Nitroimidazoles

Nitroimidazoles are prodrugs composed of an imidazole ring with an attached nitro group. Nitroimidazoles are reduced within susceptible microorganisms, leading to free radical formation and disruption of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure integrity. Metronidazole 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: Overview. These drugs are often used for intraabdominal and gynecologic infections. A disulfiram-like effect can occur with concurrent alcohol use. Other side effects include dysgeusia, peripheral neuropathy, 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.

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Table of Contents

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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 is composed of an imidazole ring with a nitro group (NO2) attached.

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

Mechanism of action

  • Nitroimidazoles passively diffuse into the microbial cell.
  • Nitroreductases (produced by susceptible organisms) → reduce the nitro group on the molecule
  • Results in the production of:
    • Free radicals
    • Cytotoxic metabolites → interact with host DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure → strand breakage and destabilization of the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure helix
  • 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 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: Overview
    • 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 (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

  • Almost completely absorbed when given orally 
  • Bioavailability > 90%

Distribution

  • Distributed widely in tissues
  • Low protein binding (< 20%)
  • Crosses the blood–brain 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
  • 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: Overview:
    • Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori 
    • 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

  • Pseudomembranous colitis Pseudomembranous colitis Pseudomembranous colitis is a bacterial disease of the colon caused by Clostridium difficile. Pseudomembranous colitis is characterized by mucosal inflammation and is acquired due to antimicrobial use and the consequent disruption of the normal colonic microbiota. C. difficile infections account for the most commonly diagnosed hospital-acquired diarrheal illnesses. Pseudomembranous Colitis
  • Gynecologic infections (including bacterial vaginosis)
  • 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. Amebiasis
  • Nongonococcal urethritis
  • Intraabdominal infections
  • Intracranial abscess

Adverse Effects and Contraindications

Adverse effects

  • GI upset
  • Disulfiram-like reaction with alcohol (due to inhibition of aldehyde dehydrogenase)
  • Dysgeusia (metallic taste) 
  • Peripheral neuropathy 
  • Headache
  • Dizziness 
  • Seizures
  • Urine discoloration (red-brown color)

Contraindications

  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine 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
  • Disulfiram: can cause acute psychosis
  • ↓ Elimination of:
    • Lithium
    • Ergots
  • ↓ Liver metabolism of:
    • Phenytoin
    • Warfarin
    • Carbamazepine

Mechanism of Resistance

Metronidazole resistance is rare, but can occur by:

  • ↓ Rate of metronidazole reduction inside anaerobes
  • ↓ Uptake of the drug 
  • ↑ Efflux of drug from the cell
  • ↑ LDH activity
  • ↑ Activity of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. 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
  • Irreversibly bind penicillin-binding proteins
  • Inhibit cell wall synthesis
Bactericidal
  • Gram-positives
  • Aerobic gram-negatives
  • Anaerobes
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 The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis
  • Cause breakage of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
Bactericidal
  • Gram-positives
  • Aerobic gram-negatives
  • Anaerobes
  • Atypical organisms
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
  • Reversibly bind to the 50S subunit
  • Inhibit bacterial protein synthesis
Bacteriostatic
  • Gram-positives
  • Anaerobes
Nitroimidazoles
  • Produce free radicals
  • Cause breakage of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • Bactericidal
  • Antiprotozoal
  • 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: Overview
  • Protozoans
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. 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/
  6. Mazuski, J.E., et al. (2017). The Surgical Infection Society revised guidelines on the management of intra-abdominal infection. Surg Infect (Larchmt) 18:1–76. https://pubmed.ncbi.nlm.nih.gov/28085573/
  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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