Therapeutic drug monitoring

Optimizing the prescription of antimicrobials is required to improve clinical outcome from infections, to reduce the development of antimicrobial resistance, and minimise to risk of toxicity. One such method to improve antimicrobial dosing in individual patients is through application of therapeutic drug monitoring (TDM) (J Roberts et al 2011). Whilst most commonly employed for drugs with a narrow therapeutic range, the need to use TDM is increasing because of the high number of critically ill patients with unpredictable pharmacokinetics, as well as the decreasing susceptibility of pathogens.

To be appropriate for TDM, an iv antibiotic must ideally satisfy the following factors:
• Drug factors:
large between subject variability;
small therapeutic index;
an established concentration–effect (or toxicity) relationship (or both);
validated analytic methods available.
• Patient factors:
pathophysiological conditions known to alter PK
suspected drug interactions;
suspected drug adverse effects/toxicity;
unexplained failure of therapy.

In an era of growing resistance problems and reduced susceptibility of commmonly used antibiotics, especially in Intensive Care Units, a primary goal of TDM may be to optimize the clinical response to treatment, rather than to avoide adverse effects. For drugs such as beta-lactams, TDM has previously been considered to be less clinically relevant. However, TDM may be used mainly to maximize efficacy in patietns with unpredictable pharmacokinetics.

Beta-lactam antibiotics

The majority of evidence suggests that empiric approaches to dosing of beta-lactam antibiotics may result in subtherapeutic antibiotic concentrations and treatment failure or the emergence of antibiotic resistance. The available studies also strongly support the need for individualized dose optimization in the critically ill, which supports the need for TDM. Despite the theoretical advantages, there remains no consistent use of agreed PK/PD targets. Furthermore, none of the studies have defined the impact of TDM on clinical outcome (F.B. Sime et al 2012).

Linezolid

Patients who experience overexposure with linezolid and/or who are long-term treated with this drug could be at higher risk of drug-related toxicity. Co-therapy with rifampicin reduces the serum concentrations of linezolid with an increased risk of underexposure but concurrent reduced toxicity due to lowered linezolid concentrations. A recent study  suggests that maintenance over time of linezolid Cmin between 2 and 7 mg/L and of AUC24 between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients with infections requiring prolonged treatment with linezolid. TDM-guided dosage adjustments may be especially necessary in patients co-treated with some P-gp modulators (omeprazole, amiodarone, clarithromycin and rifampicin), and/or in those who may present peculiar pathophysiological conditions (F. Pea et al 2012)

Colistin

New pharmacokinetic data open perspectives in terms of colistin TDM. Only limited experience suggest that TDM of colistin may be beneficial in critically ill patients with fluctuating renal function (A. Bode-Böger et al 2013). Currently, a few pilot projects and clinical studies characterise basic models and methods that include the control for the continous hydrolysis of colistimethate sodium to the active colistin base.

Leave a Reply

Your email address will not be published. Required fields are marked *