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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]

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]

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]

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]

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]

The rise in multi-drug resistant Gram-negative bacterial infections has led to an increased need for "last-resort" antibiotics such as polymyxins. However, the emergence of polymyxin-resistant strains threatens to bring about a postantibiotic era. Thus, there is a need to develop new polymyxin-based antibiotics, but a lack of knowledge of the mechanism of action of polymyxins hinders such efforts. It has recently been suggested that polymyxins induce cell lysis of the Gram-negative bacterial inner membrane (IM) by targeting trace amounts of lipopolysaccharide (LPS) localized there. We use multiscale molecular dynamics (MD), including longtimescale coarse-grained (CG) and all-atom (AA) simulations, to investigate the interactions of polymyxin B1 (PMB1) with bacterial IM models containing phospholipids (PLs), small quantities of LPS, and IM proteins. LPS was observed to (transiently) phase separate from PLs at multiple LPS concentrations, and associate with proteins in the IM. PMB1 spontaneously inserted into the IM and localized at the LPS-PL interface, where it cross-linked lipid headgroups via hydrogen bonds, sampling a wide range of interfacial environments. In the presence of membrane proteins, a small number of PMB1 molecules formed interactions with them, in a manner that was modulated by local LPS molecules. Electroporation-driven translocation of PMB1 via water-filled pores was favored at the protein-PL interface, supporting the 'destabilizing' role proteins may have within the IM. Overall, this in-depth characterization of PMB1 modes of interaction reveals how small amounts of mislocalized LPS may play a role in pre-lytic targeting and provides insights that may facilitate rational improvement of polymyxin-based antibiotics. [ABSTRACT FROM AUTHOR]

Ventilator-associated pneumonia (VAP) remains one of the most common hospital-acquired infections (HAI). Considering the complicated diagnosis and the lack of effective treatment, prophylactic measures are suggested as the new standard to prevent the disease. Although VAP often manifests a polymicrobial nature, Pseudomonas aeruginosa remains one of the pathogens associated with the highest morbidity and mortality rates within these mechanically ventilated patients. In this paper, we report on the development of an antibacterial hydrogel coating using the polymyxin B (PMB) peptide to prevent bacterial adhesion to the polymeric substrate. We fully characterized the properties of the coating using atomic force microscopy (AFM), scanning electron microscopy (SEM), wettability analyses and Fourier-transform infrared (FTIR) and Raman spectroscopy. Furthermore, several biological assays confirmed the antibacterial and anti-biofilm effect of the tubing for at least 8 days against P. aeruginosa. On top of that, the produced coating is compliant with the requirements regarding cytocompatibility stated in the ISO (International Organization for Standardization) 10993 guidelines and an extended release of PMB over a period of at least 42 days was detected. In conclusion, this study serves as a foundation for peptide-releasing hydrogel formulas in the prevention of VAP. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the in vitro drug susceptibility of various Carbapenemase-Producing Enterobacteriaceae (CPE) genotypes and elucidate the underlying mechanisms of amikacin resistance. Methods: A total of 72 unique CPE strains were collected from the Second Hospital of Jiaxing between 2019 and 2022, including 51 strains of Klebsiella pneumoniae, 11 strains of Escherichia coli, 6 strains of Enterobacter cloacae, 2 strains of Klebsiella aerogenes, 1 strain of Citrobacter freundii, and 1strain of Citrobacter werkmanii. Among these strains, 24 carried blaKPC gene, 20 carried blaNDM gene, 23 carried blaOXA−48−like gene, and 5 carried both blaKPC and blaNDM. We measured the in vitro activity of amikacin and other common antibiotics. Strains carrying blaOXA−48-like gene were selected for whole genome sequencing (WGS) via next-generation sequencing to identify genes related to antimicrobial resistance (AMR) and virulence factor (VF). Results: Out of the 72 CPE strains tested, 41.7% exhibited resistance to amikacin. The drug resistance rates for K. pneumoniae, E. coli, and Enterobacter spp. were 51.0%, 27.3%, and 10.0%, respectively. The majority of the CPE strains (> 90%) displayed resistance to cephalosporins and carbapenems, while most of them were sensitive to polymyxin B and tigecycline (97.2% and 94.4%). The amikacin resistance rate was 100% for strains carrying blaOXA−48, 20.8% for those with blaKPC, 5.0% for those with blaNDM, and 20.0% for those with both blaKPC and blaNDM. These differences were statistically significant (P < 0.05). Through sequencing, we detected aminoglycoside resistance genes rmtF and aac(6')-Ib, VF genes iucABCD and rmpA2 in OXA-48-producing multidrug resistance and highly virulent strains. These genes were located on a IncFIB- and IncHI1B-type plasmid, respectively. Both plasmids were highly homologous to the plasmid from OXA-232 strains in Zhejiang province and Shanghai province. Integration of these resistance genes into the IncFIB plasmid, facilitated by the IS6 and/or Tn3 transposons, resulted in OXA232-producing K. pneumoniae with amikacin resistance. Conclusion: This study identified significant amikacin resistance in CPE strains, particularly in those carrying the blaOXA−48 gene. Resistance genes rmtF and aac(6')-Ib were identified on plasmids. These results highlight the need for careful monitoring of amikacin resistance. [ABSTRACT FROM AUTHOR]

Sepsis and septic shock are frequent and severe clinical pictures in intensive care medicine that result from a dysregulated immune response to an infection and cause a high mortality rate. This article provides an overview of the various extracorporeal procedures used to treat sepsis. Various procedures are used to treat sepsis and septic shock. These include high-volume hemofiltration (HVHF), very high-volume hemofiltration (VHVHF), high cut-off filter (HCO), polymyxin B hemoperfusion and cytokine adsorption filters. The HVHF and VHVHF remove inflammatory mediators but show no significant benefit in terms of stabilization and survival in sepsis patients. The HCO filters effectively eliminate cytokines but so far there is no evidence of a survival benefit. Polymyxin B hemoperfusion shows promising results in initial studies in certain patient groups, while evidence for cytokine adsorption filters is limited. Combined plasma filtration and adsorption (CPFA) and therapeutic plasma exchange (TPE) have so far shown promising results in small studies. Although CPFA shows no survival benefit, TPE may have protective effects on the vascular glycocalyx. Extracorporeal procedures carry risks such as thrombosis and loss of proteins and clotting factors. The therapeutic benefit of these procedures in the treatment of sepsis remains unclear and further prospective randomized multicenter studies are needed to evaluate their efficacy and safety. There are currently no guideline recommendations for the routine use of these procedures in sepsis. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Since polymyxin B has a restricted therapeutic range and increased danger of both neurological damage and kidney damage, it is no longer the first choice for treating emerging gram-negative bacteria with multiple antibiotic resistance. The optimal dose schedule for patients with renal impairment regarding polymyxin B, it is provided as a chemically active formulation and primarily removed via methods other than kidney, is still up for debate. Similar to colistin, polymyxin-B effectively combats gram-negative aerobic bacterium that is resistant to several drugs such as Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli that produces carbapenemase, and Klebsiella pneumoniae. As a result, polymyxins cause cell apoptosis by inducing pan-caspase activation through many routes in a manner that is dependent on time and concentration. One of the most frequent and undesirable side effects of polymyxins is the development of AKI. A great deal of pharmacokinetic studies that have been published to far concur that creatinine clearance affects polymyxin B clearance; nevertheless, there is ongoing debate on the extent of this influence. [ABSTRACT FROM AUTHOR]

The problem of antimicrobial resistance (AMR) caused by the abuse of antibiotics is becoming serious. The development of antibacterial materials with synergistic efficiency and treatment of deep tissue/organ infections is imminent. Herein, synergistic antibacterial nanoparticles (MPH NPs) are prepared by loading antibacterial peptide polymyxin B (PMB) on Fe‐based MOF (MIL‐100) with hyaluronic acid (HA) modification. MPH NPs exerts antibacterial effects by chemodynamic therapy (CDT) and the release of PMB. MPH NPs have broad‐spectrum antibacterial properties on Gram‐negative bacteria (E. coli, 100%), Gram‐positive bacteria (S. aureus, 98.5 %), and MRSA (98.4%). Importantly, MPH NPs not only promote the healing of infected wounds but also target lungs to accomplish organ infection therapy. Therefore, this study provides a new strategy for designing a synergetic anti‐AMR bacteria system and the function for deep tissue/organ infection therapy in the future. [ABSTRACT FROM AUTHOR]

Lipopeptides are an important class of biomolecules for drug development. Compared with conventional acylation, a chemoselective lipidation strategy offers a more efficient strategy for late‐stage structural derivatisation of a peptide scaffold. It provides access to chemically diverse compounds possessing intriguing and non‐native moieties. Utilising an allenamide, we report the first semisynthesis of antimicrobial lipopeptides leveraging a highly efficient thia‐Michael addition of chemically diverse lipophilic thiols. Using chemoenzymatically prepared polymyxin B nonapeptide (PMBN) as a model scaffold, an optimised allenamide‐mediated thia‐Michael addition effected rapid and near quantitative lipidation, affording vinyl sulfide‐linked lipopeptide derivatives. Harnessing the utility of this new methodology, 22 lipophilic thiols of unprecedented chemical diversity were introduced to the PMBN framework. These included alkyl thiols, substituted aromatic thiols, heterocyclic thiols and those bearing additional functional groups (e.g. amines), ultimately yielding analogues with potent Gram‐negative antimicrobial activity and substantially attenuated nephrotoxicity. Furthermore, we report facile routes to transform the allenamide into a β‐keto amide on unprotected peptides, offering a powerful "jack‐of‐all‐trades" synthetic intermediate to enable further peptide modification. [ABSTRACT FROM AUTHOR]

Novel antimicrobial strategies are urgently needed to treat extensively drug‐resistant (XDR) bacterial infections due to the high mortality rate and lack of effective therapeutic agents. Herein, nanoengineered human umbilical cord mesenchymal stem cells (hUC‐MSCs), named PMZMU, are designed as a sonosensitizer for synergistic sonodynamic‐nano‐antimicrobial therapy against gram‐negative XDR bacteria. PMZMU is composed of a bacterial targeting peptide (UBI29‐41) modified hUC‐MSCs membrane (MSCm), a sonosensitizer meso‐tetra(4‐car‐boxyphenyl) porphine doped mesoporous organo‐silica nanoparticle and an acidity‐responsive metal–organic framework ZIF‐8. This innovative formulation enables efficient loading of polymyxin B, reduces off‐target drug release, increases circulation and targeting efficacy, and generates reactive oxygen species upon ultrasound irradiation. PMZMU exhibits remarkable in vitro inhibitory activity against four XDR bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PA), and Escherichia coli. Taking advantage of the bacterial targeting ability of UBI29‐41 and the inflammatory chemotaxis of hUC‐MSC, PMZMU can be precisely delivered to lung infection sites thereby augmenting polymyxin B concentration. PMZMU‐mediated sonodynamic therapy significantly reduces bacterial burden, relieves inflammatory damage by promoting the polarization of macrophages toward M2 phenotype, and improves survival rates without introducing adverse events. Overall, this study offers promising strategies for treating deep‐tissue XDR bacterial infections, and guides the design and optimization of biomimetic nanomedicine. [ABSTRACT FROM AUTHOR]

To achieve the AUC-guided dosing, we proposed three methods to estimate polymyxin B AUC across 24 h at steady state (AUCSS,24h) using limited concentrations after its first dose. Monte Carlo simulation based on a well-established population PK model was performed to generate the PK profiles of 1000 patients with normal or abnormal renal function. Polymyxin B AUCSS,24h was estimated for each subject using three methods (two-point PK approach, three-point PK approach, and four-point PK approach) based on limited concentration data in its first dose and compared with the actual AUC at steady state calculated using the linear-trapezoidal formula. In patients with normal renal function, the mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was −8.73%, 1.37%, and −0.48%, respectively. The corresponding value was −11.15%, 1.99%, and −0.28% in patients with renal impairment, respectively. The largest mean bias of two-point PK approach, three-point PK approach, and four-point PK approach was −12.63%, −6.47%, and −0.54% when the sampling time shifted. The Excel calculators designed based on the three methods can be potentially used to optimise the dosing regimen of polymyxin B in the clinic. [ABSTRACT FROM AUTHOR]

An 8‐year‐old American Quarter Horse gelding was treated with extracorporeal hemoperfusion (HP) therapy for treatment of Clostridioides difficile (C. difficile) colitis‐induced systemic inflammatory response syndrome (SIRS). The gelding developed C. difficile associated peracute colitis and severe SIRS as evidenced by a positive fecal C. difficile PCR and tachypnea, tachycardia, fever, neutropenia, altered mucous membrane color, and hyperlactatemia. Concurrent acute kidney injury in the horse limited the use of routine anti‐inflammatory and anti‐lipopolysaccharide treatments, including flunixin meglumine and polymyxin B, because of potential for nephrosis. Extracorporeal HP therapy was performed twice within 48 hours of the onset of severe SIRS during which the horse's physical examination variables stabilized. The horse was euthanized after 4 days because of laminitis. These findings support further investigation of extracorporeal HP therapy as an adjunctive treatment for severe SIRS/sepsis in horses. [ABSTRACT FROM AUTHOR]

Biofilm-associated bacterial infection brings serious threats to global public health owing to serious antibiotic resistance. It is urgently needed to develop innovative strategies to combat biofilm-associated bacterial infections. Polymyxins stand out as the last line of defense against Gram-negative bacteria. However, serious nephrotoxicity of polymyxins severely limits their clinical utility. Herein, a hypoxia-responsive liposome is designed as the nanocarrier of polymyxin B (PMB) to combat biofilms developed by Gram-negative bacteria. A metronidazole modified lipid (hypoxia-responsive lipid (HRLipid)) is synthesized to fabricate hypoxia-responsive liposomes (HRLip). PMB loaded hypoxia-responsive liposomes (HRL-PMB) is then prepared to mitigate the nephrotoxicity of PMB while preserving its excellent bactericidal activity. HRL-PMB shows very low hemolysis and cytotoxicity due to liposomal encapsulation of PMB. PMB can be readily released from HRL-PMB in response to hypoxic biofilm microenvironment, exerting its bactericidal activity to realize biofilm eradication. The excellent in vivo antibiofilm ability of HRL-PMB is confirmed by a Pseudomonas aeruginosa infected zebrafish model and a P. aeruginosa pneumonia infection model. Meanwhile, HRL-PMB can greatly reduce the nephrotoxicity of PMB after intravenous injection. The hypoxia-sensitive liposomes held great promise to improve the biosafety of highly toxic antibiotics while preserving their intrinsic bactericidal ability, which may provide an innovative strategy for combating biofilm-associated infections. [ABSTRACT FROM AUTHOR]

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Escherichia coli, a rod-shaped Gram-negative bacterium, is a significant causative agent of severe clinical bacterial infections. This study aimed to analyze the epidemiology of extended-spectrum β-lactamase (ESBL)-producing mcr-1 -positive E. coli in Shandong, China. We collected 668 non-duplicate ESBL-producing E. coli strains from clinical samples at Shandong Provincial Hospital between January and December 2018, and estimated their minimum inhibitory concentrations (MICs) using a VITEK® 2 compact system and broth microdilution. Next-generation sequencing and bioinformatic analyses identified the mcr-1 gene and other resistance genes in the polymyxin B-resistant strains. The conjugation experiment assessed the horizontal transfer capacity of the mcr-1 gene. Of the strains collected, 24 polymyxin B-resistant strains were isolated with a positivity rate of 3.59% and among the 668 strains, 19 clinical strains carried the mobile colistin resistance gene mcr-1, with a positivity rate of approximately 2.8%. All 19 clinical strains were resistant to ampicillin, cefazolin, ceftriaxone, ciprofloxacin, levofloxacin, and polymyxin B. Seventeen strains successfully transferred the mcr-1 gene into E. coli J53. All transconjugants were resistant to polymyxin B, and carried the drug resistance gene mcr-1. The 19 clinical strains had 14 sequence types (STs), with ST155 (n = 4) being the most common. The whole-genome sequencing results of pECO-POL-29_mcr1 revealed that no ISApl1 insertion sequences were found on either side of the mcr-1 gene. Our study uncovered the molecular epidemiology of mcr-1-carrying ESBL-producing E. coli in the region and suggested horizontal transmission mediated by plasmids as the main mode of mcr-1 transmission. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii emerged as one of the most important pathogens for the development of new antimicrobials due to the worldwide detection of isolates resistant to all commercial antibiotics, especially in nosocomial infections. Biofilm formation enhances A. baumannii survival by impairing antimicrobial action, being an important target for new antimicrobials. Fluopsin C (FlpC) is an organocupric secondary metabolite with broad-spectrum antimicrobial activity. This study aimed to evaluate the antibiofilm activity of FlpC in established biofilms of extensively drug-resistant A. baumannii (XDRAb) and the effects of its combination with polymyxin B (PolB) on planktonic cells. XDRAb susceptibility profiles were determined by Vitek 2 Compact, disk diffusion, and broth microdilution. FlpC and PolB interaction was assessed using the microdilution checkerboard method and time–kill kinetics. Biofilms of XDRAb characterization and removal by FlpC exposure were assessed by biomass staining with crystal violet. Confocal Laser Scanning Microscopy was used to determine the temporal removal of the biofilms using DAPI, and cell viability using live/dead staining. The minimum inhibitory concentration (MIC) of FlpC on XDRAb was 3.5 µg mL−1. Combining FlpC + PolB culminated in an additive effect, increasing bacterial susceptibility to both antibiotics. FlpC-treated 24 h biofilms reached a major biomass removal of 92.40 ± 3.38% (isolate 230) using 7.0 µg mL−1 FlpC. Biomass removal occurred significantly over time through the dispersion of the extracellular matrix and decreasing cell number and viability. This is the first report of FlpC's activity on XDRAb and the compound showed a promissory response on planktonic and sessile cells, making it a candidate for the development of a new antimicrobial product. [ABSTRACT FROM AUTHOR]

This article explores the principles of dialysis and how it can affect antibiotic therapy in critically ill patients. It specifically focuses on the challenges of dosing antibiotics during dialysis and the variability in how drugs are processed in the body. The authors use the example of colistin, an antibiotic used for multidrug-resistant infections, to highlight the importance of understanding how antibiotics are metabolized in patients undergoing dialysis. They also discuss the potential risks and challenges associated with antibiotic dosing in critically ill patients on continuous kidney replacement therapy. The article emphasizes the need for careful monitoring and appropriate drug levels to ensure effective treatment and minimize the risk of therapeutic failure. [Extracted from the article]

To investigate the characteristics and drug resistance patterns of Klebsiella pneumoniae (K. pneumoniae) infection in pediatric intensive care unit (PICU). Methods: K. pneumoniae strains from 17 domestic PICUs were analyzed for overall condition and drug resistance using WHO-NET software. Results: From 2016 to 2022, there was a linear increase in the detection rate of K. pneumoniae (P< 0.05), with a total of 2591 (9.7%) strains detected. The primary sites of K. pneumoniae detection were the respiratory tract (71.1%), blood (8.6%), and urinary tract (7.1%). K. pneumoniae's resistance to penicillin drugs exceeded 90%, and are over 50% to cephalosporins. Resistance to cefoperazone-sulbactam decreased from 51.7% to 25.7%, and ranged from 9.1% to 20.8% for ceftolozane-tazobactam. Carbapenem-resistant K. pneumoniae strains constituted 32.3%. Resistance to imipenem and meropenem have decreased to 33.8% and 40.2%, while increased to 35.2% for ertapenem. Levofloxacin and amikacin resistance rates have decreased to 25.7% and 9.1%, but remain high at 63.8% for moxifloxacin and 44.6% for ciprofloxacin. K. pneumoniae demonstrated the lowest resistance rates to polymyxin B (0.9%), tigecycline (2.2%), and polymyxin E (3.1%). No strain of K. pneumoniae was resistant to both polymyxin B and meropenem. However, some strains showed co-resistance to meropenem with other antibiotics, including tigecycline (2%), imipenem (16%), amikacin (27%), colistin (37%), and levofloxacin (41%). Conclusion: The rates of isolation and drug resistance of K. pneumoniae in PICU have significantly increased over 7 years. Careful antibiotic use, infection control strategies, and appropriate antibiotic combinations are crucial in addressing this problem. [ABSTRACT FROM AUTHOR]

Background: Hypervirulent carbapenem-resistant K. pneumoniae (hv-CRKP) has been spreading rapidly worldwide. Here, we investigated the genomic characteristics of ST11 K. pneumoniae isolate SM117 with capsular serotype KL25, co-carrying blaNDM-5, two copies of blaKPC-2 and multiple plasmid-borne virulence genes from a county level hospital in China. Methods: Antimicrobial susceptibility of K. pneumoniae SM117 was evaluated. The Illumina NovaSeq 6000 and Oxford Nanopore MinION platforms were applied to sequence the genome and then de novo assembled. The genome sequence was annotated using the NCBI Prokaryotic Genome Annotation Pipeline and further subjected to identify the sequence type (ST), capsular type, antibiotic resistance genes, plasmid replicon types and virulence genes. The phylogenetic analysis was performed based on the core genome single nucleotide polymorphisms (cgSNPs) using CSI Phylogeny 1.4, and further visualized by Interactive Tree of Life (iTOL) V5 web server. Results: The whole-genome sequence of K. pneumoniae SM117 is made up of eight contigs totaling 6,104,486 bp, contain a 5,612,620 bp single chromosome and seven plasmids. The isolate was assigned to ST11 with capsular serotype KL25, co-carrying including blaNDM-5, blaKPC-2 and multiple plasmid-borne virulence genes including rmpA2 and aerobactin genes iucABCD-iutA. The coexistence of blaKPC and blaNDM in K. pneumoniae strains exhibit a high degree of resistance to β-lactam antibiotics. The strain SM117 also carries multiple antibiotic resistance genes, making it resistant to all antibiotics except polymyxin. The closest relative of K. pneumoniae C793 was identified in 2023 from a hospital surface sample in Zhejiang, China, with just 52 SNPs difference. Conclusion: This study reported the genomic characteristics of a multidrug-resistant ST11 K. pneumoniae with capsular serotype KL25, co-carrying blaNDM-5, two copies of blaKPC-2 genes and multiple plasmid-borne virulence genes in China. These findings will provide important knowledge of the antibiotic resistance mechanisms, genomic epidemiological characteristics and transmission dynamics of multidrug-resistant K. pneumoniae. [ABSTRACT FROM AUTHOR]

China's competition authorities imposed a record penalty in the pharmaceutical sector against four pharmaceutical companies for jointly abusing their market dominance and engaging in excessive pricing behavior. This incident caused widespread concern and controversy, and has raised questions about the fairness and transparency of the pharmaceutical industry. From the perspective of antitrust enforcement, the administrative penalty decision has significant value for discussion in several aspects, including the identification of the subjects engaged in joint abuse of market dominance, the delineation of the relevant market, the determination of excessive prices, the imposition of penalties, and subsequent corrective measures. Furthermore, the coordination and cooperation between the competition authorities and the health security authorities in this case also merit discussion. This opinion provides an overview of the grounds of the decision and a detailed analysis in the context of China's anti-monopoly regulations and guidelines for the pharmaceutical sector. [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 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%.

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.

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.

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]

Abstract Due to the lack of other treatment options, a rebirth of polymyxins is urgently required. Colistin (also called polymyxin E) and polymyxin B are the only two examples of this antibiotic class that were effectively employed in such critical situations. In the present work, both of the two studied medications were quantified via a simple, green, and non-extracting spectrophotometric approach based on the formation of ion-pair complexes with Erythrosine B. Without using any organic solvents, the pink color of the created complexes was detected at wavelength = 558 nm. To achieve the highest intensity of absorbance, optimum conditions were established by the screening of many experimental factors such as pH, buffer volume, the volume of Erythrosine B, and the time consumed to undergo the reaction. For Colistin and Polymyxin B respectively, Beer-Lambert’s law was observed at the concentration ranges of 1–6, 1–9 µg mL− 1. The technique was approved and validated following ICH recommendations. Lastly, the suggested approach has been successfully implemented to quantify the cited medications colorimetrically, for the first time, in their parenteral dosage forms with excellent recoveries. Also, Content uniformity testing was implemented.

Abstract Background The study aimed to compare polymyxin B with colistimethate sodium (CMS) regarding neurotoxicity, nephrotoxicity and 30-day mortality in patients with MDR Gram-negatives. Methods All adult patients who received polymyxin B or CMS for at least 24 h for the treatment of MDR microorganisms were evaluated retrospectively. Results Among 413 initially screened patients, 147 patients who were conscious and able to express their symptoms were included in the neurotoxicity analysis. 13 of 77 patients with polymyxin B and 1 of 70 with CMS had neurotoxic adverse events, mainly paresthesias. All events were reversible after drug discontinuation. Among 290 patients included in nephrotoxicity analysis, the incidence of acute kidney injury (AKI) was 44.7% and 40.0% for polymyxin B and CMS, respectively (p = 0.425). AKI occurred two days earlier with colistin than polymyxin B without statistical significance (median (IQR): 5 (3–11) vs. 7 (3–12), respectively, p = 0.701). Polymyxin therapy was withdrawn in 41.1% of patients after AKI occurred and CMS was more frequently withdrawn than polymyxin B (p = 0.025). AKI was reversible in 91.6% of patients with CMS and 79% with polymyxin B after the drug withdrawal. Older age, higher baseline serum creatinine and the use of at least two nephrotoxic drugs were independent factors associated with AKI (OR 1.05, p

Purpose The objective of this study was to evaluate the effect of Polymyxin B hemoperfusion (PMX-HP) on patients with sepsis. Methods A systematic review and meta-analysis was performed using relevant articles retrieved from 3 databases (PubMed, Cochrane Library, EMBASE). Randomized studies from 1 January 1999 to 28 February 2022 were examined to determine the clinical results of PMX-HP. A meta-analysis was carried out using the random-effects method, meta-regression with clinical variables, and assessment of risk of bias (ROB) tool (Cochrane ROB assessment tool). Mortality was evaluated within 60 days of hospitalization (in-hospital death 28-day, 30-day, and 60-day mortality) and predictors associated with mortality were determined using meta-regression. Results There were 11 randomized studies with 548 patients included in the meta-analysis. The pooled mortality was 35% (95% CI, 27%-42%, 95% CI 0.53-0.96). Further subgroup analysis was performed according to the duration of PMX-HP. An extension of PMX-HP treatment beyond 2 hours (pooled mortality, 43%; 95% CI, 9%-76%) compared with a 2-hour session (pooled mortality, 33%. 95% CI, 27%-38%) showed an increase in mortality rates. However, this was not statistically significant. Univariate meta-regression showed that patient’s age, the acute physiology and chronic health evaluation score, and the sequential organ failure assessment score did not significantly impact mortality. Conclusion While PMX-HP is valuable in the management of septic shock, treatment duration should be based on careful assessment of the patient's condition, the risks and benefits of prolonged therapy, and the overall treatment strategy including antimicrobial management and source control.

Lixia Li,1,&ast; Xiaohui Huang,1,&ast; Jingxian Liu,2,&ast; Chao Li,1 Zhiyan Lin,1 Rongrong Ren,3 Yan Zhang,3 Haoshu Ding,3 Jihui Chen,1 Yanfei Mao3 1Department of Pharmacy, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Anesthesiology and SICU, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfei Mao; Jihui Chen, Email maoyanfei@xinhuamed.com.cn; chenjihui@xinhuamed.com.cnBackground: Polymyxin B (PMB)-based combination therapies are used to treat severe carbapenem-resistant gram-negative bacterial (CR-GNB) infections. This observational study investigated the relationship between clinical factors, including PMB concentration, and clinical efficacy and safety.Patients and Methods: Polymyxin B regimens were optimized through therapeutic drug monitoring (TDM) and area under the concentration-time curve (AUC). In all, 382 samples were tested from 130 patients. Logistic regression was used to analyze the relationships between variables with clinical efficacy and 30-day mortality factors were analyzed by Cox regression. The sensitivity and specificity of Cmin and AUC for the occurrence of acute kidney injury (AKI) were determined by ROC curve analysis.Results: The clinical effectiveness of PMB was 65.4%. Multivariate logistic regression analysis revealed that lung infection, continuous renal replacement therapy, and C-reactive protein were independent factors significantly associated with efficacy. AKI occurred in 14.6% of the patients during treatment; age > 73 years (OR: 3.63; 95% CI: 1.035– 12.727; P = 0.044), Cmin greater than 2.3 μg/mL (OR: 7.37; 95% CI: 1.571– 34.580; P = 0.011), combined vancomycin (OR: 9.47; 95% CI: 1.732– 51.731; P = 0.009), and combined piperacillin-tazobactam (OR: 21.87; 95% CI: 3.139– 152.324; P = 0.002) were independent risk factors. The identified PMB cut-offs for predicting AKI were Cmin = 2.3 μg/mL and AUC = 82.0 mg h/L.Conclusion: Polymyxin B-based combination regimens are effective in treating CR-GNB infections, particularly bloodstream infections, but have shown unsatisfactory for lung infections. Cmin ≥ 2.3 μg /mL and AUC ≥ 82.0 mg h/L may increase PMB-associated AKI incidence. PMB dose should be adjusted based on TDM to ensure efficacy.Keywords: Polymyxin B, PMB therapeutic drug monitoring, TDM, carbapenem-resistant gram-negative bacteria, CR-GNB, clinical efficacy, acute kidney injury, AKI

ESKAPE pathogens are a panel of most recalcitrant bacteria that could "escape" the treatment of antibiotics and exhibit high incidence of drug resistance. The emergence of multidrug-resistant (MDR) ESKAPE pathogens (particularly Gram-negative bacteria) accounts for high risk of mortality and increased resource utilization in health care. Worse still, there has been no new class of antibiotics approved for exterminating the Gram-negative bacteria for more than 50 years. Therefore, it is urgent to develop novel antibacterial agents with low resistance and potent killing efficacy against Gram-negative ESKAPE pathogens. Herein, we present a class of fluoropolymers by mimicking the amphiphilicity of cationic antimicrobial peptides. Our optimal fluoroamphiphilic polymer (PD45HF5) displayed selective antimicrobial ability for all MDR Gram-negative ESAKPE pathogens, low resistance, high in vitro cell selectivity, and in vivo curative efficacy. These findings implied great potential of fluoroamphiphilic cationic polymers as promising antibacterial agents against MDR Gram-negative ESKAPE bacteria and alleviating antibiotic resistance. [ABSTRACT FROM AUTHOR]

Introduction: Polymyxin B is widely used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the pharmacokinetic study data of PB in the elderly are scarce. Herein, a simple method to measure the concentration of PB in human plasma was developed and validated by high performance liquid chromatography--tandem mass spectrometry, and it was applied to a PK study in the elderly. Methods: PB was extracted from human plasma by a rapid protein-precipitation method using 0.1% formic acid in methanol and then separated on an ultimate AQ-C18 column using linear gradient elution with a 0.5-mL/min flow rate. Subsequently, PB was detected using a mass spectrometer operated in positive-ion and multiple-reaction-monitoring modes. Results: The lower limits of quantification of the method for Polymyxin B1 and Polymyxin B2 were 1.00 and 0.10 μg/mL, respectively. The linear ranges for PB1 and PB2 were 1.00-20.02 and 0.10-2.04 μg/mL, respectively. Patients receiving a 75-mg maintenance dose every 12h had AUCss, 24 h, and Css, av values of 117.70 ± 37.03 μg h/mL and 4.14 ± 1.74 μg/mL, respectively. For patients receiving a 100 mg maintenance dose, these values were 152.73 ± 70.09 μg h/mL and 5.43 ± 2.85 μg/mL, respectively. Conclusion: The validated HPLC--MS/MS method was successfully applied to a study on the pharmacokinetics of PB in elderly patients infected with multidrug-resistant Gram-negative bacteria. Both two dose strategies in this study would have a excessive PB exposure in the elderly patients then the therapeutic window recommended by guidelines. [ABSTRACT FROM AUTHOR]

Due to the lack of other treatment options, a rebirth of polymyxins is urgently required. Colistin (also called polymyxin E) and polymyxin B are the only two examples of this antibiotic class that were effectively employed in such critical situations. In the present work, both of the two studied medications were quantified via a simple, green, and non-extracting spectrophotometric approach based on the formation of ion-pair complexes with Erythrosine B. Without using any organic solvents, the pink color of the created complexes was detected at wavelength = 558 nm. To achieve the highest intensity of absorbance, optimum conditions were established by the screening of many experimental factors such as pH, buffer volume, the volume of Erythrosine B, and the time consumed to undergo the reaction. For Colistin and Polymyxin B respectively, Beer-Lambert's law was observed at the concentration ranges of 1–6, 1–9 µg mL− 1. The technique was approved and validated following ICH recommendations. Lastly, the suggested approach has been successfully implemented to quantify the cited medications colorimetrically, for the first time, in their parenteral dosage forms with excellent recoveries. Also, Content uniformity testing was implemented. [ABSTRACT FROM AUTHOR]

Background: The study aimed to compare polymyxin B with colistimethate sodium (CMS) regarding neurotoxicity, nephrotoxicity and 30-day mortality in patients with MDR Gram-negatives. Methods: All adult patients who received polymyxin B or CMS for at least 24 h for the treatment of MDR microorganisms were evaluated retrospectively. Results: Among 413 initially screened patients, 147 patients who were conscious and able to express their symptoms were included in the neurotoxicity analysis. 13 of 77 patients with polymyxin B and 1 of 70 with CMS had neurotoxic adverse events, mainly paresthesias. All events were reversible after drug discontinuation. Among 290 patients included in nephrotoxicity analysis, the incidence of acute kidney injury (AKI) was 44.7% and 40.0% for polymyxin B and CMS, respectively (p = 0.425). AKI occurred two days earlier with colistin than polymyxin B without statistical significance (median (IQR): 5 (3–11) vs. 7 (3–12), respectively, p = 0.701). Polymyxin therapy was withdrawn in 41.1% of patients after AKI occurred and CMS was more frequently withdrawn than polymyxin B (p = 0.025). AKI was reversible in 91.6% of patients with CMS and 79% with polymyxin B after the drug withdrawal. Older age, higher baseline serum creatinine and the use of at least two nephrotoxic drugs were independent factors associated with AKI (OR 1.05, p < 0.001; OR 2.99, p = 0.022 and OR 2.45, p = 0.006, respectively). Septic shock, mechanical ventilation, presence of a central venous catheter and Charlson comorbidity index (OR 2.13, p = 0.004; OR 3.37, p < 0.001; OR 2.47, p = 0.004 and OR 1.21, p p < 0.001, respectively) were the independent predictors of mortality. The type of polymyxin was not related to mortality. Conclusions: Neurotoxicity is a relatively common adverse event that leads to drug withdrawal during polymyxins, particularly polymyxin B. Nephrotoxicity is very common during polymyxin therapy and the two polymyxins display similar nephrotoxic events with high reversibility rates after drug withdrawal. Close monitoring of AKI is crucial during polymyxin therapy, particularly, for elderly patients, patients who have high baseline creatinine, and using other nephrotoxic drugs. [ABSTRACT FROM AUTHOR]

Polymyxin B (PMB) is often considered as the last line of defense for treating carbapenem‐resistant Klebsiella pneumoniae (CRKP). However, its efficacy is hindered by limited penetration across the blood‐air barrier in the lung due to its low lipid solubility. To simultaneously increase PMB in epithelial lining fluid while suppressing the excessive inflammatory response in the lung, a novel nano‐biomimetic system "Siv‐PMB@G4@MM" is designed and fabricated by encapsulating PMB‐ and anti‐inflammatory Sivelestat (Siv)‐loaded G4 PAMAM dendrimers with macrophage membranes (MM). The Siv‐PMB@G4@MM displayed a superior acidic pH‐responsive release property and can target inflamed lung tissues, greatly increasing the concentrations of PMB and Siv at the infection site. Compared with free drugs, Siv‐PMB@G4@MM demonstrated superior synergistic antibacterial and anti‐inflammatory activities. Moreover, due to the ability of MM to sequester lipopolysaccharide (LPS) and some pro‐inflammatory cytokines, Siv‐PMB@G4@MM further enhanced the anti‐inflammatory potential of Siv. In mouse models of LPS‐induced acute lung injury, pulmonary bacterial infection, and sepsis‐induced pneumonia, Siv‐PMB@G4@MM significantly reduced inflammatory responses and/or bacterial burdens, mitigated neutrophil infiltration and pulmonary edema, and decreased neutrophil extracellular trap (NET) secretion. The highly improved biocompatibility and efficiency of the multifunctional Siv‐PMB@G4@MM presents a promising strategy for the clinical treatment of antibiotic‐resistant bacterial pneumonia. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the incidence and clinical characteristics of adverse drug reactions (ADR) induced by polymyxin B (PMB), so as to provide reference for rational medication in clinic. METHODS: CNKI, Wanfang Data, VIP, CBM, PubMed, Web of Science, Scopus, the Cochrane Library and Embase databases were retrieved to identify case reports or case series related to ADR induced by clinical injection of PMB. The retrieval time was from the establishment of the database to Oct. 31st, 2023. The literature were assessed by using the quality assessment tool provided by the Joanna Briggs Institute (JBI) Centre for Evidence-Based Health Care. Various methods including percentage calculations, summary tables, and other analytical techniques were employed to quantify the results and conduct descriptive analysis. RESULTS: A total of 37 articles of ADR induced by PMB were enrolled, including 51 patients, with 35 males (68. 63%) and 16 females (31. 37%), ranging in age from 14 to 86 years. ADR induced by PMB included skin pigmentation / allergy (n = 28), neurotoxicity (n = 18), renal impairment (n = 5), and rhabdomyolysis (n = 1). The occurrence time of ADR ranged from 5 minutes to 30 d after the initiation of drug administration. ADR occurred immediately after the first drug administration in 12 cases (23. 53%), while symptoms were improved or recovered in 32 cases (62. 75%) after drug discontinuation or symptomatic treatment. CONCLUSIONS: Clinical awareness and monitoring of ADR induced by PMB need to be strengthened, with timely diagnosis and treatment to ensure the safety of clinical medication. [ABSTRACT FROM AUTHOR]

The Médecins Sans Frontières Tertiary Orthopaedic Care center in Mosul, Iraq, provides reconstructive surgery, microbiological analysis, integrated infection prevention and control, and antibiotic stewardship services. Between May 2018 and February 2020, we recorded soft tissue and/or bone infections caused by gram-negative extensively drug-resistant (XDR) bacteria in 4.9% (13/266) of the admitted patients. The XDR bacteria identified among 12 patients in this case series were extended-spectrum β-lactamase–producing Klebsiella pneumoniae (n = 5, 41.7%) with intermediate sensitivity or resistance to imipenem and/or meropenem, Acinetobacter spp (n = 3, 25.0%; 2 Acinetobacter baumannii strains) resistant to imipenem and/or meropenem, Pseudomonas aeruginosa (n = 2, 16.7%) resistant to imipenem and meropenem, and extended-spectrum β-lactamase–producing Proteus mirabilis (n = 2, 16.7%) resistant to meropenem. Most XDR isolates were sensitive only to colistin or polymyxin B, neither of which is available in Iraq. Therefore, the only treatment option was multiple rounds of surgical debridement and wound care. The infection was deemed cured before discharge in 7 patients (58.3%). Meanwhile, 4 patients (33.3%) were discharged with unhealed wounds, and outpatient follow-up was planned. One patient died in the intensive care unit of a referral hospital after developing septicemia postsurgery. XDR bacteria pose substantial health risks in Iraq. Thus, improving antimicrobial stewardship and accessibility to essential antibiotics is critical to address this issue. [ABSTRACT FROM AUTHOR]

The current investigation explores the antibacterial properties of Quercetin, a flavonoid found in plants, and lemon peel extract, renowned for its rich bioactive content, against multiple drug resistant bacteria. The study method involved the identification of multidrug-resistant bacteria through antimicrobial susceptibility testing (AST). Nine standard bacterial strains exhibited resistance to different antibiotics, with a MAR index exceeding 0.10, including Ampicillin, Vancomycin, Polymyxin B, Nitrofurantoin, Trimethoprim, and Penicillin. In the present study bioactive compounds from lemon peel were extracted using two solvents, methanol and water, and their efficacy was assessed against drug-resistant bacteria. Minimum Inhibitory Concentration (MIC) values, determined by using the well plate method, revealed higher MIC values for the water extract (LPWE) compared to the methanol extract (LPME) and quercetin. For instance, the MIC for LPWE against E. hermanniensis ATCC 700323 was 140 mg/ml, whereas it was 50 mg/ml for quercetin & 1 mg/ml for LPME. From the results, it can be interpreted that Methanol extract was most effective against drug-resistant bacteria when compared to water extract and quercetin. Furthermore, GC-MS analysis was performed to analyze the chemical entities present in each extract. Given the activity of LPME, LPWE, and Quercetin against both Gram-negative bacteria and Gram-positive bacteria, these extracts hold promise as broadspectrum antibacterial agents applicable in various fields such as medicine, food, and cosmetics. [ABSTRACT FROM AUTHOR]

Most of the Escherichia coli turned into serious pathogens or developed antibiotic resistance, mainly due to their ability to show different phenotypic traits. In order to overcome the resistance to these antibiotics, the use of essential oils (EOs) is of great significance against highly pathogenic microorganisms. This study has been made to compare the in vitro antibacterial activity and further validated the same through the molecular docking study of 13 antibiotics such as ciprofloxacin, chloramphenicol, erythromycin, ampicillin, cefotaxime, rifampicin, kanamycin, vancomycin, streptomycin, penicillin, nalidixic acid, trimethoprim, and polymyxin, and 10 EOs such as garlic, tulsi, neem, clove, thyme, peppermint, coriander, tea, lavender, and eucalyptus against the target protein (DNA gyrase) of E. coli MTCC443. E. coli Microbial Type Culture Collection 443 was found to be highly sensitive to ciprofloxacin (zone of inhibition [ZOI], 2.5 cm ±0.1) and chloramphenicol (ZOI, 1.8 cm ±0.1), whereas garlic oil (ZOI, 5.5 cm ±0.1) and coriander oil (ZOI, 4.4 cm ±0.1) were found comparatively most effective. Further, the in silico investigation observed the same; ciprofloxacin (binding affinity: −7.2 kcal/mol) and chloramphenicol (binding affinity: −6.6 kcal/mol). Penicillin (binding affinity: −4.2 kcal/mol) and polymyxin (binding affinity: −0.3 kcal/mol) were found to be least effective against the tested microbe, whereas vancomycin (binding affinity: +0.8 kcal/mol) had no effect on it. Garlic (binding affinity: −7.8 kcal/mol), coriander (binding affinity: −6.8 kcal/mol), peppermint (binding affinity: −6.2 kcal/mol), and neem (binding affinity: −6.2 kcal/mol) oil exhibited the potent antibacterial activity against E. coli MTCC443, whereas thyme (binding affinity: −6.1 kcal/mol), tea tree (binding affinity: −4.9 kcal/mol), and tulsi (binding affinity: −3.8 kcal/mol) oil were observed moderately effective. Eucalyptus (binding affinity: −2.9 kcal/mol) and lavender (binding affinity: −2.8 kcal/mol) oil were found to be the least effective among all the oils tested. The pharmacokinetics and networking were performed to the pharmacology of the potential compounds. [ABSTRACT FROM AUTHOR]

Background: Polymyxins have re‐emerged as a last‐resort therapeutic option for infections caused by carbapenem‐resistant gram‐negative bacteria. Nephrotoxicity induced by polymyxins is a significant limitation of its use in the clinic. Polymyxin B and colistin sulfate are two widely used active formulations of polymyxins. However, there is a lack of studies conducting a comparative assessment of nephrotoxicity between the two formulations. This study aimed to compare the nephrotoxicity of polymyxin B and colistin sulfate in critically ill patients. Methods: We conducted a retrospective cohort study among critically ill patients who received intravenous polymyxin B or colistin sulfate for over 48 h from January 2017 to January 2024. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, and the secondary outcome was 30‐day all‐cause mortality. Additionally, the risk factors of polymyxins‐induced AKI and 30‐day all‐cause mortality were identified by Cox proportional hazard regression analysis. Results: A total of 473 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received polymyxin B compared to those who received colistin sulfate in the unmatched cohort (20.8% vs. 9.0%, p = 0.002) and in the propensity score matching cohort (21.1% vs. 7.0%, p = 0.004), respectively. However, there was no significant difference in 30‐day all‐cause mortality between the two groups. Polymyxin type, septic shock, and concomitant use of vasopressors were identified as independent risk factors for polymyxin‐induced AKI. Conclusions: The prevalence of AKI was higher among patients who received polymyxin B compared to those treated with colistin sulfate. However, there was no significant difference in 30‐day all‐cause mortality between the two groups. Further prospective, multicenter studies with larger sample sizes are needed to validate these findings. [ABSTRACT FROM AUTHOR]