J. Nicholas O'Donnell

Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

ABSTRACT Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocols final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearmans nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0–24), the maximum concentration in plasma during the first 24 h (Cmax0–24), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0–24). A total of 52 rats received vancomycin (n = 42) or NS (n = 10). The strongest exposure-response correlations were observed between AUC0–24 and Cmax0–24 and urinary AKI biomarkers. Exposure-response correlations (rs values) for AUC0–24, Cmax0–24, and Cmin0–24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0–24 or Cmax0–24 correlates with increases in urinary AKI biomarkers.

Tree-Based Models for Predicting Mortality in Gram-Negative Bacteremia: Avoid Putting the CART before the Horse.

ABSTRACT Increasingly, infectious disease studies employ tree-based approaches, e.g., classification and regression tree modeling, to identify clinical thresholds. We present tree-based-model-derived thresholds along with their measures of uncertainty. We explored individual and pooled clinical cohorts of bacteremic patients to identify modified acute physiology and chronic health evaluation (II) (m-APACHE-II) score mortality thresholds using a tree-based approach. Predictive performance measures for each candidate threshold were calculated. Candidate thresholds were examined according to binary logistic regression probabilities of the primary outcome, correct classification predictive matrices, and receiver operating characteristic curves. Three individual cohorts comprising a total of 235 patients were studied. Within the pooled cohort, the mean (± standard deviation) m-APACHE-II score was 13.6 ± 5.3, with an in-hospital mortality of 16.6%. The probability of death was greater at higher m-APACHE II scores in only one of three cohorts (odds ratio for cohort 1 [OR1] = 1.15, 95% confidence interval [CI] = 0.99 to 1.34; OR2 = 1.04, 95% CI = 0.94 to 1.16; OR3 = 1.18, 95% CI = 1.02 to 1.38) and was greater at higher scores within the pooled cohort (OR4 = 1.11, 95% CI = 1.04 to 1.19). In contrast, tree-based models overcame power constraints and identified m-APACHE-II thresholds for mortality in two of three cohorts (P = 0.02, 0.1, and 0.008) and the pooled cohort (P = 0.001). Predictive performance at each threshold was highly variable among cohorts. The selection of any one predictive threshold value resulted in fixed sensitivity and specificity. Tree-based models increased power and identified threshold values from continuous predictor variables; however, sample size and data distributions influenced the identified thresholds. The provision of predictive matrices or graphical displays of predicted probabilities within infectious disease studies can improve the interpretation of tree-based model-derived thresholds.

Pharmacokinetics of centhaquin citrate in a dog model

Centhaquin citrate is a novel agent that is being developed for use in the resuscitation of patients with haemorrhagic shock. While pharmacokinetics have been described in small animal models, the pharmacokinetic parameters of centhaquin citrate in large mammals have yet to be described.

Doses, durations, and gender predict vancomycin-induced kidney injury in pre-clinical studies

BACKGROUND Although the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM-1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose-response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships. METHODS A systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data. RESULTS A total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4 mg/kg/day). Dose-response curves were shifted left for females vs. males (P = 0.05) and for long (i.e. ≥7 days) vs. short (i.e. <4 days) duration of vancomycin therapy (P=0.02). CONCLUSIONS The collective findings demonstrate a clear dose-response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI.

Correlation between hospital-level antibiotic consumption and incident health care facility-onset Clostridium difficile infection

Background: The purpose of this single‐center, ecologic study is to characterize the relationship between facility‐wide (FacWide) antibiotic consumption and incident health care facility‐onset Clostridium difficile infection (HO‐CDI). Methods: FacWide antibiotic consumption and incident HO‐CDI were tallied on a monthly basis and standardized, from January 2013 through April 2015. Spearman rank‐order correlation coefficients were calculated using matched‐months analysis and a 1‐month delay. Regression analyses were performed, with P < .05 considered statistically significant. Results: FacWide analysis identified a matched‐months correlation between ceftriaxone and HO‐CDI (&rgr; = 0.44, P = .018). A unit of stem cell transplant recipients did not have significant correlation between carbapenems and HO‐CDI in matched months (&rgr; = 0.37, P = .098), but a significant correlation was observed when a 1‐month lag was applied (&rgr; = 0.54, P = .014). Discussion: Three statistically significant lag associations were observed between FacWide/unit‐level antibiotic consumption and HO‐CDI, and 1 statistically significant nonlagged association was observed FacWide. Antibiotic consumption may convey extended ward‐level risk for incident CDI. Conclusions: Consumption of antibiotic agents may have immediate and prolonged influence on incident CDI. Additional studies are needed to investigate the immediate and delayed associations between antibiotic consumption and C difficile colonization, infection, and transmission at the hospital level.

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation.

To evaluate the steady‐state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia.

Carbapenems vs. alternative β-lactams for the treatment of nosocomial pneumonia: A systematic review and meta-analysis

BACKGROUND Carbapenems have shown efficacy in treating nosocomial pneumonias in clinical trials despite a reported low lung penetration compared with other β-lactams. Preserving the clinical activity of carbapenems through stewardship efforts is essential. The aim of this review was to identify any differences in outcomes potentially as a function of decreased penetration. METHODS PubMed and the Cochrane Library were systematically searched for clinical trials comparing carbapenems with other anti-pseudomonal β-lactams for treatment of nosocomial pneumonia through to end December 2016. Trials reporting clinical and microbiological outcomes associated with treatment were included. Pediatric studies and those with uneven comparators (e.g., carbapenem vs. combination Gram-negative therapy) were excluded. Fixed effects models were used to evaluate the impact of treatment on the odds of clinical failure, death, or microbiological failure. RESULTS 252 unique articles were identified; five met inclusion criteria and comprised 640 patients in the carbapenem group and 634 patients in the β-lactam group. No differences in clinical failure (odds ratio [OR] 1.08, 95% confidence interval [CI] [0.81-1.44], I2=16%) or mortality (OR 0.75, CI 0.57-1.11, I2=0%) were noted between groups. Patients infected with P. aeruginosa and treated with imipenem were more likely to experience clinical failure (OR 4.21, CI 1.51-11.12, I2=44%) and to develop resistance to the study carbapenem (OR 2.86, CI 1.08-6.44, I2= 13%) than those treated with alternative β-lactams. CONCLUSIONS No differences in clinical outcomes were observed between carbapenems and non-carbapenem β-lactams in nosocomial pneumonias. Those infected with P. aeruginosa fared worse and were more likely to have resistance develop if they were treated with imipenem. Additional studies are warranted.

Population pharmacokinetics of cefepime in febrile neutropenia: implications for dose-dependent susceptibility and contemporary dosing regimens

Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible-dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4-8 µg/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CLCr) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3-8 g/day infused over 0.5-24 h, replaced every 6-24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two-compartment PK model with BSA- and CLCr-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 ± 1.1 L/h), intercompartmental clearance (6.9 ± 2.8 L/h), and central (14.8 ± 3.8 L) and peripheral (10.9 ± 4.6 L) distribution volumes were all estimated with <50% CV. Simulated dosing regimens of 3-4 g/day administered as continuous infusions and doses of 2 g administered q6h (0-5 h infusion) to q8h (4-h infusion) achieved ≥90% PTA at MICs up to 8 µg/mL. Simulated regimens of 1 g q8h (4-h infusion) or 1 g q6h (0.5-h infusion) achieved ≥90% PTA only against MICs up to 4 µg/mL. High-dose prolonged infusion or more frequent cefepime regimens may be necessary to treat FN organisms with SDD MICs.

Correction for Rhodes et al., Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats

Nathaniel J. Rhodes,a,b Walter C. Prozialeck,c Thomas P. Lodise,d Natarajan Venkatesan,e* J. Nicholas O’Donnell,a Gwendolyn Pais,e Cameron Cluff,a Peter C. Lamar,c Michael N. Neely,f,g Anil Gulati,e Marc H. Scheetza,b Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USAa; Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USAb; Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois, USAc; Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USAd; Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, USAe; University of Southern California, Keck School of Medicine, Los Angeles, California, USAf; Laboratory of Applied Pharmacokinetics and Bioinformatics (LAPKB), Childrens Hospital of Los Angeles Saban Research Institute, Los Angeles, California, USAg

24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury.

ABSTRACT Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (Cmax), and the minimum concentration. Spearmans rank correlation coefficient (rs) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and Cmax were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for Cmax). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or Cmax.