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CP-70429, a New Penem Antibiotic

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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.
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    Supplemental Material eTable 1. Variable classification in EHR continuity cohort vs non-EHR continuity cohort mean capture proportion <60% mean capture proportion ≥60% Variable N (%) based N (%) based Stand Sensi- N (%) based N (%) based Stand Sensi-tivity on EHR on all data diff tivity on EHR on all data diff Dementia 4147 (4) 12577 (11) 0.28 0.33 1112 (5) 1350 (7) 0.05 0.82 Atrial fibrillation 8780 (7) 22493 (19) 0.34 0.39 2079 (10) 2315 (11) 0.04 0.90 Chronic lung disease 6643 (6) 25606 (21) 0.48 0.26 2901 (14) 3407 (17) 0.07 0.85 Chronic liver disease 2183 (2) 8961 (8) 0.27 0.24 1102 (5) 1355 (7) 0.05 0.81 Chronic kidney 4565 (4) 15638 (13) 0.34 0.29 2076 (10) 2372 (12) 0.05 0.88 disease Cancer 23113 (19) 56173 (47) 0.61 0.41 7260 (35) 8087 (40) 0.08 0.90 Diabetes 8225 (7) 27351 (23) 0.46 0.30 3975 (19) 4378 (21) 0.05 0.91 Hypertension 44097 (37) 98525 (82) 1.04 0.45 15796 (77) 16799 (82) 0.12 0.94 Anemia 7615 (6) 37210 (31) 0.67 0.20 3596 (18) 4674 (23) 0.13 0.77 Psychosis 1082 (1) 5486 (5) 0.23 0.20 396 (2) 557 (3) 0.05 0.71 Depression 4894 (4) 24721 (21) 0.52 0.20 2571 (13) 3290 (16) 0.10 0.78 Pneumonia 3220 (3) 11612 (10) 0.29 0.28 1102 (5) 1297 (6) 0.04 0.85 HIV 54 (0.05) 142 (0.1) 0.03 0.38 43 (0.2) 46 (0.2) 0.00 0.93 Fracture 1342 (1) 4135 (4) 0.16 0.32 391 (2) 457 (2) 0.02 0.86 RA 1260 (1) 4083 (3) 0.16 0.31 489 (2) 574 (3) 0.03 0.85 Ischemic stroke* 2335 (2) 5937 (5) 0.17 0.39 544 (3) 626 (3) 0.02 0.87 ICH* 1178 (1) 2117 (2) 0.07 0.56 229 (1) 256 (1) 0.01 0.89 MI* 324 (0.3) 1143 (1) 0.09 0.28 165 (1) 170 (1) 0.00 0.97 AKI*
  • Antibiotic Classes

    Antibiotic Classes

    Penicillins Aminoglycosides Generic Brand Name Generic Brand Name Amoxicillin Amoxil, Polymox, Trimox, Wymox Amikacin Amikin Ampicillin Omnipen, Polycillin, Polycillin-N, Gentamicin Garamycin, G-Mycin, Jenamicin Principen, Totacillin, Unasyn Kanamycin Kantrex Bacampicillin Spectrobid Neomycin Mycifradin, Myciguent Carbenicillin Geocillin, Geopen Netilmicin Netromycin Cloxacillin Cloxapen Paromomycin Dicloxacillin Dynapen, Dycill, Pathocil Streptomycin Flucloxacillin Flopen, Floxapen, Staphcillin Tobramycin Nebcin Mezlocillin Mezlin Nafcillin Nafcil, Nallpen, Unipen Quinolones Oxacillin Bactocill, Prostaphlin Generic Brand Name Penicillin G Bicillin L-A, First Generation Crysticillin 300 A.S., Pentids, Flumequine Flubactin Permapen, Pfizerpen, Pfizerpen- Nalidixic acid NegGam, Wintomylon AS, Wycillin Oxolinic acid Uroxin Penicillin V Beepen-VK, Betapen-VK, Piromidic acid Panacid Ledercillin VK, V-Cillin K Pipemidic acid Dolcol Piperacillin Pipracil, Zosyn Rosoxacin Eradacil Pivampicillin Second Generation Pivmecillinam Ciprofloxacin Cipro, Cipro XR, Ciprobay, Ciproxin Ticarcillin Ticar Enoxacin Enroxil, Penetrex Lomefloxacin Maxaquin Monobactams Nadifloxacin Acuatim, Nadoxin, Nadixa Generic Brand Name Norfloxacin Lexinor, Noroxin, Quinabic, Aztreonam Azactam, Cayston Janacin Ofloxacin Floxin, Oxaldin, Tarivid Carbapenems Pefloxacin Peflacine Generic Brand Name Rufloxacin Uroflox Imipenem, Primaxin Third Generation Imipenem/cilastatin Balofloxacin Baloxin Doripenem Doribax Gatifloxacin Tequin, Zymar Meropenem Merrem Grepafloxacin Raxar Ertapenem