Other situations affecting PK

Other clinical situations may result in changes to aminoglycoside pharmacokinetics (PK), warranting special care when managing these patients and potentially requiring dosage changes.

In this section of the course, we provide an overview of these situations, some of which we introduced briefly back in Week 2.

Sepsis

As you learned in step 2.10 many physiological changes occur in patients with sepsis. In summary, high doses of aminoglycosides are important for quickly controlling infective causes of sepsis, but close monitoring is warranted to ensure safe and effective use.

Intensive Care

Patients may be admitted to intensive care units (ICU) for a number of reasons, including those listed in this step. Additionally, the interventions used in ICU can also affect the PK of aminoglycosides. For example, mechanical ventilation has been shown to increase the Vd, reduce serum concentrations, and extend the half-life of aminoglycosides.

Renal function may also be augmented through intermittent or continuous dialysis methods. Extracorporeal membrane oxygenation (ECMO) is expected to result in an enlarged Vd, thus reducing serum concentrations, as well as a renal clearance.

Significant Burns

In the acute phase after an extensive burn, vascular permeability leads to an increased Vd and a drop in cardiac function, ultimately resulting in reduced renal function. In the subsequent hypermetabolic phase, there is an increased cardiac output and enhanced liver and renal function, resulting in enhanced aminoglycoside clearance.

This results in changeable PK profiles over time, that are difficult to predict and vary greatly between individual patients. Higher doses of aminoglycosides may be required to achieve desired systemic concentrations, and more frequent dosing may be required in the hypermetabolic phase.

Ascites and Oedema

Increased extravascular fluid results in a significant increase in the Vd, which can reduce aminoglycoside concentrations and inhibit renal clearance, thus impacting efficacy and safety.

Ascites is often a result of liver disease and these patients may have a degree of renal impairment and reduced plasma protein binding, which impacts aminoglycoside concentrations and clearance. Oedema is often the result of heart failure, which can also reduce glomerular filtration and thus aminoglycoside clearance. People with heart failure may also have hepatic dysfunction and reduced plasma proteins.

Cystic Fibrosis (CF)

Aminoglycosides are often life-saving for people with CF lung infections caused by Gram-negative bacteria. In people with CF, both the Vd and the renal clearance of aminoglycosides is increased. This can result in lower peak concentrations and a shorter half-life, which can extend the time spent in subtherapeutic concentrations, even after the post-antibiotic effect (PAE) of aminoglycosides is taken into consideration.

Larger doses of aminoglycosides are often warranted in people with CF, to achieve the concentrations needed to kill Pseudomonas aeruginosa. Therefore, both peak and trough blood concentrations may be measured to check efficacy and safety.