Antimicrobial Agents and Chemotherapy最新文献

{"title":"Overcoming amphotericin B resistance in <i>Candida auris</i> using the antiemetic drug rolapitant.","authors":"Ehab A Salama, Yehia Elgammal, Sagar M Utturkar, Nadia A Lanman, Tony R Hazbun, Mohamed N Seleem","doi":"10.1128/aac.00556-24","DOIUrl":"10.1128/aac.00556-24","url":null,"abstract":"<p><p>The emergence of <i>Candida auris</i> poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by <i>C. auris</i> are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of <i>C. auris</i> possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2,600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against <i>C. auris</i>. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) <i>C. auris</i> isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial <i>Candida</i>, <i>Cryptococcus,</i> and <i>Aspergillus</i> species. A transcriptomic study revealed that exposure to rolapitant affects oxidation reduction processes, ion transporters, and ATP production. Rolapitant triggers an elevation in cytosolic and mitochondrial calcium levels and induces oxidative stress within fungal cells. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in <i>C. auris</i>. Moreover, rolapitant enhanced the <i>in vivo</i> activity of AmB in a mouse model of disseminated <i>C. auris</i> infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in <i>C. auris</i> and other fungal species.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0055624"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456722","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}

{"title":"Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.","authors":"Allison A Bauman, Jansy P Sarathy, Firat Kaya, Lisa M Massoudi, Michael S Scherman, Courtney Hastings, Jiuyu Liu, Min Xie, Elizabeth J Brooks, Michelle E Ramey, Isabelle L Jones, Noalani D Benedict, Madelyn R Maclaughlin, Jake A Miller-Dawson, Samanthi L Waidyarachchi, Michelle M Butler, Terry L Bowlin, Matthew D Zimmerman, Anne J Lenaerts, Bernd Meibohm, Mercedes Gonzalez-Juarrero, Michael A Lyons, Veronique Dartois, Richard E Lee, Gregory T Robertson","doi":"10.1128/aac.00716-24","DOIUrl":"10.1128/aac.00716-24","url":null,"abstract":"<p><p>The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by <i>Mycobacterium tuberculosis</i>. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0071624"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339943","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}

{"title":"Shining a light on the impact of antifungals on <i>Aspergillus fumigatus</i> subcellular dynamics through fluorescence imaging.","authors":"I S R Storer, L E Sastré-Velásquez, T Easter, B Mertens, A Dallemulle, M Bottery, R Tank, M Offterdinger, M J Bromley, N van Rhijn, F Gsaller","doi":"10.1128/aac.00803-24","DOIUrl":"10.1128/aac.00803-24","url":null,"abstract":"<p><p>Fluorescent proteins (FPs) are indispensable tools used for molecular imaging, single-cell dynamics, imaging in infection models, and more. However, next-generation FPs have yet to be characterized in <i>Aspergillus</i>. Here, we characterize 18 FPs in the pathogenic filamentous fungus <i>Aspergillus fumigatus</i> spanning the visible light spectrum. We report on <i>in vivo</i> FP brightness in hyphal and spore morphotypes and show how a fluoropyrimidine-based selection system can be used to iteratively introduce four distinct FPs enabling the simultaneous visualization of the cell membrane, mitochondria, peroxisomes, and vacuoles. Using this strain, we describe and compare the dynamic responses of organelles to stresses induced by voriconazole, amphotericin B, and the novel antifungal drugs olorofim and manogepix. The expansion to the fluorescent genetic toolbox will overcome boundaries in research applications that involve fluorescence imaging in filamentous fungi.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0080324"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456726","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}

{"title":"Sentinel Surveillance reveals phylogenetic diversity and detection of linear plasmids harboring <i>vanA</i> and <i>optrA</i> among enterococci collected in the United States.","authors":"Alyssa G Kent, Lori M Spicer, Davina Campbell, Erin Breaker, Gillian A McAllister, Thomas O Ewing, Cynthia Longo, Rocio Balbuena, Mark Burroughs, Alex Burgin, Jasmine Padilla, J Kristie Johnson, Alison Laufer Halpin, Susannah L McKay, J Kamile Rasheed, Christopher A Elkins, Maria Karlsson, Joseph D Lutgring, Amy S Gargis","doi":"10.1128/aac.00591-24","DOIUrl":"10.1128/aac.00591-24","url":null,"abstract":"<p><p><i>Enterococcus faecalis</i> and <i>Enterococcus faecium</i> are frequent causes of healthcare-associated infections. Antimicrobial-resistant enterococci pose a serious public health threat, particularly vancomycin-resistant enterococci (VRE), for which treatment options are limited. The Centers for Disease Control and Prevention's Division of Healthcare Quality Promotion Sentinel Surveillance system conducted surveillance from 2018 to 2019 to evaluate antimicrobial susceptibility profiles and molecular epidemiology of 205 <i>E. faecalis</i> and 180 <i>E. faecium</i> clinical isolates collected from nine geographically diverse sites in the United States. Whole genome sequencing revealed diverse genetic lineages, with no single sequence type accounting for more than 15% of <i>E. faecalis</i> or <i>E. faecium</i>. Phylogenetic analysis distinguished <i>E. faecium</i> from 19 <i>E. lactis</i> (previously known as <i>E. faecium</i> clade B). Resistance to vancomycin was 78.3% among <i>E. faecium</i>, 7.8% among <i>E. faecalis</i>, and did not occur among <i>E. lactis</i> isolates. Resistance to daptomycin and linezolid was rare: <i>E. faecium</i> (5.6%, 0.6%, respectively), <i>E. faecalis</i> (2%, 2%), and <i>E. lactis</i> (5.3%, 0%). All VRE harbored the <i>vanA</i> gene. Three of the seven isolates that were not susceptible to linezolid harbored <i>optrA</i>, one chromosomally located and two on linear plasmids that shared a conserved backbone with other multidrug-resistant conjugative linear plasmids. One of these isolates contained <i>optrA</i> and <i>vanA</i> co-localized on the linear plasmid. By screening all enterococci, 20% of <i>E. faecium</i> were predicted to harbor linear plasmids, whereas none were predicted among <i>E. faecalis</i> or <i>E. lactis</i>. Continued surveillance is needed to assess the future emergence and spread of antimicrobial resistance by linear plasmids and other mechanisms.IMPORTANCEThis work confirms prior reports of <i>E. faecium</i> showing higher levels of resistance to more antibiotics than <i>E. faecalis</i> and identifies that diverse sequence types are contributing to enterococcal infections in the United States. All VRE harbored the <i>vanA</i> gene. We present the first report of the linezolid resistance gene <i>optrA</i> on linear plasmids in the United States, one of which co-carried a <i>vanA</i> cassette. Additional studies integrating epidemiological, antimicrobial susceptibility, and genomic methods to characterize mechanisms of resistance, including the role of linear plasmids, will be critical to understanding the changing landscape of enterococci in the United States.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0059124"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456725","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}

{"title":"Therapeutic drug monitoring and safety of voriconazole in patients with liver dysfunction.","authors":"Lin Hu, Yuan Su, Xi Tang, Yanfei Li, Jinhui Feng, Gefei He","doi":"10.1128/aac.01126-24","DOIUrl":"10.1128/aac.01126-24","url":null,"abstract":"<p><p>This study aims to describe the distribution characteristics of voriconazole (VRC) plasma trough concentrations (<i>C</i>_trough) in patients with liver dysfunction, identify factors influencing VRC <i>C</i>_trough, and provide recommendations for the use of VRC in this population. We retrospectively collected medical records of hospitalized patients with liver dysfunction who used VRC and underwent therapeutic drug monitoring (TDM) at the First Hospital of Changsha. The severity of liver dysfunction was assessed by the Child-Pugh (CP) score. Multiple linear regression was employed to explore factors affecting VRC <i>C</i>_trough in these patients. A total of 147 <i>C</i>_trough from 102 patients with liver dysfunction were analyzed. Patients were categorized into a control group (<i>n</i> = 40), CP-A (<i>n</i> = 39), CP-B (<i>n</i> = 11), and CP-C group (<i>n</i> = 12). The initial probability of target attainment of <i>C</i>_trough was 70.6%, with 6.9% of patients obtaining subtherapeutic <i>C</i>_trough and 22.5% obtaining supertherapeutic <i>C</i>_trough. The initial <i>C</i>_trough in CP-A and B were 5.05 (0.64-9.57) mg/L and 5.37 (0.26-10.01) mg/L, respectively, significantly higher than the control group (<i>P</i> = 0.021 and <i>P</i> = 0.010). The proportion of VRC <i>C</i>_trough of >5.5 mg/L in CP-A and B was 33.3% and 45.5%, respectively. Multiple linear regression analysis revealed that factors such as age ≥70 years, CP class, C-reactive protein (CRP), and direct bilirubin were significantly related to the initial VRC <i>C</i>_trough. Among all measurements, patients with severe inflammation (CRP >100 mg/L), aged ≥70 years, and albumin levels of <30 or <25 g/L had significantly higher VRC <i>C</i>_trough. The treatment success rate of VRC was 69.6% (71 of 102), and the rate of VRC-related adverse drug reactions was 29.4% (30 of 102). The recommended half-maintenance dose may lead to elevated VRC <i>C</i>_trough in patients with CP-A and CP-B. TDM is essential for patients with advanced age, severe infections, or hypoalbuminemia to prevent excessive VRC trough levels.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0112624"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456728","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}

{"title":"Detection of cefiderocol and aztreonam/avibactam resistance in epidemic <i>Escherichia coli</i> ST-361 carrying <i>bla</i>_NDM-5 and <i>bla</i>_KPC-3 from foreign fighters evacuated from Ukraine.","authors":"Melissa J Martin, Ting L Luo, Valentyn Kovalchuk, Viacheslav Kondratiuk, Henry D Dao, Iryna Kovalenko, Brandon J Plaza, Joanna M Kettlewell, Cole P Anderson, Jason R Smedberg, Ana C Ong, Yoon I Kwak, Joshua S Hawley-Molloy, Jason W Bennett, Patrick T McGann, Francois Lebreton","doi":"10.1128/aac.01090-24","DOIUrl":"10.1128/aac.01090-24","url":null,"abstract":"<p><p>Genomic surveillance detected clonal <i>Escherichia coli</i> sequence type-361 isolates carrying <i>bla</i>_NDM-5, <i>bla</i>_KPC-3, <i>bla</i>_CTX-M-15, and <i>rmtB1</i> from a patient in Ukraine and four wounded foreign soldiers evacuated to Germany. Isolates were non-susceptible to carbapenems, aminoglycosides, and cefiderocol and aztreonam/avibactam due to a PBP3 YRIN insertion and the <i>bla</i>_CMY-145 AmpC β-lactamase. Coordinated surveillance efforts across civilian, military, and veteran healthcare systems are essential to prevent further spread as international volunteers return home after medical evacuation from Ukraine.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0109024"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279669","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}

{"title":"Analogs of the anti-malaria drug mefloquine have broad-spectrum antifungal activity and are efficacious in a model of disseminated <i>Candida auris</i> infection.","authors":"Soumitra Guin, Marhiah C Montoya, Xiaoyu Wang, Robert Zarnowski, David R Andes, Marvin J Meyers, Noelle S Williams, Damian J Krysan","doi":"10.1128/aac.01301-24","DOIUrl":"10.1128/aac.01301-24","url":null,"abstract":"<p><p>Only three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad-spectrum antifungal activity including difficult-to-treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate that it penetrates the central nervous system and is active against <i>Candida auris in vivo</i>. These data strongly support the further development of mefloquine analogs as a potentially new class of antifungal molecules.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0130124"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370827","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}

{"title":"Variability of macrolide-resistant profile in <i>Mycobacterium avium</i> complex pulmonary disease.","authors":"Kiyoharu Fukushima, Yuki Matsumoto, Yuko Abe, Kazuki Hashimoto, Daisuke Motooka, Seigo Kitada, Haruko Saito, Sho Komukai, Eriko Fukui, Takayuki Niitsu, Hiroshi Nabeshima, Yasuharu Nagahama, June Yamauchi, Tadayoshi Nitta, Takuro Nii, Takanori Matsuki, Kazuyuki Tsujino, Keisuke Miki, Yasushi Shintani, Atsushi Kumanogoh, Shizuo Akira, Shota Nakamura, Hiroshi Kida","doi":"10.1128/aac.01213-24","DOIUrl":"10.1128/aac.01213-24","url":null,"abstract":"<p><p>This single-center retrospective study aimed to analyze the variability of macrolide resistance (MR) in 68 patients with <i>Mycobacterium avium</i> complex pulmonary disease. Among 25 patients treated without macrolides, 13 (52%) reverted to macrolide-susceptible (MS) profiles. Only one (2%) of 43 patients who continued macrolide treatment showed this change. We compared 30 MR isolates with recent specimens. Among them, seven shifted to MS (five attributed to clonally related strains; two resulting from reinfection or polyclonal infection).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0121324"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387502","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}

{"title":"Levofloxacin activity at increasing doses in a murine model of fluoroquinolone-susceptible and -resistant tuberculosis.","authors":"Thomas Maitre, Alexandre Godmer, Céline Mory, Aurélie Chauffour, Thi Cuc Mai, Najoua El Helali, Alexandra Aubry, Nicolas Veziris","doi":"10.1128/aac.00583-24","DOIUrl":"10.1128/aac.00583-24","url":null,"abstract":"<p><p>High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 10⁶ CFU of <i>Mycobacterium tuberculosis</i> H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose-response model, the effective concentration at 50% (EC₅₀) produced an AUC/MIC (AUC_0-24h/MIC) ratio of 167.9 ± 27.5, and at EC₈₀ it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0058324"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456706","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}

{"title":"Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?","authors":"A Boast, W Zhang, H Soeorg, G Gonis, A Di Carlo, A Daley, N Curtis, B McWhinney, J P J Ungerer, A Lei, J F Standing, A Gwee","doi":"10.1128/aac.00747-24","DOIUrl":"10.1128/aac.00747-24","url":null,"abstract":"<p><p>Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0-18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum-CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for <i>Staphylococcus aureus</i> for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1-18.5 years). The final two-compartment serum-CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For <i>S. aureus</i> (MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for <i>S. aureus</i> meningitis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0074724"},"PeriodicalIF":4.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387491","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}