Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial.

Importance: Cefepime/enmetazobactam is a novel ß-lactam/ß-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. Objective: To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis. Design, Setting, and Participants: A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens. Interventions: Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline). Main Outcomes and Measures: The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified. Results: Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events. Conclusions and Relevance: Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis. Trial Registration: ClinicalTrials.gov Identifier: NCT03687255.

Pharmacokinetics of Cefepime in Children on Extracorporeal Membrane Oxygenation: External Model Validation, Model Improvement and Dose Optimization.

BACKGROUND: Cefepime is a first-line therapy for Gram-negative infections in children on extracorporeal membrane oxygenation. Cefepime pharmacokinetics (PK) in children on extracorporeal membrane oxygenation still needs to be better established. METHODS: This was a prospective single-center PK study. A maximum of 12 PK samples per patient were collected in children <18 years old on extracorporeal membrane oxygenation who received clinically indicated cefepime. External validation of a previously published population PK model was performed by applying the model in a new data set. The predictive performance of the model was determined by calculating prediction errors. Because of poor predictive performance, a revised model was developed using NONMEM and a combined data set that included data from both studies. Dose-exposure simulations were performed using the final model. Optimal dosing was judged based on the ability to maintain free cefepime concentrations above the minimal inhibitory concentration (MIC) for 68% and 100% of the dosing interval. RESULTS: Seventeen children contributed 105 PK samples. The mean (95% CI) and median (interquartile range) prediction errors were 33.7% (19.8-47.7) and 17.5% (-22.6 to 74.4). A combined data set was created, which included 33 children contributing 310 PK samples. The final improved 2-compartment model included weight and serum creatinine on clearance and oxygenator day and blood transfusion on volume of the central compartment. At an MIC of 8 mg/L, 50 mg/kg/dose every 8 hours reached target concentrations. CONCLUSIONS: Dosing intervals of 8 hours were needed to reach adequate concentrations at an MIC of 8 mg/L. Longer dosing intervals were adequate with higher serum creatinine and lower MICs.

Evaluation of Individualized Cefepime Dosing Strategy Using Population Pharmacokinetics.

The use of population pharmacokinetics (PK) to optimize cefepime dosing could be an effective strategy, given the increasing prevalence of resistant gram-negative organisms. The objective of this study is to retrospectively compare dosing using a PK approach (intervention) vs traditional dosing (control) for cefepime in patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Adult hospitalized patients with HAP or VAP receiving cefepime for ≥72 hours were screened first from August 2018 to January 2019 to be included in the intervention group, then screened during the preintervention period from August 2017 to July 2018 for the control group. Clinical improvement on day 7 of cefepime therapy was achieved in 72% of the patients in the intervention group and 70% of the patients in the control group (P = .8110). However, the clinical cure rate in the intervention group was higher than that of the control group (50% vs 36.5%; P = .0034). Cefepime dosing using population PK appears to be a novel, effective, and safe dosing strategy for patients with HAP or VAP.

Cefepime and diclofenac sodium combined treatment-potentiated multiple organ injury: Role of oxidative damage and disrupted lipid metabolism.

Concurrent exposure to antimicrobial and nonsteroidal anti-inflammatory drugs (NSAIDs) is usually inevitable in most infections and postsurgery. Consequently, the present study was designed to assess the intertwining impact of coadministration of cefepime (CP, a wide spectrum antibiotic) and diclofenac sodium (DF, an NSAID) on rat's liver, kidney, and testes. Rats received saline, CP (180 mg/kg/day, IM), DF (10 mg/kg/day, IM), or a combination of CP and DF. After 14 days, CP or DF induced tissue damage expressed by marked biochemical alterations in hepatic and renal function tests. Besides this, disrupted lipid metabolism and testosterone levels along with significant histological changes in hepatic, renal, and testicular tissues were noticed. A significant increase in malondialdehyde and decreases in superoxide dismutase and catalase activities alongside significant upregulated caspase 3 expression in tissues following CP or DF treatment suggested a bearable influence of oxidative stress, lipid peroxidation, and cell death. Accordingly, the simultaneous therapy of CP and DF evoked more obvious tissue damage than their individual treatment. Overall, data concluded that concurrent use of CP and DF in medical practice is a worrisome matter, so it should be done cautiously to avoid synergistic deleterious outcomes.

Low prevalence of tissue detection of cefepime and daptomycin used as empirical treatment during revision for periprosthetic joint infections: results of a prospective multicenter study.

Data demonstrating that antibiotics administered intraoperatively in patients with surgical revision for periprosthetic joint infection achieve concentrations exceeding minimal inhibitory concentrations of the identified bacteria at the surgical site when the new implant is inserted are lacking. We prospectively included patients with periprosthetic joint infection operated with one- or two-stage replacement during which cefepime (2g)-daptomycin (10mg/kg) combination was administered intravenously as intraoperative empirical antibiotic treatment. Three biopsies (two bones and one synovial membrane) were taken from each patient just before the insertion of the new implant. Eighteen adults of median age 68 years were included. Knee was involved in 10 patients (55.6%) and surgery consisted in one-/two-stage replacement in 11/7 patients. A tourniquet was used during the intervention in the 10 patients with knee prosthesis. Among 54 tissue samples, cefepime and daptomycin were detected respectively in 35 (64.8%) and 21 (38.9%) cases (P=0.01). A total of 17 bacteria dominated by staphylococci (n=14) were identified in 10 patients; tissue inhibitory quotient calculated in 51 samples was >1 in 22 cases (43.1%) for cefepime and in 16 cases (31.4%) for daptomycin. The proportion of tissue samples with detectable antibiotic was significantly higher in hip versus knee prosthesis (P=0.03). The present study suggests that intraoperative empirical administration of cefepime-daptomycin combination during septic prosthetic joint replacement results in a high proportion of tissue samples in which at least one of the two antibiotics was not detected or at a low concentration despite satisfactory concomitant blood serum concentrations.

Pharmacokinetic/Pharmacodynamic Dosage Individualization of Cefepime in Critically Ill Patients: A Case Study.

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.

In vitro activity of cefepime/zidebactam (WCK 5222) against recent Gram-negative isolates collected from high resistance settings of Greek hospitals.

Cefepime/zidebactam is in clinical development for the treatment of carbapenem-resistant Gram-negative infections. MICs of cefepime/zidebactam (1:1) and comparators against Enterobacterales (n = 563), Pseudomonas (n = 172) and Acinetobacter baumannii (n =181) collected from 15 Greek hospitals (2014-2018) were determined by reference broth microdilution method. The isolates exhibited high carbapenem resistance rates [(Enterobacterales (75%), Pseudomonas (75%) and A. baumannii (98.3%)]. Cefepime/zidebactam showed MIC50/90 of 0.5/2 mg/L, against Enterobacterales including metallo-ß-lactamases (MBL)-producers. Reduced susceptibility rates to tigecycline (16.8%), colistin (47.4%), ceftazidime/avibactam (59.8%), and imipenem/relebactam (61%) indicated high prevalence of multi-drug resistance among Greek Enterobacterales. Cefepime/zidebactam exhibited MIC50/90 of 8/16 mg/L against Pseudomonas including MBL-producers. The MIC50/90 of ceftazidime/avibactam and imipenem/relebactam were high (≥32 mg/L). Cefepime/zidebactam showed MIC90 of 64 mg/L against A. baumannii which is within its therapeutic scope. Other antibiotics including colistin showed limited activity against A. baumannii. The activity of cefepime/zidebactam against multi-drug-resistant isolates is attributable to zidebactam mediated novel ß-lactam-enhancer mechanism.

Model-based approach to sampling optimization in studies of antibacterial drugs for infants and young children.

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients' small bodies. In Japan, the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic-resistant bacteria. Regulatory guidelines promote the use of model-based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model-based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Cefepime Dosing in Neonates: What is the Evidence?

OBJECTIVE: Recommended cefepime dosing strategies in neonates varies in commonly utilized dosing references with regard to dose and frequency. The objective of this review is to summarize and evaluate the available literature describing cefepime dosing in neonatal patients. STUDY DESIGN: We performed a literature review in MEDLINE using the keyword cefepime. The search was limited to the English language, humans, and patients <2 months of age. We evaluated four pharmacokinetic studies and two studies describing the use of cefepime in clinical practice. RESULTS: The available studies assessing cefepime serum concentrations in neonatal patients demonstrated maintenance of adequate pharmacokinetic parameters when utilizing a dosing frequency of every 12 hours, specifically for organisms with a minimum inhibitory concentration (MIC) ≤ 8 mg/L. In studies evaluating clinical outcomes of cefepime use in neonates, the most frequent adverse effects reported included seizures and hypophosphatemia. Microbiologic cure was demonstrated with a dosing regimen of 50 mg/kg per dose every 12 hours. CONCLUSION: Cefepime dosed 30 to 50 mg/kg per dose every 12 hours may be appropriate to achieve a concentration two to four times above an MIC ≤ 8 mg/L for at least 60% of the dosing interval in neonatal patients.

Impact of a cefepime shortage on dosing regimens and outcomes in hospitalized adults with febrile neutropenia.

BACKGROUND: Drug shortages may negatively impact outcomes in hospitalized patients. A cefepime dosing regimen of 1 gram every 6 hours (1 g q6h) has shown to provide similar exposures above target minimum inhibitory concentrations compared to the regimen of 2 g q8h approved by the United States Food and Drug Administration (FDA) for febrile neutropenia. Our objective was to determine if the dosing regimen of 1 g q6h amidst a cefepime shortage is an appropriate alternative for the treatment of febrile neutropenia. METHODS: A retrospective chart review of hospitalized patients who received cefepime for febrile neutropenia over a two-year period was performed. Patients were grouped based on cefepime dosing strategy: 2 g q8h vs. 1 g q6h. The primary objective was to compare time to defervescence after cefepime initiation. Secondary objectives included all-cause 30-day mortality, duration of antibiotic therapy, and inpatient length of stay. RESULTS: Seventy-five patients in each arm were included. There were no differences in baseline age or severity of illness between groups. There was no difference in the primary objective as median time to defervescence was similar between the 2 g q8h and 1 g q6h groups (69.0 vs. 65.3 h: p= 0.67). Additionally, no differences were found in the secondary objectives of all-cause 30-day mortality (10.7% vs. 9.3%: p = 0.79), duration of therapy (80.8 vs. 88.0 h: p = 0.34), or length of stay (9 vs. 7 days: p = 0.50). CONCLUSIONS: Our study identified no differences in clinical outcomes with cefepime 1 g q6h compared to the traditional FDA-approved 2 g q8h regimen for the treatment of febrile neutropenia.

Bio-functional hydrogel membranes loaded with chitosan nanoparticles for accelerated wound healing.

Wounds are often recalcitrant to traditional wound dressings and a bioactive and biodegradable wound dressing using hydrogel membranes can be a promising approach for wound healing applications. The present research aimed to design hydrogel membranes based on hyaluronic acid, pullulan and polyvinyl alcohol and loaded with chitosan based cefepime nanoparticles for potential use in cutaneous wound healing. The developed membranes were evaluated using dynamic light scattering, proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the novel crosslinking and thermal stability of the fabricated hydrogel membrane. The in vitro analysis demonstrates that the developed membrane has water vapors transmission rate (WVTR) between 2000 and 2500 g/m2/day and oxygen permeability between 7 and 14 mg/L, which lies in the range of an ideal dressing. The swelling capacity and surface porosity to liberate encapsulated drug (cefepime) in a sustained manner and 88% of drug release was observed. The cefepime loaded hydrogel membrane demonstrated a higher zone of inhibition against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli and excisional rat model exhibit expeditious recovery rate. The developed hydrogel membrane loaded with cefepime nanoparticles is a promising approach for topical application and has greater potential for an accelerated wound healing process.

Analysis of blood stream infections, antibiograms and clinical outcomes in haematological patients with febrile neutropenia: data from a tertiary care haematology institute in India.

Timely administration of appropriate empirical antibiotics in febrile neutropenia is crucial for favourable patient outcomes. There are guidelines in place recommending such antibiotics. However, regional variations and local epidemiological data must be evaluated to tailor the antibiotics for best possible and rational use. In this study, we audited the clinical and microbiological data of febrile neutropenic episodes occurring at a tertiary care haematology institution. Three hundred and ninety-three febrile neutropenic episodes occurring in 123 patients over a 1-year period were analysed for microbial profile, sensitivity and resistance patterns, and finally clinical outcomes. Gram-negative bacilli (GNB) blood stream infections (46.9%) were more prevalent as compared to gram-positive infections (41.9%). Overall mortality due to complicated neutropenic sepsis was 19.5% (24/123 patients). Increased resistance to carbapenems, beta-lactam beta-lactamase inhibitor combinations, aminoglycosides, fluoroquinolones, and cephalosporins were observed. Cefepime and tigecycline resistance were seen in 20% and 15% GNB isolates, respectively. Chest was the most frequent focus of infection, and acute myeloid leukaemia (AML) was the most common underlying disorder which correlated with the likelihood of death (p < 0.01). Multidrug-resistant GNB (esp. Klebsiella sp.) are still most worrisome isolates in neutropenic patients. Single-agent cefepime or piperacillin-tazobactam/tigecycline combination may be considered empirical agents. Chest infections and AML were independent predictors of poor clinical outcome in neutropenic patients. Regular audit of infections and antibiotic susceptibility data is needed to improve clinical outcomes in patients with febrile neutropenia.

ß-lactam dosing strategies: Think before you push.

OBJECTIVES: There has been interest in administering cefepime, a ß-lactam antibiotic, via intravenous push (IVP) as a means to improve time to first-dose antibiotic and reduce cost; however, the downstream impacts on antibiotic exposure and pharmacodynamic efficacy need to be further evaluated. METHODS: This study used a population pharmacokinetic model for cefepime and simulated exposures to predict the pharmacodynamic (PD) effect for cefepime regimens administered via IVP or 30-minute intermittent infusion in adults with different renal functions. FDA-approved adult dosages of 1-2 g every 8 or 12 hours were compared. This study aimed to compare the absolute difference in pharmacodynamic probability of target attainment (PTA) between IVP and intermittent infusion, defined as free cefepime concentrations above organism MIC for ≥ 70% of the time. RESULTS: At MICs of 0.25-0.5 mg/L, absolute differences in PTA were observed, with a reduction as great as 2.3% (89% to 86.7% for 30-minute intermittent infusion and IVP, respectively). At MICs of 1-4 mg/L, 30-minute intermittent infusion and IVP exhibited PTA differences as great as 5.4%, from 89.4% to 84%, respectively. At MICs of ≥8 mg/L, similar absolute differences existed; however, no regimen achieved a PTA >70%. Across renal function strata of 60, 100 and 140 mL/minute (within the same dosing group and MICs), better renal function lowered PTAs. CONCLUSIONS: Simulations demonstrated that IVP cefepime resulted in lower PTAs than traditional intermittent infusion among a subset of elevated MICs. Clinicians should exercise caution in IVP strategy, as unintended clinical consequences are possible.

Reducing acute kidney injury in pediatric oncology patients: An improvement project targeting nephrotoxic medications.

BACKGROUND: Nephrotoxic medication exposure and associated acute kidney injury (AKI) occur commonly in hospitalized children. At Cincinnati Children's Hospital Medical Center, there is an initiative to increase awareness of nephrotoxic medication exposure and decrease rates of associated AKI. The oncology service utilized these data in a quality improvement project to drive reductions in AKI rates. METHODS: Three interventions were implemented targeted at decreasing the incidence of nephrotoxic exposure, as well as protecting against the conversion of exposures to AKI episodes. Cefepime replaced piperacillin-tazobactam for febrile neutropenia, vancomycin stewardship limited empiric courses to 72 hours, and nephroprotection for intravenous contrast administration was standardized for defined high-risk patients. RESULTS: The study cohort comprised 42 520 noncritically ill patient days admitted to the oncology service at Cincinnati Children's Hospital Medical Center. A total of 273 unique patients were exposed to combination nephrotoxic medications, leading to 111 AKI episodes. The rate of nephrotoxic medication exposure within the oncology service decreased by 49% from 16.08 to 8.17 per 1000 patient days. Episodes of AKI associated with nephrotoxic medication exposure decreased by 45% from 3.48 to 1.92 per 1000 patient days. CONCLUSION: Interventions to decrease AKI took a three-pronged approach. Collectively, this approach was proven successful with significant reductions in both rates of nephrotoxic medication exposure and associated AKI among hospitalized oncology patients.

A 36-Year-Old Woman Presenting With Left Upper Quadrant Discomfort, Encephalopathy, and Respiratory Failure.

CASE PRESENTATION: A 36-year-old woman with a history of hypertension and alcoholism reported 2 days of left upper quadrant pain and jaundice. Within hours of admission, she became somnolent and hypoxic. The patient was then intubated. She had no history of drug abuse, cigarette smoking, liver disease, autoimmune disease, or pancreatitis. She had no home medications.

Effect of Cefepime on Neurotoxicity Development in Critically Ill Adults With Renal Dysfunction.

BACKGROUND: Pharmacodynamic and pathophysiologic changes in critically ill adults receiving cefepime may increase the risk of adverse events. RESEARCH QUESTION: What is the impact of cefepime exposure on neurotoxicity development in critically ill adults with renal dysfunction? STUDY DESIGN AND METHODS: Critically ill adults with creatinine clearance < 60 mL/min who received cefepime for ≥ 48 hours between January 1, 2014 and July 31, 2018 were evaluated for cefepime-associated neurotoxicity (CAN) development. Higher- and lower-dose cefepime exposure groups stratified by moderate (≥ 8 g vs < 8 g in first 48 hours) or severe (≥ 4 g vs < 4 g in first 48 hours) renal dysfunction were compared. Between-group comparisons were performed using Fisher exact tests. CAN-free survival was evaluated using Kaplan-Meier curves and log-rank tests. RESULTS: Cefepime total dose in the first 48 hours was greater in the higher-dose cefepime group (3.7 ± 1.6 g vs 7.7 ± 2.2 g; P < .001). Cefepime-associated neurotoxicity occurred infrequently in both lower- (n = 108) and higher-dose (n = 92) cefepime groups (4% vs 10%, OR 2.82, 95% CI, 0.84-9.48, P = .093). The frequencies of cefepime-associated neurotoxicity were similar between lower- and higher-dose cefepime groups when moderate renal dysfunction subgroups were compared (5% vs 7%, OR 1.42, 95% CI, 0.34-5.92, P = .72) and numerically greater in the higher-dose cefepime group in the severe renal dysfunction subgroup (0 vs 16%, P = .064). Times to cefepime-associated neurotoxicity development and resolution were similar between lower- and higher-dose groups. Durations of CAN-free survival were similar between lower- and higher-dose groups. Most patients who developed cefepime-associated neurotoxicity displayed altered mental status (n = 12, 92%). INTERPRETATION: Cefepime-associated neurotoxicity is an uncommon occurrence in critically ill adults. Patients with severe renal dysfunction receiving higher-dose cefepime may be at greater risk of cefepime-associated neurotoxicity, although this requires additional investigation.

Cefepime-Induced Neurotoxicity Presenting with Nonconvulsive Status Epilepticus Admitted as a Stroke Alert.

BACKGROUND Cefepime-induced neurotoxicity has been described in intensive care units (ICUs) and neuro ICU settings, occurring in patients started on cefepime for management of severe infections and sepsis. Most cases occur within 1 to 10 days after starting the drug. We publish a case that occurred on the general medical ward of a patient who had been on cefepime therapy for 4 weeks prior to admission. The aim of this study was to improve the knowledge of this serious condition to general internists as our patient was being managed on the general medical ward. CASE REPORT A 72-year-old female on prolonged intravenous antibiotics for sacral and pelvic osteomyelitis presented with acute encephalopathy and aphasia in the setting of an acute kidney injury. Due to the acute focal neurologic deficit, she was initially admitted as a stroke alert. After a negative magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG) was pursued and showed nonconvulsive status epilepticus (NCSE). NCSE was likely a result of cefepime therapy in the setting of an acute kidney injury. CONCLUSIONS Cefepime-induced neurotoxicity should be suspected in any patient on cefepime therapy who develops acute changes in mental status, myoclonus, or evidence of seizures. Risk factors for the disease include older age, renal dysfunction, critical illness, and inappropriate dosing based upon renal function. A high index of suspicion is required and delays in diagnosis are common as there are frequently multiple possible causes for altered mental status in systemically ill patients requiring treatment with broad-spectrum antibiotics.

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.