China Medical Journal 2019 Volume 54 No.

7 -Works- 727

Analysis about 3 cases of linezolid-induced severe anemia and literature review

NIE Li-hui, WANG Jing, CAI Bao-yun, HUANG Xue-rui, CHU Nai-hui * (Department of Tuberculosis, Beijing Chest Hospital, Capital
Medical University, Beijing 101149, China)
*
Corresponding author, Email: dongchu1994@sina.com
Objective: In order to cause clinicians’concern about hematological side effect of linezolid by cases analysis and literature review. Method
Collected and analysed clinical data of 3 cases of severe anemia treatmed with linezolid-containing regimens, and reviewed literatures relative
to linezolid. Result 3 patients got severe anemia after using linezolid-containing regimens 4-12months, the hemoglobins(Hb) returned to normal
after discontinuing linezolid 1.5-6months. Combination treatment of linezolid and vitamin B 6 might alleviate linezolid- associated hematologic
side effect. Side effect about hematological system relative to linezolid should be surveyed, blood smear and bone marrow examination should
be implemented when necessary. Conclusion Linezolid may cause severe anemia, Hb can return to normal after discontinue lizenolid reatment.
Keywords: Linezolid; Adverse reaction; Anemia; Drug-resistant tuberculosis

CLC No.: R521 Document Code: A Article ID: 1008-1070 (2019) 07-0727-04
doi: 10.3969/j.issn.1008-1070.2019.07.011

Linezolid, a synthetic antimicrobial agent year and had a normal hemoglobin level prior to
from the oxazolidinone class, is highly the use of linezolid. She was admitted to the
effective against infections caused by a broad hospital in June 2015 due to fever, chest
range of Gram-positive pathogens, including tightness, and malaise. Subsequent routine
drug-resistant bacteria[1]. Additionally, blood tests revealed leukocytes of
9 12
linezolid exhibits potent antimycobacterial 10.39×10 /L, erythrocytes of 1.55×10 /L,
effects and maintains equal antibacterial hemoglobin of 43g/L, mean erythrocyte volume of
activity against both sensitive and resistant 96.8fL (reference range: 80 to 98fL), mean
strains[2]. While linezolid's use in erythrocyte hemoglobin content of 27.7 pg
antituberculosis treatment was previously an (reference range: 27 to 34pg), platelets of
over-the-counter medication, the World Health 425×109/L, and reticulocytes of 10.3%. She had
Organization classified it as a Group A drug been on linezolid for a year when severe anemia
for treating multidrug-resistant tuberculosis was detected. Hemoglobin levels increased to
in 2018[3].The potential adverse effects of its 60g/L after 10 days of discontinuing linezolid
long-term use have generated widespread and six months later, it was 114g/L.
interest. In this paper, the clinical data of Case 2 concerns a 37-year-old male with a
three patients with severe anemia due to 5-year history of extensively drug-resistant
linezolid's antituberculosis therapy are tuberculosis. Antituberculosis regimens over
reported, with the aim of drawing clinicians' the last six months included moxifloxacin,
attention to this issue. propylthioisonicotinamide, cycloserine,
1 Clinical Data aminosalicylate sodium, linezolid, and
Case 1 concerns a 36-year-old female with a clarithromycin. He was admitted to the hospital
co-infection of extensively drug-resistant in September 2015 due to fatigue and nausea.
tuberculosis and a 3-year history of Upon admission, complete blood counts showed
tuberculosis, with no other medical history. leukocytes of 4.16×109/L, erythrocytes of
Sputum tuberculosis culture and drug 2.19×1012/L, hemoglobin of 46g/L, mean
sensitivity results indicated resistance to erythrocyte volume of 84fL, mean erythrocyte
isoniazid, rifampicin, ethambutol, hemoglobin content of 25.6 pg, and platelets of
streptomycin, amikacin, capreomycin, and 225×109/L, suggesting severe anemia.
ofloxacin. The patient had been on a regimen of Hemoglobin levels returned to normal 2 months
capreomycin, moxifloxacin, linezolid, after discontinuing linezolid.
clofazimine, and clarithromycin for the past Case 3 is about a 36-year-old female with a

Founded by: Beijing Tongzhou District “Two High” Talent Project

* :: Correspondence to: Email: dongchul994@sina.com
 728: -Works-
2-year history of extensively drug-resistant
tuberculosis. Tuberculosis culture and drug
sensitivity tests indicated resistance to
isoniazid, rifampicin, ethambutol,
streptomycin, amikacin, and levofloxacin, with
sensitivity only to capreomycin and
aminosalicylate sodium. The patient was
diagnosed with severe anemia upon presentation
in January 2016, and the antituberculosis
regimen for the four months prior consisted of
pyrazinamide, moxifloxacin, capreomycin,
clofazimine, cycloserine, and linezolid. On
January 13, 2016, complete blood count showed
white blood cells of 4.02×10 9/L, red blood
cells of 2.29×1012/L, hemoglobin of 53g/L, mean
erythrocyte volume of 72.5fL, mean erythrocyte
hemoglobin content of 22.3 pg, and platelets of
169×109/L. Before using linezolid, the
patient's hemoglobin was 108 g/L, which
decreased to 83 g/L after 1 month, and to 53
g/L after 4 months (January 2016). Two weeks
after discontinuing linezolid, a follow-up
examination showed a hemoglobin of 74 g/L,
which returned to normal (110 g/L) after 1.5
months.
2 Discussion
As per the World Health Organization's
Guidelines for the Programmatic Management of
Drug-resistant Tuberculosis (2006)[4], linezolid
falls under Group 5 of the antituberculosis
drugs, a category denoting antituberculosis
agents with unclear efficacy. Linezolid is
among the most effective drugs in Group 5 and
plays a key role in the chemotherapeutic
regimen for extensively drug-resistant
[5]
tuberculosis (XDR-TB) . The WHO Treatment
Guidelines for Drug-Resistant Tuberculosis,
2016 Update[6], categorizes antituberculosis
drugs into groups A, B, C, and D1-3, with
linezolid classified under Group C, defined as
"other core second-line agents".In general, it
is not utilized for mono- and multi-drug-
resistant TB, but solely for multidrug-
resistant tuberculosis (MDR-TB) and extensively
drug-resistant TB.
2.1 Anti-Mycobacterium tuberculosis effects of
linezolid and its mechanism Linezolid is a synthetic
antimicrobial drug effective against Gram-positive
mycobacteria. It inhibits bacterial protein synthesis by
binding to the 50S subunit of the bacterial ribosome,
hindering the attachment of mRNA to the ribosome, and
preventing the formation of the 70S initiation complex [7].
Linezolid acts at the initiation of the
China Medical Journal 2019 Volume 54 No.
7
translational system, and due to its unique
site and mode of action, it largely shows no
cross-resistance with other antimicrobials. The
mechanism of action of linezolid in
tuberculosis treatment aligns with its
resistance to multi-drug resistant Gram-
positive cocci. Due to this drug's unique mechanism
of action, it doesn't overlap with other antibacterial drugs
that inhibit protein synthesis in terms of its target of action,
and it is unlikely to induce the production of bacterial
drug-resistant genes in vitro[8]. Linezolid demonstrates
notable activity against Mycobacterium tuberculosis in
vitro, with a minimum inhibitory concentration (MIC) of <
1 mg/L, specifically 0.125 to 0.5 mg/L. It exhibits equal
antibacterial activity against sensitive and resistant strains
and possesses an antimicrobial effect on both rapidly
proliferating and quiescent bacterial populations [9]. A 2016
literature review and meta-analysis by Agyeman and
Ofori-Asenso[10] showed an overall sputum culture
negative rate of 88.45% for MDR-TB/XDR-TB treated
with a linezolid-containing regimen, and a treatment
success rate of 77.36%. This is higher than the
RR-TB/MDR-TB treatment success rate (52%) and the
XDR-TB treatment success rate (26%) reported by the
WHO in 2016. Both basic and clinical studies
have validated the effectiveness of linezolid
in the treatment of drug-resistant
tuberculosis.
2.2 Major adverse reactions to linezolid Clinical
studies have verified the efficacy of linezolid in MDR-
TB/XDR-TB treatment. However, the long-term use
of antituberculosis drugs can lead to various
adverse effects. Reports about the adverse
effects of linezolid have gained significant
attention. The most common side effects of linezolid
include neurotoxicity (encompassing peripheral
neurotoxicity and optic neurotoxicity) and
myelosuppression, with the onset of neurotoxicity usually
occurring later than myelosuppression and being primarily
linked to the duration of therapy[11].
A literature review and meta-analysis by
Sotgiu et al.[12] indicated that the incidence of
adverse events in MDR-TB, when treated with a
linezolid-containing individualized regimen,
was 58.9%, 68.4% of which were serious adverse
events. These included anemia (38.1%),
peripheral neuropathy (47.1%), optic neuritis
(13.2%), and thrombocytopenia (11.8%). The
incidence of adverse events noticeably
increased with doses exceeding 600 mg per day.
A meta-analysis by Zhang et al.[13] on the use of
linezolid in drug-resistant tuberculosis
 China Medical Journal 2019 Volume 54 No. 7
treatment showed a peripheral neuropathy
incidence of 31% and anemia incidence of 25%.
Agyeman and Ofori-Asenso[10] reported that the
primary adverse effects of linezolid were
myelosuppression and neuropathy with incidences
of 32.93% and 29.92% respectively, and
myelosuppression exhibited significant dose
dependence, with a lower incidence at reduced
drug doses.
The three patients highlighted in this
paper all had extensively drug-resistant
tuberculosis with no history of hematological
disease. They were diagnosed with severe anemia
(hemoglobin less than 60 g/L) following an
antituberculosis treatment with a linezolid-
containing regimen. None of these patients had
shown hematological adverse reactions during
antituberculosis treatment before linezolid was
introduced. The dosage of linezolid was 600 mg
per day, and the time from linezolid initiation
to the discovery of severe anemia ranged from 4
to 12 months. None of the patients showed signs
of bleeding (hemoptysis, hematochezia,
hematuria) or hemolytic manifestations, and the
two female patients maintained normal menstrual
flow. After examining the patients' medication
regimen and ruling out the possible
contribution of other drugs to the anemia,
linezolid was considered the cause and
subsequently discontinued, while other drugs in
the regimen were continued. The normalization
of hemoglobin levels upon continued use of
other drugs suggests that the other medications
in the regimen were not the cause of the severe
anemia.
2.3 Mechanisms of Linezolid-induced anemia
The causes of linezolid-induced anemia could be
multifactorial. In scientific literature, linezolid has been
reported to induce ringed sideroblastic anemia, which
improves upon drug discontinuation [14]. Sideroblastic
anemia is a group of iron utilization disorders
characterized by a high count of ringed
sideroblasts in the bone marrow, microcytic
hypochromic anemia in the peripheral blood, and
normal or slightly increased reticulocytes. In
this paper, the reticulocyte count in Case 1 was
significantly increased, indicating heightened bone marrow
activity in response to anemia. Cases 2 and 3 exhibited
microcytic anemia, but the patients did not undergo bone
marrow aspiration during their hospital stays to procure
more detailed information. Bernstein et al.[15] reported
thrombocytopenia and anemia in an elderly patient after
-Works- 729
seven days of linezolid treatment. Bone marrow biopsy
showed an adequate number of normal megakaryocytes,
ringed sideroblasts, and vesicular proerythroblasts in the
bone marrow. The presence of ringed sideroblasts and
vesicular proerythroblasts may be secondary to
chloramphenicol-like inhibition of erythropoiesis,
suggesting that the anemia could be associated with
myelosuppression.
Linezolid has also been reported to cause
erythrocyte aplasia, characterized by a
decrease in both hemoglobin and reticulocyte
counts after two weeks of treatment. Bone
marrow biopsy suggested impaired
erythropoiesis, which returned to normal after
discontinuing the drug for two weeks[16]. Cases
of anemia due to linezolid have been reported
in pediatric patients as well. In one instance,
a child patient with infective endocarditis
developed progressive anemia after two weeks of
anti-infective treatment with linezolid. After
four weeks, hemoglobin decreased to 65 g/L and
reticulocytes were less than 0.1%. Bone marrow
examination suggested a significant decrease in
erythropoiesis, accompanied by cytoplasmic
vacuolation. Hemoglobin levels were restored
after discontinuing linezolid for 19 days [17].
The mitochondrial dysfunction associated with
long-term high-dose linezolid may contribute to
pure red cell aplasia induced by the drug.
Hiraki et al.[18] found a strong correlation
between decreased clearance of linezolid and
decreased hemoglobin, suggesting that increased
plasma levels of linezolid could affect
hematopoiesis. This implies that hemoglobin
levels should be closely monitored to detect
anemia or thrombocytopenia caused by linezolid.
In patients with renal insufficiency, increased
blood concentrations of linezolid can cause
severe thrombocytopenia and anemia[19].
Youssef et al.[20] observed no anemia during
linezolid treatment when combined with a daily
dose of 50 mg of vitamin B6, while the
incidence of anemia in the control group was
5%. It is presumed that daily administration of
vitamin B6 reduces the incidence of anemia but
does not prevent linezolid-induced
thrombocytopenia and leukopenia. Deng et al. [21]
found that the combined use of linezolid and
vitamin B6 in patients with septic infections
prevented the cytopenia caused by linezolid.
2.4 Dosage and regimen of linezolid for
antituberculosisThe dosage and regimen of linezolid used
 730: -Works-
for treating tuberculosis are yet to be universally
standardized. Previous clinical studies have employed a
variety of regimens, including daily dosages of 1200 mg [22-
23]
, 600 mg[24-25], and 300 mg[26-27]. The difference in
efficacy between daily doses above or below 600 mg was
not found to be significant. However, due to adverse
effects, some patients required temporary or even
permanent discontinuation of the drug. The
effectiveness of lower doses is still a matter
of debate, as they could potentially lead to
drug resistance and not necessarily decrease
the incidence of peripheral neuropathy. As per
the China Drug-resistant Tuberculosis Treatment
Guidelines (2015), it is recommended that the dosage of
linezolid for adults be 300-600 mg/day, with a limit of 600
mg/day. A meta-analysis by Agyeman and Ofori-Asenso [10]
found no significant difference in sputum conversion and
treatment success between groups with daily doses > 600
mg or ≤ 600 mg. However, the incidence of
myelosuppression was significantly higher in the group
with a daily dose of >600mg of linezolid (50%) than in the
group with a dose of ≤ 600 mg/day (19.58%). The
incidence of drug discontinuation due to neuropathy did
not significantly differ between the two groups.
Reports in the literature show wide
variations in linezolid usage cycles, with
discontinuation due to adverse events being
quite common. A 2015 meta-analysis highlighted
that the duration of linezolid use reported in
various studies varied, with a median duration
of 6 to 24 months[13]. Given the extended
treatment cycle for multidrug-resistant
tuberculosis, it is crucial to balance
treatment efficacy with patient tolerability
and avoidance of adverse effects. According to
China's Consensus on Linezolid in the Treatment
of Tuberculosis[28], the recommended dosage of
linezolid for treating multidrug-resistant
tuberculosis is 600 mg twice daily. After 4 to
6 weeks, the dosage should be reduced to 600 mg
once daily. In the event of severe adverse
reactions, the dosage can further be reduced to
300 mg/day or even discontinued. Concurrent
intake of vitamin B6 is also recommended. The
total treatment course recommended is between 9
and 24 months.
In conclusion, the combination of linezolid
with other anti-tuberculosis drugs is a highly
valuable regime for treating multidrug-
resistant, particularly extensively drug-
resistant, tuberculosis. Anemia induced by the
drug can be reduced or reversed with timely
China Medical Journal 2019 Volume 54 No.
7
measures. Close monitoring of adverse
reactions, particularly hematological and
neurological, is essential during treatment. If
hematological adverse reactions occur, the
decision to continue observation or discontinue
the drug can be made based on the severity of
the reaction. In addition, routine blood tests
and blood smears can be monitored, and
reticulocyte count can be checked if anemia
occurs. Myeloproliferative status can be
assessed by bone marrow aspiration if
necessary. Vitamin B6 may be effective in
reducing hematological adverse effects and
could therefore be considered.
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(Accepted date: 2019-04-25；Revised date: 08/May/2019)
(Edited by: An Jing)

Excitability of central sensory nervous system in major depressive disorder

HUANG Zhao-yang, ZHAN Shu-qin, LI Ning, DING Yan, HOU Yue, WANG Yu-ping * (Department of Neurology,Xuanwu Hospital, Capital
Medical University, Beijing 100053, China)
*
Corresponding authors,Email:mdwangyp@sina.cn
Abstract: Objective Paired-pulse stimulation techniques are used as common tools to investigate excitability of sensory nervous system. In this
study, we investigated the excitability of the central sensory nervous system in patients with MDD using the method of paired-pulse
somatosensory evoked potentials (SEPs). Method Fifteen patients with MDD and 15 healthy subjects were enrolled. We applied single stimuli
and paired stimuli at interstimulus intervals (ISIs) of 20, 60, 100 and 150 ms to stimulate left median nerve. Paired-pulse SEPs and single pulse
SEPs were recorded. Result The recovery function of the N13 component showed significantly reduced suppression in patients with MDD as
compared to healthy controls(F=5.81, P=0.023). The recovery function of the P25 component showed significantly inhibited in patients with
MDD as compared to healthy controls (F= 13.50, P=0.007). The recovery function of the N9 and N20 components showed no significant
differences between these two groups (P ＞ 0.05). Conclusion This is the first study investigating changes in excitability of central sensory
nervous system in patients with MDD by examining the recovery function of median nerve SEPs. In the central sensory nervous system of
patients with MDD, the excitability of the posterior central gyrus cortex decreases and the excitability of the posterior horn of the spinal cord
increases. The changes of excitability in the central sensory nervous system in patients with MDD are multilevel, which might contribute to the
pathophysiological mechanisms of the association between MDD and somatic symptoms.
Keywords: Major depressive disorder; Somatic symptoms; Paired-pulse somatosensory evoked potentials; Central sensory nervous system;
Excitability
CLC No.: R749 Document Code: A Article ID: 1008-1070 (2019) 07-0730-05

doi:10.3969/j.issn.1008-1070.2019.07.012

Funding programs: the National Natural Science Foundation of China (81301138, 81571294) and the Natural Science Foundation of Capital Medical University (PYZ2018069).
* :: Corresponding to, Email: mdwangyp@sina.cn