This study aimed to clarify that organic anion transporters(OATs)mediate the drug–drug interaction(DDI)between imipenem and cilastatin.After co-administration with imipenem,the plasma concentrations and the plasma co...This study aimed to clarify that organic anion transporters(OATs)mediate the drug–drug interaction(DDI)between imipenem and cilastatin.After co-administration with imipenem,the plasma concentrations and the plasma concentration-time curve(AUC)of cilastatin were significantly increased,while renal clearance and cumulative urinary excretion of cilastatin were decreased.At the same time,imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1(hOAT1)-HEK293 and human OAT3(hOAT3)-HEK293 cells.Probenecid,p-aminohippurate,and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1-and hOAT3-HEK 293 cells,respectively.The uptakes of imipenem and cilastatin in hOAT1-and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 cells.Moreover,the K m values of cilastatin were increased in the presence of imipenem with unchanged V max,indicating that imipenem inhibited the uptake of cilastatin in a competitive manner.When imipenem and cilastatin were co-administered,the level of imipenem was higher compared with imipenem alone both in vivo and in vitro.But,cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1(DPEP1)was silenced by RNAi technology in hOAT1-and hOAT3-HEK 293 cells.In conclusion,imipenem and cilastatin are the substrates of OAT1 and OAT3.OAT1 and OAT3 mediate the DDI between imipenem and cilastatin.Meanwhile,cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement.展开更多
The present study identified the properties of porins in the outer membrane in Pseudomonas aeruginosa,and showed the role of outer membrane in determining imipenem diffusion in Pseudomonas a...The present study identified the properties of porins in the outer membrane in Pseudomonas aeruginosa,and showed the role of outer membrane in determining imipenem diffusion in Pseudomonas aeruginosa The molecular weight of the major outer membrane protein was analyzed by SDS PAGE The purification of the porins in Pseudomonas aeruginosa was achieved by DEAE ion exchange HPLC The purified outer membrane proteins were reconstituted with phosphatidylcholine and dicetylphosphate into membrane vesicles, and were tested by the liposomes swelling method for the diffusion of imipenem The permeability assay showed that OprC (70 kD), OprD 2 (46kD), and OprE(43 kD) were the channel forming proteins But only OprD 2 was thought to be the likely route of imipenem diffusion展开更多
BACKGROUND Imipenem is a highly effective carbapenem antibiotic,which is widely used in the treatment of many serious bacterial infections.At the same time,it can also cause some adverse reactions,mental abnormalities...BACKGROUND Imipenem is a highly effective carbapenem antibiotic,which is widely used in the treatment of many serious bacterial infections.At the same time,it can also cause some adverse reactions,mental abnormalities are the most concerned central nervous system adverse reactions.Different patients respond differently to imipenem,and the effect of imipenem on psychiatric disorders is unclear.Therefore,meta-analysis summarizing the results of multiple previous studies can provide stronger evidence support for clinical guidelines to guide clinical rational use of imipenem to minimize risks.After reviewing the literature published between 2003 and 2017,seven controlled trials with a total of 550 patients were included,with 273 and 277 patients in the control and experimental groups,respectively.The sample size of the study ranged from a minimum of 30 cases to a maximum of 61 cases.Patients in the experimental group were treated with imipenem while the control group was treated with conventional drugs.Meta-analysis showed that the incidence of mental disorders in the experimental group was higher than that in the control group(odds ratio=3.66,95%confidence interval:1.11-12.11,P=0.030);however,there was no significant difference in the incidence of adverse reactions between the two groups(odds ratio=0.05,95%confidence interval:0.00 to 0.10,P=0.060).Funnel diagrams showed that the scattered points of each study were symmetrical and distributed in an inverted funnel shape;therefore,there was no publication bias.CONCLUSION Imipenem can cause mental disorders in patients.However,the low quality of the included literature may have affected the final results.Therefore,it is necessary to conduct a high-quality randomized controlled study with multiple samples to further confirm the mechanism of imipenem-induced mental disorders and provide effective guidance for clinical treatment.展开更多
Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating in...Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating infections caused by multiresistant bacteria. We elaborated the hypothesis that it is possible to inhibit the enzymatic activity of metallo-β-lactamases by lowering the availability of zinc in the extracellular medium using metal chelating agents such as EDTA carried on nanoparticles. Chitosan, as linear cationic polysaccharide is frequently used in biomedical and pharmaceutical applications, has been studied as a biocompatible encapsulating agent in drug delivery systems and is an ideal transport agent for bioactive molecular complexes in antibiotic applications due to its ability to associate with negatively charged substances. We developed novel nanoparticles using chitosan as a transport matrix for β-lactamic antibiotics. Nanoparticles were synthesized according to the ion gelation method using tripolyphosphate as crosslinking agent. Nanoparticles were functionalized by the adsorption of EDTA, which acts as complexifying agent for Zn2+ ions causing inhibition of metallo-β-lactamases activity. We evaluate the antimicrobial effects of EDTA-functionalized nanoparticles with an imipenem cargo on the clinical isolate P. aeruginosa AG1, a carbapenem-resistant high-risk clone ST-111 carrying both blaIMP-18 and blaVIM-2 metallo-β-lactamases genes.展开更多
Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imi...Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imipenem/cilastatin is a rare condition.Patient’s Concern:A 45-year-old male patient,who previously suffered from a urinary tract infection and treated with imipenem/cilastatin antibiotic,was presented to us with acute respiratory distress,soon after the initiation of the antibiotic.Computed tomography identified pulmonary infiltrates in the upper and middle lung fields and eosinophils were found to account for 36%of differential count of the broncho-alveolar lavage fluid.He also developed peripheral eosinophilia as the disease progressed.Diagnosis:AEP,secondary to imipenem/cilastatin therapy.Interventions:Steroid therapy was administered and imipenem/cilastatin antibiotic was discontinued.Outcomes:The patient improved completely following the therapy and had clear lung fields on follow-up.Lessons:Imipenem/cilastatin is an uncommon cause of AEP and requires close monitoring during therapy.展开更多
In this work, the authors aimed to detect the clonal relatedness of the isolated imipenem-susceptible and non-susceptible Acenitobacter baumanii. This study was conducted from September 2008 through August 2009 in Abo...In this work, the authors aimed to detect the clonal relatedness of the isolated imipenem-susceptible and non-susceptible Acenitobacter baumanii. This study was conducted from September 2008 through August 2009 in Aboelreech-Elmounira paediatric-Cairo University-teaching hospital in Egypt. All the isolated acenitobacter species were identified by standard laboratory procedures. The clonal relationship of the A. baumanii （the most common detected clinical type） was studied by biotyping and AST and then confirmed using rep-PCR with primers aimed at repetitive extragenic palindromic sequences and enterobacterial repetitive intergenic consensus sequences. A total of 100 A. baumanii isolates out of 104 acenitobacter species were recovered from different clinical samples. Sixty two percent of the isolates were resistant to imipenem. The resulting rep-PCR patterns oftheA, baumanii strains revealed 8 clones, 3 clones found in the imipenem resistant group, and 5 clones in imipenem sensitive group with statistically significant clonal distribution in both groups （P-value 0.00）. Clonality was proved in imipenem resistant group with an alarming predominance of clone 1 representing 80.6% of IMP-R isolates. In accordance the prevalence of resistant acenitobacter strains seems to be correlated with inappropriate antibiotic use. These results call for strict compliance of coordinated strategy of infection control measures and judicious use of antimicrobials which is likely to effectively deal with this serious public health issue.展开更多
Objective To identify the risk factors for imipenem resistance development and transmission of clinical Pseudomonas aeruginosa isolates.Methods Thirty-seven imipenem unsusceptible Pseudomonas aeruginosa isolates colle...Objective To identify the risk factors for imipenem resistance development and transmission of clinical Pseudomonas aeruginosa isolates.Methods Thirty-seven imipenem unsusceptible Pseudomonas aeruginosa isolates collected from patients in absence of carbapenem treatment were characterized by antimicrobial susceptibility test,pulsed field gel electrophoresis(PFGE)and carbapenem resistant mechanism analysis.Results Before the collection of imipenem unsusceptible Pseudomonas aeruginosa isolates,the average time of patients treated with more than one antimicrobial(20.0±9.5 days,n=16)was significantly longer than those treated with only one antimicrobial(12.6±4.4 days,n=21;t-test,Welch,t=-2.9004,P<0.01).And 32 isolates showed resistance to more than 3 classes of antimicrobials.Six PFGE clusters were identified and 26 isolates were grouped into one dominant cluster(C2).An ISpa1328 sequence insertion in oprD was detected in 33 isolates and the function of efflux was observed in all 37 isolates in the presence of a wide spectrum efflux inhibitor.Conclusions Our data demonstrated that exposure to non-carbapenem drug classes,especially fluoroquinolones andβ-lactams,may be important risk factors for the spread of carbapenem resistant Pseudomonas aeruginosa.展开更多
Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infection...Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections Methods A total of 182 hospitalized patients were enrolled in the study 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion The duration of treatment was 7-14 days for both groups Results Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups 93 (76%) of 123 strains isolated from patients produced β lactamases Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group The adverse drug reaction rates were 9 7% and 8 6%, respectively The results showed that there were no statistical differences between these two groups ( P >0 05) Conclusion Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta lactamase producing strains展开更多
Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present stud...Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present study, the potential roles of renal organic anion transporters(OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of h OAT1 and h OAT3. Cilastatin inhibited h OAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction(DDI). Moreover,imipenem exhibited h OAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.展开更多
Background Broad-spectrum antibiotic administration promotes intestinal colonization of exogenous fungal pathogens in healthy animals and has been recognized as one of the risk factors of invasive fungal infection in ...Background Broad-spectrum antibiotic administration promotes intestinal colonization of exogenous fungal pathogens in healthy animals and has been recognized as one of the risk factors of invasive fungal infection in clinical settings. It is unclear whether broad-spectrum antibiotic treatment would change the intestinal mycobiota without exogenous fungal challenge in the context of sepsis. Methods We established a rat model of double-hit sepsis using burn injury and endotoxin challenge. Rats with burn injury or double-hit sepsis received imipenem treatment for 3 days or 9 days, and their colon contents were sampled for selective fungal culture and isolation counts. Results Imipenem treatment promoted the overgrowth of the commensal fungus Geotrichum capitatum in rats with burn injury. Imipenem treatment also promoted colon colonization by exogenous fungi in rats with burn injury and double-hit sepsis, including Trichosporon cutaneum, Candida albicans, Candida krusei, and Candida glabrata. A longer duration of imipenem treatment had a stronger impact on colon colonization by exogenous fungi. Conclusion Imipenem treatment facilitates the overgrowth of commensal fungi and colonization by exogenous, potentially pathogenic fungi in the colons of rats with burn injury or double-hit sepsis.展开更多
基金supported by a grant from the National Natural Science Foundation of China (No. 81874324,81473280,U1608283)the Natural Science Foundation of Liaoning (No. 20170540293)Dalian Science and technology innovation fund (No. 2018J12SN065).
文摘This study aimed to clarify that organic anion transporters(OATs)mediate the drug–drug interaction(DDI)between imipenem and cilastatin.After co-administration with imipenem,the plasma concentrations and the plasma concentration-time curve(AUC)of cilastatin were significantly increased,while renal clearance and cumulative urinary excretion of cilastatin were decreased.At the same time,imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1(hOAT1)-HEK293 and human OAT3(hOAT3)-HEK293 cells.Probenecid,p-aminohippurate,and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1-and hOAT3-HEK 293 cells,respectively.The uptakes of imipenem and cilastatin in hOAT1-and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 cells.Moreover,the K m values of cilastatin were increased in the presence of imipenem with unchanged V max,indicating that imipenem inhibited the uptake of cilastatin in a competitive manner.When imipenem and cilastatin were co-administered,the level of imipenem was higher compared with imipenem alone both in vivo and in vitro.But,cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1(DPEP1)was silenced by RNAi technology in hOAT1-and hOAT3-HEK 293 cells.In conclusion,imipenem and cilastatin are the substrates of OAT1 and OAT3.OAT1 and OAT3 mediate the DDI between imipenem and cilastatin.Meanwhile,cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement.
文摘The present study identified the properties of porins in the outer membrane in Pseudomonas aeruginosa,and showed the role of outer membrane in determining imipenem diffusion in Pseudomonas aeruginosa The molecular weight of the major outer membrane protein was analyzed by SDS PAGE The purification of the porins in Pseudomonas aeruginosa was achieved by DEAE ion exchange HPLC The purified outer membrane proteins were reconstituted with phosphatidylcholine and dicetylphosphate into membrane vesicles, and were tested by the liposomes swelling method for the diffusion of imipenem The permeability assay showed that OprC (70 kD), OprD 2 (46kD), and OprE(43 kD) were the channel forming proteins But only OprD 2 was thought to be the likely route of imipenem diffusion
基金Supported by the Education Research Program Project of Zhejiang Province,No.Y202043224.
文摘BACKGROUND Imipenem is a highly effective carbapenem antibiotic,which is widely used in the treatment of many serious bacterial infections.At the same time,it can also cause some adverse reactions,mental abnormalities are the most concerned central nervous system adverse reactions.Different patients respond differently to imipenem,and the effect of imipenem on psychiatric disorders is unclear.Therefore,meta-analysis summarizing the results of multiple previous studies can provide stronger evidence support for clinical guidelines to guide clinical rational use of imipenem to minimize risks.After reviewing the literature published between 2003 and 2017,seven controlled trials with a total of 550 patients were included,with 273 and 277 patients in the control and experimental groups,respectively.The sample size of the study ranged from a minimum of 30 cases to a maximum of 61 cases.Patients in the experimental group were treated with imipenem while the control group was treated with conventional drugs.Meta-analysis showed that the incidence of mental disorders in the experimental group was higher than that in the control group(odds ratio=3.66,95%confidence interval:1.11-12.11,P=0.030);however,there was no significant difference in the incidence of adverse reactions between the two groups(odds ratio=0.05,95%confidence interval:0.00 to 0.10,P=0.060).Funnel diagrams showed that the scattered points of each study were symmetrical and distributed in an inverted funnel shape;therefore,there was no publication bias.CONCLUSION Imipenem can cause mental disorders in patients.However,the low quality of the included literature may have affected the final results.Therefore,it is necessary to conduct a high-quality randomized controlled study with multiple samples to further confirm the mechanism of imipenem-induced mental disorders and provide effective guidance for clinical treatment.
基金the Inter-University Fund for Higher Education(FEES)at the National Council of Rectors(CONARE)for financial support to this project through grant agreement No ACUERDO-VI-171-2014
文摘Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating infections caused by multiresistant bacteria. We elaborated the hypothesis that it is possible to inhibit the enzymatic activity of metallo-β-lactamases by lowering the availability of zinc in the extracellular medium using metal chelating agents such as EDTA carried on nanoparticles. Chitosan, as linear cationic polysaccharide is frequently used in biomedical and pharmaceutical applications, has been studied as a biocompatible encapsulating agent in drug delivery systems and is an ideal transport agent for bioactive molecular complexes in antibiotic applications due to its ability to associate with negatively charged substances. We developed novel nanoparticles using chitosan as a transport matrix for β-lactamic antibiotics. Nanoparticles were synthesized according to the ion gelation method using tripolyphosphate as crosslinking agent. Nanoparticles were functionalized by the adsorption of EDTA, which acts as complexifying agent for Zn2+ ions causing inhibition of metallo-β-lactamases activity. We evaluate the antimicrobial effects of EDTA-functionalized nanoparticles with an imipenem cargo on the clinical isolate P. aeruginosa AG1, a carbapenem-resistant high-risk clone ST-111 carrying both blaIMP-18 and blaVIM-2 metallo-β-lactamases genes.
文摘Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imipenem/cilastatin is a rare condition.Patient’s Concern:A 45-year-old male patient,who previously suffered from a urinary tract infection and treated with imipenem/cilastatin antibiotic,was presented to us with acute respiratory distress,soon after the initiation of the antibiotic.Computed tomography identified pulmonary infiltrates in the upper and middle lung fields and eosinophils were found to account for 36%of differential count of the broncho-alveolar lavage fluid.He also developed peripheral eosinophilia as the disease progressed.Diagnosis:AEP,secondary to imipenem/cilastatin therapy.Interventions:Steroid therapy was administered and imipenem/cilastatin antibiotic was discontinued.Outcomes:The patient improved completely following the therapy and had clear lung fields on follow-up.Lessons:Imipenem/cilastatin is an uncommon cause of AEP and requires close monitoring during therapy.
文摘In this work, the authors aimed to detect the clonal relatedness of the isolated imipenem-susceptible and non-susceptible Acenitobacter baumanii. This study was conducted from September 2008 through August 2009 in Aboelreech-Elmounira paediatric-Cairo University-teaching hospital in Egypt. All the isolated acenitobacter species were identified by standard laboratory procedures. The clonal relationship of the A. baumanii （the most common detected clinical type） was studied by biotyping and AST and then confirmed using rep-PCR with primers aimed at repetitive extragenic palindromic sequences and enterobacterial repetitive intergenic consensus sequences. A total of 100 A. baumanii isolates out of 104 acenitobacter species were recovered from different clinical samples. Sixty two percent of the isolates were resistant to imipenem. The resulting rep-PCR patterns oftheA, baumanii strains revealed 8 clones, 3 clones found in the imipenem resistant group, and 5 clones in imipenem sensitive group with statistically significant clonal distribution in both groups （P-value 0.00）. Clonality was proved in imipenem resistant group with an alarming predominance of clone 1 representing 80.6% of IMP-R isolates. In accordance the prevalence of resistant acenitobacter strains seems to be correlated with inappropriate antibiotic use. These results call for strict compliance of coordinated strategy of infection control measures and judicious use of antimicrobials which is likely to effectively deal with this serious public health issue.
基金This research was supported by grant(2009BADB9B01)from the Ministry of Science and Technology of the People’s Republic of China and grant(30701039)from the National Natural Science Foundation of China.
文摘Objective To identify the risk factors for imipenem resistance development and transmission of clinical Pseudomonas aeruginosa isolates.Methods Thirty-seven imipenem unsusceptible Pseudomonas aeruginosa isolates collected from patients in absence of carbapenem treatment were characterized by antimicrobial susceptibility test,pulsed field gel electrophoresis(PFGE)and carbapenem resistant mechanism analysis.Results Before the collection of imipenem unsusceptible Pseudomonas aeruginosa isolates,the average time of patients treated with more than one antimicrobial(20.0±9.5 days,n=16)was significantly longer than those treated with only one antimicrobial(12.6±4.4 days,n=21;t-test,Welch,t=-2.9004,P<0.01).And 32 isolates showed resistance to more than 3 classes of antimicrobials.Six PFGE clusters were identified and 26 isolates were grouped into one dominant cluster(C2).An ISpa1328 sequence insertion in oprD was detected in 33 isolates and the function of efflux was observed in all 37 isolates in the presence of a wide spectrum efflux inhibitor.Conclusions Our data demonstrated that exposure to non-carbapenem drug classes,especially fluoroquinolones andβ-lactams,may be important risk factors for the spread of carbapenem resistant Pseudomonas aeruginosa.
文摘Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections Methods A total of 182 hospitalized patients were enrolled in the study 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion The duration of treatment was 7-14 days for both groups Results Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups 93 (76%) of 123 strains isolated from patients produced β lactamases Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group The adverse drug reaction rates were 9 7% and 8 6%, respectively The results showed that there were no statistical differences between these two groups ( P >0 05) Conclusion Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta lactamase producing strains
基金supported by a grant from the National Natural Science Foundation of China,China(Nos.81874324,81473280,and U1608283)Dalian Science and technology innovation found,China(No.2018J12SN065)
文摘Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present study, the potential roles of renal organic anion transporters(OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of h OAT1 and h OAT3. Cilastatin inhibited h OAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction(DDI). Moreover,imipenem exhibited h OAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 30472270）.
文摘Background Broad-spectrum antibiotic administration promotes intestinal colonization of exogenous fungal pathogens in healthy animals and has been recognized as one of the risk factors of invasive fungal infection in clinical settings. It is unclear whether broad-spectrum antibiotic treatment would change the intestinal mycobiota without exogenous fungal challenge in the context of sepsis. Methods We established a rat model of double-hit sepsis using burn injury and endotoxin challenge. Rats with burn injury or double-hit sepsis received imipenem treatment for 3 days or 9 days, and their colon contents were sampled for selective fungal culture and isolation counts. Results Imipenem treatment promoted the overgrowth of the commensal fungus Geotrichum capitatum in rats with burn injury. Imipenem treatment also promoted colon colonization by exogenous fungi in rats with burn injury and double-hit sepsis, including Trichosporon cutaneum, Candida albicans, Candida krusei, and Candida glabrata. A longer duration of imipenem treatment had a stronger impact on colon colonization by exogenous fungi. Conclusion Imipenem treatment facilitates the overgrowth of commensal fungi and colonization by exogenous, potentially pathogenic fungi in the colons of rats with burn injury or double-hit sepsis.
