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The present study evaluated the rational prescription of linezolid, the prevalence of thrombocytopenia, and major drug interactions in patients with cardiovascular diseases. We conducted a retrospective cross-sectional study on linezolid-treated patients at Shahid Chamran Heart Hospital in Isfahan from March 21, 2021, to March 20, 2022. Our research involved 132 patients who received linezolid. We reported 43.18% of linezolid prescriptions as irrational. Linezolid-induced thrombocytopenia is more common than previous studies, with a prevalence of 47.9%. We found a significant relationship between thrombocytopenia and the concomitant use of aspirin. The duration of treatment was identified as predicting factor for linezolid-induced thrombocytopenia. Moreover, the prevalence of interactions in the X and D categories was determined. Serotonergic and catecholamine medications were associated with 56.1% and 47.7% medication interactions, respectively. Our study found a high prevalence of linezolid-induced thrombocytopenia among patients with cardiovascular diseases. Based on this study, physicians should focus more closely on prescribing linezolid to patients with cardiovascular diseases. In addition to following rational antibiotic use, this susceptible group is also at an elevated risk of side effects (thrombocytopenia) and medication interactions.
Linezolid is one of the most effective antibiotics for treating Gram-positive organisms, including vancomycin-resistant species such as vancomycin-resistant enterococci (VRE), vancomycin-intermediate
Patients with cardiovascular diseases may be at higher risk for linezolid-induced thrombocytopenia due to the use of anti-platelet and/or anti-coagulant medications [
This study aims to address the following research questions: (i) What is the prevalence of the rational use of linezolid in people with cardiovascular diseases? (ii) What is the prevalence of significant drug interactions in this patient population? (iii) How prevalent is linezolid-induced thrombocytopenia in patients with cardiovascular diseases?
We conducted a retrospective cross-sectional study including all the linezolid prescriptions in adult patients (aged >18 years) over a 1-year period at Chamran Heart Hospital in Isfahan from March 21, 2021, to March 20, 2022.
The researchers developed a comprehensive checklist to collect data, which included the following elements: demographics, site and type of infection, microbiological data with related antibiogram, details on linezolid use (start and stop dates, duration of treatment, dose, and route of administration), laboratory data (including serum creatinine, baseline and daily platelet counts), request for consultation with an infectious disease specialist, simultaneous medications, occurrence of thrombocytopenia, and rationality of the prescription according to international guidelines.
Based on international guidelines, including those from IDSA and ESC, two infectious disease specialists independently analyzed the rationality of each prescription. There were four possible reasons for an irrational prescription: no indication for any antibiotic, combinations with a similar spectrum of activity, narrow-spectrum antibiotics possible, and pathogens insensitive to antibiotics. In some cases, linezolid was the only option, while in others, vancomycin was available. Finally, we provided percentage terms for the evaluation of the irrational use of linezolid [
All patients who were treated with linezolid for a minimum duration of 3 days were included in the study. Patients with the following conditions were excluded: patients with a baseline platelet count less than 100 × 109 cells/L prior to therapy, known to have haemato‐oncologic diseases or myelosuppression, who had received bone marrow-suppressing medication within 2 weeks before the study, presence of other diagnoses rather than linezolid-induced thrombocytopenia such as diffuse intravascular disorders (DIC), sepsis, and heparin-induced thrombocytopenia (HIT) with a HIT score above 3. Linezolid-induced thrombocytopenia was defined as a decrease in the patient’s platelet count to less than 100 × 109cells/L or a reduction of more than 25% from their baseline value [
To evaluate the relationship between kidney function and the incidence of thrombocytopenia, we divided the patients into three groups according to their creatinine clearance rates (CrCl ≥60 mL/min, 30 mL/min ≤ CrCl <60 mL/min, CrCl <30 mL/min) and compared the prevalence of thrombocytopenia of each group.
This part of the study included all patients who received linezolid treatment for a minimum of 24 h. Prescriptions with at least two medications, including linezolid were selected for detecting potential drug-drug interactions (DDI) using the UpToDate drug reference database. This database provides information on the mechanism, clinical outcome, and management of possible DDI. The severity of DDI is classified as “(X) avoid combination,” “(D) consider therapy modification,” “(C) monitor therapy,” “(B) no action is needed.” Besides, this reference has classified DDIs based on the clinical severity of the interaction (major, moderate, or minor) and reliability (good and fair). Since potential DDIs in the X and D categories cover most potential DDIs with clinical relevance, we included only these two categories in our analysis [
We conducted data analysis using the Statistical Package for Social Sciences version 26.0 software for Windows (IBM SPSS Statistics for Windows, Version 26.0, Armonk, NY: IBM Corp., United States). Kolmogorov-Smirnov tests were employed to assess the normal distribution of continuous variables. We presented the results as mean, standard deviation (SD), median (min-max) for continuous variables, and numbers (percentages) for categorical variables. Furthermore, a chi-square test was used to assess the possible relationship between thrombocytopenia and medications. Logistic regression was used to determine the relationship between thrombocytopenia, age, creatinine clearance (CrCl), baseline platelet counts, and duration of treatment. The possible relationship between basic platelet level and nadir platelet count was assessed by linear regression. The significance level for all tests was set at α < 0.05.
At Chamran Heart Hospital, 132 patients received linezolid prescriptions during the study period. The demographic characterization of patients including age, gender, route of administration and baseline creatinine clearance are shown in
Demographic and clinical characteristics of the included patients.
| Variables | N (%) or Mean ± SD |
|---|---|
| Sex | |
| Male | 91 (68.9) |
| Female | 41 (31.1) |
| Culture request | |
| No | 45 (34.1) |
| Yes | 87 (65.9) |
| Rout of administration | |
| PO | 55 (41.7) |
| IV | 77 (58.3) |
| Duration of treatment | 6.67 ± 5.78 |
| CrCl (mL/min) | 48.61 ± 26.43 |
| Baseline platelet count (×109 cells/L) | 223.6 ± 107.0 |
| Time to thrombocytopenia (days) | 6.25 ± 2.93 |
A total of 132 patients receiving linezolid were included in the evaluation of the rationality of the prescription. Linezolid was most frequently prescribed by infectious specialists (n = 93, 70.5%) and nephrologists (substitution of vancomycin with linezolid in order to avoid vancomycin-induced nephrotoxicity in patients with renal failure) (n = 28, 21.2%), respectively. Linezolid is most commonly used to treat pneumonia.
Rational and irrational prescriptions of Linezolid.
| Rational/Irrational indications N (%) | Indications | N (%) |
|---|---|---|
| Rational use |
Based on culture (no other options available) | 13 (9.84) |
| Other options available (mostly vancomycin) | 62 (46.96) | |
| Irrational use |
No indication to any antibiotic | 5 (3.87) |
| Combination with agents with similar spectrum of activity | 3 (3.03) | |
| Narrower-spectrum antibiotic possible | 32 (24.24) | |
| Insensitive pathogens | 17 (12.87.4) |
This section of the study included 73 patients out of 132 who were receiving linezolid. The following patients were excluded: 28 patients did not have a baseline platelet count, 24 patients were taking linezolid for less than 3 days, 4 patients had a diagnosis of DIC, 2 patients had an HIT score of 4 or higher, and 1 patient was taking carbamazepine concurrently. Out of 73 patients, 35 (47.9%) experienced linezolid-induced thrombocytopenia.
Univariate Logistic Regression model for risk factors associated with thrombocytopenia.
| Crude Model | Adjusted Model | |||
|---|---|---|---|---|
| Variables | Exp(B) (95%CI) | P | Exp(B) (95%CI) | P |
| Age | 1.01 (0.98–1.04) | 0.58 | 1.02 (0.98–1.06) | 0.29 |
| Sex (Female) | 0.88 (0.33–2.35) | 0.80 | 0.46 (0.14–1.59) | 0.22 |
| Aspirin | 2.81 (0.94–8.46) | 0.064 | 4.38 (1.1–17.3) | 0.035 |
| Duration of treatment (days) | 1.22 (1.07–1.40) | 0.002 | 1.27 (1.10–1.46) | <0.001 |
| Baseline platelet counts (×109 cells/L) | 1.00 (0.99–1.00) | 0.93 | 1.00 (0.99, 1.00) | 0.93 |
Risk factors for linezolid‐induced thrombocytopenia.
| Medications | Linezolid-induce thrombocytopenia (Yes) |
Linezolid-induce thrombocytopenia (no) |
|
|---|---|---|---|
| Sex (Female) | 25 (65.8%) | 24 (68.6%) | 0.800 |
| Aspirin | 29 (82.8%) | 24 (63.2%) | 0.059 |
| Clopidogrel | 11 (31.4%) | 15 (39.5%) | 0.473 |
| Heparin | 11 (31.4%) | 19 (50.0%) | 0.107 |
| Enoxaparin | 4 (11.4%) | 6 (15.8%) | 0.588 |
| DOAC | 0.571 | ||
| No | 31 (88.6%) | 35 (92.1%) | |
| Rivaroxaban | 1 (2.9%) | 0 (0.0%) | |
| Apixaban | 3 (8.6%) | 3 (8.6%) | |
| Warfarin | 10 (28.6%) | 9 (23.7%) | 0.634 |
| Age (years) | 63.4 ± 15.9 | 61.3 ± 16.4 | 0.303 |
| Baseline platelet count (×109 cells/L) | 225.9 ± 105.0 | 228.1 ± 120.4 | 0.93 |
| CrCl (mL/min) | 44.6 ± 24.4 | 47.7 ± 27.5 | 0.264 |
| Duration (days) | 10.7 ± 6.29 | 6.26 ± 4.01 | <0.001 |
According to UpToDate drug references, 16.7% of patients had only an X-category interaction, 20.7% had only a D-category interaction, and 34.8% had both interactions concomitantly. The prevalence of drug interactions with serotonergic and catecholamine medications was 56.1% and 47.7%, respectively. A patient who received citalopram and linezolid concomitantly developed serotonin syndrome with fever, agitation, diaphoresis, and tremor that resolved 36 h after both agents were discontinued. The aforementioned patient was receiving 40 mg of citalopram daily, which can be considered high-dose and might justify the occurrence of serotonin syndrome in combination with linezolid. Additionally, one patient who was treated with dobutamine as an inotropic agent developed recurrent ventricular tachycardia, which was subsequently controlled by changing linezolid to vancomycin. The prevalence of interactions between linezolid and serotonergic or catecholamine medications is presented in
Interactions between Linezolid and serotonergic and catecholamine medications.
| Name | Risk | Severity | Reliability | N (%) |
|---|---|---|---|---|
| Serotonergic | ||||
| Fentanyl | D | Major | Good | 33 (25) |
| Pethidine | D | Major | Good | 12 (11) |
| Methadone | X | Moderate | Fair | 13 (9.8) |
| Acetaminophen codeine | X | Major | Fair | 16 (12.1) |
| Dextromethorphan | X | Major | Fair | 5 (3.8) |
| Morphine | X | Moderate | Fair | 31 (23.5) |
| Sertraline | X | Major | Good | 2 (1.2) |
| Citalopram | X | Major | Good | 4 (3) |
| Escitalopram | X | Major | Good | 1 (0.8) |
| Catecholamine | ||||
| Norepinephrine | D | Major | Fair | 53 (40.2) |
| Epinephrine | D | Major | Fair | 11 (8.3) |
| Dopamine | D | Major | Fair | 13 (9.8) |
| Dobutamine | D | Major | Fair | 5 (3.8) |
In the present study, 43.18% of prescribed cases of linezolid were found to be irrational. Dentan et al. reported this rate as 65% [
Linezolid was most frequently prescribed by infectious specialists (70.5%), followed by nephrologists (21.2%). Nephrologists substituted all of the prescribed linezolid for vancomycin to prevent vancomycin-induced nephrotoxicity in kidney failure patients requesting nephrology consultations.
Vancomycin alone has a minimal risk of nephrotoxicity (without other risk factors), and recent studies consider this risk to be insignificant. Furthermore, recent review articles indicate the reversible nature of vancomycin-induced acute kidney injury. The toxicity of vancomycin is determined by its minimum concentration; therefore, proper dose adjustment of vancomycin in patients with renal insufficiency, either by adjusting the dose based on serum concentration or by regulating the dose as a whole, can minimize the potential for nephrotoxicity. For this reason, there is no contraindication for the use of vancomycin in patients with renal failure [
There is evidence that linezolid-induced thrombocytopenia occurs in 13–30% of patients. In the present study, the prevalence of thrombocytopenia was 47.9%, which was higher compared to other studies. In a retrospective study at Belgian hospital centers conducted by Thirot et al., the prevalence of linezolid-induced thrombocytopenia was reported to be 18.9%. In another study on 254 Chinese patients, the prevalence of linezolid-induced thrombocytopenia was 27.2%. It is possible that the higher prevalence of thrombocytopenia in this study was due to the selection of patients with cardiovascular diseases as the study population, who are more prone to the development of linezolid-induced thrombocytopenia (such as old age, antiplatelet medication use, and chronic kidney disease comorbidities) [
Among the antiplatelet and anticoagulant medications, only aspirin showed a statistically significant association with thrombocytopenia. The relationship between linezolid-induced thrombocytopenia and antiplatelet/anticoagulant use is not well studied. Choi et al. found a statistically significant correlation between aspirin and linezolid-induced thrombocytopenia [
The relation between linezolid-induced thrombocytopenia and low CrCl has been discussed in many studies [
The duration of the treatment had a statistically significant correlation with the occurrence of linezolid-induced thrombocytopenia in our study, which is consistent with findings in other studies. According to Han et al.'s study, the duration of linezolid treatment is associated with linezolid-induced thrombocytopenia [
The current study found that 72.2% of patients had major drug interactions, which can lead to serious complications, especially in patients with cardiovascular disease. Linezolid is a medication with monoamine oxidase inhibitor (MAOI) properties that is able to prevent the metabolism of serotonin, catecholamines, and certain medications in the body. The lack of metabolism of norepinephrine and dopamine in these patients can lead to sympathetic storms, myocardial infarction, ventricular tachycardia, and hypertensive crises. However, its clinical importance has not been investigated. In the heart failure guidelines (AHA/ACC 2022), caution is advised for the use of inotropic and vasopressor agents in combination with MAOIs [
Our study reported one case of the serotonin syndrome in a patient who received high dosages of citalopram and linezolid. There has been a report that citalopram and linezolid can cause serotonin syndrome, and citalopram is one of the selective serotonin reuptake inhibitors (SSRIs) with a high prevalence of serotonin syndrome [
This study reported a higher prevalence of thrombocytopenia and potential drug interactions associated with linezolid use in patients with cardiovascular diseases. According to this study, physicians should be more cautious when prescribing linezolid for patients with cardiovascular diseases. This is not only due to the rational use of antibiotics but also due to the higher risk of adverse effects and drug interactions in this vulnerable population.
The retrospective nature of the study limited the ability to comprehensively evaluate certain clinical conditions, such as serotonin syndrome prevalence. There were also limitations including the lack of data recording, such as baseline platelet and serum creatinine levels. In addition, some diagnoses are uncertain in some files. Another significant limitation of the current study is the small sample size, which restricts generalizability. To enhance the robustness and applicability of future studies, it is recommended that a larger sample size and a prospective approach be used.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving humans were approved by ethics committee of Isfahan University of Medical Sciences, Isfahan, Iran. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
The authors sincerely thank to Dr. Bashir Mosayyebi and Dr. Amir Hossein Goudarzian for their valuable assistance that significantly contributed to the revision of this manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.