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 side-chain oxidation [1-(βhydroxyethyl)- 2-hydroxymethyl-5-nitroimidazole
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
Renal clearance of metronidazole is approximately 10
mL/min/1.73 m². The average elimination half-life of metronidazole in healthy
subjects is eight hours.
Decreased renal function does not alter the single-dose
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 hydroxy-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 hydroxyl-metronidazole 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 hydroxy-metronidazole (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 half-life,
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 half-lives 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
short-lived 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
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 well-controlled clinical trials.
Bacteroides fragilis group (B. caccae, B.
Prevotella species (P. bivia, P. buccae, P.
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 community-acquired
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*†
|*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
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.1,2 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
|Bacteroides thetaiotaomicron ATCC 29741
|Clostridium difficile ATCC 700057
|Eggerthella lenta ATCC 43055
For Protozoal Parasites
Standardized tests do not exist for use in clinical
1. Clinical and Laboratory Standards Institute (CLSI). Methods
for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved
Standard - Eighth Edition. CLSI document M11-A8. 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; Twenty-fifth Informational
Supplement, CLSI document M100-S25. CLSI, 950 West Valley Road, Suite 2500,
Wayne, Pennsylvania 19087, USA, 2015.