Metronidazole

Class: Nitroimidazole.
Mol weight: 171
First used in 1960.

Mechanism of action:

Metronidazole enters the susceptible (bacterial/parasite) cells by passive diffusion. It gets activated to a nitroso compound which causes oxidative damage to the DNA. It also inhibits DNA repair.

The conversion of metronidazole to nitroso compound creates a concentration gradient, and more metronidazole enters the cells.

The aerobic bacteria lack the necessary mechanism (lack sufficient redox potential) to activate this process and are resistant.

Mechanism of resistance:

Metronidazole resistance is mostly studied in Bacteroides and H pylori. 

In Bacteroides and some other anaerobes –

• 5-nitroimidazole reductases, which reduce metronidazole to amine derivative instead of toxic nitroso compound. The nim gene encodes this enzyme. The nim has 9 variants and can exist on the chromosome, plasmid or transposon; the nim gene needs an upstream insertion sequence to exert its effect.
• Upregulation of multidrug efflux pump.
• Increase in lactate dehydrogenase activity to compensate for the decrease in pyruvate/ferredoxin oxidoreductase (PFOR) activity.
• Upregulated rhamnose catabolism preventing metronidazole activation.
• Overexpression of the DNA repair protein recA.
• Decrease in nitroreductase activity.
• Adaptations to oxidative stress.

In H pylori –

• Mutations in the rdxA and frxA nitroreductase genes.
• Overexpression of recA (protein essential for the repair and maintenance of DNA).
• Overexpression of the hefA and TolC bacterial efflux pump.
• Mutations within the ferric uptake regulator (fur) gene, which is responsible for responding to reactive oxygen species and iron uptake [Lynch 2013].
• Mutation in rpsU gene involved in protein synthesis.

Spectrum

Metronidazole susceptible:	Bacteroides, Prevotella, Porphyromonas, Fusobacterium H pylori Clostridium spp, Clostridioides difficile Giardia, Entamoeba, Dientamoeba Trichomonas
Variable susceptibility:	Veilonella, Suterella, Aggregatibacter actinomycetemcomitans, Campylobacter coli, Campylobacter fetus,
Resistant:	Mobilincus, Eikenella corrodens, Captocytophaga Actinomyces, Bifidobacterium, Lactobacillus, and Cutibacterium acne. Aerobic bacteria.

Adverse effects:

• Gastrointestinal adverse effects including metallic taste and rarely hepatitis/pancreatitis.
• Hypersensitivity/allergy.
• Neurologic, esp long term use:  peripheral neuropathy,  ataxia, encephalopathy, tremors, seizures etc.
• Others -reversible leukopenia, thrombocytopenia

Caution should be exercised when prescribing to a patient with severe hepatic disease, blood dyscrasia and CNS disease (seizure).
Concomitant alcohol use may cause a disulfiram reaction.

Indication:

Treatment of Anaerobic Infections

• Intra-abdominal Infections, including peritonitis, intra-abdominal abscess and liver abscess,
• Skin and Skin Structure Infections,
• Gynecologic Infections, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection,
• Bacterial Septicemia
• Bone and Joint Infections, as adjunctive therapy,
• Central Nervous System (CNS) Infections, including meningitis and brain abscesses, 
• Lower Respiratory Tract Infections, including pneumonia, empyema, and lung abscess, 
• Endocarditis caused by Bacteroides

Surgical Prophylaxis

C difficile-associated diarrhoea

[Ref:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018890s052lbl.pdf]

PK/PD:

• Lipophilic. Low protein binding. Moderate/ large volume of distribution.
• Concentration-dependent killing.
• Penetrates most tissue, including CSF (higher concentration is achieved if the meninges is inflamed). Good penetration in the abscess.
  The concentration in stool is higher in patients with diarrhoea and decreases as the diarrhoea settles.
  The concentration in bile in obstructive cholecystitis is low.
• T1/2 = 8 hours
• Oral bioavailability – almost 100%
• It should be taken with food – food does not alter bioavailability.
• Metabolism: Liver – some metabolites have antimicrobial activity. It enters enterohepatic circulation.
  Half-life is increased in liver impairment, and dose adjustment is necessary.
• Excretion: Urine (60 to 80% of the dose); faecal excretion accounting for 6 to 15% of the dose [FDA]

Pregnancy:

• Pregnancy Category B, Crosses placenta, secreted in breast milk.
• Teratogenic in the first trimester.
• Breastfeeding – The manufacturer advises avoiding large single doses of metronidazole though otherwise compatible