Metronidazole is well absorbed after oral administration, is widely distributed in tissues, and reaches serum levels of 4–6 mcg/mL after a 250-mg oral dose. It can also be given intravenously. The drug penetrates well into the cerebrospinal fluid and brain, reaching levels similar to those in serum. Metronidazole is metabolized in the liver and may accumulate in hepatic insufficiency.
Metronidazole is indicated for treatment of anaerobic or mixed intra-abdominal infections (in combination with other agents with activity against aerobic organisms), vaginitis (trichomonas infection, bacterial vaginosis), Clostridium difficile infection, and brain abscess. The typical dosage is 500 mg three times daily orally or intravenously (30 mg/kg/d). Vaginitis may respond to a single 2-g dose. A vaginal gel is available for topical use.
Adverse effects include nausea, diarrhea, stomatitis, and peripheral neuropathy with prolonged use. Metronidazole has a disulfiram-like effect, and patients should be instructed to avoid alcohol. Although teratogenic in some animals, metronidazole has not been associated with this effect in humans. Other properties of metronidazole are discussed in Chapter 52.
A structurally similar agent, tinidazole, is a once-daily drug approved for treatment of trichomonas infection, giardiasis, amebiasis, and bacterial vaginosis. It also is active against anaerobic bacteria, but is not approved in the USA for treatment of anaerobic infections.
Fidaxomicin is a narrow-spectrum, macrocyclic antibiotic that is active against Gram-positive aerobes and anaerobes but lacks activity against Gram-negative bacteria. Fidaxomicin inhibits bacterial protein synthesis by binding to the sigma subunit of RNA polymerase. When administered orally, systemic absorption is negligible but fecal concentrations are high. Fidaxomicin has been approved by the
U.S. Food and Drug Administration (FDA) for the treatment for C difficile infection in adults. It is as effective as oral vancomycin and may be associated with lower rates of relapsing disease. Fidaxomicin is administered orally as a 200 mg tablet twice daily for 10 days.
Rifaximin is a derivative of rifampin. It is active against Gram-positive and Gram-negative aerobes and anaerobes. Rifaximin inhibits bacterial protein synthesis by binding to the beta subunit of DNA-dependent RNA polymerase. When administered orally, systemic absorption is <0.5%, but fecal concentrations are high; following a three day course for travelers’ diarrhea, the fecal concentrations were 8000 mcg/g. Rifaximin was originally approved by the FDA for the treatment of travelers’ diarrhea, and it is now used in the management of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and, occasionally, as an adjunct in cases of recurrent or refractory C difficile infection in adults. Typical doses of rifaximin range from 200 mg to 550 mg administered orally twice to three times daily depending on the indication. Unlike other rifamycins, rifaximin is not thought to be associated with cytochrome-P450-mediated drug interactions due to its limited absorption.
Mupirocin (pseudomonic acid) is a natural substance produced by Pseudomonas fluorescens. It is rapidly inactivated after absorption, and systemic levels are undetectable. It is available as an ointment for topical application.