Yingsi Fang, Lloyd G Clarke, Brandon J Smith, Sunish Shah
This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality.
{"title":"Incidence of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents.","authors":"Yingsi Fang, Lloyd G Clarke, Brandon J Smith, Sunish Shah","doi":"10.1128/aac.00870-24","DOIUrl":"https://doi.org/10.1128/aac.00870-24","url":null,"abstract":"<p><p>This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gram-negative bacteria (GNB) pose a major global public health challenge as they exhibit a remarkable level of resistance to antibiotics. One of the factors responsible for promoting resistance against a wide range of antibiotics is the outer membrane (OM) of Gram-negative bacteria. The OM acts as a barrier that prevents the entry of numerous antibiotics by reducing their influx (due to membrane impermeability) and enhancing their efflux (with the help of efflux pumps). Our study focuses on analyzing the effect of IMT-P8, a cell-penetrating peptide (CPP), to enhance the influx of various Gram-positive specific antibiotics in multi-drug resistant Gram-negative pathogens. In the mechanistic experiments, IMT-P8 permeabilizes the OM at the same concentrations at which it enhances the activity of various antibiotics against GNB. Cytoplasmic membrane permeabilization was also observed at these concentrations, indicating that IMT-P8 acts on both the outer and cytoplasmic membranes. IMT-P8 interferes with the intrinsic resistance mechanism of GNB and has the potential to make Gram-positive specific antibiotics effective against GNB. IMT-P8 extends the post-antibiotic effect and in combination with antibiotics shows anti-persister activity. The IMT-P8/fusidic acid combination is effective in eliminating intracellular pathogens. IMT-P8 with negligible toxicity displayed good efficacy in murine lung and thigh infection models. Based on these findings, IMT-P8 is a potential antibiotic adjuvant to treat Gram-negative bacterial infections that pose a health hazard.
{"title":"IMT-P8 potentiates Gram-positive specific antibiotics in intrinsically resistant Gram-negative bacteria.","authors":"Vidhu Singh, Hemraj Nandanwar","doi":"10.1128/aac.00753-24","DOIUrl":"https://doi.org/10.1128/aac.00753-24","url":null,"abstract":"<p><p>Gram-negative bacteria (GNB) pose a major global public health challenge as they exhibit a remarkable level of resistance to antibiotics. One of the factors responsible for promoting resistance against a wide range of antibiotics is the outer membrane (OM) of Gram-negative bacteria. The OM acts as a barrier that prevents the entry of numerous antibiotics by reducing their influx (due to membrane impermeability) and enhancing their efflux (with the help of efflux pumps). Our study focuses on analyzing the effect of IMT-P8, a cell-penetrating peptide (CPP), to enhance the influx of various Gram-positive specific antibiotics in multi-drug resistant Gram-negative pathogens. In the mechanistic experiments, IMT-P8 permeabilizes the OM at the same concentrations at which it enhances the activity of various antibiotics against GNB. Cytoplasmic membrane permeabilization was also observed at these concentrations, indicating that IMT-P8 acts on both the outer and cytoplasmic membranes. IMT-P8 interferes with the intrinsic resistance mechanism of GNB and has the potential to make Gram-positive specific antibiotics effective against GNB. IMT-P8 extends the post-antibiotic effect and in combination with antibiotics shows anti-persister activity. The IMT-P8/fusidic acid combination is effective in eliminating intracellular pathogens. IMT-P8 with negligible toxicity displayed good efficacy in murine lung and thigh infection models. Based on these findings, IMT-P8 is a potential antibiotic adjuvant to treat Gram-negative bacterial infections that pose a health hazard.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04Epub Date: 2024-07-30DOI: 10.1128/aac.00549-24
Jihyun Bae, Marwa Tantawy, Yan Gong, Taimour Langaee, Margaret Lartey, Vincent Ganu, Kenneth Tachi, Oluwayemisi Ojewale, Adjoa Obo-Akwa, Isaac Boamah, Lane R Bushman, Lucas Ellison, Hongmei Yang, Peter L Anderson, Awewura Kwara
The nucleos(t)ide analogs require phosphorylation to the pharmacologically active anabolites in cells. We investigated the hypothesis that single-nucleotide polymorphisms (SNPs) in genes that encode transporters and phosphodiesterase (PDE) enzymes involved in tenofovir (TFV), disoproxil fumarate (TDF), and lamivudine (3TC) disposition will be associated with concentrations of their phosphate anabolites and virologic response. Individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection receiving TDF/3TC-containing antiretroviral therapy were enrolled. Steady-state TFV diphosphate (TFV-DP) and 3TC triphosphate (3TC-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spot samples were quantified. The relationship between genetic variants and TFV-DP and 3TC-TP concentrations as well as with virologic response were examined using multivariable linear regression. Of the 136 participants (median age 43 years; 63% females), 6.6% had HBV non-suppression, and 7.4% had HIV non-suppression. The multidrug resistance protein 2 (encoded by ABCC2 rs2273697) SNP was associated with 3TC-TP concentrations in PBMCs. The human organic anion transporter-1 (encoded by SLC28A2) rs11854484 SNP was associated with HIV non-suppression, and when evaluated together with SNPs with marginal associations (ABCC2 rs717620 and PDE1C rs30561), participants with two or three variants compared to those with none of these variants had an adjusted odds ratio of 48.3 (confidence interval, 4.3-547.8) for HIV non-suppression. None of the SNPs were associated with HBV non-suppression. Our study identified ABCC2 SNP to be associated with 3TC-TP concentrations in PBMCs. Also, a combination of genetic variants of drug transporters and PDE was associated with HIV non-suppression.
{"title":"Pharmacogenetic determinants of tenofovir diphosphate and lamivudine triphosphate concentrations in people with HIV/HBV coinfection.","authors":"Jihyun Bae, Marwa Tantawy, Yan Gong, Taimour Langaee, Margaret Lartey, Vincent Ganu, Kenneth Tachi, Oluwayemisi Ojewale, Adjoa Obo-Akwa, Isaac Boamah, Lane R Bushman, Lucas Ellison, Hongmei Yang, Peter L Anderson, Awewura Kwara","doi":"10.1128/aac.00549-24","DOIUrl":"10.1128/aac.00549-24","url":null,"abstract":"<p><p>The nucleos(t)ide analogs require phosphorylation to the pharmacologically active anabolites in cells. We investigated the hypothesis that single-nucleotide polymorphisms (SNPs) in genes that encode transporters and phosphodiesterase (PDE) enzymes involved in tenofovir (TFV), disoproxil fumarate (TDF), and lamivudine (3TC) disposition will be associated with concentrations of their phosphate anabolites and virologic response. Individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection receiving TDF/3TC-containing antiretroviral therapy were enrolled. Steady-state TFV diphosphate (TFV-DP) and 3TC triphosphate (3TC-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spot samples were quantified. The relationship between genetic variants and TFV-DP and 3TC-TP concentrations as well as with virologic response were examined using multivariable linear regression. Of the 136 participants (median age 43 years; 63% females), 6.6% had HBV non-suppression, and 7.4% had HIV non-suppression. The multidrug resistance protein 2 (encoded by <i>ABCC2</i> rs2273697) SNP was associated with 3TC-TP concentrations in PBMCs. The human organic anion transporter-1 (encoded by <i>SLC28A2</i>) rs11854484 SNP was associated with HIV non-suppression, and when evaluated together with SNPs with marginal associations (<i>ABCC2</i> rs717620 and <i>PDE1C</i> rs30561), participants with two or three variants compared to those with none of these variants had an adjusted odds ratio of 48.3 (confidence interval, 4.3-547.8) for HIV non-suppression. None of the SNPs were associated with HBV non-suppression. Our study identified <i>ABCC2</i> SNP to be associated with 3TC-TP concentrations in PBMCs. Also, a combination of genetic variants of drug transporters and PDE was associated with HIV non-suppression.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04Epub Date: 2024-08-13DOI: 10.1128/aac.00779-24
Sasikanya Thaloengsok, Chaiyaporn Chaisatit, Piyaporn Saingam, Paphavee Lertsethtakarn, Michele Spring, Sabaithip Sriwichai, Suporn Pholwat, Jennifer L Guler, Eric R Houpt, Brian A Vesely
Despite the overall decline in malaria cases in Thailand, continuous surveillance in endemic areas remains crucial. This retrospective analysis examined Plasmodium falciparum samples from Tak province, Thailand, collected in 1998, 1999, and 2001, to investigate the prevalence and evolution of antimalarial genotypic drug resistance. The study revealed a high prevalence of drug-resistant P. falciparum, particularly to mefloquine and sulfadoxine/pyrimethamine, with significant mutations in genes associated with resistance. Notably, mutations indicative of artemisinin resistance, such as those in the kelch13 gene, were detected at low frequencies, suggesting an evolving resistance pattern. The underlying cause of these resistance mutations appears to be the historical and widespread use of these antimalarial drugs, which exerted selective pressure on the parasite population. These findings underscore the necessity of ongoing surveillance and adaptive control strategies to manage drug resistance, guide treatment policies, and prevent potential outbreaks, even as malaria cases decrease. Continuous monitoring and research are imperative to sustain malaria elimination efforts and address the dynamic challenges posed by evolving drug-resistant strains.
{"title":"Prevalence and dynamics of antimalarial drug resistance mutations among the <i>Plasmodium falciparum</i> isolates in TAK Province, Thailand, during the period of 1998-2001.","authors":"Sasikanya Thaloengsok, Chaiyaporn Chaisatit, Piyaporn Saingam, Paphavee Lertsethtakarn, Michele Spring, Sabaithip Sriwichai, Suporn Pholwat, Jennifer L Guler, Eric R Houpt, Brian A Vesely","doi":"10.1128/aac.00779-24","DOIUrl":"10.1128/aac.00779-24","url":null,"abstract":"<p><p>Despite the overall decline in malaria cases in Thailand, continuous surveillance in endemic areas remains crucial. This retrospective analysis examined <i>Plasmodium falciparum</i> samples from Tak province, Thailand, collected in 1998, 1999, and 2001, to investigate the prevalence and evolution of antimalarial genotypic drug resistance. The study revealed a high prevalence of drug-resistant <i>P. falciparum</i>, particularly to mefloquine and sulfadoxine/pyrimethamine, with significant mutations in genes associated with resistance. Notably, mutations indicative of artemisinin resistance, such as those in the kelch13 gene, were detected at low frequencies, suggesting an evolving resistance pattern. The underlying cause of these resistance mutations appears to be the historical and widespread use of these antimalarial drugs, which exerted selective pressure on the parasite population. These findings underscore the necessity of ongoing surveillance and adaptive control strategies to manage drug resistance, guide treatment policies, and prevent potential outbreaks, even as malaria cases decrease. Continuous monitoring and research are imperative to sustain malaria elimination efforts and address the dynamic challenges posed by evolving drug-resistant strains.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04Epub Date: 2024-08-12DOI: 10.1128/aac.00751-24
Michael R Jacobs, Ayman M Abdelhamed, Caryn E Good, Andrew R Mack, Christopher R Bethel, Steven Marshall, Andrea M Hujer, Kristine M Hujer, Robin Patel, David van Duin, Vance G Fowler, Daniel D Rhoads, David A Six, Greg Moeck, Tsuyoshi Uehara, Krisztina M Papp-Wallace, Robert A Bonomo
Taniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against Klebsiella pneumoniae carbapenemase (KPC), Verona integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant K. pneumoniae and 197 multidrug-resistant (MDR) Pseudomonas aeruginosa to cefepime-taniborbactam and comparators was determined by broth microdilution. For K. pneumoniae (192 KPC; 7 OXA-48-related), MIC90 values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively. For cefepime-taniborbactam, 100% and 99.5% of isolates of K. pneumoniae were inhibited at ≤16 mg/L and ≤8 mg/L, respectively, while 98.0% and 95.5% of isolates were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, respectively. For P. aeruginosa, MIC90 values of β-lactam components of cefepime-taniborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam were 16, >8, >8, and >4 mg/L, respectively. Of 89 carbapenem-susceptible isolates, 100% were susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and cefepime-taniborbactam at ≤8 mg/L. Of 73 carbapenem-intermediate/resistant P. aeruginosa isolates without carbapenemases, 87.7% were susceptible to ceftolozane-tazobactam, 79.5% to ceftazidime-avibactam, and 95.9% and 83.6% to cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively. Cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively, was active against 73.3% and 46.7% of 15 VIM- and 60.0% and 35.0% of 20 KPC-producing P. aeruginosa isolates. Of all 108 carbapenem-intermediate/resistant P. aeruginosa isolates, cefepime-taniborbactam was active against 86.1% and 69.4% at ≤16 mg/L and ≤8 mg/L, respectively, compared to 59.3% for ceftolozane-tazobactam and 63.0% for ceftazidime-avibactam. Cefepime-taniborbactam had in vitro activity comparable to ceftazidime-avibactam and greater than meropenem-vaborbactam against carbapenem-resistant K. pneumoniae and carbapenem-intermediate/resistant MDR P. aeruginosa.
{"title":"ARGONAUT-III and -V: susceptibility of carbapenem-resistant <i>Klebsiella pneumoniae</i> and multidrug-resistant <i>Pseudomonas aeruginosa</i> to the bicyclic boronate β-lactamase inhibitor taniborbactam combined with cefepime.","authors":"Michael R Jacobs, Ayman M Abdelhamed, Caryn E Good, Andrew R Mack, Christopher R Bethel, Steven Marshall, Andrea M Hujer, Kristine M Hujer, Robin Patel, David van Duin, Vance G Fowler, Daniel D Rhoads, David A Six, Greg Moeck, Tsuyoshi Uehara, Krisztina M Papp-Wallace, Robert A Bonomo","doi":"10.1128/aac.00751-24","DOIUrl":"10.1128/aac.00751-24","url":null,"abstract":"<p><p>Taniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against <i>Klebsiella pneumoniae</i> carbapenemase (KPC), Verona integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant <i>K. pneumoniae</i> and 197 multidrug-resistant (MDR) <i>Pseudomonas aeruginosa</i> to cefepime-taniborbactam and comparators was determined by broth microdilution. For <i>K. pneumoniae</i> (192 KPC; 7 OXA-48-related), MIC<sub>90</sub> values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively. For cefepime-taniborbactam, 100% and 99.5% of isolates of <i>K. pneumoniae</i> were inhibited at ≤16 mg/L and ≤8 mg/L, respectively, while 98.0% and 95.5% of isolates were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, respectively. For <i>P. aeruginosa</i>, MIC<sub>90</sub> values of β-lactam components of cefepime-taniborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam were 16, >8, >8, and >4 mg/L, respectively. Of 89 carbapenem-susceptible isolates, 100% were susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and cefepime-taniborbactam at ≤8 mg/L. Of 73 carbapenem-intermediate/resistant <i>P. aeruginosa</i> isolates without carbapenemases, 87.7% were susceptible to ceftolozane-tazobactam, 79.5% to ceftazidime-avibactam, and 95.9% and 83.6% to cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively. Cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively, was active against 73.3% and 46.7% of 15 VIM- and 60.0% and 35.0% of 20 KPC-producing <i>P. aeruginosa</i> isolates. Of all 108 carbapenem-intermediate/resistant <i>P. aeruginosa</i> isolates, cefepime-taniborbactam was active against 86.1% and 69.4% at ≤16 mg/L and ≤8 mg/L, respectively, compared to 59.3% for ceftolozane-tazobactam and 63.0% for ceftazidime-avibactam. Cefepime-taniborbactam had <i>in vitro</i> activity comparable to ceftazidime-avibactam and greater than meropenem-vaborbactam against carbapenem-resistant <i>K. pneumoniae</i> and carbapenem-intermediate/resistant MDR <i>P. aeruginosa</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04Epub Date: 2024-07-31DOI: 10.1128/aac.00642-24
Soon-Ok Lee, Ki Back Chu, Keon-Woong Yoon, Gi-Deok Eom, Jie Mao, Hyeryon Lee, Joo Hwan No, Jin Ho Song, Sung-Jong Hong, Sung Soo Kim, Fu-Shi Quan
Praziquantel (PZQ) is currently the only approved drug for treating clonorchiasis, but its poor efficacy against Clonorchis sinensis larvae has highlighted the need to develop newer drugs. In this study, to address this challenge, we investigated the anti-parasitic efficacy of miltefosine (MLT), curcumin (CUR), and PZQ against C. sinensis metacercariae (CsMC), newly excysted juvenile worms (CsNEJs), and adults. Larvicidal effects of MLT and CUR surpassed those elicited by PZQ in vitro. These two drugs exerted their effect against both CsMC and CsNEJs in a dose- and time-dependent manner. To confirm the effect of these drugs in vivo, Syrian golden hamsters were orally infected with 100 CsMC and subsequently treated with MLT, CUR, or PZQ at 1 and 4 weeks post-infection (wpi). MLT and CUR reduced the worm recoveries at 1 and 4 wpi, indicating that these drugs were efficacious against both larvae and adult C. sinensis. PZQ was only efficacious against adult worms. Interestingly, both MLT and CUR showed lower levels of C. sinensis-specific IgG responses than the infection control group, implying that worm burden and bile IgG responses could be correlated. These results indicate that MLT and CUR are efficacious against both larval and adult stages of C. sinensis, thereby highlighting their potential for further development as alternative therapeutic options for clonorchiasis.
吡喹酮 (PZQ) 是目前唯一获准用于治疗克隆氏病的药物,但它对中华睾吸虫幼虫的疗效不佳,这凸显了开发新药物的必要性。为了应对这一挑战,我们在本研究中调查了米替福新(MLT)、姜黄素(CUR)和PZQ对中华蛔虫蚴(CsMC)、刚脱落的幼虫(CsNEJs)和成虫的抗寄生虫药效。在体外实验中,MLT和CUR的杀幼虫效果超过了PZQ。这两种药物对CsMC和CsNEJs的作用呈剂量和时间依赖性。为了证实这些药物在体内的作用,叙利亚金色仓鼠口服感染了100个CsMC,随后在感染后1周和4周(wpi)分别用MLT、CUR或PZQ治疗。MLT 和 CUR 可降低感染后 1 周和 4 周的虫体恢复率,表明这些药物对中华按蚊幼虫和成虫都有效。PZQ 仅对成虫有效。有趣的是,与感染对照组相比,MLT 和 CUR 都显示出较低水平的中华蛔虫特异性 IgG 反应,这意味着虫体负担和胆汁 IgG 反应可能是相关的。这些结果表明,MLT和CUR对中华蛔虫的幼虫期和成虫期均有效,从而突出了它们作为克隆氏蛔虫病替代疗法的进一步发展潜力。
{"title":"Efficacy assessment of miltefosine and curcumin against <i>Clonorchis sinensis</i> infection.","authors":"Soon-Ok Lee, Ki Back Chu, Keon-Woong Yoon, Gi-Deok Eom, Jie Mao, Hyeryon Lee, Joo Hwan No, Jin Ho Song, Sung-Jong Hong, Sung Soo Kim, Fu-Shi Quan","doi":"10.1128/aac.00642-24","DOIUrl":"10.1128/aac.00642-24","url":null,"abstract":"<p><p>Praziquantel (PZQ) is currently the only approved drug for treating clonorchiasis, but its poor efficacy against <i>Clonorchis sinensis</i> larvae has highlighted the need to develop newer drugs. In this study, to address this challenge, we investigated the anti-parasitic efficacy of miltefosine (MLT), curcumin (CUR), and PZQ against <i>C. sinensis</i> metacercariae (CsMC), newly excysted juvenile worms (CsNEJs), and adults. Larvicidal effects of MLT and CUR surpassed those elicited by PZQ <i>in vitro</i>. These two drugs exerted their effect against both CsMC and CsNEJs in a dose- and time-dependent manner. To confirm the effect of these drugs <i>in vivo</i>, Syrian golden hamsters were orally infected with 100 CsMC and subsequently treated with MLT, CUR, or PZQ at 1 and 4 weeks post-infection (wpi). MLT and CUR reduced the worm recoveries at 1 and 4 wpi, indicating that these drugs were efficacious against both larvae and adult <i>C. sinensis</i>. PZQ was only efficacious against adult worms. Interestingly, both MLT and CUR showed lower levels of <i>C. sinensis-</i>specific IgG responses than the infection control group, implying that worm burden and bile IgG responses could be correlated. These results indicate that MLT and CUR are efficacious against both larval and adult stages of <i>C. sinensis</i>, thereby highlighting their potential for further development as alternative therapeutic options for clonorchiasis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As methicillin-resistant Staphylococcus aureus (MRSA) exhibits formidable resistance to many drugs, the imperative for alternative therapeutic strategies becomes increasingly evident. At the heart of our study is the identification of a novel inhibitor through fluorescence anisotropy assays, specifically targeting the crucial multiple gene regulator A (MgrA) regulatory network in S. aureus. Isorhapontigenin (Iso), a natural compound, exhibits outstanding inhibitory efficacy, modulating bacterial virulence pathways without exerting direct bactericidal activity. This suggests a paradigm shift toward attenuating virulence instead of purely focusing on bacterial elimination. Through comprehensive in vitro and in vivo evaluations, we elucidated the complex interplay between Iso and MgrA, leading to reduced S. aureus adhesion, and overall virulence. At the cellular level, Iso offers significant protection to A549 cells infected with S. aureus, reducing cellular damage. Importantly, Iso augments the chemotaxis of neutrophils, curtailing the immune evasion capabilities of S. aureus. Furthermore, in vivo investigations highlight the notable effectiveness of Iso against MRSA-induced pneumonia and within the Galleria mellonella infection model, underscoring its pivotal role in the evolving realm of antibacterial drug discovery. Significantly, when Iso is used in combination with vancomycin, it outperforms its solo application, indicating a more pronounced therapeutic impact. This seminal research emphasizes Iso's potential as a primary defense against the surge of multidrug-resistant pathogens, heralding new prospects in antimicrobial therapy.
由于耐甲氧西林金黄色葡萄球菌(MRSA)对许多药物都表现出强大的耐药性,替代治疗策略的必要性变得越来越明显。我们研究的核心是通过荧光各向异性测定鉴定出一种新型抑制剂,专门针对金黄色葡萄球菌中关键的多基因调控因子 A(MgrA)调控网络。异芹菜甙元(Iso)是一种天然化合物,具有出色的抑制功效,能调节细菌毒力途径,而不直接产生杀菌活性。这表明,治疗模式已从单纯的消灭细菌转变为削弱毒力。通过全面的体外和体内评估,我们阐明了 Iso 和 MgrA 之间复杂的相互作用,从而降低了金黄色葡萄球菌的粘附性和整体毒力。在细胞水平上,Iso 能显著保护感染了金黄色葡萄球菌的 A549 细胞,减少细胞损伤。重要的是,Iso 能增强中性粒细胞的趋化性,抑制金黄色葡萄球菌的免疫逃避能力。此外,体内研究突出显示了 Iso 对 MRSA 引起的肺炎以及在 Galleria mellonella 感染模型中的显著疗效,从而强调了它在不断发展的抗菌药物发现领域中的关键作用。值得注意的是,当 Iso 与万古霉素联合使用时,其疗效优于单独使用,这表明它具有更明显的治疗效果。这项开创性的研究强调了 Iso 作为抵抗耐多药病原体的主要防御手段的潜力,预示着抗菌疗法的新前景。
{"title":"Elucidating the potential of isorhapontigenin in targeting the MgrA regulatory network: a paradigm shift for attenuating MRSA virulence.","authors":"Lihan Liu, Li Wang, Xiaolei Liu, Bingmei Wang, Xuerui Guo, Yueying Wang, Yueshan Xu, Jiyu Guan, Yicheng Zhao","doi":"10.1128/aac.00611-24","DOIUrl":"10.1128/aac.00611-24","url":null,"abstract":"<p><p>As methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) exhibits formidable resistance to many drugs, the imperative for alternative therapeutic strategies becomes increasingly evident. At the heart of our study is the identification of a novel inhibitor through fluorescence anisotropy assays, specifically targeting the crucial multiple gene regulator A (MgrA) regulatory network in <i>S. aureus</i>. Isorhapontigenin (Iso), a natural compound, exhibits outstanding inhibitory efficacy, modulating bacterial virulence pathways without exerting direct bactericidal activity. This suggests a paradigm shift toward attenuating virulence instead of purely focusing on bacterial elimination. Through comprehensive <i>in vitro</i> and <i>in vivo</i> evaluations, we elucidated the complex interplay between Iso and MgrA, leading to reduced <i>S. aureus</i> adhesion, and overall virulence. At the cellular level, Iso offers significant protection to A549 cells infected with <i>S. aureus</i>, reducing cellular damage. Importantly, Iso augments the chemotaxis of neutrophils, curtailing the immune evasion capabilities of <i>S. aureus</i>. Furthermore, <i>in vivo</i> investigations highlight the notable effectiveness of Iso against MRSA-induced pneumonia and within the <i>Galleria mellonella</i> infection model, underscoring its pivotal role in the evolving realm of antibacterial drug discovery. Significantly, when Iso is used in combination with vancomycin, it outperforms its solo application, indicating a more pronounced therapeutic impact. This seminal research emphasizes Iso's potential as a primary defense against the surge of multidrug-resistant pathogens, heralding new prospects in antimicrobial therapy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04Epub Date: 2024-07-24DOI: 10.1128/aac.00850-24
Junyuan Xue, Shutong Li, Liyuan Wang, Yican Zhao, Lu Zhang, Yantong Zheng, Wenxin Zhang, Zhenghong Chen, Ting Jiang, Yundong Sun
The metabolic state of bacteria significantly contributes to their resistance to antibiotics; however, the specific metabolic mechanisms conferring antimicrobial resistance in Helicobacter pylori remain largely understudied. Employing transcriptomic and non-targeted metabolomics, we characterized the metabolic reprogramming of H. pylori when challenged with antibiotic agents. We observed a notable increase in both genetic and key proteomic components involved in fatty acid biosynthesis. Inhibition of this pathway significantly enhanced the antibiotic susceptibility of the sensitive and multidrug-resistant H. pylori strains while also disrupting their biofilm-forming capacities. Further analysis revealed that antibiotic treatment induced a stringent response, triggering the expression of the hp0560-hp0557 operon regulated by Sigma28 (σ28). This activation in turn stimulated the fatty acid biosynthetic pathway, thereby enhancing the antibiotic tolerance of H. pylori. Our findings reveal a novel adaptive strategy employed by H. pylori to withstand antibiotic stress.
{"title":"Enhanced fatty acid biosynthesis by Sigma28 in stringent responses contributes to multidrug resistance and biofilm formation in <i>Helicobacter pylori</i>.","authors":"Junyuan Xue, Shutong Li, Liyuan Wang, Yican Zhao, Lu Zhang, Yantong Zheng, Wenxin Zhang, Zhenghong Chen, Ting Jiang, Yundong Sun","doi":"10.1128/aac.00850-24","DOIUrl":"10.1128/aac.00850-24","url":null,"abstract":"<p><p>The metabolic state of bacteria significantly contributes to their resistance to antibiotics; however, the specific metabolic mechanisms conferring antimicrobial resistance in <i>Helicobacter pylori</i> remain largely understudied. Employing transcriptomic and non-targeted metabolomics, we characterized the metabolic reprogramming of <i>H. pylori</i> when challenged with antibiotic agents. We observed a notable increase in both genetic and key proteomic components involved in fatty acid biosynthesis. Inhibition of this pathway significantly enhanced the antibiotic susceptibility of the sensitive and multidrug-resistant <i>H. pylori</i> strains while also disrupting their biofilm-forming capacities. Further analysis revealed that antibiotic treatment induced a stringent response, triggering the expression of the <i>hp0560-hp0557</i> operon regulated by Sigma28 (σ<sup>28</sup>). This activation in turn stimulated the fatty acid biosynthetic pathway, thereby enhancing the antibiotic tolerance of <i>H. pylori</i>. Our findings reveal a novel adaptive strategy employed by <i>H. pylori</i> to withstand antibiotic stress.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dariusz A Hareza, Sara E Cosgrove, Robert A Bonomo, Kathryn Dzintars, Sara M Karaba, Armani M Hawes, Tsigereda Tekle, Patricia J Simner, Pranita D Tamma
Few studies compare outcomes of patients with difficult-to-treat resistance (DTR) Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam. A multicenter prospective study was conducted of unique patients with DTR P. aeruginosa infections from 2018 to 2023 receiving >72 h of ceftolozane-tazobactam or ceftazidime-avibactam, with confirmation that the P. aeruginosa isolate was susceptible to the agent administered by broth microdilution. Inverse probability weighting (IPW) incorporating propensity scores was utilized to ensure balanced baseline characteristics. Regression performed on the post-IPW group determined 30-day mortality and subsequent emergence of resistance (i.e., ≥4-fold increase in MIC) to the initial treatment (i.e., ceftolozane-tazobactam or ceftazidime-avibactam). Among 186 eligible patients, 102 (55%) received ceftolozane-tazobactam and 84 (45%) received ceftazidime-avibactam. In the post-IPW cohort, balance was achieved across all variables [e.g., demographics, severity of illness, severe immunocompromise, Charlson Comorbidity Index ≥5, continuous renal replacement therapy (CRRT), source of infection, combination therapy]. Thirty-day mortality was similar between the ceftolozane-tazobactam and ceftazidime-avibactam groups [21% vs 17%; adjusted odds ratio (aOR): 1.01 (95% confidence interval, CI: 0.90-1.14)]. Emergence of resistance was higher in the ceftolozane-tazobactam group [38% vs 25%; aOR: 1.89 (95% CI: 0.98-4.88)], but did not achieve statistical significance. Prolonged treatment durations and use of CRRT were associated with increased emergence of resistance (both P = 0.04). Although the survival of patients with DTR P. aeruginosa infections appears similar regardless of whether ceftolozane-tazobactam or ceftazidime-avibactam is prescribed, the emergence of resistance may be more concerning with the former. Plausible mechanistic explanations support these findings. Modifiable risk factors were identified that may mitigate this risk.
很少有研究对难治疗耐药(DTR)铜绿假单胞菌感染患者接受头孢妥仑-他唑巴坦与头孢他啶-阿维巴坦治疗的疗效进行比较。一项多中心前瞻性研究对2018年至2023年期间接受头孢羟氨苄-他唑巴坦或头孢唑肟-阿维巴坦治疗>72小时的DTR铜绿假单胞菌感染患者进行了调查,并通过肉汤微稀释确认铜绿假单胞菌分离株对所施用的药物敏感。为确保基线特征的平衡,采用了包含倾向分数的反概率加权(IPW)方法。对 IPW 后组别进行回归,以确定 30 天死亡率以及随后出现的对初始治疗(即头孢羟氨苄-他唑巴坦或头孢唑肟-阿维巴坦)的耐药性(即 MIC 增加≥4 倍)。在186名符合条件的患者中,102人(55%)接受了头孢唑烷-他唑巴坦治疗,84人(45%)接受了头孢唑肟-阿维巴坦治疗。在IPW后队列中,所有变量[如人口统计学、病情严重程度、严重免疫力低下、夏尔森综合指数≥5、持续肾脏替代疗法(CRRT)、感染源、联合疗法]都达到了平衡。头孢羟氨苄-他唑巴坦组和头孢唑肟-阿维巴坦组的30天死亡率相似[21% vs 17%;调整赔率比(aOR):1.01(95%置信区间,CI:0.90-1.14)]。头孢妥仑-他唑巴坦组的耐药性出现率较高[38% vs 25%;aOR:1.89(95% 置信区间:0.98-4.88)],但未达到统计学意义。延长治疗时间和使用 CRRT 与耐药性的增加有关(P = 0.04)。尽管无论使用头孢妥仑-他唑巴坦还是头孢他啶-阿维巴坦,DTR铜绿假单胞菌感染患者的存活率似乎相似,但前者的耐药性出现可能更令人担忧。可信的机理解释支持这些发现。研究还发现了一些可降低这一风险的风险因素。
{"title":"Clinical outcomes and emergence of resistance of <i>Pseudomonas aeruginosa</i> infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam.","authors":"Dariusz A Hareza, Sara E Cosgrove, Robert A Bonomo, Kathryn Dzintars, Sara M Karaba, Armani M Hawes, Tsigereda Tekle, Patricia J Simner, Pranita D Tamma","doi":"10.1128/aac.00907-24","DOIUrl":"https://doi.org/10.1128/aac.00907-24","url":null,"abstract":"<p><p>Few studies compare outcomes of patients with difficult-to-treat resistance (DTR) <i>Pseudomonas aeruginosa</i> infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam. A multicenter prospective study was conducted of unique patients with DTR <i>P. aeruginosa</i> infections from 2018 to 2023 receiving >72 h of ceftolozane-tazobactam or ceftazidime-avibactam, with confirmation that the <i>P. aeruginosa</i> isolate was susceptible to the agent administered by broth microdilution. Inverse probability weighting (IPW) incorporating propensity scores was utilized to ensure balanced baseline characteristics. Regression performed on the post-IPW group determined 30-day mortality and subsequent emergence of resistance (i.e., ≥4-fold increase in MIC) to the initial treatment (i.e., ceftolozane-tazobactam or ceftazidime-avibactam). Among 186 eligible patients, 102 (55%) received ceftolozane-tazobactam and 84 (45%) received ceftazidime-avibactam. In the post-IPW cohort, balance was achieved across all variables [e.g., demographics, severity of illness, severe immunocompromise, Charlson Comorbidity Index ≥5, continuous renal replacement therapy (CRRT), source of infection, combination therapy]. Thirty-day mortality was similar between the ceftolozane-tazobactam and ceftazidime-avibactam groups [21% vs 17%; adjusted odds ratio (aOR): 1.01 (95% confidence interval, CI: 0.90-1.14)]. Emergence of resistance was higher in the ceftolozane-tazobactam group [38% vs 25%; aOR: 1.89 (95% CI: 0.98-4.88)], but did not achieve statistical significance. Prolonged treatment durations and use of CRRT were associated with increased emergence of resistance (both <i>P</i> = 0.04). Although the survival of patients with DTR <i>P. aeruginosa</i> infections appears similar regardless of whether ceftolozane-tazobactam or ceftazidime-avibactam is prescribed, the emergence of resistance may be more concerning with the former. Plausible mechanistic explanations support these findings. Modifiable risk factors were identified that may mitigate this risk.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04Epub Date: 2024-07-31DOI: 10.1128/aac.00451-24
Sebastian G Wicha, Christina Kinast, Max Münchow, Sandra Wittova, Sebastian Greppmair, Alexandra K Kunzelmann, Michael Zoller, Michael Paal, Michael Vogeser, Katharina Habler, Thomas Weig, Nicole Terpolilli, Suzette Heck, Konstantinos Dimitriadis, Christina Scharf, Uwe Liebchen
Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: nplasma = 243, nCSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), cCSF/cplasma) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II.
Clinical trials: This study is registered with ClinicalTrials.gov as NCT04426383.
{"title":"Meropenem pharmacokinetics in cerebrospinal fluid: comparing intermittent and continuous infusion strategies in critically ill patients-a prospective cohort study.","authors":"Sebastian G Wicha, Christina Kinast, Max Münchow, Sandra Wittova, Sebastian Greppmair, Alexandra K Kunzelmann, Michael Zoller, Michael Paal, Michael Vogeser, Katharina Habler, Thomas Weig, Nicole Terpolilli, Suzette Heck, Konstantinos Dimitriadis, Christina Scharf, Uwe Liebchen","doi":"10.1128/aac.00451-24","DOIUrl":"10.1128/aac.00451-24","url":null,"abstract":"<p><p>Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: n<sub>plasma</sub> = 243, n<sub>CSF</sub> = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), c<sub>CSF</sub>/c<sub>plasma</sub>) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (<i>P</i> < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II.</p><p><strong>Clinical trials: </strong>This study is registered with ClinicalTrials.gov as NCT04426383.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}