To address the pressing issue of bacterial resistance,antibiotics with new mechanisms were urgently needed;yet,the majority of efforts centered on discovering novel structural compounds,often plagued by lengthy resear...To address the pressing issue of bacterial resistance,antibiotics with new mechanisms were urgently needed;yet,the majority of efforts centered on discovering novel structural compounds,often plagued by lengthy research timelines and unpredictability.In this study,we introduce an alternative strategy that rejuvenates outdated antibiotics through a unique delivery system.Specifically,we leveraged polymyxin B(PMB)and created a liposomal carrier encapsulating PMB and Fe2þ,designated P/Fe@L-P.When administered to PMB-resistant Acinetobacter baumannii,P/Fe@L-P triggered a downregulation of Nrf2 and GPX4 proteins,accompanied by a significant surge in reactive oxygen species and malondialdehyde levels,signifying the induction of ferroptosis.This mechanism imparted potent antibacterial activity,with P/Fe@L-P achieving minimal inhibitory and bactericidal concentrations of 54 and 192 mM,respectively,outperforming free PMB(72 and 768 mM).In vivo evaluations in mice models further validated the superior efficacy of P/Fe@L-P over PMB in treating PMB-resistant Acinetobacter baumannii pneumonia.This work establishes a highly effective and practical“old drug,new trick”paradigm,potentially expediting the fight against the escalating threat of bacterial resistance.展开更多
The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative ba...The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative bacterial infections,serves as a crucial final recourse against carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Nevertheless,the clinical usage of PMB is impeded by its pronounced nephrotoxicity and poor infection site targeting.This investigation is geared to construct a nanoparticle formulation(named HA-PMB@H)comprising hyaluronic acid(HA)and PMB via a simple Schiff base reaction and further coating HA by electrostatic action.HA-PMB@H shows an average size of(153.8±24.3)nm,and a mean zeta potential of(−25.6±5.2)mV.Additionally,PMB can be released from HA-PMB@H more thoroughly and efficiently at pH 5.5 compared to pH 7.4,which demonstrates the Schiff base modification of PMB paves the way for its release at focus of infection.The uptake ratio of HA-PMB@H by alveolar epithelial cells(RLE-6TN)surpassed that of free PMB devoid of HA,which facilitates to the intracellular sterilization of PMB.Furthermore,the employment of HA-PMB@H ameliorated the toxicity of PMB towards human embryonic kidney cells(HEK 293)and pulmonary microvascular endothelial cells(HULEC-5a).What is more,HA-PMB@H effectively managed severe pneumonia induced by CRKP samples from clinical patients diagnosed with CRKP infection in vivo,substantially enhancing the survival rate of mice.Consequently,this nano-delivery system holds promising clinical significance in the combat against drug-resistant bacterial infections.展开更多
Background:Intracranial infection after craniotomy is one of the most serious postoperative complications,especially multidrug-resistant(MDR)or extensively drug-resistant(XDR)bacterial meningitis,and strongly affects ...Background:Intracranial infection after craniotomy is one of the most serious postoperative complications,especially multidrug-resistant(MDR)or extensively drug-resistant(XDR)bacterial meningitis,and strongly affects the prognosis of patients.Current treatment experience regarding these infections is scarce.Case presentation:We report a case of severe intracranial infection of XDR Acinetobacter baumannii(A.baumannii)that was treated by intravenous(IV)injection,sequential intraventricular(IVT)injection of tigecycline and polymyxin B,and other anti-infective drugs.Good results were obtained,and the patient was eventually discharged from the hospital.This case is characterized by intracranial infection.Conclusions:The polymyxin B IV+IVT pathway is an ideal treatment strategy for XDR A.baumannii.The tigecycline IVT pathway is also a safe treatment option.展开更多
Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk t...Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.展开更多
Polymyxin B(PMB)is considered as the last line of antibiotic defense available to humans.The environmental effects of the combined pollution with PMB and heavy metals and their interaction mechanisms are unclear.We ex...Polymyxin B(PMB)is considered as the last line of antibiotic defense available to humans.The environmental effects of the combined pollution with PMB and heavy metals and their interaction mechanisms are unclear.We explored the effects of the combined pollution with PMB and arsenic(As)on the microbial composition of the soil and in the earthworm gut,as well as the spread and transmission of antibiotic resistance genes(ARGs).The results showed that,compared with As alone,the combined addition of PMB and As could significantly increase the bioaccumulation factor and toxicity of As in earthworm tissues by 12.1%and 16.0%,respectively.PMB treatment could significantly increase the abundance of Actinobacteria in the earthworm gut(from 35.6%to 45.2%),and As stress could significantly increase the abundance of Proteobacteria(from 19.8%to 56.9%).PMB and As stress both could significantly increase the abundance of ARGs and mobile genetic elements(MGEs),which were positively correlated,indicating that ARGs might be horizontally transferred.The inactivation of antibiotics was the main resistance mechanism that microbes use to resist PMB and As stress.Network analysis showed that PMB and As might have antagonistic effects through competition with multi-drug resistant ARGs.The combined pollution by PMB and As significantly promoted the relative abundance of microbes carrying multi-drug resistant ARGs and MGEs,thereby increasing the risk of transmission of ARGs.This research advances the understanding of the interaction mechanism between antibiotics and heavy metals and provides new theoretical guidance for the environmental risk assessment and combined pollution management.展开更多
Aim To elucidate the genetic basis for the pronounced resistance that the oral pathogen, Porphyromonas gingivalis （P. gingivalis）, exhibits towards the cationic antimicrobial peptide, polymyxin B. Methodology A gene...Aim To elucidate the genetic basis for the pronounced resistance that the oral pathogen, Porphyromonas gingivalis （P. gingivalis）, exhibits towards the cationic antimicrobial peptide, polymyxin B. Methodology A genetic screen of P. gingivalis clones generated by a Tn4400-based random insertion mutagenesis strategy was performed to identify bacteria harboring novel genetic mutations that render P. gingivalis susceptible to killing by the cationic antimicrobial peptide, polymyxin B （PMB, 50μg·mL^-1）. Results P. gingivalis （ATCC 33277） is unusually resistant to the cationic antimicrobial peptide, PMB at relatively high concentrations （200μg·mL^-1）. Approximately 2,700 independent Tn4400 ＇-derived mutants ofP. gingivalis were examined for increased sensitivity to PMB killing at a relatively low dose （50 μg·mL^-1）. A single PMB-sensitive mutant was obtained in this phenotypic screen. We determined that the Tn4400＇ transposon was integrated into the gene encoding the lipid A 4＇-phosphatase, PGN 0524, demonstrating that this insertion event was responsible for its increased susceptibility of this clone to PMB-dependent killing. The resulting mutant strain, designated 0524-Tn4400＇, was highly sensitive to PMB killing relative to wild-type P. gingivalis, and exhibited the same sensitivity as the previously characterized strain, 0524KO, which bears a genetically engineered deletion in the PGN_0524 locus. Positive ion mass spectrometric structural （MALDI-TOF MS） analyses revealed that lipid A isolates from 0524-Tn4400＂ and 0524KO strains displayed strikingly similar MALDI-TOF MS spectra that were substantially different from the wildtype P gingivalis lipid A spectrum. Finally, intact 0524- Tn4400＇ and 0524KO mutant bacteria, as well as their corresponding LPS isolates, were significantly more potent in stimulating Toll-like receptor 4 （TLR4）-dependent E-selectin expression in human endothelial cells relative to intact wild-type P.. gingivalis or its corresponding LPS isolate. Conclusion The combined molecular evidence provided in this report suggests that PGN 0524, a lipid A 4＇-phosphatase, is the sole genetic element conferring the ability of the periodontopathogen, P. gingivalis, to evade the killing activity of cationic antimicrobial peptides, such as PMB. These data strongly implicate PGN_0524 as a critical virulence factor for the ability of P.. gingivalis to evade front-line host innate defenses that are dependent upon cationic antimicrobial peptide activity and TLR 4 sensing.展开更多
Polymyxin B(PB),as the last-line of defense against multidrug-resistant Gram-negative bacteria,has caused resistance to P.aeruginosa recently.Fortunately,synergistic treatment could preserve the last class of antibiot...Polymyxin B(PB),as the last-line of defense against multidrug-resistant Gram-negative bacteria,has caused resistance to P.aeruginosa recently.Fortunately,synergistic treatment could preserve the last class of antibiotics and reduce the emergency of drug resistance.Here,we performed a screen of 970 approved drugs synergized with PB against the P.aeruginosa DK2,which is severely resistant to PB,MIC=512μg/mL.Encouragingly,we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint(2 μg/mL).Especially,gemifloxacin achieved the highest synergistic effect with PB,leading to a 4096-fold MIC reduction(reduced from512 μg/mL to 0.125 μg/mL).Furthermore,synergistic effect was also observed in the combination of gemifloxacin and colistin.Finally,outer membrane permeabilization assay showed that gemifloxacin could increase the permeability of bacterial cell membranes for P.aeruginosa which partly explained the synergy mechanism.These results indicate that fluoroquinolones represent attractive synergists to address the emerging threat of polymyxin-resistant infections.展开更多
Humanity is facing an enormous and growing worldwide threat from the emergence of multi-drug-resistant(MDR)Gram-negative bacteria such as Escherichia coli,Klebsiella pneumoniae,and Acinetobacter baumannii.Polymyxin B ...Humanity is facing an enormous and growing worldwide threat from the emergence of multi-drug-resistant(MDR)Gram-negative bacteria such as Escherichia coli,Klebsiella pneumoniae,and Acinetobacter baumannii.Polymyxin B and E(colistin)constitute the last-line therapies for treating MDR Gram-negative bacteria.Polymyxin is a cationic antibacterial peptide that can destroy the outer membrane of Gram-negative bacteria.With the increasing clinical application of polymyxin,however,there have been many reports of the occurrence of polymyxin-resistant Gram-negative bacteria.This resistance is mainly mediated by the modification or complete loss of lipopolysaccharide(LPS).LPS is also a virulence factor of Gram-negative bacteria,and alterations of LPS may correlate with virulence.Although it is generally believed that the biological costs associated with drug resistance may enable benign susceptible bacteria to overcome resistant bacteria when antibiotic pressure is reduced,some studies have shown that polymyxin-resistant bacteria are associated with higher virulence and greater fitness compared with their susceptible counterparts.To predict the development of polymyxin resis-tance and evaluate interventions for its mitigation,it is important to understand the relative biological cost of polymyxin resistance compared with susceptibility.The impact of polymyxin resistance mecha-nisms on the virulence and fitness of these three Gram-negative bacteria are summarized in this review.展开更多
AIM： To investigate the effectiveness of direct hemoperfusion with polymyxin B-immobilized fibers （DHPPMX therapy） on warm ischemia-reperfusion （I/R） injury of the small intestine.METHODS： The proximal jejunum a...AIM： To investigate the effectiveness of direct hemoperfusion with polymyxin B-immobilized fibers （DHPPMX therapy） on warm ischemia-reperfusion （I/R） injury of the small intestine.METHODS： The proximal jejunum and distal ileum of mongrel dogs were resected. Warm ischemia was performed by clamping the superior mesenteric artery （SMA） and vein （SMV） for 2 h. Blood flow to the proximal small intestine was restored 1 h after reperfusion, and the distal small intestine was used as a stoma. The experiment was discontinued 6 h after reperfusion. The dogs were divided into two groups： the DHP-PMX group （n = 6, DHP-PMX was performed for 180 min; from 10 min prior to reperfusion to 170 rain after reperfusion） and the control group （n = 5）. The rate pressure product （RPP）, SMA blood flow, mucosal tissue blood flow, and intramucosal pH （pHi） were compared between the two groups. The serum interleukin （IL）-10 levels measured 170 min after reperfusion were also compared.RESULTS： The RPP at 6 h after reperfusion was significantly higher in the PMX group than in the control group （12174 ± 1832 mmHg/min vs 8929 ± 1797 mmHg/min, P 〈 0.05）. The recovery rates of the SMA blood flow at I and 6 h after reperfusion were significantly better in the PMX group than in the control group （61%±7% vs 44% ±4%, P 〈 0.05, and 59%±5% vs 35%±5%, P 〈 0.05, respectively）. The recovery rate of the mucosal tissue blood flow and the pHi levels at 6 h after reperfusion were significantly higher in the PMX group （61%±8% vs 31%±3%, P 〈 0.05 and 7.91±0.06 vs 7.69±0.08, P 〈 0.05, respectively）. In addition, the serum IL-IO levels just before DHP-PMX removal were significantly higher in the PMX group than in the control group （1 569 ± 253 pg/mL vs 211± 40 pg/mL, P 〈 0.05）.CONCLUSION： DHP-PMX therapy reduced warm I/R injury of the small intestine. IL-10 may play a role in inhibiting I/R injury during DHP-PMX therapy.展开更多
AIM： To investigate the usefulness of direct hemoperfusion with a polymyxin B-immobilized fiber column （DHP-PMX therapy） for warm hepatic ischemia-reperfusion （I/R） injury after total hepatic vascular exclusion ...AIM： To investigate the usefulness of direct hemoperfusion with a polymyxin B-immobilized fiber column （DHP-PMX therapy） for warm hepatic ischemia-reperfusion （I/R） injury after total hepatic vascular exclusion （THVE） using a porcine model. METHODS： Eleven Mexican hairless pigs weighing 22-38 kg were subjected to THVE for 120 min and then observed for 360 min. The animals were divided into two groups randomly： the DHP-PMX group （n = 5） underwent DHP-PMX at a flow rate of 80 mL/min for 220 min （beginning 10 rain before reperfusion）, while the control group did not （n = 6）. The rate pressure product （RPP）： heart rate x end-systolic arterial blood pressure, hepatic tissue blood flow （HTBF）, portal vein blood flow （PVBF）, and serum aspartate aminotransferase （AST） levels were compared between the two groups. RESULTS： RPP and HTBF were significantly （P 〈 0.05） higher in the DHP-PMX group than in the control group 240 and 360 min after reperfusion. PVBF in the DHP-PMX group was maintained at about 70% of the flow before ischemia and differed significantly （P 〈 0.05） compared to the control group 360 min after reperfusion. The serum AST increased gradually after reperfusion in both groups, but the AST was significantly （P 〈 0.05） lower in the DHP-PMX group 360 min after reperfusion. CONCLUSION： DHP-PMX therapy reduced the hepatic warm I/R injury caused by THVE in a porcine model.展开更多
BACKGROUND Polymyxin B hemoperfusion(PMX-HP)has been used as a treatment for intraabdominal septic shock by absorbing and removing endotoxins of gram-negative bacilli.AIM To investigate the clinical efficacy of PMX-HP...BACKGROUND Polymyxin B hemoperfusion(PMX-HP)has been used as a treatment for intraabdominal septic shock by absorbing and removing endotoxins of gram-negative bacilli.AIM To investigate the clinical efficacy of PMX-HP in patients with gram-negative septic shock who underwent abdominal surgery.METHODS From January 2012 to December 2018,patients who had septic shock secondary to peritonitis were enrolled.They were classified into PMX-HP treated and control groups based on postopreative intervention using PMX-HP.The clinical outcomes were compared using 1:1 propensity score matching methods to balance the overall distribution between the two groups.RESULTS After propensity score matching,40 patients were analyzed(20 patients in the PMX group and 20 patients in the control group).The scores of total Sequential Organ Failure Assessment(SOFA)score,renal SOFA and coagulation SOFA were significantly improved in the PMX group but not in the control group.(from 11.2±5.8 to 4.7±3.5 in PMX group vs 10.0±4.0 to 8.7±7.3 in control group,P=0.047 from 2.6±1.0 to 0.7±1.0 in PMX group vs 2.6±1.5 to 2.8±1.6 in control group,P=0.000,from 1.6±1.5 to 1.3±1.3 in PMX group vs 1.2±1.2 to 2.8±1.8 in control group,P=0.014,respectively).Further,the length of intensive care unit(ICU)stay was significantly shorter in PMX group.However,no statistically significant difference was found in ICU mortality(50%in PMX group vs 50%in control group).CONCLUSION PMX-HP is a feasible adjunct treatment for peritonitis in ICU patients with peritonitis for improved organ impairment and to stabilize hemodynamics.It would be helpful to enhance clinical outcomes especially in patients with complete elimination of the source of gram-negative bacilli infection by surgical procedure accompanied with conventional treatment of sepsis.展开更多
Acute exacerbations of idiopathic pulmonary fibrosis(IPF) is a severe respiratory condition with high mortality rate. Direct hemoperfusion with polymyxin B-immobilized fiber columns(PMX-DHP) was originally introduced ...Acute exacerbations of idiopathic pulmonary fibrosis(IPF) is a severe respiratory condition with high mortality rate. Direct hemoperfusion with polymyxin B-immobilized fiber columns(PMX-DHP) was originally introduced for the treatment of septic shock. Application of PMX-DHP to the treatment of acute exacerbations of IPF may improve oxygenation and survival of the patients with the disease. In addition to acute exacerbations of IPF, PMXDHP has been applied to acute respiratory failure fromvarious causes; an amyopathic dermatomyositis patient who developed rapidly progressive interstitial lung disease(ILD) with elevated anti-CADM-140/MDA5 autoantibody and a patient with severe amiodarone pulmonary toxicity. It is also demonstrated that PMX-DHP performed on the first day of steroid pulse therapy may improve the prognosis of patients with rapidly progressive ILDs in a case-control setting. PMX treatment decreases not only various circulating molecules but also inflammatory cells, in particular activated monocytes, producing such mediators. Although the incidence of acute exacerbations of IPF is too low for proper randomization, in order to test the effects of PMX-DHP on the disease, a cohort or casecontrol analytic study needs to be conducted, preferably from more than one center or research group.展开更多
The polymyxins are important antimicrobial agents against antibiotic-resistant gram-negative bacilli.In 2020,the Clinical and Laboratory Standards Institute modified the clinical breakpoints for polymyxin susceptibili...The polymyxins are important antimicrobial agents against antibiotic-resistant gram-negative bacilli.In 2020,the Clinical and Laboratory Standards Institute modified the clinical breakpoints for polymyxin susceptibility test by eliminating the"susceptible"interpretive category,only reporting intermediate(≤2 mg/L)and resistant(≥4 mg/L).However,the European Committee on Antimicrobial Susceptibility Testing recommended the use of clinical breakpoints of W2 mg/L as susceptible and>2 mg/L as resistant.The first-line laboratorians and clinicians in China have been perplexed by the inconsistence of international polymyxin clinical breakpoints and discouraged by the difficulty of conducting polymyxin susceptibility testing.Therefore,it is urgently needed to make it clear for the laboratorians in China to know how to accurately carry out polymyxin susceptibility testing and standardize the interpretation of susceptibility testing results.To this end,the experts from relevant fields were convened to formulate this consensus statement on the testing and clinical interpretation of polymyxin susceptibility.Relevant recommendations are proposed accordingly for laboratorians and clinicians to streamline their daily work.展开更多
Background:This study aims to assess the safety and efficacy of direct hemoperfu-sion using a new polymyxin B-immobilized resin column(disposable endotoxin ad-sorber,KCEA)in an endotoxin/lipopolysaccharide(LPS)-induce...Background:This study aims to assess the safety and efficacy of direct hemoperfu-sion using a new polymyxin B-immobilized resin column(disposable endotoxin ad-sorber,KCEA)in an endotoxin/lipopolysaccharide(LPS)-induced sepsis model.Methods:Eighteen beagles were randomized into 1 intervention group(KCEA group,n=6)and 2 control groups(sham group and model group,n=6 each).Sepsis was in-duced by continuous intravenous application of 0.5 mg/kg body weight of endotoxin for 60 min.An extracorporeal hemoperfusion device made with KCEA for endotoxin adsorption was used.Model group beagles received standard treatment with fluids and vasoactive drugs,KCEA group beagles received standard treatment and direct hemoperfusion of KCEA for 2 h,and sham group beagles were treated with standard treatment and direct hemoperfusion of a sham column for 2 h.Results:Good blood compatibility of KCEA was confirmed by assessing clinical pa-rameters.Blood endotoxin peak levels in the KCEA group were significantly lower,resulting in a significant suppression of IL-6,TNF-αand procalcitonin,which improved mean arterial pressure and significantly lowered vasopressor demand,thereby pro-tecting organ function and improving survival time and rate.In the KCEA group,MAP was significantly higher over 6 h than those recorded both in the sham group and model group.The 7-day survival rates of the KCEA,sham and model groups were 50%,0%and 0%,respectively.Conclusion:KCEA hemoadsorption was effective at detoxifying circulatory endotoxin and inflammatory mediators and contributed to the decreased mortality rate in the sepsis beagles.展开更多
BACKGROUND Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality.AIM To conducted a systematic review and meta-analysis of the prevalence ...BACKGROUND Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality.AIM To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit(ICU)patients.METHODS PubMed,EMBASE,the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30,2022.The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver.12.1.Additionally,subgroup analyses and meta-regression were conducted to assess heterogeneity.RESULTS A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis.The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%.The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B(PMB)-induced nephrotoxicity.The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval,nephrotoxicity criteria,age,publication year,study quality and sample size,which were confirmed in the univariable meta-regression analysis.Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses.Furthermore,older age,the presence of sepsis or septic shock,hypoalbuminemia,and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity,while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity.CONCLUSION Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high.It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.展开更多
Polymyxins are often considered as a last resort to treat multidrug resistant P. aeruginosa but polymyxin resistance has been increasingly reported worldwide in clinical isolates. Polymyxin resistance in P. aeruginosa...Polymyxins are often considered as a last resort to treat multidrug resistant P. aeruginosa but polymyxin resistance has been increasingly reported worldwide in clinical isolates. Polymyxin resistance in P. aeruginosa is known to be associated with alterations in either PhoQ or PmrB. In this study, mutant strains of P. aeruginosa carrying amino acid substitution, a single and/or dual inactivation of PhoQ and PmrB were constructed to further understand the roles of PhoQ and PmrB in polymyxin susceptibility. Polymyxin B resistance was caused by both inactivation and/or amino acid substitutions in PhoQ but by only amino acid substitutions of PmrB. Alterations of both PhoQ and PmrB resulted in higher levels of polymyxin B resistance than alteration of either PhoQ or PmrB alone. These results were confirmed by time-killing assays suggesting that high-level polymyxin resistance in P. aeruginosa is caused by alterations of both PhoQ and PmrB.展开更多
Lipopolysaccharides(LPS) contamination in herbal crude polysaccharides is inevitable. The present study was performed to explore the effect of polymyxin B on abolishing the influence of LPS contamination in mononuclea...Lipopolysaccharides(LPS) contamination in herbal crude polysaccharides is inevitable. The present study was performed to explore the effect of polymyxin B on abolishing the influence of LPS contamination in mononuclear cells. LPS was pretreated with polymyxin B sulfate(PB) at different concentrations for 1, 5 or 24 h, and then used to stimulate RAW264.7 and mouse peritoneal macrophages(MPMs). The nitric oxide(NO) and tumor necrosis factor-α(TNF-α) in cell culture supernatant, as the indications of cell response, were assayed. Bupleurum chinensis polysaccharides(BCPs) with trace amount contamination of LPS was treated with PB. 30 μg·mL^(–1) of PB, treating LPS(10 and 1000 ng·mL^(–1) in stimulating RAW264.7 and MPMs respectively) at 37 ℃ for 24 h, successfully abolished the stimulating effect of LPS on the cells. When the cells were stimulated with LPS, BCPs further promoted NO production. However, pretreated with PB, BCPs showed a suppression of NO production in MPMs and no change in RAW264.7. In the in vitro experiments, LPS contamination in polysaccharide might bring a great interference in assessing the activity of drug. Pretreatment with PB(30 μg·mL^(–1)) at 37 °C for 24 h was sufficient to abolish the effects of LPS contamination(10 and 1 000 ng·mL^(–1)).展开更多
Objective:To evaluate the effect of adding different values of polymyxin B (PMB) to bull semen on various motility parameters of post-thawed semen such as total motility, progressive motility and velocity parameters u...Objective:To evaluate the effect of adding different values of polymyxin B (PMB) to bull semen on various motility parameters of post-thawed semen such as total motility, progressive motility and velocity parameters using kinetic parameters of sperm by Computer Assisted Sperm Analysis.Methods: Gram negative bacteria release lipopolysaccharide, which induces the apoptotic pathway. Antibiotics are added to semen in order to prevent bacterial contaminations in bovine semen. These antibiotics kill the bacteria especially gram negative bacteria. Therefore, their endotoxins are released during bacteriolysis and bind to the head region and midpiece of sperm. PMB is a bactericidal antibiotic against multidrug resistant gram-negative bacteria and is able to neutralize the toxic effects of the released endotoxin. This study was performed on 3-year old Taleshi bulls. Results:The results showed both positive and negative significant effects of PMB on semen quality. Total motility and progressive motility were significantly increased (P<0.0001) by 100 μg per mL of PMB (55.2% and 48.8% respectively) against the control groups (43.5% and 37.7%, respectively). Moreover, they were significantly decreased (P<0.0001) by 1000 μg per mL of PMB (35.2% and 28.8% respectively) against the control groups (43.5% and 37.7% respectively) in above-mentioned parameters. In Computer Assisted Semen Analyzer, parameter VAP was significantly decreased (P<0.04) in 1000 μg (69.6 μm/s) against the control group (78.7 μm/s). Finally, using PMB in processing cryopreserved bull semen is advised, but before using it, the rate of endotoxins must be measured.Conclusions: We advise using PMB after measuring endotoxin concentration;In vitro,in vivoand in field fertilization, adding other sperm evaluation factors such as acrosomal integrity, DNA integrity, mitochondrial function to PMB treated semen.展开更多
Polymyxin B is widely used antibiotic in the clinic for resistant Gram-negative infections. In addition, polymyxin B-immobilized hemoperfusion cartridge has been used for endotoxin removal therapy in patients with sep...Polymyxin B is widely used antibiotic in the clinic for resistant Gram-negative infections. In addition, polymyxin B-immobilized hemoperfusion cartridge has been used for endotoxin removal therapy in patients with septic shock. The aim of this study was to investigate the anti-fibrotic and anti-cellular hypertrophic effects of polymyxin B, and further to explore its possible mechanism. Polymyxin B (3, 10 μM) significantly inhibited stress fiber formation induced by angiotensin II (Ang II) in rat heart-derived H9c2 cells. Furthermore, polymyxin B (1 - 10 μM) showed a potent inhibitory effect on Ang II-induced cellular hypertrophy in H9c2 cells. Under the mechanism study, the inhibitory activities of polymyxin B against kinases involved in cellular hypertrophy such as AKT1, CAMK, GRK5, GSK3β, MLCK, PKC, PKD2, AMPK, ROCK2, p70S6K, SGK1were evaluated. Polymyxin B possesses a potent G protein related kinase 5 (GKR5) inhibitory activity with IC50 value of 1.1 μM, and has an ATP non-competitive inhibitory mode. Taken together, these results indicate that polymyxin B alleviates Ang II-induced stress fiber formation and cellular hypertrophy, and propose that one mechanism underlying these effects involves inhibition of the GRK5 pathway.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:81502995)China Postdoctoral Science foundation(Grant No.:2020T130048ZX)Jiangsu Pharmaceutical Association Jin Peiying Fund Project(Grant No.:J2023008).
文摘To address the pressing issue of bacterial resistance,antibiotics with new mechanisms were urgently needed;yet,the majority of efforts centered on discovering novel structural compounds,often plagued by lengthy research timelines and unpredictability.In this study,we introduce an alternative strategy that rejuvenates outdated antibiotics through a unique delivery system.Specifically,we leveraged polymyxin B(PMB)and created a liposomal carrier encapsulating PMB and Fe2þ,designated P/Fe@L-P.When administered to PMB-resistant Acinetobacter baumannii,P/Fe@L-P triggered a downregulation of Nrf2 and GPX4 proteins,accompanied by a significant surge in reactive oxygen species and malondialdehyde levels,signifying the induction of ferroptosis.This mechanism imparted potent antibacterial activity,with P/Fe@L-P achieving minimal inhibitory and bactericidal concentrations of 54 and 192 mM,respectively,outperforming free PMB(72 and 768 mM).In vivo evaluations in mice models further validated the superior efficacy of P/Fe@L-P over PMB in treating PMB-resistant Acinetobacter baumannii pneumonia.This work establishes a highly effective and practical“old drug,new trick”paradigm,potentially expediting the fight against the escalating threat of bacterial resistance.
基金supported by the National Natural Science Foundation of China(Nos.81860543,32360237)Guizhou Provincial Science and Technology Projects(Nos.ZK[2024]235,ZK[2023]Key Project 041).
文摘The escalation in the incidence of multidrug-resistant Gram-negative bacteria is becoming a pressing global concern.Polymyxin B(PMB),a conventional antibiotic with notable therapeutic efficacy against Gram-negative bacterial infections,serves as a crucial final recourse against carbapenem-resistant Klebsiella pneumoniae(CRKP)infections.Nevertheless,the clinical usage of PMB is impeded by its pronounced nephrotoxicity and poor infection site targeting.This investigation is geared to construct a nanoparticle formulation(named HA-PMB@H)comprising hyaluronic acid(HA)and PMB via a simple Schiff base reaction and further coating HA by electrostatic action.HA-PMB@H shows an average size of(153.8±24.3)nm,and a mean zeta potential of(−25.6±5.2)mV.Additionally,PMB can be released from HA-PMB@H more thoroughly and efficiently at pH 5.5 compared to pH 7.4,which demonstrates the Schiff base modification of PMB paves the way for its release at focus of infection.The uptake ratio of HA-PMB@H by alveolar epithelial cells(RLE-6TN)surpassed that of free PMB devoid of HA,which facilitates to the intracellular sterilization of PMB.Furthermore,the employment of HA-PMB@H ameliorated the toxicity of PMB towards human embryonic kidney cells(HEK 293)and pulmonary microvascular endothelial cells(HULEC-5a).What is more,HA-PMB@H effectively managed severe pneumonia induced by CRKP samples from clinical patients diagnosed with CRKP infection in vivo,substantially enhancing the survival rate of mice.Consequently,this nano-delivery system holds promising clinical significance in the combat against drug-resistant bacterial infections.
基金supported by grants from the National Natural Science Foundation of China(81571940,81741125)the Guangzhou Science and Technology Planning Project of China(201504281714528)PLA Logistics Research Project of China(CWH17L020,17CXZ008,18CXZ030)
文摘Background:Intracranial infection after craniotomy is one of the most serious postoperative complications,especially multidrug-resistant(MDR)or extensively drug-resistant(XDR)bacterial meningitis,and strongly affects the prognosis of patients.Current treatment experience regarding these infections is scarce.Case presentation:We report a case of severe intracranial infection of XDR Acinetobacter baumannii(A.baumannii)that was treated by intravenous(IV)injection,sequential intraventricular(IVT)injection of tigecycline and polymyxin B,and other anti-infective drugs.Good results were obtained,and the patient was eventually discharged from the hospital.This case is characterized by intracranial infection.Conclusions:The polymyxin B IV+IVT pathway is an ideal treatment strategy for XDR A.baumannii.The tigecycline IVT pathway is also a safe treatment option.
基金the Shanghai Leading Talents Award,Shanghai Municipal Health Commission(No.LJ2016-01)the Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2022CRW004)。
文摘Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.
基金supported by the National Natural Science Foundation of China(Nos.41991332 and 41977323).
文摘Polymyxin B(PMB)is considered as the last line of antibiotic defense available to humans.The environmental effects of the combined pollution with PMB and heavy metals and their interaction mechanisms are unclear.We explored the effects of the combined pollution with PMB and arsenic(As)on the microbial composition of the soil and in the earthworm gut,as well as the spread and transmission of antibiotic resistance genes(ARGs).The results showed that,compared with As alone,the combined addition of PMB and As could significantly increase the bioaccumulation factor and toxicity of As in earthworm tissues by 12.1%and 16.0%,respectively.PMB treatment could significantly increase the abundance of Actinobacteria in the earthworm gut(from 35.6%to 45.2%),and As stress could significantly increase the abundance of Proteobacteria(from 19.8%to 56.9%).PMB and As stress both could significantly increase the abundance of ARGs and mobile genetic elements(MGEs),which were positively correlated,indicating that ARGs might be horizontally transferred.The inactivation of antibiotics was the main resistance mechanism that microbes use to resist PMB and As stress.Network analysis showed that PMB and As might have antagonistic effects through competition with multi-drug resistant ARGs.The combined pollution by PMB and As significantly promoted the relative abundance of microbes carrying multi-drug resistant ARGs and MGEs,thereby increasing the risk of transmission of ARGs.This research advances the understanding of the interaction mechanism between antibiotics and heavy metals and provides new theoretical guidance for the environmental risk assessment and combined pollution management.
文摘Aim To elucidate the genetic basis for the pronounced resistance that the oral pathogen, Porphyromonas gingivalis （P. gingivalis）, exhibits towards the cationic antimicrobial peptide, polymyxin B. Methodology A genetic screen of P. gingivalis clones generated by a Tn4400-based random insertion mutagenesis strategy was performed to identify bacteria harboring novel genetic mutations that render P. gingivalis susceptible to killing by the cationic antimicrobial peptide, polymyxin B （PMB, 50μg·mL^-1）. Results P. gingivalis （ATCC 33277） is unusually resistant to the cationic antimicrobial peptide, PMB at relatively high concentrations （200μg·mL^-1）. Approximately 2,700 independent Tn4400 ＇-derived mutants ofP. gingivalis were examined for increased sensitivity to PMB killing at a relatively low dose （50 μg·mL^-1）. A single PMB-sensitive mutant was obtained in this phenotypic screen. We determined that the Tn4400＇ transposon was integrated into the gene encoding the lipid A 4＇-phosphatase, PGN 0524, demonstrating that this insertion event was responsible for its increased susceptibility of this clone to PMB-dependent killing. The resulting mutant strain, designated 0524-Tn4400＇, was highly sensitive to PMB killing relative to wild-type P. gingivalis, and exhibited the same sensitivity as the previously characterized strain, 0524KO, which bears a genetically engineered deletion in the PGN_0524 locus. Positive ion mass spectrometric structural （MALDI-TOF MS） analyses revealed that lipid A isolates from 0524-Tn4400＂ and 0524KO strains displayed strikingly similar MALDI-TOF MS spectra that were substantially different from the wildtype P gingivalis lipid A spectrum. Finally, intact 0524- Tn4400＇ and 0524KO mutant bacteria, as well as their corresponding LPS isolates, were significantly more potent in stimulating Toll-like receptor 4 （TLR4）-dependent E-selectin expression in human endothelial cells relative to intact wild-type P.. gingivalis or its corresponding LPS isolate. Conclusion The combined molecular evidence provided in this report suggests that PGN 0524, a lipid A 4＇-phosphatase, is the sole genetic element conferring the ability of the periodontopathogen, P. gingivalis, to evade the killing activity of cationic antimicrobial peptides, such as PMB. These data strongly implicate PGN_0524 as a critical virulence factor for the ability of P.. gingivalis to evade front-line host innate defenses that are dependent upon cationic antimicrobial peptide activity and TLR 4 sensing.
基金supported by the National Key R&D Program of China(No.2017YFB0202600)the National Natural Science Foundation of China(Nos.21672064,21702061,81861138047)+3 种基金the Innovative Research Team of High-level Local Universities in Shanghaithe National Special Fund for State Key Laboratory of Bioreactor Engineering(No.2060204)"Shu Guang"project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.14SG28)the Shanghai Sailing Program(No.17YF1403600)。
文摘Polymyxin B(PB),as the last-line of defense against multidrug-resistant Gram-negative bacteria,has caused resistance to P.aeruginosa recently.Fortunately,synergistic treatment could preserve the last class of antibiotics and reduce the emergency of drug resistance.Here,we performed a screen of 970 approved drugs synergized with PB against the P.aeruginosa DK2,which is severely resistant to PB,MIC=512μg/mL.Encouragingly,we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint(2 μg/mL).Especially,gemifloxacin achieved the highest synergistic effect with PB,leading to a 4096-fold MIC reduction(reduced from512 μg/mL to 0.125 μg/mL).Furthermore,synergistic effect was also observed in the combination of gemifloxacin and colistin.Finally,outer membrane permeabilization assay showed that gemifloxacin could increase the permeability of bacterial cell membranes for P.aeruginosa which partly explained the synergy mechanism.These results indicate that fluoroquinolones represent attractive synergists to address the emerging threat of polymyxin-resistant infections.
基金supported by the National Key Research and Development Program of China (2017YFC1600100 and2017YFC1200203)the National Natural Science Foundation of China (81702040)the National Science Foundation of Zhejiang Province,China (LY20H190002)
文摘Humanity is facing an enormous and growing worldwide threat from the emergence of multi-drug-resistant(MDR)Gram-negative bacteria such as Escherichia coli,Klebsiella pneumoniae,and Acinetobacter baumannii.Polymyxin B and E(colistin)constitute the last-line therapies for treating MDR Gram-negative bacteria.Polymyxin is a cationic antibacterial peptide that can destroy the outer membrane of Gram-negative bacteria.With the increasing clinical application of polymyxin,however,there have been many reports of the occurrence of polymyxin-resistant Gram-negative bacteria.This resistance is mainly mediated by the modification or complete loss of lipopolysaccharide(LPS).LPS is also a virulence factor of Gram-negative bacteria,and alterations of LPS may correlate with virulence.Although it is generally believed that the biological costs associated with drug resistance may enable benign susceptible bacteria to overcome resistant bacteria when antibiotic pressure is reduced,some studies have shown that polymyxin-resistant bacteria are associated with higher virulence and greater fitness compared with their susceptible counterparts.To predict the development of polymyxin resis-tance and evaluate interventions for its mitigation,it is important to understand the relative biological cost of polymyxin resistance compared with susceptibility.The impact of polymyxin resistance mecha-nisms on the virulence and fitness of these three Gram-negative bacteria are summarized in this review.
文摘AIM： To investigate the effectiveness of direct hemoperfusion with polymyxin B-immobilized fibers （DHPPMX therapy） on warm ischemia-reperfusion （I/R） injury of the small intestine.METHODS： The proximal jejunum and distal ileum of mongrel dogs were resected. Warm ischemia was performed by clamping the superior mesenteric artery （SMA） and vein （SMV） for 2 h. Blood flow to the proximal small intestine was restored 1 h after reperfusion, and the distal small intestine was used as a stoma. The experiment was discontinued 6 h after reperfusion. The dogs were divided into two groups： the DHP-PMX group （n = 6, DHP-PMX was performed for 180 min; from 10 min prior to reperfusion to 170 rain after reperfusion） and the control group （n = 5）. The rate pressure product （RPP）, SMA blood flow, mucosal tissue blood flow, and intramucosal pH （pHi） were compared between the two groups. The serum interleukin （IL）-10 levels measured 170 min after reperfusion were also compared.RESULTS： The RPP at 6 h after reperfusion was significantly higher in the PMX group than in the control group （12174 ± 1832 mmHg/min vs 8929 ± 1797 mmHg/min, P 〈 0.05）. The recovery rates of the SMA blood flow at I and 6 h after reperfusion were significantly better in the PMX group than in the control group （61%±7% vs 44% ±4%, P 〈 0.05, and 59%±5% vs 35%±5%, P 〈 0.05, respectively）. The recovery rate of the mucosal tissue blood flow and the pHi levels at 6 h after reperfusion were significantly higher in the PMX group （61%±8% vs 31%±3%, P 〈 0.05 and 7.91±0.06 vs 7.69±0.08, P 〈 0.05, respectively）. In addition, the serum IL-IO levels just before DHP-PMX removal were significantly higher in the PMX group than in the control group （1 569 ± 253 pg/mL vs 211± 40 pg/mL, P 〈 0.05）.CONCLUSION： DHP-PMX therapy reduced warm I/R injury of the small intestine. IL-10 may play a role in inhibiting I/R injury during DHP-PMX therapy.
文摘AIM： To investigate the usefulness of direct hemoperfusion with a polymyxin B-immobilized fiber column （DHP-PMX therapy） for warm hepatic ischemia-reperfusion （I/R） injury after total hepatic vascular exclusion （THVE） using a porcine model. METHODS： Eleven Mexican hairless pigs weighing 22-38 kg were subjected to THVE for 120 min and then observed for 360 min. The animals were divided into two groups randomly： the DHP-PMX group （n = 5） underwent DHP-PMX at a flow rate of 80 mL/min for 220 min （beginning 10 rain before reperfusion）, while the control group did not （n = 6）. The rate pressure product （RPP）： heart rate x end-systolic arterial blood pressure, hepatic tissue blood flow （HTBF）, portal vein blood flow （PVBF）, and serum aspartate aminotransferase （AST） levels were compared between the two groups. RESULTS： RPP and HTBF were significantly （P 〈 0.05） higher in the DHP-PMX group than in the control group 240 and 360 min after reperfusion. PVBF in the DHP-PMX group was maintained at about 70% of the flow before ischemia and differed significantly （P 〈 0.05） compared to the control group 360 min after reperfusion. The serum AST increased gradually after reperfusion in both groups, but the AST was significantly （P 〈 0.05） lower in the DHP-PMX group 360 min after reperfusion. CONCLUSION： DHP-PMX therapy reduced the hepatic warm I/R injury caused by THVE in a porcine model.
文摘BACKGROUND Polymyxin B hemoperfusion(PMX-HP)has been used as a treatment for intraabdominal septic shock by absorbing and removing endotoxins of gram-negative bacilli.AIM To investigate the clinical efficacy of PMX-HP in patients with gram-negative septic shock who underwent abdominal surgery.METHODS From January 2012 to December 2018,patients who had septic shock secondary to peritonitis were enrolled.They were classified into PMX-HP treated and control groups based on postopreative intervention using PMX-HP.The clinical outcomes were compared using 1:1 propensity score matching methods to balance the overall distribution between the two groups.RESULTS After propensity score matching,40 patients were analyzed(20 patients in the PMX group and 20 patients in the control group).The scores of total Sequential Organ Failure Assessment(SOFA)score,renal SOFA and coagulation SOFA were significantly improved in the PMX group but not in the control group.(from 11.2±5.8 to 4.7±3.5 in PMX group vs 10.0±4.0 to 8.7±7.3 in control group,P=0.047 from 2.6±1.0 to 0.7±1.0 in PMX group vs 2.6±1.5 to 2.8±1.6 in control group,P=0.000,from 1.6±1.5 to 1.3±1.3 in PMX group vs 1.2±1.2 to 2.8±1.8 in control group,P=0.014,respectively).Further,the length of intensive care unit(ICU)stay was significantly shorter in PMX group.However,no statistically significant difference was found in ICU mortality(50%in PMX group vs 50%in control group).CONCLUSION PMX-HP is a feasible adjunct treatment for peritonitis in ICU patients with peritonitis for improved organ impairment and to stabilize hemodynamics.It would be helpful to enhance clinical outcomes especially in patients with complete elimination of the source of gram-negative bacilli infection by surgical procedure accompanied with conventional treatment of sepsis.
文摘Acute exacerbations of idiopathic pulmonary fibrosis(IPF) is a severe respiratory condition with high mortality rate. Direct hemoperfusion with polymyxin B-immobilized fiber columns(PMX-DHP) was originally introduced for the treatment of septic shock. Application of PMX-DHP to the treatment of acute exacerbations of IPF may improve oxygenation and survival of the patients with the disease. In addition to acute exacerbations of IPF, PMXDHP has been applied to acute respiratory failure fromvarious causes; an amyopathic dermatomyositis patient who developed rapidly progressive interstitial lung disease(ILD) with elevated anti-CADM-140/MDA5 autoantibody and a patient with severe amiodarone pulmonary toxicity. It is also demonstrated that PMX-DHP performed on the first day of steroid pulse therapy may improve the prognosis of patients with rapidly progressive ILDs in a case-control setting. PMX treatment decreases not only various circulating molecules but also inflammatory cells, in particular activated monocytes, producing such mediators. Although the incidence of acute exacerbations of IPF is too low for proper randomization, in order to test the effects of PMX-DHP on the disease, a cohort or casecontrol analytic study needs to be conducted, preferably from more than one center or research group.
基金the National Key Research&Development Program(2018YFC1200100,2018YFC1200105)the Major Research and Development Project of Innovative Drugs,Ministry of Science and Technology of China(2017ZX09304005).
文摘The polymyxins are important antimicrobial agents against antibiotic-resistant gram-negative bacilli.In 2020,the Clinical and Laboratory Standards Institute modified the clinical breakpoints for polymyxin susceptibility test by eliminating the"susceptible"interpretive category,only reporting intermediate(≤2 mg/L)and resistant(≥4 mg/L).However,the European Committee on Antimicrobial Susceptibility Testing recommended the use of clinical breakpoints of W2 mg/L as susceptible and>2 mg/L as resistant.The first-line laboratorians and clinicians in China have been perplexed by the inconsistence of international polymyxin clinical breakpoints and discouraged by the difficulty of conducting polymyxin susceptibility testing.Therefore,it is urgently needed to make it clear for the laboratorians in China to know how to accurately carry out polymyxin susceptibility testing and standardize the interpretation of susceptibility testing results.To this end,the experts from relevant fields were convened to formulate this consensus statement on the testing and clinical interpretation of polymyxin susceptibility.Relevant recommendations are proposed accordingly for laboratorians and clinicians to streamline their daily work.
基金This research was financially supported by Guangdong Provincial Key Laboratory of Hemoadsorption Technology(No:2020B121202021)。
文摘Background:This study aims to assess the safety and efficacy of direct hemoperfu-sion using a new polymyxin B-immobilized resin column(disposable endotoxin ad-sorber,KCEA)in an endotoxin/lipopolysaccharide(LPS)-induced sepsis model.Methods:Eighteen beagles were randomized into 1 intervention group(KCEA group,n=6)and 2 control groups(sham group and model group,n=6 each).Sepsis was in-duced by continuous intravenous application of 0.5 mg/kg body weight of endotoxin for 60 min.An extracorporeal hemoperfusion device made with KCEA for endotoxin adsorption was used.Model group beagles received standard treatment with fluids and vasoactive drugs,KCEA group beagles received standard treatment and direct hemoperfusion of KCEA for 2 h,and sham group beagles were treated with standard treatment and direct hemoperfusion of a sham column for 2 h.Results:Good blood compatibility of KCEA was confirmed by assessing clinical pa-rameters.Blood endotoxin peak levels in the KCEA group were significantly lower,resulting in a significant suppression of IL-6,TNF-αand procalcitonin,which improved mean arterial pressure and significantly lowered vasopressor demand,thereby pro-tecting organ function and improving survival time and rate.In the KCEA group,MAP was significantly higher over 6 h than those recorded both in the sham group and model group.The 7-day survival rates of the KCEA,sham and model groups were 50%,0%and 0%,respectively.Conclusion:KCEA hemoadsorption was effective at detoxifying circulatory endotoxin and inflammatory mediators and contributed to the decreased mortality rate in the sepsis beagles.
基金Supported by The Hunan Province Natural Science Foundation,No.2022JJ80043Nature Science Foundation of Changsha,No.kq2014268+1 种基金Hunan Engineering Research Center of Intelligent Prevention and Control for Drug Induced Organ Injury,No.40Scientific Research Fund Project of Hunan Pharmaceutical Society,No.2020YXH010.
文摘BACKGROUND Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality.AIM To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit(ICU)patients.METHODS PubMed,EMBASE,the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30,2022.The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver.12.1.Additionally,subgroup analyses and meta-regression were conducted to assess heterogeneity.RESULTS A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis.The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%.The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B(PMB)-induced nephrotoxicity.The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval,nephrotoxicity criteria,age,publication year,study quality and sample size,which were confirmed in the univariable meta-regression analysis.Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses.Furthermore,older age,the presence of sepsis or septic shock,hypoalbuminemia,and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity,while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity.CONCLUSION Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high.It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.
文摘Polymyxins are often considered as a last resort to treat multidrug resistant P. aeruginosa but polymyxin resistance has been increasingly reported worldwide in clinical isolates. Polymyxin resistance in P. aeruginosa is known to be associated with alterations in either PhoQ or PmrB. In this study, mutant strains of P. aeruginosa carrying amino acid substitution, a single and/or dual inactivation of PhoQ and PmrB were constructed to further understand the roles of PhoQ and PmrB in polymyxin susceptibility. Polymyxin B resistance was caused by both inactivation and/or amino acid substitutions in PhoQ but by only amino acid substitutions of PmrB. Alterations of both PhoQ and PmrB resulted in higher levels of polymyxin B resistance than alteration of either PhoQ or PmrB alone. These results were confirmed by time-killing assays suggesting that high-level polymyxin resistance in P. aeruginosa is caused by alterations of both PhoQ and PmrB.
基金supported by the National Natural Science Foundation of China(Nos.81330089,30925042,and 81274165)the State Key Program for New Drugs from the Ministry of Science and Technology,China(No.2012ZX09301001-003)the Science and Technology Commission of Shanghai Municipality(Nos.10XD1405900 and 12JC1400800)
文摘Lipopolysaccharides(LPS) contamination in herbal crude polysaccharides is inevitable. The present study was performed to explore the effect of polymyxin B on abolishing the influence of LPS contamination in mononuclear cells. LPS was pretreated with polymyxin B sulfate(PB) at different concentrations for 1, 5 or 24 h, and then used to stimulate RAW264.7 and mouse peritoneal macrophages(MPMs). The nitric oxide(NO) and tumor necrosis factor-α(TNF-α) in cell culture supernatant, as the indications of cell response, were assayed. Bupleurum chinensis polysaccharides(BCPs) with trace amount contamination of LPS was treated with PB. 30 μg·mL^(–1) of PB, treating LPS(10 and 1000 ng·mL^(–1) in stimulating RAW264.7 and MPMs respectively) at 37 ℃ for 24 h, successfully abolished the stimulating effect of LPS on the cells. When the cells were stimulated with LPS, BCPs further promoted NO production. However, pretreated with PB, BCPs showed a suppression of NO production in MPMs and no change in RAW264.7. In the in vitro experiments, LPS contamination in polysaccharide might bring a great interference in assessing the activity of drug. Pretreatment with PB(30 μg·mL^(–1)) at 37 °C for 24 h was sufficient to abolish the effects of LPS contamination(10 and 1 000 ng·mL^(–1)).
文摘Objective:To evaluate the effect of adding different values of polymyxin B (PMB) to bull semen on various motility parameters of post-thawed semen such as total motility, progressive motility and velocity parameters using kinetic parameters of sperm by Computer Assisted Sperm Analysis.Methods: Gram negative bacteria release lipopolysaccharide, which induces the apoptotic pathway. Antibiotics are added to semen in order to prevent bacterial contaminations in bovine semen. These antibiotics kill the bacteria especially gram negative bacteria. Therefore, their endotoxins are released during bacteriolysis and bind to the head region and midpiece of sperm. PMB is a bactericidal antibiotic against multidrug resistant gram-negative bacteria and is able to neutralize the toxic effects of the released endotoxin. This study was performed on 3-year old Taleshi bulls. Results:The results showed both positive and negative significant effects of PMB on semen quality. Total motility and progressive motility were significantly increased (P<0.0001) by 100 μg per mL of PMB (55.2% and 48.8% respectively) against the control groups (43.5% and 37.7%, respectively). Moreover, they were significantly decreased (P<0.0001) by 1000 μg per mL of PMB (35.2% and 28.8% respectively) against the control groups (43.5% and 37.7% respectively) in above-mentioned parameters. In Computer Assisted Semen Analyzer, parameter VAP was significantly decreased (P<0.04) in 1000 μg (69.6 μm/s) against the control group (78.7 μm/s). Finally, using PMB in processing cryopreserved bull semen is advised, but before using it, the rate of endotoxins must be measured.Conclusions: We advise using PMB after measuring endotoxin concentration;In vitro,in vivoand in field fertilization, adding other sperm evaluation factors such as acrosomal integrity, DNA integrity, mitochondrial function to PMB treated semen.
文摘Polymyxin B is widely used antibiotic in the clinic for resistant Gram-negative infections. In addition, polymyxin B-immobilized hemoperfusion cartridge has been used for endotoxin removal therapy in patients with septic shock. The aim of this study was to investigate the anti-fibrotic and anti-cellular hypertrophic effects of polymyxin B, and further to explore its possible mechanism. Polymyxin B (3, 10 μM) significantly inhibited stress fiber formation induced by angiotensin II (Ang II) in rat heart-derived H9c2 cells. Furthermore, polymyxin B (1 - 10 μM) showed a potent inhibitory effect on Ang II-induced cellular hypertrophy in H9c2 cells. Under the mechanism study, the inhibitory activities of polymyxin B against kinases involved in cellular hypertrophy such as AKT1, CAMK, GRK5, GSK3β, MLCK, PKC, PKD2, AMPK, ROCK2, p70S6K, SGK1were evaluated. Polymyxin B possesses a potent G protein related kinase 5 (GKR5) inhibitory activity with IC50 value of 1.1 μM, and has an ATP non-competitive inhibitory mode. Taken together, these results indicate that polymyxin B alleviates Ang II-induced stress fiber formation and cellular hypertrophy, and propose that one mechanism underlying these effects involves inhibition of the GRK5 pathway.
