Incidence of and risk factors for linezolid

5/5/2015
Linezolid
Incidence of and risk factors for
linezolid associated thrombocytopenia
Marie A. Corbo, PharmD
PGY1 Pharmacy Resident
Sinai-Grace Hospital, Detroit Medical Center
• Increased use of linezolid due to prevalence of drug-resistant Grampositive pathogens
• Has activity against clinically important Gram-positive pathogens
– Vancomycin-resistant Enterococcus (VRE)
– Methicillin-resistant Staphylococcus aureus (MRSA)
• Drug Class: Oxazolidinone
– Inhibits bacterial protein synthesis
• Binds to 23S rRNA in the large ribosomal subunit
• Preventing the fusion of 30S and 50S ribosomal subunits
• Bacteriostatic
– Lacks cross-resistance to other classes of drugs
Antimicrob Agents Chemother. 2007;51(3):962-7.
Antimicrob Agents Chemother. 2006;50(4):1599-602.
Infect Drug Resist. 2012;5:87-102.
The speaker has no actual or potential conflicts of interest in relation to this presentation.
Linezolid safety
Drug-induced thrombocytopenia
• Generally well-tolerated
• Primary safety concerns:
• Difficult to differentiate from other causes of thrombocytopenia
– Rule out other medical causes
– Medications associated with thrombocytopenia should be
discontinued
• May present with:
– Bruising, petechiae, and epistaxis
– Purpura and gingival bleeding
– Gastrointestinal/urinary tract bleeding, and pulmonary
hemorrhage
Warning
Myelosuppression
Comments
Anemia, leukopenia, pancytopenia, and thrombocytopenia
Neurological toxicity
Peripheral and optic neuropathy
Serotonin Syndrome
Associated with the co-administration of serotonergic agents
Lactic Acidosis
Increased blood lactate levels (0.4–5 mmol/L) with metabolic
acidosis
Infect Drug Resist. 2012;5:87-102.
ZYVOX (linezolid) [package insert]. New York, NY; Pfizer Inc.
Drug induced thrombocytopenia
Type
Immune-mediated:
increased platelet
destruction
Nonimmune-mediated:
decreased production
Mechanism
Example Drugs
Hapten-dependent
Penicillin, cephalosporins
Drug-glycoprotein complex
Quinine, quinidine, nonsteroidal
anti-inflammatory drugs,
sulfonamides
Ligand-induced binding site
Eptifibatide, tirofiban, otrafiban
Drug-specific antibody
Abciximab
Autoantibody
Gold salts, procainamide
Immune complex
Unfractionated heparin, lowmolecular-weight heparins
Bone marrow suppression
Linezolid, β-Lactams,
sulfonamide, flucytosine,
ganciclovir, valganciclovir,
foscarnet, albendazole
DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.
Infect Drug Resist. 2012;5:87-102.
Infect Drug Resist. 2012;5:87-102.
Pharmacotherapy. 2001;21(8):1010-3.
Linezolid induced thrombocytopenia
• Can lead to:
– Discontinuation of treatment
– Platelet transfusions
• Similarities between bacterial and
mitochondrial ribosomes
– 23S RNA target in prokaryotes
and genetically related
mitochondrial protein in
mammals
– Suppress protein synthesis in
the mitochondrial respiratory
chain within the bone marrow
• Reversible after discontinuation
Antimicrob Agents Chemother. 2007;51(3):962-7.
J Med Chem. 2014;57(11):4487-97.
Picture: Betts, et al. Human Anatomy and Physiology. OpenStax College. 2013.
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5/5/2015
Audience Poll
Incidence and definitions
• What is the incidence of
linezolid associated
thrombocytopenia?
A.
B.
C.
D.
<2%
2-10%
10-20%
>20%
Source
Definition of
thrombocytopenia
Incidence
(%)
Comments
Package insert
n=2,046
<112x109 platelets/L or
a 75% decrease in
platelet count
2.4%
Includes patients enrolled in seven Phase 3
comparator-controlled clinical trials, treated for up to
28 days
Attassi, et al.
Royal Oak, MI
n=19
<100x109 platelets/L
32%
Patients received linezolid for at least 5 days
Duration of therapy for patients who developed
thrombocytopenia (median, 22 days; range, 11–47
days)
Orrick, et al.
Gainsville, FL
n=48
30% decrease in
platelet count
48%
Patients received linezolid for at least 5 days
Duration of therapy for patients who developed
thrombocytopenia (median, 12 days; range, 5–34
days)
ZYVOX (linezolid) [package insert]. New York, NY; Pfizer Inc.
Clin Infect Dis. 2002;34(5):695-8.
Clin Infect Dis. 2002;35(3):348-9.
Incidence and risk factors studies
Source
Incidence and risk factors studies
Definition of
thrombocytopenia
Incidence
n(%)
Population
Risk Factors
Natsumoto, et
al.
Tokyo, Japan
n=101
≥50% decrease in
platelet count from
baseline
42(42%)
Age: 64 years
Weight: 57.3 kg
% male: 57%
Duration: 14 days
CrCl: 61.3 ml/min
Higher daily per kg dose and
elevated serum creatinine
Niwa, et al.
Gifu, Japan
n=42
≥25% decrease in
platelet count,
AND a final platelet
count of <100x109
platelets/L
7(16.7%)
Age: 59.6 years
Weight: 60.5 kg
% male: 74%
Duration: 13.6 days
CrCl: 99.5
Daily dose of ≥22 mg/kg
<100x109 platelets/L,
OR a ≥30%
decrease in platelet
count
29(38.6%)
Age: 69 years
Weight: 65.5 kg
% male: 64%
Duration: 15.7 days
Therapy for >14 days and a
low creatinine clearance rate
Hirano, et al.
Aomori, Japan
n=75
Infection. 2014;42(6):1007-12.
Int J Clin Pharm. 2014;36(4):795-9.
Clin Ther. 2009;31(10):2126-33.
CrCl: creatinine clearance
Incidence and risk factors studies
Source
Source
Definition of
thrombocytopenia
Incidence
n(%)
Population
Risk Factors
Natsumoto, et
al.
Tokyo, Japan
n=101
≥50% decrease in
platelet count from
baseline
42(42%)
Age: 64 years
Weight: 57.3 kg
% male: 57%
Duration: 14 days
CrCl: 61.3 ml/min
Higher daily per kg dose and
elevated serum creatinine
Niwa, et al.
Gifu, Japan
n=42
≥25% decrease in
platelet count,
AND a final platelet
count of <100x109
platelets/L
7(16.7%)
Age: 59.6 years
Weight: 60.5 kg
% male: 74%
Duration: 13.6 days
CrCl: 99.5
Daily dose of ≥22 mg/kg
<100x109 platelets/L,
OR a ≥30%
decrease in platelet
count
29(38.6%)
Age: 69 years
Weight: 65.5 kg
% male: 64%
Duration: 15.7 days
Therapy for >14 days and a
low creatinine clearance rate
Hirano, et al.
Aomori, Japan
n=75
Infection. 2014;42(6):1007-12.
Int J Clin Pharm. 2014;36(4):795-9.
Clin Ther. 2009;31(10):2126-33.
CrCl: creatinine clearance
Incidence and risk factors studies
Definition of
thrombocytopenia
Incidence
n(%)
Population
Risk Factors
Definition of
thrombocytopenia
Incidence
n(%)
Population
Risk Factors
Chen, et al.
Beijing, China
n=254
Criterion 1:
<100x109 platelets/L
Criterion 2: 25%
decrease in platelet
count from baseline
Criterion 1:
69(27.2%)
Criterion 2:
127(50%)
Age: 59 years
*Weight: 62 kg
% male: 67%
Duration: 9.43 days
Low pretreatment platelet
count, low body weight, low
serum albumin concentration,
long-term drug
administration, advanced
age, renal insufficiency, and
concomitant use of
caspofungin, levofloxacin,
and meropenem
Chen, et al.
Beijing, China
n=254
Criterion 1:
<100x109 platelets/L
Criterion 2: 25%
decrease in platelet
count from baseline
Criterion 1:
69(27.2%)
Criterion 2:
127(50%)
Age: 59 years
*Weight: 62 kg
% male: 67%
Duration: 9.43 days
Low pretreatment platelet
count, low body weight, low
serum albumin concentration,
long-term drug
administration, advanced
age, renal insufficiency, and
concomitant use of
caspofungin, levofloxacin,
and meropenem
Takahashi, et
al.
Nishinomiya,
Japan
n=331
>100x109 platelets/L
decrease from
baseline, OR a
≥30% decrease in
platelet count
128(38.7%)
Age: 58 years
*Weight: 54.1 kg
% male: 67%
Duration: 10.5 days
Duration of linezolid therapy
>14 days, creatinine
clearance <50 mL/min, renal
insufficiency with
hemodialysis, and
concomitant use of
fluoroquinolones
Takahashi, et
al.
Nishinomiya,
Japan
n=331
>100x109 platelets/L
decrease from
baseline, OR a
≥30% decrease in
platelet count
128(38.7%)
Age: 58 years
*Weight: 54.1 kg
% male: 67%
Duration: 10.5 days
Duration of linezolid therapy
>14 days, creatinine
clearance <50 mL/min, renal
insufficiency with
hemodialysis, and
concomitant use of
fluoroquinolones
*Thrombocytopenia group
Source
*Thrombocytopenia group
Curr Ther Res Clin Exp. 2012;73(6):195-206.
J Infect Chemother. 2011;17(3):382-7.
Curr Ther Res Clin Exp. 2012;73(6):195-206.
J Infect Chemother. 2011;17(3):382-7.
2
5/5/2015
Summary of current literature
• Wide variable incidence of thrombocytopenia
– Incidence ranges from 2.4-50%
– Lack of a standard definition for thrombocytopenia
– Differing patient populations
– Sample sizes
– Different durations of therapy
• Risk factors:
– Onset is after 10-14 days of therapy
– Renal insufficiency
• Studied in Japan/China
• Risk factors have not been adequately studied in an urban
community setting
Incidence of and risk factors for
linezolid associated thrombocytopenia
Marie A. Corbo, PharmD1
Ryan P. Mynatt, PharmD, BCPS, AQ-ID2
Keith S. Kaye, MD, MPH3
Jason M. Pogue, PharmD, BCPS, AQ-ID4
1Department
2Department
3Department
of Pharmacy Services, Sinai-Grace Hospital, Detroit, Michigan
of Pharmacy, Detroit Receiving Hospital and Wayne State University, Detroit, Michigan
of Medicine, Detroit Receiving Hospital and Wayne State University, Detroit, Michigan
of Pharmacy, Sinai-Grace Hospital and Wayne State University, Detroit, Michigan
4Department
Study objectives
• Primary
– Determine incidence of and risk factors for linezolid associated
thrombocytopenia at a large urban community hospital
• Secondary
– Identify the impact definition has on both the incidence and risk
factors for linezolid associated thrombocytopenia
Definitions
Definition of thrombocytopenia in primary investigation
≥25% decrease in platelet count in patients with a baseline ≥150x109 platelets/L count, OR
a ≥50% decrease in platelet count in patients with a baseline <150x109 platelets/L count
Definitions of thrombocytopenia in secondary investigation:
Criterion 1: <100x109 platelets/L
Criterion 2: ≥25% decrease in platelet count
<100x109 platelets/L, AND a ≥25% decrease in platelet count
<100x109 platelets/L, OR a ≥30% decrease in platelet count
>100x109 platelets/L decrease from baseline, OR a ≥30% decrease in platelet count
≥50% decrease in platelet count
Study design
Inclusion and exclusion criteria
• Retrospective case control study
• Inclusion:
– Age ≥18 years
– Treatment duration ≥48
hours
– Baseline platelet count
recorded in their medical
record
– At least one follow-up
platelet count recorded in
their medical record
• Sinai-Grace Hospital, Detroit Medical Center
• IRB approved study
• Patients receiving linezolid from January 2012-December 2014
• Exclusion:
– Age <18 years
– Patients with baseline
severe thrombocytopenia
3
5/5/2015
Methods
Statistical analysis
543 unique linezolid patients identified over study period
220 patients reviewed to date
Reasons for exclusion: lack of labs, short duration of
therapy, and severe thrombocytopenia
100 patients included in interim analysis
Thrombocytopenia
(n=27)
No
thrombocytopenia
(n= 73)
Potential risk factors analyzed:
• Demographics
• Comorbidities
• Severity of illness measures
• Drug exposures
Patient demographics
• Interim analysis:
– Categorical variables
• Fisher’s exact test
– Continuous variables
• Student’s t test for normally distributed data
• Mann-Whitney U-test for non-normally distributed data
• Full cohort:
– Bivariate and multivariate logistic regression analyses
– Variables with p value <0.2 in bivariate analyses will be added in
multivariate analysis
Baseline labs
Characteristic
Characteristic
Thrombocytopenia
(n=27)
No Thrombocytopenia
(n=73)
p value
63.2±14.4
63.1±16.0
0.99
Age >65 years
15(56%)
33(45%)
Female
12(44%)
Age (years)*
African
American
Weight (kg)*
Neutropenia
Thrombocytopenia
(n=27)
No Thrombocytopenia
(n=73)
p value
3(11.1%)
4(6.0%)**
0.41
<30 mL/min
9(33%)
31(42%)
0.49
0.38
30-59 mL/min
11(41%)
26(36%)
1
36(49%)
0.82
>60 mL/min
7(26%)
16(22%)
0.78
20(74%)
60(82%)
0.40
0(0%)
14(19%)
0.01
89.7±21.1
88.5±31.2
0.84
318.3±106.7
259.8±131.4
0.04
CrCl
Baseline platelet
count <150x109
platelets/L
Baseline platelet
count (platelets/L)*
Data presented as n(%) except *, which is presented as Mean±Standard deviation
Data presented as n(%) except *, which is presented as Mean±Standard deviation, **6 patients
excluded
CrCl: creatinine clearance
Comorbid conditions
Characteristic
Diabetes mellitus
Severity of illness measures
Thrombocytopenia
(n=27)
No Thrombocytopenia
(n=73)
p value
Characteristic
Thrombocytopenia
(n=27)
No Thrombocytopenia
(n=73)
p value
Charlson Comorbidity
Index*
3(2-5)
3(1-6)
0.41
25(93%)
32(44%)
0.0001
No SIRS
6(22%)
25(34%)
0.33
Septic
10(37%)
27(37%)
1
Septic Shock
3(11%)
10(14%)
1
Severe Sepsis
8(30%)
11(15%)
0.14
13(48%)
34(47%)
1
Chronic obstructive
pulmonary disease
3(11%)
19(26%)
0.17
Congestive heart
failure
9(33%)
21(29%)
0.81
Renal disease
11(41%)
30(41%)
1
Liver disease
1(4%)
4(5%)
1
Data presented as n(%)
ICU status while on
linezolid therapy
Data presented as n(%) except *, which is presented as Median(interquartile range)
ICU: Intensive care unit
SIRS: Systemic Inflammatory Response Syndrome
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5/5/2015
Drug exposures
Characteristic
Incidence
Thrombocytopenia
(n=27)
No Thrombocytopenia
(n=73)
p value
Linezolid daily dose
(mg/kg/day)
14.2±3.4
15.2±4.7
0.35
Linezolid daily dose
>22mg/kg/day
0(0%)
7(10%)
0.18
Length of linezolid
therapy (days)**
7(5-12)
5(3-9)
0.12
Treatment >10 days
10(37%)
17(23%)
0.21
Number of
concomitant drugs
associated with
thrombocytopenia*
3.3±1.6
3.4±1.5
0.86
Data presented as n(%) except *, which is presented as Mean±Standard deviation and **, which is
presented as Median(interquartile range)
Definition of thrombocytopenia in primary investigation
≥25% decrease in platelet count in patients with a baseline
≥150x109 platelets/L count, OR a ≥50% decrease in platelet count
in patients with a baseline <150x109 platelets/L count
Definitions of thrombocytopenia in secondary investigation
Criterion 1: <100x109 platelets/L*
Criterion 2: ≥25% decrease in platelet count
Incidence
27%
Incidence
Criterion 1: 7.5%*
Criterion 2: 27%
<100x109 platelets/L, AND a ≥25% decrease in platelet count*
6.4%*
<100x109 platelets/L, OR a ≥30% decrease in platelet count*
30%*
>100x109 platelets/L decrease from baseline, OR a ≥30% decrease
in platelet count
23%
≥50% decrease in platelet count
12%
*Six excluded
Onset of thrombocytopenia
Resolution of thrombocytopenia
• Number of patients who were discontinued on linezolid due to
thrombocytopenia: 5
• Average day of resolution after linezolid discontinuation: 5.9
Thrombocytopenia Occurrence
(Day of linezolid therapy)
Result n(%)
0-3
14(51%)
4-6
7-9
9(33%)
10-12
1(4%)
13-15
1(4%)
2(7%)
Study Limitations and Benefits
• Limitations
– Interim analysis
– Retrospective
– Electronic medical record
limitations
– Numerous confounding
factors in thrombocytopenia
• Benefits
– Large population
– First risk factor analysis in
urban community setting in
the United States
– First analysis on the impact
of definition on incidence
Characteristics of Resolution
Result n(%)
Number of cases that normalized before linezolid
discontinuation
7(26%)
Number of patients that normalized after linezolid
discontinuation
Number of patients that did not normalize after linezolid
discontinuation
7(26%)
13(48%)
Conclusions
• Incidence
• Thrombocytopenia occurred in 27% of our patients
• Ranged from 7.5%-30% based on definition
• Risk factors:
• ICU patients
• No statistical difference was seen between groups for: body
weight, creatinine clearance, and baseline platelet count
• Future directions:
• Larger analysis to be completed by the end of 2015
• Multivariate analysis with primary definition
• Analyze impact of definition on risk factors
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5/5/2015
Learning Question #1
Learning Question #1
Based upon the current literature describing linezolid associated
thrombocytopenia, which of the following is true?
Based upon the current literature describing linezolid associated
thrombocytopenia, which of the following is true?
A.
A.
B.
C.
D.
Linezolid associated thrombocytopenia is adequately studied in
the United States
There is a consistent rate of prevalence for linezolid associated
thrombocytopenia across all studies
Studies lack a standard definition for linezolid associated
thrombocytopenia
Most publications have adequately studied whether linezolid
associated thrombocytopenia reversed upon discontinuation of the
agent
B.
C.
D.
Linezolid associated thrombocytopenia is adequately studied in
the United States
There is a consistent rate of prevalence for linezolid associated
thrombocytopenia across all studies
Studies lack a standard definition for linezolid associated
thrombocytopenia
Most publications have adequately studied whether linezolid
associated thrombocytopenia reversed upon discontinuation of the
agent
Learning Question #2
Learning Question #2
Which of the following variables have not previously been linked to
linezolid associated thrombocytopenia?
Which of the following variables have not previously been linked to
linezolid associated thrombocytopenia?
A.
B.
C.
D.
A.
B.
C.
D.
Duration of therapy (>14 days)
Decreased renal function (CrCl <30 mL/min)
Low pretreatment platelet levels (<241x10^9/L platelets)
Vancomycin MIC >2
Duration of therapy (>14 days)
Decreased renal function (CrCl <30 mL/min)
Low pretreatment platelet levels (<241x10^9/L platelets)
Vancomycin MIC >2
Acknowledgements
• Jason Pogue, PharmD, BCPS, AQ-ID
Incidence of and risk factors for
linezolid associated thrombocytopenia
Marie A. Corbo, PharmD
PGY1 Pharmacy Resident
Sinai-Grace Hospital, Detroit Medical Center
The speaker has no actual or potential conflicts of interest in relation to this presentation.
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5/5/2015
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