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Nitroimidazoles

Nitroimidazoles are prodrugs composed of an imidazole ring with an attached nitro group. Nitroimidazoles are utilized primarily as antibiotics and are reduced within susceptible microorganisms, leading to free radical formation and disruption of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure integrity. Metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess and tinidazole are the most used of the class and are active against both protozoa and anaerobic 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. These drugs are often used for intra-abdominal and gynecologic 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. A disulfiram-like effect ( nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and flushing) can occur with concurrent alcohol use. Other side effects include dysgeusia, peripheral neuropathy Neuropathy Leprosy, urine discoloration, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.

Last updated: Aug 18, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Chemical structure

Nitroimidazoles are composed of an imidazole ring and an attached nitro group.

Chemical structure of metronidazole

Chemical structure of metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess:
Metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess is composed of an imidazole ring with a nitro group (NO2) attached.

Image: “Metronidazol” by NEUROtiker. License: Public Domain

Mechanism of action

Note: This animation does not have sound.
  • Nitroimidazoles passively diffuse into the microbial cell.
  • Nitroreductases (produced by susceptible organisms) → reduce the nitro group on the molecule and thus activating it
  • Results in the production of:
    • Free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage
    • Cytotoxic Cytotoxic Parvovirus B19 metabolites → interact with 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‘s DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure → strand breakage and destabilization
  • Cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death occurs.
  • Effect:
    • Bactericidal Bactericidal Penicillins against anaerobic 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
    • Antiprotozoal

Pharmacokinetics

The following describes the pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics for metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess (the prototype drug of the class) and tinidazole.

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

Distribution

  • Distributed widely in tissues
  • Low protein binding (< 20%)
  • Crosses the blood– brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification barrier

Metabolism and excretion

  • Extensively metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
  • Excreted mainly in the urine

Indications

Antimicrobial coverage

  • Anaerobic 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:
    • Helicobacter pylori Helicobacter pylori A spiral bacterium active as a human gastric pathogen. It is a gram-negative, urease-positive, curved or slightly spiral organism initially isolated in 1982 from patients with lesions of gastritis or peptic ulcers in Western Australia. Helicobacter pylori was originally classified in the genus campylobacter, but RNA sequencing, cellular fatty acid profiles, growth patterns, and other taxonomic characteristics indicate that the micro-organism should be included in the genus Helicobacter. It has been officially transferred to Helicobacter gen. Helicobacter 
    • Bacteroides Bacteroides Bacteroides is a genus of opportunistic, anaerobic, gram-negative bacilli. Bacteroides fragilis is the most common species involved in human disease and is part of the normal flora of the large intestine. Bacteroides
    • Clostridium (including C. difficile)
    • Gardnerella
  • Protozoa:
    • Giardia
    • Entamoeba
    • Trichomonas

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

  • 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
  • Gynecologic 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 bacterial vaginosis Bacterial vaginosis Polymicrobial, nonspecific vaginitis associated with positive cultures of gardnerella vaginalis and other anaerobic organisms and a decrease in lactobacilli. It remains unclear whether the initial pathogenic event is caused by the growth of anaerobes or a primary decrease in lactobacilli. Vulvovaginitis)
  • Amebiasis Amebiasis Amebiasis, or amoebic dysentery, is an infection caused by the parasite Entamoeba histolytica. Transmission is through the fecal-oral route or by consumption of contaminated food and water. Most patients infected with E. histolytica are asymptomatic, but about 10% may develop dysentery. Entamoeba spp./Amebiasis
  • Nongonococcal urethritis Urethritis Inflammation involving the urethra. Similar to cystitis, clinical symptoms range from vague discomfort to painful urination (dysuria), urethral discharge, or both. Urinary tract infections (UTIs)
  • Intra-abdominal 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
  • Intracranial abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease

Adverse Effects and Contraindications

Adverse effects

  • GI upset
  • Disulfiram-like reaction with alcohol (due to inhibition of aldehyde dehydrogenase)
  • Dysgeusia (metallic taste) 
  • Peripheral neuropathy Neuropathy Leprosy 
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome) 
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Urine discoloration (red-brown color)

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (1st trimester)
  • Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding 
  • Severe hepatic impairment

Drug interactions

  • Ethanol-containing elixirs:
    • Cough syrups
    • IV trimethroprim– sulfamethoxazole Sulfamethoxazole A bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. Its broad spectrum of activity has been limited by the development of resistance. Sulfonamides and Trimethoprim
  • Disulfiram: can cause acute psychosis
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of:
    • Lithium Lithium An element in the alkali metals family. It has the atomic symbol li, atomic number 3, and atomic weight [6. 938; 6. 997]. Salts of lithium are used in treating bipolar disorder. Ebstein’s Anomaly
    • Ergots
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy metabolism of:
    • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs
    • 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
    • Carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs

Mechanism of Resistance

Metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess 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 is rare, but can occur by:

  • ↓ Rate of metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess reduction inside anaerobes Anaerobes Lincosamides
  • ↓ Uptake of the drug 
  • ↑ Efflux of drug from the cell
  • LDH LDH Osteosarcoma activity
  • ↑ Activity of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair 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
  • ↑ Oxygen-scavenging capabilities 

Comparison of Antibiotics

The following table compares several classes of antibiotics with anaerobic coverage:

Table: Comparison of several classes of antibiotics with anaerobic coverage
Drug class Mechanism of action Effect Coverage
Carbapenems Carbapenems A group of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. Thienamycins are a subgroup of carbapenems which have a sulfur atom as the first constituent of the side chain. Carbapenems and Aztreonam
  • Irreversibly bind BIND Hyperbilirubinemia of the Newborn penicillin-binding proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
  • Inhibit cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic synthesis Synthesis Polymerase Chain Reaction (PCR)
Bactericidal Bactericidal Penicillins
Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones
  • Inhibit DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Cause breakage of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
Bactericidal Bactericidal Penicillins
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 Bacteriostatic Bacteriostatic Sulfonamides and Trimethoprim
Nitroimidazoles
  • Produce free radicals Free radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Ischemic Cell Damage
  • Cause breakage of DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
Antibiotic sensitivity chart

Antibiotic sensitivity:
Chart comparing the microbial coverage of different antibiotics for gram-positive Gram-Positive Penicillins cocci Cocci Bacteriology, gram-negative bacilli Bacilli Shigella, and anaerobes Anaerobes Lincosamides.

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

References

  1. Löfmark, S., Edlund, C., Nord, C.E. (2010). Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis 50(Suppl 1):S16–S23. https://pubmed.ncbi.nlm.nih.gov/20067388/
  2. Gardner, T.B., Hill, D.R. (2001). Treatment of giardiasis. Clinical Microbiology Reviews 14:114–128. https://pubmed.ncbi.nlm.nih.gov/11148005/
  3. Gonzales, M.L.M., Dans, L.F., Sio-Aguilar, J. (2019). Antiamoebic drugs for treating amoebic colitis. Cochrane Database Syst Rev 1(1):CD006085. https://pubmed.ncbi.nlm.nih.gov/30624763/
  4. van Schalkwyk, J., Yudin, M.H. (2015). Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. J Obstet Gynaecol Can 37:266–274. https://pubmed.ncbi.nlm.nih.gov/26001874/
  5. No authors listed. (2015). Sexually transmitted diseases: summary of 2015 CDC treatment guidelines. J Miss State Med Assoc 56:372–375. https://pubmed.ncbi.nlm.nih.gov/26975162/
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  7. Stevens, D.L., et al. (2014). Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 59:147–159. https://pubmed.ncbi.nlm.nih.gov/24973422/
  8. Bratzler, D.W., et al., American Society of Health-System Pharmacists, Infectious Disease Society of America, Surgical Infection Society, Society for Healthcare Epidemiology of America. (2013). Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 70:195–283. https://pubmed.ncbi.nlm.nih.gov/23327981/
  9. Johnson, M. (2021). Metronidazole: An overview. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 25, 2021, from https://www.uptodate.com/contents/metronidazole-an-overview
  10. Weir, C.B., Le, J.K. (2021). Metronidazole. StatPearls. Retrieved July 25, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539728/
  11. Werth, B.J. (2020). Metronidazole and tinidazole. MSD Manual Professional Version. Retrieved July 25, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/metronidazole-and-tinidazole

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