metronidazole (Flagyl, MetroGel)

Introduction

Tradename: Flagyl.

Indications

• bacterial infections caused by anaerobic bacteria (anaerobic infections)
  • intra-abdominal infections
    • antibiotic-associated pseudomembranous colitis
    • diverticulosis
    • bacterial peritonitis
    • abdominal abscess
    • hepatic abscess
    • fistulas & abscesses associated with Crohn's disease
  • urogenital infections
    • tubo-ovarian abscess
    • pelvic inflammatory disease
    • endometritis
  • brain abscess
  • endocarditis
  • lower respiratory tract infection
  • periodontitis
  • skin or soft tissue infections
    • diabetic foot infection
  • infectious arthritis
• protozoan infections
  • Trichomonas vaginalis
  • Giardia lamblia
  • Entamoeba histolytica
  • Balantidium coli
  • Dracunculus medinensis
• topical agent for treatment of rosacea
• intravaginal agent for treatment of bacterial vaginosis
• used in combination with other agents for treatment of Helicobacter pylori gastritis
• empiric treatment for fever of unknown origin
• prophylaxis for perioperative infection
  • gynecologic surgery -postoperative infection

Contraindications

• use in combination with beta lactam/beta-lactamase inhibitor combination (i.e. Zosyn, Unasyn, Augmentin)

Caution: avoid during pregnancy.

pregnancy category = b

safety in lactation = ?

Dosage

• Trichomonas:
  • 2 g PO single dose
  • 250 mg PO TID for 7 days
• Giardia: 250 mg PO TID for 5 days
• Clostridium difficile: 250-500 mg PO TID for 10 days
• Entamoeba histolytica: 750 mg PO TID for 10 days
• anaerobic infection:
  • 30 mg/kg/day PO/IV divided every 6-8 hours
  • max: 4 g/day

Tabs: 250 & 500 mg.

Topical agent (MetroGel, Metrocream) 0.75%: apply BID

Vaginal: applicator BID or QHS

Topical: 0.75% (gel: 30 g, ointment: 45 g)

Vaginal: 0.75% (70 g) with 5 g applicator

Powder for injection: 500 mg/100 mL (as HCl)

Dosage adjustment in renal failure

Table

creatinine clearance	dosage
10-50 mL/min	100%
< 10 mL/min*	50%

* dose after hemodialysis

Pharmacokinetics

• well absorbed orally
• peak serum concentration in 1-2 hours
• well distributed in most fluids & tissues, including abscesses & bone
• good penetration into CSF
• crosses placenta & appears in breast milk
• protein binding < 20%
• metabolized by the liver (30-60%)
• 20% eliminated unchanged in the urine
• 1/2life is 7-9 hours, increased with liver failure (7-21 hours ESRD)
• dose must be reduced in severe liver disease

elimination via liver

elimination via kidney

protein binding = <20 %

1/2life = 7-9 hours

elimination by hemodialysis = +

elimination by peritoneal dialysis = +

Antimicrobial activity

Anaerobes

• Bacteroides fragilis
• Bacteroides melaninogenicus
• Clostridium difficile
• Clostridium species
• Peptostreptococcus species

Adverse effects

• common (> 10%)
  • nausea/vomiting, dizziness, headache, diarrhea, loss of appetite
• less common (1-10%)
  • peripheral neuropathy, seizures
• uncommon (< 1%)
  • ataxia, hypersensitivity, leukopenia, pancreatitis, thrombophlebitis, vaginal candidiasis, taste disturbance, dry mouth, furry tongue, dark urine
• other
  • metallic taste with rapid IV infusion
  • mental status changes (rare)
  • colitis (rare)
  • 2-fold increased risk of miscarriage

Drug interactions

• inhibits cyt P450 2C9 & 3A4
  • may increase levels of drugs metabolized by cyt P450 2C9 & 3A4 (including warfarin)
• agents that increase metabolism of metronidazole
  • phenobarbital
  • hydantoin
• severe disulfiram-like reaction with alcohol
• cimetidine decreases metabolism of metronidazole
• metronidizole may diminish clearance of phenytoin, quinidine, cisapride & lithium

• drug interaction(s) of antibiotics with warfarin

Mechanism of action

• reduced by microbial nitro-reductase to form reactive intermediate that disrupts bacterial DNA & RNA synthesis

More general terms

• nitroimidazole
• antiprotozoal agent

Additional terms

• cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10)

Component of

• brilliant green/cellulose/metronidazole
• bismuth subcitrate/metronidazole/tetracycline
• bismuth subsalicylate/metronidazole/tetracycline
• metronidazole/tetracycline
• Helidac kit (triple therapy)
• metronidazole/subsalicylate/tetracycline (Pylera)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4173
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=68592