Description: Metronidazole is a synthetic antibacterial and antiprotozoal agent that belongs to the nitroimidazole class. It is effective therapy against protozoa such as Trichomonas vaginalis, amebiasis, and giardiasis. In addition, it is one of the most effective drugs available against anaerobic bacterial infections. Metronidazole is also useful in treating Crohn's disease, antibiotic-associated diarrhea, and rosacea. Metronidazole initially was approved by the FDA in 1963 and is available in oral, parenteral, and topical formulations. An extended-release oral preparation for once-daily dosing was released in December 1997.

Mechanism of Action: Metronidazole is amebicidal, bactericidal, and trichomonicidal. Unionized metronidazole is readily taken up by anaerobic organisms and cells. Its selectivity for anaerobic bacteria is a result of the ability of these organisms to reduce metronidazole to its active form intracellularly. The electron transport proteins necessary for this reaction are found only in anaerobic bacteria. Reduced metronidazole then disrupts DNA's helical structure, thereby inhibiting bacterial nucleic acid synthesis. This eventually results in bacterial cell death. Metronidazole is equally effective against dividing and nondividing cells.

Because of its mechanism of action, low molecular weight, and limited binding to serum proteins, metronidazole is a highly lethal antimicrobial. Resistance to metronidazole is almost nonexistent. Metronidazole's spectrum of activity includes protozoa and obligate anaerobes including: Bacteroides group (including B. fragilis), Fusobacterium, Veillonella, the Clostridium group (including C. difficile and C. perfringens), Eubacterium, Peptococcus, and Peptostreptococcus. It is effective against B. fragilis isolates that are resistant to clindamycin. It is not effective against the common aerobes but is active against the aerobe Gardnerella (Haemophilus) vaginalis. The protozoan coverage of metronidazole includes Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis

Pharmacokinetics: Metronidazole is administered orally, intravenously, intravaginally, and topically. Oral absorption of metronidazole is excellent. Bioavailability is at least 90%. Food decreases the rate, but not the extent, of absorption. Intravaginally administered metronidazole are absorbed systemically; but peak serum concentrations after intravaginal administration are < 2% of the levels achieved with 500 mg oral doses. Topically applied metronidazole products are only minimally absorbed; detectable serum levels are approximately 100 times lower than the peak concentrations of a single 250 mg oral dose. Both IV and oral metronidazole are widely distributed into most body tissues and fluids including bone, bile, saliva, pleural and peritoneal fluids, vaginal and seminal fluids, and the CSF. Protein binding of metronidazole is roughly 10%. Oral administration of 250 mg, 500 mg or 2 g doses in healthy, fasting adults results in peak concentrations of 4.6—6.5 µg/ml, 11.5—13 µg/ml, and 30—45 µg/ml, respectively, after 1—3 hours. Peak serum concentration after oral administration of the 750 mg extended-release preparation is roughly 19.4 µg/ml in the fed state and 12.5 µg/ml in the fasting state; AUC in the fed and fasting state is 211 µg-hr/ml and 198 µg-hr/ml, respectively. Intravenous administration of 7.5 mg/kg IV every 6 hours in healthy adults produces peak plasma concentrations of 26 µg/ml and troughs of 18 µg/ml at steady-state. CSF concentrations of metronidazole are approximately 43% of plasma concentrations. The drug crosses the placenta and enters breast milk.

A significant amount of metronidazole (30—60%) is metabolized in the liver by hydroxylation, oxidation, and glucuronide conjugation. The major metabolite is 2-hydroxymethyl metronidazole, which has some antibacterial and antiprotozoal activity. Within 24 hours, approximately 20% of metronidazole is excreted in urine and 3% in feces. After 5 days, the amount excreted in the urine increases to 77% and that excreted in feces to 14%. Both unchanged drug and metabolites are excreted in the urine and the feces. Geriatric patients may have a decreased urinary excretion of metronidazole. This medication is removed by hemodialysis, but not by peritoneal dialysis, and it can color the urine reddish-brown due to water-soluble pigments formed during metabolism. The mean elimination half-life of metronidazole is roughly 8 hours.