Cefepime Daily Exposure and the Associated Impact on the Change in Sequential Organ Failure Assessment Scores and Vasopressors Requirement in Critically Ill Patients Using Repeated-Measures Mixed-Effect Modeling.

IMPORTANCE: Sepsis and septic shock are major healthcare problems that need early and appropriate management. OBJECTIVES: To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement. DESIGN SETTING AND PARTICIPANTS: This is a retrospective study. Adult ICU patients who received cefepime for Gram-negative pneumonia or bloodstream infection (BSI) and had cefepime concentrations measured were included. Daily cefepime exposure was generated and PK/PD parameters calculated for patients. Repeated-measures mixed-effect modeling was used to evaluate the impact of PK/PD on the outcomes. MAIN OUTCOMES AND MEASURES: Change in daily SOFA score and vasopressors requirement. RESULTS: A total of 394 and 207 patients were included in the SOFA and vasopressors analyses, respectively. The mean (±sd) age was 55 years (19) and weight 81 kg (29). For the change in SOFA score, daily SOFA score, mechanical ventilation, renal replacement therapy, and number of vasopressors were included. In the vasopressors analysis, daily SOFA score, day of therapy, and hydrocortisone dose were significant covariates in the final model. Achieving cefepime concentrations above the minimum inhibitory concentration (MIC) (T>MIC) for 100% of the dosing interval was associated with 0.006 µg/kg/min decrease in norepinephrine-equivalent dose. Cefepime PK/PD did not have an impact on the daily change in SOFA score. CONCLUSIONS AND RELEVANCE: Achieving 100% T>MIC was associated with negligible decrease in vasopressors requirement in ICU patients with Gram-negative pneumonia and BSI. There was no impact on the change in SOFA score.

Using Machine Learning To Define the Impact of Beta-Lactam Early and Cumulative Target Attainment on Outcomes in Intensive Care Unit Patients with Hospital-Acquired and Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT>MIC) and the time free concentration remained above four multiples of the MIC (fT>4×MIC) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Impact of Empiric Linezolid for Necrotizing Soft Tissue Infections on Duration of Methicillin-Resistant Staphylococcus aureus-Active Therapy.

Background: Necrotizing soft tissue infections (NSTIs) require prompt surgical debridement and antimicrobial therapy. Indicated antimicrobial therapy involves broad-spectrum coverage against common pathogens and toxin inhibition. Linezolid provides both methicillin-resistant Staphylococcus aureus (MRSA) coverage and toxin inhibition, however, there is limited evidence evaluating its role in empiric treatment. The purpose of this study was to evaluate the impact of empiric linezolid use for NSTIs on the total duration of MRSA-active therapy. Patients and Methods: This retrospective, single-center study included adult surgical intensive care unit (ICU) patients treated with empiric vancomycin and clindamycin or linezolid along with gram-negative and anaerobe coverage for NSTIs. The primary end point of this study was the duration of MRSA-active therapy. Secondary end points included ICU and hospital length of stay (LOS; days), new-onset acute kidney injury (AKI), and Clostridioides difficile infection (CDI). Results: There were 21 patients in the vancomycin/clindamycin cohort and 28 patients in the linezolid cohort. The average duration of vancomycin was 3.9 days versus 2.9 days of linezolid (p = 0.04). The average hospital LOS for the vancomycin/clindamycin cohort was somewhat longer than the linezolid cohort, although the difference was not statistically significant (p = 0.07), and the incidence of new-onset AKI during hospitalization was higher in the vancomycin/clindamycin cohort (38.1% vs. 0%; p < 0.001). No differences were observed for ICU LOS or CDI. Conclusions: Empiric linezolid use for NSTI was associated with one less day of MRSA-active therapy and lower incidence of new-onset AKI during hospitalization. Linezolid was a safe and effective alternative to vancomycin/clindamycin for empiric treatment of NSTIs.

Applying Cefepime Population Pharmacokinetics to Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

Patients admitted to the intensive care unit (ICU) may need continuous renal replacement therapy (CRRT) due to acute kidney injury or worsening of underlying chronic kidney disease. This will affect their antimicrobial exposure and may have a significant impact on the treatment. We aim to develop a cefepime pharmacokinetic (PK) model in CRRT ICU patients and generate the posterior predictions for a group and assess their therapy outcomes. Adult patients, who were admitted to the ICU, received cefepime, and had its concentration measured while on CRRT were included from three different data sets. In two data sets, samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at different times within the same dosing interval. The third data set had only cefepime plasma concentration measured as part of clinical service. Patients' demographics, cefepime regimens and concentration, CRRT parameters, and therapy outcomes were recorded. NPAG was used for population PK and posterior predictions. A total of 125 patients were included. Cefepime was described by a five-compartment model, and the CRRT flow rates described the rates of cefepime transfer between compartments. The posterior predictions were generated for the third data set and the median (range) fT>MIC was 100% (27%-100%) and fT>4×MIC was 64% (0%-100%). The mortality rate was 53%. There was no difference in target attainment in terms of clinical cure and 30-day mortality. This model can be used as a precision dosing tool in CRRT patients. Future studies may address other PK/PD targets in a larger population.

Beta-Lactams Dosing in Critically Ill Patients with Gram-Negative Bacterial Infections: A PK/PD Approach.

Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their efficacy depends on the percentage of dosing interval that the concentration remains above the minimum inhibitory concentration. The Gram-negative resistance rates of pathogens are increasing in the intensive care unit (ICU), and critically ill patients often possess physiology that makes dosing more challenging. The volume of distribution is usually increased, and drug clearance is variable. Augmented renal clearance and hypermetabolic states increase the clearance of beta-lactams, while acute kidney injury reduces the clearance. To overcome the factors affecting ICU patients and decreasing susceptibilities, dosing strategies involving higher doses, and extended or continuous infusions may be required. In this review, we specifically examined pharmacokinetic models in ICU patients, to determine the desired beta-lactam regimens for clinical breakpoints of Enterobacterales and Pseudomonas aeruginosa, as determined by the European Committee on Antimicrobial Susceptibility Testing. The beta-lactams evaluated included penicillins, cephalosporins, carbapenems, and monobactams. We found that when treating less-susceptible pathogens, especially P. aeruginosa, continuous infusions are frequently needed to achieve the desired pharmacokinetic/pharmacodynamic targets. More studies are needed to determine optimal dosing strategies in the novel beta-lactams.

Optimal Antibiotic Duration for Bloodstream Infections Secondary to Intraabdominal Infection.

BACKGROUND: Bloodstream infections (BSIs) secondary to intraabdominal infections (IAIs) are common in the intensive care unit (ICU). The Surgical Infection Society guidelines recommend treatment duration after achieving source control in patients with secondary bacteremia; however, literature supporting this recommendation is limited. The purpose of this study was to compare outcomes in patients who received shorter versus extended duration of antibiotics for bacteremia secondary to IAI. MATERIALS AND METHODS: A retrospective cohort analysis was conducted in adult surgical ICU patients (n = 42) with BSIs and source control procedure(s) for IAI. The primary outcome was recurrent IAI. Secondary outcomes included surgical site infections (SSIs), Clostridium difficile infections (CDIs), secondary fungal infections, and in-hospital mortality. RESULTS: Forty-two patients met inclusion criteria and were divided into groups according to antimicrobial duration; 12 patients received <7 d, and 30 patients received >7 d of antibiotics. There were no differences in baseline characteristics between the two cohorts except for the presence of sepsis [4/12 (33.3%) versus 27/30 (90.0%); P = 0.001]. Thirty-one percent (13/42) of all organisms isolated from blood cultures were gram-negative bacteria, 12/42 (28.6%) were MDROs, and 2/42 (4.8%) patients experienced a culture mismatch in which cultured bacteria were not susceptible to empiric antibiotic therapy. Rates of recurrent IAI were similar between the two cohorts [1/12 (8.3%) versus 4/30 (13.3%), P = 0.554]. CONCLUSIONS: Among surgical ICU patients with BSI secondary to IAI, cessation of antibiotic therapy within 7 d of source control was not associated with an increased incidence of recurrent IAI.

Method of Hypertonic Saline Administration: Effects on Osmolality in Traumatic Brain Injury Patients.

Hypertonic saline (HTS) is an effective therapy for reducing intracranial pressure (ICP). The ideal method of administration is unknown. The purpose of this study was to evaluate the method of HTS infusion and time to goal osmolality. A retrospective cohort analysis was conducted in severe TBI patients with ICP monitoring in place who received 2 doses of HTS. Patients were divided into bolus versus continuous infusion HTS cohorts. The primary outcome was median time to goal osmolality. Secondary outcomes included percentage of patients reaching goal osmolality, percent time at goal osmolality, mean cerebral perfusion pressure (CPP) and ICP, ICU length of stay, and mortality. Safety outcomes included rates of hyperchloremia, hypernatremia, and acute kidney injury (AKI). 162 patients were included with similar baseline characteristics. Time to goal osmolality was similar between cohorts (bolus 9.78h vs. continuous 11.4h, p=0.817). A significant difference in the percentage of patients reaching goal osmolality favoring the continuous group was found (93.9% vs 73.3%, p=0.003). The continuous group was maintained at goal osmolality for a higher percentage of osmolality values after reaching goal (80% vs. 50%, p=0.032). No difference was seen in CPP, ICP, length of stay and mortality. Rates of hypernatremia were similar, but significant higher rates of hyperchloremia (0.77vs 1.58 events per HTS days, p<0.001) and AKI (0% vs 12.9%, p=0.025) were observed in the continuous cohort. Although no difference in time to goal osmolality was observed, continuous HTS was associated with a higher percentage of patients achieving goal osmolality.