Total and Unbound Cefazolin Pharmacokinetics and Pharmacodynamics in Non-Obese and Obese Patients

Background:

Cefazolin pharmacokinetics (PK) in obesity are limited to single dose administration for surgical prophylaxis. The objectives of this study were to evaluate the steady-state PK and pharmacodynamics (PD) of cefazolin in infected non-obese and obese patients and to evaluate probability of target attainment (PTA) at specific MICs.

Methods:

Hospitalized patients requiring treatment with cefazolin for a suspected or documented bacterial infection were enrolled. Patients weighting < 120 kg (Group 1) received 2 grams q8h, and patients weighing > 120 kg (Group 2) received 3 grams q8h. Doses were infused over 0.5 h, and serial blood samples were collected after 4 or more doses. Protein binding was determined by ultrafiltration, and total and unbound (free) serum concentrations were determined by HPLC. PK parameters were estimated, and 5,000-patient Monte Carlo simulations were performed using the PK parameters for the free concentrations to calculate PTA at specific MICs using the PD targets of 40% and 60% fT>MIC.

Results:

Twenty-two patients (11 in each group) were studied. Patient demographics for Group 1 vs. Group 2 were (mean ± SD): age, 62 ± 11 years vs. 53 ± 11 years; total body weight, 87.2 ±15.4 kg vs. 174.5 ± 69.6 kg; body mass index, 30.7 ± 6.1 kg/m² vs. 55.6 ± 20.0 kg/m². For total concentrations, Cmax and Cmin were 195.5 ± 78.4 μg/ml and 26.6 ± 25.0 μg/ml for Group 1 and 244.2 ± 91.3 μg/ml and 42.2 ± 34.7 μg/ml for Group 2, respectively. Vss was 24% larger and CL was 7% faster in Group 2. For unbound concentrations, Cmax and Cmin were 86.4 ± 48.9 μg/ml and 8.6 ± 8.3 μg/ml for Group 1 and 96.2 ± 41.8 μg/ml and 9.5 ± 7.4 μg/ml for Group 2, respectively. Vss was 34% larger and CL was 27% faster in Group 2. None of these PK differences were statistically significant between groups. However, protein binding was significantly higher in Group 2 (71.7% vs. 64.0%, p<0.001). PTA was > 90% for 2 grams q8h in Group 1 and 3 grams q8h in Group 2 at MICs ≤ 8 μg/ml for 40% fT>MIC and at MICs ≤ 4 μg/ml for 60% fT>MIC.

Conclusion:

Cefazolin pharmacokinetic parameters were not significantly different between patient groups, but protein binding was significantly higher in patients > 120 kg. Cefazolin 3 grams q8h in patients > 120 kg provides similar PD exposures to 2 grams q8h in patients < 120 kg.