The activities of various types of antiulcer agents against Helicobacter pylori (formerly called Campylobacter pylon) strains were determined by an agar dilution method. Among the compounds tested, two benzimidazole proton pump inhibitors, lansoprazole (AG-1749) and omeprazole, were found to have significant activities against this organism. The activity of lansoprazole was comparable to that of bismuth citrate, with MICs ranging from 3.13 to 12.5 ,ug/ml, and fourfold more potent than that of omeprazole. A major metabolite and two acid-converted rearrangement products of lansoprazole also exhibited good activities comparable or superior to that of the parent compound. Exposure to lansoprazole of H. pylori growing in a liquid medium led to an extensive loss of viability without a reduction in culture turbidity and produced an aberrant bacterial morphology characterized by the irregular constriction of cells and the collapse of cell surface structures. The antibacterial activity of lansoprazole and its related compounds was selective against H. pylori; common aerobic and anaerobic bacteria and Campylobacterjejuni were not inhibited by 100 ,ug/ml.

The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacterpylori cells; the 50%1 inhibitory concentrations were between 3.6 and 9.5 ,M, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents A -ethylmaleinide and idoacetamide were also examined for their inhibition of the urease activity; their 5W0 inhibitory tontentrations were 100-to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth.

TwoGram-negative bacteria were found to produce the newantibacterial antibiotics TAN-1 057 A, B, C arid D. The producing bacteria were characterized and designated as Flexibacter sp. PK-74 and PK-176.Theseantibiotics wereactive against Gram-negativeand Gram-positivebacteria, including methicillin-resistant Staphylococcus aureus. TAN-1 057 A inhibited protein biosynthesis in Escherichia coli and S. aureus.It showed excellent protective effects against an experimental methicillin-resistant S. aureus infection in mice.

Escherichia coli mutants defective in the ability to agglutinate guinea pig erythrocytes (HA-) were isolated from a nalidixic acid-resistant derivative, 31-B, of E. coli TN 675 that produces type 1 fimbriae and induces urinary tract infection in mice fed a 5% glucose solution. All nine HAmutants were defective not only in their ability to agglutinate Candida albicans cells and erythrocytes from various species, but also in their capacity to adhere to mouse bladder epithelial cells. None of the mutants were agglutinated by anti-type 1 fimbriae antiserum. Although most of the mutants were fimbriated when examined by electron microscopy, their fimbriae differed serologically from type 1 fimbriae. All of the mutants showed 100 to 1,000 times lower bacterial recovery from the bladder walls of mice 3 h after inoculation into the bladder and lacked urinary tract infectivity in mice. These results suggest that all of the HAmutants are defective in type 1 fimbriae production and that type 1 fimbriae facilitate the development of urinary tract infection in mice, probably by mediating bacterial adherence to the bladder epithelial cells.

The therapeutic effect of cefozopran (SCE-2787), a new semisynthetic parenteral cephalosporin, against experimental infections in mice was examined. Cefozopran was more effective than cefpiramide and was as effective as ceftazidime and cefpirome against acute respiratory tract infections caused by Kiebsiella pneumoniae DT-S. In the model of chronic respiratory tract infection caused by K. pneumoniae 27, cefozopran was as effective as ceftazidime. The therapeutic effect of cefozopran against urinary tract infections caused by Pseudomonas aeruginosa P9 was superior to that of cefpirome and was equal to those of ceftazidime and cefclidin. In addition, cefozopran was more effective than ceftazidime and was as effective as flomoxef in a thigh muscle infection caused by methicillin-sensitive Staphylococcus aureus 308A-1. Against thigh muscle infections caused by methicillin-resistant S. aureus N133, cefozopran was the most effective agent. The potent therapeutic effect of cefozopran in those experimental infections in mice suggests that it would be effective against respiratory tract, urinary tract, and soft tissue infections caused by a variety of gram-positive and gram-negative bacteria in humans.The search for new drugs effective as antibacterial agents requires the thorough evaluation of drugs not only in vitro but also in vivo (i.e., in the control and management of experimental infections). Systemic infections induced by an intraperitoneal injection of a bacterial suspension have been commonly used for the evaluation of new antibiotics. Such infections, however, are not always representative of infectious diseases in humans. It is therefore important to evaluate antibiotics by using animal models of infection which more closely mimic the actual situation in humans.This paper deals with the in vivo evaluation of cefozo- (Fig. 1), cefpirome, and cefclidin were prepared in the Research and Develop-* Corresponding author. ment Division of Takeda Chemical Industries, Ltd. Ceftazidime (Nippon Glaxo Co., Ltd., Tokyo, Japan), cefpiramide (Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan), and flomoxef (Shionogi & Co., Ltd., Osaka, Japan) were obtained commercially. MICs of each antibiotic were determined by an agar dilution method using an inoculum of ca.104 CFU and are shown in each table.Experimental infections and antibiotic treatment. (i) Respiratory tract infection. Acute respiratory tract infection caused by K pneumoniae DT-S was induced as described previously (19). Briefly, K pneumoniae DT-S was grown overnight at 37°C in brain heart infusion broth (Difco Laboratories, Detroit, Mich.), and cells were collected by centrifugation, washed with phosphate-buffered saline (Dulbecco formula [modified] without magnesium and calcium; Flow Laboratories, Inc., McLean, Va.), and suspended in the same buffered saline to give a suspension of ca. 109 CFU/ml. The bacterial suspension was placed in a nebulizer (Vaponefrin pocket nebulizer; USV Pharmaceutical Co., Tuckahoe, N.Y.) and aerosolized at a pressure of 1.2 kg/cm2 for ...