Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia

Objectives: The %fT.MIC of ceftazidime has been shown to correlate with microbiological outcome of Gramnegative bacteria (GNB) in preclinical studies. However, clinical data are still lacking. We explored the relationship of ceftazidime exposure and outcome in patients with nosocomial pneumonia using data from a recent randomized, double-blind Phase 3 clinical trial. Patients and methods: Pharmacokinetic (PK) and demographic data from three clinical trials were used to construct a population PK model using non-linear mixed-effects modelling. Individual concentration-time curves and PK/pharmacodynamic indices were determined for individual patients. The MICs used in the analyses were the highest MICs for any GNB cultured at baseline or end of therapy. Results: A two-compartment model best fit the data, with creatinine clearance as covariate on clearance and age on the central compartment. Classification and regression tree analysis showed a breakpoint value of 44.9% (P,0.0001) for GNB in 154 patients. The Emax model showed a good fit (R20.93). The benefit of adequate treatment increased from an eradication rate of 0.4848 at %fT.MIC of 0% to 0.9971 at 100%. The EC50 was 46.8% and the EC90 was 95.5% for %fT.MIC. Exposure correlated significantly with both microbiological and clinical outcome at test-of-cure. Conclusions: We conclude that exposures to ceftazidime predict microbiological as well as clinical outcome, and the %fT.MIC required to result in a likely favourable outcome is.45% of the dosing interval. This value is similar to that observed in animal models and underscores the principle that adequate dosing can be predicted and is beneficial to patient care.

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