Antimicrobial Agents and Chemotherapy最新文献_第7页

The effect of pregnancy on the population pharmacokinetics of levofloxacin in South Africans with rifampicin-resistant tuberculosis. 妊娠对南非利福平耐药结核病患者左氧氟沙星药代动力学的影响。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1128/aac.01626-24

Sharon Sawe, Lufina Tsirizani, Richard Court, Kamunkhwala Gausi, Asanda Poswa, Tasnim Badat, Lubbe Wiesner, Marian Loveday, Gary Maartens, Francesca Conradie, Paolo Denti

{"title":"The effect of pregnancy on the population pharmacokinetics of levofloxacin in South Africans with rifampicin-resistant tuberculosis.","authors":"Sharon Sawe, Lufina Tsirizani, Richard Court, Kamunkhwala Gausi, Asanda Poswa, Tasnim Badat, Lubbe Wiesner, Marian Loveday, Gary Maartens, Francesca Conradie, Paolo Denti","doi":"10.1128/aac.01626-24","DOIUrl":"10.1128/aac.01626-24","url":null,"abstract":"Levofloxacin is a key drug in the prevention and treatment of rifampicin-resistant tuberculosis (RR-TB). There are limited data describing the effect of pregnancy on the pharmacokinetics of levofloxacin. We aimed to characterize the pharmacokinetics of levofloxacin in adults with RR-TB, including the effect of pregnancy. We pooled data from two studies conducted in adult participants treated for RR-TB in South Africa. Treatment regimens in both studies included levofloxacin dosed at 750/1000 mg daily, depending on body weight. We analyzed data from 47 participants, 31 (66%) living with HIV, using nonlinear mixed-effects modeling in NONMEM v7.5.1. Out of 33 female participants, 21 were pregnant, of whom 12 contributed matched antepartum and postpartum pharmacokinetic profiles. Levofloxacin followed one-compartment pharmacokinetics with first-order elimination and absorption with transit absorption compartments. The clearance and volume of distribution for a typical non-pregnant participant (weight: 58 kg; age: 32 years; serum creatinine: 56.2 µmol/L) were 6.06 (95% confidence interval [CI], 5.47 to 6.53) L/h and 85.9 (95% CI, 80.6 to 91.7) L, respectively. Higher serum creatinine levels were associated with lower levofloxacin clearance using a power function with an exponent of -0.367 (95% CI, -0.493 to -0.104). Pregnancy increased levofloxacin clearance by 38.1% (95% CI, 23.4% to 57.1%), with substantially lower exposures in pregnant compared with non-pregnant participants receiving equivalent weight-based doses. To achieve non-pregnant equivalent exposures of levofloxacin, an additional 250 mg tablet may be required, although further study is needed to assess the safety implications of a higher recommended dose in pregnant women.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0162624"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750848","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}

引用次数: 0

A novel pan-fungal screening platform for antifungal drug discovery: proof of principle study. 一种新的抗真菌药物发现的泛真菌筛选平台：原理验证研究。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1128/aac.01328-24

Rebecca Inman, Adilia Warris, Elaine Bignell

{"title":"A novel pan-fungal screening platform for antifungal drug discovery: proof of principle study.","authors":"Rebecca Inman, Adilia Warris, Elaine Bignell","doi":"10.1128/aac.01328-24","DOIUrl":"10.1128/aac.01328-24","url":null,"abstract":"Broad-spectrum activity is a desirable property of novel antifungal drugs, but relevant in vitro testing is complicated by differential nutritional requirements and growth dynamics of fungal pathogens. Many screens for novel drugs are initiated against individual species or genera, with hit compounds later tested for \"pan-fungal\" activity. Hypothesizing that an optimized pan-fungal methodology would enhance the efficiency of early-stage drug discovery, a standardized assay was developed for a selection of World Health Organization-defined critical and high-priority fungal pathogens. Instead of using the standard susceptibility testing broth RPMI, an enriched media \"fungal RPMI\" (fRPMI), including multiple additional fungal growth-enhancing nutrients, was utilized. To assess utility for pan-fungal growth assessments, growth in fRPMI was compared to RPMI medium for 12 fungal pathogens. Growth was significantly improved in 7/12 species in fRPMI after 24 and/or 48 hours. For our proof-of-principle study, 500 chemical fragments from the Maybridge Ro3 Fragment library were screened at concentrations of 0.1 or 1 mM against five fungal pathogens: Aspergillus fumigatus, Candida albicans, Candida auris, Cryptococcus neoformans, and Nakaseomyces glabratus. Assay quality was assessed using z-factor analysis, and hits were normalized using a standard z-score to identify outliers. All assays achieved a high-quality z-factor (≥0.5) with readings at ≤24 hours, allowing the identification of 23 compounds with antifungal activity against at least one fungal species. From these, five compounds were identified as having pan-assay interference or broadly toxic properties. In conclusion, hits identified from pan-fungal phenotypic growth-based assays demonstrate reproducibility in all fungal species tested with carefully optimized conditions and precise timing.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0132824"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750839","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}

引用次数: 0

Population pharmacokinetic analysis of tobramycin in serum and ELF using data from patients with pneumonia. 肺炎患者血清和ELF中妥布霉素的人群药代动力学分析。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.00908-24

Scott A Van Wart, Michael Trang, M Courtney Safir, Andrew R Santulli, Christopher M Rubino, Sujata M Bhavnani

引用次数: 0

In vitro pharmacokinetic/pharmacodynamic modeling of the effect of mucin on polymyxin B activity against Acinetobacter baumannii. 粘蛋白对多粘菌素B抗鲍曼不动杆菌活性影响的体外药动动力学/药效学模型。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-03-26 DOI: 10.1128/aac.01535-24

Mathilde Lacroix, Jérémy Moreau, Claudia Zampaloni, Caterina Bissantz, Hélène Mirfendereski, Hamasseh Shirvani, Sandrine Marchand, William Couet, Alexia Chauzy

{"title":"In vitro pharmacokinetic/pharmacodynamic modeling of the effect of mucin on polymyxin B activity against Acinetobacter baumannii.","authors":"Mathilde Lacroix, Jérémy Moreau, Claudia Zampaloni, Caterina Bissantz, Hélène Mirfendereski, Hamasseh Shirvani, Sandrine Marchand, William Couet, Alexia Chauzy","doi":"10.1128/aac.01535-24","DOIUrl":"10.1128/aac.01535-24","url":null,"abstract":"The antibacterial efficacy of polymyxins in lungs may be impacted by mucin. The aim of this study was to characterize in vitro the effect of mucin on polymyxin B (PMB) activity against two multidrug-resistant Acinetobacter baumannii strains isolated from a patient before (AB121-D0) and after colistin treatment (AB122-D12), using a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. PMB binding to mucin was characterized by ultracentrifugation in cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with 1% mucin. Time-kill (TK) experiments were performed in CAMHB, with 1% mucin or without as control, and with PMB total concentrations ranging from 0.25 to 512 mg/L based on the strain's minimum inhibitory concentration (MIC). For each strain, TK data were modeled based on unbound PMB concentrations. Bacterial resistance to PMB was investigated via MIC and whole genome sequencing from bacteria that regrew in the presence of antibiotics at the end of the TK experiments. PMB unbound fraction increased nonlinearly from 6% to 60% when total concentration increased from 0.5 to 512 mg/L. In addition to binding to PMB, mucin had an impact on PMB activity, which differed between the two strains. For AB121-D0, PMB activity increased in the presence of mucin resulting in a reduction of the bacterial regrowth, whereas for AB122-D12, a decrease in PMB activity was observed. Mutations in genes involved in PMB resistance appeared randomly and explained only partially the bacterial regrowth observed in TK with antibiotics. This study showed that PMB binding to mucin had a real and important impact but was not the only factor explaining the impaired PMB efficacy in the presence of mucin.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0153524"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708248","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}

引用次数: 0

Efficacy assessments of SF001, a next-generation polyene antifungal, in a neutropenic mouse model of invasive fusariosis. 新一代多烯抗真菌药物SF001在侵袭性镰孢病中性粒细胞减少小鼠模型中的疗效评估

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-01 DOI: 10.1128/aac.01802-24

Teclegiorgis Gebremariam, Yiyou Gu, Hoja Patterson, Eman Youssef, Sondus Alkhazraji, Tasneem Elsayed, Nathan P Wiederhold, Ashraf S Ibrahim

{"title":"Efficacy assessments of SF001, a next-generation polyene antifungal, in a neutropenic mouse model of invasive fusariosis.","authors":"Teclegiorgis Gebremariam, Yiyou Gu, Hoja Patterson, Eman Youssef, Sondus Alkhazraji, Tasneem Elsayed, Nathan P Wiederhold, Ashraf S Ibrahim","doi":"10.1128/aac.01802-24","DOIUrl":"10.1128/aac.01802-24","url":null,"abstract":"Fusariosis has high mortality rates with limited treatment options. Owing to its rarity, comparative clinical trials are hard to perform. SF001 is a novel, next-generation polyene drug, rationally designed to reduce potential for systemic toxicity, with long-acting, potent, broad-spectrum fungicidal activity. We compared the in vitro activity and in vivo efficacy of SF001 with liposomal amphotericin B (LAMB) in treating immunosuppressed mice infected with hematogenously disseminated fusariosis. The minimum inhibitory concentration (MIC) of SF001 and LAMB against Fusarium solani or Fusarium oxysporum strains (at 100% inhibition) ranged between 0.5-8 µg/mL and 1->16 µg/mL, respectively. In the hematogenously disseminated fusariosis model, treatment with SF001 or LAMB enhanced the median survival time vs placebo (7, 10, and 9 days at 3, 7.5, and 30 mg/kg of SF001, respectively, and 12.5 days for LAMB at 7.5 mg/kg vs 6.5 days for placebo, P < 0.0001). SF001 and LAMB treatment enhanced the overall survival by day 21 (40% and 25% for SF001 at 7.5 mg/kg and 30 mg/kg, respectively, 30% for LAMB at 7.5 mg/kg and 0% for placebo). The survival data were mirrored in the kidney and brain fungal burden results with ~2-3 log10 reduction in conidial equivalents/gram for either treatment vs placebo. Furthermore, the reduction in tissue fungal burden was corroborated by histopathological data from target organs, showing reduced or no abscesses in SF001- or LAMB-treated mice. Our data show comparable activity of SF001 to LAMB, thereby supporting the continued development of SF001 for the treatment of invasive fusariosis.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0180224"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750840","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}

引用次数: 0

PKPD modeling of the inoculum effect of combined ceftazidime/avibactam and colistin against KPC-3 Klebsiella pneumoniae isolate. 头孢他啶/阿维巴坦联合粘菌素对KPC-3肺炎克雷伯菌接种效果的PKPD建模。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.01797-24

Romain Aubry, Julien M Buyck, Alexia Chauzy, Laure Prouvensier, Jean-Winoc Decousser, Patrice Nordmann, Sebastian G Wicha, Sandrine Marchand, Nicolas Grégoire

{"title":"PKPD modeling of the inoculum effect of combined ceftazidime/avibactam and colistin against KPC-3 Klebsiella pneumoniae isolate.","authors":"Romain Aubry, Julien M Buyck, Alexia Chauzy, Laure Prouvensier, Jean-Winoc Decousser, Patrice Nordmann, Sebastian G Wicha, Sandrine Marchand, Nicolas Grégoire","doi":"10.1128/aac.01797-24","DOIUrl":"https://doi.org/10.1128/aac.01797-24","url":null,"abstract":"The inoculum effect (IE) characterizes a decrease in the antimicrobial effect of antibiotics with increasing inoculum. To face antimicrobial resistance, antibiotic combinations are progressively used. In this context, the effect of combination may be affected by IE, especially drugs for which an IE has been described. The objective was to characterize the IE of a carbapenemase (KPC-3) Klebsiella pneumoniae isolate on the combination of ceftazidime/avibactam (CZA) and colistin (CST). In vitro time-kill curves with single and combined drugs were performed at four different inocula. The IE of each drug was described using pharmacokinetic/pharmacodynamic modeling, and interactions on IE were investigated with the general pharmacodynamic interaction model when drugs were combined. The IE was assessed by evaluating the significance of the parameters associated with the IE model compared to the no IE model and by comparing the CFU counts over time predicted with the IE model vs the no IE model. Rapid bacterial killing was observed at 104 CFU/mL. For both 5·105 and 107 CFU/mL inocula, initial decays followed by re-growth were observed with drugs alone, while the combination prevented the emergence of resistance. Eradication was never achieved at 108 CFU/mL. The IE was best modeled as a reduction of CZA maximum bactericidal effect and as an increase in CST EC50 with increasing inoculum. However, no interaction between IEs was significant, meaning that CST did not modify the IE of CZA and inversely. IE may be important at least as demonstrated by in vitro antibiotic combination studies.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0179724"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959451","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}

引用次数: 0

Comparative efficacy of levofloxacin, azithromycin, and doxycycline prophylaxis and treatment in an experimental Ureaplasma murine lung infection model. 左氧氟沙星、阿奇霉素和多西环素预防和治疗小鼠实验性脲原体肺部感染的疗效比较。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.01724-24

Derek Fleming, Maha Y Al-Jabri, Robin Patel

{"title":"Comparative efficacy of levofloxacin, azithromycin, and doxycycline prophylaxis and treatment in an experimental Ureaplasma murine lung infection model.","authors":"Derek Fleming, Maha Y Al-Jabri, Robin Patel","doi":"10.1128/aac.01724-24","DOIUrl":"https://doi.org/10.1128/aac.01724-24","url":null,"abstract":"Although lung transplant recipients who develop Ureaplasma-associated hyperammonemia syndrome are treated with Ureaplasma-targeted antibiotics, optimal therapy is incompletely defined, and typically not based on real-time antimicrobial susceptibility testing results. This study compared levofloxacin, azithromycin, and doxycycline prevention and treatment of Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) infections in an immunosuppressed murine lung infection model. For prophylaxis, mice received antibiotics before infection with UP-FS (susceptible to all study antibiotics), UP-AzmR (azithromycin-resistant), UP-LevR (levofloxacin-resistant), or UU-DoxR (doxycycline-resistant), with lung bacterial loads (color changing units [CCUs]) measured 18 hours following infection. For UP-FS, doxycycline was most active (Δ4.84 log10 CCU/g; P = 0.0006), followed by levofloxacin (Δ2.45 log10 CCU/g; P = 0.018), with azithromycin yielding a nonsignificant CCU reduction. Doxycycline (Δ1.9 log10 CCU/g; P = 0.0025) and levofloxacin (Δ1.3 log10 CCU/g; P = 0.004) showed activity against UP-AzmR. Only doxycycline showed activity against UP-LevR (Δ2.28 log10 CCU/g; P = 0.0002), and only azithromycin showed activity against UU-DoxR (Δ0.67 log10 CCU/g; P = 0.0175). For treatment, antibiotics were administered 24 hours following infection; doxycycline significantly reduced bacterial loads of all study isolates, except UU-DoxR. In addition, azithromycin was active against UP-LevR (Δ1.21 log10 CCU/g reduction; P = 0.0003). In summary, except for doxycycline-resistant UU, doxycycline was active in preventing and treating Ureaplasma lung infection in immunosuppressed mice.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0172424"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954929","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}

引用次数: 0

NDM-5-carried outer membrane vesicles impair the efficacy of antibiotics against bacterial infections. 携带ndm -5的外膜囊泡破坏抗生素抗细菌感染的效果。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.01805-24

Lin Li, Yanfang Zhang, Liangyun Weng, Qianyu Ji, Feng Gao, Shuo Yang, Linran Fu, Yiming Gao, Xuan Ma, Mengying Zhang, Qingjun Xu, Yongning Wu, Shaoqi Qu

{"title":"NDM-5-carried outer membrane vesicles impair the efficacy of antibiotics against bacterial infections.","authors":"Lin Li, Yanfang Zhang, Liangyun Weng, Qianyu Ji, Feng Gao, Shuo Yang, Linran Fu, Yiming Gao, Xuan Ma, Mengying Zhang, Qingjun Xu, Yongning Wu, Shaoqi Qu","doi":"10.1128/aac.01805-24","DOIUrl":"https://doi.org/10.1128/aac.01805-24","url":null,"abstract":"The intensifying use of antimicrobials in the rapidly growing livestock industry has heightened concerns over the proliferation of antibiotic resistance, particularly among Enterobacteriaceae producing β-lactamase. Elucidating the role of β-lactamase could unlock novel strategies to combat drug-resistant Enterobacteriaceae in livestock and poultry farming. Outer membrane vesicles (OMVs) produced by gram-negative bacteria have the ability to encapsulate and transport components derived from their parental bacteria. This raises the intriguing possibility that OMVs from drug-resistant bacteria could harbor drug-resistance enzymes, thereby conferring protection to susceptible bacteria against antibiotics. Here, we successfully extracted OMVs from New Delhi metallo-β-lactamase-5 (NDM-5)-expressing Escherichia coli and confirmed that these vesicles indeed carry NDM-5 protein. Furthermore, bacterial protection assays showed that these OMVs could cause sensitive bacteria treated with meropenem to restore growth activity, and the degradation of meropenem by the OMVs was verified using high-performance liquid chromatography. Lastly, the survival rate of the OMVs intervention group was significantly lower than that of the drug-treated group in a Galleria mellonella larvae infection model, validating the protective effect of these OMVs on sensitive bacteria and increasing their tolerance to meropenem. These findings illustrate that OMVs can serve as vehicles for resistance-related factors, thereby promoting antibiotic tolerance in susceptible bacteria.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0180524"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970389","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}

引用次数: 0

Population pharmacokinetics study on nebulized and intravenous administration of polymyxin B in patients with pneumonia caused by multidrug-resistant gram-negative bacteria. 多粘菌素B雾化和静脉给药在多重耐药革兰氏阴性菌肺炎患者中的群体药动学研究。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-16 DOI: 10.1128/aac.00044-25

Xueyong Li, Lili Zhou, Danjie Wang, Qiong Wu, Xuanxi Huang, Hui Zhang, Wenwei Wu, Maobai Liu, Xuemei Wu, Hongqiang Qiu, Yu Cheng

{"title":"Population pharmacokinetics study on nebulized and intravenous administration of polymyxin B in patients with pneumonia caused by multidrug-resistant gram-negative bacteria.","authors":"Xueyong Li, Lili Zhou, Danjie Wang, Qiong Wu, Xuanxi Huang, Hui Zhang, Wenwei Wu, Maobai Liu, Xuemei Wu, Hongqiang Qiu, Yu Cheng","doi":"10.1128/aac.00044-25","DOIUrl":"https://doi.org/10.1128/aac.00044-25","url":null,"abstract":"Polymyxin B (PMB) remains a last-line therapeutic agent for multidrug-resistant gram-negative bacteria (MDR-GNB) infections. However, reliable pharmacokinetic (PK) data to guide nebulized PMB dosing regimens in critically ill patients are limited. This study aimed to establish a population pharmacokinetic (PopPK) model for PMB in both epithelial lining fluid (ELF) and plasma of critically ill patients with MDR-GNB pneumonia and to optimize dosing regimens. A prospective PK study was conducted in 76 adult patients receiving nebulized PMB either as monotherapy or in combination with intravenous administration. PK data were analyzed using non-linear mixed-effect modeling, with PMB concentration-time profiles described by a coupled model integrating separate two-compartment models for plasma and ELF. The final model identified albumin levels and age as significant covariates influencing PK variability. Monte Carlo simulations demonstrated that nebulization therapy either alone or combined with intravenous administration significantly enhances ELF concentration and the probability of target attainment. Additionally, Pseudomonas aeruginosa requires higher nebulized doses than Klebsiella pneumoniae and Acinetobacter baumannii. This study develops a PopPK model of PMB in ELF and plasma, providing critical insights to optimize PMB treatment strategies for patients with MDR-GNB pneumonia.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0004425"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961990","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}

引用次数: 0

Bedaquiline does not enhance a clofazimine-azithromycin-ethambutol regimen against Mycobacterium avium in the hollow-fiber system. 贝达喹啉不增强氯法齐明-阿奇霉素-乙胺丁醇方案对中空纤维系统中的鸟分枝杆菌。

IF 4.1 2区医学

Antimicrobial Agents and Chemotherapy Pub Date : 2025-05-07 Epub Date: 2025-04-14 DOI: 10.1128/aac.01464-24

J Raaijmakers, S Salillas, R Aarnoutse, E Svensson, L Te Brake, R Stemkens, H Wertheim, W Hoefsloot, J van Ingen

{"title":"Bedaquiline does not enhance a clofazimine-azithromycin-ethambutol regimen against Mycobacterium avium in the hollow-fiber system.","authors":"J Raaijmakers, S Salillas, R Aarnoutse, E Svensson, L Te Brake, R Stemkens, H Wertheim, W Hoefsloot, J van Ingen","doi":"10.1128/aac.01464-24","DOIUrl":"https://doi.org/10.1128/aac.01464-24","url":null,"abstract":"Bedaquiline has been proposed as a second-line drug to treat pulmonary disease caused by Mycobacterium avium complex. Based on in vitro synergy and interactions, a logical regimen would combine bedaquiline and clofazimine as additions to an ethambutol-azithromycin backbone. Here, we evaluate the added benefit of bedaquiline in a regimen of azithromycin, ethambutol, and clofazimine. THP-1 cells infected with M. avium ATCC 700898 were seeded in a hollow-fiber model and exposed to a regimen of azithromycin, ethambutol, and clofazimine with or without bedaquiline for 3 weeks. Epithelial lining fluid pharmacokinetic profiles of azithromycin and ethambutol were simulated, while an average steady-state concentration was sought for clofazimine and bedaquiline. Pharmacokinetics and pharmacodynamics were monitored throughout the experiment. Both regimens led to sustained bacterial killing (both intracellular and extracellular) throughout the experiment. No difference in kill rate was observed between the two therapies. The extracellular kill rate for the 3-drug regimen was 0.65 (95% CI 0.63-0.67) and for the 4-drug regimen 0.65 (95% CI 0.64-0.67). The intracellular kill rate was 0.48 (95% CI 0.46-0.50) for the 3-drug regimen and 0.48 (95% CI 0.46-0.50) for the 4-drug regimen. Macrolide-tolerant subpopulations were observed with both treatment regimens at day 21. Bedaquiline does not add killing activity to a clofazimine-ethambutol-azithromycin regimen and did not improve suppression of the emergence of macrolide resistance, which makes its role as a second-line agent doubtful.","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 5","pages":"e0146424"},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962398","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}

引用次数: 0