Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials

Metronidazole, the prototype nitroimidazole antimicrobial, was originally i ntroduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericida l through toxic metabolites which cause DNA strand breakage. Resistance, bo th clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailabil ity >90% for tablets; absorption is unaffected by infection. Rectal and int ravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectivel y. Metronidazole is distributed widely and has low protein binding (<20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metr onidazole reaches 60 to 100% of plasma concentrations in most tissues studi ed, including the central nervous system, but does not reach high concentra tions in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimi nation half-life than the parent compound. The majority of metronidazole an d its metabolites are excreted in urine and faeces, with less than 12% excr eted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic re nal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and do sage alterations are unnecessary. Liver disease leads to a decreased cleara nce of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole Ig. The post-antib iotic effect of metronidazole extends beyond 3 hours after the concentratio n falls below the minimum inhibitory concentration (MIC). The concentration -dependent bactericidal activity, prolonged half-life and sustained activit y in plasma support the clinical evaluation of higher doses of metronidazol e given less frequently. Metronidazole-containing regimens for Helicobacter pylori in combination wi th proton pump inhibitors demonstrate higher success rates than antimicrobi al regimens alone. The pharmacokinetics of metronidazole in gastric fluid a ppear contradictory to these results, since omeprazole reduces peak drug co ncentration and area under the concentration-time curve for metronidazole a nd its hydroxy metabolite; however, concentrations remain above the MIC. Other members of this class include tinidazole, ornidazole and secnidazole. They are also well absorbed and distributed after oral administration. The ir only distinguishing features are prolonged half-lives compared with metr onidazole. The choice of nitroimidazole may be influenced by the longer adm inistration intervals possible with other members of this class; however, m etronidazole remains the predominant antimicrobial for anaerobic and protoz oal infections.