Four strains of Heikobacter pylori were subjected to an in vitro serial passage technique to compare the propensity of the organisms to develop resistance to seven classes of antibacterial agents. The passages were made on serially doubling concentrations of antibacterial agents incorporated into agar starting at one-half the base-line MIC. The frequency of spontaneous resistance was also determined for each strain at four and eight times the MIC of each antibacterial agent. Strains resistant to ciprofloxacin, metronidazole, erythromycin, and tobramycin were isolated. The experiments failed to select organisms resistant to bismuth subsalicylate, furazolidone, or amoxicillin, although the MIC of amoxicillin was increased 4-to 16-fold. With the exception of erythromycin, organisms with the selected resistance were stable after at least three passages on antibacterial agent-free medium. Spontaneous resistance rates were generally of a low magnitude and were not predictive of the serial passage results.Helicobacter pylori (formerly Campylobacter pylori) is accepted as the most common and most important cause of chronic active gastritis and represents one of the common chronic infections of humans. H. pylori infection and gastritis are also associated with the vast majority of cases of chronic, recurrent duodenal ulcer, with a growing body of data supporting an important etiologic role for the organism in that disease (4, 7).Antibacterial therapy resulting in the clearance of H. pylori from the gastric mucosa has led to histologic improvement or normalization of chronic active gastritis (5,17,19). In patients with duodenal ulcers associated with H. pylori infections, effective eradication of the organism has resulted in improved healing of ulcers (12) and significantly lower rates of ulcer relapse (3, 12). These findings support a role for antibacterial therapy in the treatment of H. pyloriassociated upper gastrointestinal diseases.Two major problems have been encountered in the treatment of H. pylori infections, despite its in vitro susceptibility to a wide array of antibacterial agents. First, relapse of H. pylori is common following what appears to be successful treatment (5,17,19). Relapse is presumably due to incomplete eradication of the organism. The second major problem has been the emergence of resistant strains during singleagent treatment. The development of resistance has been reported during treatment with several quinolones (10, 16; Y. Glupczynski, M. Labbe, A. Burette, M. Delmee, V. Avesani, and C. Bruck, Letter, Lancet i:1096, 1987; J. W. Stone, R. Wise, I. A. Donovan, and J. Gearty, Letter, J. Antimicrob. Chemother. 22:92-93, 1988), nitroimidazoles (6, 10), and rifampin (10).The purpose of this in vitro study was to compare the propensity of H. pylori strains to develop resistance to several antibacterial agents by using a serial passage technique (22) and to investigate the rates of spontaneous resistance to the study drugs.

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Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P < 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.

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