyrone A, a water-soluble antifungal molecule with a unique, linear polyene structure, was isolated from the fungus Epiccocum nigrum. Since small changes in a compound structure can significantly alter its cell target and mode of action, we present here a study on the antifungal mode of action of the disalt of epipyrone A (DEA) using chemical-genetic profiling, fluorescence microscopy, and metabolomics. Our results suggest the disruption of sphingolipid/fatty acid biosynthesis to be the primary mode of action of DEA, followed by the intracellular accumulation of toxic phenolic compounds, in particular p-toluic acid (4-methylbenzoic acid). Although membrane ergosterol is known to be the main cell target for polyene antifungal drugs, we found little evidence to support that is the case for DEA. Sphingolipids, on the other hand, are known for their important roles in fungal cell physiology, and their biosynthesis has been recognized as a potential fungal-specific cell target for the development of new antifungal drugs.

Harnessing Bacteriophages to Combat Antibiotic-Resistant Infections in Africa: A Comprehensive Review.

The conventional treatment of bacterial infections with antibiotics is becoming increasingly ineffective due to the emergence of multidrug-resistant (MDR) pathogens. This literature review explores the potential of bacteriophages as an alternative or adjunctive therapy to antibiotics in combating MDR infections in Africa. This analysis focuses on current research regarding the integration of phage therapy into African healthcare, highlighting its challenges and opportunities. This review begins with the AMR crisis and the need for new treatments, then covers the history, mechanisms, benefits, and limitations of phage therapy. Key African studies are summarized, identifying major obstacles such as regulatory issues, infrastructure, and research standardization. Research efforts in West Africa that have made notable progress in bacteriophage research are highlighted. This review concludes with recommendations for policymakers, researchers, and healthcare professionals to enhance the development and use of phage therapy in Africa, aiming to reduce antibiotic resistance and improve patient outcomes. By addressing the identified challenges and leveraging the unique advantages of phages, there is potential to significantly mitigate the impact of antibiotic resistance and improve patient outcomes in Africa.

Bacterial outer membrane vesicles increase polymyxin resistance in Pseudomonas aeruginosa while inhibiting its quorum sensing

The persistent emergence of multidrug-resistant bacterial pathogens is leading to a decline in the therapeutic efficacy of antibiotics, with Pseudomonas aeruginosa (P. aeruginosa) emerging as a notable threat. We investigated the antibiotic resistance and quorum sensing (QS) system of P. aeruginosa, with a particular focused on outer membrane vesicles (OMVs) and polymyxin B as the last line of antibiotic defense. Our findings indicate that OMVs increase the resistance of P. aeruginosa to polymyxin B. The overall gene transcription levels within P. aeruginosa also reveal that OMVs can reduce the efficacy of polymyxin B. However, both OMVs and sublethal concentrations of polymyxin B suppressed the transcription levels of genes associated with the QS system. Furthermore, OMVs and polymyxin B acted in concert on the QS system of P. aeruginosa to produce a more potent inhibitory effect. This suppression was evidenced by a decrease in the secretion of virulence factors, impaired bacterial motility, and a notable decline in the ability to form biofilms. These results reveal that OMVs enhance the resistance of P. aeruginosa to polymyxin B, yet they collaborate with polymyxin B to inhibit the QS system. Our research contribute to a deeper understanding of the resistance mechanisms of P. aeruginosa in the environment, and provide new insights into the reduction of bacterial infections caused by P. aeruginosa through the QS system.

PhagoScreener: A novel phagogram platform based on a capillary-wave microbioreactor

Due to the overuse of antibiotics, the number of multidrug-resistant pathogen bacteria is rising in recent years posing a serious threat to human health. One promising alternative for treatment is the application of phage therapy using highly selective bacteriophages. Because of their selectivity, individual screens called phagograms for each patient are required to select phages from a phage library. Phagograms are mostly performed via bacterial cultivation on double layer agar plates and phage addition causing bacterial lysis. However, these assays are work-intensive and have a low ability for parallelization and automation. Hence, highly parallelizable and automatable microbioreactors in the lowest microliter scale could offer an economic solution increasing the throughput of phagograms. This paper demonstrates the applicability of a novel capillary-wave microbioreactor (cwMBR) to perform phagograms. Due to its small volume of only 7 µL and the open-droplet design, it can be easily automated and parallelized in future. Furthermore, the ability of online biomass measurement makes the cwMBR a perfect phagogram platform in the future. Herein, phagograms with E. coli and different concentrations of the phages MM02 and EASG3 were performed as proof of concept for phagograms in the cwMBR. Thereby, the cwMBR was able to measure differences in lysis kinetics of different phages. Furthermore, the phagograms were compared to those in conventional microtiter plate readers revealing the cwMBR as ideal alternative for phagograms as it combines favorable mixing conditions and a phage repellent hydrophilic glass surface with online biomass measurement in an open-droplet design for future parallelization and automation.

The autophagy-targeting compound V46 enhances antimicrobial responses to Mycobacteroides abscessus by activating transcription factor EB

Mycobacteroides abscessus (Mabc) is a rapidly growing nontuberculous mycobacterium that poses a considerable challenge as a multidrug-resistant pathogen causing chronic human infection. Effective therapeutics that enhance protective immune responses to Mabc are urgently needed. This study introduces trans-3,5,4′-trimethoxystilbene (V46), a novel resveratrol analogue with autophagy-activating properties and antimicrobial activity against Mabc infection, including multidrug-resistant strains. Among the resveratrol analogues tested, V46 significantly inhibited the growth of both rough and smooth Mabc strains, including multidrug-resistant strains, in macrophages and in the lungs of mice infected with Mabc. Additionally, V46 substantially reduced Mabc-induced levels of pro-inflammatory cytokines and chemokines in both macrophages and during in vivo infection. Mechanistic analysis showed that V46 suppressed the activation of the protein kinase B/Akt-mammalian target of rapamycin signaling pathway and enhanced adenosine monophosphate-activated protein kinase signaling in Mabc-infected cells. Notably, V46 activated autophagy and the nuclear translocation of transcription factor EB, which is crucial for antimicrobial host defenses against Mabc. Furthermore, V46 upregulated genes associated with autophagy and lysosomal biogenesis in Mabc-infected bone marrow-derived macrophages. The combination of V46 and rifabutin exerted a synergistic antimicrobial effect. These findings identify V46 as a candidate host-directed therapeutic for Mabc infection that activates autophagy and lysosomal function via transcription factor EB.

Bacillus subtilis-derived peptides disrupt quorum sensing and biofilm assembly in multidrug-resistant Staphylococcus aureus.

The formation of biofilms by multidrug-resistant bacterial pathogens, such as Staphylococcus aureus, increases these microorganisms' virulence and decreases the efficacy of common antibiotic regimens. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms; however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity against S. aureus. This collection of peptides also improved antibiotic killing and protected human gut epithelial cells from S. aureus-induced toxicity by stimulating an adaptive cytokine response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections or improve bacterial sensitivity to antibiotics in clinical and agricultural settings.

Synthesized Bis-Triphenyl Phosphonium-Based Nano Vesicles Have Potent and Selective Antibacterial Effects on Several Clinically Relevant Superbugs.

The increasing emergence of multidrug-resistant (MDR) pathogens due to antibiotic misuse translates into obstinate infections with high morbidity and high-cost hospitalizations. To oppose these MDR superbugs, new antimicrobial options are necessary. Although both quaternary ammonium salts (QASs) and phosphonium salts (QPSs) possess antimicrobial effects, QPSs have been studied to a lesser extent. Recently, we successfully reported the bacteriostatic and cytotoxic effects of a triphenyl phosphonium salt against MDR isolates of the Enterococcus and Staphylococcus genera. Here, aiming at finding new antibacterial devices possibly active toward a broader spectrum of clinically relevant bacteria responsible for severe human infections, we synthesized a water-soluble, sterically hindered quaternary phosphonium salt (BPPB). It encompasses two triphenyl phosphonium groups linked by a C12 alkyl chain, thus embodying the characteristics of molecules known as bola-amphiphiles. BPPB was characterized by ATR-FTIR, NMR, and UV spectroscopy, FIA-MS (ESI), elemental analysis, and potentiometric titrations. Optical and DLS analyses evidenced BPPB tendency to self-forming spherical vesicles of 45 nm (DLS) in dilute solution, tending to form larger aggregates in concentrate solution (DLS and optical microscope), having a positive zeta potential (+18 mV). The antibacterial effects of BPPB were, for the first time, assessed against fifty clinical isolates of both Gram-positive and Gram-negative species. Excellent antibacterial effects were observed for all strains tested, involving all the most concerning species included in ESKAPE bacteria. The lowest MICs were 0.250 µg/mL, while the highest ones (32 µg/mL) were observed for MDR Gram-negative metallo-β-lactamase-producing bacteria and/or species resistant also to colistin, carbapenems, cefiderocol, and therefore intractable with currently available antibiotics. Moreover, when administered to HepG2 human hepatic and Cos-7 monkey kidney cell lines, BPPB showed selectivity indices > 10 for all Gram-positive isolates and for clinically relevant Gram-negative superbugs such as those of E. coli species, thus being very promising for clinical development.

Infections after musculoskeletal injuries in earthquake survivors.

This study aimed to investigate the infections following musculoskeletal injuries in earthquake survivors, offering a future clinical point of reference for the handling of musculoskeletal injuries resulting from earthquakes. In this single-center retrospective observational study, 225 earthquake survivors (120 females, 105 males; median: 39 years; range, 18 to 94 years) admitted between February 2023 and April 2023 were evaluated. Patients with musculoskeletal injuries and patients who had at least one month of follow-up data were included in the study. Diagnosis of healthcare-associated infections was verified by an infection control physician in accordance with the Centers for Disease Control and Prevention. Among all cultures, the most isolated pathogen was Acinetobacter baumannii (49.4%), followed by enterococci (28.6%). Colistin sensitivity of A. baumannii was 36 (94.7%). However, sensitivity rate was 5.3% for ciprofloxacin, 10.5% for piperacillin-tazobactam, and 26.4% for carbapenems, which are frequently used for skin and soft tissue infections. Among all, 76% of the microorganisms isolated from wound culture and 58% of the microorganisms isolated from deep tissue culture were found to be multidrug-resistant pathogens. During the follow-up, 12 (5.3%) patients had hospital-acquired urinary tract infections, 13 (5.7%) patients had hospitalacquired bloodstream infections, one (0.4%) patient had hospital-acquired pneumonia, and 74 (32.8%) patients had surgical site infections. Eighty (35.6%) of the patients were followed up in the intensive care unit, and the overall mortality rate was 2.7%. While gram-positive microorganisms are frequently the causative microorganisms in infections after traumatic injuries, this study revealed that gram-negative microorganisms could be observed more frequently in postearthquake traumatic injuries. Most causative microorganisms are resistant to commonly prescribed antibiotics in clinical settings, which makes them more challenging to treat.

A single-layer spot assay for easy, fast, and high-throughput quantitation of phages against multidrug-resistant Gram-negative pathogens.

Double-layer agar (DLA) overlay plaque assay is the gold standard for phage enumeration. However, it is cumbersome and time-consuming. Given the great interest in phage therapy, we explored alternative assays for phage quantitation. A total of 16 different phages belonging to Myoviridae, Siphoviridae, and Podoviridae families were quantitated with five K. pneumoniae, eight P. aeruginosa, and three A. baumannii host isolates. Phages were quantitated with the standard DLA assay (10 mL of LB soft agar 0.7% on LB hard agar 1.5%) and the new single-layer agar (SLA) assay (10 mL of LB soft agar 0.7%) with phages spread (spread) into or spotted (spot) onto soft agar. Phage concentrations with each assay were correlated with the standard assay, and the relative and absolute differences between each assay and the standard double-layer agar spread were calculated. Phage concentrations 1 × 104-8.3 x1012 PFU/mL with the standard DLA assay were quantitated with SLA-spread, SLA-spot, and DLA-spot assays, and the median (range) relative and absolute differences were <10% and <0.98 log10PFU/mL, respectively, for all phage/bacterial species (ANOVA P = 0.1-0.43), and they were highly correlated (r > 0.77, P < 0.01). Moreover, plaques could be quantified at 37°C after 4-h incubation for K. pneumoniae phages and 6-h incubation for P. aeruginosa and A. baumannii phages, and estimated concentrations remained the same over 24 hours. Compared to DLA assay, the SLA-spot assay required less media, it was 10 times faster, and generated same-day results. The SLA-spot assay was cheaper, faster, easier to perform, and generated similar phage concentrations as the standard DLA-spread assay.

Genome Mining and Genetic Manipulation Reveal New Isofuranonaphthoquinones in Nocardia Species.

The identification of specialized metabolites isolated from microorganisms is urgently needed to determine their roles in treating cancer and controlling multidrug-resistant pathogens. Naphthoquinones act as anticancer agents in various types of cancers, but some toxicity indicators have been limited in their appropriate application. In this context, new isofuranonaphthoquinones (ifnq) that are less toxic to humans could be promising lead compounds for developing anticancer drugs. The aim of this study is to identify and characterize novel furanonaphthoquinones (fnqs) from Nocardia sp. CS682 and to evaluate their potential therapeutic applications. Analysis of the genome of Nocardia sp. CS682 revealed the presence of a furanonaphthoquinone (fnq) gene cluster, which displays a similar genetic organization and high nucleotide sequence identity to the ifnq gene cluster from Streptomyces sp. RI-77, a producer of the naphthoquinones JBIR-76 and JBIR-77. In this study, the overexpression of the Streptomyces antibiotic regulatory protein (SARP) in Nocardia sp. CS682DR (nargenicin gene-deleted mutant) explicitly produced new fnqs, namely, NOC-IBR1 and NOC-IBR2. Subsequently, the role of the SARP regulator was confirmed by gene inactivation using CRISPR-Cas9 and complementation studies. Furthermore, antioxidant, antimicrobial, and cytotoxicity assays were performed for the isolated compounds, and it was found that NOC-IBR2 exhibited superior activities to NOC-IBR1. In addition, a flexible methyltransferase substrate, ThnM3, was found to be involved in terminal methylation of NOC-IBR1, which was confirmed by in vitro enzyme assays. Thus, this study supports the importance of genome mining and genome editing approaches for exploring new specialized metabolites in a rare actinomycete called Nocardia.

Is Ventilator-associated Event Algorithm Ideal for Surveillance? – Experience from a Neurosurgery Intensive Care Unit in Kerala

ABSTRACT Background: The ventilator-associated event (VAE) surveillance algorithm was brought in to replace the clinical ventilator-associated pneumonia (VAP) surveillance by NHSN in January 2013. This study intends to find the correlation of these surveillance criteria with the clinical VAP rates in a neurosurgery intensive care unit (ICU). Materials and Methods: This was a retrospective analysis of records of patients undergoing invasive mechanical ventilation in a neurosurgery ICU during a 3-month period. Results: Thirty-seven patients underwent invasive mechanical ventilation. The mean age was 56 years. Hypertension was the most common comorbidity among 22 (59.4%) patients. The neurological diagnosis was traumatic brain injury in 19 cases, nontraumatic intracranial hemorrhage in 12 cases, and ischemic stroke in 6 cases. Twenty-one patients had respiratory sample culture positivity and 14 were clinical VAP. The total ventilator days assessed were 82. The clinical VAP rate was 170.7, and the probable VAP (PVAP) rate for the same period was 12.19. Among the 14 patients who developed clinical VAP, 13 (88%) were hospital acquired and caused by multidrug-resistant pathogens. Six patients died during their ICU stay. ICU stay of more than 7 days was significantly associated with a clinical VAP. Conclusions: VAE was found to correlate poorly with a clinical diagnosis of VAP. When used as a surveillance tool in an ICU, it was found to miss important infection-related events in ventilated patients.

Discovery of novel dihydropyrrolidone-thiadiazole compound crosstalk between the YycG/F two-component regulatory pathway and cell membrane homeostasis to combat methicillin-resistant Staphylococcus aureus

The rapid emergence and spread of multidrug-resistant (MDR) Gram-positive pathogens present a significant challenge to global healthcare. Methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern because of its high resistance to most antibiotics. Based on our previously reported chemical structure of compound 62, a series of novel derivatives were synthesized and evaluated for their antibacterial activities. We found that some of these derivatives displayed effective antibacterial activity against Gram-positive pathogens, with minimal cytotoxicity (CC50>100 μM) and hemolytic activity (HC50>200 μM). Among these derivatives, the minimum inhibitory concentration (MIC) of 62-7c against Gram-positive bacterial isolates ranged from 6.25 to 25 μM. This derivative also exhibited significant synergistic antibacterial effects with daptomycin both in vitro and in vivo, with an ability to eradicate planktonic and persister cells of MRSA. Additionally, 62-7c inhibited biofilm formation and eradicated mature biofilms of MRSA. Mechanistic studies revealed that 62-7c inhibited the YycG kinase activity and disrupted the cell membrane by binding to cardiolipin (CL), leading to cell death. Importantly, no development of drug resistance was observed even after 20 serial passages. Furthermore, 62-7c exhibited high biosafety and potent effectiveness in combating infections in both mouse pneumonia and mouse wound models infected with MRSA. Thus, our study revealed that 62-7c has the potential to serve as a novel antibacterial agent for treating MRSA infections.

The Etiology of Bloodstream Infections at an Italian Pediatric Tertiary Care Hospital: A 17-Year-Long Series.

Knowledge of epidemiology is essential for guiding correct antibiotic prescription, reducing bacteremia-associated mortality, and implementing targeted infection control programs. However, only a few studies have reported on the epidemiology of bloodstream infections (BSIs) in pediatrics. We performed a retrospective analysis of all BSIs (excluding those caused by common skin contaminants) diagnosed from 2006 to 2022 in patients younger than 18 years who were treated at an Italian pediatric tertiary care hospital. Overall, 2395 BSIs were recorded, including 2207 (92.15%) due to bacteria and 188 (7.85%) due to fungi. The incidence rate (BSIs/10,000 hospital discharges, IR) of bacterial BSIs significantly increased during the study period. In particular, BSIs caused by S. aureus (including MRSA), Enterobacterales (including ESBL and AmpC producers), Enterococcus spp., and P. aeruginosa became more common. The frequency of carbapenem-resistant strains was <1% and stable over time. Conversely, there was a significant reduction in the incidence of BSIs due to S. pneumoniae. The BSIs were stratified by patient age, and S. aureus was the most frequent cause of BSIs in all age groups, while E. coli was the most frequent in the Enterobacterales family. S. agalactiae was the third most frequent cause of neonatal early-onset BSIs. The prevalence of Enterococcus spp. increased in the subgroups from 8 days to 5 years of age, while P. aeruginosa became more prevalent in children over 5 years of age. S. aureus was also the most frequent isolate in both community- and hospital-onset BSIs, followed by E. coli. The prevalence of multidrug-resistant (MDR) pathogens was very low. It was <5% for both Gram-positive (i.e., MRSA and VRE) and Gram-negative (ESBL, AmpC, and carbapenem-resistant) pathogens, and MDR pathogens were almost exclusively detected in hospital-onset BSIs. Fungi accounted for just under 8% of BSIs. C. albicans was the most frequently isolated strain, followed by C. parapsilosis. Notably, the IR of fungemia did not change significantly during the study period, in spite of an increase in the absolute number of events. The continuous monitoring of local epidemiology is essential to identify changes in the IRs of pathogens and antibiotic susceptibility and to guide antibiotic treatments, especially in the phase when antibiograms are not yet available.

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin.

The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.

Outcomes of inadequate empiric therapy and timing of newer antibacterial therapy in hospitalized adults with culture-positive Enterobacterales and Pseudomonas aeruginosa: a multicenter analysis

BackgroundInfections caused by multi-drug resistant Gram-negative pathogens are associated with worse clinical outcomes in critically ill patients. We evaluated hospital outcomes based on adequacy of overall and newer antibacterial therapy for Enterobacterales (ENT) and Pseudomonas aeruginosa (PsA) in US patients.MethodsHospitalized adults ≥ 18 years old with facility-reported antibiotic susceptibility from 2018–2022 across 161 facilities in the BD Insights Research Database were identified as ENT- or PsA-positive. Generalized linear mixed models were used to evaluate the impact of inadequate empiric therapy (IET) and time to initiate newer antibacterials (ceftazidime-avibactam; ceftolozane-tazobactam; cefiderocol; meropenem-vaborbactam; eravacycline; and imipenem-cilcastatin-relebactam) on hospital mortality and post-culture length of stay (LOS).ResultsAmong 229,320 ENT and 36,027 PsA susceptibility results, 1.7% and 16.8% were carbapenem non-susceptible (carb-NS), respectively. Median time to first susceptibility result was longer for carb-NS vs. carb susceptible in ENT (64 h vs. 48 h) and PsA (67 h vs. 60 h). For ENT, IET was associated with significantly higher mortality (odds ratio [OR],1.29 [95% CI, 1.16–1.43, P < 0.0001]) and longer hospital LOS (14.8 vs. 13.3, P < 0.0001). Delayed start to newer antibacterial therapy was associated with significantly greater hospital mortality for ENT (P = 0.0182) and PsA (P = 0.0249) and significantly longer post-culture LOS for ENT (P < 0.0001) and PsA (P < 0.0001).ConclusionsOverall, IET and delayed use of newer antibacterials are associated with significantly worse hospital outcomes. More rapid identification of high-risk patients can facilitate adequate therapy and timely use of newer antibacterials developed for resistant Gram-negative pathogens.

Plant-Derived Antimicrobials and Their Crucial Role in Combating Antimicrobial Resistance.

Antibiotic resistance emerged shortly after the discovery of the first antibiotic and has remained a critical public health issue ever since. Managing antibiotic resistance in clinical settings continues to be challenging, particularly with the rise of superbugs, or bacteria resistant to multiple antibiotics, known as multidrug-resistant (MDR) bacteria. This rapid development of resistance has compelled researchers to continuously seek new antimicrobial agents to curb resistance, despite a shrinking pipeline of new drugs. Recently, the focus of antimicrobial discovery has shifted to plants, fungi, lichens, endophytes, and various marine sources, such as seaweeds, corals, and other microorganisms, due to their promising properties. For this review, an extensive search was conducted across multiple scientific databases, including PubMed, Elsevier, ResearchGate, Scopus, and Google Scholar, encompassing publications from 1929 to 2024. This review provides a concise overview of the mechanisms employed by bacteria to develop antibiotic resistance, followed by an in-depth exploration of plant secondary metabolites as a potential solution to MDR pathogens. In recent years, the interest in plant-based medicines has surged, driven by their advantageous properties. However, additional research is essential to fully understand the mechanisms of action and verify the safety of antimicrobial phytochemicals. Future prospects for enhancing the use of plant secondary metabolites in combating antibiotic-resistant pathogens will also be discussed.

Development of Xanthoangelol-Derived Compounds with Membrane-Disrupting Effects against Gram-Positive Bacteria.

Infections caused by multidrug-resistant pathogens have emerged as a serious threat to public health. To develop new antibacterial agents to combat such drug-resistant bacteria, a class of novel amphiphilic xanthoangelol-derived compounds were designed and synthesized by mimicking the structure and function of antimicrobial peptides (AMPs). Among them, compound 9h displayed excellent antimicrobial activity against the Gram-positive strains tested (MICs = 0.5-2 μg/mL), comparable to vancomycin, and with low hemolytic toxicity and good membrane selectivity. Additionally, compound 9h demonstrated rapid bactericidal effects, low resistance frequency, low cytotoxicity, and good plasma stability. Mechanistic studies further revealed that compound 9h had good membrane-targeting ability and was able to destroy the integrity of bacterial cell membranes, causing an increase in intracellular ROS and the leakage of DNA and proteins, thus accelerating bacterial death. These results make 9h a promising antimicrobial candidate to combat bacterial infection.