Drug monitoring and individual dose optimization of antimicrobial drugs: oxazolidinones

ABSTRACT

Introduction: Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials.

Areas covered: In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug-related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers.

Expert opinion: Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven.

KEYWORDS:

• Dose optimization
• linezolid
• oxazolidinones
• pharmacokinetics
• tedizolid
• therapeutic drug monitoring

Article highlights

• LZD is a synthetic antibiotic with activity against Gram-positive infections that has been approved for the treatment of ABSSSIs (including MRSA and VRE), community-acquired pneumonia, and XDR tuberculosis.

• The PK of LZD is significantly affected by renal function, age, body weight, and co-medications.

• LZD-related adverse events are more frequent in elderly, in patients with impaired renal function and with longer treatment. The incidence of these adverse events can be reduced by TDM-guided LZD dose adjustments.

• Tedizolid has been approved as a 6 day treatment for ABSSSIs. Lack of data and clinical experience with this newly marketed agent preclude recommendations as yet for individualized dosing regimens. However, the potential use of tedizolid for other infections that might require longer therapy, such as pneumonia, bone, and joint infections, or as a second-line antituberculosis agent warrants studies to address the potential role of individual dose-optimization schemes.

• Further research is needed to assess the potential role of drug monitoring for novel oxazolidinones.

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Declaration of interests

D Cattaneo has received fees for presentations at meeting/workshops and/or travel grants from Merck Sharp & Dome, Bristol Myers Squibb and ViiV Healthcare. M Neely has no conflicts of interest. J-W Alffenaar has received financial support for investigator-initiated studies or academic symposia from Pfizer, Merck Sharp & Dome, Gilead and Astellas. He served on the advisory board of Pfizer (voriconazole) and Janssen Pharmaceutical (bedaquiline). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.