Impact of Vancomycin Loading Doses and Dose Escalation on Glomerular Function and Kidney Injury Biomarkers in a Translational Rat Model.

Vancomycin-induced kidney injury is common, and outcomes in humans are well predicted by animal models. This study employed our translational rat model to investigate temporal changes in the glomerular filtration rate (GFR) and correlations with kidney injury biomarkers related to various vancomycin dosing strategies. First, Sprague-Dawley rats received allometrically scaled loading doses or standard doses. Rats that received a loading dose had low GFRs and increased urinary injury biomarkers (kidney injury molecule 1 [KIM-1] and clusterin) that persisted through day 2 compared to those that did not receive a loading dose. Second, we compared low and high allometrically scaled vancomycin doses to a positive acute kidney injury control of high-dose folic acid. Rats in both the low- and high-dose vancomycin groups had higher GFRs on all dosing days than the positive-control group. When the two vancomycin groups were compared, rats that received the low dose had significantly higher GFRs on days 1, 2, and 4. Compared to low-dose vancomycin, the KIM-1 was elevated among rats in the high-dose group on dosing day 3. The GFR correlated most closely with the urinary injury biomarker KIM-1 on all experimental days. Vancomycin loading doses were associated with significant losses of kidney function and elevations of urinary injury biomarkers. In our translational rat model, both the degree of kidney function decline and urinary biomarker increases corresponded to the magnitude of the vancomycin dose (i.e., a higher dose resulted in worse outcomes).

Iohexol-Measured Glomerular Filtration Rate and Urinary Biomarker Changes between Vancomycin and Vancomycin Plus Piperacillin-Tazobactam in a Translational Rat Model.

Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination. Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 h. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated with the urinary biomarkers kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to the control, rats that received vancomycin had numerically lower GFRs after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin plus piperacillin-tazobactam (vancomycin+piperacillin-tazobactam) did not exhibit worse kidney function or injury biomarkers than rats receiving vancomycin alone. The combination of vancomycin and piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.

Population pharmacokinetic model of cefepime for critically ill adults: a comparative assessment of eGFR equations.

Cefepime exhibits highly variable pharmacokinetics in critically ill patients. The purpose of this study was to develop and qualify a population pharmacokinetic model for use in the critically ill and investigate the impact of various estimated glomerular filtration rate (eGFR) equations using creatinine, cystatin C, or both on model parameters. This was a prospective study of critically ill adults hospitalized at an academic medical center treated with intravenous cefepime. Individuals with acute kidney injury or on kidney replacement therapy or extracorporeal membrane oxygenation were excluded. A nonlinear mixed-effects population pharmacokinetic model was developed using data collected from 2018 to 2022. The 120 included individuals contributed 379 serum samples for analysis. A two-compartment pharmacokinetic model with first-order elimination best described the data. The population mean parameters (standard error) in the final model were 7.84 (0.24) L/h for CL1 and 15.6 (1.45) L for V1. Q was fixed at 7.09 L/h and V2 was fixed at 10.6 L, due to low observed interindividual variation in these parameters. The final model included weight as a covariate for volume of distribution and the eGFRcr-cysC (mL/min) as a predictor of drug clearance. In summary, a population pharmacokinetic model for cefepime was created for critically ill adults. The study demonstrated the importance of cystatin C to prediction of cefepime clearance. Cefepime dosing models which use an eGFR equation inclusive of cystatin C are likely to exhibit improved accuracy and precision compared to dosing models which incorporate an eGFR equation with only creatinine.

Making the case for precision dosing: visualizing the variability of cefepime exposures in critically ill adults.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Green nail syndrome complicated by pseudomonal keratitis in a teenager with artificial nails.

Green nail syndrome (GNS) is a pseudomonal nail infection that presents with characteristic green nail discoloration. It typically affects patients with preexisting nail conditions or chronic exposure to wet environments but can also be seen with local trauma. Our patient presented with a pseudomonal corneal ulcer of the left eye and was incidentally found to have GNS, which developed after home artificial nail application. This unusual case of extensive pediatric GNS illustrates a rare and serious infectious complication of prolonged artificial nails.

Glomerular Function and Urinary Biomarker Changes between Vancomycin and Vancomycin plus Piperacillin-Tazobactam in a Translational Rat Model.

Clinical studies have reported additive nephrotoxicity associated with the combination of vancomycin (VAN) and piperacillin-tazobactam (TZP). This study assessed differences in glomerular filtration rate (GFR) and urinary biomarkers between rats receiving VAN and those receiving VAN + TZP. Male Sprague-Dawley rats (n = 26) were randomized to receive 96 h of intravenous VAN at 150 mg/kg/day, intraperitoneal TZP at 1,400 mg/kg/day, or VAN + TZP. Kidney function was evaluated using fluorescein-isothiocyanate sinistrin and a transdermal sensor to estimate real-time glomerular filtration rate (GFR). Kidney injury was evaluated via urinary biomarkers, including kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to a saline control, only rats in the VAN group showed significant declines in GFR by day 4 (-0.39 mL/min/100 g body weight; 95% confidence interval [CI], -0.68 to -0.10; P = 0.008). When the VAN + TZP and VAN alone treatment groups were compared, significantly higher urinary KIM-1 marginal linear predictions were observed in the VAN alone group on day 1 (18.4 ng; 95% CI, 1.4 to 35.3; P = 0.03), day 2 (27.4 ng; 95% CI, 10.4 to 44.3; P = 0.002), day 3 (18.8 ng; 95% CI, 1.9 to 35.8; P = 0.03), and day 4 (23.2 ng; 95% CI, 6.3 to 40.2; P = 0.007). KIM-1 was the urinary biomarker that most correlated with decreasing GFR on day 3 (Spearman's rho, -0.45; P = 0.022) and day 4 (Spearman's rho, -0.41; P = 0.036). Kidney function decline and increased KIM-1 were observed among rats that received VAN only but not those that received TZP or VAN + TZP. The addition of TZP to VAN does not worsen kidney function or injury in our translational rat model.

Vancomycin Pharmacokinetics in a Pregnancy Rat Model.

Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R2 = 0.978; pup kidney Bayesian, observed versus predicted R2 = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h-1 for trimester 1 dams and 0.75 h-1 for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 µg/mL, P < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.

Does calculation method matter for targeting vancomycin area under the curve?

OBJECTIVES: To assess differences in vancomycin AUC estimates from two common, clinically applied first-order pharmacokinetic equation methods compared with Bayesian estimates. METHODS: A cohort of patients who received vancomycin and therapeutic drug monitoring was studied. First-order population pharmacokinetic equations were used to guide initial empirical dosing. After receipt of the first dose, patients had peak and trough serum levels drawn and steady-state AUC was estimated using first-order pharmacokinetic equations as standard care. We subsequently created a Bayesian model and used individual Empirical Bayes Estimates to precisely calculate vancomycin AUC24-48, AUC48-72 and AUC72-96 in this cohort. AUC at steady state (AUCSS) differences from the first-order methods were compared numerically and categorically (i.e. below, within or above 400-600 mg·h/L) to Bayesian AUCs, which served as the gold standard. RESULTS: A total of 65 adult inpatients with 409 plasma samples were included in this analysis. A two-compartment intravenous infusion model with first-order elimination fit the data well. The mean of Bayesian AUC24-48 was not significantly different from AUC estimates from the two first-order pharmacokinetic equation methods (P = 0.68); however, Bayesian AUC48-72 and Bayesian AUC72-96 were both significantly different when compared with both first-order pharmacokinetic equation methods (P < 0.01 for each). At the patient level, categorical classifications of AUC estimates from the two first-order pharmacokinetic equation methods differed from categorizations derived from the Bayesian calculations. Categorical agreement was ∼50% between first-order and Bayesian calculations, with declining categorical agreement observed with longer treatment courses. Differences in categorical agreement between calculation methods could potentially result in different dose recommendations for the patient. CONCLUSIONS: Bayesian-calculated AUCs between 48-72 and 72-96 h intervals were significantly different from first-order pharmacokinetic method-estimated AUCs at steady state. The various calculation methods resulted in different categorical classification, which could potentially lead to erroneous dosing adjustments in approximately half of the patients.

Evaluation of Fetal and Maternal Vancomycin-Induced Kidney Injury during Pregnancy in a Rat Model.

Previous literature suggests that maternal vancomycin crosses the placental barrier to the fetus. Further, early animal studies indicated that kidney injury was not observed in the progeny. These studies were conducted prior to the availability of sensitive biomarkers for kidney injury. Therefore, a previous finding of no renal damage to the infant may be misleading. Vancomycin was administered intravenously to pregnant rats at a dose of 250 mg/kg of body weight/day (N = 6 per trimester) on three consecutive gestational days (GD) during trimesters 1, 2, and 3 (T1, T2, and T3, respectively) in three independent cohorts. The dams carried to term and delivered vaginally on GD 21. Kidneys were harvested from dams and pups and homogenized. Samples were prepared by protein precipitation and injected in a liquid chromatography tandem mass spectrometer, and vancomycin was quantified. The kidney tissue homogenate from dams and pups were analyzed for kidney injury molecule-1 (KIM-1). As trimesters progressed, the quantity of vancomycin increased linearly in the kidneys of both rat dams and pups (P < 0.0001 for T1 and T3, P < 0.0001 for T2 and T3, and P < 0.0001 for T3 and T3 control for both rat dams and pups). KIM-1 concentrations in pup kidneys were significantly higher when dams were administered vancomycin in trimesters 1 (P = 0.0001) and 2 (P = 0.0024) than in controls in trimester 3. Data demonstrate persistence of vancomycin in maternal and rat pup kidneys in all three trimesters of pregnancy with associated damage to the kidney, as indicated by expression of KIM-1.

Recent advances in the treatment of type 2 diabetes mellitus using new drug therapies.

Several recent advances provide multiple health benefits to individuals with type 2 diabetes mellitus (T2DM). Pharmacological therapy is governed by person-centered factors, including comorbidities and treatment goals. Adults with T2DM who have an established/high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, require a treatment regimen that includes agents that are proven to reduce cardiorenal risk. Weight management plays a key role in reducing glucose for patients with T2DM. A glucose-reduction treatment regimen must consider weight management. Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure, cardiovascular and renal events. Glucagon-like peptide-1 (GLP-1) receptor agonists allow better control of glycemia, promote weight loss and reduce the risk of cardiovascular events. Newer Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 dual agonist, which activate GIP and GLP-1 receptors improve glycemic control and promote greater weight loss than GLP-1 receptor agonists. Several novel drugs are in the clinical development phase. This review pertains to recent advances in pharmacological management of type 2 diabetes.

Impact of humanized vancomycin infusion on kidney function and kidney injury in a translational rat model.

Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus-administration with allometric scaling is the most simple and commonly used strategy in pre-clinical kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched, bolus-administration with allometric scaling results in similar outcomes compared to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically-scaled, dose-matched, bolus-administration of vancomycin to an infusion-pump controlled, humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 h of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg·h/L [IQR 90.2-97.2] vs. 99.5 mg·h/L [IQR 95.1-104.0], P = 0.07). No significant differences in iohexol-measured kidney function nor meaningful differences in urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures. No differences in iohexol-measured GFR nor meaningful differences in urinary kidney injury biomarkers were observed among male Sprague-Dawley rats.

Past, Present, and Future Biomarkers of Kidney Function and Injury: The Relationship With Antibiotics.

Routinely used kidney biomarkers of injury and function such as serum creatinine and urine albumin to creatinine ratio, are neither sensitive nor specific. Future biomarkers are being developed for clinical use and have already been included in guidance from groups such as the U.S. Food and Drug Administration and the Predictive Safety Testing Consortium. These biomarkers have important implications for early identification of kidney injury and more accurate measurement of kidney function. Many antibiotics are either eliminated by the kidney or can cause clinically significant nephrotoxicity. As a result, clinicians should be familiar with new biomarkers of kidney function and injury, their place in clinical practice, and applications for antibiotic dosing.

Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin-induced kidney injury in a translational rat model.

BACKGROUND AND PURPOSE: Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. KEY RESULTS: Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. CONCLUSIONS AND IMPLICATIONS: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.

Twelve-month effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in treatment-naïve and treatment-experienced people with HIV: Findings from the Asia cohort of the BICSTaR study.

BACKGROUND: The ongoing, observational BICSTaR (BICtegravir Single Tablet Regimen) cohort study is evaluating real-world effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV across 14 countries over 24 months. We present 12-month data from the BICSTaR Asia cohort. METHODS: Data were pooled from retrospective and prospective cohorts of antiretroviral therapy (ART)-naïve (hereafter, TN) and ART-experienced (hereafter, TE) people with HIV (aged ≥21 years) receiving B/F/TAF in routine clinical care in the Republic of Korea, Singapore, and Taiwan. Analyses included effectiveness (primary endpoint: HIV-1 RNA <50 copies/ml, missing = excluded analysis), CD4 count, CD4/CD8 ratio, safety, treatment persistence, and patient-reported outcomes (prospective group). RESULTS: The analysis population included 328 participants (80 retrospective, 248 prospective; 65 TN, 263 TE). Participants were predominantly male (96.9% TN, 93.2% TE) with ≥1 comorbidity (52.3% TN, 57.8% TE); median age (years) was 31 (TN) and 42 (TE). Following 12 months of B/F/TAF, HIV-1 RNA was <50 copies/ml in 98.2% (54/55) of TN and 97.0% (227/234) of TE participants. Median (Q1, Q3) CD4 cell count increased by +187 (119, 291) cells/µl in the TN group (p < 0.001) and remained stable (+8 [-91, 110] cells/µl) in the TE group. B/F/TAF persistence was high in the prospective group, with 1/34 (2.9%) TN and 5/214 (2.3%) TE participants discontinuing treatment within 12 months. Drug-related adverse events occurred in 5.8% (19/328) of participants, leading to treatment discontinuation in 0.6% (2/328). CONCLUSIONS: Real-world evidence from BICSTaR supports the effectiveness, safety and tolerability of B/F/TAF in people with HIV in Asia.

Contemporary pharmacologic treatments of MRSA for hospitalized adults: rationale for vancomycin versus non-vancomycin therapies as first line agents.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) remains an important pathogen in the hospital setting and causes significant morbidity and mortality each year. Since the initial discovery over 60 years ago, vancomycin has remained a first-line treatment for many different types of MRSA infections. However, significant concerns related to target attainment and nephrotoxicity have spurred efforts to develop more effective agents in the last two decades. AREAS COVERED: Newer anti-MRSA antibiotics that have been approved since 2000 include linezolid, daptomycin, and ceftaroline. As clinical evidence has accumulated, these newer agents have become more frequently used, and some are now recommended as co-first-line options (along with vancomycin) in clinical practice guidelines. For this review, a scoping review of the literature was conducted to support our findings and recommendations. EXPERT OPINION: Vancomycin remains an important standard of care for MRSA infections but is limited with respect to nephrotoxicity and rapid target attainment. Newer agents such as linezolid, daptomycin, and ceftaroline have specific indications for treating different types of MRSA infections; however, newer agents also have unique attributes which require consideration during therapy.

Cefazolin in the treatment of central nervous system infections: A narrative review and recommendation.

Infections of the central nervous system (CNS) are complex to treat and associated with significant morbidity and mortality. Historically, antistaphylococcal penicillins such as nafcillin were recommended for the treatment of methicillin-susceptible staphylococcal CNS infections. However, the use of antistaphylococcal penicillins presents challenges, such as frequent dosing administration and adverse events with protracted use. This narrative reviews available clinical and pharmacokinetic/pharmacodynamic (PK/PD) data for cefazolin in CNS infections and produces a recommendation for use. Based on the limited available evidence analyzed, dose optimized cefazolin is likely a safe and effective alternative to antistaphylococcal penicillins for a variety of CNS infections due to methicillin-susceptible Staphylococcus aureus. Given the site of infection and wide therapeutic index of cefazolin, practitioners may consider dosing cefazolin regimens of 2 g IV every 6 h or a continuous infusion of 8-10 g daily instead of 2 g IV every 8 h to optimize PK/PD properties.

Iohexol-measured glomerular filtration rate and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model.

Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination. Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 hours. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated via the urinary biomarkers: kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to the control, rats that received vancomycin had numerically lower GFR after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin+piperacillin-tazobactam did not exhibit worse kidney function or injury biomarkers compared to vancomycin alone. The combination of vancomycin+piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.

Adequacy of cefepime concentrations in the early phase of critical illness: A case for precision pharmacotherapy.

STUDY OBJECTIVE: In critically ill patients, adequacy of early antibiotic exposure has been incompletely evaluated. This study characterized factors associated with inadequate cefepime exposure in the first 24 h of critical illness. DESIGN: Prospective cohort study. SETTING: Academic Medical Center. PATIENTS: Critically ill adults treated with cefepime. Patients with acute kidney injury or treated with kidney replacement therapy or extracorporeal membrane oxygenation were excluded. INTERVENTION: None. MEASUREMENTS: A nonlinear mixed-effects pharmacokinetic (PK) model was developed to estimate cefepime concentrations for each patient over time. The percentage of time the free drug concentration exceeded 8 mg/L during the first 24 h of therapy was calculated (%ƒT>8; appropriate for the susceptible breakpoint for Pseudomonas aeruginosa). Factors predictive of low %ƒT>8 were explored with multivariable regression. MAIN RESULTS: In the 100 included patients, a one-compartment PK model was developed with first-order elimination with covariates for weight and estimated glomerular filtration rate based on creatinine and cystatin C (eGFRSCr-CysC). The median (interquartile range) %ƒT>8 for cefepime in the first 24 h of therapy based on this model was 85% (66%, 100%). Less than 100% ƒT>8 during first 24 h of therapy occurred in 70 (70%) individuals. Lower Sequential Organ Failure Assessment score (p = 0.032) and higher eGFRSCr-CysC (p < 0.001) predicted a lower %ƒT>8. Central nervous system infection source was protective (i.e., associated with a higher %ƒT>8; p = 0.008). CONCLUSIONS: During early critical illness, cefepime concentrations were inadequate in a significant proportion of patients. Antimicrobial optimization is needed to improve the precision of pharmacotherapy in the critically ill patients.