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Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations
D P Nicolau1, C O Onyeji, M Zhong
1Department of Pharmacy Research, Hartford Hospital, Hartford, Connecticut 06102, USA.
Insights
Cefprozil effectively treats Streptococcus pneumoniae infections in children when the minimum inhibitory concentration (MIC) is 2 µg/ml or less. This study supports a susceptibility breakpoint of 2 µg/ml for cefprozil against pneumococcus.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Cefprozil is an oral cephalosporin used for pediatric respiratory infections.
- Its efficacy against Streptococcus pneumoniae requires further pharmacodynamic definition.
Purpose of the Study:
- To evaluate the pharmacodynamic profile of cefprozil against clinical isolates of Streptococcus pneumoniae.
- To determine the in vivo effectiveness of cefprozil in a pediatric pharmacokinetic model.
Main Methods:
- Utilized a neutropenic murine thigh infection model with 19 S. pneumoniae isolates.
- Simulated pediatric cefprozil pharmacokinetics by impairing mouse renal function and administering oral cefprozil suspension (6 mg/kg q12h).
- Assessed bacterial density reduction and animal survival over 24 and 96 hours, respectively.
Main Results:
- Bacterial kill ranged from 0.5 to 4.4 log(10) CFU/thigh over 24 hours, dependent on MIC.
- Significant bacterial killing (>2.6 log(10) CFU/thigh) occurred with MICs ≤3 µg/ml.
- Survival was observed for MICs ≤2 µg/ml, while higher MICs led to substantial mortality.
Conclusions:
- Cefprozil demonstrates effectiveness against S. pneumoniae isolates with MICs ≤2 µg/ml at pediatric exposure levels.
- These findings support establishing a cefprozil susceptibility breakpoint of ≤2 µg/ml for Streptococcus pneumoniae.
Abstract:
Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the treatment of respiratory-tract infections in children. While this agent has provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Streptococcus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the neutropenic murine thigh infection model. To simulate the pharmacokinetic profile of cefprozil in children, the renal function of mice was impaired with uranyl nitrate, and a commercially available cefprozil suspension (6 mg/kg of body weight) was administered orally every 12 h. Mice were infected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h postinfection, thighs were harvested to determine bacterial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was observed with MICs of < or =3 microg/ml, while either minimal killing or growth was detected with MICs of > or =4 microg/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were < or =2 microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in substantial mortality. These studies demonstrate the effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are < or =2 microg/ml using a drug exposure typically observed in children. These data support a susceptibility breakpoint of < or =2 microg/ml for cefprozil.