Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa

Abstract

We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [fT > MIC], the ratio of the minimum concentration of free drug to the MIC [fC(min)/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 microg/ml, resulting in median fT > MIC, fC(m)(in)/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an fT > MIC of < or =60% (77.8% failed cefepime therapy when fT > MIC was < or =60%, whereas 36.2% failed cefepime therapy when fT > MIC was >60%; P = 0.013). A similar fT > MIC target of < or =63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with fT > MIC values of < or =60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% fT > MIC will minimize the possibility of a poor microbiological response.

FIG. 1.

Colinearity between CART-derived breakpoints for fT > MIC and fAUC/MIC (A), fC_min/MIC (B), and fC_max/MIC (C) for patients infected with P. aeruginosa.

FIG. 2.

Probability that various cefepime doses will achieve 60% fT > MIC in infected patients with creatinine clearances of 50 to 120 ml/min (A), 30 to 49 ml/min (B), and 10 to 29 ml/min (C). q12h, every 12 h; q8h, every 8 h; INF, infusion.