Cefepime In Plasma Research Articles

211. Defining Optimal Sampling Times for Cefepime Therapeutic Drug Monitoring in Clinical Practice

Abstract Background Clinicians performing beta-lactam therapeutic drug monitoring (TDM) lack evidence on when levels should ideally be drawn after a dose. Herein, we define the optimal timing (i.e., optimal sampling) for cefepime using real-world TDM data to validate our approach.Figure 1.External validation of the Bayesian prior non-parametric population PK model Methods De-identified data from two centers performing routine cefepime TDM were extracted by InsightRX and served as an external validation cohort. Plasma cefepime was quantified using validated LC-MS/MS assays for TDM and dosing was protocolized at each site. CRRT and ECMO patients were included but other dialysis patients were not. Bias (MPE) and precision (RMSE) of a non-parametric prior were assessed. Multiple-model optimal (MM-opt) sampling strategies were estimated for the first 24 hours of treatment. To mirror clinical practice, one- and two-sample designs were evaluated. Dose and covariate values informed optimal sampling times. Bayesian PK exposures were compared using all samples, trough-only sampling, or using a single optimally timed sample. AUCs were calculated from the posteriors. For fT >MIC analysis, the MIC was fixed at 8 mg/L. We used Pmetrics 2.1.1 for R.Figure 2.Distribution of MM-optimal sampling times in external validation data using n=1 sample Results 116 patients (42% female; median age, CRCL, and weight: 62 years, 76 mL/min, and 80 kg, respectively) contributed 235 levels. The PK model demonstrated acceptable bias and precision (-6% MPE, 30.9 RMSE) as a prior for estimating exposures from the TDM data (Fig1). For a one-sample approach, the most common MM-opt sampling times varied (Fig2) but were often a mid-point or trough. In the two-sample approach, sample one was often a mid-point and sample two was often a trough (Fig3). First 24-hr AUC and fT>MIC did not significantly differ using all available samples for analysis vs. limiting sampling to a single optimized time point vs. limiting sampling to a trough-only approach (P >0.05 for all comparisons; Fig4).Figure 3.Distribution of MM-optimal sampling times in external validation data using n=2 samples Conclusion Optimal cefepime sampling times depended on dosing regimen, and renal disposition. When limited to a single sample, optimal sampling times for cefepime TDM were often midpoint/trough levels, but when two samples were obtained the optimal sampling times were often a mid-point followed by a trough. Estimation of PK and PK/PD exposures was not significantly worse when using a validated Bayesian prior and a trough-only sampling approach.Figure 4.First 24 hours PK and PK/PD exposure estimates from Bayesian analysis of all external validation data and Bayesian analysis of n=1 optimally timed samples from the same population Disclosures Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant Brandon Smith, MD, PharmD, Melinta Therapeutics: Advisor/Consultant|Shionogi, INC: Advisor/Consultant Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support Jasmine Hughes, PhD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Maria-Stephanie Hughes, PharmD, InsightRX: Employee of company|InsightRX: Stocks/Bonds (Private Company) Fekade B. Sime, PhD, S.Aust., Gilead: Grant/Research Support|Pfizer: Grant/Research Support Patrick J. Kiel, PharmD, Amgen: Employee|Amgen: Stocks/Bonds (Public Company) Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Cidara: Advisor/Consultant|DoseMe: Advisor/Consultant|Entasis: Advisor/Consultant|F2G: Advisor/Consultant|GSK: Advisor/Consultant|Lykos: Advisor/Consultant|Roche: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant|Xelia: Advisor/Consultant

P-1224. Individual Target Pharmacokinetic/Pharmacodynamic Attainment Rates among Cefepime-treated Patients Admitted to the ICU with Hospital-Acquired Pneumonia with and without ECMO

Abstract Background The impact of extracorporeal membrane oxygenation (EMCO) on cefepime (FEP) pharmacokinetics (PK) in the absence of renal replacement therapy (RRT) is unclear. Figure 1. Observed versus predicted cefepime plasma concentrations in the population (A) and for each individual (B) Methods We evaluated FEP PK in patients with hospital-acquired pneumonia from June 2018 to May 2023, with/without ECMO in the absence of RRT, in a single-center study nested within the Successful Clinical Response In Pneumonia Treatment (SCRIPT) study. Patient data were extracted from electronic health records. FEP dosing was according to institutional protocols based on renal function and indication. Plasma concentrations were quantified by validated LC-MS/MS assay. We used Pmetrics 2.1.1 for R to estimate population model parameter values [e.g., volume (V) and clearance (CL)] and individual target attainment rates, assuming a free (f) fraction of 80%. Targets of 100% fT>1xMIC and 100% fT>4xMIC were evaluated vs. the susceptible breakpoint MICs of Enterobacterales (2 mcg/mL) and P. aeruginosa (8 mcg/mL) and stratified by concurrent ECMO. Figure 2. Pharmacokinetic parameters (CL and V) standardized to body weight (kg) stratified by ECMO status. Results Sixty-two SCRIPT patients (63% male) contributed 95 plasma FEP samples (1-13 per patient). A total of 9 patients (one female) required ECMO. Patients had a mean±SD CRCL of 123±84 mL/min and a mean±SD body weight of 86±24 kg. The median/max first 24-hr FEP dose was 4/8 grams. A two-compartment PK model fitted best (Fig 1). Body weight and creatinine clearance were related to V and CL, respectively (Table 1). ECMO was not significantly associated with FEP CL (P=0.2) but was associated with V (P< 0.005) (Fig 2). ECMO patients had a median 3.5-fold greater Vd vs. non-ECMO patients. For targets of fT >1xMIC and fT >4xMIC, median individual plasma attainment rates were 100% and 100% against Enterobacterales and 100% and 49% against P. aeruginosa, respectively. Attainment rates were lowest in patients requiring ECMO vs. P. aeruginosa at a target of 100% fT >4xMIC, (Fig 3). Figure 3. Individual predicted cefepime PK/PD target attainment stratified by organism breakpoint and concurrent ECMO status for fT>1xMIC and fT>4xMIC. Conclusion We found that ECMO increased FEP V but not CL suggesting that ECMO patients may require loading doses and prolonged infusions to improve target attainment. Protocolized short infusions of FEP in ECMO patients resulted in suboptimal target attainment for a PK/PD goal of 100% fT>4xMIC against P. aeruginosa. More work is needed to identify the impact of FEP target attainment on clinical outcomes in populations such as these. Table 1. Population Median Parameters and 95% Credible Intervals for Cefepime Patients with and without the Requirement of Extracorporeal Membrane Oxygenation Support Disclosures Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Cidara: Advisor/Consultant|DoseMe: Advisor/Consultant|Entasis: Advisor/Consultant|F2G: Advisor/Consultant|GSK: Advisor/Consultant|Lykos: Advisor/Consultant|Roche: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant|Xelia: Advisor/Consultant Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant

Are We Dosing Correctly? Population Pharmacokinetics of Cefepime in Critically Ill Pediatric Patients

Abstract Background Dosing guidelines of cefepime are well defined in healthy pediatric and adult populations but have not been extensively studied in critically ill pediatric patients. Patients who are critically ill may have significant alterations in antibiotic pharmacokinetics (PK) and pharmacodynamics (PD) due to many factors. Receipt of ECMO or CRRT may further alter PK/PD due to changes in clearance and volume of distribution and the depletion of plasma proteins. Since critically ill pediatric patients are likely to receive multiple courses of antimicrobials, optimization of drug dosing and delivery is critically important for individual patient outcomes. This study will test the hypothesis that the PK of cefepime is substantially altered in critically ill pediatric patients. Methods We prospectively enrolled patients in VUMC pediatric ICUs receiving cefepime, including those receiving ECMO or CRRT. Plasma samples were collected at opportune timepoints enriched for specific PK/PD metrics. Cefepime plasma concentrations were measured by LC-MS/MS. Weight, dose, interval, and administration time were extracted from the medical record. Monolix was used to fit population PK models using one and two-compartment models with a proportional error model. Covariate modeling was performed with a priori selected covariates: ECMO, CRRT, sex, race, ethnicity, gestational age, and creatinine clearance (CrCl). The final covariate model was used to perform probability of target attainment (PTA) analysis using Monte Carlo simulation. 6,000 subjects were simulated for each dosing regimen, with 3 weight categories (≤9 kg, 9-25 kg, and >25 kg) and 2 CrCl categories (≤90 mL/min and >90 mL/min). PTA was calculated over a grid of possible MIC values based on three targets, 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC. Results Preliminary data from 84 pediatric participants receiving cefepime were analyzed. Of these, 9 received CRRT and 10 received ECMO. An average of 3 samples were collected per participant. A two compartment with proportional error model was selected as the base model. Population PK parameter estimates for the base model, base model with weight, and final covariate model were calculated. Inclusion of weight and CrCl significantly improved model fit. CRRT, ethnicity, and gestational age did significantly improve model fit, but their inclusion in the model did not provide evidence of being significantly better than the model with only weight and CrCl. The results from the PTA analysis are seen in Figure 1. We observed an overall ordering of PTA by dosing regimen across all three targets, with q8h 3-hour infusion having the highest PTA and q12h 30-minute infusion having the lowest PTA. Increased CrCl led to reduced PTA and as weight increased, PTA also increased. Conclusion This study will be among the first and largest to characterize cefepime PK in the critically ill pediatric population. Clinicians should incorporate local antibiograms with these population PK models to determine optimal dosing in critically ill pediatric patients. The use of extended infusions may be beneficial for PK/PD target achievement, particularly for resistant pathogens. Since clinical covariates affect PK parameters, this population may also benefit from therapeutic drug monitoring. Figure 1. Comparison of PTA among four dosing regimens of cefepime at targets of 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC.

Pharmacokinetic Analysis of Intravenous Push Cefepime in Burn Patients with Augmented Renal Clearance.

Patients with augmented renal clearance (ARC) are a subset of critically ill patients including burn patients that exhibit increased renal elimination of medications beyond that of similarly injured patients. Currently approved maximum regimens of medications primarily eliminated by the kidney, such as cefepime (>90% unchanged in the urine), may be inadequate (eg, compromising the bactericidal activity of cefepime) in patients with ARC. Due to recent resource limitations, centers have changed infusion practices of commonly prescribed medications to intravenous push (IVP), potentially exacerbating the problem of maintaining bactericidal cefepime concentrations. The hypothesis of the study was patients with ARC are not currently achieving adequate target attainment, when receiving cefepime 2 g every 8 h IVP. Eight blood samples were collected from each patient, and concentrations measured via LC-MS/MS. WinNonlin (version 8.3) was used to estimate the pharmacokinetic parameters of cefepime and simulate plasma concentrations of cefepime in each of the ten subjects. Simulations of cefepime plasma concentrations produced by a 2 g dose given every 8 h and a 1 g dose given every 4 h were performed and the time above a MIC of 4 mg/L, 8 mg/L, and 16 mg/L compared. The 2 g every 8 h regimen remained above the breakpoints for 92%, 85%, and 71% of the dosing interval, respectively. The 1 g every 4 h regimen remained above the same breakpoints at a frequency of 100%, 99%, and 92% of the dosing interval. Giving cefepime 1 g every 4 h is a simple approach to increase the likelihood of maintaining the optimal bactericidal activity of cefepime in patients with ARC.

Continuous Infusion of High Doses of Cefepime in Intensive Care Unit: Assessment of Steady-State Plasma Level and Incidence on Neurotoxicity.

Continuous infusion (CI) with high doses of cefepime is recommended in the empirical antimicrobial regimen of critically ill patients with suspected Gram-negative sepsis. This study aimed to determine factors associated with cefepime overdosing and the incidence of cefepime-induced neurotoxicity (CIN) in these patients. We performed a retrospective study including all patients receiving cefepime treatment between January 2019 and May 2022. The plasma level of cefepime defining overdosing was over 35 mg/L. Neurotoxicity was defined according to strict criteria and correlated with concomitant steady-state concentration of cefepime. Seventy-eight courses of cefepime treatment were analyzed. The mean cefepime plasma level at steady state was 59.8 ± 29.3 mg/L, and overdosing occurred in 80% of patients. Renal failure and a daily dose > 5 g were independently associated with overdosing. CIN was present in 30% of patients. In multivariate analysis, factors associated with CIN were chronic renal failure and a cefepime plasma concentration ≥ 60 mg/L. CIN was not associated with mortality. Overdosing is frequent in patients receiving high doses of cefepime by CI. Steady-state levels are higher than targeted therapeutic pharmacokinetic/pharmacodynamic objectives. The risk of CIN is important when the plasma concentration is ≥60 mg/L.

Use of therapeutic drug monitoring to characterize cefepime-related neurotoxicity.

Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime-related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN. This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration-time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity. Four hundred eighty-one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non-NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non-NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p= 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3-fold increased risk of CRN. Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.

Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study)

ObjectivesThis study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. MethodsSerial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (Cmin) of 8–20 mg/L. Six patients were enrolled, of which one was receiving renal replacement therapy. Cefepime was best described in a two-compartment model, with total body weight and creatinine clearance (CrCL) as significant predictors of PK parameters. The mean clearance and central volume of distribution were 2.42 L/h and 15.09 L, respectively. ResultsBased on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40–44% probability of efficacy (Cmin > 8 mg/L) and 1–6% toxicity (Cmin > 20 mg/L). Patients with CrCL 30 mL/min and 65 mL/min receiving 1 g 12-hourly dosing achieved an 84–92% and 46–53% probability of efficacy and 8–44% and 1–8% probability of toxicity, respectively. Simulations demonstrated a lower probability of efficacy and higher probability of toxicity with decreasing patient weight. ConclusionThis study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.

Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines

Background: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets. Methods: Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (Cmin), maximum serum concentration and area under the concentration–time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold. Results: In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758–0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%). Conclusions: The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with Cmin of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target.

Continuous infusion of cefepime and neurotoxicity: a retrospective cohort study

ObjectivesNeurotoxicity related to cefepime is increasingly reported in the literature but specific data concerning continuous infusion (CI) of the drug are still lacking. Our primary objective was to evaluate the incidence of neurotoxicity related to CI of cefepime and the associated risk factors. Our secondary objectives were to analyse the plasma cefepime concentrations and to define the threshold above which neurotoxicity occurs. MethodsIn this single-centre retrospective cohort study, all adult patients who underwent at least one cefepime therapeutic drug monitoring (TDM) and were treated with CI of 4 g/day between January 2017 and June 2019 were included. Neurotoxicity was evaluated according to a strict definition and was correlated with steady-state concentration at the time of toxicity presentation. ResultsNinety-eight patients with 201 cefepime TDM studies were included, with an incidence of neurotoxicity of 14.3% (14/98). Patients with neurotoxicity had more often underlying brain disease (35.7% (5/14) vs 11.9% (10/84), p = 0.030)) and higher steady-state concentrations (mean ± standard deviation 71.8 ± 32.9 mg/L vs 49.6 ± 30.6, p = 0.036) than the others. A receiver operating characteristic curve analysis yielded a cefepime steady-state concentration of 63.2 mg/L as the best cut-off point between patients with or without neurotoxicity. A mean steady-state concentration of 46.4 mg/L was achieved if the dosages of cefepime were adapted to renal function which was under our threshold concentration but above our highest pharmacokinetic/pharmacodynamic target of 32–40 mg/L. ConclusionsOur results suggest that 4 g/day of cefepime adapted to renal function and infused over 24 h is a trade-off for the risk/benefit ratio, when used empirically.

Neurotoxicity Despite a Renal Function-Adjusted Cefepime Regimen: A Case Study

An 83-year-old man, presenting decreased renal function (estimated glomerular filtration rate 21 mL/min/1.73 m), was treated for a bone and joint infection (on a trans-metatarsal right foot amputation) caused by Klebsiella Pneumonia sensitive to cefepime. The starting dose (1 g bid) was based on recommendations for patients presenting severe infections. One week after treatment initiation, the patient developed neurotoxicity, exhibiting extremely high plasma cefepime concentrations. Based on TDM, the dose was reduced by 8 times the original dose. This case report highlights the importance of therapeutic drug monitoring for cefepime, especially in patients presenting altered renal functions, as typical recommendations are estimated for standard patients.

A retrospective study to determine the cefepime-induced neurotoxicity threshold in hospitalized patients.

Cefepime-induced neurotoxicity (CIN) has been demonstrated to be associated with cefepime plasma concentrations; however, the toxicity threshold remains unclear. The primary objective of this study was to identify the cefepime plasma trough concentration at which neurotoxicity occurs. Secondary objectives were to determine the incidence of CIN at a large tertiary institution and to identify patient factors associated with the development of CIN. A retrospective review of all adult patients administered cefepime between October 2017 and May 2018 in a tertiary hospital was conducted to determine total incidence of CIN. A receiver operating characteristic (ROC) curve was constructed to review the sensitivity and specificity of using various cefepime trough plasma concentrations to predict the development of neurotoxicity. Cefepime plasma concentrations were measured using ultra-HPLC. A regression was conducted to identify patient factors associated with CIN. In total, 206 patients were administered 259 courses of cefepime, with an overall CIN incidence of 6% (16/259 courses). A total of 64 courses had a cefepime trough concentration measured (24.7%). A cefepime trough concentration of 36 mg/L provided the best differentiation between patients who experienced neurotoxicity and those who did not. No other patient covariates were identified to be significantly associated with neurotoxicity occurring. A cefepime trough plasma concentration ≥36 mg/L appears to be the most sensitive and specific cut-off to predict CIN occurring. No patient factors were associated with the development of CIN when accounting for cefepime trough plasma concentrations.

Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study

ObjectivesToxic serum cefepime trough concentrations are not well defined in the current literature. We aimed to define a more precise plasma trough concentration threshold for this antibiotic's neurological toxicity and to identify individuals at risk for developing neurotoxic side effects. MethodsRetrospective study including all individuals who underwent cefepime therapeutic drug monitoring (TDM) between 2013 and 2017. Individuals with cefepime concentrations other than trough were excluded. The primary outcome was to assess the incidence of neurotoxicity and its relationship with cefepime plasma trough concentrations. Secondary outcomes were the relationship of renal function, cefepime daily dose, age, and cerebral and general co-morbidities with the occurrence of neurotoxicity. We also compared the mortality rate during hospitalization in individuals with and without neurotoxicity, and the possible impact of neuroprotective co-medications on outcomes. ResultsCefepime concentrations were determined in 584 individuals. Among 319 individuals with available trough concentrations included, the overall incidence of neurotoxicity was 23.2% (74 of 319 individuals). Higher cefepime plasma trough concentrations were significantly associated with risk of neurotoxicity (no neurotoxicity 6.3 mg/L (interquartile range (IQR) 4.1–8.6) versus with neurotoxicity 21.6 mg/L (IQR 17.0–28.6), p <0.001). Individuals with presumed cefepime neurotoxicity had a significantly lower renal function (estimated glomerular filtration rate 82.0 mL/min/1.73 m2 (IQR 45.0–105.0) versus 35.0 mL/min/1.73 m2 (IQR 23.3–53.3], p <0.001), and significantly higher in-hospital mortality (19 (7.8%) versus 26 (35.1%) individuals, p <0.001). No neurotoxic side effects were seen below a trough concentration of 7.7 mg/L. Levels ≥38.1 mg/L always led to neurological side effects. ConclusionIn individuals with risk factors for cefepime neurotoxicity, such as renal insufficiency, TDM should be systematically performed, aiming at trough concentrations <7.5 mg/L.

1394. A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid (CSF) and Plasma Concentrations of Cefepime

BackgroundFor treatment of central nervous system infections caused by GNB, adequate cefepime concentrations are required in the cerebral spinal fluid (CSF) and brain. However, high plasma cefepime exposures have resulted in neurotoxicity. There is a need to understand the real-time pharmacokinetic (PK) relationship between plasma and CSF concentrations as serial CSF sampling is not regularly performed.MethodsMale Sprague-Dawley rats received cefepime via an internal jugular vein catheter. A total daily dose of 150 mg/kg/day was administered as a single injection every 24 hours for 4 days. Plasma samples (mean n = 5 per rat) was obtained via a second dedicated catheter, with up to five samples obtained on a single concentration–time curve. CSF sampling occurred via an intracisternal catheter, with up to two samples taken every 24 hours. Cefepime in plasma and CSF were quantified via LC–MS/MS. PK analyses were conducted using Pmetrics for R. Multiple physiologic compartmental models were fit, with the ultimate model selected by Akaike score and rule of parsimony. Each rat’s concentrations were predicted from the final model, and predictive performance was evaluated with bias and imprecision of the population and Bayesian posterior prediction models. PK parameters were estimated, and PK exposures during the first 24 hours (i.e., AUC0–24, CMAX0–24, CMIN0–24) were calculated for each rat from Bayesian posteriors.ResultsEleven rats contributed PK data. A three-compartment model fit the data well [Figure 1: Plasma, Population (a) and Bayesian (b); Figure 2: CSF, Population (a) and Bayesian (b)]. Population median parameter values (CV%) for rate constant (Ke), volume central compartment (V1), volume CSF compartment (V3), rate to/from central/peripheral compartment (KCP, KPC), rate to/from central/CSF compartment (K13, K31) were: 5.04 hour−1 (43.4%), 0.069 L (39.24%), 0.28 hour−1 (52.11%), 17.42 hour−1(34.83%), 0.32 hour−1 (165.3), 0.31 hour−1 (79.89), respectively. Noncompartmental analysis of the Bayesian posteriors revealed a plasma median half-life, AUC0–24, CMAX0–24, and CMIN0–24 of 2.6 hours, 158.1 mg hour/L, 189.3 mg/L, and 0.0003 mg/L from the first dose.ConclusionCefepime transit to the CSF is rapid and highly predictable in the rat model. This model will be highly useful for understanding neurotoxicity outcomes for cefepime. Disclosures J. Liu, Merck: Grant fund from Merck, Research grant.

299. Tolerance and Serum Concentration of Cefepime Used Subcutaneously (SC) in the Management of Bone and Joint Infections

BackgroundCefepime is a cephalosporin active against most Gram positive and negative bacteria and is used in the management of bone and joint infections (BJIs). Intravenous (IV) perfusion is the standard route of administration. The Subcutanoeous (SC) route may present an interesting alternative in case of outpatient care or when IV perfusion is not possible. The aim of this study was to demonstrate that the SC route of administation for cefepime provides effective serum concentrations in the treatment of BJIs without route-specific side effects.MethodsDescriptive analysis of a bi-center retrospective observational study from January 2011 to February 2017 in patients with an BJI treated with cefepime SC and who had a cefepime plasma level dosage. Cefepim Cmax and Cmin were considered optimal if they were superior to five MIC.ResultsEleven patients were included with 21 dosages of cefepime SC, 12 Cmax and nine Cmin. The mean age of the patients was 58 ± 17 years and the mean body mass index was 26.6 ± 5.6. Cefepime was used for the management of infections with at least one Gram-negative bacillus (GNB) (64% of infections were plurimicrobial). Combination with at least one other antibiotic was found in 68% of cases. The median Cmax and Cmin levels were 57 mg/L (39.5–124) and 14 mg/L (0–42), respectively. Cmax was above five MIC for all patient and Cmin was above this threshold in eight (80%) patients but still well above the MIC of GNB. No local complications related to the SC administration of cefepime has been described.ConclusionPlasma concentration during SC administration of cefepime seems to reach similar value to the IV route founded in the literature for BJI management. SC administration appears to be a well-tolerated alternative in the management of BJI. Further prospective clinical efficacy studies are needed.Disclosures All authors: No reported disclosures.

Analytical interference during cefepime therapeutic drug monitoring in intensive care patient: About a case report

β-lactams therapeutic drug monitoring (TDM) appears as an essential tool to ensure the achievement of pharmacokinetic-pharmacodynamic targets and prevent induced toxicity in intensive care unit patients. Indeed, those patients exhibit important pharmacokinetic variabilities that could lead to unpredictable plasma concentrations, potentially associated with poor clinical outcome, development of antibiotic resistance or increased side effects. Here, we report the case of a 48-year-old-patient admitted to intensive care unit and treated by cefepime using TDM. Due to inconsistency between observed cefepime plasma concentrations and patient clinical examination, investigations were started. After analytical tests, we highlighted an underlying analytical interference that overestimated cefepime plasma concentration with our in-house high performance liquid chromatography with ultraviolet detection (HPLC-UV) method. Only the inadequacy between plasmatic concentration and patient situation alerted pharmacologists and clinicians. As we found no previous case in literature, we believe this report must serve as an example of analytical limits that required pharmacologist awareness and expertise in TDM realization.

Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study

ObjectivesCefepime remains an important antibiotic for severe bacterial infections, yet some meta-analyses have shown elevated mortality among patients randomized to it. Therapeutic drug monitoring (TDM) of β-lactam antibiotics is increasing, but optimal plasma concentrations remain unknown. We examined clinical outcomes of patients undergoing cefepime TDM in an initial effort to define the drug's toxicity threshold. MethodsIn this single-centre retrospective cohort study, we enrolled all adult hospitalized patients receiving cefepime and undergoing TDM from January 2013 through July 2016. The primary outcome was the incidence of clinical toxicity; a secondary outcome was clinical failure. Plasma samples were analysed via high-performance liquid chromatography with ultraviolet detection. ResultsA total of 161 cefepime concentrations were drawn from 93 patients. Roughly half (82/161, 51%) and one-third (49/161, 30%) were trough and steady-state levels from patients receiving intermittent and continuous infusions, respectively; median concentrations were 17.6 mg/L (IQR 9.7-35.2) and 29.2 mg/L (IQR 18.9-45.9). Ten patients (11%) experienced a neurologic event considered at least possibly related to cefepime; neurotoxicity was associated with poorer renal function (median creatinine clearance 54 (IQR 39-97) vs. 75 mL/min/1.732 (IQR 44-104)) and longer cefepime durations (mean 8.3 (SD±6.7) vs. 13.3 days (± 14.2), p = 0.071). Patients with trough levels >20 mg/L had a fivefold higher risk for neurologic events (OR 5.05, 95% CI 1.3-19.8). ConclusionsNeurotoxicity potentially related to cefepime occurred at plasma concentrations >35 mg/L. For those receiving intermittent infusions, trough concentrations >20 mg/L should be avoided until further information is available from prospective studies.

Bioequivalence study of cefepime intramuscular injection

Abstract Background: Cefepime, a fourth generation cephalosporin, is a broad spectrum antibiotic effective against both Gram positive and Gram negative bacteria. It is available from several pharmaceutical firms in southeast Asia. We studied bioequivalence of two products. Objective: To assess the bioequivalence of two cefepime formulations: Cefamax 1 g intramuscular (Siam Pharmaceutical, Bangkok, Thailand) as the test formulation and Maxipime 1 g (Bristol-Myers Squibb, Bangkok, Thailand) as the reference formulation. Methods: The study was conducted as an open, randomized, two-period crossover trial with a 1 week washout period in 18 healthy volunteers. Each subject received a single dose of 1 g intramuscular injection of the test or reference formulation. Blood samples were collected via an intravascular catheter at several time points over a 12 h period. Plasma cefepime concentrations were quantified by HPLC with photodiode array detection at 280 nm. The statistical comparisons for pharmacokinetic parameters were made using a paired t test. Results: There was no significant difference in the logarithmically transformed values of Cmax, AUC0-12, and AUC0-∞ between Cefamax and Maxipime using an analysis of variance (ANOVA). The 90% confidence intervals (CIs) of Cmax, AUC0-12, and AUC0-∞ between the two formulations were 91.17-105.78, 90.29-97.63, and 88.89-96.57, respectively. All subjects had good tolerance and no serious adverse events were observed. Conclusion: Cefamax 1 g intramuscular formulation is bioequivalent to Maxipime 1 g intramuscular formulation based on 90% CIs for Cmax, AUC0-12, and AUC0-∞ within 80%-125%.

Continuous versus intermittent infusion of cefepime in neurosurgical patients with post-operative intracranial infections

Cefepime is administered as an intermittent infusion (II); however, continuous infusion (CI) may be advantageous because β-lactam antibiotics exhibit time-dependent antibacterial activity. This retrospective, non-randomised, comparative study included 68 neurosurgical patients with post-operative intracranial infections treated with 4g/day cefepime over 24h as a CI (n=34) or 2g every 12h as II (n=34). CI controlled the intracranial infection more rapidly and effectively than II (6.6±1.9 days vs. 7.8±2.6 days; P=0.036). By considering the minimum inhibitory concentrations (MICs) to be 4μg/mL and 8μg/mL, the percentage of time when the cefepime plasma or CSF concentrations were higher than the MIC (%T>MIC) was calculated for each patient. For plasma cefepime concentrations, the %T>MIC in the CI group was higher than in the II group (for MICs of 8μg/mL, 100% vs. 75%, respectively). The mean calculated area under the curve (AUC) in the CI group was similar to the II group (1197.99±72.15μgh/mL vs. 890.84±140.78μgh/mL; P=0.655). For CSF cefepime concentrations, the %T>MIC in the CI group was higher than in the II group (for MICs of 4μg/mL and 8μg/mL, 83.3% and 75% vs. 25% and 0%, respectively). The mean calculated AUC for the CI group was higher than the II group (220.56±13.59μgh/mL vs. 86.34±5.69μgh/mL; P=0.003). Therefore, CI of cefepime significantly enhanced the antibacterial effect and reduced the treatment duration in neurosurgical patients with post-operative intracranial infections.

Clinical and Electroencephalographic Assessment of Cefepime During Treatment of Nosocomial Infections in Neurological Patients

Cefepime neurotoxicity usually occurs in patients with renal impairment. The aim of this study was to evaluate the neurotoxicity of cefepime administered by continuous intravenous infusion during treatment of nosocomial infections in neurological patients with normal renal function. This was an open pilot study of neurological patients with infections caused by cefepime sensitive bacteria. Patients had baseline neurological assessment and electroencephalogram (EEG). Cefepime plasma concentrations were determined 48 hours after infusion was initiated and at end of treatment (EOT). Eleven patients were included. These were diagnosed with a brain tumor (9), cerebrovascular disease (1) and polyneuropathy (1). Infections were surgical site infection in 5, clinically defined nosocomial pneumonia in 4, and bacterial meningitis associated to postoperative CSF fistula in 2. Gram-negative organisms were isolated in 10 patients. Cefepime dose was 2 g/day in 9 patients and 4 g/day in 2. Mean cefepime plasma concentration at 48h was 13.6 ± 2.0 µg/mL (range 4.6 to 24.5 µg/mL), at EOT was 11.9 ± 1.8 µg/mL (range 3.0 to18.9 µg/mL ). EEG interpreted by two experts showed at baseline alpha background rhythm in 5 and theta-alpha rhythm in 6 patients. On EEG at EOT background rhythm was alpha in 4 and theta-alpha in 7, one patient presented isolated sharp and slow wave activity. No mental status changes or seizures occurred and all infections resolved. Significant EEG change was observed in 1of 11 patients. A preserved mental status may correlate with cefepime safety in neurological patients with normal renal function during cefepime treatment.

High Cefepime Plasma Concentrations and Neurological Toxicity in Febrile Neutropenic Patients with Mild Impairment of Renal Function

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.