Biology subjects

Rhodes, N. J.

Publications and source records attributed to Rhodes, N. J..

5 recordsLinked to original sources

bioRxiv2026

A novel mechanism of ceftolozane-tazobactam resistance in Pseudomonas aeruginosa mediated by L2 β-lactamase

The prevalance of non-susceptibility to ceftolozane-tazobactam (C/T) among Pseudomonas aeruginosa remains low but novel mechanisms of C/T resistance are of concern. Herein, we describe a novel Pseudomonas aeruginosa genotype associated with high-level C/T resistance (>256/4 {micro}g/mL) in a single patient. Whole genome sequencing of the isolate was compared to that of a susceptible isolate cultured from the same patient two months earlier. Analysis of the sequences revealed two different P. aeruginosa high-risk clones: ST111 followed by ST235. The C/T-resistant ST235 isolate contained five copies of a genetic element comprised of an L2 {beta}-lactamase gene (blaL2) and a truncated ampRL2 transcriptional regulator gene, which are commonly found together in Stenotrophomonas maltophilia strains and have not been reported to mediate resistance to C/T. Comparative genomic analysis with other P. aeruginosa isolates failed to identify alternative explanations for the observed C/T resistance. We found that exogenous expression of blaL2 modestly increased C/T MICs in genetically distinct P. aeruginosa strains. A screen of our archived isolates identified two P. aeruginosa clinical isolates, PS2045 and PS2046, with one and two copies, respectively, of the genetic element containing blaL2 and truncated ampRL2. Interestingly, disruption of the gene blaL2 but not the truncated ampRL2 in PS2045 led to a significant decrease in C/T MIC. Thus, we report a novel mechanism of C/T resistance in P. aeruginosa mediated by an L2 {beta}-lactamase independently of its canonical regulator AmpRL2.

microbiology↗

bioRxiv2023

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.

pharmacology and toxicology↗

bioRxiv2021

Of Rats and Men, a Translational Model to Understand Vancomycin Pharmacokinetic/Toxicodynamic relationships

BackgroundVancomycin is a first line antibiotic for many common infectious diseases and is the most commonly prescribed antibiotic in the United States hospital setting. Vancomycin is also well known to cause kidney injury; two recent prospective studies have identified that increasing vancomycin area under the concentration curve predicts vancomycin induced kidney injury (VIKI). However, outside of clinical trials, it is unclear if pre-clinical data can quantitatively describe VIKI in patients. MethodsData were simultaneously analyzed from a pre-clinical rat model and two prospective clinical studies. Logged vancomycin area under the concentration curve (AUC) data for rats (n=48) and patients from PROVIDE (n=263) and CAMERA2 (n=291) were included. VIKI was defined as urinary KIM-1 concentrations [≥]9.42 ng/mL in the rat and according to KDIGO stage 1 kidney injury for all human patients. Multiple generalized linear models were explored, and the order of magnitude was calculated between the probability of acute kidney injury (AKI) from the average obtained in the clinical studies (i.e. CAMERA2 and PROVIDE) and the rat for 0.1 increments in Log10AUC bounded common concentrations obtained in the therapeutic range (i.e. ~200 -800 mg*24h/L). ResultsA logit link model best fit the data. When calculating the multiplicative factors between the studies therapeutic range AUCs, the rat was an average 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 (i.e. log 10 AUC=2.3) and 794.3 mg*h/L (i.e. log 10 AUC=2.9), respectively. ConclusionsA pre-clinical rat model was quantitatively linked to toxicity data from two large human studies. The rat is an attractive pre-clinical model to explore exposure toxicity relationships with vancomycin. External validation is required.

pharmacology and toxicology↗

bioRxiv2020

Use of Therapeutic Drug Monitoring to Characterize Cefepime-Induced Neurotoxicity

BackgroundThe incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN. MethodsThis was a retrospective study of adult patients who had received [≥] 5 days of cefepime with [≥] 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation. ResultsOne-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L {+/-} 41.1 vs. 46.6 mg/L {+/-} 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) ([≥]72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN. ConclusionCefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM ([≤] 72 hours) had lower risk of CIN.

pharmacology and toxicology↗

bioRxiv2019

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vitro Model

The polymyxins are last-line defense for highly resistant infections. Nephrotoxicity, however, is a dose-limiting factor. Yet, approaches to mitigate nephrotoxicity are poorly defined. This study aimed to investigate the impact of dose fractionated (once, twice and thrice daily) polymyxin B (PB) on acute kidney injury (AKI) in a pre-clinical model. Secondarily, we aimed to describe the pharmacokinetic (PK) profile of PB. Sprague-Dawley rats were assigned to experimental groups with different dosing intervals but constant total daily exposure (12 mg/kg/day into single, twice daily, and thrice daily doses) and controls received normal saline subcutaneously over 3 days. Blood and urine samples were collected, and kidneys were harvested at necropsy. A three-compartment model best described the data and Bayesian observed vs. predicted concentration demonstrated bias, imprecision, and R2 of 0.129 mg/L, 0.729 mg2/L2 and 0.652, respectively. PB exposure (i.e. AUC24h) were similar across treatment groups over time (p=0.87). As a representative, urinary KIM-1 were elevated on days 1 and 2 for experimental groups compared to controls, and thrice daily group experienced the most KIM-1 increase [mean increase (95% CI) day 1 from day -1, 4.44 (0.89, 8.00) ng/mL; p=0.018] as compared to control [mean increase (95% CI) day 1 from day -1, 0.03 (-0.42, 0.49) ng/mL; p=0.99]. Correspondingly, significant histopathological damage was observed with the same group (p=0.013) (controls as a referent). Our findings suggested that fractionating the PB dose thrice daily resulted in the most injury in a rat model.

pharmacology and toxicology↗