Cefepime Dosing in the Morbidly Obese Patient Population

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...

Section: Discussionmentioning

confidence: 93%

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

Sime

Roberts

Tiong

et al. 2015

“…Studies on prophylaxis with narrow-spectrum cephalosporins showed that dosages needed to be doubled to reach target concentrations in obese patients (15,16,26). A dose of 2 g twice daily of cefepime was insufficient to reach PD targets (17). Serum concentrations of ertapenem were lower in obese patients than in nonobese patients (18).…”

Section: Discussionmentioning

confidence: 93%

Case-Control Study of Drug Monitoring of β-Lactams in Obese Critically Ill Patients

Hites

Taccone

Wolff

et al. 2013

117

Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum ␤-lactams (meropenem, ceftazidime/cefepime, and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinetics of these agents. We reviewed our data on critically ill obese patients (body mass index of >30 kg/m 2 ) treated with a broadspectrum ␤-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically nonobese patients (body mass index of <25 kg/m 2 ) to assess whether there were differences in reaching optimal drug concentrations for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was considerable variability in ␤-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard drug regimens of ␤-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a protective factor for insufficient ␤-lactam serum concentrations. The serum drug levels from the obese cohort were well matched for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 nonobese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of ␤-lactams should be continued in obese critically ill patients.

“…However, specific targets of percent TAM for each cephalosporin and each patient group are still not well defined and require assessments of factors that may impact host response to the infection, such as age and immune status, and factors that impact the treating clinician's willingness to take a risk of treatment failure (e.g., the severity of infection). To achieve the maximum bactericidal effect in animal models, 60 to 70% TAM is required, particularly for cephalosporins (27,28), and several recent articles used 60% TAM of ␤-lactams as their target (25,29,30). Therefore, we also used this value in our current analysis.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms

Shoji

Bradley

Reed

et al. 2016

The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints for Enterobacteriaceae in 2014, and MICs of 4 and 8 g/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 g/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, >30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 g/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 g/ml. Prolonged i.v. infusions may be useful for this population. Health care-associated infections (HAI), such as ventilator-associated pneumonia, catheter-associated urinary tract infection, surgical site infection, and catheter-related bloodstream infection, may lead to morbidity and mortality in children (1-3). Infections caused by Gram-negative bacilli (GNB) are a major cause of HAI, including infections caused by Pseudomonas aeruginosa and the Enterobacteriaceae, such as Klebsiella pneumoniae and Escherichia coli (4, 5). The incidence of multidrug-resistant GNB, based on the presence of extended-spectrum ␤-lactamases (ESBLs) and AmpC ␤-lactamases, is increasing globally (6-9). Infections caused by these organisms are associated with a poor prognosis (10, 11). Further complicating this clinical challenge is that development of new antibiotics effective against these important pathogens has been slow (12). It is important to use existing antibiotics effectively whenever possible, using pharmacokinetics (PK) and pharmacodynamics (PD) analyses. Cefepime (CFP), a fourth-generation cephalosporin, is widely used to treat infections caused by GNB in both adult and pediatric patients (13,14). Several studies have shown the effectiveness and safety of CFP in treating urinary tract and lower respiratory infections in children (15,16). Further, CFP is also an important choice to treat multidrug-resistant GNB, such as AmpC ␤-lactamase-producing strains and several strains of ESBL-producing organisms with MICs that correspond to clinically achievable pl...