Antibiotic Susceptibility and Resistance

Excerpt

The realization that peptic ulcer disease was caused by an infectious agent has led to the still ongoing search for the most appropriate therapy. Many therapies have been tried, with the conclusion that multiple drug combinations are at present essential to the achievement of acceptable outcomes; cure of infection in >80% of patients is based on intention to treat. One class of drugs, which has been a constant from the early work of Marshall and Warren, is the 5-nitroimidazoles, principally tinidazole and metronidazole (103), agents that had been used in the treatment of anaerobic bacterial and selected protozoan infections (133). Two other drugs were also used with success in the following years: a macrolide compound, clarithromycin, and a β-lactam compound, amoxicillin.

The MACH-1 (94) and MACH-2 (110) studies provided data that the combination of a proton pump inhibitor together with clarithromycin and metronidazole or clarithromycin and amoxicillin represented the most effective drug combinations for the treatment of Helicobacter pylori infection. Yet these combinations are subject to failure due to resistance (4). While the mechanisms of macrolide resistance in H. pylori are well understood, the same cannot be said for resistance to 5-nitroimidazoles. Indeed, the issue of resistance to the 5-nitroimidazoles is confused by apparent problems in relation to the accuracy and reproducibility of susceptibility testing, the definition of resistance, and the perceived clinical relevance of resistance.

The issues relating to drug selection and antibiotic resistance as well as the prospect of using genomics for drug discovery will be reviewed in this chapter.