ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2010, p. 4605–4610 Vol. 54, No.

11
0066-4804/10/$12.00 doi:10.1128/AAC.00177-10
Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Therapeutic Drug Monitoring of Linezolid: a Retrospective

Monocentric Analysis䌤
Federico Pea,1* Mario Furlanut,1 Piergiorgio Cojutti,1 Francesco Cristini,2 Eleonora Zamparini,2
Loretta Franceschi,1 and Pierluigi Viale3
Institute of Clinical Pharmacology and Toxicology, Azienda Ospedaliero Universitaria Santa Maria Misericordia, Department of
Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine, Italy1; Clinic of
Infectious Diseases, Department of Medical and Morphological Research, Medical School, University of
Udine, Udine, Italy2; and Clinic of Infectious Diseases, Department of Internal Medicine,
Geriatrics and Nephrologic Diseases, University of Bologna, Bologna, Italy3

Downloaded from http://aac.asm.org/ on November 9, 2020 by guest

Received 8 February 2010/Returned for modification 22 April 2010/Accepted 14 August 2010

The objective of the present retrospective observational study carried out in patients receiving a standard
dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindi-
vidual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics,
and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid
plasma concentrations (trough [Cmin] and peak [Cmax] levels) were analyzed by means of a high-performance
liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma
concentration-time curve [AUC24]). The final database included 280 Cmin and 223 Cmax measurements per-
formed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n ⴝ 58)
or orally (n ⴝ 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to
7.53 mg/liter] for Cmin, 14.70 mg/liter [10.57 to 19.64] for Cmax, and 196.08 mg 䡠 h/liter [144.02 to 312.10
mg 䡠 h/liter] for estimated AUC24). Linezolid Cmin was linearly correlated with estimated AUC24 (r2 ⴝ 0.85).
Optimal pharmacodynamic target attainment (defined as Cmin of >2 mg/liter and/or AUC24/MIC90 ratio of
>80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as Cmin of >10 mg/liter
and/or AUC24 of >400 mg 䡠 h/liter) was documented in about 12% of cases. A significantly higher proportion
of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our
study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent
of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

Linezolid is the first commercially available oxazolidinone, significantly according to renal and/or hepatic failure and/or to
whose use in the treatment of infection caused by multidrug- polytherapy (32). The oxidative metabolism of linezolid is non-
resistant (MDR) Gram-positive bacteria is continuously in- enzymatic and does not involve the hepatic microsomal oxida-
creasing (37). tive system CYP450. Nonrenal clearance accounts for 65% of
Among the several reasons for this, two appear to be the an administered linezolid dose, with roughly 30% of the dose
most clinically relevant. First, linezolid retains its efficacy even appearing unchanged in the urine (31). Additionally, in con-
against bacterial strains which become tolerant of glycopep- trast to those of more hydrophilic antimicrobial agents such as
tides. This fact may justify even its empirical use in settings the beta-lactams, linezolid pharmacokinetics did not appear to
with high incidences of bacterial strains with borderline sus- be substantially affected by the pathophysiological changes oc-
ceptibility to vancomycin (23) or its use for salvage therapy curring during sepsis and/or septic shock (36).
(13). Second, it presents very favorable rates of penetration However, some recent studies suggest that TDM of linezolid
into tissues (33), even in the presence of intact anatomical could be especially helpful for dosage adjustment in some
barriers (18). This suggests a potential pharmacokinetic advan- settings. Significant underexposure with increased risk of ther-
tage over glycopeptides in the treatment of deep-seated infec- apeutic failure was documented in patients with major thermal
tions, such as pneumonia (1, 33) and/or central nervous system injuries (10, 17) and with cystic fibrosis (4), whereas, con-
infections (27). versely, significant overexposure with increased toxicity risk
Based on the drug’s intrinsic chemicophysical and pharma- was observed in some critically ill patients (21, 25).
cokinetic characteristics, it is expected that dosing adjustment To the best of our knowledge, no observational data in daily
and intensive therapeutic drug monitoring (TDM) may be un- clinical practice on linezolid plasma exposure during routine
necessary in most cases. Linezolid is a moderately lipophilic use at standard fixed doses are available to date.
drug whose pharmacokinetic behavior is not expected to vary On the basis of an institutional program devoted to improv-
ing knowledge of the pharmacokinetic behavior of newly com-
mercially available antimicrobial agents in the clinical setting,
* Corresponding author. Mailing address: Institute of Clinical Phar- in 2003 we started to measure plasma levels of linezolid in
macology and Toxicology, DPMSC, University of Udine, P.le S. Maria
della Misericordia 3, 33100 Udine, Italy. Phone: 39 0432 559833. Fax:
patients treated because of documented and/or suspected
39 0432 559819. E-mail: pea.federico@aoud.sanita.fvg.it. MDR Gram-positive bacterium-related infections.
䌤
Published ahead of print on 23 August 2010. The present retrospective observational study aimed to as-

4605
4606 PEA ET AL. ANTIMICROB. AGENTS CHEMOTHER.

sess the interindividual pharmacokinetic variability in plasma TABLE 1. Patient characteristicsa

exposure to linezolid, to identify the prevalence of optimal Characteristic Value
pharmacodynamic exposure enabled by the standard dosing
No. of patients ..................................................................92
regimen according to the pharmacokinetic/pharmacodynamic Age (yr) .............................................................................57.2 ⫾ 14.3
principles and to the pattern of susceptibility to this antibiotic, Gender (no. M/no. F)......................................................67/25
and to define if an intensive program of TDM may be war- Body wt (kg) .....................................................................75.2 ⫾ 18.2
ranted in some categories of patients. CLCR (ml/min)b ................................................................84.8 (6.1–349.5)
Normalized dose of linezolid (mg/kg/12 h) ..................8.37 ⫾ 1.74

Hospital admission (no. 关%兴 of patients)

MATERIALS AND METHODS Surgical ward ................................................................40 (43.5)
Study design. Plasma TDM of linezolid carried out in the period between ICU ................................................................................28 (30.4)
December 2003 and May 2009 at the Institute of Clinical Pharmacology and Medical ward ................................................................24 (26.1)
Toxicology, Azienda Ospedaliero-Universitaria, University of Udine, repre-
sented the starting database. Patients included in this retrospective observational Main reason for linezolid treatment

Downloaded from http://aac.asm.org/ on November 9, 2020 by guest

study were those admitted in intensive care units (ICUs) or medical or surgical (no. 关%兴 of patients)
wards who were treated intravenously or orally with linezolid at the standard Bloodstream infections ................................................18 (19.6)
daily dosage of 600 mg every 12 h (q12h) because of documented or suspected CNS infections..............................................................18 (19.6)
MDR Gram-positive bacterial infections and who underwent TDM. At our Empirical use for severe sepsis ..................................16 (17.4)
institution linezolid TDM is performed three times a week (on Monday, Intra-abdominal infections ..........................................11 (12.0)
Wednesday, and Friday) and the feedback to the clinician is given in real time Hospital-acquired pneumonia.....................................10 (10.9)
(within the same day). However, since the aim of this study was to assess the Bone/joint infections ....................................................10 (10.9)
degree of interindividual variability in plasma exposure to linezolid observed Cardiosurgical infections/endocarditis .......................8 (8.7)
during the standard fixed-dosing regimen, only the TDM carried out before the SST infections ...............................................................1 (0.9)
eventual application of TDM-guided dosage adjustments was considered in this a
Values are expressed as means ⫾ standard deviations, median (range), or
analysis. numbers (percentages). Abbreviations: CLCR, estimated creatinine clearance by
The study was approved by the Ethical Committee. means of the Cockcroft and Gault formula; CNS, central nervous system; ICU,
Measurement of linezolid plasma concentrations. Venous blood samples were intensive care unit; SST, skin and soft tissue; TDM, therapeutic drug monitoring;
drawn just before the next administration to assess trough plasma concentration M, male; F, female.
b
(Cmin) and 30 min after a 1-h intravenous infusion or 2 h after oral administra- At time of first TDM.
tion to assess peak plasma concentration (Cmax). Times for blood collections
were carefully checked and recorded in each single case, and whenever doubts on
appropriate sampling arose, samples were excluded from this analysis. Linezolid dependent toxicity with linezolid (37). Concomitant drug treatments were re-
concentrations in plasma were analyzed by means of a validated high-perfor- viewed in order to identify the frequency of recurrence.
mance liquid chromatography (HPLC) analysis method, as previously described Statistical analysis. The Kolmogorov-Smirnov test was performed to assess
(25, 26). Precision and accuracy were assessed by performing replicate analyses whether data were normally or nonnormally distributed. Accordingly, descriptive
of quality control samples against calibration standards, intra- and interassay data were expressed as means ⫾ standard deviations (SD) or as medians and
coefficients of variation always being less than 10%. The low limit of detection interquartile (IQ) ranges. Categorical variables were compared by the ␹2 test
was 0.2 mg/liter. with Yates’ correction or Fisher’s exact test when necessary, and continuous
Estimation of CLCR. Creatinine clearance (CLCR) was estimated by means of variables were compared using Student’s t test. A P value of ⬍0.05 was required
the Cockcroft and Gault formula (5). to achieve statistical significance. The statistical analysis was carried out with
Pharmacokinetic analysis. Pharmacokinetic analysis of linezolid was per- SigmaStat version 3.1.
formed using the Abbottbase Pharmacokinetic System (PKS) program using
Bayesian forecasting (16). Intravenous administration data were fitted to a stan-
dard one-compartment model with zero-order input (1-h drug infusion) and RESULTS
first-order elimination. For oral administration, the concentration data were
fitted to a standard one-compartment model with first-order absorption and Patient characteristics are shown in Table 1. The most fre-
first-order elimination. The calculated pharmacokinetic parameters were clear- quent hospital admission was surgical (43.5%), and the main
ance and volume of distribution. Daily area under the plasma concentration-time reasons for linezolid therapy were bloodstream infections
curve (AUC24) was estimated using the pharmacokinetic parameters. Only pa-
tients having at least one complete set of Cmin and Cmax measurement samples
(19.6%) and central nervous system infections (19.6%).
drawn at steady state were included for AUC24 estimation. The database included 280 Cmin (median per patient ⫽ 3; IQ
Assessment of pharmacodynamics. (i) Efficacy thresholds. Optimal theoreti- range, 1 to 4) and 223 Cmax measurements performed in 92
cal pharmacodynamic determinants of efficacy for the time-dependent antibac- patients, who were treated with the fixed 600-mg q12h dosing
terial activity of linezolid against methicillin-resistant (MR) staphylococci and regimen of linezolid intravenously in 58 cases and orally in the
against vancomycin-resistant (VR) enterococci were defined as plasma Cmins of
ⱖ2 mg/liter and/or AUC/MIC ratios of ⬎80. The rationale behind these choices
other 34.
derives from the notion that the MIC90 for linezolid against both MR staphylo- Median pharmacokinetic values (IQ ranges) were 3.80 mg/
cocci and VR enterococci is 2 mg/liter (14) and from the finding that, in one liter (1.75 to 7.53 mg/liter) for Cmin, 14.70 mg/liter (10.57 to
study conducted in seriously ill adult patients, higher success rates were achieved 19.64 mg/liter) for Cmax, and 196.08 mg/liter 䡠 h (144.02 to
when the cumulative percentage of a 24-h period that the drug concentration 312.10 mg 䡠 h/liter) for estimated AUC24.
exceeded the MIC under steady-state pharmacokinetic conditions (%TMIC)
exceeded 85% of the dosing interval and AUC/MIC ratios were between 80
No significant linear relationships between linezolid Cmin
and 120 (28). Indeed, the achievement of these targets may become especially and either estimated CLCR (r2 ⫽ 0.01) (Fig. 1) or body weight
relevant for critically ill septic patients, who may often be immunocompro- (r2 ⫽ 0.06) (Fig. 2) were found. Conversely, linezolid Cmin was
mised (24, 28). linearly correlated with estimated AUC24 (r2 ⫽ 0.85) (Fig. 3).
(ii) Toxicity thresholds. Conversely, the thresholds of potential overexposure
For linezolid trough levels sorted according to patients’ hos-
to linezolid were arbitrarily defined as Cmins of ⱖ10 mg/liter and/or AUC24 of
ⱖ400 mg 䡠 h/liter. The reason for this choice is that exposures higher than these,
pital admissions (Fig. 4), medians (IQ ranges) of Cmin were
being more than 2-fold higher than those normally observed with similar dosages 4.78 mg/liter (2.12 to 7.68 mg/liter) in surgical patients, 2.94
in healthy volunteers (12, 32), might significantly increase the risk of dose- mg/liter (1.10 to 6.93 mg/liter) in intensive care unit (ICU)
VOL. 54, 2010 TDM OF LINEZOLID 4607

Downloaded from http://aac.asm.org/ on November 9, 2020 by guest

FIG. 3. Relationship between linezolid trough levels (Cmin) and
FIG. 1. Relationship between linezolid trough levels (Cmin) and
estimated daily area under the plasma concentration-versus-time curve
patients’ estimated creatinine clearance (CLCR).
(AUC24) (n ⫽ 223).

patients, and 2.94 mg/liter (1.66 to 7.25 mg/liter) in medical

patients. Although a trend toward higher exposure was ob- route of administration of linezolid were similar (Table 2).
served among surgical patients, these differences were not sta- However, a significantly higher proportion of the patients with
tistically significant. linezolid Cmins of ⱖ10 mg/liter received cotreatment with omep-
As far as pharmacokinetic/pharmacodynamic relationships razole (78.8 versus 27.5%, P ⬍ 0.001), amiodarone (21.2 versus
are concerned, optimal pharmacodynamic exposure in terms of 2.4%, P ⬍ 0.001), or amlodipine (21.2 versus 5.2, P ⬍ 0.003).
Cmin being higher than MIC90 was documented in 71.4% of
cases and AUC/MIC90 ratios were estimated to be ⬎80 in as
DISCUSSION
many as 61.9% of the 223 evaluable cases.
The trend over time of linezolid Cmin showed that median Our findings suggest that during routine clinical use linezolid
values persisted above the pharmacodynamic threshold of ef- exposure after standard fixed daily dosages may vary among
ficacy from day 2 onward (Fig. 5). Potential overexposure in patients, irrespective of the type of ward of admission.
terms of Cmins of ⱖ10 mg/liter was found in 11.8% of instances Indeed, although median values for Cmin, Cmax, and AUC24
(33 instances of TDM in 23 patients; median, 12.40 mg/liter; were similar to those observed in healthy volunteers (17, 32),
range, 11.0 to 19.2 mg/liter), and AUC24 was estimated to be their ranges were significantly wider.
⬎400 mg 䡠 h/liter in 8.1% of cases. From this perspective, it would be of interest to clarify if
When patients with potential overexposure were compared
with those having trough levels within the lower range (⬍10
mg/liter), normalized daily doses per kg of body weight and

FIG. 4. Box (median and 25th to 75th percentile) and whisker (5th
and 95th percentile) plots of trough plasma concentrations (Cmin) of
linezolid observed according to the type of ward of admission (surgical
FIG. 2. Relationship between linezolid trough levels (Cmin) and wards [Surg], intensive care units [ICU], and medical wards [Med]).
patients’ weight. Filled circles are outliers.
4608 PEA ET AL. ANTIMICROB. AGENTS CHEMOTHER.

In a pharmacodynamic study with linezolid, it was shown

that the two parameters most strongly associated with linezolid
efficacy were AUC/MIC ratios of ⬎80 to 100 and %TMIC of 85
(28). Additionally, it has been postulated that a Cmin higher
than the MIC may be especially useful for linezolid efficacy in
immunocompromised patients (24, 28). Considering that 2 mg/
liter is the MIC90 of linezolid against staphylococci and entero-
cocci (14) and that from our estimates the achievable AUC24
in the presence of Cmin of ⬎2 mg/liter is ⬎160 mg 䡠 h/liter, this
means that for a Cmin of linezolid greater than 2 mg/liter both
the pharmacodynamic targets of efficacy (Cmin higher than
MIC90 and AUC/MIC90 ratio of ⬎80) may be attained. Ac-
cordingly, this plasma trough value could be proposed as the

Downloaded from http://aac.asm.org/ on November 9, 2020 by guest

lower threshold for efficacy with the standard dosage of lin-
ezolid.
In our study standard dosages of linezolid ensured the at-
FIG. 5. Box (median and 25th to 75th percentile) and whisker (5th tainment of these pharmacodynamic targets in the majority of
and 95th percentile) plots of trough plasma concentrations (Cmin) of cases (almost 70 to 75%). Interestingly, median Cmin was ⬎2
linezolid observed over time. Filled circles are outliers; n is the number mg/liter just on day 2 and then it was maintained over this
of observations on each day of treatment. The dashed line refers to 2 threshold throughout the entire treatment period, even if the
mg/liter, namely, the MIC90 of linezolid for staphylococci and entero-
cocci. Median Cmin was almost always above the MIC90 of linezolid for range of variability was consistent. This fact seems to suggest
staphylococci and enterococci, regardless of the day of treatment. that perhaps the role of TDM in order to avoid potential
underexposure with linezolid could be limited if the suscepti-
bility breakpoint for staphylococci was lower than that cur-
some patient characteristics, pathophysiological conditions, rently recommended (i.e., 2 mg/liter rather than 4 mg/liter).
and/or drug cotreatments might account for this variability. The role of TDM might be especially valuable in lowering
Indeed, in our study neither estimated CLCR nor body weight the risk of exposure-dependent toxicity with linezolid, which in
was found to be a useful predictor of linezolid exposure. The our study could have related to the 12% of cases with potential
absence of a significant relationship between linezolid Cmin overexposure. It was shown that some adverse events with
and estimated CLCR is attributable to the mainly nonrenal linezolid, namely, hematological alterations and hyperlactaci-
clearance of linezolid (32). This finding allows us to confirm demia, are dose dependent (37) and may be related to a re-
that no major dosage adjustments need to be recommended in versible inhibition of the mitochondrial protein synthesis (8).
patients with impaired renal function. Likewise, linezolid Cmin In our study potential overexposure was not correlated with
did not show a clear relationship with patients’ body weight. In the use of higher dosage per kg of body weight or with different
our study very low drug exposures in terms of Cmin, Cmax, and administration routes and, of note, its onset seemed to be
AUC24 among obese patients were observed only in some unrelated to the length of treatment. Some years ago we re-
cases, even if the limited number of instances of TDM carried ported the case of a liver transplant patient who experienced
out in this subpopulation did not enable any definite conclu-
sion. Indeed, we recognize that linezolid pharmacokinetics
may be influenced by the degree of obesity, but considering TABLE 2. Comparison of linezolid dosages, administration routes,
that existing data for this patient demographic are quite sparse and most frequent drug cotreatments in cases with trough levels
(Cmin) of ⱖ10 mg/liter versus those with
and variable (11, 19), no empirical alterations of linezolid dos- trough levels of ⬍10 mg/liter
age in obese patients can be suggested to date (19).
Overall, these observations and the wide interpatient vari- No. (%) of cases by linezolid Cmin:
ability seen in this study suggest that it would be difficult to Parameter ⱖ10 mg/liter ⬍10 mg/liter P value
accurately predict the pharmacokinetic disposition of linezolid (n ⫽ 33) (n ⫽ 247)
in all patients, so that the application of TDM, at least in some Linezolid administration
cases, seems logical. route
The good linear relationship between Cmin and estimated Intravenous 21 (63.6) 157 (63.6) 0.847
AUC24 (r2 ⫽ 0.85) suggests that Cmin may represent a useful Oral 12 (36.4) 90 (36.4) 0.845
predictor of linezolid total body exposure in daily clinical prac- Linezolid dosage,
tice. Interestingly, our hypothesis is in agreement with a recent median (IQ range)
population pharmacokinetic study carried out in patients with (mg/kg/q12h)
MDR tuberculosis treated with linezolid which showed that Overall 9.3 (7.5–10.2) 8.0 (7.1–10.0) 0.067
Intravenous 10.0 (7.9–10.0) 8.0 (7.1–10.0) 0.071
the estimation of AUC based on a trough concentration did Oral 7.9 (7.9–10.3) 8.5 (7.1–10.0) 0.876
not differ significantly from that based on multiple samples (3).
Accordingly, it may be speculated that TDM of Cmin could be Cotreatments
used to guide dosage adjustment with linezolid in individual Omeprazole 26 (78.8) 68 (27.5) ⬍0.001
patients with the intent of avoiding either the risk of toxicity or Amiodarone 7 (21.2) 6 (2.4) ⬍0.001
Amlodipine 7 (21.1) 13 (5.2) 0.003
that of therapeutic failure.
VOL. 54, 2010 TDM OF LINEZOLID 4609

an unexpected early onset of hyperlactacidemia due to a con- (median, 1.21 mg/liter; IQ range, 0.68 to 1.73 mg/liter) were
sistent linezolid overexposure (Cmin, 26.99 mg/liter; AUC12, observed in these cases.
412.55 mg 䡠 h/liter) (21). Among the various hypotheses, we Obviously, further prospective studies are warranted before
postulated that this overexposure could have been due to drug- any definitive conclusion about the major factors which may
drug interaction. affect linezolid pharmacokinetics can be drawn.
Of note, in the present study patients experiencing linezolid We are well aware of the methodological limitations of our
overexposure were found to be more frequently cotreated with study, particularly its retrospective nature; the limited sample
omeprazole, amiodarone, and/or amlodipine than were those size, which is too small to allow us to draw definite conclusions;
with Cmins of ⬍10 mg/liter, and all of these drugs are potent and the fact that the observational nature of the study obliged
inhibitors of P-glycoprotein (P-gp) (7, 15, 20). These findings us to limit sampling to only two time points. However, the good
seem to suggest that linezolid overexposure might occur espe- correlation between Cmin and estimated AUC24 supports the
cially in patients cotreated with some drugs which may act as idea that TDM of trough levels might represent a useful pre-
P-gp inhibitors, who might especially benefit from TDM in the dictor of linezolid efficacy and/or toxicity in routine clinical

Downloaded from http://aac.asm.org/ on November 9, 2020 by guest

prevention of linezolid-related toxicity. Unfortunately, this practice. Indeed, the thresholds for Cmin here proposed have
study was not set up to verify this hypothesis and its retrospec- not yet been validated and might change with future data that
tive nature did not allow us to assess the incidence of toxicity may emerge on this topic.
in these cases. In conclusion, our study suggests that the standard fixed
Likewise, TDM could be relevant for avoiding potential 600-mg q12h dosage may ensure adequate pharmacodynamic
underexposure, which may have occurred in 28% of cases. exposure to linezolid in about 60 to 70% of cases but also that,
Conflicting opinions exist about the role that severe sepsis and conversely, in the remaining 30 to 40% of cases the application
septic shock may have in affecting linezolid pharmacokinetics. of TDM might be especially worthwhile with the intent of
Some authors found no major influence (36), whereas others avoiding the risk of treatment failure or of dose-dependent
found a very wide interindividual variability (2, 35) and rec- toxicity.
ommended the use of TDM (35). In our study, the lack of A prospective study focused on assessing the clinical rele-
relevant differences in linezolid exposure among patients ac- vance of the correlation between linezolid TDM and efficacy or
cording to the type of ward of admission suggests that the toxicity is ongoing.
pharmacokinetic variability in ICU patients does not seem to
be significantly higher than that in surgical and/or medical ACKNOWLEDGMENTS
patients. Additionally, considering the intrinsic characteristics No financial support was received for this study.
of linezolid (a moderately lipophilic drug with mainly nonre- Federico Pea has been on the speakers’ bureau of Pfizer. Mario
nal, nonenzymatic clearance), it is expected that the patho- Furlanut has received grant support from Pfizer. Pierluigi Viale has
physiological changes occurring during sepsis should be less been a consultant to, has been on the speakers’ bureau of, and has
received grant support from Pfizer. None of the other authors has a
relevant than they would be for hydrophilic compounds, like potential conflict of interest to report.
the beta-lactams (29). Indeed, we recognize that measurement
of the free moiety rather than of total concentration would REFERENCES
have enabled more exhaustive consideration. However, the 1. Abunasser, J., and M. L. Metersky. 2009. A comparison of linezolid with
relatively small extent of protein binding of linezolid (around glycopeptides in severe MRSA pneumonia. Expert Rev. Anti Infect. Ther.
7:951–955.
30%), which could be even lower in hypoalbuminemic patients, 2. Adembri, C., S. Fallani, M. I. Cassetta, S. Arrigucci, A. Ottaviano, P. Pecile,
is expected to affect to a limited extent its pharmacokinetics. T. Mazzei, R. De Gaudio, and A. Novelli. 2008. Linezolid pharmacokinetic/
pharmacodynamic profile in critically ill septic patients: intermittent versus
Besides, in this population of patients, according to phar- continuous infusion. Int. J. Antimicrob. Agents 31:122–129.
macokinetic/pharmacodynamic principles, continuous infu- 3. Alffenaar, J. W., J. G. Kosterink, R. V. Altena, T. S. van der Werf, D. R. Uges,
sion may be considered a useful tool to improve linezolid and J. H. Proost. 2010. Limited sampling strategies for therapeutic drug
monitoring of linezolid in patients with multidrug-resistant tuberculosis.
activity since it has theoretical advantages over intermittent Ther. Drug Monit. 32:97–101.
infusion (2). 4. Bosso, J. A., P. A. Flume, and S. L. Gray. 2004. Linezolid pharmacokinetics
In any case, the wide variability observed and the complex in adult patients with cystic fibrosis. Antimicrob. Agents Chemother. 48:281–
284.
management of critically ill patients should induce clinicians to 5. Cockcroft, D. W., and M. H. Gault. 1976. Prediction of creatinine clearance
consider TDM an invaluable tool for the management of an- from serum creatinine. Nephron 16:31–41.
6. Egle, H., R. Trittler, K. Kummerer, and S. W. Lemmen. 2005. Linezolid and
tibiotic therapy in this setting (22). This could be especially rifampin: drug interaction contrary to expectations? Clin. Pharmacol. Ther.
true for patients with severe burn injuries and/or with cystic 77:451–453.
fibrosis, in whom linezolid clearance was recently shown to be 7. Fenner, K. S., M. D. Troutman, S. Kempshall, J. A. Cook, J. A. Ware, D. A.
Smith, and C. A. Lee. 2009. Drug-drug interactions mediated through P-
significantly increased (4, 10, 17, 30). Interestingly, in patients glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin
with cystic fibrosis, among the various mechanisms that could as a probe drug. Clin. Pharmacol. Ther. 85:173–181.
be responsible for the well-known enhanced clearance of an- 8. Garrabou, G., A. Soriano, S. Lopez, J. P. Guallar, M. Giralt, F. Villarroya,
J. A. Martinez, J. Casademont, F. Cardellach, J. Mensa, and O. Miro. 2007.
timicrobial drugs, it has been suggested that the overexpression Reversible inhibition of mitochondrial protein synthesis during linezolid-
of P-gp may play a major role (30, 34). Additionally, the over- related hyperlactatemia. Antimicrob. Agents Chemother. 51:962–967.
9. Gebhart, B. C., B. C. Barker, and B. A. Markewitz. 2007. Decreased serum
expression of P-gp was recently cited to explain the significant linezolid levels in a critically ill patient receiving concomitant linezolid and
drop of linezolid concentration during coadministration of ri- rifampin. Pharmacotherapy 27:476–479.
fampin, a potent inducer of P-gp (6, 9). Indeed, although in our 10. Hallam, M. J., J. M. Allen, S. E. James, P. M. Donaldson, J. G. Davies, G. W.
Hanlon, and B. S. Dheansa. 2010. Potential subtherapeutic linezolid and
database only four patients with rifampin cotreatment under- meropenem antibiotic concentrations in a patient with severe burns and
went TDM, it is noteworthy that very low Cmins of linezolid sepsis. J. Burn Care Res. 31:207–209.
4610 PEA ET AL. ANTIMICROB. AGENTS CHEMOTHER.

11. Hanley, M. J., D. R. Abernethy, and D. J. Greenblatt. 2010. Effect of obesity 25. Pea, F., P. Viale, M. Lugano, F. Pavan, L. Scudeller, G. Della Rocca, and M.
on the pharmacokinetics of drugs in humans. Clin. Pharmacokinet. 49:71–87. Furlanut. 2004. Linezolid disposition after standard dosages in critically ill
12. Islinger, F., P. Dehghanyar, R. Sauermann, C. Burger, C. Kloft, M. Muller, patients undergoing continuous venovenous hemofiltration: a report of 2
and C. Joukhadar. 2006. The effect of food on plasma and tissue concen- cases. Am. J. Kidney Dis. 44:1097–1102.
trations of linezolid after multiple doses. Int. J. Antimicrob. Agents 27:108– 26. Peng, G. W., R. P. Stryd, S. Murata, M. Igarashi, K. Chiba, H. Aoyama, M.
112. Aoyama, T. Zenki, and N. Ozawa. 1999. Determination of linezolid in plasma
13. Jang, H. C., S. H. Kim, K. H. Kim, C. J. Kim, S. Lee, K. H. Song, J. H. Jeon, by reversed-phase high-performance liquid chromatography. J. Pharm.
W. B. Park, H. B. Kim, S. W. Park, N. J. Kim, E. C. Kim, M. D. Oh, and Biomed. Anal. 20:65–73.
K. W. Choe. 2009. Salvage treatment for persistent methicillin-resistant 27. Peppard, W. J., C. J. Johnston, and A. M. Urmanski. 2008. Pharmacologic
Staphylococcus aureus bacteremia: efficacy of linezolid with or without car- options for CNS infections caused by resistant Gram-positive organisms.
bapenem. Clin. Infect. Dis. 49:395–401. Expert Rev. Anti Infect. Ther. 6:83–99.
14. Jones, R. N., T. R. Fritsche, H. S. Sader, and J. E. Ross. 2007. Zyvox annual 28. Rayner, C. R., A. Forrest, A. K. Meagher, M. C. Birmingham, and J. J.
appraisal of potency and spectrum program results for 2006: an activity and Schentag. 2003. Clinical pharmacodynamics of linezolid in seriously ill pa-
spectrum analysis of linezolid using clinical isolates from 16 countries. Diagn. tients treated in a compassionate use programme. Clin. Pharmacokinet.
Microbiol. Infect. Dis. 59:199–209. 42:1411–1423.
15. Katoh, M., M. Nakajima, H. Yamazaki, and T. Yokoi. 2001. Inhibitory effects 29. Roberts, J. A., and J. Lipman. 2009. Pharmacokinetic issues for antibiotics in
of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated the critically ill patient. Crit. Care Med. 37:840–851.
transport. Eur. J. Pharm. Sci. 12:505–513. 30. Santos, R. P., C. B. Prestidge, M. E. Brown, B. Urbancyzk, D. K. Murphey,

Downloaded from http://aac.asm.org/ on November 9, 2020 by guest

16. Lacarelle, B., P. Pisano, T. Gauthier, P. H. Villard, F. Guder, J. Catalin, and C. M. Salvatore, H. S. Jafri, G. H. McCracken, Jr., N. Ahmad, P. J. Sanchez,
A. Durand. 1994. Abbott PKS system: a new version for applied pharmaco- and J. D. Siegel. 2009. Pharmacokinetics and pharmacodynamics of linezolid
kinetics including Bayesian estimation. Int. J. Biomed. Comput. 36:127–130. in children with cystic fibrosis. Pediatr. Pulmonol. 44:148–154.
17. Lovering, A. M., R. Le Floch, L. Hovsepian, J. Stephanazzi, P. Bret, G.
31. Slatter, J. G., D. J. Stalker, K. L. Feenstra, I. R. Welshman, J. B. Bruss, J. P.
Birraux, and C. Vinsonneau. 2009. Pharmacokinetic evaluation of linezolid
Sams, M. G. Johnson, P. E. Sanders, M. J. Hauer, P. E. Fagerness, R. P.
in patients with major thermal injuries. J. Antimicrob. Chemother. 63:553–
Stryd, G. W. Peng, and E. M. Shobe. 2001. Pharmacokinetics, metabolism,
559.
and excretion of linezolid following an oral dose of [(14)C]linezolid to
18. Myrianthefs, P., S. L. Markantonis, K. Vlachos, M. Anagnostaki, E. Bout-
healthy human subjects. Drug Metab. Dispos. 29:1136–1145.
zouka, D. Panidis, and G. Baltopoulos. 2006. Serum and cerebrospinal fluid
concentrations of linezolid in neurosurgical patients. Antimicrob. Agents 32. Stalker, D. J., and G. L. Jungbluth. 2003. Clinical pharmacokinetics of
Chemother. 50:3971–3976. linezolid, a novel oxazolidinone antibacterial. Clin. Pharmacokinet. 42:1129–
19. Pai, M. P., and D. T. Bearden. 2007. Antimicrobial dosing considerations in 1140.
obese adult patients. Pharmacotherapy 27:1081–1091. 33. Stein, G. E., and E. M. Wells. 2010. The importance of tissue penetration in
20. Pauli-Magnus, C., S. Rekersbrink, U. Klotz, and M. F. Fromm. 2001. Inter- achieving successful antimicrobial treatment of nosocomial pneumonia and
action of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. complicated skin and soft-tissue infections caused by methicillin-resistant
Naunyn Schmiedebergs Arch. Pharmacol. 364:551–557. Staphylococcus aureus: vancomycin and linezolid. Curr. Med. Res. Opin.
21. Pea, F., L. Scudeller, M. Lugano, U. Baccarani, F. Pavan, M. Tavio, M. 26:571–588.
Furlanut, G. D. Rocca, F. Bresadola, and P. Viale. 2006. Hyperlactacidemia 34. Susanto, M., and L. Z. Benet. 2002. Can the enhanced renal clearance of
potentially due to linezolid overexposure in a liver transplant recipient. Clin. antibiotics in cystic fibrosis patients be explained by P-glycoprotein trans-
Infect. Dis. 42:434–435. port? Pharm. Res. 19:457–462.
22. Pea, F., and P. Viale. 2009. Bench-to-bedside review: appropriate antibiotic 35. Swoboda, S., M. C. Ober, C. Lichtenstern, S. Saleh, V. Schwenger, H. G.
therapy in severe sepsis and septic shock—does the dose matter? Crit. Care Sonntag, W. E. Haefeli, G. Hempel, T. Hoppe-Tichy, and M. A. Weigand.
13:214. 2010. Pharmacokinetics of linezolid in septic patients with and without ex-
23. Pea, F., and P. Viale. 2009. Could de-escalation of antibiotic therapy be tended dialysis. Eur. J. Clin. Pharmacol. 66:291–298.
feasible even for documented methicillin-resistant Staphylococcus aureus 36. Thallinger, C., C. Buerger, N. Plock, S. Kljucar, S. Wuenscher, R. Sauer-
ventilator-associated pneumonia? J. Trauma 67:893–894. mann, C. Kloft, and C. Joukhadar. 2008. Effect of severity of sepsis on tissue
24. Pea, F., and P. Viale. 2007. Pharmacodynamics of antibiotics to treat multi- concentrations of linezolid. J. Antimicrob. Chemother. 61:173–176.
drug-resistant Gram-positive hospital infections. Expert Rev. Anti Infect. 37. Vinh, D. C., and E. Rubinstein. 2009. Linezolid: a review of safety and
Ther. 5:255–270. tolerability. J. Infect. 59(Suppl. 1):S59–S74.