Download High plasma linezolid concentration and impaired renal function

J Antimicrob Chemother 2013; 68: 2128 – 2133
doi:10.1093/jac/dkt133 Advance Access publication 26 April 2013
High plasma linezolid concentration and impaired renal function affect
development of linezolid-induced thrombocytopenia
Yoko Nukui1, Shuji Hatakeyama2*, Koh Okamoto2, Takehito Yamamoto3, Akihiro Hisaka4, Hiroshi Suzuki3,
Nahoko Yata5, Hiroshi Yotsuyanagi2 and Kyoji Moriya1
1
Department of Infection Control and Prevention, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;
Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 3Department of
Pharmacy, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 4Pharmacology and Pharmacokinetics, 22nd
Century Medical and Research Center, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; 5Department of
Clinical Research, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu-shi, Tokyo 183-8561, Japan
2
*Corresponding author. Tel: +81-3-3815-5411; Fax: +81-3-5800-8805; E-mail: [email protected]
Received 23 January 2013; returned 15 February 2013; revised 17 March 2013; accepted 18 March 2013
Objectives: Thrombocytopenia is sometimes observed during linezolid therapy. Here, we aimed to investigate
the factors affecting linezolid-induced thrombocytopenia.
Methods: A prospective observational study was performed between October 2009 and February 2011; 30
patients were included. Plasma linezolid trough concentrations were measured on days 3, 7 and 14 after
initial drug administration. Platelet counts and haemoglobin levels were also monitored.
Results: Thrombocytopenia occurred in 17 patients (56.7%). Median linezolid trough concentrations on day 3
were significantly higher in patients with renal impairment (creatinine clearance ,60 mL/min) than in patients
without renal impairment (14.7 versus 4.8 mg/L; P,0.0001). Median linezolid trough concentrations on day 3
in patients who developed thrombocytopenia were also significantly higher than those in patients who did not
(13.4 versus 4.3 mg/L, P,0.0001). Development of thrombocytopenia occurred significantly more frequently in
patients with linezolid trough concentration .7.5 mg/L (OR, 90.0; P,0.0001) and renal impairment (OR, 39.0;
P ¼ 0.0002). The Kaplan –Meier plot showed that the median time from the initiation of therapy to development
of thrombocytopenia was 11 days.
Conclusions: Patients with renal impairment are more likely to have a high plasma linezolid concentration. In
addition, a high plasma linezolid concentration and renal impairment significantly affected the development of
linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction.
Keywords: anti-MRSA agents, adverse effects, haematological toxicity, renal dysfunction, therapeutic drug monitoring
Introduction
Linezolid is an oxazolidinone antibiotic with a broad spectrum of
activity against Gram-positive bacteria, including methicillinresistant Staphylococcus aureus and vancomycin-resistant enterococci.1 EUCAST and CLSI have defined the susceptibility
breakpoint for linezolid as an MIC of ≤4 mg/L for Staphylococcus
spp. The availability of intravenous and oral formulations, with
the latter having nearly 100% bioavailability,2 is expected to facilitate the treatment of infections caused by these organisms.
In addition, linezolid has very favourable rates of penetration into
tissues.3 This suggests a potential pharmacokinetic advantage of
linezolid over glycopeptides in the treatment of deep-seated infections such as pneumonia4 and CNS infections.5
Prolonged use of linezolid can lead to haematological side
effects, particularly thrombocytopenia.6 Indeed, several studies
have reported that the incidence of thrombocytopenia associated with linezolid therapy is much higher (7.5%–64.7%)6 – 11
than the incidence reported in an early clinical study (2.4%) conducted by the manufacturer.12 The risk factors reported for the
development of thrombocytopenia during linezolid therapy are
renal insufficiency,10,13 – 15 chronic liver disease,14 – 16 malignancy17 and previous vancomycin use.18 Reversible myelosuppression with red-cell hypoplasia after linezolid therapy has
# The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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High linezolid concentration affects thrombocytopenia
also been reported during Phase 3 clinical trials of linezolid and in
another recent study.19 Consequently, weekly monitoring of
haematological parameters is recommended for patients on
linezolid therapy.
Considering the findings of case reports that patients with
thrombocytopenia retain adequate numbers of megakaryocytes
in their bone marrow, it is thought that linezolid-induced
thrombocytopenia is not attributable to bone marrow suppression.20,21 Bernstein et al.20 speculated that linezolid-induced
thrombocytopenia is caused by immune-mediated platelet destruction, based on a decreased rate of decline in platelet
counts following immunoglobulin therapy. However, the
mechanisms underlying linezolid-related haematological toxicity
remain to be clarified.
Currently, therapy with linezolid does not include therapeutic
drug monitoring (TDM) and dose adjustment based on the
results of early studies, which suggested that linezolid clearance
was not altered in patients with renal dysfuncion22 and that the
oxidative metabolism of linezolid was non-enzymatic and did not
involve the CYP450 hepatic microsomal oxidative system.23
However, recent observations that thrombocytopenia may be
more likely to occur during linezolid therapy in patients with
renal insufficiency or liver cirrhosis than in patients without
these conditions10,13 – 16 have prompted us to investigate the
influences of plasma linezolid concentrations on haematological
toxicity.
Patients and methods
Patients
This study was conducted between October 2009 and February 2011 at
the University of Tokyo Hospital, Japan, and involved patients who were
treated with linezolid. Patients younger than 20 years were excluded
from this study. Written informed consent was obtained from each
patient, and the Ethics Committee of the University of Tokyo reviewed
and approved this study.
Measurement of plasma linezolid concentrations
The patients were treated with 1200 mg of linezolid daily (600 mg twice
daily) by either the parenteral or the oral route. On days 3, 7 and 14 after
initial administration, venous blood samples were collected just before
subsequent administration of the drug to assess the trough plasma concentration. Linezolid concentrations in plasma were analysed by validated liquid chromatography –tandem mass spectrometry, according
to a previous study by Phillips et al.24 with minor modifications. Precision
and accuracy were assessed by performing replicate analyses of quality
control samples against calibration standards, and the intra- and interassay coefficients of variation were found to be always ,10%. The
lower limit of detection was 0.2 mg/L.
Evaluation of haematological parameters
and creatinine clearance (CLCR)
Changes in the haematological parameters were assessed every 2–4 days
during linezolid therapy. Thrombocytopenia was defined as a decrease
in platelet count to ,75% of the baseline levels and anaemia as a
≥2 g/dL decrease in haemoglobin concentration from the baseline.7,25
No well-known potential thrombocytopenia-inducing agents (e.g.
quinidine, quinine, rifampicin and trimethoprim/sulfamethoxazole) were
administered to any of the patients. CLCR was estimated by means of
the Cockcroft and Gault formula.26
Statistical analysis
Categorical variables were compared using Fisher’s exact test. The
Mann–Whitney U-test was used for continuous variables. A P value of
,0.05 was required to achieve statistical significance. The cut-off value
of plasma linezolid concentration that had the best combination of sensitivity and specificity for distinguishing between patients who developed
thrombocytopenia and patients who did not was determined by receiver
operating characteristic (ROC) curve analysis. The time from initiation of
linezolid therapy to development of thrombocytopenia was estimated
using the Kaplan– Meier method. All statistical analyses were performed
using JMP Pro version 9 (SAS Institute, NC, USA).
Results
Of the 31 Japanese patients who participated in this study, we
excluded 1 patient who had a haematological malignancy and
had received frequent red blood and platelet transfusions
during the study period. Consequently, 30 patients were included
in the primary analysis. The patients’ characteristics and the conditions for which the patients were treated with linezolid are
listed in Table 1. The main indications for linezolid therapy were
intravascular device-related bloodstream infections (50.0%)
and surgical site infections (33.3%). No patient was diagnosed
with disseminated intravascular coagulation. We recorded 69
trough plasma concentrations of linezolid in the 30 patients, of
whom 18 were treated intravenously with the fixed dosing
regimen of 600 mg of linezolid twice daily, and 12 were
treated orally with the same regimen. Median linezolid trough
concentrations on day 3 did not differ significantly between
patients who received linezolid orally and those who received it
intravenously (7.0 versus 8.1 mg/L, P ¼ 0.78). Linezolid was administered for a median of 12.0 days (IQR, 7.0–17.3 days). Median
CLCR was 78.5 mL/min (IQR, 39.6– 110.3 mL/min), 90.0 mL/min
(IQR, 41.0– 117.0 mL/min), 84.0 mL/min (IQR, 45.0 –121.0) and
95.5 mL/min (IQR, 49.5–121.8 mL/min) before linezolid administration and at days 3, 7 and 14, respectively. Fourteen patients
(46.7%) had renal impairment (CLCR ,60 mL/min) at baseline
(before linezolid administration).
Thrombocytopenia developed in 17 of the 30 patients (56.7%)
during linezolid therapy. Of the 17 patients who developed
thrombocytopenia, 10 developed concurrent anaemia. Platelet
decrease was more commonly observed in patients with high
linezolid trough concentrations in their blood and with baseline
CLCR levels of ,60 mL/min. Median linezolid trough concentrations were significantly higher in patients with renal impairment
(CLCR ,60 mL/min) than in patients without renal impairment
(P,0.0001): 14.7 mg/L (IQR, 10.9–24.8 mg/L) versus 4.8 mg/L
(IQR, 3.1 –6.9 mg/L) on day 3, 16.3 mg/L (IQR, 12.4– 28.9 mg/L)
versus 4.9 mg/L (IQR, 3.5–9.0 mg/L) on day 7 and 13.6 mg/L
(IQR, 7.2 –25.2 mg/L) versus 7.3 mg/L (IQR, 3.0–13.7 mg/L) on
day 14 (Figure 1). Median linezolid trough concentrations in
patients who developed thrombocytopenia were also found to
be significantly higher than those in patients who did not
(P,0.0001): 13.4 mg/L (IQR, 8.4 –23.1 mg/L) versus 4.3 mg/L
(IQR, 2.1 –6.0 mg/L) on day 3, 15.3 mg/L (IQR, 10.9– 27.3 mg/L)
versus 3.8 mg/L (IQR, 3.1–6.1 mg/L) on day 7 and 15.2 mg/L
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Nukui et al.
Table 1. Characteristics and underlying medical conditions of patients
who received linezolid therapy
Baselinea characteristics of patients
no. of patients
age (years)b
gender (male/female)
body weight (kg)b
CLCR (mL/min)b
Dosage of linezolid (mg/kg/12 h)b
Duration of linezolid treatment (days)b
30
46 (34 –69)
21/9
55.0 (46.5–64.0)
78.5 (39.6–110.3)
10.9 (9.4– 12.9)
12.0 (7.0– 17.3)
Platelet count (× 104 cells/mm3)b
baselinea (n¼30)
day 3 (n¼30)
day 7 (n¼25)
day 14 (n ¼14)
21.7 (16.8–29.0)
18.8 (15.4–26.2)
19.4 (14.9–26.0)
18.7 (16.1–21.3)
Haemoglobin level (mg/dL)b
baselinea (n¼29)
day 3 (n¼29)
day 7 (n¼24)
day 14 (n ¼13)
10.3 (9.3– 11.7)
9.8 (9.1– 11.7)
9.6 (8.6– 11.5)
9.6 (7.7– 11.4)
Reason for linezolid treatment, n (%)
intravascular device-related bloodstream
infections
surgical site infections
hospital-acquired pneumonia
osteomyelitis
CNS infection
CLCR <60 mL/min
CLCR ≥60 mL/min
60
P<0.0001
40
20
0
(n = 14) (n = 16) (n = 12) (n = 13) (n = 6)
Day 3
Day 7
(n = 8)
Day 14
Figure 1. Box (median and 25th to 75th percentiles) and whisker (5th
and 95th percentiles) plots of linezolid trough concentrations on days
3, 7 and 14 after starting therapy in patients with CLCR ,60 or
≥60 mL/min. Open circles indicate outliers.
15 (50.0)
10 (33.3)
2 (6.7)
2 (6.7)
1 (3.3)
CLCR, estimated creatinine clearance by the Cockcroft– Gault formula.
a
Before linezolid administration.
b
Median (IQR).
(IQR, 8.0 –21.4 mg/L) versus 5.0 mg/L (IQR, 1.3 –6.7 mg/L) on
day 14 (Figure 2).
The ROC curves showed that the best cut-off value of linezolid
trough concentration, which could be used to distinguish
between thrombocytopenic patients and non-thrombocytopenic
patients, was 7.6 mg/L. Development of thrombocytopenia during
linezolid therapy was significantly more frequent in patients
with linezolid trough concentrations .7.5 mg/L in plasma on
day 3 (OR, 90.0; 95% CI, 7.3– 1115.9; P,0.0001), and if CLCR
was ,60 mL/min (OR, 39.0; 95% CI, 3.8 –399.8; P ¼0.0002)
(Table 2). The Kaplan – Meier plot revealed that the overall
median time from the initiation of therapy to development of
thrombocytopenia was 11 days (Figure 3). Among the patients
who developed thrombocytopenia, the median relative platelet
levels expressed as a percentage of the baseline level decreased
to 87.9% on day 3, 74.0% on day 7 and 61.0% on day 14. Linezolid therapy had to be discontinued in 10 patients because of
severe thrombocytopenia.
During anaemia analysis, we excluded a patient who experienced haemorrhage after surgical debridement and received a
red blood cell transfusion. Consequently, 29 patients were
included in the anaemia analysis. Twelve of the 29 patients
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Linezolid concentration (mg/L)
Value
80
Linezolid concentration (mg/L)
Characteristics and underlying medical conditions
80
Thrombocytopenia (+)
Thrombocytopenia (−)
P<0.0001
60
40
20
0
(n = 17) (n = 13) (n = 15) (n = 10) (n = 9)
Day 3
Day 7
(n = 5)
Day 14
Figure 2. Box (median and 25th to 75th percentiles) and whisker (5th
and 95th percentiles) plots of linezolid trough concentrations on days
3, 7 and 14 after starting therapy in patients with or without
thrombocytopenia. Open circles indicate outliers.
(41.4%) developed anaemia during treatment with linezolid.
Among the patients who developed anaemia, the median relative haemoglobin levels expressed as a percentage of the baseline level were 87.9% on day 3, 92.4% on day 7 and 75.2% on
day 14. However, no significant relationship was observed
between development of anaemia and CLCR levels, linezolid
trough concentrations or any other factors listed in Table 2
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High linezolid concentration affects thrombocytopenia
(data not shown). Linezolid therapy had to be discontinued in
two patients because of severe anaemia.
Discussion
In this study, high plasma trough concentrations of linezolid and
renal impairment were identified as risk factors for the development of thrombocytopenia in patients receiving linezolid therapy.
In addition, renal impairment was found to be associated with a
significant increase in plasma trough levels of linezolid. Recent
studies have reported that the incidence of linezolid-induced
thrombocytopenia was higher in patients with renal failure than
in patients with normal renal function, although the underlying
mechanisms explaining this toxicity remain unknown.10,13,14,27,28
Takahashi et al.14 recently identified renal dysfunction as one of
the four variables associated with thrombocytopenia (defined as
a ≥10×104 cells/mm3 decrease from the baseline or a ≥30% reduction) in patients treated with linezolid: duration of linezolid
therapy ≥14 days (OR, 3.0; P,0.001); CLCR ,50 mL/min (OR, 2.3;
P,0.001); chronic liver disorders (OR, 1.6; P¼0.09); and respiratory
tract infections (OR, 1.8; P¼0.03). Lin et al.10 reported that the development of severe thrombocytopenia (,10×104 cells/mm3)
was significantly more common in patients who had renal insufficiency and were treated with linezolid (64.7% versus 35.6%,
Table 2. Factors affecting the development of thrombocytopenia during
linezolid therapy
Factor
OR (95% CI)
P value
Age ≥65 years
4.9 (0.8– 29.1)
0.12
Gender male
0.3 (0.04–1.6)
0.23
Weight ,50 kg
2.3 (0.5– 11.7)
0.44
CLCR ,60 mL/min
39.0 (3.8– 399.8)
0.0002
Duration of linezolid treatment ≥14 days
1.8 (0.4– 7.8)
0.48
Linezolid trough concentrationa .7.5 mg/L 90.0 (7.3– 1115.9) ,0.0001
Intravenous administration of linezolid
0.5 (0.1– 2.3)
0.47
Previous vancomycin use
0.5 (0.1– 2.3)
0.47
CLCR, estimated creatinine clearance by the Cockcroft– Gault formula.
a
Linezolid trough concentration in plasma on day 3 after initiation of drug
administration.
P¼0.039). Although these studies were not aimed at investigating
plasma linezolid concentrations, their data regarding the possible
association between thrombocytopenia and renal insufficiency
were in agreement with our study results.
Brier et al.22 demonstrated that renal function had little effect
on the overall clearance of the drug. Pea et al.29 also demonstrated that neither the estimated CLCR nor body weight were
useful predictors of linezolid exposure. However, since renal dysfunction may be associated with linezolid-induced thrombocytopenia, we have discussed the effects of high concentrations of
the drug and its metabolites. Pharmacokinetic studies of linezolid
have indicated that 30% of linezolid is eliminated unchanged
via the kidneys,23,30 – 34 while the majority is metabolized by the
oxidation of its morpholino ring (mediated by ubiquitous reactive
oxygen species) to create two metabolites, an aminoethoxyacetic
acid metabolite (PNU-142586) and a hydroxyethyl glycine metabolite (PNU-142300).35 It has been reported that the total exposure
to both metabolites (area under the plasma concentration versus
time curve) is approximately more than 7- to 8-fold greater in
patients with severe renal insufficiency (CLCR ,30 –40 mL/min)
than in subjects with normal renal function.22,35 Although the clinical significance of the accumulation of these metabolites remains
undetermined, further studies are required to assess the effect of
the metabolites on haematological toxicities.
To date, few studies have assessed the effects of plasma linezolid concentrations on haematological toxicity. Moreover, it is
not clear whether high linezolid concentration or renal insufficiency is a more important predictor of linezolid-associated
thrombocytopenia. Several recent Japanese studies have discussed the relationship between linezolid concentration and
thrombocytopenia. Matsumoto et al. 36 reported that the
trough linezolid concentration of thrombocytopenic patients
(n¼ 4) was higher than that of non-thrombocytopenic patients
(n¼ 2) (14.4 –35.6 versus 6.9– 7.2 mg/L), although the number
of patients was too small for statistical analysis. Hiraki et al.37
showed that low total body clearance of linezolid (L/h), determined by the Bayesian estimation method, was weakly correlated with low platelet counts (r 2 ¼ 0.31) and moderately
correlated with low haemoglobin levels (r 2 ¼0.54) in 16 patients
treated with linezolid. A subsequent subanalysis, in which they
evaluated data from eight pneumonia patients in their study,
showed that the high linezolid trough concentrations in patients
with renal dysfunction correlated with platelet counts in a logit
Probability of developing
thrombocytopenia
1
0.5
0
0
10
20
Days after initiation of linezolid therapy
30
Figure 3. Kaplan– Meier plot showing the time from initiation of linezolid therapy to development of thrombocytopenia.
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Nukui et al.
analysis model, and a significant decrease in platelet count
was observed in patients with trough linezolid concentrations
.22.1 mg/L.38 Similarly, Tsuji et al.27 reported that platelet
and haemoglobin levels decreased with an increase in the linezolid AUC from 0 to 24 h (AUC0 – 24) in three patients with renal insufficiency. Despite the small sample sizes, these results are in
agreement with those of our study, suggesting that the high
blood linezolid levels possibly influence the haematological toxicity. Further studies, particularly those focusing on differences
between races, may be required.
Several studies have indicated that linezolid-induced thrombocytopenia typically occurs gradually if the therapy continues for
.14 days. In a prospective study of 20 adult patients with Grampositive bacterial infections treated with linezolid, the development of thrombocytopenia (,15×104 cells/mm3) was observed
40 days after starting linezolid therapy, on average.18 Another
study showed that long-term therapy with linezolid (.14 days)
increased the risk of thrombocytopenia from 2.9% to 4.1%,
although this increase was not significant.39 In the current
study, however, the decrease in platelet count occurred rapidly
after the initiation of linezolid therapy; among patients who developed thrombocytopenia, about one-half were estimated to
experience thrombocytopenia within 11 days of starting linezolid.
Therefore, attention should be paid to this adverse effect even
early in the course of linezolid therapy.
A drop in haemoglobin levels was observed in 40% of
treated patients, although there was no significant association
between the trough linezolid concentrations and haemoglobin
levels. Linezolid-related anaemia has been thought to be
induced by inhibition of mitochondrial protein synthesis and respiration,20,40 and this condition rarely occurs before day 14 of
linezolid therapy.19 Monson et al.41 reported a case of reversible
pure red cell aplasia in a patient who had been on linezolid
therapy for 8 weeks, and Green et al.42 reported reversible
linezolid-associated hypoproliferative anaemia in three
patients who were receiving 600 mg of linezolid twice daily for
6 –12 weeks. Clinicians should also pay attention to monitoring
this adverse effect, and further research is required to assess
the precise mechanism underlying linezolid-related anaemia.
The current study showed that impaired renal function was
associated with high plasma linezolid concentrations on day 3
after the start of therapy, and that a linezolid trough concentration of .7.5 mg/L on day 3 was a possible predictor of the development of thrombocytopenia. Monitoring of linezolid trough
concentrations on day 3 may therefore be useful in predicting
haematological adverse events, particularly in patients with
renal insufficiency. In a recent pharmacokinetic –pharmacodynamic simulation study consisting of 50 Japanese individuals,
patients who had renal insufficiency (CLCR ,30 mL/min) and
received a standard dose of linezolid (1200 mg/day) had a remarkably increased risk of thrombocytopenia, while patients
with normal renal function (CLCR .50 mL/min) and without
liver cirrhosis did not.15 The estimated probability of thrombocytopenia at 14 days after the start of linezolid treatment in
patients with insufficient renal function (CLCR 30–10 mL/min)
was 32.6%–51.0%, which is comparable to the incidence reported
in the current study. For these high-risk patients, the current standard dose of 1200 mg/day was considered too high with respect to
safety, and a reduced regimen of 600 mg/day was thought to be
appropriate on the basis of the AUC/MIC ratio. Furthermore, in
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patients with severe renal insufficiency (CLCR ,10 mL/min) or
severe liver cirrhosis, a high incidence of thrombocytopenia was
estimated even at 600 mg/day, probably because of the elevated
exposure levels.15 A recent small retrospective study showed that
TDM-guided dosage adjustment (reduction) to maintain linezolid
trough concentrations between 2 and 7 mg/L and/or AUC0 – 24
between 160 and 300 mg.h/L allowed recovery from thrombocytopenia and enabled the achievement of favourable outcomes
for therapy.43 Taken together, our results indicate that further
large prospective studies are required to evaluate whether
TDM-guided dose adjustment of linezolid leads to decreased
adverse effects while maintaining treatment efficacy.
One of the main limitations of most previous studies, including ours, on linezolid-associated haematological toxicities is the
heterogeneous definition of thrombocytopenia and anaemia.
In addition, the mechanisms of linezolid-induced thrombocytopenia and anaemia remain unclear. Nevertheless, several
studies have suggested that attention must be paid to thrombocytopenia during linezolid therapy, particularly in patients with
renal dysfunction.
In summary, a high plasma linezolid trough concentration
(.7.5 mg/L) and renal dysfunction (CLCR ,60 mL/min) significantly affected the development of thrombocytopenia during
linezolid therapy. Furthermore, plasma linezolid trough concentrations were significantly higher in Japanese patients with
renal dysfunction than in those without renal dysfunction.
Funding
This work was a self-funded project of the Department of Infectious
Diseases, University of Tokyo.
Transparency declarations
None to declare.
References
1 Vinh DC, Rubinstein E. Linezolid: a review of safety and tolerability.
J Infect 2009; 59 Suppl 1: S59–74.
2 Stevens DL, Dotter B, Madaras-Kelly K. A review of linezolid: the first
oxazolidinone antibiotic. Expert Rev Anti Infect Ther 2004; 2: 51– 9.
3 Stein GE, Wells EM. The importance of tissue penetration in achieving
successful antimicrobial treatment of nosocomial pneumonia and
complicated skin and soft-tissue infections caused by methicillinresistant Staphylococcus aureus: vancomycin and linezolid. Curr Med
Res Opin 2010; 26: 571– 88.
4 Abunasser J, Metersky ML. A comparison of linezolid with glycopeptides
in severe MRSA pneumonia. Expert Rev Anti Infect Ther 2009; 7: 951–5.
5 Peppard WJ, Johnston CJ, Urmanski AM. Pharmacologic options for CNS
infections caused by resistant Gram-positive organisms. Expert Rev Anti
Infect Ther 2008; 6: 83 –99.
6 Attassi K, Hershberger E, Alam R et al. Thrombocytopenia associated
with linezolid therapy. Clin Infect Dis 2002; 34: 695–8.
7 Soriano A, Gomez J, Gomez L et al. Efficacy and tolerability of
prolonged linezolid therapy in the treatment of orthopedic implant
infections. Eur J Clin Microbiol Infect Dis 2007; 26: 353–6.
High linezolid concentration affects thrombocytopenia
JAC
8 Rao N, Hamilton CW. Efficacy and safety of linezolid for Gram-positive
orthopedic infections: a prospective case series. Diagn Microbiol Infect Dis
2007; 59: 173–9.
25 Legout L, Valette M, Dezeque H et al. Tolerability of prolonged linezolid
therapy in bone and joint infection: protective effect of rifampicin on the
occurrence of anaemia? J Antimicrob Chemother 2010; 65: 2224 –30.
9 Niwa T, Suzuki A, Sakakibara S et al. Retrospective cohort chart review
study of factors associated with the development of thrombocytopenia
in adult Japanese patients who received intravenous linezolid therapy.
Clin Ther 2009; 31: 2126 –33.
26 Cockcroft DW, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron 1976; 16: 31– 41.
10 Lin YH, Wu VC, Tsai IJ et al. High frequency of linezolid-associated
thrombocytopenia among patients with renal insufficiency. Int J
Antimicrob Agents 2006; 28: 345–51.
11 Bishop E, Melvani S, Howden BP et al. Good clinical outcomes but high
rates of adverse reactions during linezolid therapy for serious infections: a
proposed protocol for monitoring therapy in complex patients. Antimicrob
Agents Chemother 2006; 50: 1599 –602.
12 French G. Safety and tolerability of linezolid. J Antimicrob Chemother
2003; 51 Suppl 2: ii45–53.
13 Wu VC, Wang YT, Wang CY et al. High frequency of
linezolid-associated thrombocytopenia and anemia among patients
with end-stage renal disease. Clin Infect Dis 2006; 42: 66– 72.
14 Takahashi Y, Takesue Y, Nakajima K et al. Risk factors associated with
the development of thrombocytopenia in patients who received linezolid
therapy. J Infect Chemother 2011; 17: 382–7.
15 Sasaki T, Takane H, Ogawa K et al. Population pharmacokinetic and
pharmacodynamic analysis of linezolid and a hematologic side effect,
thrombocytopenia, in Japanese patients. Antimicrob Agents Chemother
2011; 55: 1867– 73.
16 Ikuta S, Tanimura K, Yasui C et al. Chronic liver disease increases the
risk of linezolid-related thrombocytopenia in methicillin-resistant
Staphylococcus aureus-infected patients after digestive surgery. J Infect
Chemother 2011; 17: 388– 91.
17 Smith PF, Birmingham MC, Noskin GA et al. Safety, efficacy and
pharmacokinetics of linezolid for treatment of resistant Gram-positive
infections in cancer patients with neutropenia. Ann Oncol 2003; 14:
795–801.
18 Rao N, Ziran BH, Wagener MM et al. Similar hematologic effects of
long-term linezolid and vancomycin therapy in a prospective
observational study of patients with orthopedic infections. Clin Infect
Dis 2004; 38: 1058 –64.
19 Senneville E, Legout L, Valette M et al. Risk factors for anaemia in
patients on prolonged linezolid therapy for chronic osteomyelitis: a
case-control study. J Antimicrob Chemother 2004; 54: 798–802.
20 Bernstein WB, Trotta RF, Rector JT et al. Mechanisms for
linezolid-induced anemia and thrombocytopenia. Ann Pharmacother
2003; 37: 517–20.
21 Ebeling F, Helminen P, Anttila VJ. Appearance of ring sideroblasts in
bone marrow during linezolid therapy. Scand J Infect Dis 2009; 41:
480–2.
22 Brier ME, Stalker DJ, Aronoff GR et al. Pharmacokinetics of linezolid in
subjects with renal dysfunction. Antimicrob Agents Chemother 2003; 47:
2775– 80.
23 Slatter JG, Stalker DJ, Feenstra KL et al. Pharmacokinetics,
metabolism, and excretion of linezolid following an oral dose of
[14C]linezolid to healthy human subjects. Drug Metab Dispos 2001; 29:
1136– 45.
24 Phillips OA, Abdel-Hamid ME, al-Hassawi NA. Determination of
linezolid in human plasma by LC-MS-MS. Analyst 2001; 126: 609–14.
27 Tsuji Y, Hiraki Y, Matsumoto K et al. Thrombocytopenia and anemia
caused by a persistent high linezolid concentration in patients with
renal dysfunction. J Infect Chemother 2011; 17: 70– 5.
28 Matsumoto K, Takeda Y, Takeshita A et al. Renal function as a
predictor of linezolid-induced thrombocytopenia. Int J Antimicrob
Agents 2009; 33: 98– 9.
29 Pea F, Furlanut M, Cojutti P et al. Therapeutic drug monitoring of
linezolid: a retrospective monocentric analysis. Antimicrob Agents
Chemother 2010; 54: 4605 –10.
30 Abe S, Chiba K, Cirincione B et al. Population pharmacokinetic analysis
of linezolid in patients with infectious disease: application to lower body
weight and elderly patients. J Clin Pharmacol 2009; 49: 1071– 8.
31 McGee B, Dietze R, Hadad DJ et al. Population pharmacokinetics of
linezolid in adults with pulmonary tuberculosis. Antimicrob Agents
Chemother 2009; 53: 3981 –4.
32 Meagher AK, Forrest A, Rayner CR et al. Population pharmacokinetics
of linezolid in patients treated in a compassionate-use program.
Antimicrob Agents Chemother 2003; 47: 548– 53.
33 Plock N, Buerger C, Joukhadar C et al. Does linezolid inhibit its own
metabolism? Population pharmacokinetics as a tool to explain the
observed nonlinearity in both healthy volunteers and septic patients.
Drug Metab Dispos 2007; 35: 1816 –23.
34 Whitehouse T, Cepeda JA, Shulman R et al. Pharmacokinetic studies
of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother
2005; 55: 333–40.
35 MacGowan AP. Pharmacokinetic and pharmacodynamic profile of
linezolid in healthy volunteers and patients with Gram-positive
infections. J Antimicrob Chemother 2003; 51 Suppl 2: ii17– 25.
36 Matsumoto K, Takeshita A, Ikawa K et al. Higher linezolid exposure
and higher frequency of thrombocytopenia in patients with renal
dysfunction. Int J Antimicrob Agents 2010; 36: 179–81.
37 Hiraki Y, Tsuji Y, Matsumoto K et al. Influence of linezolid clearance on
the induction of thrombocytopenia and reduction of hemoglobin. Am J
Med Sci 2011; 342: 456– 60.
38 Hiraki Y, Tsuji Y, Hiraike M et al. Correlation between serum linezolid
concentration and the development of thrombocytopenia. Scand J
Infect Dis 2012; 44: 60– 4.
39 Gerson SL, Kaplan SL, Bruss JB et al. Hematologic effects of linezolid:
summary of clinical experience. Antimicrob Agents Chemother 2002; 46:
2723– 6.
40 Swaney SM, Aoki H, Ganoza MC et al. The oxazolidinone linezolid
inhibits initiation of protein synthesis in bacteria. Antimicrob Agents
Chemother 1998; 42: 3251 –5.
41 Monson T, Schichman SA, Zent CS. Linezolid-induced pure red blood
cell aplasia. Clin Infect Dis 2002; 35: E29–31.
42 Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible
myelosuppression. JAMA 2001; 285: 1291.
43 Pea F, Viale P, Cojutti P et al. Therapeutic drug monitoring may
improve safety outcomes of long-term treatment with linezolid in adult
patients. J Antimicrob Chemother 2012; 67: 2034 –42.
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