The case for precision dosing: medical conservatism does not justify inaction.

2021

2021 Apr 12

1460-2091

<p>The need for precision dosing has been challenged on the basis of insufficient evidence. Herein, we argue that adequate evidence exists to conduct therapeutic drug monitoring (TDM) and precisely target antibiotic exposures. While achievement of any antibiotic concentration does not guarantee efficacy sans toxicity for any single patient, stochastic control optimizes the probability of achieving favourable responses across patients. We argue that variability in targets (such as the organism's MIC) can be considered with models. That is, complexity alone does not relegate the decision-making framework to 'clinician intuition'. We acknowledge the exposure-response relationships are modified by patient-specific factors (other drugs, baseline organ functional status etc.) and describe how precision dosing can inform clinical decision making rather than protocolize it. Finally, we call for randomized, controlled trials; however, we suggest that these trials are not necessary to make TDM standard of care for multiple classes of antibiotics.</p>

10.1093/jac/dkab086

J Antimicrob Chemother

33843994

Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model.

2020

2020 Feb 03

1460-2091

<p><strong>BACKGROUND: </strong>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.</p>

<p><strong>OBJECTIVES: </strong>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.</p>

<p><strong>METHODS: </strong>(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®.</p>

<p><strong>RESULTS: </strong>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 &lt; 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P &lt; 0.001, KIM-1; P &lt; 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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

10.1093/jac/dkz563

J. Antimicrob. Chemother.

32011685

Comparative performance of urinary biomarkers for vancomycin induced kidney injury according to timeline of injury.

2019

2019 Apr 15

1098-6596

<p>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 (n=125) were randomized to receive 150 to 400 mg/kg/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 hours prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic curves (ROC) were employed to assess urinary biomarker performance of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologic defined VIKI (using a national standard pathologic assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL according to sensitivity and specificity. For the earliest injury, urinary KIM-1 (AUC 0.662, p&lt;0.001) and clusterin (AUC 0.706, p&lt;0.001) were most sensitive to predicting even low-level histopathologic damage at 24 h when compared to NGAL. KIM-1 and clusterin are earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin and OPN define the extent of damage best.</p>

10.1128/AAC.00079-19

Antimicrob. Agents Chemother.

30988153