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JAMA Oct 2023Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been...
IMPORTANCE
Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial.
OBJECTIVE
To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction.
DESIGN, SETTING, AND PARTICIPANTS
The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022.
INTERVENTIONS
Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam.
MAIN OUTCOMES AND MEASURES
The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days.
RESULTS
There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95]).
CONCLUSIONS AND RELEVANCE
Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05094154.
Topics: Humans; Adult; Female; Middle Aged; Male; Anti-Bacterial Agents; Cefepime; Coma; Piperacillin; Drug Therapy, Combination; Retrospective Studies; Piperacillin, Tazobactam Drug Combination; Sepsis; Acute Kidney Injury; Kidney; Delirium
PubMed: 37837651
DOI: 10.1001/jama.2023.20583 -
Critical Care (London, England) Nov 2017Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric... (Review)
Review
BACKGROUND
Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions.
METHODS
A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting.
RESULTS
Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis.
CONCLUSIONS
Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.
Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Consciousness Disorders; Drug-Related Side Effects and Adverse Reactions; Humans; Neurotoxicity Syndromes; Seizures
PubMed: 29137682
DOI: 10.1186/s13054-017-1856-1 -
JAMA Oct 2022Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections. (Comparative Study)
Comparative Study Randomized Controlled Trial
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 β-lactam/β-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.
Topics: Acute Disease; Anti-Bacterial Agents; Cefepime; Double-Blind Method; Drug Combinations; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pyelonephritis; Urinary Tract Infections; beta-Lactamase Inhibitors
PubMed: 36194218
DOI: 10.1001/jama.2022.17034 -
Clinical Pharmacokinetics Jul 2022Cefepime is a broad-spectrum fourth-generation cephalosporin with activity against Gram-positive and Gram-negative pathogens. It is generally administered as an infusion... (Review)
Review
Cefepime is a broad-spectrum fourth-generation cephalosporin with activity against Gram-positive and Gram-negative pathogens. It is generally administered as an infusion over 30-60 min or as a prolonged infusion with infusion times from 3 h to continuous administration. Cefepime is widely distributed in biological fluids and tissues with an average volume of distribution of ~ 0.2 L/kg in healthy adults with normal renal function. Protein binding is relatively low (20%), and elimination is mainly renal. About 85% of the dose is excreted unchanged in the urine, with an elimination half-life of 2-2.3 h. The pharmacokinetics of cefepime is altered under certain pathophysiological conditions, resulting in high inter-individual variability in cefepime volume of distribution and clearance, which poses challenges for population dosing approaches. Consequently, therapeutic drug monitoring of cefepime may be beneficial in certain patients including those who are critically ill, have life-threatening infections, or are infected with more resistant pathogens. Cefepime is generally safe and efficacious, with a goal exposure target of 70% time of the free drug concentration over the minimum inhibitory concentration for clinical efficacy. In recent years, reports of neurotoxicity have increased, specifically in patients with impaired renal function. This review summarizes the pharmacokinetics, pharmacodynamics, and toxicodynamics of cefepime contemporarily in the setting of increasing cefepime exposures. We explore the potential benefits of extended or continuous infusions and therapeutic drug monitoring in special populations.
Topics: Adult; Anti-Bacterial Agents; Cefepime; Cephalosporins; Critical Illness; Humans; Microbial Sensitivity Tests
PubMed: 35764774
DOI: 10.1007/s40262-022-01137-y -
Intensive Care Medicine Sep 2022Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association...
PURPOSE
Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion.
METHODS
We included patients enrolled in the Molecular Epidemiology of SepsiS in the ICU (MESSI) prospective cohort who were treated for ≥ 48 h with vancomycin + piperacillin-tazobactam or vancomycin + cefepime. Kidney function biomarkers [creatinine, cystatin C, and blood urea nitrogen (BUN)] were measured before antibiotic treatment and at day two after initiation. Creatinine-defined AKI and dialysis were examined through day-14, and mortality through day-30. Inverse probability of treatment weighting was used to adjust for confounding. Multiple imputation was used to impute missing baseline covariates.
RESULTS
The study included 739 patients (vancomycin + piperacillin-tazobactam n = 297, vancomycin + cefepime n = 442), of whom 192 had cystatin C measurements. Vancomycin + piperacillin-tazobactam was associated with a higher percentage increase of creatinine at day-two 8.04% (95% CI 1.21, 15.34) and higher incidence of creatinine-defined AKI: rate ratio (RR) 1.34 (95% CI 1.01, 1.78). In contrast, vancomycin + piperacillin-tazobactam was not associated with change in alternative biomarkers: cystatin C: - 5.63% (95% CI - 18.19, 8.86); BUN: - 4.51% (95% CI - 12.83, 4.59); or clinical outcomes: dialysis: RR 0.63 (95% CI 0.31, 1.29); mortality: RR 1.05 (95%CI 0.79, 1.41).
CONCLUSIONS
Vancomycin + piperacillin-tazobactam was associated with creatinine-defined AKI, but not changes in alternative kidney biomarkers, dialysis, or mortality, supporting the hypothesis that vancomycin + piperacillin-tazobactam effects on creatinine represent pseudotoxicity.
Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Biomarkers; Cefepime; Creatinine; Critical Illness; Cystatin C; Drug Therapy, Combination; Humans; Penicillanic Acid; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Renal Dialysis; Retrospective Studies; Vancomycin
PubMed: 35833959
DOI: 10.1007/s00134-022-06811-0 -
BMC Infectious Diseases Jun 2017Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective,... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli.
BACKGROUND
Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective, randomized, open-label comparison of the therapeutic efficacy of piperacillin-tazobactam (PTZ), cefepime, and ertapenem in febrile nosocomial urinary tract infection with ESBL-producing Escherichia coli (ESBL-EC).
METHODS
This study was conducted at three university hospitals between January 2013 and August 2015. Hospitalized adult patients presenting with fever were screened for healthcare-associated urinary tract infection (HA-UTI). When ESBL-EC was solely detected and susceptible to a randomized antibiotic in vitro, the case was included in the final analysis. Participants were treated for 10-14 days with PTZ, cefepime, or ertapenem.
RESULTS
A total of 66 participants were evenly assigned to the PTZ and ertapenem treatment groups. After the recruitment of six participants, assignment to the cefepime treatment group was stopped because of an unexpectedly high treatment failure rate. The baseline characteristics of these participants did not differ from participants in other treatment groups. The clinical and microbiological response to PTZ treatment was estimated to be 94% and was similar to the response to ertapenem treatment. The efficacy of cefepime was 33.3%. In the cefepime group, age, Charlson comorbidity index, genotype, and minimal inhibitory concentration (MIC) did not significantly affect the success of treatment. Similarly, genotype seemed to be irrelevant with respect to clinical outcome in the PTZ group. Expired cases tended to involve septic shock with a high Charlson comorbidity index and high MIC.
CONCLUSION
Results from this study suggest that PTZ is effective in the treatment of urinary tract infection caused by ESBL-EC when the in vitro test indicates susceptibility. In addition, cefepime should not be used as an alternative treatment for urinary tract infection caused by ESBL-EC.
TRIAL REGISTRATION
The trial was registered with the Clinical Research Information Service of Korea Centers for Disease Control and Prevention. (KCT0001895).
Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefepime; Cephalosporins; Cross Infection; Ertapenem; Escherichia coli; Escherichia coli Infections; Female; Genotype; Humans; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Republic of Korea; Tazobactam; Urinary Tract Infections; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 28592240
DOI: 10.1186/s12879-017-2502-x -
Journal of Clinical Microbiology May 2023Multidrug-resistant (MDR) bacteria are important public health problems. Antibiotic susceptibility testing (AST) currently uses time-consuming culture-based procedures,...
Multidrug-resistant (MDR) bacteria are important public health problems. Antibiotic susceptibility testing (AST) currently uses time-consuming culture-based procedures, which cause treatment delays and increased mortality. We developed a machine learning model using Acinetobacter baumannii as an example to explore a fast AST approach using metagenomic next-generation sequencing (mNGS) data. The key genetic characteristics associated with antimicrobial resistance (AMR) were selected through a least absolute shrinkage and selection operator (LASSO) regression model based on 1,942 A. baumannii genomes. The mNGS-AST prediction model was accordingly established, validated, and optimized using read simulation sequences of clinical isolates. Clinical specimens were collected to evaluate the performance of the model retrospectively and prospectively. We identified 20, 31, 24, and 3 AMR signatures of A. baumannii for imipenem, ceftazidime, cefepime, and ciprofloxacin, respectively. Four mNGS-AST models had a positive predictive value (PPV) greater than 0.97 for 230 retrospective samples, with negative predictive values (NPVs) of 100% (imipenem), 86.67% (ceftazidime), 86.67% (cefepime), and 90.91% (ciprofloxacin). Our method classified antibacterial phenotypes with an accuracy of 97.65% for imipenem, 96.57% for ceftazidime, 97.64% for cefepime, and 98.36% for ciprofloxacin. The average reporting time of mNGS-based AST was 19.1 h, in contrast to the 63.3 h for culture-based AST, thus yielding a significant reduction of 44.3 h. mNGS-AST prediction results coincided 100% with the phenotypic AST results when testing 50 prospective samples. The mNGS-based model could be used as a rapid genotypic AST approach to identify A. baumannii and predict resistance and susceptibility to antibacterials and could be applicable to other pathogens and facilitate rational antimicrobial usage.
Topics: Acinetobacter baumannii; Retrospective Studies; Cefepime; Ceftazidime; Prospective Studies; Anti-Bacterial Agents; Imipenem; Ciprofloxacin; Anti-Infective Agents; Drug Resistance, Multiple, Bacterial; High-Throughput Nucleotide Sequencing; Microbial Sensitivity Tests
PubMed: 37022167
DOI: 10.1128/jcm.01805-22 -
Cureus Sep 2021Cefepime is a common antibiotic used to treat various infections such as pneumonia, skin infections, and intra-abdominal infections due to its broad gram-positive and...
Cefepime is a common antibiotic used to treat various infections such as pneumonia, skin infections, and intra-abdominal infections due to its broad gram-positive and gram-negative spectrum. However, patients with acute kidney injury, end-stage renal disease, and renal transplantation are disproportionately at higher risk of developing complications from administration of cefepime, secondary to its predominant renal excretion. Current guidelines prescribe cefepime renal-dosing, dependent on the glomerular filtration rate, to prevent toxicity. This study presents a rare case where an acutely hospitalized patient undergoing chronic renal transplant rejection was administered renal-dose cefepime. Despite renal dosing, the patient developed neurotoxicity that manifested as delirium, inability to tolerate oral intake, and non-convulsive status epilepticus. Solely adjusting for renal dysfunction may be inadequate to prevent the accumulation of cefepime metabolites, which may present in an atypical manner in the patient. Such possibilities emphasize the need for continued evaluation of a patient's mentation in case of cefepime administration. Cefepime-induced neurotoxicity incidences need to be evaluated and researched thoroughly.
PubMed: 34660040
DOI: 10.7759/cureus.17831 -
The Medical Clinics of North America Jul 1995Because of the popularity of some third-generation cephalosporins, emergence of resistant organisms (e.g., selected Enterobacteriaceae) that produce inducible and... (Review)
Review
Because of the popularity of some third-generation cephalosporins, emergence of resistant organisms (e.g., selected Enterobacteriaceae) that produce inducible and extended-spectrum beta-lactamases has been a problem. Cefepime's twice-a-day dosage schedule and enhanced activity against Enterobacteriaceae and gram-positive organisms give it several advantages over older drugs. The clinical efficacy of cefepime has been demonstrated in comparative and noncomparative trials in the United States and Europe. Cefepime with twice-daily dosing has been useful in the treatment of lower respiratory tract infections, urinary tract infections, skin and skin structure infections, and in serious infection, including those with associated bacteremia. Cefepime is comparable to ceftazidime in clinical and bacteriologic response rates when both agents are administered three times a day in febrile neutropenic patients. Cefepime is also active against organisms that show resistance to other agents. Several studies have shown that cefepime retains its activity against E. cloacae and E. coli strains resistant to other cephalosporins and against many strains of P. aeruginosa resistant to ceftazidime. Cefepime exhibits a low level of cross-resistance with third-generation cephalosporins and a low propensity for selection of resistant mutants and offers a low potential for the induction of bacterial resistance, which complicates the course of many patients treated with single-agent third-generation therapy. Cefepime should be used in place of ceftazidime based on resistance potential, activity against resistant organisms, and cost.
Topics: Bacterial Infections; Cefepime; Cephalosporins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests
PubMed: 7791419
DOI: 10.1016/s0025-7125(16)30035-9 -
Clinical Infectious Diseases : An... Nov 2019In a multicenter, observational, propensity-score-weighted cohort of 249 adults with uncomplicated Pseudomonas aeruginosa bacteremia, patients receiving short-course... (Randomized Controlled Trial)
Randomized Controlled Trial
In a multicenter, observational, propensity-score-weighted cohort of 249 adults with uncomplicated Pseudomonas aeruginosa bacteremia, patients receiving short-course (median, 9 days; interquartile range [IQR], 8-10) therapy had a similar odds of recurrent infection or death within 30 days as those receiving longer courses (median, 16 days; IQR, 14-17).
Topics: Aged; Bacteremia; Cefepime; Female; Humans; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa
PubMed: 30882137
DOI: 10.1093/cid/ciz223