CLINICAL PHARMACOLOGY
Absorption
Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms.
FLAGYL ER 750 mg tablets contain 750 mg of metronidazole in an extended release formulation which allows for once-daily dosing. The steady state pharmacokinetics were determined in 24 healthy adult female subjects with a mean ± SD age of 28.8 ± 8.8 years (range: 19–46).2 The pharmacokinetic parameters of metronidazole after administration of FLAGYL ER 750 mg under fed and fasting conditions are summarized in the following table.
Steady State Pharmacokinetic Parameters of Metronidazole after 750 mg of FLAGYL ER Given Once a Day for 7 Days
|
FLAGYL ER 750 mg daily Mean±SD (N=24) |
Parameter |
fed |
fasted |
AUC(0–24) (µg∙hr/mL) |
211±60.0 |
198±75.3 |
Cmax (µg/mL) |
19.4±4.7 |
12.5±4.8 |
Cmin (µg/mL) |
3.4±2.0 |
4.2±2.2 |
Tmax (hrs) |
4.6±2.4 |
6.8±2.8 |
T½ (hrs) |
7.4±1.6 |
8.7±2.2 |
Relative to the fasting state, the rate of metronidazole absorption from the extended release tablet is increased in the fed state resulting in alteration of the extended release characteristics.
Distribution
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.
Metabolism/Excretion
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-(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. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity.
Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2.1 The average elimination half-life of metronidazole in healthy subjects is eight hours.
Renal Impairment
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.
Subjects with end-stage renal disease (ESRD; CLCR=8.1±9.1mL/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.
Hepatic Impairment
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. FLAGYL ER tablets should not be administered to patients with severe (Child-Pugh C) hepatic impairment unless it is deemed that the benefits outweigh the risks in these patients. No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with hepatic impairment who receive the usual recommended dose of FLAGYL ER tablet should be monitored for metronidazole associated adverse events (see
PRECAUTIONS
and
DOSAGE AND ADMINISTRATION).
Geriatric Patients
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).
Pediatric Patients
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.
Microbiology
Mechanism of Action
Metronidazole exerts antibacterial effects in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intracellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of the bacteria.
Metronidazole is active against most obligate anaerobes, but does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.
Activity In Vitro and In Vivo
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.
Gram-positive anaerobes:
Clostridium species
Eubacterium species
Peptococcus species
Peptostreptococcus species
Gram-negative anaerobes:
Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus) Fusobacterium species
Porphyromonas species
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.
Gram-negative anaerobes
Bacteroides fragilis group (B. caccae, B. uniformis)
Prevotella species (P. bivia, P. buccae, P. disiens)
Susceptibility Test Methods
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 and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Anaerobic techniques
Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs) provide reproducible 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 dilution method3,4. The MIC values obtained should be interpreted according to the following criteria:
Susceptibility Test Interpretive Criteria for Metronidazole
MIC (mcg/mL) |
Interpretation |
≤ 8 |
Susceptible (S) |
16 |
Intermediate (I) |
≥ 32 |
Resistant (R) |
A report of "Susceptible" 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" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control
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
QC Strain |
Minimum Inhibitory Concentration (mcg/mL) |
|
Agar |
Broth |
Bacteroides fragilis ATCC 25285 |
0.25–1.0 |
0.25–2.0 |
Bacteroides thetaiotaomicron ATCC 29741 |
0.5–2.0 |
0.5–4.0 |
|