Pharmacokinetics and Nephrotoxicity of Polymyxin Antibiotics

Polymyxin antibiotics, notably colistin and polymyxin B, have re-emerged as vital agents in the fight against multidrug-resistant Gram-negative pathogens. Their pharmacokinetic profile is defined by extensive tissue distribution, concentration-dependent bacterial killing and a narrow therapeutic window. Colistin is administered as an inactive prodrug that undergoes in vivo conversion, while polymyxin B is delivered in its active form. Both compounds exhibit complex elimination pathways, with non-renal clearance predominating for polymyxin B and mixed renal/non-renal routes for colistin. Key pharmacodynamic indices such as the 24-hour area under the concentration-time curve to minimum inhibitory concentration ratio (AUC24/MIC) strongly correlate with efficacy. However, attaining exposures at the upper boundary of this window increases the risk of nephrotoxicity, characterised by acute tubular injury, mitochondrial dysfunction and oxidative stress in renal proximal tubule cells. Clinical risk factors for acute kidney injury include elevated trough concentrations, co-administration of other nephrotoxins and patient comorbidities. Recent efforts focus on optimising dosing through therapeutic drug monitoring, population pharmacokinetic modelling, adaptive dosing algorithms and alternative administration routes to balance maximal antibacterial activity with renal safety.

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Pharmacokinetics and Nephrotoxicity of Polymyxin Antibiotics publication trend

The graph below shows the total number of articles in pharmacokinetics and nephrotoxicity of polymyxin antibiotics across all publications each year (not limited to Nature Index journals).

Technical terms

AUC24/MIC: The ratio of the area under the concentration-time curve over 24 hours to the minimum inhibitory concentration, a principal index of antibiotic exposure relative to bacterial susceptibility.

Trough concentration (Cmin): The lowest serum drug level measured immediately before the next dose, used to assess drug accumulation and toxicity risk.

Acute kidney injury (AKI): A rapid decline in renal function, often defined by increases in serum creatinine or reductions in urine output, associated with drug-induced tubular damage.

Population pharmacokinetic model: A mathematical representation of drug concentration variability within a patient population, informing dosing recommendations.

Monte Carlo simulation: A computational method that predicts the likelihood of achieving pharmacokinetic/pharmacodynamic targets across heterogeneous patient profiles.

Therapeutic window: The range of drug exposure between the minimum effective concentration and the threshold for significant toxicity.

References

1. Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study. Critical Care (2023).
2. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infectious Diseases (2013).
3. Personalizing Polymyxin B Dosing Using an Adaptive Feedback Control Algorithm. Antimicrobial Agents and Chemotherapy (2018).
4. Molecular Mechanisms of Colistin-Induced Nephrotoxicity. Molecules (2019).
5. A Review of the Clinical Pharmacokinetics of Polymyxin B. Antibiotics (2019).
6. Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Annals of Intensive Care (2011).
7. Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study. Critical Care (2013).