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 integrity. Metronidazole and tinidazole are the most used of the class and are active against both protozoa and anaerobic bacteria. 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.

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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 → strand breakage and destabilization of the DNA helix
  • Cell death occurs
  • Effect:
    • Bactericidal against anaerobic bacteria
    • Antiprotozoal

Pharmacokinetics

The following describes the pharmacokinetics for metronidazole (the prototype drug of the class) and tinidazole.

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
  • Excreted mainly in the urine

Indications

Antimicrobial coverage

  • Anaerobic bacteria:
    • Helicobacter pylori 
    • Bacteroides
    • Clostridium (including C. difficile)
    • Gardnerella
  • Protozoa:
    • Giardia
    • Entamoeba
    • Trichomonas

Types of infections

  • Pseudomembranous colitis
  • Gynecologic infections (including bacterial vaginosis)
  • 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 (1st trimester)
  • 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 repair 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 classMechanism of actionEffectCoverage
Carbapenems
  • Irreversibly bind penicillin-binding proteins
  • Inhibit cell wall synthesis
Bactericidal
  • Gram-positives
  • Aerobic gram-negatives
  • Anaerobes
Fluoroquinolones
  • Inhibit DNA synthesis
  • Cause breakage of DNA
Bactericidal
  • Gram-positives
  • Aerobic gram-negatives
  • Anaerobes
  • Atypical organisms
Lincosamides
  • Reversibly bind to the 50S subunit
  • Inhibit bacterial protein synthesis
Bacteriostatic
  • Gram-positives
  • Anaerobes
Nitroimidazoles
  • Produce free radicals
  • Cause breakage of DNA
  • Bactericidal
  • Antiprotozoal
  • Anaerobic bacteria
  • 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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