cefepime and Critical-Illness

COVID-19 as a viral disease has brought up the need to exercise more than before due to its physiological effects on health. Therefore, this study investigates the effect of 12-week of aerobic exercise on female students' hormone levels and lipid profile with polycystic ovary syndrome (PCOS) during the COVID-19 pandemic.. Using a 12-week quasi-experimental with pretest, posttest research design among 40 Iranian female students aged 18-14 with PCOS, we randomly allocated the participants to either an experimental (they performed aerobic exercises three 60-minute sessions per week at home using content production) or a control condition. Their anthropometric and blood samples (e.g., testosterone, estrogen, prolactin, and lipid profile) were taken in two stages before and after the training protocol.. Findings demonstrated that performing aerobic exercises is an effective and non-invasive method that could have a positive effect on young girls' PCOS during COVID-19 pandemic.. La pandémie de COVID-19, en tant que maladie virale, a fait ressortir la nécessité de faire de l’exercice plus que jamais en raison de ses effets physiologiques sur la santé. Par conséquent, cette étude examine l’effet de 12 semaines d’exercice aérobique sur les niveaux hormonaux et le profil lipidique d’étudiantes atteintes du syndrome d’ovaires polykystiques (SOPK) pendant la pandémie de COVID-19.. En utilisant un modèle de recherche quasi-expérimental de 12 semaines avec pré-test, post-test auprès de 40 étudiantes iraniennes âgées de 18 à 14 ans atteintes du SOPK, nous avons réparti au hasard les participantes entre une série expérimentale (elles ont effectué des exercices aérobiques à raison de trois séances de 60 minutes par semaine à la maison) et une série contrôle. Les échantillons anthropométriques et sanguins (testostérone, œstrogène, prolactine et profil lipidique) ont été prélevés en deux étapes, avant et après le protocole d’entraînement.. Les résultats ont démontré que la pratique d’exercices d’aérobic est une méthode efficace et non invasive qui pourrait avoir un effet positif sur le SOPK des jeunes filles pendant la pandémie de COVID-19.. Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.. The online version contains supplementary material available at 10.1007/s13204-023-02822-5.. Embelin is predicted to have a high probability of immunotoxicity potential and affect drug metabolism by inhibiting CYP2D6. In addition, it affects food intake, weight gain, and the number of implantations in pregnant rats. Therefore, it is highly recommended not to take embelin and embelin-rich plants during pregnancy. Further. The online version contains supplementary material available at 10.1007/s42965-023-00306-9.. The online version contains supplementary material available at 10.1007/s11696-023-02771-x.. The online version contains supplementary material available at 10.1007/s00477-023-02476-3.. This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.. Inflammation response do not seem to be enough to explain all the Essure-related adverse outcomes, suggesting the involvement of other biological mechanisms.. NCT03281564.. Inflammation and fibrosis are found in the surrounding tubal tissue around the Essure. Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.. dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.. Inverted microscopy showed that compared with the NC group, the OGD/R group had poor cell status, swollen cytosol, visible cell lysis fragments and significantly lower cell activity [(49.1±2.7)% vs. (100.0±9.7)%, P < 0.01]; compared with the OGD/R group, the HW group had improved cell status and remarkably higher cell activity [(63.3±1.8)% vs. (49.1±2.7)%, P < 0.01]. Transmission electron microscopy showed that the neuronal nuclear membrane of cells in the OGD/R group was lysed and a higher number of autophagic lysosomes were visible compared with the NC group; compared with the OGD/R group, the neuronal damage of cells in the HW group was reduced and the number of autophagic lysosomes was notably decreased. The results of immunofluorescence assay showed that the expressions of LC3 and Beclin-1 were outstandingly enhanced in the OGD/R group compared with the NC group, and the expressions of LC3 and Beclin-1 were markedly weakened in the HW group compared with the OGD/R group. Western blotting assay showed that the expressions were prominently higher in both LC3II/I and Beclin-1 in the OGD/R group compared with the NC group (LC3II/I: 1.44±0.05 vs. 0.37±0.03, Beclin-1/β-actin: 1.00±0.02 vs. 0.64±0.01, both P < 0.01); compared with the OGD/R group, the protein expression of both LC3II/I and Beclin-1 in the HW group cells were notably lower (LC3II/I: 0.54±0.02 vs. 1.44±0.05, Beclin-1/β-actin: 0.83±0.07 vs. 1.00±0.02, both P < 0.01).. Hydrogen-rich water has a significant protective effect on OGD/R-causing HT22 cell injury, and the mechanism may be related to the inhibition of autophagy.. The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.. We recommend using the Art/Zn complex owing to its moderate inhibitory and antiviral effects against the SARS-CoV-2 with a low cytotoxic effect on host (Vero E6) cells. We suggest conducting further prospective studies to investigate the biological effects of Art/Zn in animal models at different concentrations for testing its clinical efficacy and safety in inhibiting SARS-CoV-2 activities.. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Topics: Actin Cytoskeleton; Actins; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenosine Triphosphate; Adsorption; Adult; Africa, Eastern; Aged; Air Pollutants; Air Pollution; Air Pollution, Indoor; Alcohol Drinking; Allergens; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antibodies; Antibodies, Immobilized; Antigen Presentation; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Aptamers, Nucleotide; Asthma; Asthma, Exercise-Induced; Atrophy; Autophagy; Azoospermia; Bacillus cereus; Bacterial Infections; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biofouling; Biological Monitoring; Biomarkers; Biomarkers, Tumor; Biosensing Techniques; Blastocyst; Bone Neoplasms; Bone Regeneration; Bronchoconstriction; Burkitt Lymphoma; C9orf72 Protein; Campylobacter; Campylobacter Infections; Campylobacter jejuni; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Cardiomyopathies; Caregivers; Carmine; Case-Control Studies; Catalysis; Cattle; Cause of Death; CCAAT-Enhancer-Binding Protein-alpha; CD8-Positive T-Lymphocytes; Cefepime; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Transdifferentiation; Chelating Agents; Chemical and Drug Induced Liver Injury, Chronic; Chemoradiotherapy, Adjuvant; Child; Child, Preschool; China; Chlorquinaldol; Cholangiocarcinoma; Cholera; Chromatin; Clinical Trials as Topic; Cognitive Dysfunction; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Colorimetry; Cooking; Coordination Complexes; COVID-19; Creatinine; CRISPR-Cas Systems; Critical Care; Critical Illness; Cross-Sectional Studies; Cryopreservation; Cryoprotective Agents; Cysteine; Cytokines; Device Removal; Diet; Diet, High-Fat; Diet, Mediterranean; Dietary Supplements; Dimethyl Sulfoxide; Dipeptides; Disease Models, Animal; Dithiothreitol; DNA; DNA Repeat Expansion; DNA, Bacterial; DNA, Complementary; Dopamine; Electrochemical Techniques; Electrodes; Endocannabinoids; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Erlotinib Hydrochloride; Escherichia coli; Escherichia coli O157; Esophageal Neoplasms; Esophagitis, Peptic; Ethylene Glycol; Europium; Exanthema; Fallopian Tubes; Feces; Female; Fertilization in Vitro; Fluoresceins; Fluorescent Dyes; Follicle Stimulating Hormone; Follow-Up Studies; Food Microbiology; Forced Expiratory Volume; Forkhead Transcription Factors; Frontotemporal Dementia; G-Quadruplexes; Galactose; Gastroenteritis; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Gastrointestinal Tract; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genital Neoplasms, Female; Genome-Wide Association Study; Genome, Viral; Genomics; Genotype; Glucose; Glutathione; Glycerol; Gold; Graphite; GTPase-Activating Proteins; Heat-Shock Proteins; Heme Oxygenase-1; Hepacivirus; Hepatitis C; Hepatocytes; Histamine; Histocompatibility Antigens Class II; Hoarseness; Hospice and Palliative Care Nursing; Humans; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydroxybenzoates; Hydroxyl Radical; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperthermia, Induced; Hysteroscopy; Immunoassay; Indigo Carmine; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intensive Care Units; Interleukin-11; Interleukin-6; Interleukins; Iodine Radioisotopes; Iran; Iridium; Islets of Langerhans; Kinetics; Lactation; Lactobacillus; Lactobacillus plantarum; Lamins; Latin America; Lead; Lectins; Leukopenia; Ligands; Limit of Detection; Lipopolysaccharides; Lipoprotein Lipase; Liver; Liver Cirrhosis; Liver Neoplasms; Lolium; Luminescent Measurements; Luminol; Lung; Luteinizing Hormone; Macrophages; Magnetic Phenomena; Magnetic Resonance Imaging; Male; Malnutrition; Maltose; Manganese Compounds; Maternal Nutritional Physiological Phenomena; Melatonin; Metabolic Engineering; 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Polymorphism, Single Nucleotide; Polysomnography; Postoperative Complications; Pregnancy; Pregnant Women; Prenatal Exposure Delayed Effects; Prevalence; Printing, Three-Dimensional; Probability; Probiotics; Prognosis; Prophages; Prospective Studies; Proteomics; Proto-Oncogene Proteins; Pseudomonas aeruginosa; Pseudomonas putida; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Pyridines; Pyrroles; Quality of Life; Quinolones; Rabbits; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Histamine; Receptors, Histamine H2; Recombinases; Rectal Neoplasms; Reperfusion Injury; Respiration; Respiratory Function Tests; Respiratory Rate; Respiratory Sounds; Retrospective Studies; rho GTP-Binding Proteins; Risk Assessment; Risk Factors; RNA; RNA, Messenger; RNA, Ribosomal, 16S; Robotic Surgical Procedures; Running; Rural Population; Saccharomyces cerevisiae; Salpingectomy; Sarcopenia; SARS-CoV-2; Seeds; Semen; Sensitivity and Specificity; Sepsis; Shock, Septic; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Skin Neoplasms; Sleep Apnea, Obstructive; Soil; Spain; Spectrum Analysis, Raman; Sperm Retrieval; Spermatozoa; Spirometry; Staphylococcus aureus; STAT3 Transcription Factor; Stereoisomerism; Sterilization, Tubal; Stroke Volume; Sulfadiazine; Sulfites; Superoxide Dismutase; Surface Plasmon Resonance; tau Proteins; Testis; Testosterone; Thioredoxin-Disulfide Reductase; Thyroid Neoplasms; Thyroidectomy; Trans-Activators; Transcription Factor AP-1; Treatment Outcome; Triazoles; Triclosan; Trifluridine; Tumor Microenvironment; Tumor Necrosis Factor-alpha; United States; Uracil; Vagina; Vegetables; Ventricular Function, Left; Ventricular Pressure; Vibrio cholerae; Vietnam; Virulence; Vital Capacity; Vitrification; Walking; Water; Water Pollutants, Radioactive; Whole Genome Sequencing; Wind; YAP-Signaling Proteins; Zeolites; Zinc Oxide

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

To summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin-tazobactam, meropenem, and cefepime.. Gram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin-tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy.. Based on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Humans; Infusions, Intravenous; Intensive Care Units; Length of Stay; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors; Treatment Outcome

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Computer Simulation; Critical Illness; Humans; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Penicillanic Acid; Piperacillin; Renal Replacement Therapy; Sepsis; Tazobactam; Thienamycins

Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.. We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.. A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.. The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefepime; Cefpirome; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Infections; Meropenem; Piperacillin; Thienamycins

Sepsis and nosocomial infections continue to be a significant problem in intensive care, contributing heavily to mortality and prolonged hospital stay. Early and appropriate antibiotic therapy is critical for optimising outcomes. However, the emergence of highly resistant bacteria, coupled with reduced development of novel antibiotics, means that there is a real threat of development of untreatable nosocomial infections. Cefepime and ceftazidime are broad-spectrum cephalosporins that are widely used to treat Gram-negative nosocomial infections in critically ill patients. Available data suggest that cefepime may have advantages over ceftazidime owing to a broader spectrum of activity and reduced potential for development of bacterial resistance. However, whether either of these agents is superior can only be determined by a head-to-head study evaluating clinical and bacteriological outcomes. Such a study to determine whether apparent differences translate into clinically relevant differences in outcome is indicated.

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Community-Acquired Infections; Critical Illness; Cross Infection; Drug Resistance; Economics, Pharmaceutical; Humans; Pneumonia, Bacterial

COVID-19 as a viral disease has brought up the need to exercise more than before due to its physiological effects on health. Therefore, this study investigates the effect of 12-week of aerobic exercise on female students' hormone levels and lipid profile with polycystic ovary syndrome (PCOS) during the COVID-19 pandemic.. Using a 12-week quasi-experimental with pretest, posttest research design among 40 Iranian female students aged 18-14 with PCOS, we randomly allocated the participants to either an experimental (they performed aerobic exercises three 60-minute sessions per week at home using content production) or a control condition. Their anthropometric and blood samples (e.g., testosterone, estrogen, prolactin, and lipid profile) were taken in two stages before and after the training protocol.. Findings demonstrated that performing aerobic exercises is an effective and non-invasive method that could have a positive effect on young girls' PCOS during COVID-19 pandemic.. La pandémie de COVID-19, en tant que maladie virale, a fait ressortir la nécessité de faire de l’exercice plus que jamais en raison de ses effets physiologiques sur la santé. Par conséquent, cette étude examine l’effet de 12 semaines d’exercice aérobique sur les niveaux hormonaux et le profil lipidique d’étudiantes atteintes du syndrome d’ovaires polykystiques (SOPK) pendant la pandémie de COVID-19.. En utilisant un modèle de recherche quasi-expérimental de 12 semaines avec pré-test, post-test auprès de 40 étudiantes iraniennes âgées de 18 à 14 ans atteintes du SOPK, nous avons réparti au hasard les participantes entre une série expérimentale (elles ont effectué des exercices aérobiques à raison de trois séances de 60 minutes par semaine à la maison) et une série contrôle. Les échantillons anthropométriques et sanguins (testostérone, œstrogène, prolactine et profil lipidique) ont été prélevés en deux étapes, avant et après le protocole d’entraînement.. Les résultats ont démontré que la pratique d’exercices d’aérobic est une méthode efficace et non invasive qui pourrait avoir un effet positif sur le SOPK des jeunes filles pendant la pandémie de COVID-19.. Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.. The online version contains supplementary material available at 10.1007/s13204-023-02822-5.. Embelin is predicted to have a high probability of immunotoxicity potential and affect drug metabolism by inhibiting CYP2D6. In addition, it affects food intake, weight gain, and the number of implantations in pregnant rats. Therefore, it is highly recommended not to take embelin and embelin-rich plants during pregnancy. Further. The online version contains supplementary material available at 10.1007/s42965-023-00306-9.. The online version contains supplementary material available at 10.1007/s11696-023-02771-x.. The online version contains supplementary material available at 10.1007/s00477-023-02476-3.. This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.. Inflammation response do not seem to be enough to explain all the Essure-related adverse outcomes, suggesting the involvement of other biological mechanisms.. NCT03281564.. Inflammation and fibrosis are found in the surrounding tubal tissue around the Essure. Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.. dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.. Inverted microscopy showed that compared with the NC group, the OGD/R group had poor cell status, swollen cytosol, visible cell lysis fragments and significantly lower cell activity [(49.1±2.7)% vs. (100.0±9.7)%, P < 0.01]; compared with the OGD/R group, the HW group had improved cell status and remarkably higher cell activity [(63.3±1.8)% vs. (49.1±2.7)%, P < 0.01]. Transmission electron microscopy showed that the neuronal nuclear membrane of cells in the OGD/R group was lysed and a higher number of autophagic lysosomes were visible compared with the NC group; compared with the OGD/R group, the neuronal damage of cells in the HW group was reduced and the number of autophagic lysosomes was notably decreased. The results of immunofluorescence assay showed that the expressions of LC3 and Beclin-1 were outstandingly enhanced in the OGD/R group compared with the NC group, and the expressions of LC3 and Beclin-1 were markedly weakened in the HW group compared with the OGD/R group. Western blotting assay showed that the expressions were prominently higher in both LC3II/I and Beclin-1 in the OGD/R group compared with the NC group (LC3II/I: 1.44±0.05 vs. 0.37±0.03, Beclin-1/β-actin: 1.00±0.02 vs. 0.64±0.01, both P < 0.01); compared with the OGD/R group, the protein expression of both LC3II/I and Beclin-1 in the HW group cells were notably lower (LC3II/I: 0.54±0.02 vs. 1.44±0.05, Beclin-1/β-actin: 0.83±0.07 vs. 1.00±0.02, both P < 0.01).. Hydrogen-rich water has a significant protective effect on OGD/R-causing HT22 cell injury, and the mechanism may be related to the inhibition of autophagy.. The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.. We recommend using the Art/Zn complex owing to its moderate inhibitory and antiviral effects against the SARS-CoV-2 with a low cytotoxic effect on host (Vero E6) cells. We suggest conducting further prospective studies to investigate the biological effects of Art/Zn in animal models at different concentrations for testing its clinical efficacy and safety in inhibiting SARS-CoV-2 activities.. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Topics: Actin Cytoskeleton; Actins; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenosine Triphosphate; Adsorption; Adult; Africa, Eastern; Aged; Air Pollutants; Air Pollution; Air Pollution, Indoor; Alcohol Drinking; Allergens; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antibodies; Antibodies, Immobilized; Antigen Presentation; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Aptamers, Nucleotide; Asthma; Asthma, Exercise-Induced; Atrophy; Autophagy; Azoospermia; Bacillus cereus; Bacterial Infections; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biofouling; Biological Monitoring; Biomarkers; Biomarkers, Tumor; Biosensing Techniques; Blastocyst; Bone Neoplasms; Bone Regeneration; Bronchoconstriction; Burkitt Lymphoma; C9orf72 Protein; Campylobacter; Campylobacter Infections; Campylobacter jejuni; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Cardiomyopathies; Caregivers; Carmine; Case-Control Studies; Catalysis; Cattle; Cause of Death; CCAAT-Enhancer-Binding Protein-alpha; CD8-Positive T-Lymphocytes; Cefepime; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Transdifferentiation; Chelating Agents; Chemical and Drug Induced Liver Injury, Chronic; Chemoradiotherapy, Adjuvant; Child; Child, Preschool; China; Chlorquinaldol; Cholangiocarcinoma; Cholera; Chromatin; Clinical Trials as Topic; Cognitive Dysfunction; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Colorimetry; Cooking; Coordination Complexes; COVID-19; Creatinine; CRISPR-Cas Systems; Critical Care; Critical Illness; Cross-Sectional Studies; Cryopreservation; Cryoprotective Agents; Cysteine; Cytokines; Device Removal; Diet; Diet, High-Fat; Diet, Mediterranean; Dietary Supplements; Dimethyl Sulfoxide; Dipeptides; Disease Models, Animal; Dithiothreitol; DNA; DNA Repeat Expansion; DNA, Bacterial; DNA, Complementary; Dopamine; 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Neurocritically ill patients have clinically significant alterations in pharmacokinetic parameters of renally eliminated medications that may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations.. We conducted a prospective randomized open-label study of adult neurocritically ill patients treated with vancomycin and cefepime. Vancomycin 15 mg/kg and cefepime 2 g were dosed at every-8- or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic (PD) targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT > MIC ≥ 60%) for β-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin.. Twenty patients were included in the study. They were divided equally between the every-12-hour and every-8-hour dosing groups. Patients (mean age 51.8 ± 11 yrs) were primarily male (60%) and white (95%), and most had an admission diagnosis of intracranial hemorrhage (80%). Compared with the every-12-hour group, the every-8-hour vancomycin group achieved target trough concentrations (higher than 15 μg/ml) significantly more frequently at initial measurement (0% vs 80%, p<0.01) and at 7-10 days (0% vs 90%, p=0.045) and achieved PD targets more frequently at increasing MICs. Similarly, compared with every-12-hour dosing, the every-8-hour cefepime dosing strategy significantly increased PD target attainment (fT > MIC ≥ 60%) at an MIC of 8 μg/ml (20% vs 70%, p=0.02).. This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal PD targets in adult neurocritically ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance.

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Drug Administration Schedule; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Vancomycin

Several population pharmacokinetic models for cefepime in critically ill patients have been described, which all indicate that variability in renal clearance is the main determinant of the observed variability in exposure. The main objective of this study was to determine which renal marker best predicts cefepime clearance.. A pharmacokinetic model was developed using NONMEM based on 208 plasma and 51 urine samples from 20 ICU patients during a median follow-up of 3 days. Four serum-based kidney markers (creatinine, cystatin C, urea and uromodulin) and two urinary markers [measured creatinine clearance (CLCR) and kidney injury molecule-1] were evaluated as covariates in the model.. A two-compartment model incorporating a renal and non-renal clearance component along with an additional term describing haemodialysis clearance provided an adequate description of the data. The Cockcroft-Gault formula was the best predictor for renal cefepime clearance. Compared with the base model without covariates, the objective function value decreased from 1971.7 to 1948.1, the median absolute prediction error from 42.4% to 29.9% and the between-subject variability in renal cefepime clearance from 135% to 50%. Other creatinine- and cystatin C-based formulae and measured CLCR performed similarly. Monte Carlo simulations using the Sanford guide dose recommendations indicated an insufficient dose reduction in patients with a decreased kidney function, leading to potentially toxic levels.. The Cockcroft-Gault formula was the best predictor for cefepime clearance in critically ill patients, although other creatinine- and cystatin C-based formulae and measured CLCR performed similarly.

Topics: Aged; Anti-Bacterial Agents; Biomarkers; Cefepime; Cephalosporins; Critical Illness; Female; Humans; Intensive Care Units; Kidney; Kidney Function Tests; Male; Metabolic Clearance Rate; Plasma; Urine

The study aimed to characterize the pharmacokinetics (PK) of four β-lactams (piperacillin, ceftazidime, cefepime, and meropenem) in patients comedicated with amikacin (AMK), and to confirm the predictive performance of AMK data, obtained from therapeutic drug monitoring (TDM), on these PK, using a population modeling approach.. Serum samples were collected in 88 critically ill septic patients. For each β-lactam, the covariate model was optimized using renal function. Furthermore, predictive performance of AMK concentrations and PK parameters was assessed on β-lactam PK.. A two-compartment model with first-order elimination best fitted the β-lactam data. Results supported the superiority of AMK concentrations, over renal function and AMK PK parameters, to assess the β-lactam PK.. The study confirmed the significant link between the exposure to AMK and to β-lactams, and presented population models able to guide β-lactam dosage adjustments using renal biomarkers or TDM-related aminoglycoside data.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Amikacin; Anti-Bacterial Agents; beta-Lactams; Cefepime; Ceftazidime; Cephalosporins; Critical Illness; Drug Monitoring; Female; Humans; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Models, Biological; Piperacillin; Sepsis; Thienamycins; Tissue Distribution; Treatment Outcome

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups--26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K(slope) pharmacokinetic model relating the elimination rate constant (K(10)) to renal function, as defined by creatinine clearance (CL(CR)), and central distribution volume (V(1)) to total body weight (TBW). The final model was described by the following equations: K(10) = 0.0027 x CL(CR) + 0.071 h(-1) and V(1) = TBW x 0.21 liter/kg. The median intercompartmental transfer constants K(12) and K(21) were 0.780 h(-1) and 0.472 h(-1), respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 microg/ml, 24.0 microg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of -1.64 microg/ml, 17.1 microg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 microg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefepime; Cephalosporins; Critical Illness; Humans; Metabolic Clearance Rate; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Ventilator-Associated

This study evaluated retrospectively the efficacy of treatment with cefepime vs. a carbapenem, in combination with amikacin or ciprofloxacin, for seriously-ill patients infected with ESBL-producing Enterobacter aerogenes who were admitted to an intensive care unit. Forty-four episodes of infection were investigated in 43 patients: 21 treated with cefepime; 23 with a carbapenem. The two treatment groups did not differ statistically in terms of age, APACHE II scores, and infection sites, but the average duration of antibiotic exposure was significantly shorter in the cefepime group (8.5 days vs. 11.4 days; p 0.04). Clinical improvement was seen in 62% of patients receiving cefepime vs. 70% of patients receiving a carbapenem (p 0.59). Bacteriological eradication was achieved in 14% of patients receiving cefepime vs. 22% of patients receiving a carbapenem (p 0.76). The 30-day mortality rates related to infection were 33% in the cefepime group and 26% in the carbapenem group (p 0.44). Thus, outcome parameters did not differ significantly between the two groups. Nevertheless, a statistically significant increase in failure to eradicate ESBL-producing E. aerogenes was observed as the MICs of cefepime rose (p 0.017). Pulsed-field gel electrophoresis revealed three distinct clones, but one predominant clone harbouring the bla(TEM-24) gene was associated with most (42/44) of the episodes of infection. It was concluded that cefepime may be an alternative agent for therapy of severe infections caused by TEM-24 ESBL-producing E. aerogenes, although further studies are required to confirm these observations.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Cefepime; Cephalosporins; Critical Illness; Cross Infection; Drug Therapy, Combination; Enterobacter aerogenes; Enterobacteriaceae Infections; Female; Humans; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Treatment Outcome

The aim of this study was to compare the pharmacokinetic and pharmacodynamic parameters of a continuous infusion of cefepime vs. an intermittent regimen in critically ill adult patients with Gram-negative bacilli infection. The prospective randomized parallel study was carried out in 50 patients with severe pneumonia (n = 41) or bacteremia (n = 9). They received cefepime 4 g/d either as a continuous infusion or intermittent administration 2 x 2 g in combination with amikacin. Patient characteristics and the minimal inhibitory concentration (MIC) of the isolated bacteria were comparable. Clinical outcomes were assessed along with pharmacodynamic indices and compared in both groups (chi2 and Mann-Whitney U-tests). Mechanical ventilation, clinical outcome and bacteriological eradication did not significantly differ between the two groups. Also, the area under the plasma cefepime concentration curve at steady state (AUCss: 612 +/- 369 vs. 623 +/- 319 mg x 1(-1) x h), AUCss > MIC (595 +/- 364 vs. 606 +/- 316 mg x 1(-1) x h) and the area under the inhibitory concentration curve (AUICss: 4258 +/- 5819 vs. 5194 +/- 7465 mg x 1(-1) x h) were similar. If the time above MIC (t > MIC) was not significantly higher in Group 1 (100 +/- 0%) than in Group 2 (90 +/- 11%), t > five-fold MIC in Group 1 (100 +/- 0%) was significantly higher (p < 0.01) than in Group 2 (82 +/- 25%). The mean time over the French breakpoint (4 mg/l) was 100 +/- 0% and 72 +/- 27% in Group 1 and 2 (p < 0.001), respectively. In contrast to intermittent cefepime administration, continuous infusion of cefepime consistently maintained a serum concentration > 5 x the MIC of typical Gram-negative nosocomial pathogens. This results in greater bactericidal activity against organisms with a higher (2 mg/l) cefepime breakpoint even if the clinical outcome is not significantly modified.

Topics: Adult; Aged; Amikacin; Anti-Bacterial Agents; Area Under Curve; Cefepime; Cephalosporins; Critical Illness; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome

The pharmacokinetics of cefepime were studied in 12 adult patients in intensive care units during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) with a Multiflow60 AN69HF 0.60-m(2) polyacrylonitrile hollow-fiber membrane (Hospal Industrie, Meyzieu, France). Patients (mean age, 52.0 +/- 13.0 years [standard deviation]; mean weight, 96.7 +/- 18.4 kg) received 1 or 2 g of cefepime every 12 or 24 h (total daily doses of 1 to 4 g/day) by intravenous infusion over 15 to 30 min. Pre- and postmembrane blood (serum) samples and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, 8, and 12 or 24 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t(1/2)) of cefepime were 35.9 +/- 6.0 ml/min and 12.9 +/- 2.6 h during CVVH versus 46.8 +/- 12.4 ml/min and 8.6 +/- 1.4 h during CVVHDF, respectively. Cefepime clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 40 and 59% of CL(S), respectively. The results of this study confirm that continuous renal replacement therapy contributes substantially to total CL(S) of cefepime and that CVVHDF appears to remove cefepime more efficiently than CVVH. Cefepime doses of 2 g/day (either 2 g once daily or 1 g twice daily) appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC

Topics: Adult; Aged; Area Under Curve; Cefepime; Cephalosporins; Chromatography, High Pressure Liquid; Critical Illness; Female; Hemofiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Spectrophotometry, Ultraviolet

The pharmacokinetics of a 2-g bolus of cefepime were measured in critically ill patients with normal renal function. Variable and low trough plasma drug concentrations were found, and 8 of 10 patients had levels below the MIC at which 50% of the isolates are inhibited for Pseudomonas aeruginosa. Computer simulations predicted that continuous infusion and shorter dosing intervals would increase trough levels.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefepime; Cephalosporins; Computer Simulation; Critical Illness; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Pseudomonas aeruginosa

The aim of this study was to compare the achievement of therapeutic pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for beta-lactam antibiotics using product information dosing or guideline-based dosing for the treatment of serious infections.. In silico study.. ID-ODS. None.. In silico product information and guideline-based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK-PD targets. A multiple linear regression model was constructed to identify the effect of guideline-based dosing covariates on achieving pre-defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline-based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline-based and product information-based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline-based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA.. Our study demonstrated that achievement of PK-PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline-based dosing; especially at 48 h.

Topics: Adult; Anti-Bacterial Agents; Cefepime; Ceftazidime; Critical Illness; Humans; Lactams; Meropenem; Microbial Sensitivity Tests

Evidence regarding acute kidney injury associated with concomitant administration of vancomycin and piperacillin-tazobactam is conflicting, particularly in patients in the ICU.. Does a difference exist in the association between commonly prescribed empiric antibiotics on ICU admission (vancomycin and piperacillin-tazobactam, vancomycin and cefepime, and vancomycin and meropenem) and acute kidney injury?. This was a retrospective cohort study using data from the eICU Research Institute, which contains records for ICU stays between 2010 and 2015 across 335 hospitals. Patients were enrolled if they received vancomycin and piperacillin-tazobactam, vancomycin and cefepime, or vancomycin and meropenem exclusively. Patients initially admitted to the ED were included. Patients with hospital stay duration of < 1 h, receiving dialysis, or with missing data were excluded. Acute kidney injury was defined as Kidney Disease: Improving Global Outcomes stage 2 or 3 based on serum creatinine component. Propensity score matching was used to match patients in the control (vancomycin and meropenem or vancomycin and cefepime) and treatment (vancomycin and piperacillin-tazobactam) groups, and ORs were calculated. Sensitivity analyses were performed to study the effect of longer courses of combination therapy and patients with renal insufficiency on admission.. Thirty-five thousand six hundred fifty-four patients met inclusion criteria (vancomycin and piperacillin-tazobactam, n = 27,459; vancomycin and cefepime, n = 6,371; vancomycin and meropenem, n = 1,824). Vancomycin and piperacillin-tazobactam was associated with a higher risk of acute kidney injury and initiation of dialysis when compared with that of both vancomycin and cefepime (Acute kidney injury: OR, 1.37 [95% CI, 1.25-1.49]; dialysis: OR, 1.28 [95% CI, 1.14-1.45]) and vancomycin and meropenem (Acute kidney injury: OR, 1.27 [95%, 1.06-1.52]; dialysis: OR, 1.56 [95% CI, 1.23-2.00]). The odds of acute kidney injury developing was especially pronounced in patients without renal insufficiency receiving a longer duration of vancomycin and piperacillin-tazobactam therapy compared with vancomycin and meropenem therapy.. VPT is associated with a higher risk of acute kidney injury than both vancomycin and cefepime and vancomycin and meropenem in patients in the ICU, especially for patients with normal initial kidney function requiring longer durations of therapy. Clinicians should consider vancomycin and meropenem or vancomycin and cefepime to reduce the risk of nephrotoxicity for patients in the ICU.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Cefepime; Critical Illness; Drug Therapy, Combination; Humans; Meropenem; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Vancomycin

We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis.. A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions.. The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion.. Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as individual patients' renal function, our PTA results may represent useful references for physicians to make dosing decisions.

Topics: Anti-Bacterial Agents; Cefepime; Chromatography, Liquid; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method; Prospective Studies; Tandem Mass Spectrometry

To investigate and describe the variability in cefepime exposures among 'real-world', critically ill patients by using population pharmacokinetic modelling and simulations, and with translation of these findings to visualizations.. A cohort of adult medical ICU patients who received cefepime with therapeutic drug monitoring was studied. Two compartment models were developed to estimate cefepime clearance (Model 1) and simulate cefepime exposures among 1000 patients, each with identical creatinine clearance of 60 mL/min and receiving a regimen of cefepime 1 gram IV over 30 minutes, every 8 hours (Model 2). Variability in the relationship between cefepime clearance and creatinine clearance (CrCL) was visualized, and a random, representative sample of 10 simulated patients was utilized to illustrate variability in cefepime exposures.. A total of 75 adult medical ICU patients (52% female) and 98 serum cefepime samples were included in the study. Population parameter estimates for cefepime displayed a wide range of variation in Model 1 (CV: 45% to 95%), with low bias at the individual level at 0.226 mg/L but high bias in the population model 10.6 mg/L. Model 2 displayed similar fits, demonstrating that correcting for individual patient creatinine clearance slightly improves the bias of the population model (bias = 4.31 mg/L). Among 10 simulated patients that a clinician would deem similar from a dosing perspective (i.e. equivalent creatinine clearance), maximum concentrations after three simulated doses varied more than 8-fold from 41.2 to 339 mg/L at the 5th and 95th percentiles, and clearance profiles were highly different.. Creatinine clearance estimates alone are inadequate for predicting cefepime exposures. Wide variations in cefepime exposure exist among ICU patients, even for those with similar kidney function estimates. Current population adjustment schemes based solely on creatinine clearance will result in unintended high and low exposures leading to safety and efficacy concerns, respectively.

Topics: Adult; Anti-Bacterial Agents; Cefepime; Creatinine; Critical Illness; Drug Monitoring; Female; Humans; Male

Cefepime is an antibiotic commonly used to treat sepsis and is cleared by renal excretion. Cefepime dosing requires adjustment in patients with decreased kidney function and in those receiving continuous kidney replacement therapy (CKRT). We aimed to characterize cefepime PK in a diverse cohort of critically ill paediatric patients on CKRT.. Patients were identified from an ongoing pharmacokinetic/pharmacodynamic (PK/PD) study of beta-lactam antibiotics, and were included if they had received at least two cefepime doses in the ICU and were on CKRT for at least 24 h. PK parameters were estimated using MwPharm++ with Bayesian estimation and a paediatric population PK model. Target attainment was assessed as time of free cefepime concentrations above minimum inhibitory concentration (fT > 1× or 4 × MIC).. Seven patients were included in the study (ages 2 to 20 years). CKRT indications included liver failure (n = 1), renal failure (n = 4) and fluid overload (n = 2). Total effluent flow rates ranged from 1833 to 3115 (mean 2603) mL/1.73 m2/h, while clearance was 2.11-3.70 (mean 3.0) L/h/70 kg. Effluent flows were lower, but clearance and fT > MIC were similar to paediatric data published previously. Using Pseudomonas aeruginosa MIC breakpoints, all patients had 100% of dosing interval above MIC, but only one had 100% of dosing interval above 4× MIC.. Since most patients failed to attain stringent targets of 100% fT > 4×  MIC, model-informed precision dosing may benefit such patients.

Topics: Anti-Bacterial Agents; Bayes Theorem; Cefepime; Child; Continuous Renal Replacement Therapy; Critical Illness; Humans; Microbial Sensitivity Tests; Young Adult

β-Lactams are the most commonly used antibiotics in intensive care units (ICUs). As critically ill patients often experience pharmacokinetic aberrations, and rates of antimicrobial resistance vary between hospital settings, reliance on tertiary sources or package labeling to guide empiric dosing often results in suboptimal β-lactam exposure. The primary objective was to identify β-lactam regimens capable of achieving ≥90% cumulative fraction of response (CFR) against 7 Gram-negative pathogens within 4 ICUs at our institution. Unit-specific minimal inhibitory concentration (MIC) distribution data was used in combination with published pharmacokinetic parameters in critically ill patients to perform Monte Carlo simulations. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (%ƒT > MIC) was used as the pharmacodynamic target: 70%ƒT >MIC for cefepime, 40%ƒT > MIC for meropenem, and 50%ƒT > MIC for piperacillin/tazobactam. Regimens were modeled to determine the likelihood of achieving ≥90% CFR. Overall, intermittently dosed cefepime, meropenem, and piperacillin/tazobactam failed to achieve ≥90% CFR for every organism. Cefepime 2 g intermittent bolus every 8 hours failed to achieve ≥90% CFR for Klebsiella pneumoniae or Enterobacter cloacae despite susceptibility rates exceeding 90%. Piperacillin/tazobactam 4.5 g prolonged infusion (PI) every 6 hours achieved <85% CFR for Pseudomonas aeruginosa and <50% CFR for Acinetobacter baumannii in every ICU. Meropenem 2 g PI every 8 hours and meropenem 2 g PI every 6 hours were the only regimens capable of achieving ≥90% CFR for P aeruginosa in all units. Use of Monte Carlo simulations, with incorporation of local MIC distribution data, provides a mechanism to effectively predict optimal agent and dose selection within specific hospital systems, thereby enhancing pharmacokinetic/pharmacodynamic optimization and improving clinical efficacy.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefepime; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Piperacillin; Pseudomonas aeruginosa; Tazobactam

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Cefepime; Continuous Renal Replacement Therapy; Critical Illness; Humans; Intensive Care Units; Renal Replacement Therapy

The risk of acute kidney injury (AKI) associated with concomitant vancomycin and piperacillin/tazobactam in the intensive care unit (ICU) remains controversial. The aim of this study was to compare the AKI incidence associated with concomitant vancomycin and piperacillin/tazobactam compared to either cefepime or meropenem with vancomycin in the ICU.. A multicenter, retrospective, propensity score-matched cohort study was conducted in adult ICU patients administered vancomycin in combination with either piperacillin/tazobactam, cefepime, or meropenem were included. Patients developing AKI ≤48 h following combination therapy initiation were excluded. The primary endpoint was to compare the incidence of AKI associated with concomitant antimicrobial therapy. Multivariable Cox regression modeling in predicting AKI was also conducted.. A total of 1044 patients were matched. The AKI incidence in vancomycin- piperacillin/tazobactam and vancomycin-cefepime/meropenem groups were 21.9% and 16.8%, respectively (p = 0.068). Multivariable prediction models showed concomitant vancomycin-piperacillin/tazobactam was an independent risk factor of AKI using serum creatinine only (HR 1.52, 1.10-2.10, p = 0.011) and serum creatinine with urine output-based KDIGO criteria (HR 1.77, 1.18-2.67, p = 0.006). No significant differences between groups were observed for AKI recovery patterns or mortality.. Concomitant vancomycin and piperacillin/tazobactam administration in adult ICU patients was independently associated with an increased risk of AKI.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Cefepime; Cohort Studies; Critical Illness; Drug Therapy, Combination; Humans; Meropenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Propensity Score; Retrospective Studies; Vancomycin

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.. 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.. 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.. 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.

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Prospective Studies

This study aimed to determine optimal extended-infusion dosing regimens for cefepime and ceftazidime in critically ill patients receiving continuous renal replacement therapy using Monte Carlo Simulations (MCS).. Pharmacokinetic models were built using published pharmacokinetic/demographic data to predict drug disposition in 5000 virtual critically ill patients receiving continuous venovenous hemofiltration (CVVH) with the standard (20-30 mL/kg/h) and a higher (40 mL/kg/h) effluent rates. MCS was performed to assess the probability of target attainment (PTA) of four cefepime and ceftazidime doses administered over 4-h with the target of ≥60% fT > 4×MIC. The lowest dose attaining PTA ≥90% during the first 48-h was considered optimal. Additionally, risk of drug toxicity was assessed at 48-h using suggested neurotoxicity thresholds.. Cefepime 2 g loading dose (LD), then extended-infusion of 2 g q8hr was optimal in CVVH at 20 mL/kg/h and the same ceftazidime dose was optimal in CVVH at 20-30 mL/kg/h. Higher cefepime and ceftazidime doses were required to be optimal at higher effluent rates. This optimal dose particularly for cefepime likely increases neurotoxicity risk in most virtual patients with all CVVH settings.. Cefepime and ceftazidime 2 g LD, followed by extended-infusion 2 g q8hr may be optimal in CVVH with standard effluent rates.

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Continuous Renal Replacement Therapy; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Continuous Renal Replacement Therapy; Critical Illness; Humans; Renal Replacement Therapy

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Continuous Renal Replacement Therapy; Critical Illness; Humans; Renal Replacement Therapy

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Microbial Sensitivity Tests

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

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.. 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.. 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).. 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

Optimization of antimicrobial therapy is a challenge in critically ill patients who develop extreme interindividual and intraindividual pharmacokinetic variability. Therapeutic drug monitoring is a valuable tool for maximizing the effect of a drug and minimizing its adverse and unwanted effects. The aim of the current work was to develop and validate an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine multiple antibiotics in clinical plasma samples from critically ill patients; low sample volume and rapid processing of samples were considered the main criteria.. A separation method based on an online combination of UHPLC-MS/MS was developed for the simultaneous determination of 4 β-lactam antibiotics (cefepime, meropenem, cefotaxime, and piperacillin), tazobactam, and linezolid in human plasma samples. The volume of plasma sample used for analysis was 20 µL. The developed method was validated according to Food and Drug Administration guidelines.. The chromatographic run time was 8 minutes. Calibration curves were linear for concentration ranges of 0.1-100 mcg/mL (r 2 > 0.99) for tazobactam, meropenem, cefotaxime, linezolid, and piperacillin and 1-100 mcg/mL (r 2 > 0.99) for cefepime. The intraday and interday accuracy of the method ranged from 92.4% to 110.7% and 93.6% to 113.3%, respectively. The intraday and interday precision values were ≤17.3% and ≤17.4%, respectively. No interfering and carryover analytes were observed.. The developed UHPLC-MS/MS method is an appropriate and practical tool for therapeutic drug monitoring of the selected antibiotics. Owing to its rapidity, requirement of low sample volume, and high selectivity, sensitivity, and reliability, it can be effectively implemented in routine clinical laboratory tests for critically ill patients.

Topics: Anti-Bacterial Agents; Cefepime; Cefotaxime; Chromatography, High Pressure Liquid; Critical Illness; Drug Monitoring; Humans; Linezolid; Meropenem; Monobactams; Piperacillin; Reproducibility of Results; Tandem Mass Spectrometry; Tazobactam

The average body weight is smaller in Asian patients compared with Western patients, but influence of body weight in antibiotic dosing is unknown. This study was to predict the optimal ceftazidime, cefepime, meropenem, piperacillin/tazobactam doses in Asian patients undergoing continuous venovenous hemofiltration (CVVH).. Monte Carlo simulations (MCS) were performed using published Asian demographics and pharmacokinetics parameters in 5000 virtual patients at three CVVH effluent rates (Qeff; 20, 30, 40 mL/kg/h). Various dosing regimens were assessed for the probability of target attainments using 60% fT > 1 × MIC or 4xMIC and neurotoxicity risk at 48-h using suggested neurotoxicity thresholds.. Ceftazidime 1 g q12h, meropenem 1 g q12h, and piperacillin/tazobactam 3.375 g q6h were optimal for all Qeff settings against fT > 1 × MIC. Cefepime 2 g q24h and 2 g q12h were optimal at 20 and 30-40 mL/kg/h respectively. For the aggressive PD target (4 × MIC), optimal ceftazidime regimens were 1.25 g q8h (20-30 mL/kg/h) and 1.5 g q8h (40 mL/kg/h). Cefepime 2 g q8h and meropenem 1 g q8h were optimal at all Qeff settings. No simulated piperacillin doses attained the aggressive PD target. Increased neurotoxicity risk was predicted with ceftazidime and cefepime doses attaining the efficacy.. MCS enabled the prediction of optimal β-lactam dosing regimens for Asian patients receiving CVVH at varying Qeff. Clinical validation is warranted.

Topics: Anti-Bacterial Agents; Body Weight; Cefepime; Ceftazidime; Critical Illness; Humans; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination

Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality rates are high in this patient population. The high mortality rates are suspected to be, in part, a result of significantly altered drug disposition by the ECLS circuit, resulting in suboptimal antimicrobial dosing. Cefepime is commonly used in critically ill patients with serious infections. Cefepime dosing is not routinely guided by therapeutic drug monitoring and treatment success is dependent upon the percentage of time of the dosing interval that the drug concentration remains above the minimum inhibitory concentration of the organism. This

Topics: Cefepime; Critical Illness; Extracorporeal Membrane Oxygenation; Hemofiltration; Humans; Renal Dialysis

There has been increasing interest in incorporating β-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

Topics: Adolescent; Anti-Bacterial Agents; beta-Lactams; Cefepime; Child; Child, Preschool; Comorbidity; Critical Illness; Feasibility Studies; Female; Humans; Intensive Care Units, Pediatric; Male; Meropenem; Piperacillin; Prospective Studies

Topics: Adolescent; Anti-Bacterial Agents; Cefepime; Continuous Renal Replacement Therapy; Critical Illness; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Renal Replacement Therapy

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).. 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.. Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software.. 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.. 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.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Cefepime; Critical Illness; Drug Dosage Calculations; Humans; Male; Middle Aged; Precision Medicine

Pharmacodynamic and pathophysiologic changes in critically ill adults receiving cefepime may increase the risk of adverse events.. What is the impact of cefepime exposure on neurotoxicity development in critically ill adults with renal dysfunction?. 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.. 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%).. 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.

Topics: Aged; Anti-Bacterial Agents; Cefepime; Critical Care; Critical Illness; Female; Hospital Mortality; Hospitalization; Humans; Kidney Diseases; Male; Middle Aged; Neurotoxicity Syndromes; Retrospective Studies

Topics: Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; beta-Lactams; Betacoronavirus; Cefepime; Coinfection; Confusion; Coronavirus Infections; COVID-19; Critical Illness; Cross Infection; Deep Sedation; Delirium; Drug Monitoring; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Pandemics; Pneumonia, Ventilator-Associated; Pneumonia, Viral; Respiration, Artificial; SARS-CoV-2; Sepsis

Acute encephalopathy (AE) is a common complication of critical illness and is associated with increased short and long-term mortality. In this study, we evaluated the role of cefepime in causing AE.. Retrospective case-control study involving consecutive patients enrolled in the intensive care units (ICUs) of Mayo Clinic Rochester, MN between July 1, 2004 and December 31, 2015. AE was defined by the presence of delirium or depressed level of consciousness in the absence of deep sedation. Controls were identified as patients not developing AE and were matched by propensity score for age, Charlson Comorbidity Index, 24-h Apache III score and invasive ventilation use.. The total number of eligible ICU admissions during our study period was 152,999. AE was present in 57,726 (37.7%) with a median AE duration of 17 (interquartile range [IQR] 4.0-51.8) hours. We matched 14,645 cases with AE with the same number of controls. Cefepime was used in 1241 (4.2%) patients and its use was associated with greater incidence of AE [713 (4.9%) vs 528 (3.6%), p < 0.001] and duration [unit estimate 0.73; (95% CI 0.542-0.918)]. On multivariate analysis, cefepime was associated with an increased likelihood of AE after controlling for shock, midazolam infusion and acute kidney injury [OR 1.24 (95% CI 1.10-1.27)]. These associations were also present after controlling for prior chronic kidney disease.. The use of cefepime is associated with increased likelihood and duration of AE. These associations are stronger among patients with impaired renal function, but can also occur in patients without renal impairment.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Brain Diseases; Case-Control Studies; Cefepime; Critical Illness; Female; Humans; Intensive Care Units; Male; Middle Aged; Retrospective Studies

Topics: Brain Diseases; Case-Control Studies; Cefepime; Critical Illness; Delirium; Humans; Retrospective Studies

Topics: Brain Diseases; Case-Control Studies; Cefepime; Critical Illness; Delirium; Humans; Retrospective Studies

Topics: Brain Diseases; Case-Control Studies; Cefepime; Critical Illness; Humans; Retrospective Studies

There continues to be uncertainty about whether piperacillin/tazobactam (TZP) increases the risk of AKI in critically ill pediatric patients. We sought to compare rates of AKI among critically ill children treated with TZP or cefepime, an alternative frequently used in intensive care units, with and without vancomycin.. We conducted a retrospective cohort study assessing the risk of AKI in pediatric intensive care unit patients after exposure to vancomycin, TZP, and cefepime, alone or in combination, within 48 hours of admission. The primary outcome was development of stage 2 or 3 AKI or an increase in AKI stage from 2 to 3 within the 6 days after the 48-hour exposure window. Secondary outcomes included lengths of stay, need for RRT, and mortality.. Of 5686 patients included, 494 (8.7%) developed stage 2 or 3 AKI. The adjusted odds of developing AKI after medication exposure were 1.56 for TZP (95% confidence interval [95% CI], 1.23 to 1.99), 1.13 for cefepime (95% CI, 0.79 to 1.64), and 0.86 for vancomycin (95% CI, 0.69 to 1.07). The adjusted odds of developing AKI for vancomycin plus TZP versus vancomycin plus cefepime was 1.38 (95% CI, 0.85 to 2.24).. Observational data in critically ill children show that TZP use is associated with increased odds of AKI. A weaker, nonsignificant association between vancomycin plus TZP and AKI compared with vancomycin plus cefepime, creates some uncertainty about the nature of the association between TZP and AKI. However, cefepime is an alternative not associated with AKI.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Cefepime; Child; Child, Preschool; Critical Illness; Female; Humans; Infant; Male; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Vancomycin

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

Topics: Anti-Bacterial Agents; Cefepime; Chromatography, Liquid; Critical Illness; Intensive Care Units; Tandem Mass Spectrometry

Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations.. The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups.. The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09).. Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefepime; Cohort Studies; Critical Illness; Female; Humans; Intensive Care Units; Kidney Function Tests; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas; Pseudomonas Infections; Severity of Illness Index; Vancomycin

Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling.. Multicenter, prospective observational study.. The pediatric and cardiac ICUs of six sites of the Collaborative Pediatric Critical Care Research Network.. Seventeen critically ill children (30 d to < 2 yr old) on extracorporeal membrane oxygenation who received cefepime as standard of care between January 4, 2014, and August 24, 2015, were enrolled.. None.. A pharmacokinetic model was developed to evaluate cefepime disposition differences due to extracorporeal membrane oxygenation. A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg) for a patient weighing 5.8 kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1,170 mL. In the setting of blood transfusions, V1 increased by over two-fold but was reduced with increasing age of the extracorporeal membrane oxygenation circuit oxygenator.. Cefepime clearance was reduced in pediatric patients treated with extracorporeal membrane oxygenation compared with previously reported values in children not receiving extracorporeal membrane oxygenation. The model demonstrated that the age of the extracorporeal membrane oxygenation circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT_minimum inhibitory concentration of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on extracorporeal membrane oxygenation might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing.

Topics: Anti-Bacterial Agents; Body Weight; Cefepime; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Infant; Intensive Care Units, Pediatric; Male; Metabolic Clearance Rate; Models, Biological; Protein Binding

Critically ill patients are frequently treated with empirical antibiotic therapy, including vancomycin and β-lactams. Recent evidence suggests an increased risk of acute kidney injury (AKI) in patients who received a combination of vancomycin and piperacillin-tazobactam (VPT) compared with patients who received vancomycin alone or vancomycin in combination with cefepime (VC) or meropenem (VM), but most studies were conducted predominately in the non-critically ill population. A retrospective cohort study that included 2,492 patients was conducted in the intensive care units of a large university hospital with the primary outcome being the development of any AKI. The rates of any AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, were 39.3% for VPT patients, 24.2% for VC patients, and 23.5% for VM patients (

Topics: Acute Kidney Injury; Aged; Cefepime; Critical Illness; Female; Humans; Incidence; Male; Meropenem; Middle Aged; Multivariate Analysis; Piperacillin; Retrospective Studies; Tazobactam; Vancomycin

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Tazobactam

The objective of this study was to evaluate AKI incidence with concomitant vancomycin and piperacillin/tazobactam (PTZ) compared to vancomycin and cefepime (FEP) in critically ill patients.. A retrospective, cohort study was conducted in adult critically ill patients from January 1, 2014 to December 31, 2017. The primary aim was to compare the incidence of AKI during concomitant therapy or until hospital discharge. Secondary analyses included AKI severity, time to AKI as well as recovery, and clinical outcomes.. Overall, 333 patients were evaluated. The AKI rate in the vancomycin/PTZ group and vancomycin/FEP group were similar (19.5% vs. 17.3%, respectively, p = .612). Renal replacement therapy (RRT) was initiated in 10.0% and 3.8% administered vancomycin/PTZ and vancomycin/FEP groups, respectively (p = .04). Multivariate regression found vancomycin/PTZ was not associated with an increased risk of developing AKI although the presence of shock was identified as an independent risk factor (odds ratio, 3.22; 95% CI, 1.66-6.26). No significant differences in hospital or ICU length of stay or in-hospital mortality were observed between study groups.. Concomitant PTZ and vancomycin in ICU patients was not associated with an increased risk of developing AKI compared to FEP and vancomycin combinations. More patients administered vancomycin/PTZ received RRT.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Cefepime; Critical Illness; Female; Humans; Incidence; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Sepsis

The combination of vancomycin and piperacillin-tazobactam has been associated with an increased risk of acute kidney injury (AKI) in non-critically ill patient populations, but it is still unknown if this association exists in critically ill patients. The objective of this study was to compare the incidence of AKI development during therapy or within 72 hours after completion of therapy in adult critically ill patients who received vancomycin with concomitant piperacillin-tazobactam or cefepime.. Retrospective cohort study.. Medical, surgical, and neuroscience intensive care units (ICUs) within a single tertiary care hospital.. A total of 122 critically ill patients who received at least 48 hours of combination therapy with vancomycin and piperacillin-tazobactam (49 patients) or vancomycin and cefepime (73 patients) during an ICU admission between September 2012 and December 2014.. The primary outcome was AKI development, as determined by the Acute Kidney Injury Network criteria, during combination therapy or within 72 hours of completion of combination therapy. The inverse probability of the treatment-weighting (IPTW) approach was used to account for potential treatment selection bias. AKI incidence was assessed in the unadjusted and propensity score-weighted cohorts. Of the 122 patients, 37 patients (30.3%) developed AKI. In the unadjusted analysis, the incidence of AKI was similar in the piperacillin-tazobactam group compared with the cefepime group (32.7% vs 28.8%, p=0.647). The average treatment effect between the groups was not significant, showing no association between β-lactam choice and AKI (β = -0.004, p=0.958). Secondary outcomes were ICU length of stay, hospital length of stay, AKI duration, and need for renal replacement therapy. The choice of β-lactam was not a significant predictor of any of these outcomes: ICU length of stay (β = 0.436, p=0.780), hospital length of stay (β = 3.819, p=0.125), AKI duration (β = -4.027, p=0.283), and need for renal replacement therapy (β = 2.828, p=0.161).. After adjusting for propensity to receive each of the treatment choices, no significant difference was found in the incidence of AKI development or other outcomes between the groups. The previously described finding that concomitant vancomycin and piperacillin-tazobactam increases AKI in non-critically ill patients may not be generalizable to the critically ill population. Prospective evaluation of this hypothesis is warranted.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Arkansas; Cefepime; Cephalosporins; Critical Illness; Drug Therapy, Combination; Female; Humans; Incidence; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Vancomycin

To report the first case of Rhizobium radiobacter bacteremia in a critically ill trauma patient.. A 36-year-old female trauma patient hospitalized at The Regional Medical Center at Memphis developed bacteremia due to Rhizobium radiobacter on hospital day 9. The central line catheter tip culture from the same hospital day was negative. No source for the R radiobacter bacteremia was identified. Empirical and definitive antibiotic therapy consisted of cefepime 2 g intravenously every 8 hours for at total of 8 days. On completion of antibiotics, the patient demonstrated clinical resolution by immediate defervescence and gradual normalization of her white blood cell count. She demonstrated microbiologic success of therapy with negative blood cultures on hospital days 22, 34, 45, and 61. She was discharged on hospital day 80.. Rhizobium species are common soil and plant pathogens that rarely cause infections in humans. Previous reports of Rhizobium infections have been in immunocompromised patients; generally those with cancer or HIV infection. Intravenous catheters have commonly been cited as the source of infection. The trauma patient in this case constitutes a unique presentation of R radiobacter bacteremia when compared with other case reports. Her indwelling catheter was not the source of her infection, and her only identifiable risk factor for R radiobacter infection was hospitalization. However, she did possess potential reasons for development of an infection with an unusual organism such as R radiobacter. Potential immune modulating therapies included blood transfusions, opioid analgesics, benzodiazepines, general anesthetics, and surgical procedures. Finally, trauma itself has been associated with some degree of immunosuppression. All these issues may have placed the patient in this case at risk of an opportunistic infection like R radiobacter.. Based on this case, R radiobacter may be considered a potential pathogen causing bacteremia in critically ill trauma patients.

Topics: Adult; Agrobacterium tumefaciens; Anti-Bacterial Agents; Bacteremia; Cefepime; Cephalosporins; Critical Illness; Female; Humans; Opportunistic Infections; Treatment Outcome; Wounds and Injuries

To report a case of Chryseobacterium indologenes ventilator-associated pneumonia (VAP) in a critically ill trauma patient.. This report describes a 66-year-old critically ill trauma patient who developed VAP, which was caused by C indologenes. The patient was injured in a riding lawn mower accident that trapped him underwater in a pond. The patient required surgery for intra-abdominal injuries and was mechanically ventilated in the trauma intensive care unit. On hospital day 5, the patient developed signs and symptoms of VAP. A diagnosis of C indologenes VAP was confirmed based on a quantitative culture from a bronchoscopic bronchoalveolar lavage. The patient's infection was successfully treated with moxifloxacin for 2 days followed by cefepime for 7 days.. Formally known as Flavobacterium indologenes, C indologenes is a Gram-negative bacillus normally found in plants, soil, foodstuffs, and fresh and marine water sources. Recently, worldwide reports of C indologenes infections in humans have been increasing, though reports from the United States are still rare. Bacteremia and pneumonia are the most commonly reported infections, and most patients are immunocompromised. The current case differs from most previous reports because this patient was in the United States and did not have any traditional immunocompromised states (eg, transplant, cancer, HIV/AIDS, or corticosteroid use).. This case report demonstrates that C indologenes can cause VAP in a trauma ICU patient.

Topics: Aged; Anti-Bacterial Agents; Aza Compounds; Cefepime; Cephalosporins; Chryseobacterium; Critical Illness; Flavobacteriaceae Infections; Fluoroquinolones; Humans; Intensive Care Units; Male; Moxifloxacin; Pneumonia, Ventilator-Associated; Quinolines; Radiography; Wounds and Injuries

Cefepime-induced thrombocytopenia is a rare adverse event (incidence <1.0%), based on data from clinical trials. However, there is limited post-marketing surveillance documentation on thrombocytopenia associated with cefepime. We describe a 45-year-old male who was admitted to the intensive care unit after allegedly being hit by a large metal bar in the right upper chest and shoulder. Rhabdomyolysis secondary to the trauma, pneumothorax, acute renal failure, and nosocomial sepsis were subsequently diagnosed. Four days after intravenous cefepime initiation, the patient developed thrombocytopenia with platelet count dropping from 102 × 10(3)/μL to 15 × 10(3)/μL. Cefepime was discontinued and the platelet count normalized to 140 × 10(3)/μL after 6 days. Use of the Naranjo adverse drug reaction probability scale indicated a possible relationship between the patient's thrombocytopenia and cefepime therapy.. Although cefepime-induced thrombocytopenia is rare, clinicians should be alert to this potential adverse effect among critically ill patients.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Cefepime; Cephalosporins; Critical Illness; Cross Infection; Humans; Intensive Care Units; Male; Middle Aged; Pneumothorax; Rhabdomyolysis; Sepsis; Thrombocytopenia

Cefepime is a fourth-generation cephalosporin with a broad spectrum of antimicrobial activity against gram-positive and gram-negative micro-organisms. It is a useful option for treating infections in critically ill patients in intensive care due to its high degree of activity and its tolerability.. The aim of this study was to characterize in vitro the permeability to cefepime of 2 membranes frequently used in continuous renal replacement therapies (CRRTs). An in vivo study was also carried out to determine the pharmacokinetics of cefepime in critically ill patients undergoing CRRT.. In vitro procedures were conducted in 3 different fluids using polyacrylonitrile (AN69) or polysulfone (PS) membranes. Continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) were simulated. Four male patients undergoing CVVH or continuous venovenous hemodiafiltration, who received 2000 mg of cefepime intravenously every 8 hours, entered the in vivo study. Prefilter and ultrafiltrate samples were collected, and concentrations of cefepime were measured using high-performance liquid chromatography. The sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, and the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, were analyzed. Pharmacokinetic parameters were determined according to a noncompartmental analysis.. The patients ranged in age from 18 to 75 years and weighed from 65 to 80 kg. By analyzing Sc and Sa values in the in vitro procedures, no differences were detected in the permeability of AN69 or PS membranes to cefepime in CVVH or CVVHD. Sc/Sa values were between 0.93 and 1.03 in Ringer's lactate and in bovine albumin-containing Ringer's lactate samples, but Sc/Sa values were lower in plasma samples (0.82-0.95). In the in vivo portion of the study, the patients' mean (SD) Sc/Sa value was 0.76 (0.21) and correlated well with the fraction unbound to proteins (0.79 [0.09]). Clearance by CRRT (mean [SD]) was 29.0 (16.8)% of the total clearance. Serum elimination t(1/2) was 4.6 (0.9) hours, and the volume of distribution at steady state was 0.6 (0.3) L/kg (mean [SD] values).. Cefepime was significantly removed by CRRT. No significant differences were found in the Sc or Sa of cefepime between AN69 and PS membranes used in the CVVH or CVVHD procedures. The clearance of cefepime by CRRT must be considered when dosing critically ill patients.

Topics: Acrylic Resins; Acrylonitrile; Adolescent; Aged; Anti-Bacterial Agents; Area Under Curve; Cefepime; Cephalosporins; Chromatography, High Pressure Liquid; Critical Illness; Hemofiltration; Humans; Intensive Care Units; Male; Membranes, Artificial; Metabolic Clearance Rate; Middle Aged; Permeability; Polymers; Sulfones