Cefepime exposure in prolonged or intermittent infusion in critically ill children

Cefepime exposure in prolonged or intermittent infusion in critically ill children | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 29 July 2025 V1 Latest version Share on Cefepime exposure in prolonged or intermittent infusion in critically ill children Authors : Marc Hobeika 0009-0009-2907-6387 [email protected] , Déborah Hirt , Emmanuelle Bille , Sihem Benaboud , Julie Toubiana , Pierre-Louis Léger , Jérôme Rambaud , … Show All … , agathe beranger , Delphine Callot , Sylvain Renolleau , Jean-Marc Tréluyer 0000-0002-2045-4742 , Mehdi Oualha 0000-0002-0488-5948 , and Noémie De Cacqueray 0009-0002-4280-4683 Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.175381766.64058132/v1 357 views 164 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Introduction : Cefepime is commonly used in critically ill children for whom there is a high between subject variability. To reach the therapeutic pharmacokinetic (PK) target in critically ill patients, beta-lactams prolonged infusion seems to be the most efficient. The aim of this study was to compare cefepime exposure between prolonged and intermittent infusions in critically ill children. Methods : This prospective observational study was conducted in two pediatric intensive care units. Children with a cefepime plasma concentration measurement were included. Steady-state free residual and plateau concentrations were estimated using Bayesian forecasting. The PK target was defined as 100% f T ≥4xMIC . Exposure was compared using the minimum inhibitory concentrations (MIC) of the pathogens identified in the patients. The probability of target attainment (PTA) was also compared using various MICs. Results : Seventy-eight antibiotic courses in 75 patients were included, divided into 19 prolonged infusions and 59 intermittent infusions. Prolonged and intermittent infusions were comparable for optimal exposure (n=10/19, 53% vs n=35/59, 59%, p=0.79). Overexposure tended to be more frequent with prolonged infusion (n=8/19, 42% vs n=16/59, 27%, p=0.26), while underexposure tended to be less common with prolonged infusion (n=1/19, 5% vs n=8/59, 14%, p=0.44). Considering the wide range of MICs, the PTA was comparable for MIC < 1 mg/L, but was significantly higher for prolonged infusion for MIC ≥ 1 mg/L (p<0.05). Conclusion : Prolonged infusion of cefepime provides a higher PTA when MIC is ≥ 1 mg/L compared with intermittent infusion. This result suggests the superiority of prolonged infusion for high MIC bacteria. Cefepime exposure in prolonged or intermittent infusion in critically ill children Marc Hobeika 1 , Deborah Hirt 2,3 , Emmanuelle Bille 4, 5 , Sihem Benaboud 2 , Julie Toubiana 6 , Pierre-Louis Léger 7 , Jérôme Rambaud 7 , Agathe Béranger 1, 3 , Delphine Callot 8 , Sylvain Renolleau 1 , Jean-Marc Treluyer 2, 3 , Mehdi Oualha 1, 3 , Noémie de Cacqueray 1, 3 1 Department of Pediatric Intensive Care, Necker-Enfants Malades Hospital, AP-HP.Centre, Université Paris Cité, Paris, Ile-de-France, France 2 Department of Clinical Pharmacology, Cochin Hospital, Paris, Ile-de-France, France 3 INSERM UMR1343 Pharmacology and Therapeutics Evaluation for Children and Pregnant Women, Paris, Ile-de-France, France 4 Department of Clinical Microbiology, Necker-Enfants Malades Hospital, APHP, Ile-de-France, France 5 INSERM U1151 CNRS UMR8253, Paris, Ile-de-France, France 6 Department of General Pediatrics and Pediatric Infectious Diseases, Necker-Enfants Malades Hospital, Paris, Ile-de-France, France 7 Department of Pediatric Intensive Care, Armand Trousseau Hospital, APHP, Sorbonne Université, Paris, Ile-de-France, France 8 Regional Pharmacovigilance Center, Cochin Hospital, Paris, Ile-de-France, France Abstract Introduction : Cefepime is commonly used in critically ill children for whom there is a high between subject variability. To reach the therapeutic pharmacokinetic (PK) target in critically ill patients, beta-lactams prolonged infusion seems to be the most efficient. The aim of this study was to compare cefepime exposure between prolonged and intermittent infusions in critically ill children. Methods : This prospective observational study was conducted in two pediatric intensive care units. Children with a cefepime plasma concentration measurement were included. Steady-state free residual and plateau concentrations were estimated using Bayesian forecasting. The PK target was defined as 100% f T ≥4xMIC . Exposure was compared using the minimum inhibitory concentrations (MIC) of the pathogens identified in the patients. The probability of target attainment (PTA) was also compared using various MICs. Results : Seventy-eight antibiotic courses in 75 patients were included, divided into 19 prolonged infusions and 59 intermittent infusions. Prolonged and intermittent infusions were comparable for optimal exposure (n=10/19, 53% vs n=35/59, 59%, p=0.79). Overexposure tended to be more frequent with prolonged infusion (n=8/19, 42% vs n=16/59, 27%, p=0.26), while underexposure tended to be less common with prolonged infusion (n=1/19, 5% vs n=8/59, 14%, p=0.44). Considering the wide range of MICs, the PTA was comparable for MIC < 1 mg/L, but was significantly higher for prolonged infusion for MIC ≥ 1 mg/L (p<0.05). Conclusion : Prolonged infusion of cefepime provides a higher PTA when MIC is ≥ 1 mg/L compared with intermittent infusion. This result suggests the superiority of prolonged infusion for high MIC bacteria. Key words : continuous infusion, beta-lactam, pharmacokinetics, pediatric intensive care unit Running title: Prolonged vs intermittent Cefepime in Children Corresponding author: Marc Hobeika, [email protected] PI statement: The authors confirm that the PI for this paper is Noémie de Cacqueray and that she had direct clinical responsibility for patients. Word count: 2742 Data availability: The dataset generated and analyzed during the current study is available from the corresponding author on reasonable request. What is known about this subject Pharmacokinetic research suggest that prolonged beta-lactam infusion increases the likelihood of reaching maximal bactericidal activity by enhancing the duration above the target concentration. However, prolonged infusion of cefepime is still rarely used in pediatric intensive care unit. What this study adds Overexposure tended to be more frequent with prolonged infusion of cefepime, while underexposure tended to be less common with prolonged infusion. Prolonged infusion of cefepime provides a higher probability of target attainment when MIC is ≥ 1 mg/L compared with intermittent infusion. This suggests the superiority of prolonged infusion for high MIC bacteria. Abbreviations CRP: C-reactive protein ECMO: extracorporeal membrane oxygenation ECOFF: epidemiological cut-off eGFR: estimated glomerular filtration rate EUCAST: European Committee on Antimicrobial Susceptibility Testing MIC: minimum inhibitory concentration PELOD: Pediatric Logistic Organ Dysfunction PICU: pediatric intensive care unit PK: pharmacokinetic PTA: probability of target attainment RRT: renal replacement therapy Introduction Cefepime is a fourth-generation cephalosporin commonly used in pediatric intensive care units (PICUs) to treat Gram-negative bacterial infections, including Pseudomonas aeruginosa . Recent guidelines have also recommended cefepime as a first-line empirical antibiotic therapy in febrile patients with neutropenia (1). In critically ill patients, pathophysiologic changes and therapeutic interventions affect drugs pharmacokinetics (PK), leading to changes in volume of distribution and clearance. Patients undergo unpredictable within and between subject variability that may limit the PK target attainment (2). In children, organ growth and maturation also contribute to PK variabilities (3). Therefore, specific PK studies of anti-infective agents in PICU are needed to optimize dosing regimens (4). The latest guidelines on pediatric sepsis management recommend antibiotics therapeutic drug monitoring to achieve maximal effect while minimizing toxicity (5). Underexposure can lead to therapeutic failure, prolonged organ dysfunction, and development of antimicrobial resistance, while overexposure carries the risk of drug toxicity (5). Beta-lactams have a time-dependent antimicrobial activity, with efficacy depending on the percentage of time the free plasma concentration remains above the minimum inhibitory concentration (MIC) (% f T ≥MIC ). Several targets are described in the literature. Recent guidelines recommend an aggressive PK target of 100% f T ≥4xMIC in critically ill patients to optimize clinical efficacy and prevent the selection of resistant bacteria (6). PK research suggest that prolonged beta-lactam infusion (continuous or extended) increases the likelihood of reaching maximal bactericidal activity by enhancing the duration above the target concentration (7,8). Pediatric studies have shown improved PK profiles under continuous infusion for beta-lactams such as cefotaxime, piperacillin, meropenem and cefazolin (9,10). However, prolonged infusion is still rarely used in PICU (11). The aim of the present study was to compare cefepime PK exposure in critically ill children between prolonged and intermittent infusions. Patients and settings This prospective observational study was conducted in two PICUs at the Necker-Enfants Malades and Armand Trousseau hospitals (Paris, France), from September 2015 to July 2023. All children under 18 years of age and weighing more than 3 kg who received cefepime and had at least one cefepime concentration measurement were eligible for inclusion. Patients receiving renal replacement therapy (RRT) at the time of treatment were excluded. Only the first cefepime measurement after treatment initiation was analyzed, to assess the exposure obtained with the initial dosing. Patients who received several courses of cefepime, separated by at least one week, could be included more than once. Collected demographic and clinical data were sex, age, weight, height, length of PICU stay, occurrence of death during hospitalization, mechanical ventilation, hemodynamic support with vasopressors, extracorporeal membrane oxygenation (ECMO), serum creatinine (µmol/L), albumin levels (g/L), and C-reactive protein (CRP, mg/L). The number of organ dysfunctions according to Goldstein et al. (12), and the Pediatric Logistic Organ Dysfunction (PELOD) score were calculated (13). Creatinine clearance was estimated using the 1976 Schwartz formula (14). Augmented renal clearance was defined by an estimated glomerular filtration rate (eGFR) greater than 140 mL/min/1.73m² (15). Bacteriological data were infection site, identified pathogen, and MIC (mg/L) for cefepime if available. Pharmacological data were dosing regimen, time and duration of infusion, and time of cefepime concentration measurement. Each patient’s medical records were searched for adverse events attributed to cefepime and the pharmacovigilance database was queried. Minimal inhibitory concentration Cefepime MICs were determined for the isolated pathogens by the E-test methodology (Etest® by bioMérieux™) in the microbiology laboratories at Necker-Enfants Malades University Hospital (Paris, France). For pathogens without an available MIC, we used epidemiological data from EUCAST (European Committee on Antimicrobial Susceptibility Testing) and considered the epidemiological cut-off (ECOFF) value for cefepime (16). In the absence of an identified pathogen, we considered the treatment to be empirical. Antibiotic administration and concentration measurement Cefepime (1g, Mylan TM ) was supplied as a powder and reconstituted in normal saline (Baxter TM ) to obtain a diluted solution of 100 mg/mL. The type of infusion (intermittent or prolonged) was at the physician’s discretion, guided by local practices and patient’s characteristics. The two comparison groups were defined as follows: intermittent infusions (i.e. infusion < 3 hours) and prolonged infusions, which include continuous infusions and extended infusions (i.e. infusion ≥ 3 hours). Routinely collected plasma samples were assayed for cefepime, regardless of the time since last administration. Blood samples (1.5 mL in heparinized tube) were centrifuged (4,000 g, 5 min) then frozen at -80°C until analysis. Cefepime was quantified by high-performance liquid chromatography coupled with mass spectrometry detection. Interpretation of the concentration Total plasma concentrations enabled to estimate steady-state free residual or plateau concentrations, for intermittent or prolonged infusions respectively. We used a Bayesian approach based on a previously published population PK model in critically ill children (17), assuming a protein binding of 20% (18). NONMEM software (version 6.2) was used for the Bayesian estimation. The steady-state free cefepime concentration equation was: \begin{equation} & f_{\text{ss}}=\ 0,8\ \times\ \frac{\text{Ds}}{T_{\inf}}\times\frac{1}{V\times k10}\times\left(1-\ e^{-\left(k10\times T_{\inf}\right)}\right)\ \times\frac{e^{-k10(Tho-T_{\inf})}}{\left(1-\ e^{-\left(k10\times Tho\right)}\right)\ } & \nonumber \\ \end{equation} where Ds is the dose received, T inf is the infusion duration, V is the volume of distribution, k10 is the elimination rate constant, and Tho is the interval between two infusions. Based on the estimated free plasma concentrations, cefepime exposure was assessed according to two targets: - By comparing exposure levels defined as follows; (i) underexposure corresponded to free residual or plateau concentration < 4xMIC, (ii) overexposure corresponded to concentration above toxicity thresholds, and (iii) optimal exposure when concentration was within the therapeutic range. The toxicity thresholds for cefepime were 22 and 35 mg/L for residual and plateau total concentrations, respectively (19–21). Assuming a protein binding of 20% (18), the toxicity thresholds for free concentrations were 17.6 and 28 mg/L for residual and plateau concentrations respectively. PK targets used the MIC of the identified pathogen or, failing that, its ECOFF. In case of empirical treatment, ECOFF of P. aeruginosa (8 mg/L), which represents the least favorable situation, could not be retained, as the PK target (4 x 8 = 32 mg/L) would be higher than the toxicity thresholds. Thus, we assigned to empirical treatments the clinical breakpoint for Enterobacterales (1 mg/L), as it covered all Enterobacterales and other pathogens commonly targeted by cefepime apart from P. aeruginosa . It should be noted that documented P. aeruginosa infections retained their measured MIC or, failing that, the ECOFF of 8 mg/L. - By comparing the probability of target attainment (PTA) of the study cefepime concentrations according to various given MICs, using 100% f T ≥4xMIC . Statistical analysis Discrete variables were expressed as numbers (percentages), continuous variables as medians and ranges (min-max). Statistical comparisons were made using Fisher’s exact test or the Mann-Whitney U test, depending on the variables. A p-value < 0.05 was considered statistically significant. Ethics The study was approved by the institutional review board at Necker-Enfants-Malades University Hospital (CPP Ile-de-France, Paris 7/06/2015) and was registered at www.clinicaltrials.gov (NCT02539407). Consent was obtained from each child’s parent(s) before inclusion in the study. The research was conducted in accordance with the Declaration of Helsinki Results Patients Over the study period, 94 cefepime courses with at least one plasma concentration measurement were performed. Of these, 16 were excluded because the patient underwent RRT. Of the 78 cefepime courses included, 19 (24%) cefepime courses in 19 patients were administered using prolonged infusions, and 59 (76%) cefepime courses in 56 patients were administered with intermittent infusions. The flow chart is shown in Figure 1. Patient characteristics and antibiotic courses are shown in Table 1. Figure 1: Flow chart Table 1: Characteristics of the patients and antibiotic courses Demographic data Sex ratio M/F 38/40 10/9 28/31 0.79 Age (month) 12.25 (0.5-214) [3.7-89.4] 89.4 (1-214) [7-153] 10.7 (0.5-210.5) [3.5-58.5] 0.080 Age < 1 year, n 37 (47%) 7 (37%) 30 (51%) 0.31 Weight, kg 8.5 (3-61) [5.1-23] 13.9 (4.2-51) [6.64-34] 6.4 (3-61) [4.5-15] 0.024 Clinical data Organ dysfunction, n 2 (0-6) [1-2] 1 (0-6) [0-2] 2 (0-4) [1-2] 0.04 PELOD score 1.5 (0-22) [1-10] 2 (0-13) [0-10] 1 (0-22) [1-10] 0.84 Mechanical ventilation, n 53 (68%) 11 (58%) 42 (71%) 0.40 Vasopressors, n 19 (24%) 2 (11%) 17 (29%) 0.13 ECMO, n 4 (5%) 1 (5%) 3 (5%) 1 Length of stay in PICU, days 28.5 (4-393) [19-60] 22 (4-227) [9-97] 29 (4-393) [19-54] 0.63 Death, n 13 (17%) 1 (5%) 12 (20%) 0.17 Biological data Serum creatinine level, µmol/L 20 (9-156) [15-31] 21 (13-156) [19-32] 18 (9-154) [14-28] 0.06 eGFR, mL/min/1.73m² 166 (12-867) [110-224] 174 (12-394) [117-262] 161 (46-867) [109-213] 0.63 eGFR 140 mL/min/1.73m², n 49 (63%) 12 (63%) 37 (63%) 1 Serum albumin level, g/L 28 (15-43) [23.7-34] 27 (16-37.3) [23.2-31.2] 28.5 (15-43) [23.9-34.2] 0.16 Bacteriological data Documented infections, n 57 (73%) 14 (74%) 43 (73%) 1 Measured MIC/ECOFF, mg/L 0.125 (0.047-8) [0.125-0.19] 0.157 (0.064-8) [0.094-1.5] 0.125 (0.047-8) [0.125-0.125] 0.27 Pharmacological data Daily dosing, mg/kg/day 144 (50-200) [114-150] 103 (50-200) [100-147] 147 (84-163) [126-150] 0.08 n: number; IQR: Interquartile range; PELOD: Pediatric Logistic Organ Dysfunction; ECMO: Extra-corporeal Membrane Oxygenation; PICU: pediatric intensive care unit; eGFR: estimated glomerular filtration rate using the Schwartz 1976 formula; MIC: Minimum inhibitory concentration; ECOFF: Epidemiological cut-off In patients receiving intermittent infusion, median weight was lower (p=0,024), and the age tended to be lower. Beside the number of organ dysfunctions, patients had similar markers of severity in the two groups. Patients receiving prolonged infusions tended to have lower daily doses of cefepime (103 vs 147 mg/kg/day, p=0.08). Of the 19 prolonged infusions, 18 were continuous infusions and 1 was an extended infusion with a duration of administration of 3 hours every 8 hours. Of the 18 continuous infusions, 15 (83%) were preceded by a loading dose. Among the 59 intermittent infusions, the median (range) infusion duration was 20 (10-180) minutes, and the intervals between two infusions were 8 hours (n=52, 88%), 6 hours (n=3, 5%), 12 hours (n=3, 5%), and 24 hours (n=1, 2%). One patient received a 180-minute infusion but with a 24-hour interval between infusions and was therefore classified as an intermittent infusion. Infection characteristics Infection was documented for 57/78 (73%) cefepime courses. For each documented infection, one or more pathogens were identified. A total of 67 pathogens were identified (Table S1). The most common documented infections were respiratory (n=27, 47%) and bacteremia (n=19, 33%) (Figure S1). Of the 67 identified germs, the most common were: Enterobacter cloacae (n=32, 48%), Klebsiella pneumoniae (n=9, 13%), Pseudomonas aeruginosa (n=7, 10%), and Serratia marcescens (n=6, 9%). Among non-empirical treatments, MIC/ECOFF values were low and comparable between the two groups (0.157 vs. 0.125 mg/L for prolonged and intermittent infusion, respectively; p=0.27). The distribution of MICs/ECOFFs is shown in Figure S2. Of the 57 MICs/ECOFFs available, 47 (82%) were below 1 mg/L. Of the 10 MICs ≥ 1 mg/L, 7 (70%) concerned P. aeruginosa infections. Compared to patients with low MIC germ (i.e. < 1 mg/L), patients whose identified pathogen had high MIC (≥ 1mg/L) tended to have longer ICU stays (median of 65.5 vs 29 days, p=0.18). No difference was found in terms of mortality rate. Cefepime exposure Estimated free concentrations were higher for prolonged infusion at the plateau than residuals for intermittent infusion (median (range) 25.9 mg/L (7.1-70.1) vs 7.8 mg/L (1.1-88.6), p<0.001), as expected based on PK principles and despite lower daily dosing. Comparison of daily dosing-adjusted free concentrations between each group is shown in Figure S3. The comparison of exposure levels according to patient MIC or a MIC of 1 mg/L for empirical treatment is shown in Figure 2. Optimal exposure was comparable between the two groups. Prolonged infusions tended to reduce underexposures but also tended to increase overexposures. The PTA according to various MIC levels and considering the PK target 100% f T ≥4xMIC is shown in Figure 3. The PTA was comparable between prolonged and intermittent infusion for MICs superior to intermittent infusion. Up to a MIC of 4 mg/L, prolonged infusions enabled PTA in 80% of the cases. As for intermittent infusions, the PTA was less than 80% when MIC is ≥ 1 mg/L. Figure 2: Exposure levels according to patient MIC Figure 3: PTA for various given MIC The dotted line corresponds to a PTA of 80%; Concentrations and dosing used were those of study cohort, i.e. median 103 mg/kg/day in prolonged group and 147 mg/kg/day in intermittent group *= p<0.05; MIC: minimum inhibitory concentration; PTA: probability of target attainment (100% fT ≥4xMIC ). Toxicity Plasma overexposure tended to be more frequent for prolonged (n = 8/19, 42%) compared to intermittent infusions (n = 16/59, 27%) (p=0.26). No adverse events attributed to cefepime were identified in the study population. Discussion This study found that free cefepime concentrations were higher with prolonged infusion than with intermittent infusion, despite lower daily dosing. Prolonged infusions were superior to intermittent infusions in achieving the usual target in ICU of 100% f T ≥4xMIC for MIC ≥ 1 mg/L. Interestingly, despite higher free concentrations, when considering the MIC of the patient’s clinical situation, prolonged infusion showed no significant superiority over intermittent infusion to attain the PK target (i.e. 100% f T ≥4xMIC and below the toxicity threshold). This result is explained by the fact that most MICs in the cohort were low, within a range where prolonged infusion failed to demonstrate superiority, as PK targets were easily achieved regardless of the administration route. Although most of our patients had low MICs, approximately one-fifth had an MIC ≥ 1 mg/L and appeared to have more severe conditions, with longer PICU stays. This highlights the importance of reaching optimal antibiotic exposure early in treatment. Therefore, these findings suggest that prolonged cefepime infusions should be preferred in critically ill children without renal failure for high MIC or whenever pathogen MIC is not known in order to increase the likelihood of therapeutic success. In this study, prolonged infusions tended to increase overexposure. However, this result should be interpreted with caution, as despite a significant proportion of pharmacological overexposure (nearly one-third of the concentrations), no cefepime-related adverse events were observed in this study. This result must be qualified by the size of the cohort, and by the possible underestimation of neurological side effects which may be difficult to assess in critically ill children. This result also raises questions about the relevance of toxicity thresholds. Since cefepime is known to have neurological toxicity (22), risk factors have been identified in adults: renal failure, reduced protein binding and increased organic acid (23–25). One can assume that these mechanisms could affect children differently, implying different toxicity thresholds in the two populations. Based on a cohort of 30 adults, Lamoth et al. have shown that a residual concentration greater than 22 mg/L is associated with a 50% risk of neurotoxicity (19). Then, based on simulated data from 93 adults, Huwyler et al. defined a toxicity threshold at 20 mg/L residual concentration and 35 mg/L plateau concentration (21). Several pediatric case reports describe cefepime neurotoxicity in case of renal failure (26–29), with high cefepime concentrations when available: 81 mg/L without specifying the time of dosing (27), and a residual concentration of 80 mg/L (29). No studies have identified toxicity thresholds specific to pediatric patients. Cefepime use in intensive care units is increasing (30), especially in case of infections caused by P. aeruginosa, which have a high mortality rate (31). The toxicity thresholds described raise a question about the use of cefepime against germs with high MICs such as P. aeruginosa . The ECOFF of P. aeruginosa is 8 mg/L, which is notably higher than the ECOFFs of the other germs usually covered by cefepime. The PK target (4x8 = 32 mg/L) exceeds the toxicity thresholds (17.6 mg/L and 28 mg/L for respectively free residual and plateau concentrations). Further pediatric-specific research is necessary to determine clinically relevant toxicity thresholds in the PICU in order to optimize therapeutic windows for high-MIC pathogens and clarify cefepime role in the treatment of P. aeruginosa . This also highlights the importance of measuring MIC in case of infection due to P. aeruginosa. Children undergoing RRT were not included in this study, as data were insufficient for these populations with specific PK. Several studies in adults undergoing RRT have examined the PK of cefepime, with suggested dosing regimens (32–34). Studies of cefepime in children undergoing RRT are scarce; the most recent study included 4 children and concluded that a dosage of 100 mg/kg/day with an intermittent infusion is generally insufficient to achieve optimal pharmacological exposure (35). Regular therapeutic drug monitoring is mandatory in this situation (36). There is a growing literature on the administration of prolonged beta-lactam infusion in critical care, particularly in adults (6–8,37–41). Several studies in adults have demonstrated the superiority of prolonged versus intermittent beta-lactam administration in terms of mortality, clinical cure rate and microbiological success (8,38–42). PK studies in children comparing continuous and intermittent administration have developed (9–11,17,43). However, there is a need for large-scale morbidity-mortality studies on the impact of prolonged infusion in children. This study has some limits. First, the intermittent group has younger patients than the other group which could bias the results of the study. This difference may be due to limited sample sizes but could also indicate a reluctance among practitioners to use prolonged infusion in younger patients. By simulating the concentrations obtained under continuous infusion at 100 mg/kg/day on the intermittent group population, we found that they were comparable to the prolonged group, suggesting the relevance of prolonged infusion even on this lower-weight population (Figure S4). Secondly, cefepime concentrations were measured in plasma samples only while bacteremia accounted for only one third of infections in the study. Most infections were in tissues and cefepime tissue concentration, at the infected site, was not measured and could be lower than plasmatic concentrations. Further studies are needed to assess exposure at the infection site, but it cannot be ruled out that higher cefepime plasma concentrations allow better exposure at the infection site. Finally, only the first cefepime concentrations were analyzed, as they reflect cefepime exposure obtained with initial dosing. Initial antibiotic exposure is crucial since the patients are the most severe and the inoculum is at the highest at this phase. However, our study does not evaluate the monitoring of concentrations over time, which is a relevant element in the emergence of resistant bacteria and should be further evaluated. Conclusion In summary, cefepime prolonged infusion provides a higher probability to attain the PK target when MIC is ≥ 1 mg/L compared to intermittent infusion but tends to increase the risk of pharmacological overexposure. 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Walker MC, Lam WM, Manasco KB. Continuous and extended infusions of β-lactam antibiotics in the pediatric population. Ann Pharmacother. nov 2012;46(11):1537‑46. Information & Authors Information Version history V1 Version 1 29 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Marc Hobeika 0009-0009-2907-6387 [email protected] Hopital Universitaire Necker-Enfants Malades Reanimation et unites de soins continus medico-chirurgicale pediatriques View all articles by this author Déborah Hirt Hopital Cochin View all articles by this author Emmanuelle Bille INSERM View all articles by this author Sihem Benaboud Hopital Cochin View all articles by this author Julie Toubiana Hopital universitaire Necker-Enfants malades Service de Pediatrie generale View all articles by this author Pierre-Louis Léger Hopital Armand-Trousseau Service d'Anesthesie reanimation View all articles by this author Jérôme Rambaud Hopital Armand-Trousseau Service d'Anesthesie reanimation View all articles by this author agathe beranger Hopital Universitaire Necker-Enfants Malades Reanimation et unites de soins continus medico-chirurgicale pediatriques View all articles by this author Delphine Callot Hopital Cochin View all articles by this author Sylvain Renolleau Hopital Universitaire Necker-Enfants Malades Reanimation et unites de soins continus medico-chirurgicale pediatriques View all articles by this author Jean-Marc Tréluyer 0000-0002-2045-4742 Hopital Cochin View all articles by this author Mehdi Oualha 0000-0002-0488-5948 Hopital Universitaire Necker-Enfants Malades Reanimation et unites de soins continus medico-chirurgicale pediatriques View all articles by this author Noémie De Cacqueray 0009-0002-4280-4683 Hopital Universitaire Necker-Enfants Malades Reanimation et unites de soins continus medico-chirurgicale pediatriques View all articles by this author Metrics & Citations Metrics Article Usage 357 views 164 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Marc Hobeika, Déborah Hirt, Emmanuelle Bille, et al. 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