Background. Contemporary vancomycin dosing schemes are designed to achieve an area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio of ≥400. However, scant clinical data exist to ...support this target and available data relied on pharmacokinetic formulas based on daily vancomycin dose and estimated renal function (demographic pharmacokinetic model) to estimate AUCs. Methods. A cohort study of hospitalized, adult, nondialysis patients with methicillin-resistant Staphylococcus aureus bloodstream infections treated with vancomycin was performed to quantitatively evaluate the relationship between vancomycin exposure and outcomes. Bayesian techniques were used to estimate vancomycin exposure profile for day 1 and 2 of therapy for each patient based on their dosing schedule and collected concentrations. Classification and Regression Tree (CART) analysis was used to identify day 1 and 2 exposure thresholds associated with an increased risk of failure. Failure was defined as 30-day mortality, bacteremia was ≥7 days, or recurrence. Results. During the study period, 123 cases met criteria. Failure was uniformly less pronounced (approximately 20% less in absolute value) in patients who achieved the CART-derived day 1 and 2 thresholds for AUC/MIC by broth microdilution and AUC/MIC by Etest. In the multivariate analyses, all risk ratios were approximately 0.5 for all CART-derived AUC/MIC exposure thresholds, indicating that achievement of CART-derived AUC/MIC exposure thresholds was associated with a 2-fold decrease in failure. Conclusions. These findings establish the critical importance of daily AUC/MIC ratios during the first 2 days of therapy. As with all observational studies, these findings should be interpreted cautiously and validated in a multicenter randomized trial before adoption into practice.
Temporal relationships between the time to appropriate antibiotic therapy and outcomes are not well described.
A systematic literature review and meta-analysis was performed to examine this ...relationship in patients hospitalized with Klebsiella pneumoniae or Escherichia coli infections.
Twenty identified studies contained data for patients who received delayed appropriate therapy (DAT) versus appropriate antibiotic therapy for these pathogens. Of the 20 included studies, the majority (19/20) focused on patients with bloodstream infections, and only 1 study evaluated patients with pneumonia. When all DAT results were combined (any delay > 24 h from culture collection or any delay after culture and susceptibility reporting C& SR), there was an increased risk of mortality (odds ratio OR, 1.60 95% CI, 1.25-2.50). The risk of mortality was greater when DAT > 48 h from culture collection or DAT > C&SR results were combined (OR, 1.76 95% CI, 1.27-2.44).
Our findings suggest there is a need to shift current treatment practices away from antibiotic escalation strategies that contribute to delayed appropriate therapy and toward early, relatively aggressive and comprehensive, antibiotic therapy, especially among patients with bloodstream infections due to K. pneumoniae or E. coli.
Optimization of the antibiotics for patients with infections due to MDR Pseudomonas aeruginosa (MDR-PA) often requires consideration of alternate dose and infusion times that can be influenced by ...renal function.
We sought to identify ceftolozane/tazobactam dosing schemes that optimized the probability of target attainment (PTA) against infections due to MDR-PA with ceftolozane/tazobactam MICs between 4 and 32 mg/L across different categories of renal function.
A prior validated ceftolozane/tazobactam population pharmacokinetic model was used for Monte Carlo simulation of 128 alternate permutations of dose, infusion time and renal function in 5000 cases/permutation. Four ceftolozane/tazobactam doses (250/125 mg to 2/1 g) every 8 h with infusion durations of 1-7 h and as continuous infusions were simulated. The model simulated ceftolozane/tazobactam clearance as a function of creatinine clearance (CLCR) within four categories of estimated renal function: 15-29, 30-50, 51-120 and 121-180 mL/min. The PTA was benchmarked on 40% free ceftolozane/tazobactam concentration time above the MIC.
The 512 alternate scenarios identified the current ceftolozane/tazobactam dose of 1/0.5 g to be optimal for MICs ≤32 mg/L (CLCR 15-50 mL/min), ≤16 mg/L (CLCR 51-120 mL/min) and ≤8 mg/L (CLCR 121-180 mL/min). Extended infusion of 4-5 h had a higher PTA than shorter and continuous infusions in simulations of augmented renal clearance across infections with MICs of 4-32 mg/L.
Extended infusion ceftolozane/tazobactam regimens should be investigated as a potential dosing solution to improve the PTA against infections due to MDR-PA with higher ceftolozane/tazobactam MICs.
Abstract
Objectives
Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus ...bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration–time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations.
Methods
The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding.
Results
Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin’s protein binding was estimated to be approximately 99%.
Conclusions
Dalbavancin has very high protein binding. Given dalbavancin’s high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure–response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.
This analysis of nearly 10,000 hospital-associated urinary tract infection (UTI) episodes due to Escherichia coli showed that fluoroquinolone and third-generation-cephalosporin resistance rates were ...34.5% and 8.6%, respectively; the rate of concurrent resistance to both agents was 7.3%. Fluoroquinolone resistance rates exceeded 25% regardless of geographic location or hospital characteristics. The findings suggest that fluoroquinolones should be reserved and third-generation cephalosporins be used with caution as empirical agents for hospitalized patients with UTIs due to E. coli.
Abstract
Background
Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, ...only that serum creatinine increases.
Objectives
To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies.
Methods
(i) Male Sprague–Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®.
Results
Urinary output increased from Day −1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin.
Conclusions
All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.
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•Hospital admissions for complicated urinary tract infections (cUTI) are rising.•There is scant information on the clinical acuity of hospitalized cUTI patients.•This study describes ...the characteristics of hospitalized cUTI patients in the United States.•Approximately 1 in 5 cUTI admissions occurred in patients with low acuity and may be avoidable.•Results highlight need to develop well-defined criteria for cUTI admissions.
Hospital admissions for complicated urinary tract infections (cUTI) in the United States are increasing but there are limited information on the acuity of patients who are admitted.
Describe hospitalization patterns among adult cUTI patients who present to the hospital with cUTI and to determine the proportion of admissions that were of low acuity.
A retrospective multi-center analysis using data from the Premier Healthcare Database (2013-2018) was performed. Inclusion criteria: age ≥ 18 years, cUTI diagnosis, positive blood or urine culture. Hospital admissions were stratified by presence of sepsis, systemic symptoms but no sepsis, and Charlson Comorbidity Index (CCI).
187,789 patients met the inclusion criteria. The mean (SD) age was 59.7 (21.9), 40.4% were male, 29.4% had sepsis, 16.7% had at least 1 systemic symptom (but no sepsis), and 53.9% had no sepsis or systemic symptoms. The median inter-quartile range CCI was 1 0, 3. Sixty-four percent of patients were admitted to hospital, and 18.9% of admissions occurred in patients with low acuity (no sepsis or systemic symptoms and a CCI ≤ 2). The median IQR LOS and costs for low acuity inpatients who were admitted were 3 2, 5 days and $5,575 $3,607, $9,133, respectively.
Nearly 1 in 5 cUTI hospital admissions occurred in patients with low acuity, and therefore may be avoidable.
Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney ...injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats (
= 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve AUC, 0.662;
< 0.001) and clusterin (AUC, 0.706;
< 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage.
The objective of this study was to determine the effect of delayed therapy on morbidity and mortality associated with nosocomial Staphylococcus aureus bacteremia. The study included all episodes of ...S. aureus bacteremia that developed >2 days after hospital admission during 1999 to 2001. Classification and regression tree analysis (CART) was used to select the mortality breakpoint between early and delayed treatment. During the 25-month study period, 167 patients met the inclusion criteria. The breakpoint between delayed and early treatment derived using CART was 44.75 hours. On multivariate analysis, delayed treatment was found to be an independent predictor of infection-related mortality (odds ratio, 3.8; 95% confidence interval, 1.3-11.0; P = .01) and was associated with a longer hospital stay than was early treatment (20.2 days versus 14.3 days; P = .05). These findings support the notion that delay of therapy has deleterious effects on clinical outcomes, and efforts should be made to ensure that appropriate therapy is initiated promptly.
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