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Oxazolidinones

The oxazolidinones (linezolid and tedizolid) are bacterial protein synthesis Synthesis Polymerase Chain Reaction (PCR) inhibitors. The unique binding site on the 23S ribosomal RNA Ribosomal RNA The most abundant form of RNA. Together with proteins, it forms the ribosomes, playing a structural role and also a role in ribosomal binding of mRNA and tRNAs. Individual chains are conventionally designated by their sedimentation coefficients. In eukaryotes, four large chains exist, synthesized in the nucleolus and constituting about 50% of the ribosome. RNA Types and Structure of the 50S ribosome prevents bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology from developing cross-resistance when exposed to other antibiotics. These medications are readily absorbed and widely distributed in the body, and they are indicated for gram-positive Gram-Positive Penicillins infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, including MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus and vancomycin-resistant Enterococcus Enterococcus Enterococcus is a genus of oval-shaped gram-positive cocci that are arranged in pairs or short chains. Distinguishing factors include optochin resistance and the presence of pyrrolidonyl arylamidase (PYR) and Lancefield D antigen. Enterococcus is part of the normal flora of the human GI tract. Enterococcus. Adverse effects include GI upset, myelosuppression, peripheral or optic neuropathy Neuropathy Leprosy, and lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis. Linezolid is a weak monoamine oxidase Oxidase Neisseria inhibitor, which can increase the risk for serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS syndrome when coadministered with other serotonergic medications.

Last updated: Dec 22, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Chemical structure

  • Oxazolidinone medications contain the same 5-membered ring (2-oxazolidone) containing nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle (N) and oxygen (O).
  • Similar to a N- and O-containing azole (oxazole), with a carbon oxidized to a ketone

Mechanism of action

  • Inhibits bacterial protein synthesis Synthesis Polymerase Chain Reaction (PCR)
    • Binds to the bacterial 23S ribosomal RNA Ribosomal RNA The most abundant form of RNA. Together with proteins, it forms the ribosomes, playing a structural role and also a role in ribosomal binding of mRNA and tRNAs. Individual chains are conventionally designated by their sedimentation coefficients. In eukaryotes, four large chains exist, synthesized in the nucleolus and constituting about 50% of the ribosome. RNA Types and Structure ( rRNA rRNA The most abundant form of RNA. Together with proteins, it forms the ribosomes, playing a structural role and also a role in ribosomal binding of mRNA and tRNAs. Individual chains are conventionally designated by their sedimentation coefficients. In eukaryotes, four large chains exist, synthesized in the nucleolus and constituting about 50% of the ribosome. RNA Types and Structure) of the 50S subunit 
    • Blocks the formation of the 70S initiation complex → prevents translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation
  • Prevents:
    • Bacterial growth
    • Toxin production
  • Primarily bacteriostatic Bacteriostatic Sulfonamides and Trimethoprim (exception: bactericidal Bactericidal Penicillins against most streptococcal strains)
  • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • Can occur because of a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations at the binding site on 23S rRNA rRNA The most abundant form of RNA. Together with proteins, it forms the ribosomes, playing a structural role and also a role in ribosomal binding of mRNA and tRNAs. Individual chains are conventionally designated by their sedimentation coefficients. In eukaryotes, four large chains exist, synthesized in the nucleolus and constituting about 50% of the ribosome. RNA Types and Structure
    • No cross-resistance with other protein synthesis Synthesis Polymerase Chain Reaction (PCR) inhibitor antibiotics
Linezolid site of action oxazolidinones

Linezolid site of action on the 50S ribosomal subunit:
This construction inhibits the initiation of protein synthesis and prevents bacterial replication.

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption and distribution

  • Tedizolid is a prodrug Prodrug Nitroimidazoles → converted to active form by phosphatases
  • Protein binding:
    • Linezolid: poor
    • Tedizolid: highly bound
  • Readily distributes into well-perfused tissues
  • Volume of distribution for linezolid is similar to total body water Total body water Body Fluid Compartments (↑ for tedizolid).

Metabolism

  • Hepatic:
    • Linezolid: metabolized by nonenzymatic oxidation into 2 inactive metabolites
    • Tedizolid: sulfation into inactive sulfate conjugates
  • Neither induce nor inhibit cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes

Excretion

  • Linezolid: urine > feces
  • Tedizolid: feces > urine

Indications

Antimicrobial coverage

  • Oxazolidinones are used to treat infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease caused by gram-positive Gram-Positive Penicillins bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, including:
    • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus
    • Enterococcus Enterococcus Enterococcus is a genus of oval-shaped gram-positive cocci that are arranged in pairs or short chains. Distinguishing factors include optochin resistance and the presence of pyrrolidonyl arylamidase (PYR) and Lancefield D antigen. Enterococcus is part of the normal flora of the human GI tract. Enterococcus, including vancomycin-resistant Enterococcus Enterococcus Enterococcus is a genus of oval-shaped gram-positive cocci that are arranged in pairs or short chains. Distinguishing factors include optochin resistance and the presence of pyrrolidonyl arylamidase (PYR) and Lancefield D antigen. Enterococcus is part of the normal flora of the human GI tract. Enterococcus (VRE)
    • Coagulase-negative Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus
    • Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess, including MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus
    • Bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus 
    • Corynebacterium Corynebacterium Corynebacteria are gram-positive, club-shaped bacilli. Corynebacteria are commonly isolated on tellurite or Loeffler’s media and have characteristic metachromatic granules. The major pathogenic species is Corynebacterium diphtheriae, which causes a severe respiratory infection called diphtheria. Corynebacterium
    • Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes/Listeriosis
  • Activity has also been demonstrated in vitro against Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium species.

Types of infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

These medications are FDA-approved for:

  • Linezolid:
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and soft tissue Soft Tissue Soft Tissue Abscess infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • VRE infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Tedizolid: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and soft tissue Soft Tissue Soft Tissue Abscess infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Adverse Effects

Adverse effects

  • GI upset
  • Myelosuppression (all blood cell lineages)
  • Peripheral and optic neuropathy Neuropathy Leprosy
  • Lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Note: The more severe side effects occur more frequently with prolonged use.

Warnings

Linezolid may cause a hypertensive crisis in the following conditions:

  • Uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or “uncontrolled” hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. Uncontrolled Hypertension
  • Hyperthyroidism Hyperthyroidism Hypersecretion of thyroid hormones from the thyroid gland. Elevated levels of thyroid hormones increase basal metabolic rate. Thyrotoxicosis and Hyperthyroidism/ thyrotoxicosis Thyrotoxicosis A hypermetabolic syndrome caused by excess thyroid hormones which may come from endogenous or exogenous sources. The endogenous source of hormone may be thyroid hyperplasia; thyroid neoplasms; or hormone-producing extrathyroidal tissue. Thyrotoxicosis is characterized by nervousness; tachycardia; fatigue; weight loss; heat intolerance; and excessive sweating. Thyrotoxicosis and Hyperthyroidism
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma

Drug interactions

  • Serotonergic agents: linezolid can reversibly inhibit monoamine oxidase Oxidase Neisseria → ↑ risk of serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS syndrome
  • Warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants: ↑ PT
  • Sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs, vasopressor Vasopressor Acute Cholangitis, or dopaminergic medications: ↑ blood pressure

Comparison of Antibiotics

Table: Comparison of several classes of bacterial protein synthesis Synthesis Polymerase Chain Reaction (PCR) inhibitor antibiotics
Drug class Mechanism of action Coverage Adverse effects
Amphenicols
  • Gram positives
  • Gram negatives
  • Atypicals
  • GI upset
  • Optic neuritis Optic neuritis Inflammation of the optic nerve. Commonly associated conditions include autoimmune disorders such as multiple sclerosis, infections, and granulomatous diseases. Clinical features include retro-orbital pain that is aggravated by eye movement, loss of color vision, and contrast sensitivity that may progress to severe visual loss, an afferent pupillary defect (Marcus-Gunn pupil), and in some instances optic disc hyperemia and swelling. Inflammation may occur in the portion of the nerve within the globe (neuropapillitis or anterior optic neuritis) or the portion behind the globe (retrobulbar neuritis or posterior optic neuritis). Cranial Nerve Palsies
  • Aplastic anemia Aplastic Anemia Aplastic anemia (AA) is a rare, life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow (in the absence of any abnormal cells) reflecting damage to hematopoietic stem cells. Aplastic anemia can be acquired or inherited, however, most cases of AA are acquired and caused by autoimmune damage to hematopoietic stem cells. Aplastic Anemia
  • Gray baby syndrome Gray Baby Syndrome Chloramphenicol
Lincosamides Lincosamides The lincosamides, lincomycin and clindamycin, are inhibitors of bacterial protein synthesis. Drugs in this class share the same binding site as that of macrolides and amphenicols; however, they differ in chemical structure. Lincosamides target the 50S ribosomal subunit and interfere with transpeptidation. Lincosamides
  • Gram-positive Gram-Positive Penicillins cocci Cocci Bacteriology:
    • MSSA
    • MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus
    • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus
  • Anaerobes Anaerobes Lincosamides
  • GI upset
  • Allergic reactions Allergic Reactions Type I hypersensitivity reaction against plasma proteins in donor blood Transfusion Reactions
  • Pseudomembranous colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis
Macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides
  • Gram positives
  • Gram negatives
  • Atypicals
  • Mycobacterium avium Mycobacterium avium A bacterium causing tuberculosis in domestic fowl and other birds. In pigs, it may cause localized and sometimes disseminated disease. The organism occurs occasionally in sheep and cattle. It should be distinguished from the m. avium complex, which infects primarily humans. Mycobacterium complex
  • GI upset
  • QT prolongation
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis exacerbation
Oxazolidinones
  • Bind BIND Hyperbilirubinemia of the Newborn to the 23S rRNA rRNA The most abundant form of RNA. Together with proteins, it forms the ribosomes, playing a structural role and also a role in ribosomal binding of mRNA and tRNAs. Individual chains are conventionally designated by their sedimentation coefficients. In eukaryotes, four large chains exist, synthesized in the nucleolus and constituting about 50% of the ribosome. RNA Types and Structure of the 50S subunit
  • Prevent initiation complex formation
Gram-positive Gram-Positive Penicillins cocci Cocci Bacteriology:
  • MSSA
  • MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus
  • VRE
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus
  • Myelosuppression
  • Neuropathy Neuropathy Leprosy
  • Lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS syndrome
rRNA: ribosomal RNA
VRE: vancomycin-resistant Enterococcus
Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive cocci, gram-negative bacilli, and anaerobes.

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. Norrby R. (2001). Linezolid—a review of the first oxazolidinone. Expert Opin Pharmacother 2:293–302. https://pubmed.ncbi.nlm.nih.gov/11336587/
  2. Hamel JC, Stapert D, Moerman JK, Ford CW. (200). Linezolid, critical characteristics. Infection 28:60–64. https://pubmed.ncbi.nlm.nih.gov/10697798/
  3. Diekema DI, Jones RN. (200). Oxazolidinones: a review. Drugs 59:7–16. https://pubmed.ncbi.nlm.nih.gov/10718097/
  4. Deck DH, Winston LG. (2012). Tetracyclines, macrolides, clindamycin, chloramphenicol, streptogramins, & oxazolidinones. In Katzung BG, Masters SB, Trevor AJ (Eds.), Basic & Clinical Pharmacology, 12th ed., pp. 809–819. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  5. Drew RH, Peel T. (2020). Linezolid and tedizolid (oxazolidinones): An overview. In Baron, E.L. (Ed.), UpToDate. Retrieved June 28, 2021, from https://www.uptodate.com/contents/linezolid-and-tedizolid-oxazolidinones-an-overview
  6. Azzouz A, Preuss CV. (2021). Linezolid. StatPearls. Retrieved June 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539793/
  7. Werth BJ. (2020). Lincosamides, oxazolidinones, and streptogramins. MSD Manual Professional Version. Retrieved June 28, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/lincosamides,-oxazolidinones,-and-streptogramins
  8. Pandit N, Singla RK, Shrivastava B. (2012). Current updates on oxazolidinone and its significance. International Journal of Medicinal Chemistry. https://doi.org/10.1155/2012/159285

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