Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

Abstract

i While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT >MIC ). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT >MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT >MIC in the 3rd and 6th dosing intervals. A 100% fT >MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is <4 mg/liter but may fail to cover less susceptible organisms.T he introduction of cefepime into clinical practice was widely accepted due to its broad-spectrum activity. Cefepime is active against such organisms as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae with relatively low MICs compared to those of other broad-spectrum ␤-lactam antibiotics (1, 2). Therefore, it is considered a good choice for the empirical management of febrile neutropenia, either as a monotherapy agent or as part of combination regimens (3, 4).While several comparative outcome trials suggest cefepime is clinically as effective as other ␤-lactam antibiotics, meta-analyses (5, 6) of data from these trials report an increased risk of mortality associated with cefepime therapy, which was particularly high in febrile neutropenic patients (7). Conversely, a later meta-analysis by the U.S. Food and Drug Administration (FDA), which included several additional unpublished trials, concluded that there is no such association (8, 9). In addition, specific analysis of trials of febrile neutropenic patients did not show any statistically significant increase in mortality (9). The controversy continues as the methodological issues of the FDA's and previous meta-analyses are challenged and debated (7,(10)(11)(12). However, there is little biological plausibility for the claimed risk of mortality, which was originally suggested to be related to unrecognized toxicity or poor in viv...

Optimization of Vancomycin Dosing Regimen in Cancer Patients using Pharmacokinetic/Pharmacodynamic Modeling

“…For example, it has been reported that in febrile patients with neutropenia the traditional doses of cefepime (2 g intravenously every 12 hours) may not be appropriate and a higher dose (2 g intravenously every 8 hours) is required to achieve therapeutic antibiotic exposure. 20,21 Similarly, it has been demonstrated in several studies that vancomycin PKs are affected in accordance with changes in the pathophysiology of the patients. Therefore, it is critical to assess the appropriateness of vancomycin traditional doses, mainly the administration of the right dose for patients with neutropenic cancer.…”

Optimization of the treatment with beta-lactam antibiotics in critically ill patients—guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique—SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d’Anesthésie et Réanimation—SFAR)

“…Modifications of the volume of distribution (Vd) and renal clearance of beta-lactams are major sources of PK variability observed in critical care patients. For instance, mean Vd and clearance of cefepime could vary in ICU patients from 0.08 to 0.55 L/kg and 0.062 to 0.131 L/kg/h, respectively [16–24]. Patients’ diseases also influence antibiotic PK.…”

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation

“…PK can be described as the drug dose, route, and frequency as it relates to drug concentrations in the body over the dosing interval, whereas PD can be defined by the relationship between drug concentrations at the site of the infection and the killing effect produced. Because the PD killing effects of β‐lactams are mechanistically linked to PK exposures (i.e., maintaining the percentage of time that the drug concentration remains above the minimum inhibitory concentration [ f T>MIC] at critical levels), acute alterations in individual patient PK exposures in the setting of febrile neutropenia may significantly increase the risk for underexposure and thus adversely affect clinical outcomes …”

“…Because the PD killing effects of b-lactams are mechanistically linked to PK exposures (i.e., maintaining the percentage of time that the drug concentration remains above the minimum inhibitory concentration [fT>MIC] at critical levels), acute alterations in individual patient PK exposures in the setting of febrile neutropenia may significantly increase the risk for underexposure and thus adversely affect clinical outcomes. [2][3][4][5] Multiple studies have identified wide interpatient variability in the PK profile of various antibacterials in patients with febrile neutropenia. [6][7][8] Common conditions in patients with hematologic malignancies, such as cachexia, hypoalbuminemia, and pleural effusions, can lead to inadequate dosing due to an increase in the apparent volume of distribution (Vd).…”