Journal article
Determining an appropriate fosfomycin (ZTI-01) dosing regimen in pneumonia patients by utilizing minimal PBPK modeling and target attainment analysis
Antimicrobial agents and chemotherapy, Vol.69(6), e01869-24
06/04/2025
DOI: 10.1128/aac.01869-24
PMCID: PMC12135528
PMID: 40323339
Abstract
Fosfomycin, a broad-spectrum antibiotic used for uncomplicated cystitis, represents a potential promising candidate in combating resistant pneumonia. To facilitate the transition of fosfomycin to broader indications, including pneumonia, a minimal physiologically based pharmacokinetics (m-PBPK) model for fosfomycin was developed based on data from plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs) obtained from 37 healthy participants in a recently completed intrapulmonary PK study. Utilizing this mechanistic m-PBPK model enabled us to predict drug concentrations at the infection site in pneumonia patients, taking into consideration the pathophysiological changes occurring during the infection. Our prediction shows that the drug concentrations at the infection site reduced, while plasma levels remain unchanged. Monte Carlo simulations were conducted to evaluate the probability of target attainment (PTA) for various dosing regimens infused over 1 h against major hospital-acquired pneumonia pathogens in plasma and ELF. Our PTA analysis suggested that if plasma concentrations are the appropriate efficacy indicator, a dose of 4 g q8h is sufficient for Pseudomonas aeruginosa and Staphylococcus aureus infections. However, if ELF concentrations are a more accurate indicator, this dose is only effective for S. aureus pneumonia. For P. aeruginosa pneumonia, a dose of 6 g q8h is recommended, with an even higher dose of 8 g q8h necessary for pneumonia patients. In conclusion, our model provides critical insights into fosfomycin dosing for pneumonia treatment, guiding clinical study design. Furthermore, it serves as a platform to evaluate intrapulmonary pharmacokinetics for other antibiotics.
Details
- Title: Subtitle
- Determining an appropriate fosfomycin (ZTI-01) dosing regimen in pneumonia patients by utilizing minimal PBPK modeling and target attainment analysis
- Creators
- Jomana Al Hroot - University of IowaJoshua Reeder - University of IowaXuanzhen Yuan - University of IowaKenan Gu - ,Emmanuel B. Walter - ,Lindsay Boole - Duke University School of MedicineLoretta G. Que - Duke University School of MedicineGuohua An - University of Iowa
- Contributors
- Benjamin P. Howden (Editor)
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.69(6), e01869-24
- DOI
- 10.1128/aac.01869-24
- PMID
- 40323339
- PMCID
- PMC12135528
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- American Society for Microbiology; WASHINGTON
- Number of pages
- 17
- Grant note
- HHSN272201300017I / National Institute of Allergy and Infectious Diseases (http://dx.doi.org/10.13039/100000060)
- Language
- English
- Electronic publication date
- 05/05/2025
- Date published
- 06/04/2025
- Academic Unit
- Stead Family Department of Pediatrics; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984820566702771
Metrics
3 Record Views