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Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole
Keith A Rodvold1, David P Nicolau, Thomas P Lodise
1College of Pharmacy, University of Illinois, Chicago, Illinois, USA.
Abstract:
Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log(10) cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log(10) and 2 log(10) CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log(10) and 2 log(10) CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log(10) and 2-log(10) CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log(10) CFU/g kill and 79.7% for a 2-log(10) CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.
Insights
Ceftobiprole effectively penetrates epithelial lining fluid (ELF) to combat methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Achieving specific drug exposure targets in ELF is crucial for optimizing treatment outcomes in patients.
Area of Science:
- Pharmacology
- Infectious Diseases
- Clinical Microbiology
Background:
- Ceftobiprole exhibits potent activity against methicillin-resistant Staphylococcus aureus (MRSA).
- Severe staphylococcal pneumonia necessitates understanding drug exposure at the infection site for effective treatment.
- Epithelial lining fluid (ELF) is a critical site for drug penetration and efficacy against respiratory pathogens.
Purpose of the Study:
- To determine the drug exposure targets for ceftobiprole in ELF required for bacterial killing in a preclinical model.
- To evaluate ceftobiprole penetration into ELF in healthy volunteers.
- To assess the attainment rates of established exposure targets with standard dosing regimens against MRSA.
Main Methods:
- A murine model of staphylococcal pneumonia was used to determine time above the minimum inhibitory concentration (MIC) in ELF and plasma.
- Ceftobiprole penetration into ELF was assessed in healthy volunteers.
- Target attainment rates were calculated using preclinical kill targets and volunteer penetration data against a panel of MRSA isolates.
Main Results:
- Ceftobiprole demonstrated significant penetration into ELF, with a median ratio of 69% (ELF AUC/plasma AUC).
- In mice, 15% and 25% of the dosing interval as time>MIC in ELF were required for 1-log(10) and 2-log(10) CFU/g reduction, respectively.
- Standard ceftobiprole dosing (0.5 g every 8 h) achieved >90% target attainment for 1-log(10) and 2-log(10) kill targets at MICs of 1 and 0.5 mg/L, respectively, with an overall attainment of 85.6% and 79.7% against a large MRSA isolate collection.
Conclusions:
- Preclinical models are essential for deriving site-of-infection exposure targets for antibiotics like ceftobiprole.
- Ceftobiprole's penetration and exposure profile support its efficacy against MRSA pneumonia.
- Established exposure targets should be evaluated in clinical trials to optimize ceftobiprole's use in treating severe staphylococcal infections.
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