ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, JUlY 1993, P. 1547-1551 Vol. 37, No. 7 0066-4804/93/071547-05$02.00/0 Copyright © 1993, American Society for Microbiology In Vitro Antibacterial Activity and ,-Lactamase Stability of CP-70,429, a New Penem Antibiotic MASASHI MINAMIMURA, YUMI TANIYAMA, EIKO INOUE,* AND SUSUMU MITSUHASHI Episome Institute, 2220 Kogure, Fujimi-mura, Seta-gun, Gunma, Japan Received 14 January 1993/Accepted 15 April 1993 In in vitro susceptibility tests, the new penem CP-70,429 showed potent antibacterial activity against gram-positive and gram-negative bacteria except Pseudomonas aeruginosa and Xanthomonas maltophilia. CP-70,429 was stable to various types of 13-lactamases except for the enzyme from X. maltophilia and was 16- to 128-fold more active than the other compounds against 13-lactamase-producing strains of Enterobacter cloacae and Citrobacterfreundii. In the past several years, many 1-lactam antibiotics with cus aureus, like the other agents against which CP-70,429 broad antibacterial activities have undergone clinical trials. was compared. CP-70,429 showed potent activity against The penem antibiotics FCE22101 and SY5555 have broad streptococci, as did the other compounds tested. Against antimicrobial spectra and high levels of stability to ,B-lacta- Enterococcus faecalis, CP-70,429 was 4- to 16-fold more mases (4, 9). The in vitro activity of CP-65,207 was previ- active than the cephems tested, on the basis of the MIC90s. ously reported by Gootz et al. (3); CP-65,207 is a mixture of CP-70,429 was the most active compound against Esche- stereoisomers of the optically pure CP-70,429. CP-70,429 is a richia coli, Kebsiella pneumoniae, Morganella morganii, new penem antibiotic, which is stable to renal dehydropep- and Providencia rettgeni. Its activity was 4- to 16-fold greater tidase I (2, 8). We report here the in vitro antibacterial than those of the other penems and 2- to 8-fold greater than activity of CP-70,429 and its stability to various types of those of the cephems. The MIC90s of CP-70,429 were 0.39 P-lactamases. The following antibacterial agents were used: and 0.78 jig/ml for Citrobacter freundii and Enterobacter CP-70,429, Pfizer Pharmaceuticals Inc., Tokyo, Japan; cloacae, respectively; these two strains were resistant to FCE22101, Farmitalia Carlo Erba Co., Ltd., Tokyo, Japan; ceftazidime and cefuzonam. Its activity was 8- to 16-fold SY5555, Suntory Co., Ltd., Tokyo, Japan; ceftazidime, greater than those of the other penems. Nihon Glaxo Co., Ltd., Tokyo, Japan; and cefuzonam, CP-70,429 had poor activity against Serratia marcescens, Lederle Japan Co., Ltd., Tokyo, Japan. The clinical isolates as did the other compounds tested. CP-70,429, like ceftazi- of bacteria used in the present study were collected from dime, was four- to eightfold more active than the other several hospitals in Japan from 1984 to 1990. The 3-lacta- penems and cefuzonam against the Proteus group of organ- were from mase-producing strains tested selected stock isms. CP-70,429 was four- to eightfold more active than the were determined by cultures in our laboratory (1, 7). MICs other penems against Haemophilus influenzae. At a concen- the twofold agar dilution method by using Sensitivity Disk of 0.10 CP-70,429 inhibited all Neisseria unless other- tration j.g/ml, Agar (Nissui Pharmaceutical, Tokyo, Japan), gonorrhoeae and Branhamella catarrhalis isolates tested, as wise The final cell inoculum was approximately specified (5). did ceftazidime. CP-70,429 was inactive against Pseudo- 104 CFU per spot. monas aeruginosa, as were the other penems tested and The various types of ,-lactamases used in the present cefuzonam. CP-70,429 was inactive against Xanthomonas study were totally or partially purified by the methods maltophilia, as were the other compounds tested. and were stored at -80°C (6). The reported previously The antibacterial activity of CP-70,429 against 3-lacta- stability of the antibiotics to was measured by a P-lactamase mase-producing strains of various species was tested. CP- spectrophotometric assay (10). tested The MICs of CP-70,429 and the other agents for 1,555 70,429 showed potent activity against the organisms except for Pseudomonas aeruginosa and Xanthomonas mal- clinical isolates are summarized in Table 1. CP-70,429 had a In CP-70,429 was 16- to 128- broad spectrum of antibacterial activity and was highly tophilia (Table 2). particular, fold more active than the comparison compounds against active against gram-positive and gram-negative bacteria, and particularly members of the family Enterobacteraceae. In P-lactamase-producing strains of Enterobacter cloacae was more active than ceftazidime against Citrobacterffreundii. general, CP-70,429 to hydrolysis gram-positive cocci. The MIC of CP-70,429 for 90% of The susceptibility of CP-70,429 enzymatic was tested with various types of ,B-lactamases. Hydrolysis of isolates tested which was similar to those of (MIC0), the tested was expressed as the relative rate of and SY5555, was 0.10 p.g/ml for methicillin- compounds FCE22101 hydrolysis normalized with respect to the rate of hydrolysis susceptible Staphylococcus aureus. In contrast, CP-70,429 of cephaloridine or penicillin G, which was set at 100 (Table poor activity against methicillin-resistant Staphylococ- had 3). CP-70,429 was stable to various types of 3-lactamases but was hydrolyzed by Xanthomonas maltophilia oxyimi- nocephalosporinase type II, that is, type 3 of the classifica- * Corresponding author. tion of Bush (1), as were the comparison compounds. The 1547 1548 NOTES ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Antibacterial activity of CP-70,429 against clinical isolates MIC (jg/rMI)a Organism (no. of isolates) Antibiotic Range 50% 90% Staphylococcus aureus, methicillin susceptible (75) CP-70,429 0.05-0.10 0.10 0.10 FCE22101 0.10-0.20 0.10 0.10 SY5555 0.10-0.20 0.20 0.20 Ceftazidime 3.13-12.5 6.25 6.25 Cefuzonam 0.20-0.78 0.39 0.39 Staphylococcus aureus, methicillin resistant (97) CP-70,429 0.39->100 12.5 100 FCE22101 0.20-> 100 1.56 100 SY5555 0.39-> 100 12.5 >100 Ceftazidime 12.5->100 >100 >100 Cefuzonam 0.39-> 100 50 100 Streptococcus pneumoniae (50) CP-70,429 C0.006-0.78 .0.006 0.10 FCE22101 C0.006-1.56 0.025 0.20 SY5555 <0.006-0.39 S0.006 0.05 Ceftazidime 0.025-0.78 0.10 0.39 Cefuzonam C0.006-0.39 .0.006 0.10 Streptococcus pyogenes (92) CP.70,429 <0.006-0.025 0.012 0.025 FCE22101 C0.006-0.10 0.05 0.05 SY5555 <0.006-0.025 0.012 0.025 Ceftazidime 0.025-0.20 0.10 0.10 Cefuzonam <0.006-0.10 50.006 0.012 Enterococcus faecalis (104) CP-70,429 0.78-50 3.13 6.25 FCE22101 1.56-12.5 1.56 3.13 SY5555 0.39-6.25 0.78 1.56 Ceftazidime 12.5->100 50 >100 Cefuzonam 0.39-> 100 1.56 25 Escherichia coli (100) CP-70,429 0.012-0.20 0.025 0.05 FCE22101 0.39-0.78 0.39 0.78 SY5555 0.10-3.13 0.78 0.78 Ceftazidime 0.012-1.56 0.20 0.39 Cefuzonam 0.025-0.78 0.10 0.20 Klebsiella pneumoniae (123) CP-70,429 0.025-0.10 0.025 0.05 FCE22101 0.39-0.78 0.78 0.78 SY5555 0.20-25 0.39 0.78 Ceftazidime 0.025-12.5 0.10 0.39 Cefuzonam 0.025-0.78 0.10 0.20 Klebsiella oxytoca (100) CP-70,429 0.025-0.39 0.05 0.10 FCE22101 0.20-6.25 0.78 0.78 SY5555 0.10-3.13 0.39 1.56 Ceftazidime .0.006-0.39 0.05 0.10 Cefuzonam 50.006-0.39 0.05 0.10 Citrobacterfreundii (96) CP-70,429 0.025-3.13 0.10 0.39 FCE22101 0.78-50 3.13 6.25 SY5555 0.39-25 1.56 6.25 Ceftazidime 0.05-> 100 0.78 >100 Cefuzonam 0.10->100 0.39 50 Enterobacter cloacae (100) CP-70,429 0.012-1.56 0.20 0.78 FCE22101 0.78-25 3.13 6.25 SY5555 0.39-12.5 3.13 6.25 Ceftazidime 0.05->100 0.39 100 Cefuzonam 0.05->100 0.39 50 Serratia marcescens (100) CP-70,429 0.05->100 0.78 50 FCE22101 1.56-> 100 6.25 50 SY5555 1.56->100 25 >100 Ceftazidime 0.10-> 100 0.78 >100 Cefuzonam 0.20-> 100 1.56 >100 Continued on followingpage VOL. 37,1993 NOTES 1549 TABLE 1-Continued MIC (p.g/ml)a Organism (no. of isolates) Antibiotic MIC (,ug/ml Range 50% 90% Morganella morganii (70) CP-70,429 0.05-1.56 0.39 0.78 FCE22101 0.78-6.25 3.13 3.13 SY5555 0.39-25 1.56 3.13 Ceftazidime 0.05->100 0.05 3.13 Cefuzonam 0.025-12.5 0.05 3.13 Providencia rettgeri (48) CP-70,429 s0.006-0.39 0.20 0.20 FCE22101 0.39-3.13 0.78 1.56 SY5555 0.10-6.25 1.56 3.13 Ceftazidime 50.006-3.13 0.10 0.39 Cefuzonam <0.006-6.25 0.05 0.78 Proteus mirabilis (101) CP-70,429 0.012-0.39 0.10 0.20 FCE22101 0.39-1.56 0.78 1.56 SY5555 0.05-6.25 0.78 3.13 Ceftazidime 0.05-1.56 0.10 0.39 Cefuzonam 0.05-1.56 0.39 0.78 Proteus vulgaris (95) CP-70,429 0.025-0.39 0.05 0.10 FCE22101 0.39-3.13 0.78 0.78 SY5555 0.20-1.56 0.39 1.56 Ceftazidime 0.05-1.56 0.10 0.20 Cefuzonam 0.025-12.5 0.39 0.78 Neisseria gonorrhoeae (21) CP-70,429 .0.006-0.10 0.025 0.05 FCE22101 .0.006-0.10 0.05 0.05 SY5555 .0.006-0.05 0.025 0.05 Ceftazidime 0.012-0.10 0.012 0.05 Cefuzonam C0.006-0.10 C0.006 0.05 Haemophilus influenzae (48) CP-70,429 0.025-0.39 0.20 0.20 FCE22101 0.10-1.56 0.20 0.78 SY5555 0.10-3.13 0.20 1.56 Ceftazidime 0.025-3.13 0.10 0.39 Cefuzonam .0.006-0.20 0.012 0.10 Branhamella catarrhalis (33) CP-70,429 .0.006-0.10 0.025 0.10 FCE22101 0.05-0.39 0.10 0.20 SY5555 0.025-0.39 0.10 0.39 Ceftazidime 0.012-0.10 0.05 0.05 Cefuzonam 0.025-0.39 0.10 0.39 Pseudomonas aeruginosa (54) CP-70,429 12.5-200 25 100 FCE22101 25->400 100 400 SY5555 50->400 >400 Ceftazidime 0.39-100 1.56 100 Cefuzonam 6.25->400 50 >400 Xanthomonas maltophilia (48) CP-70,429 3.13-> 100 100 >100 FCE22101 3.13-> 100 >100 >100 SY5555 25-> 100 >100 >100 Ceftazidime 0.39->100 50 100 Cefuzonam 0.20-> 100 25 100 a 50% and 90%, MICs for 50 and 90% of organisms tested, respectively.