ArticleAntimicrobial agents and chemotherapy2009
Pharmacodynamics of levofloxacin in a murine pneumonia model of Pseudomonas aeruginosa infection: determination of epithelial lining fluid targets.
Article in Antimicrobial agents and chemotherapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Pharmacokinetic/pharmacodynamic analysis of sulbactam againstJAC-antimicrobial resistance · 2024Article
- Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model.American journal of respiratory and critical care medicine · 2024Article
- Selected strategies to fight pathogenic bacteria.Journal of enzyme inhibition and medicinal chemistry · 2023Review
- Pharmacokinetic and pharmacodynamic properties of polymyxin B in Escherichia coli and Klebsiella pneumoniae murine infection models.The Journal of antimicrobial chemotherapy · 2023Article
- Pharmacodynamics of Temocillin in Neutropenic Murine Infection Models.Antimicrobial agents and chemotherapy · 2023Article
- Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia.Frontiers in pharmacology · 2023Article
- Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time-Kill Approaches.Antibiotics (Basel, Switzerland) · 2021Review
- Generating Robust and Informative NonclinicalAntimicrobial agents and chemotherapy · 2019Review
- The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection.Antimicrobial agents and chemotherapy · 2017Article
- Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1.Antimicrobial agents and chemotherapy · 2015Review
- Combination Therapy for Extreme Drug-Resistant Acinetobacter baumannii: Ready for Prime Time?Critical care medicine · 2015Article
- Combination treatment with meropenem plus levofloxacin is synergistic against Pseudomonas aeruginosa infection in a murine model of pneumonia.The Journal of infectious diseases · 2015Article
- Time-kill effect of levofloxacin on multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii: synergism with imipenem and colistin.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2015Article
- Impact of meropenem in combination with tobramycin in a murine model of Pseudomonas aeruginosa pneumonia.Antimicrobial agents and chemotherapy · 2013Article
- Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents.Clinical pharmacokinetics · 2011Review
- Saturability of granulocyte kill of Pseudomonas aeruginosa in a murine model of pneumonia.Antimicrobial agents and chemotherapy · 2011Article
- Pharmacodynamic modeling of anti-cancer activity of tetraiodothyroacetic acid in a perfused cell culture system.PLoS computational biology · 2011Article
- Impact of burden on granulocyte clearance of bacteria in a mouse thigh infection model.Antimicrobial agents and chemotherapy · 2010Article
- Pharmacodynamics of vancomycin at simulated epithelial lining fluid concentrations against methicillin-resistant Staphylococcus aureus (MRSA): implications for dosing in MRSA pneumonia.Antimicrobial agents and chemotherapy · 2009Article
- Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole.Antimicrobial agents and chemotherapy · 2009Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The dose choice for Pseudomonas aeruginosa remains a matter of debate. The actual exposure targets required for multilog killing of organisms at the primary infection site have not been delineated. We studied Pseudomonas aeruginosa PAO1 using a murine model of pneumonia. We employed a large mathematical model to fit all the concentration-time data in plasma and epithelial lining fluid (ELF) as well as colony counts in lung simultaneously for all drug doses. Penetration into ELF was calculated to be approximately 77.7%, as indexed to the ratio of the area under the concentration-time curve for ELF (AUC(ELF)) to the AUC(plasma). We determined the ELF concentration-time profile required to drive a stasis response as well as 1-, 2-, or 3-log(10)(CFU/g) kill. AUC/MIC ratios of 12.4, 31.2, 62.8, and 127.6 were required to drive these bacterial responses. Emergence of resistance was seen only at the two lowest doses (three of five animals at 50 mg/kg [body weight] and one of five animals at 100 mg/kg). The low exposure targets were likely driven by a low mutational frequency to resistance. Bridging to humans was performed using Monte Carlo simulation. With a 750-mg levofloxacin dose, target attainment rates fell below 90% at 4 mg/liter, 1 mg/liter, and 0.5 mg/liter for 1-, 2-, and 3-log kills, respectively. Given the low exposure targets seen with this strain, we conclude that levofloxacin at a 750-mg dose is not adequate for serious Pseudomonas aeruginosa pneumonia as a single agent. More isolates need to be studied to make these observations more robust.
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