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Article
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Linezolid is the first oxazolidinone antimicrobial marketed in the United States. It exhibits monoamine oxidase (MAO) type A and MAO type B inhibitory effects. The concomitant administration of nonselective MAO inhibitors or MAO-A inhibitors with drugs that increase serotonin concentrations is associated with serotonin toxicity. We requested from t...

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... Serotonin syndrome (SS) is caused by supra-therapeutic serotonin levels in the synapses of the brain, and it can lead to hyperthermia [94,95]. This drug-induced condition is often caused by a combination of two or more of the following: SSRIs, monoamine oxidase inhibitors (MAOIs), TCAs, venlafaxine, trazodone, tramadol, linezolid, 3,4-methylenedioxymethamphetamine (MDMA), and several other drugs [95][96][97][98][99][100][101][102]. These agents often share common mechanisms, including the inhibition of serotonin uptake, decreased serotonin metabolism, increased serotonin synthesis, increased serotonin release, activation of serotonergic receptors, and inhibition of cytochrome P450 enzymes [101]. ...
... The clinical diagnosis of serotonin syndrome was not standardized in the clinical record. We attempted to mitigate this by retrospectively applying the Hunter diagnostic criteria to the possible cases, an approach that has been used previously in studies attempting to retrospectively diagnose serotonin toxicity [9,10]. As in other studies, missing clinical data often made retrospective application of these criteria inconclusive. ...
Article
Background Serotonin toxicity (also referred to as serotonin syndrome) results from medications that affect the neurotransmitter serotonin. The antibiotic linezolid and the opioids methadone and buprenorphine are all reported to cause serotonin toxicity, but the degree of risk with use of linezolid in combination with methadone or buprenorphine is unknown. Methods We conducted a retrospective cross-sectional analysis of adult patients hospitalized from November 2015 to October 2019 who were administered linezolid in combination with methadone and/or buprenorphine within 24 hours and a subgroup which received the combination for 3 or more days. Cases of serotonin toxicity were identified from the clinical notes in the electronic medical record and were classified as possible or definite based on the clinical record. The Hunter diagnostic criteria were retrospectively applied. Results There were 494 encounters in which linezolid was administered concurrently with methadone and buprenorphine. The mean patient age was42.5 years and 52.4% of encounters were of female patients. The mean duration of concurrent administration was 2.0 days. There were 106 encounters with a duration of concurrent administration ≥ 3 days (mean 5.9 days). Two cases of possible serotonin toxicity and 0 cases of definite serotonin toxicity occurred; neither possible case met the Hunter criteria from the available information. Possible cases occurred in 0.40% of all encounters and 1.89% of encounters with ≥ 3 days of overlap (upper 1-sided 95% confidence interval, 0.87% and 4.06%). Conclusions Serotonin toxicity occurring during the administration of linezolid in combination with methadone and/or buprenorphine occurred rarely among 494 hospital encounters, including 106 encounters with ≥ 3 days of overlap. Limitations include potential missed diagnoses of serotonin toxicity and short durations of overlap. Further study evaluating the short-term risk of this combination is needed.
... Linezolid is also a weak monoamine oxidase inhibition. As such, there is a theoretical risk of serotonin syndrome, particularly in patients on multiple serotonergic medications [106]. Multiple studies have suggested that this risk is lower than previously thought; however, some medications have been associated with higher risk than others, including specific selective serotonin reuptake inhibitors and methadone [107][108][109]. ...
Article
Mycobacterium chimaera, a member of the Mycobacterium avium complex, can cause infections in individuals after open-heart surgery due to contaminated heater-cooler units. The diagnosis can be challenging, as the incubation period can be quite variable, and symptoms are non-specific. In addition to aggressive surgical management, combination pharmacologic therapy is the cornerstone of therapy, which should consist of a macrolide, a rifamycin, ethambutol, and amikacin. Multiple second-line agents may be utilized in the setting of intolerances or toxicities. In vitro susceptibility of these agents is similar to activity against other species in the Mycobacterium avium complex. Drug-drug interactions are frequently encountered, as many individuals have chronic medical comorbidities and are prescribed medications that interact with first-line agents used to treat M. chimaera. Recognition of these drug-drug interactions and appropriate management are essential for optimizing treatment outcomes.
... Linezolid is an oxazolidinone antibiotic against Methicillin resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus (VRE) and Drug resistant Streptococcus pneumoniae (DRSP) infections. The structure of linezolid is similar to a selective reversible monoamine oxidase inhibitor (MAO-A) toloxatone that used for depression treatment [1]. ...
... Regarding this structure-activity relationship similarities between Linezolid and toloxatone, this antibiotic has non-selective MAO-A inhibition properties [2]. Some drugs including SNRIs, TCAs, SSRIs, stimulants and opioid analgesics such as tramadol, meperidine, methadone and dextromethorphan increase serotonin levels and interact with linezolid [3,4].The use of linezolid with this drugs increase concentrations of serotonin in the central nervous system and result in serotonin syndrome [1]. ...
Preprint
We present a case of serotonin syndrome due to administration of linezolid in a patient with Methadone addiction. This challenging entity is potentially life threatening but proper education and awareness about serotonin syndrome will improve the accuracy of diagnosis and prevent significant morbidity and mortality.
... Linezolid is an oxazolidinone antibiotic against methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and drug resistant Streptococcus pneumoniae (DRSP) infections. The structure of linezolid is similar to a selective reversible monoamine oxidase inhibitor (MAO-A) toloxatone that used for depression treatment [1]. ...
... Regarding this structure-activity relationship similarities between Linezolid and toloxatone, this antibiotic has non-selective MAO-A inhibition properties [2]. Some drugs including SNRIs, TCAs, SSRIs, stimulants and opioid analgesics such as tramadol, meperidine, methadone and dextromethorphan increase serotonin levels and interact with linezolid [3,4].The use of linezolid with this drugs increase concentrations of serotonin in the central nervous system and result in serotonin syndrome [1]. ...
Preprint
We present a case of serotonin syndrome due to administration of linezolid in a patient with methadone addiction. This challenging entity is potentially life threatening but proper education and awareness about serotonin syndrome will improve the accuracy of diagnosis and prevent significant morbidity and mortality.
... 97 The protracted use of linezolid (over 14 days) resulting in three manifestations; a-Remarkable thrombocytopenia, 98 therefore weekly complete blood counts is essential in cases treated with linezolid, 99 b-Mitochondrial dysfunction, which is incriminated in lactic acidosis and neuropathy, 100 c-Serotonin toxicity, as linezolid is a non-potent monoamine-oxidase (MAO) inhibitor. 101 The evaluation of the antimicrobial activity of Sidr honey against MRSA strains recovered from catfish in Egypt was investigated. The clinical findings revealed the ability of Sidr honey to inhibit or inactivate coa and spa virulence genes of the examined MRSA strains. ...
Article
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Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen and a historically emergent zoonotic pathogen with public health and veterinary importance. In humans, MRSA commonly causes severe infectious diseases, including food poisoning, pyogenic endocarditis, suppurative pneumonia, otitis media, osteomyelitis, and pyogenic infections of the skin, soft tissues. In the horse, MRSA could cause a localized purulent infection and botryomycosis; in cattle and ewe, localized pyogenic infection and severe acute mastitis with marked toxemia; in sheep, abscess disease resembles caseous lymphadenitis caused by anaerobic strains; in dogs and cats, pustular dermatitis and food poisoning; in pig, exudative epidermatitis "greasy pig disease; in birds, MRSA causes bumble-foot. The methicillin resistance could be determined by PCR-based detection of the mecA gene as well as resistance to cefoxitin. In Egypt, MRSA is one of the important occasions of subclinical and clinical bovine mastitis, and the prevalence of MRSA varies by geographical region. In this review, we are trying to illustrate variable data about the host susceptibility, diseases, epidemiology, virulence factors, antibiotic resistance, treatment, and control of MRSA infection.
... 97 The protracted use of linezolid (over 14 days) resulting in three manifestations; a-Remarkable thrombocytopenia, 98 therefore weekly complete blood counts is essential in cases treated with linezolid, 99 b-Mitochondrial dysfunction, which is incriminated in lactic acidosis and neuropathy, 100 c-Serotonin toxicity, as linezolid is a non-potent monoamine-oxidase (MAO) inhibitor. 101 The evaluation of the antimicrobial activity of Sidr honey against MRSA strains recovered from catfish in Egypt was investigated. The clinical findings revealed the ability of Sidr honey to inhibit or inactivate coa and spa virulence genes of the examined MRSA strains. ...
Article
Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen and a historically emergent zoonotic pathogen with public health and veterinary importance. In humans, MRSA commonly causes severe infectious diseases, including food poisoning, pyogenic endocarditis, suppurative pneumonia, otitis media, osteomyelitis, and pyogenic infections of the skin, soft tissues. In the horse, MRSA could cause a localized purulent infection and botryomycosis; in cattle and ewe, localized pyogenic infection and severe acute mastitis with marked toxemia; in sheep, abscess disease resembles caseous lymphadenitis caused by anaerobic strains; in dogs and cats, pustular dermatitis and food poisoning; in pig, exudative epidermatitis "greasy pig disease; in birds, MRSA causes bumble-foot. The methicillin resistance could be determined by PCR-based detection of the mecA gene as well as resistance to cefoxitin. In Egypt, MRSA is one of the important occasions of subclinical and clinical bovine mastitis, and the prevalence of MRSA varies by geographical region. In this review, we are trying to illustrate variable data about the host susceptibility, diseases, epidemiology, virulence factors, antibiotic resistance, treatment, and control of MRSA infection.
... [7] Nonetheless, linezolid can be associated with gastrointestinal intolerance, mitochondrial toxicity (resulting in lactic acidosis, myelosuppression, and peripheral neuropathy), and significant drug interactions including serotonin syndrome potentiated when used concurrently with other serotonergic agents. [8][9][10] While recent data demonstrate the effectiveness of regimens using linezolid, concerns remain regarding prolonged linezolid drug exposure and adverse effects. [11] To date, data on incidence of adverse effects secondary to medications used to treat MDR-TB collected in US surveillance systems have not been systematically analyzed. ...
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Background In 2019, the World Health Organization released guidelines reflecting major changes in multidrug-resistant tuberculosis (MDR-TB) management—prioritizing fluoroquinolones, bedaquiline, and linezolid (LZD) while de-emphasizing previously favored injectable agents. In some cases, linezolid use is associated with gastrointestinal intolerance, mitochondrial toxicity, and significant drug interactions. CDC’s Division of Tuberculosis Elimination supports a network of regional TB Centers of Excellence, which provide medical consultation to healthcare providers. Consultations are documented in a medical consultation database (MCD) enabling evaluation of management questions and recommendations. We describe the scope of clinical inquiries and responses specific to linezolid use for MDR-TB in the US. Research Question What are the major themes of provider and patient challenges regarding the use of linezolid for the treatment of MDR-TB in the US? Methods We queried MCD consults categorized as “MDR/XDR-TB” from 1/1/2013 to 12/31/2018. Only linezolid-specific consultations were included; incomplete and duplicate entries were excluded as were those citing linezolid historically or theoretically. Subgroup characteristics were assessed (e.g., Center, year, provider type). A descriptive coding scheme was developed through inductive thematic analysis. Results In 2013–2018 of the 1889 consults regarding MDR/XDR-TB, 934 MDR-TB consults referenced linezolid; 137 met inclusion criteria, representing between 4 and 10% of MDR-TB consults annually. Four main themes emerged: adverse effects (71.5%); concerns about linezolid use due to co-morbidities or concurrent medication use (15.3%); dosing adjustments (8.8%); and monitoring and maintenance logistics (4.4%). Interpretations Linezolid consults consistently exceeded 4% of all consults annually over the 6-year period, suggesting a need for access to expert opinion for providers using linezolid to manage MDR-TB. While only a snapshot of MDR-TB in the US, this evaluation summarizes major provider concerns regarding particular adverse effects, and highlights a need for evidence-based guidance regarding linezolid dosing and toxicity management.
... Linezolid is an oxazolidinone antibiotic with activity against multidrug-resistant Gram-positive organisms [1], showing lipophilic features, excellent tissue penetration including the central nervous system (CNS), and weak reversible non-selective monoamine oxidase (MAO) inhibitory effects at therapeutic serum concentrations (according to an inhibitory binding affinity constant (Ki) of 56 μM and 0.71 μM, respectively for MAO-A and MAO-B) [2,3]. MAO is involved in the metabolism of the monoamine neurotransmitters, and its inhibition may potentially lead to excess of serotonin (5-hydroxytriptamine (5-HT)) in the CNS and occurrence of serotonin syndrome (SS), a potential lifethreatening condition [4,5]. ...
... Several drugs may cause serotonin excess through different pathways [6], thus posing concerns when concomitant treatments with linezolid are needed. Although reports describing occurrence of SS due to drug-drug interactions (DDIs) with linezolid were reported [3,7,8], and the Food and Drug Administration (FDA) warned against co-administration of linezolid with serotonergic drugs recommending a 2-week washout period in patients already receiving these medications [9], treatment of lifethreatening infections may not be delayed, especially if secondline alternatives are not effective or available. However, it remains unclear whether all serotonergic agents carry similar risk of SS, and the infectious disease consultant faces a "dilemma," with relevant implications on rational drug use in specific clinical scenarios, as exemplified in Fig. 1. ...
Article
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Purpose: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). Discussion: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.
... Regarding the other contraindicated pDDIs, the combination of linezolid and amitriptyline may cause a serotoninergic additive effect. This interaction may result in hyperthermia, hyperreflexia, myoclonus, changes in mental state (Lawrence, 2006). The pDDI between sildenafil and sodium nitroprusside is contraindicated due to the risk of severe hypotension (Micromedex Healthcare Series, 2019). ...
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Children are exposed to drug-drug interactions (DDI) risks due to their organism's complexity and the need for several medicines prescriptions in pediatric intensive care units (PICU). This study aimed to assess the prevalence of potential DDIs in a Brazilian PICU. We carried out a cross-sectional study at a pediatric teaching hospital from Rio de Janeiro (Brazil) over one year. Potential DDIs (pDDIs) between prescribed medicines for hospitalized children in PICU (n 143) were analyzed according to severity using Micromedex ®. Sex, age group, number of drugs prescribed, vasoactive amines use (a proxy of clinical complexity), and the PICU length of stay were summarized using descriptive statistics. Association between the PICU length stay, and variables sex, age, clinical condition complexity, number of drugs prescribed, and severity of pDDI were examined by univariate and multiple linear regression. Seventy percent of patients aged three days to 14 years old were exposed at least one potential DDIs during PICU stay. Two hundred eighty-four different types of pDDIs were identified, occurring 1,123 times. Nervous system drugs were implicated in 55% of the interactions, and fentanyl (10%) was most involving in pDDIs. Most pDDIs were classified as higher severity (56.2%), with reasonable documentation (64.6%) and unspecified onset time (63.8%). Worse clinical condition, ten or more drugs prescribed, and most severe pDDIs were associated with a longer PICU length of stay. Multiple linear regression analysis showed an increase of 9.83 days (95% confidence interval: 3.61-16.05; p 0.002) in the PICU length of stay in children with major or contraindicated pDDIs. The results of this research may support the monitoring and prevention of pDDIs related to adverse events in children in intensive care and the design and conduction of new studies.