H. Knothe, P. M. Shah

In Vitro Activity of Cefodizime Summary: Cefodizime is a bactericidal cephem with the typical broad spectrum activity of an aminothiazolyl cephalosporin, including both gram-positive and gram-negative bacteria: its MIC90 is 0.125 mg/1 for Streptococcus pneumoniae, Streptococcus" pyogenes and other streptococci; and 0.05 mg/l for Haemophilus spp., Neisseria meningitidis, Neisseria gonorrhoeae and Moraxella catarrhalis; while [5-1actamase positive strains of M. catarrhalis require 1 mg/1. Less than 1 mg/l is needed for Escherichia coli, Klebsiella spp., Proteus spp. and Shigella spp. The MICg0 is 4 mg/1 for methicillin-sensitive Staphylococcus aureus, Morganella

morganii, Providencia spp. and most strains of Serratia marcescens, Citrobacter spp. and Enterobacter spp. Staphylococcus epidermidis, Enterococcus faecalis and most strains of Pseudomonas spp. and Acinetobacter spp. are considered cefodizime-resistant. Cefodizime is unaffected by plasmid-mediated IMactamases, but it is hydrolyzed by some chromosomally mediated enzymes, thus resembling other third-generation cephalosporins. Cefodizime has high affinity for PBP 3 and PBP IA and IB (Escherichia coli); in S. aureus it shows the highest affinity for PBP t.

Zusammenfassung: In vitro Aktivitiit yon Cefodizim. Cefodizim ist ein bakterizides Cephem mit dem typischen breiten Spektrum eines AminothiazolylCephalosporins, das sowohl grampositive als auch gramnegative Bakterien einschlie6t: Die MHK90 betr~igt 0,125 mg/1 gegeniiber Streptococcus pneumoniae, Streptococcus pyogenes und anderen Streptokokken. Sie liegt ftir Haemophilus spp., Neisseria meningitidis, Neisseria gonorrhoeae und Moraxella catarrhalis bei 0,05 mg/l. 13-Laktamase positive St/imme von M. catarrhalis ben6tigen 1 mg/1. Weniger als 1 mg/1 wird f/Jr Escherichia coli, Klebsiella spp., Proteus spp. und Shigella spp. ben6tigt; die MHKg0 betr/igt 4 mg/1 gegeniJber Methicillin-empfindlichen Stfimmen von

Staphylococcus aureus, sowie gegen Morganella morganii, Providencia spp., die meisten Stamme von Serratia marcescens, Citrobacter spp. und Enterobacter spp. Als Cefodizim-resistent sind Staphylococcus epidermidis, Enterococcus faecalis sowie die Mehrzahl der St~imme von Pseudomonas spp. und Acinetobacter spp. anzusehen. Cefodizim wird von plasmidgebundenen ~-Laktamasen nicht angegriffen, wie andere Cephalosporine der dritten Generation wird es aber von einigen chromosomal gebundenen [3-Laktamasen hydrolysiert. Cefodizim besitzt eine hohe Affinitfit zu PBP 3 sowie PBP IA und IB (Escherichia coli); bei S. aureus entfaltet es seine h6chste Affinit/it zu PBP 1.

Introduction

In Vitro Activity

Cefodizime is a new cephalosporin with an extended antibacterial spectrum. Like cefotaxime, cefodizime possesses an aminothiazolyl-a-syn-methoximinoacetamide side chain in the 7-position. This moiety - also common to ceftriaxone, ceftizoxime and cefmenoxime contributes to 13-1actamase stability and provides high antibacterial activity against gram-negative organisms, while conserving a major part of the gram-positive activity of previous cephalosporins [1-6]. Cefodizime has an additional substituent, a 4-methyl, 5-carboxymethyl, 1,3,thiazole-2-thio group in the 3'-position [7]. This specific side chain confers prolonged elimination half-life in animals and man, together with high metabolic stability [8,9]. In this review the in vitro antimicrobial profile of cefodizime is summarized, with particular attention given to results from well standardized, comparative investigations which compared cefodizime with cefotaxime - now regarded as the reference compound in this field and other cephalosporins. A geographically widespread range of pathogens was obtained by including studies from Europe, Japan and the USA.

Table 1 summarizes the minimum inhibitory concentrations (MICs) of cefodizime for members of Enterobacteriaceae in comparison to cefotaxime, cefotiam, cefotetan and cefoperazone, as reported by different investigators [6,10-13]. Against Enterobacteriaceae, cefodizime exhibits potent in vitro activity which resembles that of cefotaxime, the latter generally having MICs of one to two dilution steps lower. The MIC90 values of cefodizime for Escherichia coli, Klebsiella spp., Proteus spp., Salmonella spp. and Shigella spp. are generally less than 1 mg/1. High activity, clearly superior to those of cefotiam and cefotetan, is also shown against Morganella morganii and Providencia spp. The majority of Serratia marcescens strains, Citrobacter spp. and Enterobacter spp. are susceptible to cefodizime at concentrations in the range of 4 to 8 mg/1, easily achievable in vivo; large numbers of these strains, usually producers of 13-1actamases, are inhibited at a concentration of 1 mg~. Prof. Dr. H. Knothe, Prof. Dr. P. M. Shah, Zentrum der Inneren Medizin, Labor fiir Klinische Mikrobiologie,J. W.-Goethe-Universit~it,Theodor Stern Kai 7-14, W-6000Frankfurt/Main 70, Germany.

Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1992

S3

H . K n o t h e , P. M . S h a h : I n V i t r o A c t i v i t y o f C e f o d i z i m e

Table 1 .: In vitro activity of cefodizime and other cephalosporins against members of Enterobacteriaceae.

Escherichia Escherichia Escherichia Escherichia Escherichia

coli

coli coli coli coli

(95) (108) (27) (25) (25)

(50) (87) Klebsiella p n e u m o n i a e (25) Klebsiella p n e u m o n i a e (26) Klebsiella spp. (25) Proteus mirabilis (98) Proteus mirabilis (54) Proteus mirabilis (23) Proteus mirabilis (25) Proteus mirabilis (25) Proteus vulgaris (84) Proteus vulgaris (12) Proteus vulgaris (15) Proteus vulgaris (10) S a l m o n e l l a spp. (108) S a l m o n e l l a spp. (40) Shigella spp. (108) M o r g a n e l l a m o r g a n i i (93) M o r g a n e l l a m o r g a n i i (22) M o r g a n e l l a m o r g a n i i (11) M o r g a n e l l a m o r g a n i i (10) Providencia spp. (29) Providencia rettgeri (58) Providencia rettgeri (21) Serratia m a r c e s c e n s (108) Serratia m a r c e s c e n s (24) Serratia m a r c e s c e n s (25) Serratia m a r c e s c e n s (25) Citrobacterfreundii (75) Otrobacterfreundii (20) Citrobacter spp. (21) Citrobacter spp. (21) Enterobacter cloacae (100) Enterobacter cloacae (20) Enterobacter spp. (71) Enterobacter spp. (25) Enterobacter spp. (48)

Klebsiella p n e u m o n i a e

Klebsiella p n e u m o n i a e

0.10 0.125 0.03 0.39 0.25 0.10 0.25 0.20 0.25 0.07 0.13 0.004 0.004 0.024 0.015 0.025 0.03 0.20 0.06 0.20 0.25 0.10 0.10 0.13 0.39 0.06 1 0.025 0.39 3.13 1.92 12.50 4 0.78 8 2.52 1 3.13 12.50 2 0.44 0.50

0.39 0.50 0.13 0.39 0.50 0.20 4 0.78 0.50 0.33 0.025 0.25 0.02 0.10 0.015 0.78 8.97 1.56 16 0.39 0.50 0.20 3.13 3.40 3.13 4 8 0:39 3.13 50 15.22 100 16 >100 64 126 2 100 100 512 19.24 32

0.025 0.03 0.02 0.10 0.06 0.025 0.125 0.10 0.06 0.03 0.013 0.015 0.01 0.024 0.015 0.025 0.01 0.39 0.06 0.05 0.03 0.025 0.05 0.04 0.39 0.12 0.25 0.013 0.20 0.78 0.37 3.13 0.50 0.20 2 0.11 0.12 0.78 3.13 1 0.12 0.12

0.05 0.006 0.07 0.20 0.12 0.05 0.50 0.20 0.12 0.19 0.025 0.125 0.03 0.10 0.015 0.78 0.27 3.13 16 0.10 0.06 0.05 3.13 2.06 1.56 2 2 0.10 0.78 12.50 1.33 50 4 50 16 5.40 0.50 100 50 128 4.42 8

0.10 0.20 . . . 0.06 0.17 . . . 0.20 0.39 . . . . . . 0.09 0.61 0.39 0.39 . . . 0.27 3.22 . . . 6.25 >100 6.86 >128 . . . 0.20 0.20 . . . 0.05 0.20 6.25 50 0.39 14.49 . . . . . . 0.20 6.25 100 >100 53.59 >128 . . . 0.78 >100 . . . 1.08 25.49 . . . 100 >100 . . . 0.96 61.57 . . .

Resistance of Enterobacteriaceae to cefodizime is infrequent, usually limited to some strains of Citrobacter spp., Enterobacter spp. and S. marcescens - although very rarely strains of Klebsiella spp. and indole-positive Proteus are included - and is due to overproduction of [3-1actamases. Table 2 summarizes the MICs of cefodizime and the above-mentioned cephalosporins for other (nonenterobacterial) aerobic gram-negative organisms

[6,10-16]. Cefodizime shows exceptional antibacterial activity against Haemophilus influenzae, which is even more sensitive to cefodizime than to cefotaxime. Furthermore, the activity of cefodizime exceeds those of cefotiam and cefotetan. Hyodo et al. [10] reported inhibition of all H. inftuenzae strains tested at concentrations of 0.05 mg/1 or

S4

0.10

0.20

. 0.10 . 0.025 . 0.10 . 0.20 . 0.20 . 0.20 0.78 . 0.05 . 0.05 1.56 12.50 . . 0.39 3.13 3.13 25 . 1.56 . . 50 100 . .

0.39 .

-

-

1 1.10

4 5.76

-

-

. 0.05 0.20

.

-

4

128

-

-

0.13

14.19

. 0.20 0.39

.

-

-

2 0.25

16 80.63

-

-

. 0.39 1.56

.

-

-

>128

>128

-

-

-

-

. 0.05

0.10 6.25 12.50 . . . . 6.25 6.25 50 >100 . . >100 . . >100 >100 .

-

.

2

4

-

-

-

-

>128

>128

-

-

-

-

-

-

-

-

>128

>128

-

-

256 >128

512 >128

-

-

512 35.44

>128

et al. (10) et al. (11) L i m b e r t et al. (12) K a s a i et al. (13) Jones et al. (19) H y o d o et al. (10) Stitle et a l . ( l l ) K a s a i et al. (13) Jones et al. (19) L i m b e r t et al. (12) H y o d o et al. (10) Stille et al. (11) L i m b e r t et al. (12) K a s a i et aL (13) Jones et al. (19) H y o d o et al. (10) L i m b e r t et al. (12) K a s a i et al. (13) Jones et al. (19) H y o d o et al. (10) Stille et al. (11) H y o d o et al. (10) H y o d o et al. (10) L i m b e r t et al. (12) K a s a i et al. (13) Jones et al. (19) Jones et al. (19) H y o d o et aL (10) K a s a i et al. (13) H y o d o et al. (10) L i m b e r t et al. (12) K a s a i et al. (13) Jones et al. (19) H y o d o et'al. (10) Stille et al. (11) L i m b e r t et al. (12) Jones et al. (19) H y o d o et aL (10) K a s a i et al. (13) StilIe et al. (11) L i m b e r t et al. (12) Jones et al. (19) Hyodo Stille

less. Jones et al. [6] observed practically no difference in susceptibility to cefodizime between ampicillin-sensitive and ampicillin-resistant isolates of/4. influenzae. Neisseria meningitidis is highly susceptible to cefodizime: concentrations as low as 0.008 mg/l or less were sufficient to inhibit 90% of the strains [6]. Cefodizime also shows high potency against Neisseria gonorrhoeae, with MIC90 values of 0.016--0.024 mg/l encompassing not only non-peniciUinase-producing N. gonorrhoeae (non-PPNG) but also PPNG strains. With regard to Moraxella catarrhalis, Maesen et al. [14] reported a distinct susceptibility pattern between non-[A-lactamase producing isolates, which were inhibited by 0.06 mg/1, and the [5-1actamase positive strains, for which the MIC90 of cefodizime was 1 mg/l.

Infection 20 (1992) Suppl. 1

© M M V Medizin Verlag G m b H Mfinchen, MiJnchen 1992

I-I. Knothe, P. M. Shah: In Vitro Activity of Cefodizime

Table 2.: In vitro activity of cefodizime and other cephalosporins against other aerobic gramrnegative organisms and non-fermenting organisms.

i!iiiiiiiiiiiiiiiiiiiiiti!i Haemophilus influenzae (63) Haemophilusinfluenzae(11) Haemophilus influenzae (60) Haemophilus influenzae (84) Haernophilus influenzae ampicillin R (21) ampicillin S (20)

Neisseria rneningitidis (25) Neisseria gonorrhoeae (10) Neisseria gonorrhoeae (28) Neisseria gonorrhoeae (20) Neisse(ia gonorrhoeae Non-PPNG (392) PPNG (32)

256

1 16

2 128

. .

4 4 6.25

8 16 25

1 1 3.13

2 4 12.50

0.20 . .

. . 0.05

.

. 0.23 >100

.

. 0.78 0.66 -

ii:ii!i li Iili i!iiii!ii ili!i!! i iiiiiiiiiiii!i!iii ilili!iiiiiiliiiiii! ! 1.56 3.13 . . 1.56 . -

3.13 3.13 . . . . 1.56 . . 0.04

>100 . 6.25 6.25

>100 . . 12.5 0.17 12.5 -

-

-

0.17 -

0.76 -

Hyodo et al. (10) Kasai et al. (13) Jones et al. (19) Maesen et al. (14) Hyodo et al. (10) Jones et al. (19) Limbert et al.(12) Hyodo et al. (10) Jones et al. (19) Hyodo et al. (10) Limbert et al. (12) Kasai et al. (13)

Staphylococus aureus

MSSA (48) MRSA (10)

. .

. .

. .

. .

. .

Jones'et al. (19)

Staphylococcus aureus

PeniciUinase negative (48) Penicillinase positive (38) Staphylococcus epidermidis (107)

including both reference strains and clinical isolates, and found that about 80% of the strains were inhibited by 3.125 rag/1 cefodizime, the other 20% being resistant. These authors concluded that cefodizime was active against many of the 209 anaerobic strains investigated, including Clostridium perfringens, Bacteroides bivius, Bacteroides intermedius, Bacteroides corporis, Fusob a c t e r i u m n u c l e a t u m and Peptostreptococcus spp. In this

comparative study, the spectrum of cefodizime resembled those of cefotaxime and cefmenoxime. Clostridium innocuum, Clostridium septicum and Bacteroides thetaiotaomicron exhibited resistance.

Cellular Permeability, ~-Lactamase Stability and Binding to Penicillin-Binding Proteins (PBPs) Cefodizime shows a high penetration of the porins in gram-negative organisms, similar to cefotaxime [19]. Likewise, in E. coil and P. aeruginosa mutants with reduced permeability, the MICs of cefodizime increased in proportion to those of cefotaxime [20]. Like cefotaxime and other compounds having an iminomethoxy substituent, cefodizime is not affected by the majority of plasmid- or chromosomally mediated enzymes [21]. H y o d o et al. [10] showed that cefodizime was stable against several different penicillinases and cephalosporinases. Cefodizime's resistance to hydrolysis was similar to that shown by cefotaxime, cefotetan and cefbuperazone, but markedly higher than that of cefotiam. These authors found that cefodizime was unstable against oxyimino-cephalosporin hydrolyzing enzymes from Proteus vulgaris and Klebsiella oxytoca. 13-1actamases which hydrolyze cefotaxime can also cleave cefodizime and are more active against the latter [12]. S6

. . . . . . 0.78 3.13

. . 25

50

0.25 0.50

0.10 2

-

-

Stille et al. (11) Hyodo et al. (10)

H y o d o et al. [10] investigated induction of 13-1actamase

production by different antibiotics and found very little activity in the case of cefodizime. Cefodizime and cefotiam exerted the lowest degree of induction when compared to cefotaxime, cefoxitin and cefbuperazone. Cefodizime showed a PBP-binding profile similar to that of cefotaxime, with high affinity for PBP 3 of E. coli, followed by affinity for PBP IA, IB and PBP 2 [12]. Similar results were observed by H y o d o et al. [10], who demonstrated that cefodizime possessed acceptable affinity for all PBP targets except PBP 5. In S. aureus, cefodizime showed the highest affinity for PBP 1, followed by PBP 2 and PBP 3 in decreasing order [10]. At subinhibitory concentrations the binding of cefodizime, like cefotaxime, results in filamentous transformations. At inhibitory and higher levels, cefodizime induced protoplast formation with subsequent bacteriolysis [12].

Influence of Inoculum Size and Other Test Conditions on the MIC The inoculum size had little or no effect on the in vitro activity of cefodizime against non-13-1actamase producing bacteria [12]. Jones et al. [6] reported no effect of inoculum on the MICs of cefodizime for S. aureus, but increased MICs for Citrobacter, Enterobacter and indole-positive Proteus spp. using a dense inoculum of 107 CFU/ml. This effect is more evident for strains producing chromosomally .mediated 13-1actamases [21]. In contrast, even very large inocula did not substantially affect the in vitro activity of cefodizime when strains containing plasmid-mediated [5-1actamases, the clinically more relevant group, were tested [12].

Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, Mfinchen 1992

H. Knothe, P. M. Shah: In Vitro Activity of Cefodizime

The activity of cefodizime against Enterobacteriaceae and S. aureus was not appreciably affected by the culture medium composition [12,21]. Similarly, modifications in pH of the medium in the range pH 5.5 to pH 8 did not lead to clinically relevant changes in activity [12,21].

Bactericidal Activity

Jones et al. [6] reported the bactericidal properties of cefodizime. They showed that in over 90% of the isolates tested, the minimum lethal (bactericidal) concentration (MBC) was at or within a log2 dilution of the corresponding MIC; the maximum MBC90/MICg0 ratio observed in this study was 4. Scully et al. [21] found that the presence of 50% normal human serum increased the MBC for E. coli, Klebsiella pneumoniae and S. marcescens without affecting the corresponding MICs. By investigating cefodizime bactericidal activity against E. coli and S. aureus, Limbert et al. [12] demonstrated that both pathogens were efficiently killed at MIC-equivalent concentrations. Shah [22] analyzed killing activity in a model with declining antibiotic concentrations, simulating plasma elimination half-life; under these conditions cefodizime was rapidly bactericidal against E. coli, K. pneumoniae, Proteus mirabilis, Enterobacter spp. and Citrobacter spp. The rapid onset of cefodizime bactericidal activity was a result of its high affinity for PBP 3 and PBP IA and lB.

Discussion

Cefodizime is a bactericidal cephem structure with the typical broad spectrum of an aminothiazolyl cephalosporin, including both gram-positive and gram-negative bacteria. Its in vitro activity resembles that of cefotaxime, the latter having MICs generally one or two dilution steps lower. Cefodizime possesses potent activity against Enterobacteriaceae: the MIC90 values for E. coli, Klebsiella spp., Proteus spp. and ShigeUa spp. are usually less than 1 mg/1, while those for M. morganii and Providencia spp. as well as most strains of S. marcescens, Citrobacter and Enterobacter are around 4 mg/l. Among other gram-negative organisms, Haemophilus spp., N. meningitidis and N. gonorrhoeae are extremely sensitive to cefodizime, with MICg0 values of 0.05 mg/1. Similar concentrations inhibit non-[Llactamase producing M. catarrhalis, whilst [I-lactamase positive strains require 1 mg/1. In contrast, the non-fermenting organisms are predominantly cefodizime-resistant. Cefodizime shows high activity against most of the clinically important aerobic gram-positive organisms: 90% of S. pneumoniae, S. pyogenes and other streptococci are usually inhibited by 0.125 mg/1, and methicillin-sensitive S. aureus by 4 mg/1. MRSA strains, S. epidermidis and E. faecalis are considered cefodizime-resistant. Cefodizime is virtually unaffected by plasmid-mediated [3-1actamases, but it is hydrolyzed by some chromosomally mediated enzymes, thus resembling cefotaxime and other third-generation cephalosporins. Cefodizime has high affinity for PBP 3 and PBP IA and IB (E. coli); in S. aureus it shows the highest affinity for PBP 1.

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aminothiazolyl cephalosporin. V. Synthesis and structure-activity relationships in the cefodizime series. J. Antibiot. 40 (1987) 29-42. Klesd, N., lambert, M , Seeger, K., Seibert, G., Winkler, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. II. Comparative studies on the pharmacokinetic behavior in laboratory animals. J. Antibiot. 37 (1984) 901-909. Dagrosa, E. E , Hajdfi, P , Malerczyk, V., de I_ooze, S., Seeger, IL, GrOtsch, H.: Dose linearity and other pharmacokinetics of cefodizime after single-dose intravenous administration. Clin. Ther. 10 (1987) 18-31. Hyodo, A., Higashitani, F., Mitsuhashi, S., Inoue, M.: In vitro and in vivo antibacterial activity of eefodizime. Chemotherapy 36 (S-5) (1988) 1-24. Stifle, W., Spieler, S.: Antibacterial activity of cefodizime (HR 221). Proceedings of the 14th International Congress of Chemotherapy, Antimicrobial Section 2. Recent Adv. Chemother. (1985) 923-924. Limbert, M., Klesei, N., Seeger, K., Seibert, G., Winider, I., Schrinner, E.: Cefodizime, an aminothiazolyl cephalosporin. I. In vitro activity. J. Antibiot. 37 (1984) 892-900. Kasai, K., Tsuji, A., Miyazald, S., Goto, S., Fujimoto, IL, Masuyoshi, S., Arai, S.: In vitro antibacterial activity and [$-laetamase stability of cefodizime, a new cephalosporin antibiotic. Jpn. J. Antibiot. 37 (1984) i294-1305. Maesen, F. P. V., Davies, B. I., van den Bergh, J. J. A. M., Gubbelmans, H. L. L , Meek, J. C. E., Geraedts, W. H.: Cefodizime

Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GrnbH Miinchen, Miinchen 1992

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H. Knothe, P. M. Shah: In Vitro Activity of Cefodizime and cefotaxime in acute exacerbations of chronic bronchitis: a randomized double-blind prospective stud)' in 180 patients. J. Antimicrob. Chemother. 25 (1990) 413-422. 15. van der Willigen, A. H., Wagenvoort, J. H. T., Schalla, W. O., Knapp, J. S., Boot, J. M., Heeres-Weststrate, P. L., Michel, M. Fo, van Klingeren, B., Stoiz, E.: Randomized comparative stud)' of 0.5 and 1 g of cefodizime (HR 221) versus 1 g of cefotaxime for acute uncomplicated urogenital gonorrhea, Antimicrob. Agents Chemother. 32 (1988) 426--429. 16. Khan, M. Y., Gruninger, R. P., Nelson, S. M., Obaid, S. R.: Comparative in vitro activity of cefodizime, ceftazidime, aztreonam, and other selected antimicrobial agents against Neisseria gonorrheae. Antimicrob. Agents Chemother. 23 (1983) 477-478. 17. Pascual, A., Borobio, V., Gareia-Iglesias, M. C., Perea, E. J.: Comparative in-vitro activity of cefodizime, cefpirome, carumonam and RU-28965 with other antimicrobials against anaerobes. Antimicrob. Agents Chemother. 19 (1987) 701-703,

S8

18. Watanabe, K., Sawa, K., Sawamura, H., Yamaoka, K., Aoki, M., Kato, N., Ueno, K.: In vitro and in vivo activity of cefodizime against anaerobic bacteria. Chemotherapy 36 (S-5) (1988) 77-94. 19. Jones, R. N., Wilson, H. W.: Comparative heta-lactamase hydrolysis of and inhibition by 7-aminothiazolyl alpha-methoxyimino cephalosporins. Infection 10 (1982) 303-304. 20. Seibert, G.: Studies on the penetration properties of HR 221 through the cell wall of gram-negative bacteria. Hoechst AG, Frankfurt 1982, data on cefodizime submission file. 21. Scully, B. E., Jules, I~, Nell, H. C.: In vitro activity and 13-1actamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin. Antimicrob. Agents Chemother. 23 (1983) 907-913. 22. Shah, P. M.: Bactericidal activity of cefodizime under conditions simulating serum pharmaeokinetic parameters. Proceedings of the 14th International Congress of Chemotherapy, Antimicrobial Section 2. Recent Adv. Chemother., Kyoto (1985) 935-936.

Infection 20 (1992) Suppl. 1 © MMV Medizin Verlag GmbH Miinchen, M~inchen 1992