Cefepime and Linezolid Toxicity and Therapeutic Drug Monitoring

Abstract

While the clinical impact of antimicrobial TDM on efficacy is evident, the impact of TDM to avoid toxicity is less clear. Cefepime and linezolid are two last-line antimicrobials with serious toxicities associated with drug exposure. Further investigation into the impact of TDM on their toxicities are required.

Chapter 2 assessed patients for cefepime-induced neurotoxicity (CIN), identified associated patient factors and the cefepime trough concentration (Cmin) that predicted CIN. Results showed a CIN incidence of 6%, and identified that patient risk factors were no longer associated CIN when cefepime Cmin was accounted for. A Cmin of 36mg/L was identified as the cefepime toxicity threshold.

Chapter 3 utilised the cohort from Chapter 2 to validate cefepime population pharmacokinetic models to assess pharmacokinetic parameters to predict CIN. Simulations were used to evaluate cefepime guidelines to achieve therapeutic exposures. A cefepime Cmin of 49mg/L was the toxicity threshold, and only 29% of simulated patients achieved therapeutic concentrations.

Chapter 4 systematically reviewed literature on CIN and cefepime Cmin. Data from eligible studies were obtained to perform an individual patient data meta-analysis (IPD-MA) to refine the toxicity threshold. Of 9 included studies, 115/571 patients experienced CIN. IPD-MA identified a cefepime Cmin of 34mg/L associated with CIN.

Chapter 5 evaluated incidence and patient factors associated with linezolid toxicity. 105/622 patients experienced linezolid toxicity, who had a lower baseline platelet count, higher baseline creatinine and received a longer course compared to those who did not. TDM-guided dose adjustment was the only factor that significantly reduced the odds of linezolid toxicity.

This thesis identifies that cefepime and linezolid toxicity are important issues associated with patient risk factors. Where available, cefepime and linezolid TDM may be effective strategies to diagnose and prevent toxicity occurring.