Efficacy of ceftaroline fosamil in a staphylococcal murine pneumonia model
Amira A Bhalodi1, Jared L Crandon, Donald Biek
1Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Abstract:
Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log(10) kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log(10) CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log(10) kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.
Insights
Ceftaroline fosamil effectively treats methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in mice. The humanized dosing regimen achieved pharmacodynamic targets, demonstrating efficacy against MRSA and MSSA lung infections.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Ceftaroline fosamil is a cephalosporin antibiotic with demonstrated activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA).
- Understanding the dose-response relationship and pharmacokinetic/pharmacodynamic (PK/PD) targets of antibiotics is crucial for optimizing treatment efficacy, particularly in challenging infections like pneumonia.
Purpose of the Study:
- To characterize the dose-response relationship of ceftaroline fosamil against Staphylococcus aureus (S. aureus) in an immunocompromised murine pneumonia model.
- To evaluate the efficacy of a humanized dosing regimen (600 mg intravenously every 12 hours) of ceftaroline fosamil in this model.
- To determine the PK/PD targets, specifically the percentage of time free drug concentrations remain above the minimum inhibitory concentration (fT>MIC), required for effective bacterial killing.
Main Methods:
- Seventeen S. aureus isolates (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) with varying ceftaroline MICs were used.
- Pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated in infected and uninfected mice using single and human-simulated doses.
- Dose-ranging studies were conducted to determine the fT>MIC required for a 1-log(10) reduction in bacterial CFU.
- The efficacy of the humanized regimen was assessed by measuring bacterial burden in lung homogenates.
Main Results:
- An fT>MIC of 17% to 43% was required to achieve a 1-log(10) kill of S. aureus in the dose-ranging studies.
- The humanized dosing regimen (600 mg i.v. every 12 h) readily achieved these pharmacodynamic targets.
- Significant bacterial reductions (0.64 to 1.95 log(10) CFU) were observed against 13 MRSA and both MSSA isolates with the humanized regimen.
- ELF concentrations of ceftaroline were comparable to serum concentrations.
- The fT>MIC targets for stasis and 1-log(10) kill were determined to be 16% and 41%, respectively.
- The PK/PD targets identified in the murine pneumonia model were similar to those previously observed in a murine thigh infection model.
Conclusions:
- The simulated human dose of ceftaroline fosamil (600 mg i.v. every 12 h) achieved established pharmacodynamic targets against S. aureus, including MRSA and MSSA, in a murine pneumonia model.
- These findings support the potential efficacy of this regimen for treating S. aureus pneumonia in humans.
- The study highlights the importance of PK/PD modeling in guiding antibiotic dosing strategies for infectious diseases.
