Search

Introduction: The gut microbiota plays a pivotal role in influencing host health, through the production of metabolites and other key signalling molecules. While the impact of specific metabolites or taxa on host cells is well-documented, the broader impact of a disrupted microbiota on immune homeostasis is less understood, which is particularly important in the context of the increasing overuse of antibiotics. Methods: Female C57BL/6 mice were gavaged twice daily for four weeks with Vancomycin, Polymyxin B, or PBS (control). Caecal microbiota composition was assessed via 16S rRNA sequencing and caecal metabolites were quantified with NMR spectroscopy. Immune profiles of spleen and mesenteric lymph nodes (MLNs) were assessed by flow cytometry, and splenocytes assessed for ex vivo cytokine production. A generalised additive model approach was used to examine the relationship between global antibiotic consumption and IBD incidence. Results: Antibiotics significantly altered gut microbiota composition, reducing alpha-diversity. Acetate and butyrate were significantly reduced in antibiotic groups, while propionate and succinate increased in Vancomycin and PmB-treated mice, respectively. The MLNs and spleen showed changes only to DC numbers. Splenocytes from antibiotic-treated mice stimulated ex vivo exhibited increased production of TNF. Epidemiological analysis revealed a positive correlation between global antibiotic consumption and IBD incidence. Discussion: Our findings demonstrate that antibiotic-mediated dysbiosis results in significantly altered short-chain fatty acid levels but immune homeostasis in spleen and MLNs at steady state is mostly preserved. Non-specific activation of splenocytes ex vivo, however, revealed mice with perturbed microbiota had significantly elevated production of TNF. Thus, this highlights antibiotic-mediated disruption of the gut microbiota may program the host towards dysregulated immune responses, predisposing to the development of TNF-associated autoimmune or chronic inflammatory disease. [ABSTRACT FROM AUTHOR]

Background: Polymyxin B sulfate (PBS) and colistin sulfate (CS) are the last-line treatments for infections caused by multidrug-resistant Gram-negative bacteria, but their efficacy and safety have not been validated. The aims of the current study were to (1) determine their efficacy and safety among critically ill patients and the influencing factors, and (2) determine the relationships of drug exposure with efficacy and safety, to provide evidence for the precision dosing. Method: This retrospective study included 100 critically ill patients treated with PBS and 80 treated with CS. The efficacy outcomes were clinical efficacy and 30-day mortality, while the safety indicator was acute kidney injury (AKI) incidence. Result: There was no significant difference between the two drugs in clinical efficacy, 30-day mortality, or overall AKI incidence, but the incidence of stage 3 AKI was significantly higher in the PBS cohort than the CS cohort. Therapeutic drug monitoring (TDM) and trough concentration (Cmin) were significantly associated with clinical efficacy and AKI in both cohorts. Classification and regression tree analysis revealed that Cmin values of ≥0.91 mg/L for PBS and Cmin ≥ 0.53 mg/L for CS were associated with higher clinical efficacy. Conclusion: There is basically no significant difference in the efficacy and safety of PBS and CS. TDM can significantly improve the clinical efficacy of both drugs and reduce the incidence of AKI. TDM is therefore recommended to improve the clinical efficacy while reducing the adverse reactions. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the synergistic effect of a ceftibuten and polymyxin B combination and to determine its capacity to overcome polymyxin B resistance in polymyxin/carbapenem-resistant (PC-R) Klebsiella pneumoniae. Methods To investigate the combination's antibacterial efficacy, antimicrobial susceptibility tests using broth microdilution methods, chequerboard assays and time–kill testing were performed. Antibiofilm activity was also assessed. The treatment's effect on the bacterial cell membrane was examined by quantifying intracellular protein leakage and conducting scanning electron microscopy. Haemocompatibility tests were conducted to evaluate toxicity. Additionally, an infection model was established using Swiss mice to assess in vivo antimicrobial activity. Results The ceftibuten/polymyxin B combination demonstrated synergistic effects against several PC-R strains of K. pneumoniae , as determined by the FIC index (FICI) values, which ranged from 0.15 to 0.37. This combination was efficacious, exhibiting bactericidal activity at twice the MIC. Ceftibuten/polymyxin B also demonstrated antibiofilm activity. Additionally, ceftibuten/polymyxin B neither damaged the bacterial membrane nor exhibited haemolytic activity. Based on these findings, the in vivo therapeutic potential was investigated and it was found that ceftibuten/polymyxin B significantly decreased the bacterial load in the peritoneal lavage fluid of mice, revealing its effectiveness in treating infections caused by PC-R K. pneumoniae. Conclusions The ceftibuten/polymyxin B combination exhibited synergistic effects in vitro and in vivo , and thus might be a promising therapeutic alternative for treating PC-R K. pneumoniae infections. As the combination was efficacious in preclinical models, researchers may further investigate its potential in clinical studies. [ABSTRACT FROM AUTHOR]

ABSTRACT Acute liver failure is a serious, life‐threatening disease. Although the gut microbiota has been considered to play a role in liver failure, the extent to which it is involved in the pathogenesis of this disease has not been fully elucidated to date. Therefore, we here analyzed the importance of the presence of intestinal microbiota in the pathogenesis of acute liver injury, using D‐galactosamine (D‐GalN)/lipopolysaccharide (LPS)‐treated mice, which is a widely used experimental model of acute liver injury. First, administration of the antibiotic polymyxin B markedly alleviated liver injury. Liver injury was also reduced in germ‐free mice, leading to the conclusion that the presence of intestinal microbiota aggravates D‐GalN/LPS‐induced liver injury. The amount of bacteria and LPS transferred from the gut to the blood was not increased by D‐GalN/LPS, suggesting that the worsening of liver injury was not simply owing to the entry of bacteria into the circulation. In conclusion, acute liver injury in polymyxin B‐pretreated or germ‐free mice was ameliorated by modulation of the gut microbiota. Modification of the gut microbiota using polymyxin B may hence have the potential to alleviate acute liver injury in human patients. [ABSTRACT FROM AUTHOR]

Exploring effective combination antibacterial therapies has become a research focus. This study selected seven common antibiotics to perform a series of tests on different Gram-negative bacteria isolated from clinical samples of chronic obstructive pulmonary disease patients. More than 70% of the strains exhibited multidrug resistance but remained sensitive to polymyxin B. The checkerboard assay revealed a significant synergistic effect between polymyxin B and tetracycline against different resistant strains, with fractional inhibitory concentration index values consistently below 0.5. Further time-kill curve analysis demonstrated that the use of minimal inhibit concentration of polymyxin B or tetracycline alone had limited bactericidal effects, while their combination significantly reduced bacterial counts by 2–3 log colony-forming units within 12 h. Additionally, the survival rate of larvae treated with the polymyxin B and tetracycline combination was significantly higher than that of the mono-therapy and untreated groups. In brief, this study demonstrates that the combination of polymyxin B and tetracycline exhibits potent antibacterial activity against multidrug resistant Gram-negative bacteria both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Chiral separation techniques play a crucial role in the pharmaceutical industry, where the enantiomeric purity of drugs can have a significant impact on their efficacy and safety. Macrocyclic antibiotics are highly effective chiral selectors used in various chiral separation techniques, including LC, HPLC, SMB, and TLC, offering reproducible results and a wide range of applications. However, developing robust and efficient immobilization mechanisms for these chiral selectors remains a challenge. This review article focuses on various immobilization approaches, such as immobilization, coating, encapsulation, and photosynthesis, that have been applied to immobilize macrocyclic antibiotics on their support. Commercially available macrocyclic antibiotics for conventional liquid chromatography include Vancomycin, Norvancomycin, Eremomycin, Teicoplanin, Ristocetin A, Rifamycin, Avoparcin, Bacitracin, and others. In addition, capillary (nano) liquid chromatography has also been used in chiral separation utilizing Vancomycin, Polymyxin B, Daptomycin, and Colistin Sulfate. Macrocyclic antibiotic-based CSPs have been extensively applied due to their reproducible results, ease of use, and broad range of applications, capable of separating a large number of racemates. [ABSTRACT FROM AUTHOR]

Polymyxin B is a viable option for treating antibiotic‐resistant infections; however, current data on its pharmacokinetics, particularly in patients with renal insufficiency, remain inconclusive and necessitates further investigation. To address this gap, we conducted an open‐label, single‐center, single‐dose, parallel‐group pharmacokinetic study. Participants received an intravenous dose of 0.75 mg/kg of polymyxin B and were categorized based on their renal function: those with normal function (creatinine clearance [CLcr] ≥ 90 mL/min), mild renal insufficiency (CLcr 60–89 mL/min), and end‐stage kidney disease patients on intermittent hemodialysis (IHD) (CLcr < 10 mL/min). The pharmacokinetic parameters assessed included the area under the curve (AUC), maximum concentration (Cmax), clearance rate (CL), volume of distribution (Vz), and half‐life (t1/2). Results indicated that subjects with mild renal insufficiency exhibited pharmacokinetic profiles similar to healthy individuals. Nevertheless, in patients undergoing long‐term IHD, we observed significant differences: the AUC was 58% higher, Cmax was 29% lower, CL was 42% lower, Vz was 60% larger, and t1/2 was extended by 10 h compared to healthy controls. Secondary outcomes revealed good tolerability of polymyxin B across all groups, with no serious adverse effects related to renal function. In summary, while kidney function may have a slight impact on the pharmacokinetic of polymyxin B, it does not compromise the drug's therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Background: Klebsiella pneumoniae (KP) accounts for high antimicrobial resistance and mortality rates of bloodstream infections (BSIs). Objectives: To investigate incidence, antimicrobial resistance and risk factors for mortality of KP BSIs in East China. Methods: A retrospective study of patients with KP BSIs was conducted in a tertiary care hospital from 2018 to 2022. Medical records of all hospitalised patients with KP BSIs were reviewed and analysed. The incidence, antimicrobial resistance and mortality of KP BSIs were evaluated. The Kaplan-Meier method was used to plot survival curves and logistic regression was used to analyse risk factors for crude 30-day mortality. Results: A total of 379 inpatients with KP BSIs were enrolled. The incidence of patients with KP BSIs was fluctuating between 4.77 and 9.40 per 100,000 patient-days. The crude 30-day mortality rate of these patients was 26.39%. Of the 379 KPisolates, 197 (51.98%) were carbapenem-resistant (CR) and 252 (66.49%) were multidrug-resistant (MDR). All isolates showed the lowest resistance to tigecycline (13.77%) and polymyxin B (14.61%). Cases with MDR/CR isolates had significantly longer length of hospital stay, higher crude 30-day mortality and medical costs than non-MDR/non-CR isolates. Age, CR phenotype, paracentesis, indwelling central venous catheter (CVC), use of carbapenems, tetracyclines, polymyxins B, and irrational empiric treatment were independently associated with crude 30-day mortality. Conclusion: MDR/CR KP BSIs are associated with increased mortality, healthcare costs and prolonged hospitalisation. Patients with advanced age, CR phenotype, paracentesis, CVC, exposure to some antibiotics, and irrational empirical antibiotic treatment are at higher mortality risk. [ABSTRACT FROM AUTHOR]

Purpose: With the development of extracorporeal membrane oxygenation (ECMO) technology, the duration of ECMO support has gradually increased, leading to an increased risk of ECMO-related bacterial resistance. Polymyxin B (PMB) is used to treat drug-resistant bacterial infections. However, the pharmacokinetic (PK) parameters of antibiotics may change during ECMO, resulting in over- or under-exposure. This study aimed to clarify the changes in PK parameters and identify factors influencing PMB levels in patients receiving venovenous or venoarterial ECMO. Patients and Methods: A prospective PK study was performed in 11 patients receiving ECMO with resistant bacteria. After reaching a steady state, the drug concentrations of PMB pre- and post-oxygenator were measured. Nonlinear mixed-effects modelling was used to construct a population PK model for PMB. Microbial results were assessed using repeated cultures at the end of treatment. Semiquantitative microbial culture results were used to form clearance and uncleared groups. Results: The PMB concentrations were not significantly different between pre- and post-oxygenator. A two-compartment model best described the PK of PMB. ECMO flow rate was included as a covariate of clearance (CL). Continuous renal replacement therapy (CRRT) were included as covariates on the volume of the central compartment. The PK parameters central compartment, volume of the peripheral compartment, CL, and inter-compartmental clearance or flow rate(Q) were 20.41 L, 9.86 L, 3.75 L/h, and 3.82 L/h. 7 patients (63.64%) had two consecutive negative bacterial cultures at discharge. The Css,avg shows a significant difference between clearance group (2.26± 0.72) and uncleared group (1.25± 0.24), P< 0.05. Conclusion: There were no significant differences in PMB concentrations between pre- and post-oxygenator. The PK of PMB may be altered in patients receiving CRRT-ECMO. The ECMO flow rate is strongly correlated with the CL. The Css,avg is correlated with the bacterial clearance rate. In clinical practice, increasing the incidence of therapeutic drug monitoring may improve the clinical outcomes. Plain Language Summary: The duration of ECMO support has gradually increased, leading to a heightened risk of ECMO-related bacterial resistance. PMB is used to treat drug-resistant bacterial infections. However, the PK parameters of antibiotics may change during ECMO, resulting to over- or under-exposure. CRRT in combination with ECMO may impact the PK of PMB. The ECMO flow rate is strongly correlated with CL. Css,avg is correlated with the pathogen bacterial clearance rate. In clinical practice, increasing the use of therapeutic drug monitoring may improve the clinical outcomes. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the in vitro activity of omadacycline (OMC) and OMC-based combination therapy against carbapenem-resistant Klebsiella pneumoniae (CRKP). Methods: The broth microdilution assay assessed the in vitro susceptibility of CRKP to OMC. The checkerboard assay was performed to evaluate the activity of OMC combined with polymyxin B (PB), amikacin (AN), or meropenem (MEM) against KPC-producing (class A) CRKP strains, and OMC combined with PB, aztreonam (ATM), MEM, or AN against class B and class A plus class B CRKP strains. Synergistic effects of OMC and PB were further evaluated by time-kill assays in the KPC-producing CRKP strains. Results: Broth microdilution assays revealed a notable variation in susceptibility between KPC-producing and class B CRKP strains, with MIC50/90 of 32/32 mg/L and 0.5/8 mg/L, respectively. Although KPC-producing CRKP strains were resistant to OMC, a synergistic effect was observed in 37.5% of KPC-producing CRKP strains when OMC was combined with PB. In the nine KPC-producing CRKP strains, time-kill assays found that cell densities of six strains (66.7%) decreased by 3.61 ± 0.23 log10 CFU/mL compared to the initial inoculum after 2 hours of PB exposure. The cell densities further decreased by an average of 2.38 ± 0.23 log10 CFU/mL when the six strains were exposed to OMC plus PB, confirming their potent synergism. Conclusion: OMC monotherapy is ineffective against KPC-producing CRKP strains, but OMC plus PB has a potent synergistic effect on them, suggesting that OMC plus PB is the preferred combination therapy against KPC-producing CRKP in vitro. [ABSTRACT FROM AUTHOR]

Acid adaptation in Escherichia coli can induce antimicrobial resistance (AMR), posing challenges to global public health. We investigated the effects of acid adaptation on antimicrobial susceptibility, gene expression, zeta potential, and the outer membrane (OM) properties of Escherichia coli NCCP 13719. The acid-adapted (AA) strain exhibited increased resistance to multiple antimicrobials, with minimum inhibitory concentrations for colistin and polymyxin B increasing eight- and two-fold, respectively. Transcriptomic analysis identified 2225 differentially expressed genes, including upregulated genes associated with resistance to cationic antimicrobial peptides such as arnCTE, marA, and tolC. The upregulation of the arn operon suggests modifications in lipid A of lipopolysaccharides (LPS), reducing the negative charge of the OM and decreasing polymyxin binding affinity. Zeta potential measurements indicated a shift toward a less negative surface charge in the AA strain, which is consistent with LPS modifications. The AA strain also showed decreased OM permeability, which correlated with increased resistance to antimicrobials that penetrate the OM. These mechanisms collectively diminish the efficacy of polymyxins and highlight the potential for environmental factors to drive antimicrobial resistance. In conclusion, the acid adaptation of E. coli NCCP 13719 enhances AMR through changes in gene expression and OM modifications, highlighting the need for careful control of acidic environments during the treatment of medical devices and wastewater from food processing to prevent the emergence of resistant strains. [ABSTRACT FROM AUTHOR]

Polymyxin B (PMB) is considered a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections. Model-informed precision dosing with population pharmacokinetics (PopPK) models could help to individualize PMB dosing regimens and improve therapy. However, the external prediction ability of the established PopPK models has not been fully elaborated. This study aimed to systemically evaluate eleven PMB PopPK models from ten published literature based on a new independent population, which was divided into four different populations, patients with liver dysfunction, kidney dysfunction, liver and kidney dysfunction, and normal liver and kidney function. The whole data set consisted of 146 patients with 391 PMB concentrations. The prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. In the overall evaluation process, none of the models exhibited satisfactory predictive ability in both prediction- and simulation-based diagnostic simultaneously. However, the evaluation of the models in the subgroup of patients with normal liver and kidney function revealed improved predictive performance compared to those with liver and/or kidney dysfunction. Bayesian forecasting demonstrated enhanced predictability with the incorporation of two to three prior observations. The external evaluation highlighted a lack of consistency between the prediction results of published models and the external validation dataset. Nonetheless, Bayesian forecasting holds promise in improving the predictive performance of the models, and feedback from therapeutic drug monitoring is crucial in optimizing individual dosing regimens. [ABSTRACT FROM AUTHOR]

To facilitate clinical therapeutic drug monitoring (TDM) of polymyxin B (PB) and polymyxin E (PE), we developed and validated a simple LC–MS/MS method for simultaneous determination of PB (including polymyxin B1 (PB1), polymyxin B2 (PB2), polymyxin B3 (PB3) and isoleucine‐polymyxin B1 (ile‐PB1)) and PE (including polymyxin E1 (PE1) and polymyxin E2 (PE2)) in human plasma. PB or PE was extracted from 20.0 μL plasma using a 5% (v/v) formic acid acetonitrile solution and separated on a BEH‐C18 column (2.1 × 100 mm, 1.7 μm) with a mobile phase consisting of 0.8% formic acid aqueous solution and 0.2% formic acid acetonitrile solution. Gradient elution was performed over 5.5 min at a flow rate of 0.250 mL/min. Quantitative analysis was conducted in positive ion scanning mode by electrospray ionization and multiple reaction monitoring. The method validation was conducted based on bioanalytical method validation guidance, including specificity, calibration curve, precision, accuracy, recovery, matrix effect, stability and dilution integrity and all of the results satisfied the requirements. The method was simple, robust and high‐throughput and is currently being used to provide a TDM service to enhancing therapeutic efficacy and safety use of the PB and PE. [ABSTRACT FROM AUTHOR]

This study aimed to provide an alternative and effective delivery system to combat polymyxin B (PMB) toxicity and bacterial resistance through inhalation therapy. PMB was formulated as liposomal dry powder for inhalation using thin-film hydration and spray-dried methods. PMB formulations were characterized physically. The aerodynamic properties were determined using next-generation impactor (NGI). In vitro drug release was done in a phosphate buffer pH 7.4 for 2 h. Cytotoxicity was evaluated by the MTT cell viability assay. Antimicrobiological activities were done using bioassay and flow cytometry. Particle sizes of the spay-dried formulations were between 259.83 ± 9.91 and 518.73 ± 27.08 nm while the zeta potentials ranged between 3.07 ± 0.27 and 4.323 ± 0.36 mV. The Fourier-transform infrared spectroscopy shows no interaction between PMB and other excipients. Differential scanning calorimetry thermograms revealed amorphousness of the formulated powders and SEM revealed spherical PMB formulations. Similarly, mass media aerodynamic diameter results were 1.72–2.75 nm, and FPF was 25%–26%. The cumulative release of the PMB formulations was 90.3 ± 0.6% within 2 h. The killing kinetics revealed total cell death at 12 and 24 h for Pseudomonas aeruginosa and Escherichia coli, respectively. The PMB inhalation liposome showed better activity and was safe for lung-associated cell lines. [ABSTRACT FROM AUTHOR]

Background/Objectives: The feasibility of repurposing selective serotonin reuptake inhibitors as adjunctive antibacterial agents is an area of current investigation. We sought to evaluate if fluoxetine will achieve synergistic killing with relevant antibacterial drugs against skin and soft tissue pathogens and multidrug-resistant pathogens. Methods: The MIC of fluoxetine was determined using broth microdilution for a diverse isolate collection of 21 organisms. Checkerboard experiments were then conducted using fluoxetine and clinically relevant antibacterial drugs. If fluoxetine and an anti-infective agent achieved synergy denoted by a fractional inhibitory concentration index ≤ 0.5, then the combination was further evaluated in 24 h time-killing experiments. Synergy in time-killing experiments was defined as a ≥2 log10 CFU/mL reduction in fluoxetine combined with an antibacterial agent at any point in the experiment in comparison to whichever agent in the combination resulted in the lowest bacterial counts individually. Results: The fluoxetine MICs ranged from 64 to 128 mcg/mL for Gram-positive isolates and 8–512 mcg/mL for Gram-negative organisms. Against Gram-positive isolates, vancomycin, linezolid, clindamycin, and gentamicin failed to achieve synergy in checkerboard experiments. Levofloxacin and fluoxetine were the only combination that demonstrated synergy against a Gram-positive pathogen in both checkerboard and time-killing experiments (1/6 isolates, 16.7%). Against Gram-negative organisms, the most promising combination was fluoxetine and polymyxin B, which achieved synergistic killing in both checkerboard experiments and time-killing experiments in 12/15 isolates (80%). In comparison, fosfomycin and meropenem achieved synergy in both experiments against 6/15 (40%) and 3/15 (20%) Gram-negative isolates, respectively. Conclusions: The combination of fluoxetine and polymyxin B may be a potential strategy for combatting difficult-to-treat Gram-negative pathogens. [ABSTRACT FROM AUTHOR]

Polymyxin B (polyB) is a lipopeptide used as a last-line treatment against antibiotic-resistant Gram-negative bacteria. However, the application of polyB is limited by expressive nephrotoxicity. So, encapsulation of peptides into nanoparticles has been a tool to circumvent toxicity problems. Polymeric nanoparticles have been prepared with poly (lactic-co-glycolic acid), PLGA, a biodegradable polymer that allows the controlled release of drugs, increasing their selectivity and making them less toxic to adjacent tissues. PLGA nanoparticles were synthesized by nanoprecipitation and characterized by dynamic light scattering. PolyB was encapsulated as a free form and also linked to a dansyl fluorescent probe to be quantified. Antimicrobial assays were carried out in Escherichia coli and Pseudomonas aeruginosa. Hemolysis was evaluated with human red blood cells. In vitro cytotoxicity was evaluated against LLC-PK and CMHI kidney cells. In vivo studies were carried out in the Galleria mellonella infection model. PolyB-PLGA nanoparticles exerted bactericidal action against E. coli and P. aeruginosa at 11.8 μg/mL and showed no hemolytic activity. PolyB-PLGAs did not promote cellular viability decrease in renal cells. In vivo tests with G. mellonella indicated that in addition to not showing toxicity, the nanosystem inhibited disease progression on larvae infected by E. coli. [ABSTRACT FROM AUTHOR]

Abstract This untargeted metabolomics study investigated the synergistic antibacterial activity of polymyxin B and Leu10-teixobactin, a depsipeptide inhibitor of cell wall biosynthesis. Checkerboard microdilution assays revealed a significant synergy against polymyxin-susceptible and -resistant A. baumannii, excluding lipopolysaccharide-deficient variants. Time-kill assays confirmed bactericidal synergy, reducing bacterial burden by approximately 4-6-log10CFU/mL. The combination (2xMIC polymyxin B and 0.5xMIC Leu10-teixobactin) prevented bacterial regrowth after 24 h, indicating sustained efficacy against the emergence of resistant mutants. The analysis of A. baumannii ATCC™ 19606 metabolome demonstrated that the polymyxin B–Leu10-teixobactin combination produced more pronounced perturbation compared to the individual antibiotics across all time points (1, 3 and 6 h). Pathway analysis revealed that lipid metabolism, cell envelope biogenesis, and cellular respiration were predominantly impacted by the combination, and to a lesser extent by polymyxin B monotherapy. Leu10-teixobactin treatment alone had only a minor impact on the metabolome, primarily at the 6 h time point. Peptidoglycan assays confirmed the combination’s concerted deleterious effects on bacterial cell envelope integrity. Electron microscopy further substantiated these findings, revealing pronounced cell envelope damage, membrane blebbing, and vacuole formation. These findings highlight the potential of the polymyxin B–Leu10-teixobactin combination as an effective treatment in preventing resistance in A. baumannii.

Abstract Background Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results. Methods In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury. Results Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman’s rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group. Conclusion The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.

Abstract The prevalence of carbapenem-resistant gram-negative bacterial (CRGNB) infection is continuously increasing, and polymyxin B and colistin are considered last-resort drugs. This study compared the cost-effectiveness of polymyxin B with that of colistin for the treatment of intensive care unit patients with CRGNB infection from the Chinese healthcare perspective. A decision-analytic Markov model was constructed to assess the cost-effectiveness of polymyxin B compared with colistin over a period of 5 years using evidence from phase trials and other publicly available studies. The model was developed in Treeage Pro 2022 and comprises a decision tree depicting initial hospitalization and a Markov model with four states projecting long-term health and economic impacts following discharge. Uncertainty was tested with one-way sensitivity analyses and probabilistic sensitivity analyses. The quality-adjusted life years (QALYs), direct medical costs, and incremental cost-effectiveness ratio (ICER) were estimated at willingness-to-pay (WTP) thresholds of $12,674 to $38,024 per QALY. According to the base analyses, the cost incurred by patients receiving colistin treatment was $12,244.77, leading to a gain of 1.35 QALYs. In contrast, patients treated with polymyxin B had a lower cost of $7,306.71 but yielded 1.07 QALYs. The ICRE of colistin was $18032.25/QALY. At a $12,674/QALY threshold, the results were sensitive to several variables, including the probability of cure with polymyxin B, the cost of drugs, the utility of discharge to home, the utility of discharge to long-term care, and the cost of nephrotoxicity with renal replacement therapy. After all model inputs varied across a wide range of reasonable values, only the probability of being cured with polymyxin B resulted in an ICER above the $38,024/QALY threshold. According to the probabilistic sensitivity analyses, colistin was the optimal strategy in 38.2% and 62.8% of the simulations, at $12,674/QALY and $38,024/QALY, respectively. Our study findings suggest that, when considering the Chinese healthcare perspective, colistin is likely to be more cost-effective than polymyxin B for patients with CRGNB infection, especially when the WTP threshold is set at one-time the per capita GDP. However, as the WTP threshold increases from one to three times the per capita GDP, the cost-effectiveness acceptability of colistin improves, increasing from 38.2 to 62.8%.

Polymyxins are a well-known class of antimicrobial agents that have been used in clinical practice since the 1950s but lost their clinical significance for several decades. The rise of antibiotic resistance has led to the resurgence of polymyxins in practice and triggered an "explosive growth" in their use for treating hospital-acquired infections caused by carbapenem-resistant Gram-negative bacteria. This review provides a characterization of polymyxins, results from clinical studies, and defines the role of polymyxin B and colistin in the therapy of patients with severe infections considering current data on pathogen susceptibility in Russia and relevant clinical guidelines.

Aim: to assess the sorption capacity of various devices for endotoxin removal modelled in in vitro patient with septic shock experiment.Materials and Methods. Endotoxin adsorption was evaluated in vitro by using circulating endotoxin solution in bovine serum in a closed circuit. The following columns were chosen for the experiment: Toraymyxin PMX-20R (РМ Х), Alteco® LPS Adsorber, Efferon LPS, Toray Filtryzer BK-2.1U. Lipopolysaccharide (LPS) doses corresponding to severity of the septic process were sequentially added to a column pre-washed with physiological solution. The first LPS dose of 12.5 µg was added to a flask containing 1500 ml (1.5 L) of fetal bovine serum, a second LPS dose of 37.5 µg was added at 120 minute; the serum samples were collected before the onset of experiment, as well as 30, 60, 120 (before the second dose), 120 (after the second dose), 150 and 240 minutes after the start of circulation. LPS measurement was carried out by mixing the prepared serum sample with LAL reagent at 1:1 ratio in a measuring tube.Results. All columns can reduce endotoxin levels below the 12.5 µg and even 50 µg levels, although none of devices were able to reduce the LPS level from “supercritical” 50 µg to “critical” 12.5 µg. However, at the same time, the capacity of the Toraymyxin PMX-20R column turned out to be 5-13 times greater than that of other products. This result suggests that while removing endotoxin under similar conditions, the Toraymyx in PMX-20R column will have a much higher reserve of sorption capacity and, therefore, greater opportunities for lowering a risk of septic shock progression.Conclusion. The study we presented provides insights into whether sorption capacity of the tested cartridges is sufficient to remove endotoxin at initial (12.5 µg) load that corresponds to the onset of systemic inflammatory response syndrome in a typical patient. Additionally, it elucidates to what extent a cartridge can reduce the endotoxin load in severe septic shock with a total LPS load of up to 50 µg.

Salmonella Enteritidis is a major foodborne pathogen, and the emergence of multidrug-resistant (MDR) S. Enteritidis poses a serious public health challenge. In this study, we report the genomic characterization of five S. Enteritidis isolates from clinical. These isolates exhibited resistance to seven classes of antimicrobials with four of the five characterized as MDR. Isolate 33 A exhibited resistance to colistin and polymyxin B, while no associated antimicrobial resistance genes (ARGs) were identified in its genome. Isolate 21 A and 44 A were extended-spectrum beta-lactamases-producing (ESBLs). Whole genome sequencing analysis revealed the presence of multiple mobile genetic elements (MGEs), including plasmids, prophages, and genomic islands, which may have facilitated the acquisition and dissemination of ARGs. Notably, several ARGs, including blaCTX−M−55, blaTEM−141, blaTEM−1B, aph(3')-IIa, aph(3")-Ib, aph(6)-Id, tet(A), floR, fosA3, and sul2, were identified on plasmids. In addition, chromosomal point mutations in gyrA (D87G and D87Y) and acrB (F28L and L40P) were also observed in each isolate. Multiple virulence genes associated with the type III secretion system were identified on Salmonella pathogenicity islands (SPIs) SPI-1 and SPI-2. Phylogenetic analysis revealed that the five isolates, along with a clinical and chicken origin isolates in the database, clustered together, suggesting a probable common source of infection. Our findings highlight the intricate genetic mechanisms behind MDR in S. Enteritidis, emphasizing the ongoing necessity for surveillance and appropriate antimicrobial usage. This contributes to our understanding of S. Enteritidis transmission within the food chain. [ABSTRACT FROM AUTHOR]

Background: This study aimed to describe and compare therapeutic approaches for horses with acute diarrhea in different geographic regions worldwide. Methods: Clinical information was retrospectively collected from diarrheic horses presented to participating institutions between 2016 and 2020, including fluid therapy on admission, antimicrobial drugs, probiotics, anti-endotoxic medications, anti-inflammatory drugs, gastroprotectants, digital cryotherapy, and toxin-binding agents. Seasonal and geographic differences were investigated. Results: 1438 horses from 26 participating hospitals from 5 continents were included. On admission, 65% (926/1419) of horses were administered a fluid bolus. Antimicrobial drugs were administered to 55% (792/1419) within the first 24 hours of admission, with penicillin and gentamicin being the most used combination (25%, 198/792). Horses with leukopenia (OR: 2.264, 95%CI: 1.754 to 2.921; P<0.001) or meeting systemic inflammatory response syndrome criteria (OR: 2.542, 95%CI: 1.919 to 3.368; P<0.001) had higher odds of being administered antimicrobial drugs. Other treatments administered included probiotics (15%, 215/1438), polymyxin B (13%; 187/1438), pentoxifylline (8%; 118/1438), gastroprotectants (44%; 626/1419), digital cryotherapy (34%; 489/1435), plasma transfusion (13%; 182/1410) and toxin-binding agents (36%; 515/1438). Limitations: Due to the retrospective nature of the study, the rationale for treatment decisions was unavailable, and associations with survival could not be evaluated. Conclusions: Treatments varied between hospitals from different geographic regions. Prospective clinical trials are required to evaluate the effects of various treatments on survival. [ABSTRACT FROM AUTHOR]

Thanatin is a β-hairpin antimicrobial peptide cyclised by a single disulfide bond that has shown potent broad-spectrum activity towards bacterial and fungal pathogens. Towards Gram-negative species, thanatin acts both by forming trans-membranal pores and inhibiting outer membrane biogenesis by binding to LptA and blocking lipopolysaccharide (LPS) transport. Inspired by previous modifications of thanatin, an analogue was prepared which demonstrated potent but selective activity towards E. coli. Furthermore, this compound was shown to act in synergy with the highly potent FDA-approved lipopeptide antibiotic polymyxin B, which engages LPS at the cytoplasmic membrane. Four analogues of thanatin in which the disulfide was substituted for vinyl sulfide bridge mimetics were prepared, all of which retained similar secondary structures. Two of these retained substantial potency and selectivity towards E. coli. Importantly, synergy with polymyxin B was also maintained for the lead analogue. The vinyl sulfide potentially offers a facile replacement strategy for labile disulfide bonds and the selective activity and drug synergy of the reported thanatin analogues is promising for the development of narrow spectrum antimicrobials with reduced likelihood of resistance emerging in clinical settings. [ABSTRACT FROM AUTHOR]

Multidrug-resistant (MDR) Acinetobacter baumannii are of major concern worldwide due to their resistance to last resort carbapenem and polymyxin antibiotics. To develop an effective treatment strategy, it is critical to better understand how an A. baumannii MDR bacterium interacts with its mammalian host. Pattern-recognition receptors sense microbes, and activate the inflammasome pathway, leading to pro-inflammatory cytokine production and programmed cell death. Here, we examined the effects of a systemic MDR A. baumannii infection and found that MDR A. baumannii activate the NLRP3 inflammasome complex predominantly via the non-canonical caspase-11-dependent pathway. We show that caspase-1 and caspase-11-deficient mice are protected from a virulent MDR A. baumannii strain by maintaining a balance between protective and deleterious inflammation. Caspase-11-deficient mice also compromise between effector cell recruitment, phagocytosis, and programmed cell death in the lung during infection. Importantly, we found that cytosolic immunity - mediated by guanylate-binding protein 1 (GBP1) and type I interferon signalling - orchestrates caspase-11-dependent inflammasome activation. Together, our results suggest that non-canonical inflammasome activation via the (Interferon) IFN pathway plays a critical role in the host response against MDR A. baumannii infection. Genetic and Immunological analysis reveal that non-canonical inflammasome activation via type I Interferon pathway plays a critical role in the host response against a multidrug-resistant Acinetobacter baumannii infection in mice. [ABSTRACT FROM AUTHOR]

This untargeted metabolomics study investigated the synergistic antibacterial activity of polymyxin B and Leu10-teixobactin, a depsipeptide inhibitor of cell wall biosynthesis. Checkerboard microdilution assays revealed a significant synergy against polymyxin-susceptible and -resistant A. baumannii, excluding lipopolysaccharide-deficient variants. Time-kill assays confirmed bactericidal synergy, reducing bacterial burden by approximately 4-6-log10CFU/mL. The combination (2xMIC polymyxin B and 0.5xMIC Leu10-teixobactin) prevented bacterial regrowth after 24 h, indicating sustained efficacy against the emergence of resistant mutants. The analysis of A. baumannii ATCC™ 19606 metabolome demonstrated that the polymyxin B–Leu10-teixobactin combination produced more pronounced perturbation compared to the individual antibiotics across all time points (1, 3 and 6 h). Pathway analysis revealed that lipid metabolism, cell envelope biogenesis, and cellular respiration were predominantly impacted by the combination, and to a lesser extent by polymyxin B monotherapy. Leu10-teixobactin treatment alone had only a minor impact on the metabolome, primarily at the 6 h time point. Peptidoglycan assays confirmed the combination's concerted deleterious effects on bacterial cell envelope integrity. Electron microscopy further substantiated these findings, revealing pronounced cell envelope damage, membrane blebbing, and vacuole formation. These findings highlight the potential of the polymyxin B–Leu10-teixobactin combination as an effective treatment in preventing resistance in A. baumannii. [ABSTRACT FROM AUTHOR]

Multiple drug resistance to Acinetobacter baumannii infection treatment is a great challenge for neuro‐intensivists due to poor drug penetration through the blood–brain barrier (BBB). Fortunately, the intraventricular administration of polymyxin‐B and tigecycline seems to be effective; there are few case reports demonstrating the effectiveness of such treatments. Here, we report the case of a 24‐year‐old male who presented with fever and neck rigidity after intracranial drainage following lung infection caused by MDR Acinetobacter baumannii. Due to the presence of turbid CSF, the administration of the intrathecal (ITH) route polymyxin‐B and tigecycline is not possible. In this situation, the neuro‐intensivist decided to start intraventricular tigecycline and polymyxin‐B administration along with IV tigecycline and polymyxin‐B via the intraventricular route, which was feasible because the patient had an external ventricular drain (EVD) due to obstructive hydrocephalus caused by the neurosurgeon after excision of the tumor. [ABSTRACT FROM AUTHOR]

Purpose: Corneal epithelial defects from trauma or surgery heal as new epithelial cells grow centripetally from the limbus and replenish the epithelium. Corneal wound healing requires cell signalling molecules. However, a topical treatment with these components is not available. Human breast milk (HBM) offers a potential, novel treatment as it contains bioactive molecules important in epithelial cell healing. This study seeks to investigate the potential of HBM in cornea wound healing. Methods: Balb/c mice, 8–12 weeks old, were anesthetized prior to creating a 2 mm central cornea epithelial defect. Mice were randomly assigned to a treatment group: HBM, ophthalmic ointment containing neomycin, polymyxin B, dexamethasone (RxTx), or saline and treated 4x/day for 2 days. Wound area was quantified by fluorescein and ImageJ at 0, 8, 24, and 48 h post wounding and eyes used for histology, RT-qPCR, and ELISA. Results: Wounded corneas treated with HBM demonstrated increased re-epithelialization at 8 h post injury compared to saline treatments. ELISA showed significantly higher Ki67 in HBM treated eyes vs. saline control at 8 h (p = 0.0278). Additionally, immunohistology revealed more Ki67 positive cells in the HBM group compared to saline at 8 h and 24 h (p = 0.0063 8 h; p = 0.0007 24 h). For inflammatory analysis, HBM group IL-1β levels were similar to the saline group, and higher than RxTx treated eyes (p < 0.05). Immunohistochemical staining for CD11b (macrophage marker) revealed HBM-treated eyes had significantly more positive cells vs. saline. RT-qPCR of limbal stem cell markers (LESCs) revealed upregulation of Integrin αV at 8 h with HBM vs. saline. Conclusions: HBM treatment on corneas with debridement of epithelium demonstrated improved healing, cellular proliferation, and upregulation of the LESC gene transcript, integrin αV, after wounding. Future studies could investigate LESC response to different signalling molecules in HBM to better understand the efficacy of this potential therapy. [ABSTRACT FROM AUTHOR]

The clinical application of polymyxin B (PMB) is limited by its nephrotoxic effects, making the reduction of PMB‐induced nephrotoxicity has become a pressing concern for clinicians. Tetrahydrocurcumin (THC), known for its beneficial characteristics in biological functions, presents an attractive option for intervention therapy to mitigate PMB‐induced nephrotoxicity. However, the underlying mechanism of how THC mitigates PMB‐induced nephrotoxicity is still poorly understood. Here, we first evaluated the potential of THC intervention therapy to mitigate PMB‐induced nephrotoxicity in an in vitro model of PMB‐induced cell injury. Moreover, we demonstrated that THC effectively protected HK‐2 cells from PMB‐induced apoptosis by using cell counting kit‐8 and flow cytometry assay. THC could also suppress PMB‐induced endoplasmic reticulum (ER) stress via PERK/eIF2α/ATF4/CHOP pathway. In addition, using PERK inhibitor GSK2606414 to inhibit ER stress also alleviated PMB‐induced apoptosis. Taken together, these findings provide novel insights that THC possesses the ability to alleviate PMB‐induced nephrotoxicity by inhibiting the ER stress‐mediated PERK/eIF2α/ATF4/CHOP axis, which sheds light on the benefits of THC as an intervention strategy to reduce PMB‐induced nephrotoxicity, thus providing a potential avenue for improved clinical outcomes in patients receiving PMB treatment. [ABSTRACT FROM AUTHOR]

Despite the benefits derived from the use of pharmaceuticals, these compounds are currently considered contaminants of emerging concern because of their presence and persistence in the environment. This study aimed to determine the toxicity of 27 pharmaceuticals and the interaction effects of binary mixtures of selected compounds towards two model organisms: the microcrustacean Daphnia magna and the bacterium Aliivibrio fischeri (Microtox test). Six compounds, namely polymyxin B, polymyxin E, fluoxetine, diphenhydramine, clenbuterol and ketoprofen exhibited moderate toxicity towards D. magna. Additionally, three compounds (cefotaxime, polymyxin B, polymyxin E) also showed a moderate toxic effect on A. fischeri. The comparison of such results with model estimations showed inaccuracy in the predicted data, highlighting the relevance of experimental ecotoxicological assays. The assayed mixtures contained four selected drugs of high-hazard according to their reported concentrations in wastewater and surface water (diphenhydramine, trimethoprim, ketoprofen, and fluoxetine); data revealed interactions only in the fluoxetine-containing mixtures for D. magna, while all mixtures showed interactions (mostly synergistic) for Microtox. Chronic effects on the reproduction of D. magna were observed after exposure to fluoxetine and diphenhydramine, although higher sensitivity was determined for the latter, while the mixture of these compounds (which showed acute synergy in both models) also affected the reproduction patterns. Nonetheless, all the effects described at the acute or chronic level (for individual compounds or mixtures) were determined at concentrations higher than commonly reported at environmental levels. This work provides valuable ecotoxicological information for the risk assessment of pharmaceuticals and their mixtures in the environment. [ABSTRACT FROM AUTHOR]

Purpose: Gram-negative bloodstream infection (GNBI) poses a serious threat to critically ill patients. This retrospective study aimed to uncover drug resistance of pathogens and the GNBI effect on in-hospital death and distinguish death risk factors in a medical intensive care unit (ICU). Patients and Methods: A retrospective study of all GNBI patients in the medical ICU of the Third Xiangya Hospital over 9 nine years was conducted. Blood samples were performed by a BACTEC 9240 system, MALDI-TOF MS, Bruker and Vitek-2 system. Logistic regression was used for analyzing risk factors for death. Results: Seventy-five episodes of GNBI developed in 68 (1.4%) out of 4954 patients over a span of 9 years. The most frequently isolated bacterium was Klebsiella pneumoniae, with the lungs as the predominant source of GNBI. The resistance rate of Gram-negative bacteria to polymyxin B was 11.6% after excluding those intrinsically resistant non-fermentative bacteria. All Enterobacter spp. were susceptible to ceftazidime/avibactam. Thirty-three (48.5%) patients underwent inappropriate empirical antibiotic treatment and 48 (70.6%) patients died during the hospitalization. Multivariate logistic regression analysis identified that lymphocyte count at GNBI onset ≤ 0.5× 109/L, invasive mechanical ventilation, and septic shock were related to in-hospital death. Body mass index ≥ 23 and appropriate empirical antibiotic use after GNBI were negatively associated with in-hospital death. Conclusion: GNBI was a frequent complication among patients in the medical ICU. This study underscored the presence of diverse factors that either heightened or attenuated the risk of in-hospital death. [ABSTRACT FROM AUTHOR]

Polymyxin antibiotics B and colistin are considered drugs of last resort for the treatment of multi-drug and carbapenem-resistant Gram-negative bacteria. With the emergence and dissemination of multi-drug resistance, monitoring the use and resistance to polymyxins imparted by mobilised colistin resistance genes (mcr) is becoming increasingly important. The Aeromonas genus is widely disseminated throughout the environment and serves as a reservoir of mcr–3, posing a significant risk for the spread of resistance to polymyxins. Recent phylogenetic studies and the identification of insertion elements associated with mcr–3 support the notion that Aeromonas spp. may be the evolutionary origin of the resistance gene. Furthermore, mcr–3-related genes have been shown to impart resistance in naïve E. coli and can increase the polymyxin MIC by up to 64-fold (with an MIC of 64 mg/L) in members of Aeromonas spp. This review will describe the genetic background of the mcr gene, the epidemiology of mcr-positive isolates, and the relationship between intrinsic and transferable mcr resistance genes, focusing on mcr–3 and mcr–3-related genes. [ABSTRACT FROM AUTHOR]

Background: The burden of bacterial bloodstream infections (BSIs) is rapidly increasing in Africa including Rwanda. Methods: This is a retrospective study that investigates the diversity, distribution, and antimicrobial susceptibility profiles of BSI bacteria in three tertiary referral hospitals in Rwanda between 2020 and 2022. Results: A total of 1532 blood culture tests were performed for visiting patients. Overall, the proportions of Gram-negative and Gram-positive bacteria were 48.2% and 51.8, respectively. Staphylococcus aureus was the predominant species accounting for 25% of all Gram-positive BSI species, and Klebsiella species represented 41% of all Gram-negative BSI species. Antimicrobial susceptibility testing revealed that Amikacin exhibited the highest activity against Enterobacter spp., Serratia spp., and Escherichia coli in >92% of cases and Klebsiella spp. in 75.7%. Meropenem and Imipenem were highly efficacious to Salmonella spp. (100% susceptibility), Enterobacter spp. (96.2% and 91.7%, respectively), and Escherichia coli (94.7% and 95.5%, respectively). The susceptibility of Enterococcus spp., S. aureus, and Streptococcus spp. to Vancomycin was 100%, 99.5%, and 97.1%, respectively. Klebsiella spp. was highly sensitive to Colistin (98.7%), Polymyxin B (85.6%), Imipenem (84.9%), and Meropenem (78.5%). Conclusions: We recommend strengthening the implementation of integrated transdisciplinary and multisectoral One Health including AMR stewardship for the surveillance, prevention, and control of AMR in Rwanda. [ABSTRACT FROM AUTHOR]

Enterobacterales (especially carbapenem-resistant) are considered an urgent threat to public health. The available antibiotic therapy is limited due to the increase of multidrug-resistant (MDR) strains. Tigecycline, a minocycline derivative, has emerged as a potential key agent in the treatment ofMDR isolates. The aim of the study was to evaluate the synergistic effect of tigecycline in combination with nine antimicrobial agents--ceftazidime/avibactam, colistin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem/vaborbactam, polymyxin B, and rifampicin. Eighty clinical Enterobacter cloacae strains were obtained frompatients of two University Hospitals in Bialystok, Poland. The E-test method was used to determine synergistic interactions. Among all combinations, synergy was reported in 61% of cases, addition in 32%, and indifference in 7%. The highest synergy rates were observed in tigecycline combinations with: ceftazidime/avibactam(60/80; 75%), imipenem(60/80; 75%), polymyxin B (55/80; 68.75%) and rifampicin (55/80; 68.75%), while the lowest synergy rate was noted in tigecycline-levofloxacin (26/80; 32.5%). The tigecycline-gentamicin showed the highest rate of indifference; antagonism, was not observed in any combination. In conclusion, tigecycline appears more suitable for use in combination therapy rather than as monotherapy and can be effectively paired with various antimicrobial agents against MDR E. cloacae. Further research will be necessary to confirm these results. [ABSTRACT FROM AUTHOR]

Phages and phage-encoded lytic enzymes are promising antimicrobial agents. In this study, we report the isolation and identification of bacteriophage KP2025 from Klebsiella pneumoniae. Bioinformatics analysis of KP2025 revealed a putative endolysin, LysKP213, containing a T4-like_lys domain. Purified LysKP213 was found to be highly thermostable, retaining approximately 44.4% of its lytic activity after 20 h of incubation at 95°C, and approximately 57.5% residual activity after 30 min at 121°C. Furthermore, when administered in combination with polymyxin B or fused at the N-terminus with the antimicrobial peptide cecropin A (CecA), LysKP213 exhibited increased antibacterial activity against Gram-negative pathogens, including K. pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli, both in vitro and in vivo. These results indicated that LysKP213 is a highly thermostable endolysin that, when combined with or fused with an outer membrane permeabilizer, has enhanced antibacterial activity and is a candidate agent for the control of infections by Gram-negative pathogens. [ABSTRACT FROM AUTHOR]

Bacterial biofilms, often forming on medical devices, can lead to treatment failure due to their increased antimicrobial resistance. Cefepime-avibactam (CFP-AVI) exhibits potent activities against Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumoniae (K. pneumoniae) when used with polymyxin B (PMB). However, its efficacy in biofilm-related infections is unknown. The present study aimed to evaluate the activity of PMB combined with CFP-AVI against the biofilms of PMB-resistant Gram-negative bacteria. Five K. pneumoniae strains and three P. aeruginosa strains known to be PMB-resistant and prone to biofilm formation were selected and evaluated. Antimicrobial susceptibility assays demonstrated that the minimal biofilm inhibitory and eradication concentrations of PMB and CFP-AVI for biofilms formed by the eight strains were significantly higher than the minimal inhibitory concentrations of the antibiotics for planktonic cells. The biofilm formation inhibition and eradication assays showed that PMB combined with CFP-AVI cannot only suppress the formation of biofilm but also effectively eradicate the preformed mature biofilms. In a modified in vitro pharmacokinetic/pharmacodynamic biofilm model, CFP-AVI monotherapy exhibited a bacteriostatic or effective activity against the biofilms of seven strains, whereas PMB monotherapy did not have any activity at 72 h. However, PMB combined with CFP-AVI demonstrated bactericidal activity against the biofilms of all strains at 72 h. In an in vivo Galleria mellonella infection model, the 7-day survival rates of larvae infected with biofilm implants of K. pneumoniae or P. aeruginosa were 0-6.7%, 40.0-63.3%, and 46.7–90.0%, respectively, for PMB alone, CFP-AVI alone, and PMB combined with CFP-AVI; the combination therapy increased the rate by 6.7–33.3% (P < 0.05, n = 6), compared to CFP-AVI monotherapy. It is concluded that PMB combined with CFP-AVI exhibits effective anti-biofilm activities against PMB-resistant K. pneumoniae and P. aeruginosa both in vitro and in vivo, and thus may be a promising therapeutic strategy to treat biofilm-related infections. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical efficacy of different species of polymyxin drugs in the treatment of Carbapenem- Resistant Gram-negative bacilli (CR-GNB) resistant to ceftazidime-avibactam (CZA). Methods: Patients infected by CR-GNB strains and treated with polymyxin drugs were selected and divided into colistin methanesulfonate (CMS) group and colistin sulfate/polymyxin B (CSPB) group to observe clinical efficacy and safety. Results: 65 patients were eventually included (CMS group, n = 29; CSPB group, n = 36). The clinical efficacy, microbiological eradication rate and 28-day mortality between the two groups were similar, with no statistical significance (51.72% vs. 50.00%, p = 0.890; 55.17% vs. 52.78%, p = 0.847; 17.24% vs. 25.00%, p = 0.449). With regard to renal safety, the incidence of acute kidney injury (AKI) in the CMS group was significantly higher than that in the CSPB group (34.48% vs. 5.56%, p = 0.003). Among them, the incidence of AKI grade 3 in the CMS group tended to be higher than that in the CSPB group (24.14% vs. 5.56%, p = 0.066). Conclusion: The results based on small sample size from a single center showed that clinical response to the treatment of ceftazidime-avibactam resistant Gram-negative bacillus infections is similar for CMS and Colistin Sulfate/Polymyxin B, but the nephrotoxicity of CMS is greater than that of polymyxin sulfates. [ABSTRACT FROM AUTHOR]