Background: This study analyzed the relationship between vancomycin area under the concentration-time curve (AUC) and acute kidney injury (AKI) reported across recent studies.Methods: A systematic review of PubMed, Medline, Scopus, and compiled references was conducted. We included randomized cohort and case-control studies that reported vancomycin AUCs and risk of AKI (from 1990 to 2018). The primary outcome was AKI, defined as an increase in serum creatinine of ≥0.5 mg/L or a 50% increase from baseline on ≥2 consecutive measurements. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Primary analyses compared the impact of AUC cutpoint (greater than ~650 mg × hour/L) and AKI. Additional analysis compared AUC vs trough-guided monitoring on AKI incidence.Results: Eight observational studies met inclusion/exclusion criteria with data for 2491 patients. Five studies reported first-24-hour AUCs (AUC0-24) and AKI, 2 studies reported 24- to 48-hour AUCs (AUC24-48) and AKI, and 2 studies reported AKI associated with AUC- vs trough-guided monitoring. AUC less than approximately 650 mg × hour/L was associated with decreased AKI for AUC0-24 (OR, 0.36 [95% CI, .23–.56]) as well as AUC24-48 (OR, 0.45 [95% CI, .27–.75]). AKI associated with the AUC monitoring strategy was significantly lower than trough-guided monitoring (OR, 0.68 [95% CI, .46–.99]).Conclusions: AUCs measured in the first or second 24 hours and lower than approximately 650 mg × hour/L may result in a decreased risk of AKI. Vancomycin AUC monitoring strategy may result in less vancomycin-associated AKI. Additional investigations are warranted.

Polymyxin B remains an antibiotic of last resort because of its toxicities. Although newer therapies are becoming available, it is anticipated that resistance to these agents will continue to emerge, and understanding the safest and most efficacious manner to deliver polymyxin B will remain highly important. Recent data have demonstrated that polymyxin B may be less nephrotoxic than colistin. Pharmacokinetically, polymyxin B is primarily eliminated via non-renal pathways, and most do not recommend adjusting the dose for renal impairment. However, some recent studies suggest a weak relationship between polymyxin B clearance and patient creatinine clearance. This review article will describe the clinical pharmacokinetics of polymyxin B and address relevant issues in chemistry and assays available.

Polymyxin B (PB) has reemerged as a common treatment against multidrug-resistant Gram-negative pathogens. However, nephrotoxicity remains a significant dose-limiting side effect, and contemporary pharmacokinetic (PK) data are limited. This study sought to evaluate PB exposure differences in various loading and nonloading strategies according to total body weight (TBW) and adjusted body weight (ABW). Patients treated with PB had plasma samples obtained for clinical care and analyzed using liquid chromatography-tandem mass spectrometry. Compartmental PK models with linear and allometric scaling of TBW were explored. Semiparametric Monte Carlo simulation evaluated the total (i.e., protein bound plus unbound) area under the plasma concentration-time curve (AUC _total ) during the first 24 h of therapy and at 96 h posttherapy for each regimen at the 10th, 50th, and 90th percentiles of TBW and ABW in the derivation cohort. Literature-based values of the 24-h total AUC/MIC ratio (AUC/MIC _total ) of ≥50 defined efficacy, and literature-based values of the 72- to 96-h AUC _total of ≥100 μg · h/ml defined toxicity. Fifty-two patients contributed 156 PB plasma samples. A two-compartment model with allometric scaling of TBW produced a comparable fit (Akaike information criterion [AIC] = 376.7) to that achieved with linear scaling (AIC = 378). The regimen of a loading dose of 2.5 mg/kg of body weight plus a fixed dose of 100 mg every 12 h had the highest probability of achieving a 24-h AUC/MIC _total of ≥50 with the lowest probability of toxicity in all groups at 24 h, aside from those with the lowest 10th percentile of body weight. This is the first study to suggest that a weight-based loading and fixed maintenance (i.e., weight-independent) dosing strategy for polymyxin B may maximize efficacy while balancing toxicity concerns for most patients.

Objectives: The objectives of this study were to: 1) evaluate the prevalence of augmented renal clearance in critically ill pediatric patients using vancomycin clearance; 2) derive the pharmacokinetic model that best describes vancomycin clearance in critically ill pediatric patients; and 3) correlate vancomycin clearance with creatinine clearance estimated by modified Schwartz or Cockcroft-Gault. Design: Retrospective, two-center, cohort study from 2003 to 2016. Setting: Clinical drug monitoring services in the PICUs at two tertiary care, teaching hospitals. Patients: Children from 1 to 21 years old. Interventions: None. Measurements and Main Results: Identify patients with augmented renal clearance (vancomycin clearance ≥ 130 mL/min/1.73 m² used as definition of augmented renal clearance). Derive final population-based pharmacokinetic model and estimate individual patient pharmacokinetic parameters. Compare estimated glomerular filtration rate (modified Schwartz or Cockcroft-Gault depending on age < or ≥ 17 yr) with vancomycin clearance. Augmented renal clearance was identified in 12% of 250 total subjects. The final population-based pharmacokinetic model for vancomycin clearance (L/hr) was 0.118 × weight (e^{–1.13 × [serum creatinine (Scr) – 0.40]}). Median vancomycin clearance in those with versus without augmented renal clearance were 141.3 and 91.7 mL/min/1.73 m², respectively (p < 0.001). By classification and regression tree analysis, patients who were more than 7.9 years old were significantly more likely to experience augmented renal clearance (17% vs 4.6% in those ≤ 7.9 yr old; p = 0.002). In patients with augmented renal clearance, 79% of 29 had vancomycin trough concentrations less than 10 µg/mL, compared with 52% of 221 in those without augmented renal clearance (p < 0.001). Vancomycin clearance was weakly correlated to the glomerular filtration rate estimated by the modified Schwartz or Cockcroft-Gault method (Spearman R ² = 0.083). Conclusions: Augmented renal clearance was identified in one of 10 critically ill pediatric patients using vancomycin clearance, with an increase of approximately 50 mL/min/1.73 m² in those with augmented renal clearance. As augmented renal clearance results in subtherapeutic antibiotic concentrations, optimal dosing is essential in those exhibiting augmented renal clearance.