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Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms. 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.
Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.
The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from sidechain oxidation [1-(β-hydroxyethyl) 2-hydroxymethyl5nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity.
Renal clearance of metronidazole is approximately 10 mL/min/1.73 m². The average elimination halflife of metronidazole in healthy subjects is eight hours.
Decreased renal function does not alter the singledose-pharmacokinetics of metronidazole.
Subjects with end-stage renal disease (ESRD; CLCR = 8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxyl-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CLCR = 126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).
Effect Of Dialysis
Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered (see DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.
Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC24 of hydroxylmetronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE AND ADMINISTRATION). No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Following a single 500 mg oral or IV dose of metronidazole, subjects > 70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxymetronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls < 40 years old. In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).
In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination halflife, measured during the first 3 days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination halflives ranged from 109 to 22.5 hours.
Mechanism Of Action
Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a shortlived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear.
A potential for development of resistance exists against metronidazole.
Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair.
Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.
Activity In Vitro And In Clinical Infections
Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Bacteroides fragilis group (B. fragilis, B.
distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus)
The following in vitro data are available, but their clinical significance is unknown:
Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC's) of 8 mcg/mL or less against most ( ≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and wellcontrolled clinical trials.
Bacteroides fragilis group (B. caccae, B.
Prevotella species (P. bivia, P. buccae, P. disiens)
When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial or communityacquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference broth and/or agar method1,2.
The MIC values should be interpreted according to the criteria provided in the following Table
Susceptibility Test Interpretive Criteria for
Metronidazole against Anaerobes*†
|≤ 8||Susceptible (S)|
|≥ 32||Resistant (R)|
|*Agar dilution method is recommended for all anaerobes
†Broth dilution method is recommended for testing of Bacteroides fragilis group only; for this group, MIC values by agar and broth dilution methods are considered equivalent
A report of “Susceptible” (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” (I) implies that an infection due to the isolate may be appropriately treated in the body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. A report of “Resistant” (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard metronidazole powder should provide a value within the MIC ranges noted in the following table:
Acceptable Quality Control Ranges for Metronidazole
|Quality control strain||Minimum Inhibitory Concentration (mcg/mL)|
|Bacteroides fragilis ATCC 25285||0.25-1.0||0.25-2.0|
|Bacteroides thetaiotaomicron ATCC 29741||0.5-2.0||0.5-4.0|
|Clostridium difficile ATCC 700057||0.125-0.5||-|
|Eggerthella lenta ATCC 43055||-||0.125-0.5|
For protozoal parasites
Standardized tests do not exist for use in clinical microbiology laboratories.
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard Eighth Edition. CLSI document M11A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twentyfifth Informational Supplement, CLSI document M100S25. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
Last reviewed on RxList: 8/30/2016
This monograph has been modified to include the generic and brand name in many instances.
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