Antimicrobial Agents and Chemotherapy最新文献_第2页

Metabolomic analysis reveals an important role of sphingosine 1-phosphate in the development of HFMD due to EV-A71 infection.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-18 DOI: 10.1128/aac.01272-24

Wangquan Ji, Dejian Dang, Guangyuan Zhou, Ling Tao, Tiantian Sun, Dong Li, Cheng Cheng, Huifen Feng, Jinzhao Long, Shuaiyin Chen, Haiyan Yang, Guangcai Duan, Yuefei Jin

{"title":"Metabolomic analysis reveals an important role of sphingosine 1-phosphate in the development of HFMD due to EV-A71 infection.","authors":"Wangquan Ji, Dejian Dang, Guangyuan Zhou, Ling Tao, Tiantian Sun, Dong Li, Cheng Cheng, Huifen Feng, Jinzhao Long, Shuaiyin Chen, Haiyan Yang, Guangcai Duan, Yuefei Jin","doi":"10.1128/aac.01272-24","DOIUrl":"https://doi.org/10.1128/aac.01272-24","url":null,"abstract":"Hand, foot, and mouth disease (HFMD) is a serious pediatric infectious disease that causes immeasurable physical and mental health burdens. Currently, there is a lack of information on the mechanisms of HFMD severity and early diagnosis. We performed metabolomic profiling of sera from 84 Enterovirus A71 (EV-A71) infections and 45 control individuals. Targeted metabolomics assays were employed to further validate some of the differential metabolic molecules. We identified significant molecular changes in the sera of HFMD patients compared to healthy controls (HCs). A total of 54, 60, 35, and 62 differential metabolites were screened between mild cases and HCs, severe cases and HCs, severe cases and mild cases, and among the three groups, respectively. These differential metabolites implicated dysregulation of the tricarboxylic acid cycle, alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine biosynthesis. The diagnostic panel based on some overlapped differential metabolites could effectively discriminate severe cases from mild cases with an AUC of 0.912 (95% CI: 0.85-0.97) using the logistic regression model. Next, we found the elevation of serum sphingosine 1-phosphate (S1P) level in EV-A71 infection mice, which was similar to clinical observation. Importantly, after blocking the release of S1P by MK571, the clinical symptoms and survival of mice were significantly improved, involving the reduction of leukocyte infiltration in infected brain tissues. Collectively, our data provided a landscape view of metabolic alterations in EV-A71 infected children and revealed regulating S1P metabolism was an exploitable therapeutic target against EV-A71 infection.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0127224"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845681","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}

引用次数: 0

Single-dose tolerability and pharmacokinetics of leritrelvir in Chinese patients with hepatic impairment and healthy matched controls. 中国肝功能损害患者和健康匹配对照组对来瑞特韦的单剂量耐受性和药代动力学研究。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-17 DOI: 10.1128/aac.01377-24

Cuiyun Li, Jiajia Mai, Min Wu, Hong Zhang, Xiaojiao Li, Haijun Li, Youyun Li, Yanhua Ding

{"title":"Single-dose tolerability and pharmacokinetics of leritrelvir in Chinese patients with hepatic impairment and healthy matched controls.","authors":"Cuiyun Li, Jiajia Mai, Min Wu, Hong Zhang, Xiaojiao Li, Haijun Li, Youyun Li, Yanhua Ding","doi":"10.1128/aac.01377-24","DOIUrl":"https://doi.org/10.1128/aac.01377-24","url":null,"abstract":"This study evaluated the safety and pharmacokinetics (PK) of a single dose of leritrelvir, a novel inhibitor of 3-chymotrypsin-like cysteine protease (3CLpro), in patients with hepatic impairment versus healthy participants with normal hepatic function. Eight participants with mild (Child-Pugh A) hepatic impairment, eight with moderate (Child-Pugh B) hepatic impairment, and eight healthy matched control participants were enrolled in this open-label, parallel clinical trial. After administration of leritrelvir of 400 mg, PK parameters were calculated and compared across groups. In total, 24 participants were enrolled and completed the study. Leritrelvir was generally well tolerated, with no serious adverse events or deaths reported during the study. Compared to the group with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-∞ of leritrelvir in participants with mild hepatic impairment were 96.9% (69.3%, 135%), 92.2% (69.6%, 122%), and 92.1% (69.7%, 122%), respectively. For moderate hepatic impairment, the corresponding ratios were 91.6% (61.7%, 136%), 113% (80.0%, 160%), and 113% (80.0%, 159%). Leritrelvir exposures were comparable among the three groups. Overall, there was no clinically relevant difference in leritrelvir exposure in participants with hepatic impairment compared to normal controls. No dose adjustment is required for leritrelvir in patients with mild or moderate hepatic impairment.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06161259.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0137724"},"PeriodicalIF":4.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833524","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}

引用次数: 0

Efficient in vitro assay for evaluating drug efficacy and synergy against emerging SARS-CoV-2 strains.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-17 DOI: 10.1128/aac.01233-24

Maximillian Woodall, Samuel Ellis, Shengyuan Zhang, Japhette Kembou-Ringert, Kerry-Anne Kite, Laura Buggiotti, Amy I Jacobs, Akosua Adom Agyeman, Tereza Masonou, Machaela Palor, Timothy D McHugh, Judith Breuer, Joseph F Standing, Claire M Smith

{"title":"Efficient in vitro assay for evaluating drug efficacy and synergy against emerging SARS-CoV-2 strains.","authors":"Maximillian Woodall, Samuel Ellis, Shengyuan Zhang, Japhette Kembou-Ringert, Kerry-Anne Kite, Laura Buggiotti, Amy I Jacobs, Akosua Adom Agyeman, Tereza Masonou, Machaela Palor, Timothy D McHugh, Judith Breuer, Joseph F Standing, Claire M Smith","doi":"10.1128/aac.01233-24","DOIUrl":"https://doi.org/10.1128/aac.01233-24","url":null,"abstract":"Novel and repurposed antiviral drugs are available for the treatment of coronavirus disease 2019 (COVID-19). However, antiviral combinations may be more potent and lead to faster viral clearance, but the methods for screening antiviral combinations against respiratory viruses are not well established and labor-intensive. Here, we describe a time-efficient (72-96 h) and simple in vitro drug-sensitivity assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using standard 96-well plates. We employ different synergy models (zero interaction potency, highest single agent, Loewe, Bliss) to determine the efficacy of antiviral therapies and synergistic combinations against ancestral and emerging clinical SARS-CoV-2 strains. We found that monotherapy of remdesivir, nirmatrelvir, and active metabolite of molnupiravir (EIDD-1931) demonstrated baseline EC50s within clinically achievable levels of 4.34 mg/L (CI: 3.74-4.94 mg/L), 1.25 mg/L (CI: 1.10-1.45 mg/L), and 0.25 mg/L (CI: 0.20-0.30 mg/L), respectively, against the ancestral SARS-CoV-2 strain. However, their efficacy varied against newer Omicron variants BA.1.1.15 and BA.2, particularly with the protease inhibitor nirmatrelvir. We also found that remdesivir and nirmatrelvir have a consistent, strong synergistic effect (Bliss synergy score >10) at clinically relevant drug concentrations (nirmatrelvir 0.25-1 mg/L with remdesivir 1-4 mg/L) across all SARS-CoV-2 strains tested. This method offers a practical tool that streamlines the identification of effective combination therapies and the detection of antiviral resistance. Our findings support the use of antiviral drug combinations targeting multiple viral components to enhance COVID-19 treatment efficacy, particularly in the context of emerging viral strains.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0123324"},"PeriodicalIF":4.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833376","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}

引用次数: 0

In vitro test of the novel antibiotic lefamulin alone and in combination with doxycycline against Mycoplasma genitalium.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-13 DOI: 10.1128/aac.01346-24

Kirsten Salado-Rasmussen, Christina Nørgaard, Thomas Roland Pedersen, Susanne Paukner, Jørgen Skov Jensen

{"title":"In vitro test of the novel antibiotic lefamulin alone and in combination with doxycycline against Mycoplasma genitalium.","authors":"Kirsten Salado-Rasmussen, Christina Nørgaard, Thomas Roland Pedersen, Susanne Paukner, Jørgen Skov Jensen","doi":"10.1128/aac.01346-24","DOIUrl":"https://doi.org/10.1128/aac.01346-24","url":null,"abstract":"Mycoplasma genitalium, a sexually transmitted bacterium, is a significant cause of urethritis in men and various reproductive tract infections in women, including cervicitis, pelvic inflammatory disease, endometritis, and potentially infertility. Treatment has become increasingly challenging due to the emergence of resistance to both first-line (azithromycin) and second-line (moxifloxacin) antibiotics. The need for new treatment options is critical. This study evaluates the in vitro efficacy of the novel antibiotic lefamulin against 54 M. genitalium isolates, including highly resistant variants. Additionally, the potential synergistic effects of combining lefamulin with doxycycline were assessed in eight selected isolates. Lefamulin exhibited strong antibacterial activity across all tested isolates, with minimal inhibitory concentrations (MICs) ranging from 0.0005 to 0.064 µg/mL. Minimal bactericidal concentrations ranged from 0.001 to 0.128 µg/mL and were equal to the MIC in 40 of 54 isolates and within two- and fourfold MIC in the rest of the isolates. Notably, lefamulin's MIC values were significantly lower than those of azithromycin, doxycycline, and moxifloxacin, underscoring its potent efficacy. Checkerboard assays revealed no antagonistic interaction between lefamulin and doxycycline, with some additive effects observed in certain isolates. These findings highlight lefamulin's potential as a highly effective treatment for M. genitalium infections, particularly those involving multi-drug-resistant strains. Given the increasing rates of resistance and the limitations of current therapies, lefamulin may represent a promising new option for managing this challenging pathogen. Further clinical studies are warranted to confirm these in vitro results and explore the therapeutic potential of lefamulin in combination with doxycycline.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0134624"},"PeriodicalIF":4.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817052","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}

引用次数: 0

Evaluation of a potent LpxC inhibitor for post-exposure prophylaxis treatment of antibiotic-resistant Burkholderia pseudomallei in a murine infection model.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-13 DOI: 10.1128/aac.01295-24

Henry S Heine, Bret K Purcell, Clayton Duncan, Lynda Miller, John E Craig, Amanda Chase, Lynne Honour, Michael Vicchiarelli, George L Drusano, Pei Zhou

{"title":"Evaluation of a potent LpxC inhibitor for post-exposure prophylaxis treatment of antibiotic-resistant Burkholderia pseudomallei in a murine infection model.","authors":"Henry S Heine, Bret K Purcell, Clayton Duncan, Lynda Miller, John E Craig, Amanda Chase, Lynne Honour, Michael Vicchiarelli, George L Drusano, Pei Zhou","doi":"10.1128/aac.01295-24","DOIUrl":"https://doi.org/10.1128/aac.01295-24","url":null,"abstract":"LPC-233 (a.k.a. VB-233) is a potent antibiotic targeting the essential enzyme LpxC in Gram-negative bacteria. We present herein the pharmacokinetics and pharmacodynamics data of LPC-233 for treating murine infections caused by Burkholderia pseudomallei, a potential biodefense pathogen. A range of doses was evaluated in a post-aerosol exposure model of B. pseudomallei-infected mice. After the aerosol challenge with the B. pseudomallei strain K96243, treatment was initiated with 10, 30, or 90 mg/kg of LPC-233 orally every 12 h (q12h) or 90 mg/kg intraperitoneally q12h for 14 days. A vehicle-control arm and a positive-control arm consisting of one of the recommended standards of care, ceftazidime (150 mg/kg, q6h) injected subcutaneously, were included. LPC-233 significantly and dose-dependently rescued mice from B. pseudomallei infection in comparison with the vehicle (P < 0.0001). At dose levels of 30 mg/kg or higher, the survival rate with LPC-233 was significantly higher than that from the ceftazidime arm (P range: 0.001-0.05). LPC-233 reversed the murine body weight loss caused by the B. pseudomallei infection more rapidly than ceftazidime did, suggesting that it is a faster-acting antibiotic in this dosing regimen. Despite the outstanding survival advantage of LPC-233 over ceftazidime, no significant differences in tissue burdens (liver, lung, spleen, and blood) were observed among any of the treatment groups surviving to the termination of the experiment, suggesting that similar to commercial antibiotics, LPC-233 treatment for lethal B. pseudomallei infection may likely require both an acute phase of intensive treatment and an eradication phase of prolonged treatment.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0129524"},"PeriodicalIF":4.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817055","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}

引用次数: 0

TolCV1 inhibition by NPPB renders Vibrio vulnificus less virulent and more susceptible to antibiotics.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-13 DOI: 10.1128/aac.00502-24

Yue Gong, Rui Jiang, Rui Hong Guo, Se Jin Jo, Hyeongju Jeong, Kyuho Moon, Joon Haeng Rhee, Young Ran Kim

{"title":"TolCV1 inhibition by NPPB renders Vibrio vulnificus less virulent and more susceptible to antibiotics.","authors":"Yue Gong, Rui Jiang, Rui Hong Guo, Se Jin Jo, Hyeongju Jeong, Kyuho Moon, Joon Haeng Rhee, Young Ran Kim","doi":"10.1128/aac.00502-24","DOIUrl":"https://doi.org/10.1128/aac.00502-24","url":null,"abstract":"Bacterial efflux pumps play important roles in the antibiotic resistance and excretion of virulence factors. We previously characterized that TolCV1, a component of efflux pumps, plays critical roles in resistance to antibiotics and bile and also RtxA1 toxin secretion of Vibrio vulnificus. In this context, we speculated that TolCV1 blockers would have a dual effect of enhancing susceptibility to antibiotics and suppressing virulence of V. vulnificus. Here, we show that the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) increases susceptibility to antibiotics and suppresses cytotoxicity of V. vulnificus through inhibition of TolCV1. NPPB significantly decreased TolCV1 in V. vulnificus cells by liberating the protein from the cell body. Checkerboard assay showed that NPPB enhanced the antimicrobial activities of antibiotics such as kanamycin, tetracycline, erythromycin, and ampicillin against V. vulnificus. Moreover, NPPB inhibited the secretion of RtxA1 toxin and protected host cells from V. vulnificus-induced cytotoxicity. In addition, NPPB markedly suppressed V. vulnificus growth in the presence of bile salts and enhanced the therapeutic effect of tetracycline in V. vulnificus-infected mice. The safety and efficacy of NPPB were confirmed at the cellular and animal levels. Collectively, TolCV1 inhibition by NPPB renders V. vulnificus less virulent and more susceptible to antibiotics.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0050224"},"PeriodicalIF":4.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817063","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}

引用次数: 0

New Perspectives on Antimicrobial Agents: Rezafungin.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-12 DOI: 10.1128/aac.00646-23

Nicholas M Forrister, Todd P McCarty, Peter G Pappas

引用次数: 0

Stage-specific pharmacodynamic chloroquine and pyronaridine action on artemisinin ring-stage resistant Kelch C580Y mutation Plasmodium falciparum correlates to hemozoin inhibition process.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-12 DOI: 10.1128/aac.01208-24

Abeer Sayeed, Revie Atkinson, Peter G Vekilov, Jeffrey D Rimer, David J Sullivan

{"title":"Stage-specific pharmacodynamic chloroquine and pyronaridine action on artemisinin ring-stage resistant Kelch C580Y mutation Plasmodium falciparum correlates to hemozoin inhibition process.","authors":"Abeer Sayeed, Revie Atkinson, Peter G Vekilov, Jeffrey D Rimer, David J Sullivan","doi":"10.1128/aac.01208-24","DOIUrl":"https://doi.org/10.1128/aac.01208-24","url":null,"abstract":"The antimalarial quinolines pyronaridine and chloroquine both inhibit hemozoin crystallization, predominately produced by Plasmodium falciparum intra-erythrocytic trophozoite stage parasites. Pyronaridine extends activity to ring-stage chloroquine-sensitive parasites, in contrast to chloroquine. Here, we investigated chloroquine and pyronaridine hemozoin inhibition type correlated to stage-specific activity on chloroquine-resistant ring-stage artemisinin sensitive and resistant P. falciparum CamWT and CamWT-C580Y parasites. Pyronaridine (2.8 μM) is tenfold more potent at beta-hematin nucleation than chloroquine (40 μM). Both pyronaridine and chloroquine (0.2 and 0.7 μM, respectively) had similar sub-μM inhibition of beta-hematin extension. P. falciparum CamWT-C580Y parasites produce smaller width hemozoin crystals which extend less than isogenic CamWT hemozoin. Stage-specific pulse dose pyronaridine and chloroquine on CamWT-C580Y or CamWT isogenic parasites observed 3- to 4-fold higher pyronaridine IC50s compared to 10- to 15-fold higher chloroquine on most CamWT-C580Y to CamWT stages. These findings collectively show that hemozoin nucleation inhibition widens stage-specific pyronaridine activity on P. falciparum drug-resistant parasites.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0120824"},"PeriodicalIF":4.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811988","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}

引用次数: 0

Cefiderocol pharmacokinetics during acute pulmonary exacerbations in hospitalized adult persons with cystic fibrosis.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-10 DOI: 10.1128/aac.01539-24

Christina Koenig, Marguerite L Monogue, Ryan K Shields, Colleen M Sakon, Andrew J Fratoni, Hanna F Roenfanz, James D Finklea, James S Pope, David P Nicolau, Joseph L Kuti

{"title":"Cefiderocol pharmacokinetics during acute pulmonary exacerbations in hospitalized adult persons with cystic fibrosis.","authors":"Christina Koenig, Marguerite L Monogue, Ryan K Shields, Colleen M Sakon, Andrew J Fratoni, Hanna F Roenfanz, James D Finklea, James S Pope, David P Nicolau, Joseph L Kuti","doi":"10.1128/aac.01539-24","DOIUrl":"https://doi.org/10.1128/aac.01539-24","url":null,"abstract":"Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR). Blood sampling collected at steady state. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. Ten pwCF were enrolled; nine completed the study with six receiving 2 g q8 h and three 2 g q6 h. A two-compartment model best fitted the data. Mean (SD) PK parameters were clearance, 5.66 (1.28) L/h; volume of central compartment, 5.81 (3.52) L, and intercompartment transfer constants, k12, 4.29 (3.46) and k21, 2.25 (2.76) h-1. Protein binding was 48% (35-57). The 2 g q8 h regimen achieved a mean free time above the MIC (fT >MIC) of 99% (94-99), 90% (69-100), and 64% (41-81) at MICs of 4 (susceptible), 8 (intermediate), and 16 (resistant) mg/L, respectively, with AUC24h of 1,191 (781-1,496) mg/L*h. In pwCF with eGFR >120 mL/min, 2 g q6 h attained 100% fT >MIC up to 8 mg/L and 87% (83-92) at 16 mg/L, with AUC24h of 1,279 (1,054-1,590) mg/L*h. Among these nine pwCF with APE with normal or augmented renal clearance, cefiderocol using label prescribed dosing regimens according to eGFR was well tolerated and achieved optimal fT >MIC exposure for pathogens up to MICs of 8 mg/L and AUC24h estimates similar to previously reported estimates in non-CF patients.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0153924"},"PeriodicalIF":4.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799252","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}

引用次数: 0

Ex vivo assessment of sulbactam-durlobactam clearance during continuous renal replacement therapy to guide dosing recommendations.

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-10 DOI: 10.1128/aac.01674-23

Yasmeen Abouelhassan, Yuwei Shen, April Chen, Xiaoyi Ye, David P Nicolau, Joseph L Kuti

{"title":"Ex vivo assessment of sulbactam-durlobactam clearance during continuous renal replacement therapy to guide dosing recommendations.","authors":"Yasmeen Abouelhassan, Yuwei Shen, April Chen, Xiaoyi Ye, David P Nicolau, Joseph L Kuti","doi":"10.1128/aac.01674-23","DOIUrl":"https://doi.org/10.1128/aac.01674-23","url":null,"abstract":"Sulbactam-durlobactam is approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. Patients with serious Acinetobacter infections may require support with continuous renal replacement therapy (CRRT), which presents challenges for optimal dosing of antibiotics. Sulbactam-durlobactam dosing regimens were derived for this population using an ex vivo CRRT model and Monte Carlo simulation (MCS). Transmembrane clearance (CLTM) was determined in hemofiltration (CVVH) and hemodialysis (CVVHD) modes using the Prismaflex M100 and HF1400 hemofilter sets and with effluent rates of 1, 2, and 3 L/h. Pre-filter, post-filter blood, and effluent samples were collected over 60 min to calculate sieving (SC) and saturation (SA) coefficients for CVVH and CVVHD, respectively. An established population pharmacokinetic model was integrated with the CLTM; then, a 1,000 patient MCS was conducted to determine exposures of potential dosing regimens. Adsorption and degradation in the ex vivo CRRT model were negligible. The overall mean ± standard deviation SC/SA was 1.14 ± 0.12 and 0.93 ± 0.08 for sulbactam and durlobactam, respectively. In multivariable regression analyses, effluent rate was the primary driver of CLTM for both drugs. For effluent rates <3 L/h, sulbactam-durlobactam 1 g-1g q8h as 3 h infusion achieved a high probability of pharmacodynamic target attainment while retaining area under the curve exposures consistent with the standard dose in non-CRRT patients. For effluent rates ≥3 to 5 L/h, the optimal regimen was 1 g-1g q6h 3 h infusion. Sulbactam-durlobactam regimens that provide optimum drug exposures for efficacy and safety were identified for CRRT based on the prescribed effluent rate.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0167423"},"PeriodicalIF":4.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799246","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}

引用次数: 0