Prospective assessment of breakthrough infections and neurotoxicity and their association with cefepime trough concentrations in patients with febrile neutropenia.

Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) and free cefepime trough concentration were 101 (85-112) mL/min/1.73m2 and 8.6 (4.9-16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P < 0.001). This study provides real-world clinical data showing that high cefepime dosage is efficacious and safe in FN patients. Routine TDM does not appear to be needed in FN patients with preserved renal function. However, TDM might be reserved for FN patients at high risk of cefepime-induced neurotoxicity or when intended to cover pathogens with a minimum inhibitory concentration >1 mg/L.

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

OBJECTIVES: This 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. METHODS: Serial 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. RESULTS: Based 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. CONCLUSION: This 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.

A case of recovery from aphasia following dose reduction of cefepime by bayesian prediction-based therapeutic drug monitoring.

Cefepime is known to exert bactericidal activity against Pseudomonas aeruginosa. Cefepime-induced neurotoxicity, most likely caused by increased exposure, has recently become a major concern in clinical practice; therefore, appropriate dose reduction of cefepime should be applied with respect to patients with low cefepime clearance (mostly eliminated by the kidneys). Here, we report a case in which Bayesian prediction-based therapeutic drug monitoring (Bayes-TDM) was effectively used to reduce the dose of cefepime in a patient with pneumonia to prevent neurotoxic complications. A woman (age: 59 years, body weight: 32.5 kg, serum creatinine concentration: 1.02 mg/dL) developed pneumonia caused by P. aeruginosa while receiving treatment for scleroderma and systemic lupus erythematosus. She started treatment with a dosing regimen of 1.0 g of cefepime every 8 h (day X). On day X+5, aphasia developed, and the serum cefepime concentration was 71.3 mg/L at trough. This concentration was twice or thrice higher than the reported safe concentration of cefepime (22 or 35 mg/L at trough). Therefore, we reduced the dose of cefepime to 0.5 g every 12 h using Bayes-TDM from day X+7. As a result, the severity of aphasia decreased by day X+10, and this dose was successfully continued up to day X+13 without further adjustment. In conclusion, individualizing doses by Bayes-TDM may be useful in preventing adverse effects associated with cefepime treatment.

Measurement uncertainty of ß-lactam antibiotics results: estimation and clinical impact on therapeutic drug monitoring.

Background Despite that measurement uncertainty data should facilitate an appropriate interpretation of measured values, there are actually few reported by clinical laboratories. We aimed to estimate the measurement uncertainty of some ß-lactam antibiotics (ß-LA), and to evaluate the impact of reporting the measurement uncertainty on clinicians' decisions while guiding antibiotic therapy. Methods Measurement uncertainty of ß-LA (aztreonam [ATM], cefepime [FEP], ceftazidime [CAZ], and piperacillin [PIP]) values, obtained by an UHPLC-MS/MS based-method, was estimated using the top-down approach called the single laboratory validation approach (EUROLAB guidelines). Main uncertainty sources considered were related to calibrators' assigned values, the intermediate precision, and the bias. As part of an institutional program, patients with osteoarticular infections are treated with ß-LA in continuous infusion and monitored to assure values at least 4 times over the minimal inhibitory concentration (4×MIC). We retrospectively evaluated the impact of two scenarios of laboratory reports on clinicians' expected decisions while monitoring the treatment: reports containing only the ß-LA values, or including the ß-LA coverage intervals (ß-LA values and their expanded measurement uncertainties). Results The relative expanded uncertainties for ATM, FEP, CAZ and PIP were lower than 26.7%, 26.4%, 28.8%, and 25.5%, respectively. Reporting the measurement uncertainty, we identified that clinicians may modify their decision especially in cases where 4×MIC values were within the ß-LA coverage intervals. Conclusions This study provides a simple method to estimate the measurement uncertainty of ß-LA values that can be easily applied in clinical laboratories. Further studies should confirm the potential impact of reporting measurement uncertainty on clinicians' decision-making while guiding antibiotic therapy.

Meropenem, Cefepime, and Piperacillin Protein Binding in Patient Samples.

BACKGROUND: The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the available therapeutic options is required. Beta-lactams are time-dependent antibiotics and their efficacy is determined by the amount of time the free concentration remains above the minimum inhibitory concentration. Therefore, the aim of this study was to assess the extent and variability of protein binding for meropenem, cefepime, and piperacillin. METHODS: Plasma samples for the analysis of meropenem, cefepime, and piperacillin were collected from patients admitted to a tertiary care hospital as part of the standard care. The bound and unbound drug fractions in the samples were separated by ultrafiltration. Validated liquid chromatography-tandem mass spectrometry assays were used to quantify the total and free plasma concentrations, and the protein binding was determined. RESULTS: Samples from 95 patients were analyzed. The median (range) age of patients was 56 years (17-87) and the median (range) body mass index was 25.7 kg/m (14.7-74.2). Approximately 59% of the patients were men. The median (range) unbound fraction (fu) was 62.5% (41.6-99.1) for meropenem, 61.4% (51.6-99.2) for cefepime, and 48.3% (39.4-71.3) for piperacillin. In the bivariate analysis, as the total meropenem concentration increased, the fu increased (r = 0.37, P = 0.045). A decrease in piperacillin fu was observed as the albumin concentration increased (r = -0.56, P = 0.005). CONCLUSIONS: The average fu values were lower than those reported in the literature. There was also a large variability in fu; hence, it should be considered when managing patients administered with these drugs through direct measurements of free drug concentrations.

Development and validation of a volumetric absorptive microsampling- liquid chromatography mass spectrometry method for the analysis of cefepime in human whole blood: Application to pediatric pharmacokinetic study.

Cefepime is a fourth-generation cephalosporin antibiotic with an extended spectrum of activity against many Gram-positive and Gram-negative bacteria. There is a growing need to develop sensitive, small volume assays, along with less invasive sample collection to facilitate pediatric pharmacokinetic clinical trials and therapeutic drug monitoring. The volumetric absorptive microsampling (VAMS™) approach provides an accurate and precise collection of a fixed volume of blood (10 µL), reducing or eliminating the volumetric blood hematocrit assay-bias associated with the dried blood spotting technique. We developed a high-performance liquid chromatographic method with tandem mass spectrometry detection for quantification of cefepime. Sample extraction from VAMS™ devices, followed by reversed-phase chromatographic separation and selective detection using tandem mass spectrometry with a 4 min runtime per sample was employed. Standard curves were linear between 0.1-100 µg/mL for cefepime. Intra- and inter-day accuracies were within 95.4-113% and precision (CV) was < 15 % based on a 3-day validation study. Recoveries ranged from 40.8 to 62.1% and the matrix effect was within 89.5-96.7% for cefepime. Cefepime was stable in human whole blood under assay conditions (3 h at room temperature, 24 h in autosampler post-extraction). Cefepime was also stable for at least 1 week (7 days) at 4 °C, 1 month (39 days) at -20 °C and 3 months (91 days) at -78 °C as dried microsamples. This assay provides an efficient quantitation of cefepime and was successfully implemented for the analysis of whole blood microsamples in a pediatric clinical trial.

Target-Controlled Infusion of Cefepime in Critically Ill Patients.

Attainment of appropriate pharmacokinetic-pharmacodynamic (PK-PD) targets for antimicrobial treatment is challenging in critically ill patients, particularly for cefepime, which exhibits a relative narrow therapeutic-toxic window compared to other beta-lactam antibiotics. Target-controlled infusion (TCI) systems, which deliver drugs to achieve specific target drug concentrations, have successfully been implemented for improved dosing of sedatives and analgesics in anesthesia. We conducted a clinical trial in an intensive care unit (ICU) to investigate the performance of TCI for adequate target attainment of cefepime. Twenty-one patients treated with cefepime according to the standard of care were included. Cefepime was administered through continuous infusion using TCI for a median duration of 4.5 days. TCI was based on a previously developed population PK model incorporating the estimated creatinine clearance based on the Cockcroft-Gault formula as the input variable to calculate cefepime clearance. A cefepime blood concentration of 16 mg/liter was targeted. To evaluate the measured versus predicted plasma concentrations, blood samples were taken (median of 10 samples per patient), and total cefepime concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. The performance of the TCI system was evaluated using Varvel criteria. Half (50.3%) of the measured cefepime concentrations were within ±30% around the target value of 16 mg liter-1 The wobble was 11.4%, the median performance error (MdPE) was 21.1%, the median absolute performance error (MdAPE) was 32.0%, and the divergence was -3.72% h-1 Based on these results, we conclude that TCI is useful for dose optimization of cefepime in ICU patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02688582.).

[Cefepime-induced encephalopathy]. / Encéphalopathie au céfépime.

Since 2017 the world suffers from a piperacillin/tazobactam shortage. Cefepime is then proposed as a broad spectrum antibiotic alternative. Up to 15 % of the patients under treatment develop neurotoxicity, mostly in kidney failure settings. Cefepime serum concentration and electroencephalogram guide diagnosis. Treatment consists in withholding or reducing the dose. Most of the patients recover without neurologic sequelae.

Depuis 2017, une pénurie de pipéracilline/tazobactam sévit dans le monde. Le céfépime est proposé comme alternative antibiotique à large spectre. Lors de l'utilisation de cet antibiotique, jusqu'à 15% des patients traités développent une neurotoxicité, se produisant majoritairement en cas d'insuffisance rénale. Le taux sérique et l'électroencéphalogramme permettent d'orienter le diagnostic. La diminution de la posologie, voire l'arrêt du traitement suffisent à corriger les symptômes et les patients ne gardent en général pas de séquelles neurologiques.

Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of enmetazobactam and cefepime in human plasma.

A simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous analysis enmetazobactam (also known as AAI101) and cefepime in human plasma. Sample preparation was based on protein precipitation with acetonitrile. Separation was performed on Acquity BEH HILIC column (50 mm × 2.1 mm, 1.7 µm) with a mobile phase containing ammonium formate in water and acetonitrile. The analytes were analyzed with the corresponding isotopically labeled internal standards and were detected in multiple reactions monitoring (MRM) using API 5000 triple-quadrupole mass spectrometer with electrospray (ESI) source operating in positive ion mode. The calibration curves were linear over the selected ranges (r > 0.9970 for both analytes). The intra and inter-assay precision of the Quality Control samples showed CV ≤ 15% and the accuracy was within 85 and 115% in all cases for both compounds. The lower limit of quantification was 0.05 µg/mL for enmetazobactam and 0.5 µg/mL for cefepime.

Beta-lactam carryover in arterial and central venous catheters is negligible.

BACKGROUND: Therapeutic drug monitoring is used for aminoglycosides and vancomycin, and has been proposed for ß-lactam antibiotics. Clinical blood samples in the ICU are often obtained via an existing vascular catheter rather than fresh needle phlebotomy. If antibiotics had previously been infused through a vascular catheter then used for blood sampling, carryover of antibiotic from the infusion to the sample might result in misleading assessments of target attainment. To address this concern we conducted a series of in vitro measurements of carryover for three commonly used antibiotics. METHODS: We infused piperacillin-tazobactam, meropenem, and cefepime at pharmacologic concentrations through commonly used vascular catheters at our hospital and flushed the catheters. We then aspirated warmed citrated bovine blood through each catheter and measured antibiotic concentrations in each aspirate. RESULTS: Carryover was below the limits of detection for piperacillin-tazobactam, meropenem, and vancomycin. Cefepime carryover, in contrast, was not negligible and needs to be investigated more fully. CONCLUSION: Carryover from prior infusions does not appear to jeopardize measurements of piperacillin-tazobactam, meropenem, or vancomycin in commonly used vascular catheters at our institution. Caution in interpreting samples obtained for cefepime measurements appears advised until more data is available.

Quantification of Cefepime, Meropenem, Piperacillin, and Tazobactam in Human Plasma Using a Sensitive and Robust Liquid Chromatography-Tandem Mass Spectrometry Method, Part 1: Assay Development and Validation.

The highly variable pharmacokinetics of ß-lactam antibiotics and ß-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of plasma concentrations is important for individualization of antimicrobial therapy. Accordingly, a simple and robust analytical method for the simultaneous measurement of multiple ß-lactam antibiotics and ß-lactamase inhibitors is highly desirable to ensure quick decisions on dose adjustments. In this study, a sensitive, simple, and robust method for the simultaneous quantification of cefepime, meropenem, piperacillin, and tazobactam in human plasma was developed and rigorously validated according to FDA guidance. Sample extraction was accomplished by simple protein precipitation. Chromatographic separation of analytes was achieved using stepwise gradient elution. Analytes were monitored using tandem mass spectrometry (MS/MS) with a turbo ion spray source in positive multiple-reaction-monitoring mode. The calibration curve ranged from 0.5 to 150 µg/ml for cefepime, 0.1 to 150 µg/ml for meropenem and piperacillin, and 0.25 to 150 µg/ml for tazobactam. Inter- and intraday precision and accuracy, sensitivity, selectivity, dilution integrity, matrix effect, extraction recovery, and hemolysis effect were investigated for all four analytes, and the results met the acceptance criteria. Compared to other reported methods, our method is more robust because of the combination of the following features: (i) a simple sample extraction procedure, (ii) a short sample run time, (iii) a wide dynamic range, and (iv) the small plasma sample volume needed. Since our method already covers ß-lactams and a ß-lactamase inhibitor with highly heterogeneous physicochemical properties, further antibiotic candidates may easily be incorporated into this multianalyte method.

A Randomized Pharmacokinetic and Pharmacodynamic Evaluation of Every 8-Hour and 12-Hour Dosing Strategies of Vancomycin and Cefepime in Neurocritically ill Patients.

PURPOSE: Neurocritically ill patients have clinically significant alterations in pharmacokinetic parameters of renally eliminated medications that may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations. METHODS: We conducted a prospective randomized open-label study of adult neurocritically ill patients treated with vancomycin and cefepime. Vancomycin 15 mg/kg and cefepime 2 g were dosed at every-8- or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic (PD) targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT > MIC ≥ 60%) for ß-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin. RESULTS: Twenty patients were included in the study. They were divided equally between the every-12-hour and every-8-hour dosing groups. Patients (mean age 51.8 ± 11 yrs) were primarily male (60%) and white (95%), and most had an admission diagnosis of intracranial hemorrhage (80%). Compared with the every-12-hour group, the every-8-hour vancomycin group achieved target trough concentrations (higher than 15 µg/ml) significantly more frequently at initial measurement (0% vs 80%, p<0.01) and at 7-10 days (0% vs 90%, p=0.045) and achieved PD targets more frequently at increasing MICs. Similarly, compared with every-12-hour dosing, the every-8-hour cefepime dosing strategy significantly increased PD target attainment (fT > MIC ≥ 60%) at an MIC of 8 µg/ml (20% vs 70%, p=0.02). CONCLUSIONS: This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal PD targets in adult neurocritically ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance.

Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects.

WCK 5222 is a combination of cefepime and the novel ß-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug (Cmax) and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC0-8 values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC0-8 values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.