cefepime and Renal-Insufficiency

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.

Topics: Anti-Bacterial Agents; Brain Diseases; Cefepime; Humans; Renal Insufficiency

Cefepime is increasingly used as empiric treatment for fever in the setting of neutropenia. We present a patient with acute-on-chronic renal disease who received cefepime at the appropriate dose for his glomerular filtration rate but developed cefepime-associated encephalopathy. Here, we review neurologic toxicities of cefepime and present suggestions for work-up and management.

Topics: Adolescent; Anti-Bacterial Agents; Cefepime; Cephalosporins; Fever of Unknown Origin; Humans; Male; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Renal Insufficiency

Cefepime is a 'fourth' generation cephalosporin that has a broader spectrum of antibacterial activity than the third generation cephalosporins and is more active in vitro against Gram-positive aerobic bacteria. The fact that cefepime is stable to hydrolysis by many of the common plasmid- and chromosomally-mediated beta-lactamases, and that it is a poor inducer of type I beta-lactamases, indicates that cefepime may be useful for treatment of infections resistant to earlier cephalosporins. In comparative trials, cefepime 1 to 2 g, usually administered intravenously twice daily, was as effective as ceftazidime 1 to 2 g, usually administered 3 times daily, for treatment of bacteraemia and infections of the lower respiratory tract, urinary tract, pelvis and skin and skin structures. Furthermore, cefepime was as effective as ceftazidime and piperacillin or mezlocillin in combination with gentamicin when administered as empirical treatment for fever in patients with neutropenia. A limited number of trials have found cefepime to be as effective as cefotaxime for the treatment of gynaecological and lower respiratory tract infections. Similarly, cefepime 2 g twice daily intravenously (alone or in combination with metronidazole) was as effective as gentamicin in combination with mezlocillin or clindamycin, respectively, for the treatment of intra-abdominal infection. Cefepime has a linear pharmacokinetic profile, an elimination half-life of approximately 2 hours and is primarily excreted by renal mechanisms as unchanged drug. Cefepime has a tolerability profile similar to that of other parenteral cephalosporins; adverse events are primarily gastrointestinal in nature. A total of 1.4 and 2.9% of patients receiving cefepime < or = 2 g/day and > 2 g/day, respectively, required treatment withdrawal as a result of any adverse event. Thus, cefepime has the advantage of an improved spectrum of antibacterial activity, and is less susceptible to hydrolysis by some beta-lactamases, compared with third generation cephalosporins. Despite these advantages, cefepime has not been found to be more effective than ceftazidime and cefotaxime in clinical trials, although most trials selected patients with organisms sensitive in vitro to both comparator agents. Further trials, particularly in areas of widespread bacterial resistance, are required to confirm the positioning of cefepime for treatment of serious infection, and in particular to further explore whether its potential advantag

Topics: Aging; Animals; Bacteria; Bacterial Infections; Cefepime; Cephalosporins; Clinical Trials as Topic; Cystic Fibrosis; Drug Administration Schedule; Humans; Microbial Sensitivity Tests; Renal Insufficiency

The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P<0.001) than patients with an AUIC<250. Patients with T>MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P<0.001) than patients with T>MIC of <100%. Both microbiological and clinical cure rates were suboptimal in patients receiving cefepime or ceftazidime for the treatment of serious infections if the AUIC was <250 or T>MIC was <100%.

Topics: Aged; Anti-Bacterial Agents; APACHE; Area Under Curve; Bacteremia; Bacterial Infections; Cefepime; Ceftazidime; Cephalosporins; Endpoint Determination; Escherichia coli; Female; Humans; Klebsiella; Male; Microbial Sensitivity Tests; Predictive Value of Tests; Pseudomonas aeruginosa; Renal Insufficiency; Sepsis; Treatment Outcome

Cefepime is a fourth-generation cephalosporin with a broad spectrum coverage and anti-pseudomonal activity. The safety profile of cefepime was relatively favourable until neurotoxicity was first reported in 1999. Despite cefepime-induced neurotoxicity (CIN), it continues to be a principal part of parenteral treatment for various infections.. The study aimed to determine the incidence and risk factors for CIN compared to other antibiotics.. A retrospective cohort study was conducted involving 738 patients over eight months in Kasturba Medical College and Hospital, Manipal, India. Patients with cefepime were selected as study cohort (SC; n= 496), and other antibiotics were included in the reference cohort (RC; n=242).. The results showed that 53 (10.7%) patients developed neurotoxicity in the SC, whereas 12 (5%) patients in the RC. A significant association was found between neurotoxicity and cefepime use (X. The study found a higher incidence of CIN compared to other antibiotics-induced neurotoxicity and a harmful association between cefepime use and CIN development. Besides, renal failure is a risk factor for CIN. Therefore, the study warrants the use of cefepime, where no other alternatives are available.

Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Humans; Neurotoxicity Syndromes; Renal Insufficiency; Retrospective Studies; Tertiary Healthcare

Cefepime is commonly used in pediatric intensive care units, where unpredictable variations in the patients' pharmacokinetic (PK) variables may require drug dose adjustments. The objectives of the present study were to build a population PK model for cefepime in critically ill children and to optimize individual initial dosing regimens.. Children (aged from 1 month to 18 years; body weight >3 kg) receiving cefepime were included. Cefepime total plasma concentrations were measured using high performance liquid chromatography. Data were modelled using nonlinear, mixed-effect modeling software, and Monte Carlo simulations were performed with a PK target of 100% fT. Fifty-nine patients (median (range) age: 13.5 months (1.1 months to 17.6 years)) and 129 cefepime concentration measurements were included. The cefepime concentration data were best fitted by a one-compartment model. The selected covariates were body weight with allometric scaling and estimated glomerular filtration rate on clearance. Mean population values for clearance and volume were 1.21 L/h and 4.8 L, respectively. According to the simulations, a regimen of 100 mg/kg/d q12 h over 30 min or 100 mg/kg/d as a continuous infusion was more likely to achieve the PK target in patients with renal failure and in patients with normal or augmented renal clearance, respectively.. Appropriate cefepime dosing regimens should take renal function into account. Continuous infusions are required in critically ill children with normal or augmented renal clearance, while intermittent infusions are adequate for children with acute renal failure. Close therapeutic drug monitoring is mandatory, given cefepime's narrow therapeutic window.

Topics: Anti-Bacterial Agents; Body Weight; Cefepime; Child; Critical Illness; Humans; Infant; Kidney; Microbial Sensitivity Tests; Renal Insufficiency

Taniborbactam, an investigational β-lactamase inhibitor that is active against both serine- and metallo-β-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Anticipating the use of cefepime-taniborbactam in patients with impaired renal function, an open-label, single-dose clinical study was performed to examine the pharmacokinetics of both drugs in subjects with various degrees of renal function. Hemodialysis-dependent subjects were also studied to examine the amounts of cefepime and taniborbactam dialyzed. Single intravenous infusions of 2 g cefepime and 0.5 g taniborbactam coadministered over 2 h were examined, with hemodialysis-dependent subjects receiving doses both on- and off-dialysis. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The majority of adverse events observed were mild in severity, and there were no trends in the safety of cefepime-taniborbactam related to declining renal function or the timing of hemodialysis. Clinically significant and similar decreases in drug clearance with declining renal function were observed for both cefepime and taniborbactam. The respective decreases in geometric mean clearance for subjects with mild, moderate, and severe renal impairment compared to subjects with normal renal function were 18%, 63%, and 78% for cefepime and 15%, 63%, and 81% for taniborbactam, respectively. Decreases in clearance were similar for both drugs and were shown to be proportional to decreases in renal function. Both cefepime and taniborbactam were dialyzable, with similar amounts removed during 4 h of hemodialysis. This study is registered at ClinicalTrials.gov as NCT03690362.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Borinic Acids; Carboxylic Acids; Cefepime; Humans; Renal Insufficiency; Serine

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.. 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 (C

Topics: Adult; Aged; Anti-Bacterial Agents; Cefepime; Drug Monitoring; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Neurotoxicity Syndromes; Pseudomonas aeruginosa; Pseudomonas Infections; Renal Insufficiency; Retrospective Studies; Risk Factors

Cefepime is an antibiotic that is widely used in patients with haematological malignancies (HM). Although its use has been reported to be associated with encephalopathy, only case reports or small case series have been reported so far.. We conducted a retrospective cohort study of 243 patients with HM treated with cefepime at our hospital between August 2011 and May 2013. We also investigated the clinical features of patients with cefepime-induced encephalopathy (CIE).. Among 243 HM patients treated with cefepime, 10 were diagnosed with CIE, indicating a cumulative incidence of approximately 4.1%. The median creatinine level on commencement of treatment was 2.13 mg/dl (range 0.60-19.85) and the median initial dose of cefepime was 4.0 g/day (range 1.0-6.0). The median time between commencement of treatment and symptoms was 4.0 days (range 2-5). The most common clinical manifestations were decreased level of consciousness and myoclonus. Symptoms resolved fully in all patients. Univariate analyses showed that impaired renal function (creatinine clearance (CLCr) < 30 ml/min, acute renal failure, and chronic dialysis) was significantly associated with the development of CIE (univariate p < 0.0001, p = 0.020, and p = 0.0025, respectively). Receiver operating characteristic (ROC) analysis demonstrated that the threshold levels of creatinine, CLCr, and estimated glomerular filtration rate for CIE were 1.22 mg/dl, 22.96 ml/min, and 43.9 ml/min/1.73 m(2), respectively.. This study indicated that the development of CIE is associated with severely impaired renal function in patients with HM.

Topics: Aged; Aged, 80 and over; Brain Diseases; Cefepime; Cephalosporins; Electroencephalography; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; ROC Curve

The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime).. The maximum dose of cefepime in the USA (6 g per day) is higher than that in Japan (4 g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem.. A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2 years at Ehime University Hospital. Cefepime or meropenem-associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem.. The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders.. Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime-associated convulsions.

Topics: Adult; Aged; Anti-Bacterial Agents; Brain Diseases; Cefepime; Cephalosporins; Female; Hospitals, University; Humans; Infusions, Intravenous; Japan; Male; Meropenem; Neurotoxicity Syndromes; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Renal Insufficiency; Retrospective Studies; Risk; Seizures; Staphylococcal Infections; Staphylococcus aureus; Thienamycins

Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Creatinine; Critical Pathways; Drug Administration Schedule; Humans; Meropenem; Pneumonia, Ventilator-Associated; Quality Assurance, Health Care; Renal Insufficiency; Thienamycins

Topics: Aged; Anti-Bacterial Agents; Cefepime; Cephalosporins; Female; Humans; Intensive Care Units; Renal Insufficiency; Status Epilepticus

Cases of cefepime neurotoxicity have been sporadically reported in patients with renal failure. The neurotoxicity of cefepime might be underestimated and the frequency of its neurotoxic effects may be insufficiently recognized.. We retrospectively reviewed the files of patients with renal failure who were treated with cefepime and who developed neurological complications.. All 8 patients developed decreased conscience, confusion, agitation, global aphasia, myoclonus, chorea-athetosis, convulsions and coma. The latency, the period between the start of treatment and neurological deterioration, was 4,75 +/- 2,55 days (range: 1-10 days). All patients died 17 +/- 14,7 days (range: 1-42 days) after becoming symptomatic. Three of them died shortly after neurological deterioration. Five patients developed a neurological "tableau" with global aphasia. Three patients showed clinical improvement after the discontinuation of cefepime. Electroencephalography revealed diffuse slow-wave activity (delta) and triphasic sharp wave activity. These findings confirm the possible neurotoxicity of treatment with cefepime in patients with renal failure. In none of the deceased patients have we been able to directly demonstrate a causal relationship between neurotoxicity and mortality. However, when a patient treated with cefepime develops neurological deterioration or aphasia, one must be aware of cefepime's potential neurotoxicity and treatment should be stopped.. We recommend that, in view of the high and unexplained mortality, the use of cefepime in patients with kidney failure should be carefully considered.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Cefepime; Cephalosporins; Dose-Response Relationship, Drug; Electroencephalography; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Neurotoxicity Syndromes; Renal Insufficiency; Retrospective Studies; Treatment Outcome

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL(CR)) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C(min)). C(min) in this group was found to be 3.3 +/- 3.6 mg/liter (mean and standard deviation), compared to 19.5 +/- 21.5 mg/liter in patients with a CL(CR) of between 60 and 100 ml/min (P = 0.025) and 14.0 +/- 11.5 mg/liter in patients with a CL(CR) of <60 ml/min (P = 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL(CR) were highly correlated (P = 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 x CL(CR)). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h(-1), respectively. The time-concentration profiles for 1,000 patients (CL(CR)s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C(min) that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs < or = 2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are > or = 4 mg/liter), particularly when CL(CR) exceeds 120 ml/min.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefepime; Cephalosporins; Computer Simulation; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Prospective Studies; Pseudomonas aeruginosa; Renal Insufficiency

Nonconvulsive status epilepticus is an unusual complication of cephalosporin therapy, with only a few isolated cases reported.. We reviewed the clinical and electroencephalographic (EEG) characteristics of 10 patients with renal failure in whom developed alteration of consciousness without convulsions associated with continuous epileptiform EEG activity while being treated with cephalosporins.. Nonconvulsive status epilepticus developed in 5 men and 5 women, with a mean (+/- SD) age of 69 +/- 14 years, while receiving intravenous cephalosporins (ceftriaxone, 2 patients; ceftazidime, 2; and cefepime, 6). All patients had renal failure; 1 also had hepatic failure. Patients presented with progressive disorientation or agitation, sometimes associated with mild facial or limb myoclonus, that had begun 1 to 10 days (mean, 5 +/- 2 days) after starting cephalosporin treatment. The EEG showed continuous or intermittent bursts of generalized, high-voltage, 1 to 2 Hz sharp wave activity or sharp and slow wave activity that resembled, but could be differentiated from, the triphasic waves seen in metabolic encephalopathies. Intravenous clonazepam suppressed the epileptiform activity completely in 5 patients and partially in the other 5. Cephalosporins were withdrawn, and antiepileptic therapy was started for all patients. All patients improved, 2 in less than 24 hours and the remainder within 2 to 7 days.. Cephalosporins can cause nonconvulsive status epilepticus in patients with renal failure. The clinical picture is difficult to differentiate from a that of metabolic encephalopathy unless an EEG is obtained. Physicians should be aware of this potentially dangerous complication.

Topics: Adult; Aged; Aged, 80 and over; Brain; Cefepime; Ceftazidime; Ceftriaxone; Cephalosporins; Electroencephalography; Female; Humans; Infusions, Intravenous; Male; Meningitis, Bacterial; Middle Aged; Osteomyelitis; Renal Insufficiency; Respiratory Tract Infections; Status Epilepticus

Topics: Aged; Brain Diseases; Cefepime; Cephalosporins; Dialysis; Electroencephalography; Female; Humans; Renal Insufficiency