Update on the appropriate use of linezolid in clinical practice

Figures & data

Table 1 Factors which contribute at various levels to the choice of empirical or selective antimicrobial chemotherapy, when resistant Gram-positive cocci may be of concern

– Local epidemiology maps, and hospital epidemiology (nosocomial) maps – Ethiological diagnosis and in vitro antimicrobial susceptibility assays – Patient's conditions and eventual underlying disorders and supporting conditions – Patient's status of immune competence – Predisposing conditions – Appropriate physician's prescription – Spectrum of activity of prescribed antimicrobial agents, and their eventual association (to exploit additive or synergistic activity) – Drug bioavailability characteristics (including drug disposition and diffusion, protein link, volume of distrubution, tissue and intracellular penetration, pharmacokinetic and pharmacodynamic properties) – Serum and tissue half-life of selected compounds – Expected or assessed antimicrobial resistance pattern – Drug metabolism, eventual post-antibiotic effect, elimination routes – Peak levels, minimal inhibitory concentrations (MIC), mimimal bactericidal concentrations (MBC), area under the curve (AUC), and related pharmacokinetic/pharmacodynamic parameters – Drug-drug interactions (increased or reduced activity and toxicity), drug metabolism (active or inactive metabolites) – Comprehensive duration of antimicrobial chemotherapy courses – Comprehensive tolerabilily, and toxicity issues in otherwise healthy, or compromised subjects – Patient's compliance (also related to eventual concomitant pharmacological treatments) – Crude and comprehensive costs of administration and delivery of each single drug in the relevant context (including possibility to switch from a parenteral to an oral route of administration) – Comprehensive pharmacoeconomic issues

Figure 1 Chemical structure of linezolid, the first oxazolidinone antimicrobial compound.The first ring (from the left) contains a morpholino group, which enhances its pharmacokinetic profile and improves water solubility. In the second ring (from the left), the strategically located fluorine atom enhances drug activity.The “bridge” structure after the third ring (from the left) bears a necessary 5-(S) configuration.The terminal (right) C-5 acylaminomethyl group is essential for ensuring the unique drug characteristics.

Table 2 Mean multiple-dose pharmacokinetics of linezolid, administered twice daily, as recommended (modified from Stevens et al 2004)

Parameter	600 mg oral tablet	600 mg IV
Cmax (mcg/mL)	21.2 ± 5.78	15.10 ± 2.52
Cmin(mvg/mL)	6.15 ± 2.94	3.68 ± 2.36
Tmax(hours)	1.03 ± 0.62	0.51 ± 0.03
AUC (mcgh/mL)	138.0 ± 42.1	89.7 ± 31.0
Half-life (hours)	5.40 ± 2.06	4.80 ± 1.70
Clearance (mL/min)	80.0 ± 29.0	123.0 ± 40.0

Abbreviations: AUC, area under the curve.

Table 3 Pharmacoeconomic variables of antimicrobial agents to be evaluated, especially when when an agent burdened by a proportionally elevated crude cost has to be addressed (modified from Nathwani 2006)

OVERALL EXPENDITURES

– Direct

– Indirect

– Intangible ones

TIME HORIZON CONSIDERED

– Short-term

– Medium-term

– Long-term

DIFFERENT PERSPECTIVES

– Society

– Patient

– Payer

– Provider

Table 4 Some key mode and resource use with antimicrobials specific for resistant Gram-positive infections. Linezolid compared with standard of care antimicrobials for methicillin-resistant Gram-positive cocci infections (vancomycin and teicoplanin), and with the currently available alternatives recently introduced into the market (quinupristin/dalfopristin, and daptomycin)

	Linezolid	Vancomycin	Teicoplanin	Quinupristin/dalfopristin	Daptomycin	Tigecycline	Dalbavancin
IV and oral route, both available	Yes	No*	No*	No	No	No	No
Ambulatory (outpatient)	Yes	No	Yes	Yes?	?	?	Yes
administration feasible
Need of serum drug level monitoring	No	Yes	No	Yes	Yes?	No	No
Frequency of drug administration	Twice daily	At least twice daily, to 24 h continue infusion	Once daily	Once daily	Once daily	Twice daily	Once weekly

Abbreviations: IV, intravenous.

* Note: indication restricted to the management of Clostridium difficile-associated diarrhea.

StevensDLDotterBMadaras-KellyAA review of linezolid: the first oxazolidinone antibioticExpert Rev Anti-Infective Ther20042519

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NathwaniD2006 Personal communication

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