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Sir, Clarithromycin is the most active macrolide against Helicobacter pylori, but pH reduction markedly decreases its activity. This is a cause of concern because H. pylori is found on the gastric mucosa, where the pH is low, c. 5.5. In addition, clarithromycin resistance is increasing in H. pylori, with prevalences attaining at least 10% in several countries. Telithromycin is a new ketolide antibiotic that has been found to be highly active against a variety of microorganisms. We determined its activity, at pH 7.4, 6.5 and 5.9, against 30 macrolide-susceptible and 15 -resistant clinical strains of H. pylori isolated from gastric biopsies in Henri-Mondor hospital between 1997 and 1999. H. pylori ATCC 43504 was used as a control strain. MICs of clarithromycin and telithromycin were determined by the agar dilution technique using Mueller–Hinton agar (Oxoid, Lyon, France) supplemented with 10% fresh horse blood. A Steers inoculating device was used to place 10–10 cfu per spot (2 L per spot) on to the plates (52 spots per plate), which were examined for growth after 72 h of incubation at 37 C under microaerophilic conditions. Strains were considered resistant to clarithromycin if the MIC was 1 mg/L. At pH 7.4, telithromycin was four-fold less active than clarithromycin against clarithromycin-susceptible strains, the MIC50 of telithromycin being 0.125 mg/L (Table). In agreement with previous findings, pH reduction caused a marked increase in the MICs of clarithromycin for clarithromycin-susceptible strains: at pH 6.5, the MIC50 and MIC90 increased twoand eight-fold, respectively; at pH 5.9, eightand 16-fold increases were observed (Table). The activity of telithromycin against clarithromycinsusceptible strains was similarly affected by pH reduction (Table). None the less, the MICs of telithromycin at pH 5.9 for most strains remained below the maximum achievable serum concentration of telithromycin: 2.27 mg/L after 800 mg od for 7 days. The A2142G and A2143G mutations in the 23S rRNA gene that are implicated in clarithromycin resistance of H. pylori were detected by restriction fragment length polymorphism analysis of PCR-amplified DNA, using MboII and BsaI restriction enzymes (New England Biolabs, Beverly, MA, USA), as described previously. All clarithromycin-resistant strains carried either a A2142G (five strains) or A2143G mutation (10 strains). H. pylori possesses two 23S rRNA genes and both were mutated in all strains. In agreement with previous findings, MICs of clarithromycin at pH 7.4 were significantly higher for A2142G mutants (64–128 mg/L) than for A2143G mutants (8–32 mg/L) (Table). Telithromycin was not spared by resistance but the two mutations, and especially the A2142G mutation, were associated with a lower increase in the MICs of telithromycin, MICs for A2142G and A2143G mutants being 8–32 and 4–32 mg/L, respectively (Table). Macrolides and ketolides interact with bacterial 23S rRNA making contacts with the peptidyl transferase loop in domain V but also with the hairpin 35 in domain II. A2142 and A2143 are included in this loop and mutations such as those observed in H. pylori, as well as methylation of A2142 (the principal resistance mechanism in Grampositive bacteria but which has not been described in H. pylori) markedly decrease the affinity of both classes of drugs for the loop. However, while interactions of macrolides and ketolides with domain V are similar, their interactions with domain II differ. The stronger interaction of ketolides with hairpin 35 could explain their good activity against strains that contain ribosomes with methylated rRNA. This could also explain why ketolides are less affected by rRNA gene mutations in H. pylori. In the future, it may be possible to discover new ketolides whose interaction with hairpin 35 is sufficient for the binding of the antibiotic, so that these drugs could remain active against macrolide-resistant rRNA mutants of H. pylori. Correspondence Journal of Antimicrobial Chemotherapy (2001) 48, 735–748

Effect of pH on the susceptibility ofHelicobacter pylori to the ketolide telithromycin (HMR 3647) and clarithromycin