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
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
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
Objective: To evaluate the efficacy and tolerance of a local treatment combining two antibacterials and one antifungal in patients with a clinical presentation suggesting infectious vaginitis. Patients and methods: 16...Objective: To evaluate the efficacy and tolerance of a local treatment combining two antibacterials and one antifungal in patients with a clinical presentation suggesting infectious vaginitis. Patients and methods: 169 patients presenting with clinical criteria for vaginitis were included in an open, multicenter trial. Vaginal samples were taken for microbiological analyses and a triple-combination product of nystatin, neomycin and polymyxin B was then started as local treatment, without waiting for the test results. The treatment was continued with the usual dosage (1 vaginal capsule at bedtime for 12 days) for vaginal infections in the scope of the combination product with approved labeling. A second vaginal sample was performed at the end of the treatment. The main efficacy criterion was the clinical success rate (cure or improvement of the clinical signs and symptoms) according to the investigator.Results: 93 patients were included in the efficacy population. Non-exclusively fungal vaginitis (strictly bacterial or bacterial + fungal) represented 31.2% of the cases. The clinical success rate was 97.8% according to the investigator and 95.7% according to the patients. The microbiological success rate was 81.3%, with no differences between etiologies (Candida spp., bacteria or both). The combination product was well-tolerated, despite the local inflammation before treatment. Discussion and conclusion: Given the etiological diversity of vaginitis, this trial supports the efficacy of a triple-combination product (nystatin, neomycin, polymyxin B) as a first-line local treatment of Candida, bacterial or mixed vaginitis.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 (THVE)usin...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 120 min(beginning 10 min before reperfusion),while the control group did not(n=6).The rate pressure product (RPP):heart rate×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 afterreperfusion 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
AIM: To investigate the effectiveness of direct hemo- perfusion with polymyxin B-immobilized fibers (DHP- PMX therapy) on warm ischemia-reperfusion (I/R) injury of the small intestine. METHODS: The proximal jejunum an...AIM: To investigate the effectiveness of direct hemo- perfusion with polymyxin B-immobilized fibers (DHP- PMX 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 min 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 (12 174 ± 1832 mmHg/min vs 8929 ± 1797 mmHg/min, P < 0.05). The recovery rates ofthe SMA blood flow at 1 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-10 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
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
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
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
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
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.
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.
文摘Objective: To evaluate the efficacy and tolerance of a local treatment combining two antibacterials and one antifungal in patients with a clinical presentation suggesting infectious vaginitis. Patients and methods: 169 patients presenting with clinical criteria for vaginitis were included in an open, multicenter trial. Vaginal samples were taken for microbiological analyses and a triple-combination product of nystatin, neomycin and polymyxin B was then started as local treatment, without waiting for the test results. The treatment was continued with the usual dosage (1 vaginal capsule at bedtime for 12 days) for vaginal infections in the scope of the combination product with approved labeling. A second vaginal sample was performed at the end of the treatment. The main efficacy criterion was the clinical success rate (cure or improvement of the clinical signs and symptoms) according to the investigator.Results: 93 patients were included in the efficacy population. Non-exclusively fungal vaginitis (strictly bacterial or bacterial + fungal) represented 31.2% of the cases. The clinical success rate was 97.8% according to the investigator and 95.7% according to the patients. The microbiological success rate was 81.3%, with no differences between etiologies (Candida spp., bacteria or both). The combination product was well-tolerated, despite the local inflammation before treatment. Discussion and conclusion: Given the etiological diversity of vaginitis, this trial supports the efficacy of a triple-combination product (nystatin, neomycin, polymyxin B) as a first-line local treatment of Candida, bacterial or mixed vaginitis.
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 120 min(beginning 10 min before reperfusion),while the control group did not(n=6).The rate pressure product (RPP):heart rate×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 afterreperfusion 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AIM: To investigate the effectiveness of direct hemo- perfusion with polymyxin B-immobilized fibers (DHP- PMX 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 min 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 (12 174 ± 1832 mmHg/min vs 8929 ± 1797 mmHg/min, P < 0.05). The recovery rates ofthe SMA blood flow at 1 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-10 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.
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.
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.
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.