CLINICAL PHARMACOLOGY
Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of eight hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60 - 80% of the dose), with fecal excretion accounting for 6-15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73m2.
Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity against most strains of anaerobic bacteria and in vitro trichomonacidal activity.
Metronidazole appears in cerebrospinal fluid, saliva, and human milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.
Following oral administration metronidazole is well absorbed, with peak plasma concentrations occurring between one and two hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower.
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.
Microbiology
Trichomonas vaginalis, Entamoeba histolytica. Metronidazole possesses direct trichomonacidal and amebacidal activity against T. vaginalis and E. histolytica. The in vitro minimal inhibitory concentration (MIC) for most strains of these organisms is 1 mcg/mL or less.
Anaerobic Bacteria
Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to have in vitro and clinical activity against the following organisms:
Anaerobic gram-negative bacilli, including:
Bacteroides species including the Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium species
Anaerobic gram-positive bacilli, including:
Clostridium species and susceptible strains of Eubacterium
Anaerobic gram-positive cocci, including:
Peptococcus niger
Peptostreptococcus species
Susceptibility Tests
Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to metronidazole; however, the rapid, routine susceptibility testing of individual isolates of anaerobic bacteria is not always practical, and therapy may be started while awaiting these results.
Quantitative methods give the most precise estimates of susceptibility to antibacterial drugs. A standardized agar dilution method and a broth microdilution method are recommended.1
Control strains are recommended for standardized susceptibility testing. Each time the test is performed, one or more of the following strains should be included: Clostridium perfringens ATCC 13124, Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC 29741. The mode metronidazole MlC’s for these three strains are reported to be 0.25, 0.25, and 0.5 mcg/mL, respectively.
A clinical laboratory is considered under acceptable control if the results of the control strains are within one doubling dilution of the mode MlC’s reported for metronidazole.
A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more than 16 mcg/mL. An organism is considered resistant if the MIC is greater than 16 mcg/mL. A report of “resistant” from the laboratory indicates that the infecting organism is not likely to respond to therapy.
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