Alexander J Lepak, Justin Massey, Robert Zarnowski, Tine K Olesen, Ryley Jones, David R Andes
{"title":"新型硝司他丁衍生物 BSG005 在侵袭性念珠菌病和侵袭性肺曲霉病小鼠模型中的体内药效学评价。","authors":"Alexander J Lepak, Justin Massey, Robert Zarnowski, Tine K Olesen, Ryley Jones, David R Andes","doi":"10.1128/aac.01234-24","DOIUrl":null,"url":null,"abstract":"<p><p>Nystatin, a polyene, is one of the oldest antifungal drugs with wide <i>in vitro</i> potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using <i>in vivo</i> invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including <i>Aspergillus fumigatus</i>, <i>Candida albicans</i>, <i>Candida auris</i>, and <i>Candida glabrata</i>. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for <i>A. fumigatus</i> studies. For all <i>Candida</i> studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate <i>Aspergillus</i> in the lung and colony forming units (CFU) counts for <i>Candida</i> in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (<i>C</i><sub>max</sub>)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for <i>C. glabrata</i>. Increasing exposures were needed for same outcome for <i>C. auris</i> at 18.7, <i>C. albicans</i> at 29.3, and <i>A. fumigatus</i> at 102.4. <i>C</i><sub>max</sub>/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. <i>C</i><sub>max</sub>/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0123424"},"PeriodicalIF":4.1000,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619234/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>In vivo</i> pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models.\",\"authors\":\"Alexander J Lepak, Justin Massey, Robert Zarnowski, Tine K Olesen, Ryley Jones, David R Andes\",\"doi\":\"10.1128/aac.01234-24\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Nystatin, a polyene, is one of the oldest antifungal drugs with wide <i>in vitro</i> potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using <i>in vivo</i> invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including <i>Aspergillus fumigatus</i>, <i>Candida albicans</i>, <i>Candida auris</i>, and <i>Candida glabrata</i>. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for <i>A. fumigatus</i> studies. For all <i>Candida</i> studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate <i>Aspergillus</i> in the lung and colony forming units (CFU) counts for <i>Candida</i> in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (<i>C</i><sub>max</sub>)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for <i>C. glabrata</i>. Increasing exposures were needed for same outcome for <i>C. auris</i> at 18.7, <i>C. albicans</i> at 29.3, and <i>A. fumigatus</i> at 102.4. <i>C</i><sub>max</sub>/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. <i>C</i><sub>max</sub>/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.</p>\",\"PeriodicalId\":8152,\"journal\":{\"name\":\"Antimicrobial Agents and Chemotherapy\",\"volume\":\" \",\"pages\":\"e0123424\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-12-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619234/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Antimicrobial Agents and Chemotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1128/aac.01234-24\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/29 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.01234-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/29 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
In vivo pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models.
Nystatin, a polyene, is one of the oldest antifungal drugs with wide in vitro potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using in vivo invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including Aspergillus fumigatus, Candida albicans, Candida auris, and Candida glabrata. For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for A. fumigatus studies. For all Candida studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate Aspergillus in the lung and colony forming units (CFU) counts for Candida in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration (Cmax)/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for C. glabrata. Increasing exposures were needed for same outcome for C. auris at 18.7, C. albicans at 29.3, and A. fumigatus at 102.4. Cmax/MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. Cmax/MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.
期刊介绍:
Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.