Disposition of Cefepime in the Central Nervous System of Patients With External Ventricular Drains

Denise H. Rhoney, Pharm.D., Vincent H. Tam, Pharm.D., Dennis Parker, Jr., Pharm.D., Peggy S. McKinnon, Pharm.D., William M. Coplin, M.D.

Disclosures

Pharmacotherapy. 2003;23(3) 

In This Article

Discussion

We found that cefepime CNS penetration in adults is similar to that reported in children[3] and was 4-34% in our study. A two-compartment model provided a reasonable fit to our data. The simulated Cmin CSF concentrations were above the MIC90 of many pathogens seen in both community-acquired and nosocomial meningitis, suggesting that cefepime may be useful for treating meningitis.

In a prospective, randomized clinical trial of cefepime in bacterial meningitis in infants and children, CNS penetration varied from 9-67% with CSF concentrations of 3.3-5.7 µg/ml during the dosing interval.[3] We found similar variability in CNS penetration. The measured CSF cefepime concentrations in our patients were 0.34-11.8 µg/ml during the dosing interval. Variability in CNS penetration may be explained by various mechanisms. Drug transport in the CNS is highly regulated not only by the blood-brain and the blood-CSF barriers, but also by membrane drug transporters. Cefepime appears to be a substrate for one such transporter, P-glycoprotein. Rats coadministered cyclosporine, a P-glycoprotein inhibitor, and cefepime had a significant increase in brain AUC.[9] The clinical significance of increasing cefepime concentrations with P-glycoprotein inhibitors has yet to be determined. It was beyond the scope of this investigation to establish this association, but it may deserve further exploration. Other possible explanations include patient factors that alter blood-brain barrier penetration including administration of osmotic agents,[10] although none of the patients in this analysis received osmotherapy during cefepime administration.

Because -lactam antibiotics exhibit time-dependent bactericidal activity, the goal of therapy is to maintain the concentration in serum and CSF above a pathogen's MIC during most of the dosing interval; therefore, we assessed CNS penetration based on the Cmin ratio. Previous studies report that CSF cefepime concentrations varied from 55-95 times greater than the maximal MIC required by the causative organisms.[3] We did not evaluate the MIC of organisms isolated in our patients because none had pathogens in their CSF. Instead, we evaluated the achieved CSF concentrations compared with published MIC90 of various pathogens.[7] Similar to previous studies, we observed that concentrations in our patients were above that of organisms commonly isolated in nosocomial meningitis. Our observed CSF concentrations did not appear sufficient to provide optimal monotherapy for P. aeruginosa or S. aureus meningitis. Further evaluation is necessary to evaluate the time above the MIC and correlation with clinical efficacy in patients with meningitis. The patients in this study had no evidence of meningeal inflammation. Patients with inflammatory meningitis likely would have higher cefepime CNS penetration.

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