Vol. 35, No. 6

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1991, p. 1245-1246

0066-4804/91/061245-02$02.00/0 Copyright X 1991, American Society for Microbiology

In Vitro and In Vivo Studies of ME1228, a New Parenteral Cephalosporin with Potent Activity against Pseudomonas aeruginosa SHUICHI MIYAZAKI,* YOKO MIYAZAKI, AKIYOSHI TSUJI, MINORU NISHIDA, AND SACHIKO GOTO

Department of Microbiology, Toho University School of Medicine, Omori-nishi 5-21-16, Ota-ku, Tokyo 143, Japan Received 19 November 1990/Accepted 13 March 1991

The therapeutic effect of ME1228,

a new

parenteral cephalosporin,

was

compared with that of broad-

spectrum cephems in normal and neutropenic mice infected with various species of bacteria. The results

showed that ME1228 was more active than were the other cephems against infections with various pathogens.

ME1228 is a new parenteral cephalosporin with a broad antibacterial spectrum that includes Pseudomonas aeruginosa and other opportunistic pathogens (2, 3). We report here the therapeutic effect of subcutaneous ME1228 in mice infected with various species of bacteria. Four-week-old male strain ICR mice weighing 19 ± 1 g (Charles River Japan Inc., Atsugi, Japan) were challenged

with Staphylococcus aureus Smith, Klebsiella pneumoniae 3K25, P. aeruginosa E-7, Escherichia coli ML1410 RGN 823, or Proteus mirabilis GN79. Almost all organisms used in this study were new isolates from patients in several hospitals in Japan. The minimum lethal dose of each species was determined by intraperitoneal challenge of groups of 6 mice (total, 36 mice) with a fourfold-diluted solution of

TABLE 1. Protective effects of ME1228 and other cephems on experimental infections in mice Mice

Normal

Organism (challenge dose, CFU/mouse), no. of minimum lethal doses

S. aureus Smith (1 x 107), 2

E. coli ML1410 RGN823 (4 x 108), 1

K. pneumoniae 3K25 (7 x 103), 7

P. mirabilis GN79 (6 x 108), 1

P. aeruginosa E-7 (9 x 103), 16

MIC (l.g/ml) ED5o (Mg/kg)a DE8 1(6

Drug

ME1228 Cefepime Cefpirome Ceftazidime Flomoxef ME1228 Cefepime

Cefpirome Ceftazidime Flomoxef ME1228 Cefepime Cefpirome Ceftazidime Flomoxef ME1228

Cefepime Cefpirome Ceftazidime Flomoxef ME1228 Cefepime Cefpirome Ceftazidime Flomoxef

Neutropenic

P. aeruginosa E-7 (1 x 103), 16

ME1228

Cefepime Cefpirome Ceftazidime Flomoxef a

*

Numbers in parentheses represent the

95% confidence interval.

Corresponding author. 1245

0.20 0.39 0.20 0.78 0.39 0.10 0.05 0.05 0.39 0.20 0.10 0.78 0.78 0.20 0.78 3.13 6.25 50 3.13 >100

3.13 >100

1.95 (1.30-2.95) 1.95 1.25 (0.90-1.70) 31.25 0.30 (0.25-0.40) 31.25 (20.65-47.25) 49.60 (33.70-73.00) 49.60 (33.70-73.00) 78.75 (58.80-105.50) 39.35 (25.70-60.30) 7.80 (5.65-10.85) 15.65 (11.45-21.30) 24.80 (17.10-36.00) 39.35 (31.25-49.60) 99.20 (78.75-125.00) 9.85 (6.80-14.30) 15.65 (10.75-22.70) 15.65 (11.45-21.30) 24.80 (15.45-39.80) 99.20 (78.75-125.00) 3.10 (1.90-5.05) 3.90 (2.50-6.15) 19.70 (12.15-31.95) 6.20 (3.85-9.95) >250

3.13 6.25 50 3.13 >100

1.56 3.13 6.25 3.13 >100

99.20 157.50 250.00 99.20 >250

6.25 1.56 0.78 12.5 0.39

6.25 1.56 0.39 12.5 0.39 0.05 0.05 0.05 0.39 0.10 0.025 0.025 0.025 0.20 0.05 0.10 0.39 0.39 0.20 0.78 1.56 3.13 6.25

(68.35-144.00) (108.50-228.60) (183.35-340.85) (68.35-144.00)

1246

ANTIMICROB. AGENTS CHEMOTHER.

NOTES

TABLE 2. Pharmacokinetic parameters of ME1228 and other drugs in mice and humansa Species (n)

Mice (6)

Humans (5)

ME1228 Cefepime Cefpirome Ceftazidime Flomoxef

14.2 15.8 17.6 15.3 14.7

± ± ± ± ±

ME1228 Cefepime Cefpirome Ceftazidime Flomoxef

1.8 1.9 1.7 2.1 0.9

± ± ± ±

0.2 0.5 0.4 0.3 0.5

± 0.1 0.1 0.1 0.1 0.1

Protein(%) AUC ACbinding

Cmax (p.g/ml)

tl/2

Drug

min min min min min

79.4 78.3 68.6 73.8 54.8

± ± ± ±

5.2 5.1 5.6 6.1 4.8

2,535.0 2,302.5 2,284.0 2,179.4 1,891.3

h h h h h

57.4 79.7 57.0 80.6 45.2

± ± ± ± ±

3.2 4.5 4.2 5.4 1.5

131.8 158.1 127.0 187.6 66.6

t

0.4 1.5 0.2 0.2 0.8

± 95.7 p.g min/ml ± 86.2 ,ug* min/mI ± 95.2 ,ug min/ml

5.9 29.0 11.0 17.9 37.0

± ± ± ± ±

± 6.5 ,ug h/ml ± 7.0 ,ug h/ml ± 5.7 p.g h/ml ± 6.2 ,ug h/ml ± 5.2 ,ug h/ml

3.6 16.0 7.0 20.8 35.0

± 0.3 ± 0.3 ± 0.2 ± 0.3 ± 0.5

± 86.5 ,ug min/ml ± 97.0 ,ug min/ml

tj12,

a Data are given as means ± standard deviations. half-life; Cmax, maximum concentration in serum; AUC, area under the curve. Mice were given 50 mg of drug per kg subcutaneously; humans were given 1 g of drug intravenously for 1 h.

bacteria in 0.9% NaCl with 5% mucin (Difco Laboratories, Detroit, Mich.). Neutropenia was induced as follows. Cyclophosphamide monohydrate (Sigma, St. Louis, Mo.) was injected intraperitoneally at 250 mg/kg 4 days before challenge. One hour after challenge, the animals were given a single subcutaneous dose of ME1228 or the reference antibiotics. Five days after infection, the efficacies of the test substances were evaluated by the van der Waerden method (4). MICs were determined by the agar dilution method in accordance with the reference procedure recommended by the Japanese Society for Chemotherapy (1). Mueller-Hinton agar (Difco) was used as the test medium. ME1228 was a gift of Meiji Seika Kaisha Ltd., Yokohama, Japan. The other antibiotics were obtained as follows: cefepime, Bristol-Myers Co., Ltd., Tokyo, Japan; cefpirome, Hoechst Japan Co., Ltd., Tokyo, Japan; and flomoxef, Shionogi Pharmaceutical Co., Ltd., Osaka, Japan. The protective effects of ME1228 and the reference cephems on infection are shown in Table 1. The 50% effective dose (ED50) of ME1228 against S. aureus Smith infection was 1.95 mg/kg, a dose 16 times lower than the dose of ceftazidime needed to obtain a similar effect but larger than the dose of flomoxef needed to obtain a similar effect. ME1228 was more effective against E. coli ML1410 RGN823 (ED50, 31.25 mg/kg) than was ceftazidime and was somewhat more potent than were the other cephems tested. It also was the most active agent against K. pneumoniae 3K25, with an ED50 of 7.8 mg/kg, indicating a potency five times greater than that of ceftazidime. Against P. mirabilis GN79, ME1228 also was superior in activity (ED50, 9.85 mg/kg) to the other cephems tested, and against P. aeruginosa E-7, it was very active, with an ED50 of 3.1 mg/kg. In the latter case, its activity was almost the same as that of

cefepime but was superior to those of the other cephems. Although all the antibiotics were less active against infection with P. aeruginosa E-7 in neutropenic mice than in normal controls, ME1228, like ceftazidime, was superior in activity to cefepime and cefpirome. The pharmacokinetic parameters of ME1228 and other drugs in mice and humans are shown in Table 2. There were no statistically significant differences between ME1228 and cefepime, cefpirome, or ceftazidime for half-life, maximum concentration in serum, and area under the curve. The pharmacokinetic parameters of ceftazidime were higher than were those of the other drugs in humans. The percentage of protein binding was lowest for ME1228 among the drugs tested in both mice and humans. The results demonstrate that ME1228 is more active in vivo against most pathogens than are other newly developed parenteral cephems. We believe that ME1228 is a promising drug for the treatment of infectious diseases. REFERENCES 1. Japanese Society for Chemotherapy. 1981. The modified method of determination of minimum inhibitory concentration (MIC).

Chemotherapy (Tokyo) 29:76-79. (In Japanese.) 2. Neu, H. C., G. Saha, and N. X. Chin. 1989. In vitro activity of ME1228, a new parenteral cephalosporin. Antimicrob. Agents Chemother. 33:1260-1267. 3. Shibahara, S., T. Okonogi, T. Yoshida, Y. Murai, T. Kudo, S. Inouye, and S. Kondo. 1990. A new aminothiazolylcephalosporin having 1-carboxyethoxyimino group, ME1228. J. Antibiot. 43:

62-69. 4. van der Waerden, B. L. 1940. Wirksamkeits und Konzentrations Bestimmung durch Tierversuche. Arch. Exp. Pathol. Pharmakol.

195:389-412.