METRONIDAZOLE (Generic for FLAGYL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Regular-release tablets or capsules: Administer without regard to meals.
-Extended-release tablets: Swallow whole; do not crush, break, or chew. Administer on an empty stomach, at least 1 hour before or 2 hours after meals.

Oral Liquid Formulations
Oral Suspension
-Storage: Discard 10 days after opening the container.

Oral Powder for Suspension

Reconstitution

-Available as a compounding kit containing 1 bottle of metronidazole powder and 1 bottle of grape-flavored diluent.
-Reconstitution produces a 50 mg/mL metronidazole oral suspension.
-Tap the bottom edges of the bottle containing the metronidazole powder on a hard surface to loosen the powder.
-Remove the cap from the bottle containing the metronidazole powder. Tap the top of the induction seal to loosen any powder which may have adhered to the seal. Slowly peel back the foil seal.
-Shake the diluent bottle for a few seconds prior to removing the cap.
-Open the diluent bottle and pour about half of the diluent into the metronidazole powder bottle.
-Replace the cap and shake the mixture bottle vigorously for approximately 60 seconds.
-Empty the remaining diluent into the metronidazole powder bottle. Allow remaining diluent to drain into the powder bottle for 10 seconds.
-Replace the cap and shake the mixture bottle vigorously for approximately 60 seconds.
-Wait at least 1 hour before administering the first dose.
-Storage: Store reconstituted solution at room temperature (15 to 30 degrees C; 59 to 86 degrees F); Do not freeze. Keep container tightly closed and protect from light. Discard any unused solution after 30 days.

Administration
-Shake bottle well prior to each administration.
-Measure dosage with a calibrated spoon, cup, or oral syringe.

Extemporaneous Compounding-Oral
NOTE: Extemporaneously prepared suspensions are not FDA-approved.

Extemporaneous preparation of 50 mg/mL metronidazole oral suspension:
-Using a mortar and pestle, grind 24 x 250 mg metronidazole tablets to a fine powder.
-To make the base solution: In a separate container, mix 1 of the following combinations: 1) 60 mL of Ora-Sweet with 60 mL of Ora-Plus; or 2) 60 mL of Ora-Sweet SF with 60 mL of Ora-Plus; or 3) 120 mL cherry syrup (cherry syrup concentrate diluted 1:4 with simple syrup).
-Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution and mix well after each addition.
-Transfer to a graduated cylinder and add additional base solution to make a total of 120 mL. Mix well.
-Place in amber plastic bottles. Shake well before each use.
-Storage: This oral suspension is stable for at least 60 days when stored at room temperature or refrigerated.

Extemporaneous preparation of 10 mg/mL metronidazole oral suspension:
-Using a mortar and pestle, grind 5 x 250 mg metronidazole tablets to a fine powder.
-To make the base solution: In a separate container, mix 62.5 mL of Ora-Sweet with 62.5 mL of Ora-Plus and shake well.
-Add a small amount of the base solution to the fine powder and mix into a uniform paste. Add geometric amounts of the base solution and mix well after each addition.
-Transfer to a graduated cylinder and add additional base solution to make a total of 125 mL. Mix well.
-Place in amber plastic bottles. Shake well before each use.
-Storage: This oral suspension is stable for at least 90 days when stored at room temperature.



Injectable Administration
-Administer by slow IV infusion only, either as a continuous or intermittent infusion.
-Do not admix with other drugs. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Preparation of Intravenous Infusion
-Supplied as 5 mg/mL ready to use single-use infusion bags. No dilution required prior to administration.
-Do not refrigerate.

Intermittent Intravenous Infusion
-Remove from foil wrapping just prior to administration.
-Infuse by slow intermittent IV infusion over 30 to 60 minutes.
-Do not use in series connections; air embolism may occur.
-Do not use equipment containing aluminum (e.g., needles, cannulae) that would come in contact with the drug solution during administration as precipitates may form.



Topical Administration
-Topical products differ in pH from vaginal products; therefore, topical cream, gel, and lotion are for topical application to the skin only. Do not use topical products orally or vaginally.
-Avoid contact with the eyes.
-Prior to administration, cleanse area with a mild, nonirritating cleanser.
Cream/Ointment/Lotion Formulations
-Cream/Gel application: A thin layer should be rubbed into the affected areas. Cosmetics, sunscreens, and/or moisturizers may be used after applying cream, if needed.
-Lotion application: Apply a thin layer to entire affected areas. Cosmetics, sunscreens, and/or moisturizers may be applied after the lotion has dried and 5 minutes have passed.



Intravaginal Administration
-Vaginal and topical products differ in pH, therefore, vaginal gel is for vaginal use only; do not use vaginal products orally or topically.
-Instruct patient on proper use.
-Use special applicator supplied by the manufacturer.

Gastrointestinal adverse reactions to metronidazole therapy include nausea (10% systemic; 1.6% to 4% vaginal product), vomiting (less than 1% to 4% vaginal product), xerostomia (dry mouth) (2% systemic and vaginal products), dysgeusia (usually manifested as a metallic taste) (9% systemic; 2% vaginal product), anorexia (less than 1% vaginal product), epigastric distress, abdominal cramping, constipation (less than 1% vaginal product), diarrhea (4% systemic; 1% to 2% vaginal product), abdominal pain or discomfort (4% systemic; 5% vaginal product), gastrointestinal discomfort (7% vaginal product), decreased appetite (1% vaginal product), abdominal bloating/gas, thirst, asthenia, flatulence (less than 1% vaginal product), gingivitis (less than 1% vaginal product), and dyspepsia (less than 1% vaginal product). Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Central and peripheral neurotoxicity has occurred from metronidazole. Severe neurological disturbances that have been reported include encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis. Encephalopathy may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on MRI of the brain. Cerebellar toxicity may manifest as ataxia, dizziness (4% ER tab; less than 1% to 2% vaginal product), dysarthria, nystagmus, and saccadic pursuit (saccadic eye movement). It is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy, or seizures. CNS symptoms and CNS lesions are generally reversible, with symptoms resolving within days to weeks after discontinuation of metronidazole therapy. Peripheral neuropathy, usually symmetric and mainly of sensory type, is characterized by numbness and paresthesias of the extremities. Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolves after discontinuation of therapy. Advise patients to report neurologic symptoms; discontinue treatment if any abnormal neurologic symptoms occur. Other adverse reactions during metronidazole therapy include confusion, depression (less than 1% vaginal product), insomnia (less than 1% vaginal product), hypoesthesia, headache (18% ER tab; 2.2% topical product; 2.2% to 7% vaginal product), somnolence (drowsiness), syncope, vertigo, incoordination, irritability, weakness, and psychosis. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Blood and lymphatic system disorders that have been reported with the use of metronidazole include agranulocytosis, leukopenia, neutropenia, thrombocytopenia, and eosinophilia. Increased/decreased white blood cell counts have been reported in 1.7% of patients receiving the vaginal products. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Hypersensitivity and anaphylactoid reactions have been reported in patients receiving metronidazole. Hypersensitivity or skin adverse events include toxic epidermal necrolysis, swelling of the face (angioedema), pruritus (1.6% to 6% vaginal product; less 3% than topical product), urticaria (less than 1% vaginal product), hyperhidrosis, erythema, rash (1% vaginal product), Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), flushing, nasal congestion (1.1% topical product), fever, acne vulgaris (less than 1% vaginal product; 0.5% topical product), sweating/diaphoresis (less than 1% vaginal product), and dryness of the vagina or vulva. Localized effects that have been reported in association with the use of topical (dermal) formulations include contact dermatitis (1.3% to 3%), application site reaction (0.5%), aggravated condition (0.5% to less than 3%), ocular irritation, skin irritation (burning/stinging) (less than 3%), transient skin erythema (less than 3% to 6%), dry skin/xerosis (1.1%), and redness. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal metronidazole products.

Phlebitis can occur from IV infusion of metronidazole and can be prevented by avoiding prolonged use of indwelling IV catheters. Patients receiving parenteral metronidazole should be monitored for an injection site reaction.

Urinary side effects of metronidazole include chromaturia (urine discoloration), dysuria (less than 1% vaginal product), cystitis, polyuria, urinary incontinence, increased urinary frequency (less than 1% vaginal product), and a sense of pelvic pressure. Although the pigment that is responsible darkened urine has not been positively identified, it is likely a metabolite of metronidazole and seems to have no clinical significance. Abnormal urine was noted in 3% of patients receiving the ER tablet. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Pancreatitis has been reported with the use of metronidazole. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

As with any antibiotic, the use of metronidazole alters the normal flora and may result in superinfection. Metronidazole therapy may cause Candida overgrowth and candidiasis (3% ER tabs; 12% vaginal product) including oral candidiasis or vaginal candidiasis (0.2% topical product; 5.6% to 10% vaginal product). Other adverse effects include furry tongue, glossitis, and stomatitis which may be related to Candida overgrowth. Other types of infection have been reported in studies including unspecified bacterial infection (7% ER tab), influenza-like symptoms (6% ER tab; 1.4% topical product; less than 1% vaginal product), upper respiratory tract infection (4% ER tab; 2.5% topical product), urinary tract infection (2% ER tab; 1.1% topical product; less than 1% vaginal product), unspecified infection (1% vaginal product), pyelonephritis (less than 1% vaginal product), and salpingitis (less than 1% vaginal product). Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Metronidazole is mutagenic in vitro and carcinogenic in rodents. However, human data are not available to describe the potential for new cancer secondary to use. Crohn's disease patients are known to have an increased incidence of new primary malignancy, including GI and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole systemically at high doses for extended periods of time. A cause and effect relationship has not been established. Basal cell carcinoma was reported in 0.2% of patients using the topical gel product.

Genital and reproductive adverse events have been reported with the use of metronidazole and include dyspareunia, proctitis, and libido decrease. Vaginitis was reported in 15% of patients receiving the ER tablet and in less than 1% of patients using the vaginal gel. Dysmenorrhea occurred in 3% of patients using the ER tablet and 1.2% to 3% of patients using the vaginal gel. Genital pruritus/pruritus ani was reported in 5% of patients receiving the ER tablet. Other side effects reported with the vaginal gel include vaginal discharge (12%), vulva or vaginal irritation or dryness (9%), pelvic discomfort (3%), breast pain (1%), and metrorrhagia (1%). Adverse events occurring in less than 1% of patients using the vaginal gel include breast enlargement, female lactation, labial edema, leukorrhea, menorrhagia, and vulvovaginal disorder. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Dyspnea, rhinitis (4% ER tabs; less than 1% vaginal product), sinusitis (3% ER tabs; 1.4% topical product), pharyngitis (3% ER tabs; 3.1% topical product; 2% vaginal product), bronchitis (1.1% topical product), and asthma (less than 1% vaginal product) have been noted in metronidazole clinical studies. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Palpitations and sinus tachycardia have occurred with the use of metronidazole. Hypertension was reported in 1.1% of patients using the topical gel. Also, QT prolongation and ST-T wave changes (flattening of the T-wave) have been reported with metronidazole use.

Arthralgia, muscle spasms (muscle cramps), myalgia, and fleeting joint pain sometimes resembling serum sickness has been reported with metronidazole use. Back pain was reported in less than 1% of patients receiving the vaginal gel. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

General adverse events reported with metronidazole include malaise, face edema, peripheral edema, chest pain (unspecified), chills, and hiccups. Fatigue, unspecified cramping (1%), mucous membrane disorder (less than 1%), and unspecified pain (less than 1%) were reported with the use of metronidazole vaginal gel. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Severe, irreversible hepatotoxicity and acute hepatic failure have been reported in patients with Cockayne syndrome that have been treated with systemic metronidazole. Some of these cases have been fatal with rapid onset after therapy initiation; latency from drug start to signs of liver failure have been as short as 2 days. Elevated hepatic enzymes have also been reported with metronidazole. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.

Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. Systemic metronidazole should be used with care in patients with evidence of or history of hematological disease; monitor complete blood count (CBC) in these patients. Agranulocytosis, leukopenia, and neutropenia have been associated with systemic metronidazole administration.

Systemic metronidazole and its metabolites may accumulate significantly in patients with severe renal impairment or end stage renal disease (renal failure), including in patients receiving peritoneal dialysis, due to reduced urinary excretion. Monitor for metronidazole-associated adverse events.

QT prolongation has been reported with metronidazole use, particularly when administered with other drugs with the potential to prolong the QT interval. Use metronidazole with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Metronidazole, when given systemically, has been reported to be carcinogenic in mice and rats. Similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage. Human data are not available to describe the potential for a new primary malignancy secondary to use. The boxed warning states that systemic metronidazole use should be reserved for conditions where the drug is clearly needed; avoid unnecessary use. Vaginal and topical forms of metronidazole do not carry the boxed warning regarding carcinogenicity.

Oral, injectable, and intravaginal dosage forms should be used with caution in patients with alcoholism or ethanol intoxication. Metronidazole may interfere with the metabolism of ethanol, resulting in disulfiram-like effects. Adolescent patients of appropriate age should be counseled to avoid ethanol ingestion to avoid the risk of undesirable side effects. It is recommended that alcoholic beverages or medicines not be used concurrently with metronidazole or for at least 3 days following the discontinuation of the drug. Psychotic reactions have been reported in alcoholic patients on metronidazole and disulfiram therapy. Additionally, QT prolongation has been reported in a limited number of case reports with metronidazole; therefore, use it with caution in patients with other conditions that may increase the risk of QT prolongation, including alcoholism.

Metronidazole use may result in candidal overgrowth. Known or previously unrecognized candida fungal infection may present more prominent symptoms during therapy with metronidazole and requires treatment with an appropriate antifungal agent.

Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.

Topical metronidazole gels or creams contain ingredients that may cause burning and irritation of the eye. In the event of accidental ocular exposure, rinse the eye with copious amounts of cool tap water.

Reduce metronidazole dose in patients with severe hepatic disease or impairment (Child-Pugh C) or hepatic encephalopathy due to slowed metabolism and accumulation in plasma, which may cause exacerbations of CNS adverse events in patients with hepatic encephalopathy. Monitor patients with mild to moderate hepatic impairment for metronidazole-associated adverse effects.

Systemic metronidazole is contraindicated in patients with Cockayne syndrome. Cases of severe irreversible hepatotoxicity and acute hepatic failure, including fatal outcomes with very rapid onset after treatment initiation with systemic metronidazole, have been reported in these patients. The latency period from starting metronidazole to signs of liver failure was as short as 2 days.

Use parenteral metronidazole with caution in patients requiring sodium restriction or corticosteroid therapy or in patients predisposed to edema. Certain formulations of parenteral metronidazole contain sodium.

Systemic metronidazole therapy may cause laboratory test interference with certain laboratory measurements, such as AST, ALT, LDH, triglycerides, and hexokinase glucose; values of zero may be noted. All of the assays in which interference has been observed use enzymatic coupling of the assay to oxidation reduction of nicotinamide adenine dinucleotide. Interference is due to the similarity in the absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at a pH of 7. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values. Antimicrobials are also known to suppress H. pylori; thus, ingestion of these agents within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of metronidazole in the 4 weeks prior to the test.

Description: Metronidazole is a synthetic antibacterial and antiprotozoal agent that belongs to the nitroimidazole class. It is one of the most effective drugs available against anaerobic bacterial infections and is an effective therapy against protozoal infections such as trichomoniasis, amebiasis, and giardiasis. It is commonly used in children for intra-abdominal infections, including perforated appendicitis. Oral metronidazole is also used off-label as first-line therapy to treat Clostridioides difficile-associated disease (CDAD). Metronidazole can be used as a component of multiple regimens that have been shown to be effective for treatment of Helicobacter pylori (H. pylori) gastrointestinal infection. Combination therapy is necessary for successful eradication of H. pylori and to avoid the development of resistance, especially metronidazole resistance, which is prevalent in the US (approximately 25% to 37%) and many other countries. High eradication rates for H. pylori gastrointestinal infection have been documented with triple-drug regimens that include a proton pump inhibitor (PPI), clarithromycin, and metronidazole (or amoxicillin). Neurotoxicity, generally reversible, has been reported with metronidazole therapy. The immediate-release oral formulations are FDA-approved for use in pediatric patients as young as infants. Although not FDA-approved in children, the intravenous formulation is used off-label in pediatric patients as young as neonates. Vaginal products are FDA-approved for use in adolescent females; topical formulations are not FDA-approved for use in pediatric patients.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides sp., Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus, Clostridioides difficile, Clostridium perfringens, Clostridium sp., Entamoeba histolytica, Eubacterium sp., Fusobacterium sp., Mobiluncus sp., Parabacteroides distasonis, Peptococcus niger, Peptococcus sp., Peptostreptococcus sp., Porphyromonas asaccharolytica, Porphyromonas gingivalis, Porphyromonas sp., Prevotella bivia, Prevotella buccae, Prevotella disiens, Prevotella intermedia, Prevotella melaninogenica, Prevotella oralis, Prevotella sp., Trichomonas vaginalis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Balantidium coli, Blastocystis hominis, Campylobacter fetus, Dientamoeba fragilis, Dracunculus medinensis, Entamoeba polecki, Gardnerella vaginalis, Giardia lamblia, Helicobacter pylori, Mycoplasma hominis, Veillonella sp.
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of central nervous system infections*, including meningitis* and brain abscess*:
Oral dosage (immediate-release):
Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours.
Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours.
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours. Optimal treatment duration is not well-defined and will depend on causative pathogen and clinical course; treatment durations of 1 to 6 weeks for meningitis and 4 to 6 weeks for brain abscess have been reported in small studies and case reports.
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 8 hours.
Neonates older than 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 10 mg/kg/dose IV every 8 hours.
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours. Optimal treatment duration is not well-defined and will depend on causative pathogen and clinical course; treatment durations of 1 to 6 weeks for meningitis and 4 to 6 weeks for brain abscess have been reported in small studies and case reports.

For the treatment of intraabdominal infections*, including peritonitis*, appendicitis, intraabdominal abscess*, neonatal necrotizing enterocolitis*, peritoneal dialysis-related peritonitis*, and peritoneal dialysis catheter-related infection*:
-for the treatment of acute appendicitis* without perforation with adequate source control:
Intravenous dosage:
Infants, Children, and Adolescents weighing less than 80 kg: 30 mg/kg/dose (Max: 1 g/dose) IV as a single dose as part of combination therapy, typically in combination with ceftriaxone. Antibiotics should be discontinued within 24 hours.
Children and Adolescents weighing 80 kg or more: 30 mg/kg/dose (Max: 1.5 g/dose) IV as a single dose as part of combination therapy; generally in combination with ceftriaxone. Antibiotics should be discontinued within 24 hours.
-for the treatment of acute appendicitis* without perforation without definitive source control:
Intravenous dosage:
Infants, Children, and Adolescents weighing less than 80 kg: 30 mg/kg/dose (Max: 1 g/dose) IV every 24 hours for at least 48 hours, followed by oral step-down therapy for a total treatment duration of 5 to 10 days as part of combination therapy; generally in combination with ceftriaxone.
Children and Adolescents weighing 80 kg or more: 30 mg/kg/dose (Max: 1.5 g/dose) IV every 24 hours for at least 48 hours, followed by oral step-down therapy for a total treatment duration of 5 to 10 days as part of combination therapy; generally in combination with ceftriaxone.
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for a total treatment duration of 5 to 10 days as step-down therapy after initial parenteral therapy as part of combination therapy. Uncomplicated infections include traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
-for the treatment of appendicitis complicated by rupture with adequate source control:
Intravenous dosage:
Infants, Children, and Adolescents weighing less than 80 kg: 30 mg/kg/dose (Max: 1 g/dose) IV every 24 hours as part of combination therapy for 3 to 7 days, typically in combination with ceftriaxone.
Children and Adolescents weighing 80 kg or more: 30 mg/kg/dose (Max: 1.5 g/dose) IV every 24 hours as part of combination therapy for 3 to 7 days, typically in combination with ceftriaxone.
-for the treatment of complicated community-acquired, health care-acquired, or hospital-acquired intraabdominal infections* with adequate source control:
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose IV every 12 hours as part of combination therapy for 7 to 10 days. Metronidazole is an option for necrotizing enterocolitis.
Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose IV every 8 hours as part of combination therapy for 7 to 10 days. Metronidazole is an option for necrotizing enterocolitis.
Neonates older than 40 weeks postmenstrual age: 7.5 mg/kg/dose IV every 8 hours as part of combination therapy for 7 to 10 days. Metronidazole is an option for necrotizing enterocolitis.
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours as part of combination therapy for 3 to 7 days. Complicated infections include peritonitis complicated by rupture and intraabdominal abscess.
Oral dosage (immediate-release):
Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours as part of combination therapy for 7 to 10 days. Metronidazole is an option for necrotizing enterocolitis. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours as part of combination therapy for 7 to 10 days. Metronidazole is an option for necrotizing enterocolitis. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours as part of combination therapy for 7 to 10 days. Metronidazole is an option for necrotizing enterocolitis. Although oral dosing is not specified in the guidelines for neonates, oral absorption of metronidazole is nearly complete, and the same dose that is given IV is given orally.
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours as part of combination therapy for 3 to 7 days. Complicated infections include peritonitis complicated by rupture and intraabdominal abscess.
-for the treatment of uncomplicated intraabdominal infections* with adequate source control:
Intravenous dosage:
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours as part of combination therapy. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours as part of combination therapy. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
-for the treatment of uncomplicated intraabdominal infections* without definitive source control:
Intravenous dosage:
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided 8 hours for at least 48 hours, followed by oral step-down therapy for a total treatment duration of 5 to 10 days as part of combination therapy. Uncomplicated infections include traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for a total treatment duration of 5 to 10 days as step-down therapy after initial parenteral therapy as part of combination therapy. Uncomplicated infections include traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
-for the treatment of peritoneal dialysis-related peritonitis*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for 14 to 21 days.
-for the treatment of peritoneal dialysis catheter-related infection*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for at least 14 to 28 days.

For surgical infection prophylaxis*, including bowel preparation* in persons undergoing colorectal surgery:
-for general surgical infection prophylaxis*:
Intravenous dosage:
Premature Neonates weighing less than 1.2 kg: 7.5 mg/kg/dose IV as a single dose within 60 minutes prior to the surgical incision; no intraoperative redosing is necessary. The duration of prophylaxis should not exceed 24 hours.
Neonates weighing 1.2 kg or more: 15 mg/kg/dose IV as a single dose within 60 minutes prior to the surgical incision; no intraoperative redosing is necessary. The duration of prophylaxis should not exceed 24 hours.
Infants, Children, and Adolescents: 15 mg/kg/dose (Max: 500 mg/dose) IV as a single dose within 60 minutes prior to the surgical incision; no intraoperative redosing is necessary. May continue 15 mg/kg/dose (Max: 500 mg/dose) IV every 8 hours for no more than 24 hours post-operatively if necessary.
-for surgical infection prophylaxis for acute appendicitis:
Intravenous dosage:
Infants, Children, and Adolescents weighing less than 80 kg: 30 mg/kg/dose (Max: 1 g/dose) IV as a single dose within 60 minutes prior to the surgical incision; no intraoperative redosing is necessary. May continue 15 mg/kg/dose (Max: 500 mg/dose) IV every 8 hours for no more than 24 hours post-operatively if necessary.
Children and Adolescents weighing 80 kg or more: 30 mg/kg/dose (Max: 1.5 g/dose) IV as a single dose within 60 minutes prior to the surgical incision; no intraoperative redosing is necessary. May continue 15 mg/kg/dose (Max: 500 mg/dose) IV every 8 hours for no more than 24 hours post-operatively if necessary.
-for bowel preparation in persons undergoing colorectal surgery*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 15 mg/kg/dose (Max: 1 g/dose) PO in combination with neomycin for 3 doses given over 10 hours beginning the afternoon and evening prior to the surgery. Intravenous antimicrobial prophylaxis should also be given prior to the surgical incision.

For the treatment of pseudomembranous colitis* due to C. difficile infection*:
-for the treatment of non-severe initial episode of pseudomembranous colitis* due to C. difficile infection*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) PO every 6 to 8 hours for 10 days as first line therapy.
-for the treatment of fulminant initial episode of pseudomembranous colitis* due to C. difficile infection*:
Intravenous dosage:
Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) IV every 6 to 8 hours for 10 days plus vancomycin.
-for the treatment of non-severe first recurrence of pseudomembranous colitis* due to C. difficile infection*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) PO every 6 to 8 hours for 10 days as first-line therapy.

For Helicobacter pylori (H. pylori) eradication*:
-for Helicobacter pylori (H. pylori) eradication* as part of clarithromycin-based triple therapy:
Oral dosage (immediate-release):
Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents weighing 25 to 34 kg: 500 mg PO once daily in the morning and 250 mg PO once daily in the evening or 375 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 14 days.
-for Helicobacter pylori (H. pylori) eradication* as part of clarithromycin-based initial quadruple/concomitant therapy:
Oral dosage (immediate-release):
Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with clarithromycin, amoxicillin, and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents weighing 25 to 34 kg: 500 mg PO once daily in the morning and 250 mg PO once daily in the evening or 375 mg PO twice daily in combination with clarithromycin, amoxicillin, and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with clarithromycin, amoxicillin, and a proton pump inhibitor (PPI) for 14 days.
-for Helicobacter pylori (H. pylori) eradication* as part of clarithromycin-based sequential therapy after initial amoxicillin and proton pump inhibitor therapy:
Oral dosage (immediate-release):
Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 5 days after initial 5-day therapy with amoxicillin and a PPI.
Children and Adolescents weighing 25 to 34 kg: 500 mg PO once daily in the morning and 250 mg PO once daily in the evening or 375 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 5 days after initial 5-day therapy with amoxicillin and a PPI.
Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with clarithromycin and a proton pump inhibitor (PPI) for 5 days after initial 5-day therapy with amoxicillin and a PPI.
-for Helicobacter pylori (H. pylori) eradication* as part of metronidazole-based triple therapy:
Oral dosage (immediate-release):
Children weighing 15 to 24 kg: 250 mg PO twice daily in combination with amoxicillin and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents weighing 25 to 34 kg: 500 mg PO once daily in the morning and 250 mg PO once daily in the evening or 375 mg PO twice daily in combination with amoxicillin and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents weighing 35 kg or more: 500 mg PO twice daily in combination with amoxicillin and a proton pump inhibitor (PPI) for 14 days.
-for Helicobacter pylori (H. pylori) eradication* as part of bismuth-based quadruple therapy:
Oral dosage (immediate-release):
Children 1 to 8 years weighing 15 to 24 kg: 250 mg PO twice daily in combination with bismuth subsalicylate, amoxicillin, and a proton pump inhibitor (PPI) for 14 days.
Children 1 to 8 years weighing 25 to 34 kg: 500 mg PO once daily in the morning and 250 mg PO once daily in the evening or 375 mg PO twice daily in combination with bismuth subsalicylate, amoxicillin, and a proton pump inhibitor (PPI) for 14 days.
Children 1 to 8 years weighing 35 kg or more: 500 mg PO twice daily in combination with bismuth subsalicylate, amoxicillin, and a proton pump inhibitor (PPI) for 14 days.
Children 9 to 12 years weighing 15 to 24 kg: 250 mg PO twice daily in combination with bismuth subsalicylate, tetracycline, and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents 9 to 17 years weighing 25 to 34 kg: 500 mg PO once daily in the morning and 250 mg PO once daily in the evening or 375 mg PO twice daily in combination with bismuth subsalicylate, tetracycline, and a proton pump inhibitor (PPI) for 14 days.
Children and Adolescents 9 to 17 years weighing 35 kg or more: 500 mg PO twice daily in combination with bismuth subsalicylate, tetracycline, and a proton pump inhibitor (PPI) for 14 days.

For the treatment of acute intestinal amebiasis (amebic dysentery) and disseminated amebiasis, including hepatic abscess:
-for the treatment of mild to moderate intestinal amebiasis (amebic dysentery):
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 30 to 50 mg/kg/day PO divided every 8 hours (Max: 750 mg/dose) for 5 to 10 days followed by either iodoquinol or paromomycin.
-for the treatment of severe intestinal amebiasis (amebic dysentery) or disseminated amebiasis, including hepatic abscess:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 30 to 50 mg/kg/day PO divided every 8 hours (Max: 750 mg/dose) for 5 to 10 days followed by either iodoquinol or paromomycin.
Intravenous dosage*:
Infants, Children, and Adolescents: 30 to 50 mg/kg/day IV divided every 8 hours (Max: 750 mg/dose) for 5 to 10 days followed by either iodoquinol or paromomycin.

For the treatment of trichomoniasis*:
-for the initial treatment of trichomoniasis*:
Oral dosage (immediate-release):
Children weighing less than 45 kg: 45 mg/kg/day PO in 3 divided doses for 7 days.
Female Children weighing 45 kg or more and Adolescents: 500 mg PO twice daily for 7 days. Sexual partners should be referred and evaluated for appropriate treatment.
Male Children weighing 45 kg or more and Adolescents: 2 g PO as a single dose. Sexual partners should be referred and evaluated for appropriate treatment.
-for the treatment of recurrent or resistant trichomoniasis*:
Oral dosage (immediate-release):
Female Children weighing 45 kg or more and Adolescents: 500 mg PO twice daily for 7 days if treatment failure occurs with reexposure. If treatment failure occurs with no reexposure, treat with 2 g PO once daily for 7 days. Sexual partners should be referred and evaluated for appropriate treatment.
Male Children weighing 45 kg or more and Adolescents: 2 g PO as a single dose if treatment failure occurs with reexposure. If treatment failure occurs with no reexposure, treat with 500 mg PO twice daily for 7 days. Treatment with 2 g PO once daily for 7 days can be considered for resistant infections. Sexual partners should be referred and evaluated for appropriate treatment.

For the treatment of bacterial vaginosis:
Vaginal dosage (0.75% gel):
Adolescents (post-menarchal): 1 applicatorful (5 g of 0.75% metronidazole gel) intravaginally once daily for 5 days; administer at bedtime. In patients with multiple recurrences, metronidazole gel administered twice weekly for more than 3 months has been shown to reduce recurrences, but the benefit may not persist when therapy is stopped. Limited data suggest that an oral nitroimidazole followed by intravaginal boric acid with suppressive metronidazole gel for 4 to 6 months may be an option for recurrent bacterial vaginosis.
Vaginal dosage (1.3% gel):
Children and Adolescents 12 to 17 years: 1 applicatorful (5 g of 1.3% gel containing 65 mg of metronidazole) intravaginally as a single dose at bedtime as an alternative.
Oral dosage (immediate-release)*:
Infants and Children weighing less than 45 kg: 15 to 25 mg/kg/day PO in 3 divided doses for 7 days.
Children weighing 45 kg or more and Adolescents: 500 mg PO twice daily for 7 days. For patients with multiple recurrences, limited data suggest that an oral nitroimidazole, such as metronidazole 500 mg PO twice daily for 7 days, followed by intravaginal boric acid with suppressive metronidazole gel may be an option. Monthly oral metronidazole 2 g PO with fluconazole has been evaluated as suppressive therapy.

For the treatment of gynecologic infections*, including endometritis*, endomyometritis*, pelvic inflammatory disease (PID)*, and tubo-ovarian abscess*:
-for the treatment of unspecified gynecologic infections*, including endometritis* and endomyometritis*:
Oral dosage (immediate-release):
Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for 7 to 10 days.
Intravenous dosage:
Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours for 7 to 10 days.
-for the treatment of mild-to-moderate PID*:
Oral dosage (immediate-release):
Adolescents: 500 mg PO twice daily in combination with doxycycline for 14 days and either single dose ceftriaxone IM, cefoxitin IM plus probenecid, or other parenteral third generation cephalosporin. For patients with cephalosporin allergy, if the community prevalence and individual risk of gonorrhea are low, and if follow-up is assured, metronidazole in combination with a fluoroquinolone (levofloxacin, moxifloxacin) or azithromycin for 14 days may be considered. Patients who fail to respond within 72 hours should be reevaluated to confirm diagnosis and switched to IV therapy.
-for the treatment of severe PID* or tubo-ovarian abscess*:
Oral dosage (immediate-release):
Adolescents: 500 mg PO twice daily in combination with doxycycline as part of initial treatment with ceftriaxone and as stepdown from IV treatment for a total of 14 days of therapy.
Intravenous dosage:
Adolescents: 500 mg IV twice daily in combination with doxycycline and ceftriaxone. IV therapy should be continued for at least 24 to 48 hours after clinical improvement, and then stepdown to oral metronidazole and doxycycline for a total of 14 days of therapy.

For the treatment of giardiasis*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 5 mg/kg/dose (Max: 250 mg/dose) PO every 8 hours for 5 to 7 days.

For the treatment of Crohn's disease*:
Oral dosage (immediate-release):
Children and Adolescents: 15 to 20 mg/kg/day PO in 2 to 3 divided doses based on limited data in pediatric patients. In adult studies of patients with Crohn's disease, usual doses have ranged from 1,000 to 1,500 mg/day in 2 to 4 divided doses. Metronidazole, in combination with ciprofloxacin or azithromycin, has been shown to improve the clinical symptoms of Crohn's disease and may be effective in inducing remission in patients with active Crohn's disease.

For the treatment of dental infection* or dentoalveolar infection*, including periodontitis*:
Oral dosage (immediate-release):
Adolescents 16 to 17 years: 250 mg PO 3 or 4 times daily for 10 days or 500 mg PO three 3 daily for 8 days has been recommended. For severe periodontitis, 250 mg PO 3 times daily with amoxicillin for 7 to 10 days has been used.

For bacterial vaginosis prophylaxis* or trichomoniasis prophylaxis* in victims of sexual assault:
Oral dosage (immediate-release):
Adolescents: 500 mg PO twice daily for 7 days.

For the treatment of lower respiratory tract infections*, including pleural empyema*, pneumonia*, and lung abscess*:
-for the treatment of pneumonia* and lung abscess*:
Oral dosage (immediate-release):
Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours.
Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours.
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours.
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 8 hours.
Neonates older than 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 10 mg/kg/dose IV every 8 hours.
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours.
-for the treatment of pleural empyema*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours. Use in combination with a second- or third-generation cephalosporin for community-acquired empyema or with vancomycin and cefepime for hospital-acquired or postprocedural empyema. Treat for at least 2 weeks after drainage and defervescence.
Intravenous dosage:
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours. Use in combination with a second- or third-generation cephalosporin for community-acquired empyema or with vancomycin and cefepime for hospital-acquired or postprocedural empyema. Treat for at least 2 weeks after drainage and defervescence.

For the treatment of tetanus*:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for 7 to 10 days.
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 12 hours for 7 to 10 days.
Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 8 hours for 7 to 10 days.
Neonates older than 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 10 mg/kg/dose IV every 8 hours for 7 to 10 days.
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 2 g/day) IV divided every 6 to 8 hours for 7 to 10 days.

For the treatment of skin and skin structure infections*, including cellulitis*, erysipelas*, and necrotizing infections*:
-for the treatment of unspecified skin and skin structure infections:
Oral dosage (immediate-release):
Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours.
Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours.
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours.
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 8 hours.
Neonates older than 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 10 mg/kg/dose IV every 8 hours.
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours.
-for the treatment of cellulitis or erysipelas:
Oral dosage (immediate-release):
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours for 5 to 14 days.
Intravenous dosage:
Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) IV every 8 hours for 5 to 14 days.
-for the treatment of necrotizing infections of the skin, fascia, and muscle:
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 12 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus cefotaxime or aminoglycoside for mixed necrotizing infections.
Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg IV once, then 7.5 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus cefotaxime or aminoglycoside for mixed necrotizing infections.
Neonates older than 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 10 mg/kg/dose IV every 8 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus cefotaxime or aminoglycoside for mixed necrotizing infections.
Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) IV every 6 hours until further debridement is not necessary, the patient has improved clinically, and fever has been absent for 48 to 72 hours plus cefotaxime or aminoglycoside for mixed necrotizing infections.

For the treatment of bacteremia* and sepsis*:
Intravenous dosage:
Neonates 34 weeks postmenstrual age and younger: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 7.5 mg/kg/dose IV every 8 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from guideline scope.
Neonates older than 40 weeks postmenstrual age: 15 mg/kg/dose IV once, then 10 mg/kg/dose IV every 8 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from guideline scope.
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well-defined and dependent on patient- and infection-specific factors. Assess patient daily for deescalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.
Oral dosage (immediate-release):
Neonates 34 weeks postmenstrual age and younger: 7.5 mg/kg/dose PO every 12 hours.
Neonates 35 to 40 weeks postmenstrual age: 7.5 mg/kg/dose PO every 8 hours.
Neonates older than 40 weeks postmenstrual age: 10 mg/kg/dose PO every 8 hours.
Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO every 8 hours.

For bacterial infection prophylaxis* after penetrating trauma:
-for bacterial infection prophylaxis after penetrating brain trauma with gross contamination or penetrating spinal cord trauma with abdominal cavity involvement*:
Intravenous dosage:
Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours plus cefazolin for 5 days or until CSF leak is closed, whichever is longer.
-for bacterial infection prophylaxis after penetrating chest trauma with esophageal disruption or penetrating abdominal trauma*:
Intravenous dosage:
Infants, Children, and Adolecents: 22.5 to 40 mg/kg/day (Max: 2 g/day) IV divided every 6 to 8 hours plus cefazolin for 1 day after definitive washout.

For the treatment of small intestinal bacterial overgrowth*:
Oral dosage (immediate-release):
Children and Adolescents: 10 mg/kg/dose PO twice daily (Max: 750 mg/day) for 7 to 10 days.

Maximum Dosage Limits:
-Neonates
Post-menstrual age (PMA) 34 weeks and younger: Safety and efficacy have not been established; however, doses up to 15 mg/kg/day IV have been used off-label.
PMA 35 to 40 weeks: Safety and efficacy have not been established; however, doses up to 22.5 mg/kg/day IV have been used off-label.
PMA older than 40 weeks: Safety and efficacy have not been established; however, doses up to 30 mg/kg/day IV have been used off-label.
-Infants
50 mg/kg/day PO; safety and efficacy of IV use have not been established; however, doses up to 40 mg/kg/day IV have been used off-label.
-Children
50 mg/kg/day (Max: 2,250 mg/day) PO; safety and efficacy of IV use have not been established; however, doses up to 40 mg/kg/day (Max: 2,250 mg/day) IV have been used off-label.
-Adolescents
50 mg/kg/day (Max: 2,250 mg/day) PO; safety and efficacy of IV use have not been established; however, doses up to 40 mg/kg/day (Max: 2,250 mg/day) IV have been used off-label.

Patients with Hepatic Impairment Dosing
Reduce the dose of systemic metronidazole by 50% in patients with severe hepatic impairment (Child-Pugh C). Single systemic doses may not need to be adjusted.

Patients with Renal Impairment Dosing
CrCl 10 ml/minute/1.73 m2 or more: No dosage adjustment is necessary.
CrCl less than 10 ml/minute/1.73 m2: 16 mg/kg/day IV/PO (i.e., 4 mg/kg/dose IV/PO every 6 hours).

Intermittent hemodialysis
16 mg/kg/day IV/PO (i.e., 4 mg/kg/dose IV/PO every 6 hours). Systemically administered metronidazole is significantly removed (up to 65% of a dose) during a standard hemodialysis session.

Peritoneal dialysis
16 mg/kg/day IV/PO (i.e., 4 mg/kg/dose IV/PO every 6 hours).

Continuous Renal Replacement Therapy
No dosage adjustment is necessary.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Metronidazole is amebicidal, bactericidal, and trichomonicidal. Unionized metronidazole is readily taken up by passive diffusion and activated in the cytoplasm of susceptible 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. 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. The electron transport proteins necessary for this reaction are found only in anaerobic bacteria. Due to the alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug's intracellular transport. Reduced metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation. This eventually results in bacterial cell death. Metronidazole is equally effective against dividing and nondividing cells. The precise mechanism of action is unclear.

The susceptibility interpretive criteria for metronidazole are delineated by pathogen. The MICs are defined for anaerobes as susceptible at 8 mcg/mL or less, intermediate at 16 mcg/mL, and resistant at 32 mcg/mL or more.

The mechanism of resistance for metronidazole appears to be multifactorial and includes decreased drug uptake, higher efflux activity, and/or altered nitroreductase activity.

Pharmacokinetics: Metronidazole is administered orally, intravenously, intravaginally, and topically. Protein binding is less than 20%. Metronidazole is widely distributed into various body tissues and fluids including cerebrospinal fluid (CSF), pelvic tissue and peritoneal fluid, pancreas, colorectal tissue, bone, saliva, and gingival fluid. CSF concentrations of metronidazole are similar to plasma concentrations. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Metronidazole is extensively metabolized in the liver by hydroxylation, oxidation, and glucuronide conjugation. The major metabolite is 2-hydroxymethyl metronidazole, which has some antibacterial and antiprotozoal activity (30% to 65% of metronidazole). The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with approximately 20% appearing as unchanged metronidazole. Fecal excretion accounts for 6% to 15% of the dose. Metronidazole is cleared by the kidneys at a rate of 10 mL/minute/1.73 m2. The mean elimination half-life is approximately 8 hours.

Affected cytochrome P450 isoenzymes and drug transporter: none
Although previously reported as an inhibitor of CYP3A4 based on assumptions inferred from isolated case reports, controlled in vitro and in vivo studies show that metronidazole does not significantly inhibit CYP3A4/5 activity. Additionally, a study in humans examined S-warfarin and tolbutamide as probes for the CYP2C9 isoenzyme. Metronidazole interacted with S-warfarin, but not tolbutamide. This lessens the likelihood of a potential CYP2C9 interaction, which was originally postulated. It is unknown whether metronidazole alters transport proteins.


-Route-Specific Pharmacokinetics
Oral Route
Metronidazole is well absorbed after oral administration (bioavailability more than 90%).

Immediate-release tablets

Peak concentrations (Cmax) occur 1 to 2 hours after administration.

Extended-release tablets
Food increases the rate of absorption. The Cmax occurs approximately 4.6 and 6.8 hours after administration under fed and fasted conditions, respectively.

Oral suspension
Peak plasma concentrations occur 0.25 to 6 hours after administration. Food delays Tmax and lowers Cmax when compared to fasted conditions in adults, but systemic exposure (AUC) is similar in fed and fasted states.

Intravenous Route
After IV administration, the plasma concentrations are proportional to the administered dose. An 8-hour IV infusion of 100 to 4,000 mg of metronidazole showed a linear relationship between dose and peak plasma concentration.

Topical Route
Topically applied metronidazole products are only minimally absorbed. Peak concentrations of the lotion are approximately 80 times lower than the peak concentrations of a single 250 mg oral dose. The mean Cmax and AUC are less than 1% of the value reported for a single 250 mg oral dose.

Other Route(s)
Intravaginal Route
Intravaginally administered metronidazole is absorbed systemically; but peak serum concentrations (Cmax) and exposure (AUC) are 2% and 4%, respectively, of the concentrations achieved with 500 mg oral doses. The Cmax is achieved approximately 9.5 hours (range, 4 to 17 hours) after administration.


-Special Populations
Pediatrics
Neonates
The clearance of metronidazole is significantly longer in neonates compared with children and adults. Elimination half-life has been shown to be inversely related to gestational age. In a small study in neonates (n = 11; 28 to 40 weeks gestational age), mean elimination half-life values were 75.3, 35.4, and 24.8 hours for neonates 28 to 30 weeks, 32 to 35 weeks, and 36 to 40 weeks gestational age, respectively. Volume of distribution ranged from 0.54 to 0.81 L/kg. In another population pharmacokinetic study in preterm neonates (n = 32; 30 infants younger than 32 weeks gestational age), a mean elimination half-life of 29 hours was reported in neonates with a postmenstrual age (PMA) younger than 32 weeks (n = 20) and 15.7 hours for neonates with a PMA 32 weeks or older (n = 12). The predicted elimination half-life for neonates with a PMA of 25 weeks was 40 hours, decreasing to 19 hours at 32 weeks' PMA. Volume of distribution ranged from 0.5 to 0.99 L/kg.

Infants and Children
The elimination half-life of metronidazole in infants (older than 8 weeks) and children is similar to that seen in adults (7 to 9 hours). In a study in infants (n = 12), a mean elimination half-life of 18.4 hours was observed in infants younger than 8 weeks of age (n = 7) after a single IV dose of 20 mg/kg.

Hepatic Impairment
Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. After a single 500 mg IV dose, the mean AUC of metronidazole was 54%, 53%, and 114% higher in patients with mild (Child-Pugh A) impairment, moderate (Child-Pugh B) impairment, and severe (Child-Pugh C) hepatic impairment, respectively, compared to healthy controls. There was no significant change in the AUC of hydroxy-metronidazole (the active metabolite) in these hepatically impaired patients. Metronidazole half-life increases are dependent on the degree of hepatic insufficiency, with Child-Pugh scores predicting decreased elimination. In a study of 35 patients with cirrhosis, the half-life increased from 7.4 hours in healthy volunteers to 10.7 hours in patients with Child-Pugh class A, 13.5 hours in patients with Child-Pugh class B, and 21.5 hours in patients with Child-Pugh class C.

Renal Impairment
The half-life of metronidazole is not significantly altered in patients with mild to moderate renal impairment. In patients with severe renal impairment or end-stage renal disease (ESRD), metronidazole and its metabolites may accumulate significantly. Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Patients with ESRD (CrCl = 8.1 +/- 9.1 mL/minute) who received a single 500 mg IV dose had no significant change in metronidazole pharmacokinetics, but had a 2-fold higher Cmax of hydroxy-metronidazole (the active metabolite) and a 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CrCl = 126 +/- 16 mL/minute).

Metronidazole is dialyzable. Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. After a single 500 mg IV or PO dose, the clearance of metronidazole was studied in ESRD patients undergoing hemodialysis. 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.

Accumulation of metronidazole metabolites may occur with peritoneal dialysis. After a single 500 mg IV or PO dose, the clearance of metronidazole was studied in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose.

Gender Differences
Studies show no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma concentrations in males are generally lower.