ANTIMICROBIAL AGENTS AND CHEMOTHERApY, Nov. 1979, p. 54-548

Vol. 16, No. 5

0066-4804/79/11-0540/09$02.00/0

Ceftizoxime (FK 749), a New Parenteral Cephalosporin: In Vitro and In Vivo Antibacterial Activities TOSHIAKI KAMIMURA,' YOSHIMI MATSUMOTO,' NAOHIKO OKADA,' YASUHIRO MINE,' MINORU NISHIDA,'* SACHIKO GOTO,2 AND SHOGO KUWAHARA2 Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka 532,1 and Department of Microbiology, Toho University, School of Medicine, Tokyo,2 Japan

Received for publication 30 July 1979 FK 749 is a new parenteral cephalosporin derivative which is more active against various gram-negative bacilli, including the opportunistic pathogens such as Enterobacter, Citrobacter species, and Serratia marcescens, than cephalosporins and cephamycins such as cefotiam, cefamandole, cefuroxime, cefotaxime, and cefmetazole. FK 749 was especially active against gram-negative organisms resistant to these related antibiotics. FK 749 was more potent in bactericidal activity than the other antibiotics, and the activity was clearly enhanced in the presence of 90% defibrinated rabbit blood. The therapeutic effect of subcutaneously injected FK 749 in mice infected with various gram-negative bacilli was far superior to that of cefotiam, cefamandole, cefuroxime, and cefmetazole and was almost the same as that of cefmetazole in mice infected with Staphylococcus aureus and that of ticarcillin in mice infected with Pseudomonas aeruginosa. FK 749 has, in general, nearly the same in vitro and in vivo antibacterial activities as cefotaxime. The former had more potent bactericidal activity in the presence of the blood than the latter and showed more excellent therapeutic effect than cefotaxime against infections caused by large inoculum sizes. cham Pharmaceuticals, Betchworth, England), piperacillin (T 1220; Toyama Chemical Co., Ltd., Toyama, Japan), and gentamicin (Schering Corp., Bloomfield, N.J.). Bacterial strains. Standard strains from the culture collection of this laboratory were used in the study. Clinical isolates of various species of bacteria were obtained from several hospitals in Japan. parenteral cephalosporin derivative, was reAntibiotic susceptibility. Minimum inhibitory cently developed (Fig. 1). FK 749 has been concentrations (MICs) were determined by the agar proven to exert excellent antibacterial activity dilution method using heart infusion agar (HI agar, in vitro. In animal experiments with FK 749, it Difco Laboratories, Detroit, Mich.), unless otherwise was also found that the drug is more (potently) specified. For testing Haemophilus influenzae, Neisseria species, and streptococcal species, except Strepactive, especially against various gram-negative tococcus faecalis, the medium was supplemented with bacilli including the opportunistic pathogens, 5% defibrinated blood. The inoculum was grown than other known cephalosporins and cepha- in Trypticase soyhorse broth (BBL Microbiology Systems, mycins tested. Preliminary evaluations suggest Cockeysville, Md.) overnight at 37°C. The broth was that FK 749 will be a valuable antibiotic for a supplemented with 10% Fildes enrichment (Difco) for wide range of clinical applications. We report H. influenzae and with 5% defibrinated horse blood for Neisseria species and streptococcal species. An here the results. overnight broth culture and decimal dilutions thereof MATERIALS AND METHODS Antibiotics. The antibiotics used in this study in- were streaked or spot-inoculated onto the agar media cluded ceftizoxime (FK 749; Fujisawa Pharmaceutical containing graded concentrations of the test antibiCo., Ltd., Osaka, Japan), cefotiam (SCE 963; Takeda otics. MICs were read after incubation at 37°C for 20 Chemical Industries, Ltd., Osaka, Japan), cefamandole h. For testing anaerobic bacteria, incubation was per(Eli Lilly & Co. Indianapolis, Ind.), cefuroxime (Glaxo formed by the GasPak method (BBL) at 37°C; GAM Research Ltd., Greenford, England), cefotaxime (HR broth (Nissui, Tokyo) and GAM agar (Nissui) were 756; Hoechst-Roussel, Frankfurt, West Germany), ce- used for the preculture and test culture, respectively. Bactericidal activity. (i) Viable celi count. HI foxitin (Merck Institute for Therapeutic Research, Rahway, N.J.), cefmetazole (CS 1170, Sankyo Co., broth or 90% defibrinated rabbit blood, containing a Ltd., Tokyo, Japan), ticarcillin and carbenicillin (Bee- concentration of 5 ,g of each of the test antibiotics per 540

The cephalosporins cefazolin (4) and ceftezole (5) resulted from our drug development program. In the continuing search for new cephalosporins with even greater antibacterial activity against a wide variety of gram-positive and gram-negative organisms, including the opportunistic pathogens, FK 749, a distinctive new

ANTIMICROB. AGENTS CHEMOTHER.

KAMIMURA ET AL.

541

Ceftizoxime (FK 749) N -j-C-CO-NH

N-OCH3

5

H2N

H

tN

COONa

Cefotiam (SCE 963) N

S

CH2-CO-NH

N-N

C O H2N H2NICJVCH2-COsH

N ,N

2HC1

N

CH2CH2N-CH3

COOH

\CH3

Cefamandole (D) %4CH-CO-NH N-N

OH

CH2-Sk ,N COONa

CH3

Cefuroxime

S

-C-CO-NH

N-OCH3

>

CH2-OCONH2

COONa

Cefotaxime (HR 756) N

H2N

X

S

S

C-CO-NH

N-OCH3

CH2-OCOCH3

o

COONa

Cefmetazole (CS 1170) OCH3

N-CCH2SCH2-CO-NH

S

f

CH2

oJN>^H~CH2 -S COONa

N-N N CH3

FIG. 1. Chemical structures of FK 749 and related antibiotics. ml, was inoculated with Escherichia coli 5 to obtain pended in 5% mucin, using the quantity necessary to yield the required cell counts per milliliter of mucin. about 106 or 108 colony-forming units (CFU) per in and were then incubated at 370C for 1 or 3 h. Viable Male JCL-ICR strain mice aged 4 weeks (18.5 to 21.5 cell counts in the culture fluids were determined by g) were used, and each group consisted of 10 mice. Mice were inoculated intraperitoneally with 0.5 ml of conventional plating techniques. (ii) MBC. Each HI broth sample containing graded the suspension and were given a single subcutaneous concentrations of the test antibiotics was inoculated dose of the test antibiotics 1 h after challenge. The with organisms to obtain a concentration about 106 50% effective dose (ED50) was determined by the CFU/ml. After incubation at 37°C for 18 h, the mini- probit method from the number of mice surviving mum bactericidal concentration (MBC) was estimated after 4 days of observation. as the lowest antibiotic concentration that killed 99.9% of the original inoculum. RESULTS Therapeutic effect on experimental infection Antibacterial spectrum. FK 749, like the in mice. Organisms were cultured ovemight in Trypticase soy agar (BBL) at 370C and were then sus- other cephalosporins, showed a broad spectrum

KAMIMURA ET AL. 542 of antibacterial activity against aerobic grampositive and gram-negative bacteria (Table 1). FK 749 was superior to closely related antibiotics in antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes, but had inferior activity against Staphylococcus aureus and Bacillus subtilis among the gram-positive bacteria. Against gram-negative bacteria, including opportunistic pathogens, FK 749 was more potent than the other related antibiotics. The antibiotic was also effective against anaerobic bacteria, and its activity against gram-negative anaerobes including species of Bacteroides was nearly the same as that of cefoxitin (Table

2).

Antibacterial activity. To compare antibacterial activity of FK 749 with that of the other related antibiotics, the susceptibility of 19 bacterial species was determined, and the drug concentrations necessary to inhibit 50 and 80% of the test strains were compared (Table 3). The concentrations of FK 749 required to inhibit 80% of the test strains of S. aureus and Staphylococcus epidermidis were 3.13 to 6.25

ANTIMICROB. AGENTS CHEMOTHER.

jig/ml, respectively, i.e., about the same as those of cefuroxime, cefotaxime, and cefmetazole, and were slightly higher than those of cefotiam and cefamandole. However, the 80% inhibitory concentration of FK 749 against the test strains of S. pyogenes, i.e., _0.025 ,ug/ml, was about the same as those of cefuroxime and cefotaxime, but was much lower than those of the other related antibiotics. The 80% inhibitory concentrations of FK 749 against the test strains of E. coli, Klebsiella pneumoniae, Proteus mirabilis and indole-positive Proteus species (except Proteus morganii), and Serratia marcescens were much lower, i.e., '0.025 to 1.56 jig/ml, than those of the other drugs tested. On the other hand, against P. morganii, Citrobacter freundii, Enterobacter species, H. influenzae, and Bacteroides fragilis, the 50% inhibitory concentrations of FK 749 ranged from '0.025 to 1.56 ,ug/ ml, and the 80% inhibitory concentrations (_0.025 to 50 ,tg/ml) were almost the same as those of cefotaxime. However, the antibacterial activity of the drug was far greater than those of the other drugs tested. FK 749 inhibited the

TABLE 1. Antibacterial spectra of FK 749 and related antibiotice (aerobic bacteria) MIC (,ug/ml)

Organism Staphylococcus aureus 209P JC-1 S. aureus Newman Bacillus subtilis ATCC-6633 Micrococcus luteus PCI-1001 Streptococcus pneumoniae HIb S. pyogenes S-23b S. faecalis 6783b Corynebacterium diphtheriae A-7b Neisseria meningitidis 68b N. gonorrhoeae CDC-116b Haemophiius influenzae 1b Escherichia coli NIHJ JC-2 E. coli Yukitoshi E. coli 28 E. coli 35 Klebsiella pneumoniae NCTC-418 Proteus mirabilis 1 P. vulgaris IAM-1025 P. morganii 97 P. rettgeri 14 P. inconstans B-2 Pseudomonas aeruginosa LAM-1095 P. cepacia ATCC-25416 Citrobacter feundii 61 Enterobacter cloacae 1

FK 749

Cefotiam

6.25 3.13 25 0.78 0.05 '0.025 >100 3.13 50.025 1.56 50.025 0.06 '0.025 0.2 12.5 50.025 50.025 0.05 6.26

0.78 0.78 0.39 0.78 0.1 0.05 >100 0.78 0.05 0.78 0.78 0.39 0.39 >100 >100 0.78 0.78 >100 >100 >100 >100 >100 >100 >100 >100 >100 0.2 0.2

Cefamandole 0.39 0.39

Cefuroxime

0.2 0.1 50 0.78

1.56 1.56 6.25 0.2 0.05 50.025 >100 1.56

0.06

'0.026

0.05 0.06

0.78 0.78 0.78 0.39 >100 100 3.13 3.13 >100 100 50 0.1 25 0.2 >100 100 >100 25 6.26 100 >100 12.5 12.6 >100 E. aerogenes 11 0.2 SalmoneUa tphi T-287 S0.025 0.2 S. paratyphi A-1015 50.025 0.2 0.1 50.026 S. typhimuriu 1406 0.2 0.1 S. enteritidis 1891 50.025 0.2 0.2 0.39 ShigeUa dysenteriae A-1 Shiga 0.39 0.39 0.05 S. flexneri la EW-8 0.39 0.2 0.05 S. sonnei I EW-33 Conditions: HI agar, streak method, 37°C, 20 h, inoculum of J0O CFU/mI. b Supplemented with 5% horse blood.

Cefota3ime 3.13 3.13 6.25 0.1

0.026

;0.025 25 3.13

90.026

0.78

1.56

0.39

S0.026

3.13 0.78 50 6.25 3.13 3.13 100 50

60 >100 >100 >100 50 >100 >100

0.1 0.05 0.2 1.56 0.1

0.06 6.26 26 1.66 &13 25

60 12.5 25

26

1.66

0.1

0.2

50.025

1.66 0.2 0.78 3.13

1.66

S0.026 S0.026 0.05 0.2

90.026

Cefmetazole 1.56 1.56

1.66 0.39 0.2 0.39 >100

1.66 0.2 1.56 12.5 1.56 0.78

1.66 25 1.56 6.25

26 26 26 60 >100 50 100 50 >100 0.78 0.78 0.78

0.78 1.56 3.13 0.78

VOL. 16, 1979

CEFTIZOXIME (FK 749): NEW CEPHALOSPORIN

543

TABLE 2. Antimicrobial spectra of FK 749 and related antibiotics' (anaerobic bacteria) MIC (pg/mi) Organism Cefamgln- Cefuro- Cefota- Cefe Cefoxt FK 749

Cefotiam

Ceoin

0.1 0.78 1.56 0.39

zole 0.2 0.39 0.39 0.1

ximne

xime

0.2 0.78 0.78 0.39

Peptococcus aerogenes Z-1003 P. prevotii ATCC-9321 P. anaerobius ATCC-14955 Peptostreptococcus anaerobius G-1 NCTC-9801 Eubacterium lentum H-1 E. Iimosum ATCC-8486 Clostridiumperfringens (Sakai) Veillonella akalescens subsp. alcalescens H-3

50.025 1.56 3.13 3.13

0.78 6.25 0.39 1.56

dole 0.78 0.39 0.39 0.1

12.5 6.25 0.2 0.2

25 25 0.39 0.39

12.5 6.25 0.39 0.2

6.25 3.13 0.39 0.39

12.5 0.39 0.1 0.2

6.25 0.78 0.1 0.2

3.13 1.56 0.78 0.39

Fusobacterium varium ATCC-8501 F. necrophorum W-12

12.5 0.39

6.25

12.5 0.2

6.25 0.39

12.5 0.78

12.5 1.56

12.5 1.56

0.2 25 12.5 12.5 12.5 12.5

0.2 25 6.25 12.5 6.25 12.5

0.39 0.2

0.2 0.2 0.05 0.1 F. nucleatum B-1 6.25 3.13 25 1.56 0.78 F. mortiferum H-14 6.25 100 50 50 12.5 Bacteroides fragilis subsp. fragilis H-6 6.25 100 50 25 100 B. fragilis subsp. distasonis W-7 3.13 100 100 25 12.5 B. fragilwi subsp. vulgatus W-6 100 100 12.5 6.25 B. fragilis subsp. ovatus JU-1 100 'Conditions: GAM agar (Niii), 37°C, 24 h, inoculum of 106 CFPJ/ml stamp method, GasPak method.

growth of 50% of the strains of Alcaligenes faecalis and Acinetobacter calcoaceticus at 6.25 ,Ag/ml. The 50 and 80% inhibitory concentrations of FK 749 against 102 strains of Pseudomonas aeruginosa were higher than those of gentamicin and were almost the same as those of ticarcillin. Antibacterial activity of FK 749 against cephalosporin- and cephamycin-resistant strains. The antibacterial activity of FK 749 against strains resistant to the other related antibiotics was investigated. From the results of susceptibility testing shown in Table 3, the strains of S. aureus, E. coli, K. pneumoniae, and P. mirabilis that were resistant to the other related antibiotics tested (MIC, '25,ug/ml) were chosen for testing the MIC of FK 749. One strain of S. aureus was resistant to all the test drugs including FK 749, indicating complete cross-resistance between FK 749 and the other drugs (Table 4). FK 749 was highly active against E. coli, K. pneumoniae, and P. mirabilis strains that were resistant to the other antibiotics tested with the exception of cefotaxime. These resistant strains showed no cross-resistance between FK 749 and cefotiam, cefamandole, cefuroxime, and cefmetazole, and only one strain of K. pneumoniae was resistant to FK 749 as well as cefotaxime. Bactericidal activity. The effect of the test antibiotics on the viable cell count of E. coli 5 was investigated with inocula of 106 and 10' CFU/ml in both HI broth and 90% defibrinated rabbit blood. Low inoculum size (10' CFU/ml). Figure 2A shows the changes in viable cell count of E. coli 5 inoculated in HI broth containing 5 ,ug of

0.1 0.39 0.39 0.05

the test antibiotics per ml. The bactericidal activity of FK 749 and cefotaxime at 5 jig/ml was greater than that of the other antibiotics tested, and the viable cell counts were decreased markedly in 1 h by both drugs. The other drugs showed almost the same bactericidal activity as that of FK 749 when tests were carried out for 3 h. In the presence of 90% defibrinated rabbit blood (Fig. 2B), the bactericidal activity of FK 749 did not decrease and, in fact, was superior to its activity in HI broth. The activity of cefotaxime, however, decreased in the presence of blood. The activity of cefuroxime was almost the same in the presence of blood as that of FK 749 in 3-h incubations. Heavy inoculum size (10 CFU/ml). The bactericidal activities of the test antibiotics were compared as above except that a heavy inoculum (10' CFU/ml) was used. Figure 3A shows that the bactericidal activity of the antibiotics except cefamandole at 10' CFU/ml was nearly the same as that at 106 CFU/ml when HI broth was used as the culture medium. In the presence of blood, most of the bactericidal activity of the antibiotics except FK 749 was lost; however, that of FK 749 was retained and was, in fact, enhanced (Fig. 3B). MBC. MBCs of the test antibiotics against eight strains of E. coli, eight strains of K. pneumoniae, and five strains of P. mirabilis were measured (Table 5). The mean MBC of FK 749 against E. coli was almost the same as that of cefotaxime, but was lower for the other organisms than any other antibiotics tested. That is, the bactericidal activity of FK 749 from values of the mean MBC was from 8 (cefotiam) to 138

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CEFTIZOXIME (FK 749): NEW CEPHALOSPORIN

VOL. 16, 1979

times (cefamandole) higher against E. coli than the other test drugs except for cefotaximne; about 4 (cefotaxime) to 134 times (cefamandole) higher against K. pneumoniae than any other test antibiotic; and about 4.6 (cefotaxime) to >111 times (cefamandole) higher against P. mirabilis than any other antibiotic tested. Therapeutic effect on infections in mice. The therapeutic effect of FK 749 in mice infected TABLE 4. Antibacterial activity of FK 749 against cephalosporin- and cephamycin-resistant strainsa Mean MIC (no.Organism of resistant

D)rug

strains)

compared

Du

(igWm1)

cor-

FK 749

pared Cefotiam

S. aureus E. coli K. pneumoniae P. mirabilis

(1) (2) (7) (1)

100 35 100 200

200 8.84 0.07 50.03

Cefamandole

S. aureus E. coli K. pneumoniae P. mirabilis

(1) (30) (38) (5)

50 32 63 38

200 0.16 0.05

Cefuroxime

S. aureus E. coli K. pneumoniae P. mirabilis

(1) (14) (12) (5)

200 34 75 50

200 1.49 0.12 0.03

Cefotaxime

S. aureus E. coli K. pneumoniae P. mirabilis

(1)

200

200

(0) 100

100

(1) (0)

Cefmetazole

90.03

S. aureus (1) 200 200 E. coli (5) 38 4.74 K. pneumoniae (2) 100 4.42 P. mirabilis 34 (5) 0.03 a Resistant strain is defined as one having an MIC of W25 &gml. Inoculum was 1 CFU/ml.

L

6

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5

545

with various species of organisms was compared with that of the other antibiotics as described under Materials and Methods. Table 6 shows the ED50 values in mice given the test antibiotics subcutaneously 1 h after challenge. The ED50 values of FK 749 for S. aureus 47 infections were 1.44 mg/kg and were about the same as those of cefotaxime and cefamandole. The therapeutic effect of FK 749 was slightly inferior to that of cefamandole and cefuroxime but was superior to that of cefotiam. The therapeutic effect of FK 749 on infections due to E. coli, K. pneumoniae, indole-negative and -positive Proteus species, and Enterobacter cloacae 63 was almost the same as that of cefotaxime and was by far superior to that of the other test drugs. In contrast, FK 749 was more effective than cefotaxine against infections due to C. freundii 13 and S. marcescens 32 and was equal to ticarcillin and piperacillin in effect against infections due to P. aeruginosa 93. Influence of challenge dose on the protective effect of FK 749 and cefotaxime against infections in mice. The therapeutic effect of FK 749 was compared with that of cefotaxime against all infections due to various challenge doses of E. coli, P. vulgaris, and S. marcescens. As shown in Table 7, the therapeutic effect of FK 749 was nearly the same as that of cefotaxime against all infections due to the challenge size of 1 minimum lethal dose (MLD) of the test organisms. FK 749, however, was more effective than cefotaxime against all infections due to large challenge doses (100 or 10,000 MLD) of the test organisms. Specifically, ED50 values of FK 749 were increased by a factor of '9 to 85 when the challenge dose was 100 or 10,000 MLD rather than 1 MLD. Similar results were obtained in the case of cefotaxime using the same organisms, but the extent of the decrease of ED50 values of

=3

6 5

a

4

4

3 TIME (HR)

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FIG. 2. Bactericidal activity of FK 749 and related antibiotics against E. coli 5 in HI broth (A) and defibrinated rabbit blood (B). Inoculum size: 10( CFU/ml.

546

ANTIMICROB. AGENTS CHEMOTHER.

K"IMURA ET AL. 9.

XCONTROL

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CEFMETAZOLE CEFOTAXIME

-i

J:

ME

CEFOTIAM

51 6

-j

J:

FK749

A 3

1 TIME (HR)

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FIG. 3. Bactericidal activity of FK 749 and related antibiotics against E. coli 5 in HI broth (A) and defibrinated rabbit blood (B). Inoculum size: IO& CFU/ml.

TABLE 5. MBC' of FK 749 and related antibiotics Mean MBC (mean MIC) (sAg/ml) Antibiotic

K. pneuE. coi ( 8)b (8)b )moniae

FK 749

Cefotiam

0.78 (0.39) 6.25

(0.78)

Cefamandole

Cefuroxime

108

(6.7)

11.5

0.16 (0.07) 2.9 (1.56) 21.5

(25) 14

P. mira(5)b bilis

3.6 (1.03) 170 (22) 400

(25)

300

(13) (29) (6.7) 0.64 16.4 0.6 (0.28) (3.6) (0.21) 4.7 340 7.2 Cefmetazole (33) (3.6 (2.5) a Conditions: HI broth (Difco), 370C, 18 h, inoculum size, 10' CFU/ml. The MBC was determined as the lowest concentration that kills 99.9% of the inoculum. b Number of strains. Cefotaxime

cefotaxime (factor: 62 to 1,290) was always greater than that of FK 749.

DISCUSSION Recent years have seen the development of a succession of new cephalosporins such as cefotiam (8), cefamandole (1), cefuroxime (6), and cefotaxime (2) and cephamycins such as cefmetazole (S. Sugawara, M. Tajima, I. Igarashi, S. Ohya, and Y. Utsui, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 16th, Chicago, Ill., abstr. no. 231, 1976) and cefoxitin (9). These drugs have been reported to have better antibacterial activity against gram-negative ba-

cilli than cephalosporins currently available and better activity against some cephalosporin-resistant organisms. On the other hand, indole-positive Proteus species and opportunistic pathogens such as Enterobacter, Citrobacter, and Serratia species and P. aeruginosa isolated from clinical materials have recently increased, and there are some problems in treating infections caused by this kind of pathogen. Since the antibacterial activity of the antibiotics described above is not sufficient to inhibit these pathogens, antibiotics with greater antibacterial activity are needed. FK 749 has greater antibacterial activity against various gram-negative bacilli, especially the opportunistic pathogens, than the antibiotics described above, and has almost the same in vitro and in vivo antibacterial activity against P. aeruginosa as that of ticarcillin. FK 749 is also active against strains of gram-negative bacilli that are resistant to related antibiotics, with the exception of cefotaxime. Cross-resistance between FK 749 and other related antibiotics was not seen in the resistant strains tested. The

potent broad-spectrum antibacterial activity of FK 749 against a wide variety of gram-positive and gram-negative organisms is in part due to the fact that this drug is stable to various kinds of 8-lactamases (3). Cephamycin derivatives such as cefoxitin (7) and cefmetazole (Sugawara et al., 16th ICAAC, abstr. no. 231) are very stable to fi-lactamases. However, their antibacterial activity is sometimes weaker than expected from consideration of their ,8-lactamase stability. The comparatively high ability of FK 749 to penetrate through the outer membrane of gram-neg-

CEFTIZOXIME (FK 749): NEW CEPHALOSPORIN

VOL. 16, 1979

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ANTIMICROB. AGENTS CHEMOTHER.

TABLE 7. Influence of challenge dose on the protective effect of FK 749 and cefotaxime against experimental infections in mice" FK 749

Organism

LDw

ED60 (mg/kg)

Cefotaxime Factor

ED,0 (mg/kg)

Factor

10,000

1

0.04 1.33

P. vulgari.s 63

1oo

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056.06

1,290c

S. marcescens 31

1001

Ceftizoxime (FK 749), a new parenteral cephalosporin: in vitro and in vivo antibacterial activities.

ANTIMICROBIAL AGENTS AND CHEMOTHERApY, Nov. 1979, p. 54-548 Vol. 16, No. 5 0066-4804/79/11-0540/09$02.00/0 Ceftizoxime (FK 749), a New Parenteral C...
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