Special Addendum
In Vitro Evaluation of Cefpodoxime, a New Oral Cephalosporin of the Third Generation, Editors: W. Marget, R. Kiehn, H. Kraeft A. Bauernfeind, R. Jungwirth
Antibacterial Activity of Cefpodoxime in Comparison with Cefixime, Cefdinir, Cefetamet, Ceftibuten, Loracarbef, Cefprozil, BAY 3522, Cefuroxime, Cefaclor and Cefadroxil Summary: The new oral cephalosporins cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate enhanced activity against Enterobacteriaceae susceptible to the established compounds as well (e.g. cefuroxime, cefaclor, cefadroxil). In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten include in their spectrum species hitherto resistant to oral cephalosporins (Proteus vulgaris, Providencia spp., Yersinia enterocolitica). Besides, the majority of these compounds demonstrate relevant activity (MICs0 equal to or below 2 mg/1) against Enterobacter spp., Citrobacter freundii, Serratia spp. and Morganella morganii. Ceftibuten is the most potent oral cephalosporin against most of the Enterobacteriaceae. Non-fermentative bacilli (Acinetobacter spp., Pseudomonas spp.) remain completely resistant to oral cephalosporins (except some Acinetobacter species against cefdinir and Pseudomonas cepacia against ceftibuten). Antistaphylococcal activity for oral cephalosporins is highest for cefdinir followed by BAY 3522, cefprozil, cefuroxime and cefpodoxime. Loracarbef, cefaclor and cefadroxil are about equally active, while the other compounds are only weakly active (cefixime) or inactive (cefetamet, ceftibuten).
Enterococci are insensitive to new generation oral cephalosporins as they have been to established compounds. The most active oral cephalosporins against hemolytic streptococci are cefdinir and cefprozil. Streptococcus pneumoniae, Streptococcus milleri and Streptococcus mitior are most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522. Penicillin resistant pneumococci have to be regarded as resistant to all oral cephalosporins. Fastidious pathogens like Haemophilus spp., Moraxella catarrhalis and Neisseria gonorrhoeae are more susceptible to cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten than to the other oral cephalosporins. The activity of oral cephalosporins is only weak against Listeria spp., Helicobacter pylori and anaerobic pathogens (except BAY 3522). Bordetella pertussis remains resistant to all absorbable cephalosporins. Progress in antibacterial activity of oral cephalosporins was mainly achieved by cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten against Enterobacteriaceae and the fastidious pathogens and against staphylococci and the nonenterococcal streptococci by cefdinir, BAY 3522, cefprozil and cefpodoxime.
Zusammenfassung:AntibakterielleAktivitiit yon Cefpodoxirn im
etablierten Substanzen. Die aktivsten oralen Cephalosporine gegen h/~molysierende Streptokokken sind Cefdinir und Cefprozil. Streptococcuspneumoniae, Streptococcus milleri und Streptococcus mitior sind am empfindlichsten gegen Cefpodoxim, Cefdinir, Cefuroxim und BAY 3522. Penicillinresistente Pneumokokken mtissen als resistent gegeniiber allen oralen Cephalosporinen betrachtet werden. Anspruchsvolle Erreger wie Haemophilus spp., Moraxella catarrhalis und Neisseria gonorrhoeae sind gegen Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten empfindlicher als gegen die anderen oralen Cephalosporine. Die Aktivit/it oraler Cephalosporine gegen Listeria spp., Helicobacterpylori und Anaerobier (Ausnahme BAY 3522) ist nur schwach. Bordetella pertussis bleibt gegen alle resorbierbaren Cephalosporine resistent. Der Fortschritt in der antibakteriellen Aktivit/it oraler Cephalosporine wurde gegen Enterobacteriaceae und anspruchsvoUe Erreger haupts/ichlich durch Cefpodoxim, Certain, Cefdinir, Cefetamet und Ceftibuten erlangt, gegen Staphylokokken und Streptokokken (aul3er Enterokokken) durch Cefdinir, BAY 3522, Cefprozil und Cefpodoxim.
Vergleichrnitanderen oralen Cephalosporinen. Die neuen oralen Cephalosporine Cefpodoxim, Cef'trdm, Cefdinir, Cefetamet und Ceftibuten zeigen eine verst/irkte Aktivit/it auch gegen solche Enterobacteriaceae, die gegen etablierte Substanzen empfindlich sind (z.B. Cefuroxim, Cefaclor, Cefadroxil). Zus/itzlich schlieBt das Spektrum von Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten Spezies ein, die gegen die bisherigen oralen Cephalosporine resistent waren (Proteus vulgaris, Providencia spp., Yersinia enterocolitica). Daneben zeigt die Mehrheit der neuen Substanzen erh6hte Aktivit/it (MHKs0 < 2 mg/1) gegen Enterobacter spp., Citrobacter freundii, Serratia spp. und MorganeUa morganii. Gegen die meisten Enterobacteriaceae ist Ceftibuten das wirksamste orale Cephalosporin. Non-Fermenter (Acinetobacter spp., Pseudomonas spp.) bleiben gegeniJber oralen Cephalosporinen vollst/indig resistent (mit Ausnahme einiger Acinetobacter-Spezies gegen Cefdinir und Pseudomonas cepacia gegen Ceftibuten). Die Antistaphylokokken-Aktivit/it oraler Cephalosporine ist am h6chsten bei Cefdinir, gefolgt von BAY 3522, Cefprozil, Cefuroxim und Cefpodoxim. Loracarbef, Cefaclor und Cefadroxil sind etwa gleich aktiv, w/ihrend die anderen Substanzen nur schwach aktiv (Cefixim) oder inaktiv sind (Cefetamet, Ceftibuten). Enterokokken sind gegeniiber der neuen Generation oraler Cephalosporine ebenso unempfindlich wie gegeniiber den
Prof. Dr. A. Bauernfeind, R. Jungwirth, Max-von-Pettenkofer-Institut, Pettenkoferstr. 9a, W-8000 Mfinchen 2, Germany. * Supported by Luitpold-Werk, a company of the Sankyo group.
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, M6nchen 1991
353 / 63
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime Introduction
Oral cephalosporins established their role in therapy of infections of the respiratory tract, skin and skin structure, urinary tract and bone infections. The use of the established compounds (e.g. cephalexin, cefadroxil, cefaclor) is limited by their restricted activity against Haemophilus, Moraxella, Neisseria, alpha-hemolytic streptococci (Streptococcus miUeri group, Streptococcus mitior) and most species among Enterobacteriaceae except Escherichia coli, Klebsiella, Proteus mirabilis [1-3]. However, beta-lactamases hydrolyzing established cephalosporins are emerging in Escherichia coli and Klebsiella [4]. These limitations as well as the short serum half-life (between 30 and 90 rain) necessitating frequent dosing and limited chemical stability (e.g. of cefaclor) of established oral cephalosporins initiated the development o f absorbable cephalosporins with improved characteristics. The new compounds are structural derivatives of ancestor cephalosporins: 1. of the aminothiazole-methoximino type (e.g. cefdinir, ceftibuten, cefetamet (pivoxil-ester), cefpodoxime (proxetil-ester); 2. of the glycyl-cephalosporin type (e.g. loracarbef, cefprozil, BAY 3522); 3. of the furanyl-methoximino-cephalosporin type (e.g. cefuroxime-axetil). Progress achieved by the new compounds in comparison with established oral cephalosporins as to their in vitro activity against a broad spectrum of human pathogens is presented in this investigation. Materials and Methods
erythrocytes and 2% horse serum) were incubated in a candle jar for growth of Haemophilus spp., Neisseria gonorrhoeae and Bordetella pertussis. Helicobacter pylori was grown on Columbia-Agar (Oxoid, supplemented by 5% human blood) in a microaerophilic atmosphere produced by the gas generating kit BR 56 (Oxoid). Wilkins-Chalgren-Agar (Oxoid), supplemented by 10% sheep blood frozen and thawed twice prior to addition as used for anaerobes together with the oxoid gas generating kit BR 38. E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923 were used as MIC reference strains. Results
Enterobacteriaceae The activity of established cephalosporins (e.g. cefuroxime, cefaclor, cefadroxil) against Enterobacteriaceae was mainly restricted to the majority of isolates of E. coli, Klebsiella spp., Enterobacter sakazakii, P. mirabilis, Salmonella spp. and Shigella spp. This holds true as well for loracarbef, cefprozil and BAY 3522 among the newer compounds (Table 1). Cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten are, however, more potent against these pathogens, in particular cefixime and ceftibuten against P. mirabilis. In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten expand the antibacterial spectrum of oral cephalosporins within Enterobacteriaceae to include species hitherto resistant to oral cephalosporins, namely Proteus vulgaris (except cefdinir), Providencia spp., Yersinia enterocolitica (except cefixime). Besides cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate remarkable activity (MICs0 equal to or below 2 mg/1) against Enterobacter cloacae (except cefpodoxime and cefdinir), Enterobacter aerogenes, Hafnia alvei (only cefdinir and ceftibuten), Citrobacter freundii, Serratia marcescens (except cefpodoxime and cefdinir), Serratia liquefaciens (except cefdinir) and Morganella morganii (except cefdinir and cefetamet). The enhanced activity against these pathogens indicates improved stability of the new compounds against the chromosomal cephalosporinases produced by the majority of these organisms. This effect is most impressive for ceftibuten, the most potent among the oral cephalosporins against Enterobacteriaceae except for Proteus spp., whereas cefixime is one log 2 more active.
Antibiotics compared in this investigation were cefpodoxime (Sankyo Europe), cefixime (Merck), cefdinir (Fujisawa), cefetamet (Hoffmann- LaRoche Inc.), ceftibuten (ScheringPlough Corporation), cefuroxime (Hoechst AG), loracarbef and cefaclor (Eli Lilly and Co.), cefprozil and cefadroxil (Bristol-Myers) and BAY 3522 (Bayer AG). These compounds were obtained from the manufacturers as powders with stated potency. Determination of minimal inhibitory concentrations (MICs): Minimal inhibitory concentrations (MICs) were determined by agar dilution technique. An inoculum of 104 CFU per spot (105 CFU per spot for anaerobes) was delivered by a multipoint inoculator (Denley) to a series of agar plates which obtained the antibiotic in twofold dilutions. Incubation was usually for t6 h (24 h for methicillin resistant staphylococci, 48 h for anaerobes, Bordetella pertussis and Helicobacter pylori). Incubation tempe- Non-Fermentative Bacilli (NFB) rature was at 35°C except for methicillin resistant staphylococci (32°C). The MIC was determined as the lowest concentration of Taxonomy within the genus Acinetobacter has changed antibiotic at which no visible growth or growth -- 64 8 > 64
0.06> 64 2 > 64
0.25> 64
0.25> 64
Escherichia coli AMP-S (20)
Range MICso MICgo
0.5
1
1
2
0.54 2 4
0.030.25 0.06 0.13
0.52 0.5 1
).58 4 8
164 2 32
18 2 8
0.516 0.5 8
816 8 16
0.061 0.13 0.5
0.030.25 [).06 9.13
0.52 0.5 2
).516 4 8
132 2 16
18 2 8
0.251 0.5 1
8
0.13> 64 16 > 64
0.25, 64 1 - 64
9.03,64 0.5 ,64
1> 54 > 54 > 54
864 64 64
254 54 54
4> 64 16 > 64
2> 64 > 64 > 64
0.25>64 0.5 32
0.25,64 0.5 64
1> 54 32 > 54
1664 64 64
864
32 64
Klebsiella pneumoniae (20)
Range MICso MICgo
Klebsiella oxytoca (20)
Range MICso MICgo
8 8
Enterobacter cloacae (66)
Range MIC5o MICgo
4> 54 > 54 > 54
Enterobacter aerogenes (13)
Range MICso MICgo
1
1
64
> 64
0.5>64 1 > 64
0.131 0.25 0.5
0.0160.5 0.06 0.25
0.034 0.5 1
0.132 0.25 0.5
.0160.13 0.03 0.06
0.516 1 2
18 2 4
232 16 32
1> 64 4 > 64
0.5> 64 4 32
0.2564 2 32
0.13> 64 8 64
0.1316 0.5 8
2> 64 64 > 64
864 64 64
64 64 64
0.2532 1 8
0.1364 1 8
0.13> 64 0.5 16
0.138 1 2
0.0632 0.5 4
1> 64 8 32
464 64 64
0.5> 64 4 64
0.25> 64 1 16
2> 64 8 > 64
0.25> 64 2 64
0.068 0.25 2
32> 64 > 64 > 64
6464 64 64
. 64 .64 .64 .64
0.25> 64 2 > 64
0.2532 2 32
0.5> 64 4 > 64
0.2516 0.5 16
0.138 !> 0.25 8 >
0.060.13 0.06 0.13
0.0160.06 0.016 0.06
0.138 0.13 0.5
0.060.13 0.06 0.13
2-
> 64 8 > 64
8-
> 64 > 64 > 64
8-
> 54 > 54 > 54
Enterobacter sakazakii (11)
Range MICso MICgo
0.516 2 8
116 4 8
0 131 0 25 t.5
Hafnia alvei (15)
Range MICso MIC9o
8-
1-
4-
8-
> 64 4 > 64
> 64 16 > 64
> M > 54 > 54
2> 64
4> 64 32 > 64
4> 64 64 > 64
32> 64 > 64 > 64
16> 64 > 64 > 64
32> 64 > 64 > 64
16> 64 64
> 64
32> 64 > 64 > 64
Citrobacter freundii (38)
Range MICso MIC9o
2,64
64 . 64
4 64
Serratia marcescens (38)
Range MICso MIC9o
Serratia liquefaciens (15)
Range MICso MIC9o
1664 64 64
64
• 64
64 64
• 64 • 64
14 2 2
416 8 16
> 64
> 64 > 64
Proteus mirabilis (20)
Range MICso MICgo
Infection 19 (1991) No. 5
0.03 0.03 0.03
© M M V Mcdizin Verlag G m b H Miinchen, Mtinchen 1991
14 2 4
18 4 4
14 4 4
416 8 8
355 / 65
A. B a u e r n f e i n d , R. Jungwirth: Comparative Antibacterial Activity of C e f p o d o x i m e
Table 1 (continued) ......................
N~
ii i!INIiNNi!iilINNNNiiNN:NII iiiiiili?il!iiNi?iii! i ! i i! !iliN iii iiiiliiN!? ?i! N ii!i i!il!Nll iiNiiiiNiiii!i!;!i!iiiiiiiigNii!iiiiiiiiiiiiiiiiiiiii:ii!iiiiiiii!;iii
~i~!~:~ ~
I~!ii~it~'iii;!ii!ii
~~i i ~
...........................
iilill:!gl!ii~;iI
Nil
64> 64 > 64 > 64
> 64 > 64 > 64
16> 64 > 64 > 64
6i4 i4 i4
1. . . . i4 > 64 i4 > 64 i4 > 64
Proteus vulgar& Range
(36)
MICso MICgo
0.0162 0.13 1
0.0040,06 0.016 0.03
164 8 32
0
4)8- I )6 > 64
0 0
)3 )6
0.0028 0.06 0.5
0.0024 0.016 0.13
0.0088 0.06 0.5
0
)2- I 1[3 > 64 )8 64 [3 > 64
2> 64 16 > 64
1> 64 64 > 64
0.03> 64 2 8
0.030.5 0.06 0.5
0.0080.25 0.016 0.13
0.038 0.06 2
0.1
)8- I 1[3 >64 [6 32 16 > 64
4>64 64 > 64
4> 64 32 64
116 2 4
4i4 i4 ;,4
,,-E > 64 I 32 I > 64 I
0.1364 0.5 64
0.2564 2 64
0.532 16 32
)6- I 1~2 > 64 ~.5 32 ~2 > 64
32> 64 > 64 > 64
4-> 64 > 64 > 64
16> 64 > 64 > 64
i4i4 i4 i4
16> 64 > 64 > 64
I I I I
0.132 0.25 0.5
0.030.13 0.03 0.13
0.031 0.13 0.5
C
t6- 1 )6 )3 )6
0.52 0.5 1
0.251 0.5 1
0.532 4 32
0.516 8 16
L3)2 2 8
0.2516 x x
I I I i
0.250.5 0.25 0.25
14 2 2
0.060.25 0.13 0.25
£
)6-! ~5 13 25
0.51 0.5 1
28 2 8
24 2 4
24 2 4
12 1 1
0.5 2 1 2
28 4 8
0.51 0.5 1
(
361.5 13 25
4> 64 16 64
1632 16 32
16> 64 32 > 64
28 4 4
> 64 > 64
32> b4 >64 >64
I t I I
Providencia rettgeri Range
(51)
MICso MICgo
0 0
I I I
Providencia stuartii Range
(20)
MICso MIC~
0
Morganella morganii Range
(20)
MIC5o MICgo
Salmonella spp. Range
(12)
MICso MICgo
Salmonella Salmonella Salmonella Salmonella Salmonella Shigella spp.
typhimurium enteritidis brandenburg angona mendocina
(22)
Range MICs0 MICro
,*--, " ~ , ~
Yersinia enterocolitica (15)
Range MICso MICro
and Acinetobacter lwoffi (MIC50 1 rag/I) (Table 2). Pseudomonas species remain resistant to the new oral cephalosporins as they have been to the established compounds. Minor improvements were made in activity against Pseudomonas stutzeri. The activity of ceftibuten against Pseudomonas cepacia (MICs0 2 mg/1) could be of therapeutic concern due to the resistance of this organism to the majority of antibiotics.
(
16 16 I6
m- I 32 1 16 32
3522, cefprozil, cefuroxime and cefpodoxime (Table 3). Loracarbef, cefaclor and cefadroxil are about equally active against the majority of staphylococcal species. Cefixime demonstrates only low antistaphylococcal activity, while cefetamet and ceftibuten are inactive. The methicillin resistant strains are insensitive to the oral cephalosporins of all generations.
Enterococci Staphylococci Cefdinir was found to be the most active oral cephalosporin against staphylococci, followed by BAY 66 / 356
Enterococci are insensitive to oral cephalosporins. Minor activity was found for cefdinir, cefprozil and BAY 3522 (Table 4).
Infection 19 (1991) No. 5
© MMV Medizin Verlag GmbH Miinchen, Mfinchen 1991
A. B a u e r n f e i n d ,
Table 2: Comparative
R. J u n g w l r t h : C o m p a r a t i v e A n t i b a c t e r i a l A c t i v i t y o f C e f p o d o x i m e
invitro
activity of cefpodoxime against non-fermentative bacilli.
iiiiiiii!;i;i;.i;.i~.i.;i;.i;i.;i~.iiiiiiiii.i~ii!iiiiiiiiiii ..i;i.;i.~.i~.i .!i;i.;!i;.ii'~'' ~.i.i;~.i;i.;li.i~i.~.il.~!i.!l;.~.i.!~. ........................................ ;!iiiiiiii!~iiMiiiiiil ::==:= .......................
ii
iiiliiiil)iiiiiiiiiiiiiiiiiiiiiNi4iiii l
Acinetobacter baumannii Range
(20)
0.5 -
8-
1-
32
16 4 4
32 16 32
2-
1-
> 64 32 32
8-
> 64 > 64 > 64
4> 64 > 64 > 64
2> 64 > 64 > 64
2> 64 32 64
> 64
2> 64 > 64 > 64
MICso MICgo
16 32
> 64 16 32
Range
0.516 4 8
2> 64 8 16
0.54 1 2
0.532 2 8
0.0364 1 16
0.2516 0.5 4
264 4 16
164 1 16
416 4 8
16- I > 64 32 64
432 16 32
3264 32 64
28 4 8
832 16 32
832 16 32
32> 64 64 > 64
16> 64 > 64 > 64
8> 64 64 > 64
864 32 64
64- I 32> 64 > 64 > 64 > 64 > 64 > 64
0.532 4 16
264 8 32
0.258 0.5 4
0.532 2 16
0.516 2 8
0.134 2 4
232 8 16
232 8 32
264 4 32
2> 64 2 > 64
8> 64 8 > 64
0.5.16 I 16
2> 64 2 64
4> 64 64 > 64
0.5> 64 4 64
0.564 8 16
2> 64 32 64
0.2516 2 4
0.5> 64 8 16
32> 64 64 > 64
24 2 4
28 8 8
0.252 0.5 1
0.54 2 4
> 64 > 64
Acinetobacter lwoffi (20)
MICso MIC9o
264 8 8
Acinetobacter catcoaceticus (12)
Range MICsa MICgo
Acinetobacter johnsonii (12)
Range MICso MIC9o
4-1 64 8 32
264 8 32
Acinetobacter strain 84 (7)
Range MIC5o MICgo
32 >64
>64 64 >64
>64 4 >64
4-1 4>64 >64 8 16 >64 >64
8> 64 64 > 64
32>64 >64 >64
32>64 >64 >64
2>64 32 64
32- I 64>64 >64 >64 >64 >64 >64
28 4 8
032 1 2
416 8 16
432 8 32
28 4 8
16> 64 64 > 64
> 64
>64
>64
>64
>64
>64
> 64 > 64
>64 > 64
>64 > 64
>64 > 64
>64 > 64
>64 > 64
32> 64 > 64 > 64
> 64
>64
>64
>64
>64
>64
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
> 64
>64
>64
>64
>64
! >64
> 64 > 64
> 64 >64
> 64 >64
> 64 >64
> 64 >64
> 64 >64
8->64 64 > 64
>64
>64
> 64 > 64
> 64 > 64
>64
>64
>64 >64
>64 >64
8>64
4-
4-
Acinetobacter genospecies 3 (9)
Range MICso MICgo
Acinetobacter genospecies 12 (6)
Range MICso MICgo
4- I 16 8 16
432 16 32
Pseudomonas aeruginosa (30)
Range
> 64
> 64
> 64
> 64
MICso MICgo
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
Range
> 64
> 64
> 64
MICso MICgo
> 64 > 64
8> 64 > 64 > 64
> 64 > 64
> 64 > 64
Range
> 64
> 64
> 64
MICro MICgo
> 64 > 64
32>64 > 64 > 64
> 64 > 64
> 64 > 64
Range
8> 64 32 64
16> 64 64 > 64
4> 64 > 64 > 64
1664 32 64
832 16 32
> 64
>64
>64
> 64 > 64
> 64 > 64
> 64 > 64
8>64 64 > 64
1>64 8 > 64
8>64 32 64
0.25>64 2 64
> 64
>64
>64
MICro MICgo
2>64 8 64
> 64 > 64
>64 >64
>64 >64
4> 64 16 >64
Range
> 64
> 64
> 64
> 64
> 64
>64
>64
>64
>64
>64
MICso MIC9o
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
16> 64 > 64 > 64
> 64 > 64
>64 >64
>64 >64
>64 >64
>64 >64
>64 >64
Pseudomonas fluorescens (20)
Pseudomonas putida (20)
32>64 > 64 > 64
Pseudomonas stutzeri (8)
MIC5o MICgo
Pseudomonas cepacia (24)
Range
Pseudomonas maltophilia (20)
Infection 19 (1991) NO. 5
© M M V Medizin Verlag G m b H Miinchen, MiJnchen 1991
357 / 67
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime
Table 3: Comparativein vitro activity of cefpodoxime against staphylococci.
Staphylococcus aureus MET-R (20)
Range
4- I
16- I
MICso MICro
32 16 32
1>64 > 64 > 64
Range
0.5- I 0.25-
8-
1>64 I > 64 > 64
> 64
I > 64
> 64 > 64
> 64 > 64
Staphylococcus aureus PEN-R (20)
MICro MIC~
4t 1 4
1-
X I 0.5 1
2-
28
4 2 2
16
8
12
4
?
1 2
4
4
Staphylococcus aureus PEN-S (20)
Range MICso MICgo
0.25- I 0.1311o.5 f 0.5 0,5
0.25 0.5
Staphylococcus epidermidis MET-R (20)
Range
4-1 64
4-1 I
32
MIC5o MICgo
16 32
Range
0.5- I 0.13-
MIC5o MICgo
32 0.5 32
Range
0.5- I 0 . 1 3 - I
I
8 16
564 4 64
g~
> 64 16 64
4--
> 64 64 > 64
I
Staphylococcus epidermidis PEN-R (8)
I
1 0.25 1
0.25I
2 0.5 2
Staphylococcus epidermidis PEN-S (19)
0.25-
1
1 0.25
1
MICso MICgo
0.5 0,5
0.13 0.13
0.5 1
Range
> 64
MICso MICgo
> 64 > 64
16I > 64 64 > 64
64> 64 > 64 > 64
Staphylococcus haemolyticus MET-R (5)
Staphylococcus haemolyticus MET-S (19)
Range
0.25-I
0.13-
21o.5
MICso MICgo
0.5 2
0.25 0.5
0.5-
I
2
1 2
0.25-I
1-
1
2
; 44
Staphylococcus simulans (14)
Range MICso MICgo
0.25- I o.~31 0.5 0.5
10.25 0.13 0.25
o.13I
1 0.5 1
Staphylococcus hominis (12)
Range MICso MICgo
0.25-1 0-°6-I 0.252 I 0.5 1
0.13 10.25
2
0.5
1
Staphylococcus cohnii (10)
Range
0.25- ] 0.252 I 1 2 1 2 1
0.54 2 4
0.25- I
1-
4
8
Range
0.25-I
2-
MICro MICgo
1
2
Range
1-
2-
MICro MICgo
2
2
MICro MICgo
Staphylococcus saprophyticus (9)
; 44
Staphylococcus wameri (4)
68 / 358
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1991
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity o f C e f p o d o x i m e
Table 4: Comparative in vitro activity of cefpodoxime against streptococci.
Will/lira
Enterococcus faecalis (20)
Range
> 64
> 64
MICso MIC90
> 64 >64
> 64 > 64
Range
> 64
> 64
432 8 16
64
> 64
> 64
64 64
> 64 >64
> 64 >64
64
> 64
>64
®®
i~i!i~ii~!iiiii!~ilii~i~ ..........................................
416 8 8
> 64
64
> 64 > 64
64 64
3264 64 64
Enterocococcus faecium (17)
416 8 16
MICs0 MICg0
>64 > 64
> 64 > 64
Range
> 64
64>64 ! >64 >64 i
1 64 64
> 64 > 64
> 64 > 64
64
>64
>64
1
416 16 16
> 64 > 64 > 64
64> 64 64 > 64
> 64 > 64 > 64
Enterococcus liquefaciens (13)
MICso MICg0
>64 >64
28 4 8
1 64 64
>64 >64
>64 >64
1
416 4 8
> 64 > 64 > 64
1664 32 64
1664 32 64
Streptococcus pneumoniae PEN-R (15) (MIC PEN 1-4 mg/l)
Range MICs0 MIC9o
0.54 2 4
1664 32 64
3264 64 64
1664 32 64
16> 64 64 > 64
,062 1 1
48 4 4
14 2 2
0.0
6 6
18 2 4
0.58 2 4
64> 64 > 64 > 64
16> 64 > 64 > 64
0.060.25 0.06 0.13
0.0160.06 0.03 0.03
14 2 2
216 4 16
0.03 0.5 0.06 0.5
0.030.5 0.13 0.25
216 8 16
216 4 16
0.06 0.25 0.13 0.25
0.030.13 0.03 0.06
216 4 16
216 4 16
i
Streptococcus pneumoniae PEN-S (20)
i 0.25! 8 i 2 [ 4
Range MICso MICgo
0.0160.13 0.03 0.06
0.5-10.0080.25 0.5 I 0,06 ~ I 0.13
0. 0.
Streptococcus milleri group (11)
Range MICso MICgo
0.0160.25 0.06 0.13
0.134 1 4
i0.016[ 0.25 i 0.06 ! 0.25
116 2 16
464 16 64
0.54 2 4
0.1
0.0160.13 0.06 0.13
0.134 0.5 4
0.0160.25 0.03 0.25
~.516 2 16
264 32 64
0.54 1 4
0.1
0.016-0.06 0.03 0.06
0.130.5 0.13 0.25
0.0080.06 0.016 0.03
.031 .06 .25
0.254 1 1
0.060.5 0.13 0.13
0.0t 0.1 0.( 0.(
0.03 0.13 0.06 0.13
0.0160.25 0.03 0.06
0.060.5 0.13 0.25
0.060.25 0.13 0.25
0.030.25 0.06 0.25
0.52 1 2
0.0080.03 0.016 0.03
.251 0.5 1
16 16 16
0.060.5 0.06 0.5
0.01 0A 0.( 0.(
0.03 0,13 0.13 0.13
0.030.13 0.06 0.13
0,016-0.25 0.06 0.25
0.060.25 0.25 0.25
0.030.5 0.5 0.5
0.251 0.5 1
0.0080.016 0.008 0.016
.030.5 .13 0.5
0.51 1 1
0.060.13 0.06 0.13
0.01 01 0.01 0.(
0.016 0.13 0.03 0.13
0.0161 1 1
0.0160.13 0.03 0.13
0.060.13 0.06 0.13
0.0160.06 0.03 0.06
0.130.5 0.13 0.25
0.0080.03 0.016 0.016
.03'.25 .13 0.5
0.51 1 1
0.060.25 0.13 0.13
0.01 0.1 0.( O.I
0.0160.13 0.03 0.06
0.060:25 0.13 0.13
0.060.25 0.13 0.25
0.2
Streptococcus mitior (7)
Range MICs0 MICgo
Hemolytic streptococci group A (19)
Range MICso MIC90
Hemolytic streptococci group B (16)
Range MIC50 MICgo
Hemolytic streptococci group C (5)
Range MIC50 MICg0
Hemolytic streptococci group G (21)
Range MICs0 MICgo
Non-Enterococcal Hemolytic Streptococci Non-enterococcal hemolytic streptococci are about equally susceptible to all oral cephalosporins (except Infection 19 (1991) No, 5
0.2
0.030.13 0.06 0.13
ceftibuten against hemolytic streptococci group B), cefdinir and cefprozil being the most potent compounds (Table 4).
© MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1991
359 / 69
A. Bauernfeind, R. J u n g w i r t h : Comparative Antibacterial Activity of Cefpodoxime
Table 5: Comparative in vitro activity of cefpodoxime against Listeria, Haemoph#us, Moraxella, Neisseria, Brucella, Bordetella.
MICro
> 64
>64 > 64 >64 > 64
28 4 8
2>64 32 >64
64>64 >64 >64
18 4 8
18 2 8
0.252 1 2
1>64 32 >64
16>64 32 >64
1632 32 32
Hemophilus influenzae AMP-R (21) (MIC AMP 16-64 rag/l)
Range
0.030.25 0.06 0.13
L0160.25 0.03 0.13
0.131 0.25 0.5
0.060.5 0.13 0.25
0.030.25 0.06 0.25
0.251 0.5 1
432 8 16
0.25 1 0.5 1
0.52 1 1
432 8 32
864 16 32
0.030.13 0.06 0.13
0.030.5 0.13 0.25
0.130.5 0.25 0.5
0.060.5 0.13 0.25
0.030.13 0.03 0.06
0.250.5 0.5 0.5
432 8 16
0.251 0.5 1
0.251 1 1
216 8 16
832 16 32
0,060.13 0.06 0.13
0.030.06 0.03 0.06
0.130.25 0.25 0.25
0.060.5 0.13 0.5
0.030.06 0.06 0.06
0.251 1 1
0.54 2 4
0.251 1 1
0.131 0.5 1
416 8 16
416 8 16
0.060.5 0.25 0.5
0.060.5 0.13 0.5
0.130.5 0.25 0.5
0.060.5 0.13 0.5
0.54 1 4
0.51 0.5 1
14 1 4
0.50.254 2 2 i 0.5 4 2
0.54 4 4
12 1 2
0,0040.13 0.03 0.06
).0020.06 ).016 0.03
0.0040.06 0.0:16 0.06
).0080.13 0.03 0.06
0.030.5 0.13 0.5
0,254 1 4
8> 64 16 > 64
232 8 32
0.031 0.25 1
2> 64 > 16 > 64
464 16 64
MICro MICgo
0.0040.06 0.008 0.03
).002).016 ).008 ).016
0.0020.03 0.008 0.03
).0040.13 ).016 0.06
0.0080.25 0.06 0.25
0.132 0.5 2
164 8 32
18 4 8
0.0160.13 0.06 0.13
0.2564 8 32
164 8 64
Range
0.25
MICro MICgo
0.25 0.25
0.062 0.5 2
0.130,25 0.25 0.25
0.251 0.5 1
0.138 1 8
0.251 1
Range
8> 64 32 > 64
MICro MICro
Haemophilus influenzae AMP-S (35)
Range MICro MIC90
Haemophilus parainfluenzae (6)
Range MICs0 MICg0
MoraxeUa catarrhalis (13)
Range MIC50 MICgo
i
Neisseria gonorrhoeae PEN-R (20) (MIC PEN 16-64 nag/l)
Range MIC50 MICg0
Neisseria gonorrhoeae PEN-S (24)
Range
Brucella spp. (5)
2
8
2 2
8 8
MICro MICgo
2> 64 32 > 64
4> 64 32 > 64
Streptococcus pneumoniae
4
4
4 !
4
48 4
4
8
!
Bordetella pertussis (7)
1
4
64> 64 > 64 > 64
64> 64 64 > 64
16- > 6 4 64 >64 64 64 [ > 6 4
3264 64 64
cefuroxime and compounds.
I
BAY
3522
8-,I
> 64
64-
>64
i > 64
>64
L>64
>64
>64
r>64
>64
are the most potent
S. pneumoniae is most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522 (MIC90 between 0.03 and 0.13 mg/1). However, the MICs of penicillin resistant pneumococci are between 32 and 128 times above the MICs of penicillin susceptible strains (Table 4). The lowest MIC90 were 4 mg/l indicating resistance to all oral cephalosporins. S. milleri and S. mitior are less susceptible than the other non-enterococcal streptococci; however, against these two cefpodoxime, cefdinir, 70 / 3 6 0
Fastidious Pathogens
Haemophilus spp., Moraxella catarrhalis, N. gonorrhoeae are more susceptible to cefpodoxime, cefdinir, cefetamet and ceftibuten than the other oral cephalosporins included (Table 5). Loracarbef is more active than cefaclor against the TEM producing strains of E. coli,
Haemophilus influenzae, M. catarrhalis, N. gonorrhoeae,
Infection 19 (1991) No. 5
© MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1991
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime
Table 6: Comparative in vitro activity of cefpodoxime against anaerobes, Helicobacter pylori.
~N®i~ !i~ii~iiii ~iiii!il~i i~iiiiii~i!~~iii~Nii~i!iiilii~i®~i Niii2iMN:?i!jii iiiiiNi~Jiii!il;ii IiNi~iNi'i~ii
Clostridium difficile (12)
Range MICs0 MICg0
64> 64 > 64 > 64
> i4
64
>64
64
• 64 > >
0.5.
1
64> 64 > 64 > 64
16 32 16 32
0.130.5 0.25 0.5
).54 2 4
4 16 4 16
).5> 64 16 64
8 16 16 16
6
>6
i4 i4
64 64
>64 > 64
64 64
0.5 1
64 > 6
1
3.54 2 4
4 > 64 4 >64
1 64 4 64
32
3.516
64 64 64 64
& 64 64 64
16
0.5, > 64 I 0.5 ~>64
64 64 64 64
16 32 32 32
16 8 16
0.250.5 0.25 0.5
14 2 4
8' 16 16 16
0.06 4 2 4
0 258
0.516
Clostridium spp. (5)
Range MIC~0 MICg0
0 2516 8 16
i4
1 i4
16 32 32
16
Bacteroides spp. (11)
Range MICs0 MICg0
1
0 25> 64 ).5 > 64
1
1
L6
16
64 > 64 >64 >64
i4
64 >64 > 64 >64 4 16 16 16
[6
16
8
Peptococcus magnus (4)
Range MICs0 MICg0
832 8 32
> i4 > i4
4 16 8 16
0.54 2 4
.5 8 1 4
).N 2 ).5 2
>
Helicobacter pylori (16)
Range MIC~0 MICg0
Progress in activity is less pronounced for Brucella spp. (except for cefpodoxime, cefdinir and loracarbef). Listeria spp. are only moderately susceptible to some of the oral cephalosporins (BAY 3522, cefprozil, loracarbef, cefdinir), while B. pertussisis resistant to all oral cephalosporins [5], however, susceptible to parenteral cephalosporins, namely cefotaxime, cefepime and cefpirome [6]. The in vitro activity of the oral cephalosporins is low against anaerobes except for BAY 3522 (Table 6). H. pylori is moderately susceptible to the majority of the oral cephalosporins, cefdinir, loracarbef and cefaclor being the most active. Discussion The antibacterial activity of established oral cephalosporins 'is restricted to a limited number of pathogens. Some of the gaps in the activity spectrum of established cephalosporins remain open for most of the new compounds of this group as well (no or only moderate activity against Enterobacter spp., Morganella, Listeria (except BAY 3522), Pseudomonas and Acinetobacter, methicillin resistant staphylococci, Enterococcus spp., penicillin resistant pneumococci and anaerobes (except BAY 3522). The resistance mechanisms - inadequate binding affinity of PBPs, incomplete penetration or
.252 0.5 2
0.2
1
8
4
16
instability against [3-1actamases - remain effective against the majority of the new compounds as well. On the other hand, therapeutically significant progress was made against various other species both in activity and spectrum. Thus, for example, cefpodoxime exceeds the activity of cefaclor against Klebsiella pneumoniae 16-fold, against Haemophilus spp. 128- to 256-fold, against gonococci 1024-fold. Furthermore, new compounds (cefpodoxime, cefixime, cefdinir, cefetamet, ceftibuten) extend the spectrum of oral cephalosporins within. Enterobacteriaceae (including Citrobacter with cefetamet and ceftibuten [7]; Proteus, Providencia rettgeri with cefpodoxime, cefixime, cefetamet, ceftibuten). The compounds with enhanced antibacterial activity are structurally related to parenteral cephalosporins of the aminothiazole type. Activity in the magnitude of parenteral third generation cephalosporins is reached by some of the new absorbable compounds. Improvements in in vitro activity against staphylococci by new oral cephalosporins are confined to cefdinir, BAY 3522 and cefprozil. Among the new cephalosporins, ceftibuten, cefetamet and cefixime have no therapeutically significant antistaphylococcal activity, whereas the antistaphylococcal efficacy of cefpodoxime and loracarbef corresponds to that of cefuroxime, cefaclor and cefadroxil [8]. The oral cephalosporins with the broadest antibacterial spectrum are cefpodoxime and cefdinir.
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, Miinchen t991
361 / 71
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime
New oral cephalosporins signify an advance in therapy with pathogens which are also susceptible to established
oral cephalosporins, and especially of infections caused by pathogens resistant to established oral cephalosporins.
References
5. Hoppe, J. E., Miiller, J.: In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to six new oral cephalosporins. Antimicrob. Agents Chemother. 34 (1990) 1442-1443. 6. Bauernfeind, A.: In vitro activity and stability against novel beta-lactamases of flomoxef in comparison with latamoxef, SCE 2787, cefpirome, cefepime, cefotaxime, piperacillin and piperacillin plus tazobactam. Infection (in press). 7. Bauernfeind, A.: Comparative antimicrobial spectrum and activity of ceftibuten against clinical isolates from West Germany. Diagnost. Microbiol. Infect. Dis. 4 (1991) 63-74. 8. Banernfeind, A., Przyklenk, B., Matthias, C., Jungwirth, R., Bertele, R. M., Harms, IL: Selection of antibiotics for treatment and prophylaxis of staphylococcal infections in cystic fibrosis patients. Infection t8 (1990) 126-130.
1. Neu, H. C., Fu, K. P.: Cefaclor: In vitro spectrum of activity and beta-lactamase stability. Antimicrob. Agents Chemother. 13 (1978) 584- 588. 2. Grimm, H.- Bakteriologische in vitro Untersuchungen mit Cefaclor. Infection 7 Suppl. 6 (1979) 540-542. 3. Mittermayer, H.: In vitro activity of cefetamet (Ro 15-8074) Eur. J. Clin. Microbiol. 5 (1986) 530-534. 4. Mabilat, C., Conrvalin, P.: Development of "oligotyping" for characterization and molecular epidemiology of TEM [5-1actamasesin members of the family Enterobacteriaceae. Antimicrob. Agents Chemother. 34 (I990) 2210-2216.
72 / 362
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, M~inchen 1991
In Vitro Evaluation of Cefpodoxime, a New Oral Cephalosporin of the Third Generation, Editors: W. Marget, R. Kiehn, H. Kraeft A. Bauernfeind, R. Jungwirth
Antibacterial Activity of Cefpodoxime in Comparison with Cefixime, Cefdinir, Cefetamet, Ceftibuten, Loracarbef, Cefprozil, BAY 3522, Cefuroxime, Cefaclor and Cefadroxil Summary: The new oral cephalosporins cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate enhanced activity against Enterobacteriaceae susceptible to the established compounds as well (e.g. cefuroxime, cefaclor, cefadroxil). In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten include in their spectrum species hitherto resistant to oral cephalosporins (Proteus vulgaris, Providencia spp., Yersinia enterocolitica). Besides, the majority of these compounds demonstrate relevant activity (MICs0 equal to or below 2 mg/1) against Enterobacter spp., Citrobacter freundii, Serratia spp. and Morganella morganii. Ceftibuten is the most potent oral cephalosporin against most of the Enterobacteriaceae. Non-fermentative bacilli (Acinetobacter spp., Pseudomonas spp.) remain completely resistant to oral cephalosporins (except some Acinetobacter species against cefdinir and Pseudomonas cepacia against ceftibuten). Antistaphylococcal activity for oral cephalosporins is highest for cefdinir followed by BAY 3522, cefprozil, cefuroxime and cefpodoxime. Loracarbef, cefaclor and cefadroxil are about equally active, while the other compounds are only weakly active (cefixime) or inactive (cefetamet, ceftibuten).
Enterococci are insensitive to new generation oral cephalosporins as they have been to established compounds. The most active oral cephalosporins against hemolytic streptococci are cefdinir and cefprozil. Streptococcus pneumoniae, Streptococcus milleri and Streptococcus mitior are most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522. Penicillin resistant pneumococci have to be regarded as resistant to all oral cephalosporins. Fastidious pathogens like Haemophilus spp., Moraxella catarrhalis and Neisseria gonorrhoeae are more susceptible to cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten than to the other oral cephalosporins. The activity of oral cephalosporins is only weak against Listeria spp., Helicobacter pylori and anaerobic pathogens (except BAY 3522). Bordetella pertussis remains resistant to all absorbable cephalosporins. Progress in antibacterial activity of oral cephalosporins was mainly achieved by cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten against Enterobacteriaceae and the fastidious pathogens and against staphylococci and the nonenterococcal streptococci by cefdinir, BAY 3522, cefprozil and cefpodoxime.
Zusammenfassung:AntibakterielleAktivitiit yon Cefpodoxirn im
etablierten Substanzen. Die aktivsten oralen Cephalosporine gegen h/~molysierende Streptokokken sind Cefdinir und Cefprozil. Streptococcuspneumoniae, Streptococcus milleri und Streptococcus mitior sind am empfindlichsten gegen Cefpodoxim, Cefdinir, Cefuroxim und BAY 3522. Penicillinresistente Pneumokokken mtissen als resistent gegeniiber allen oralen Cephalosporinen betrachtet werden. Anspruchsvolle Erreger wie Haemophilus spp., Moraxella catarrhalis und Neisseria gonorrhoeae sind gegen Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten empfindlicher als gegen die anderen oralen Cephalosporine. Die Aktivit/it oraler Cephalosporine gegen Listeria spp., Helicobacterpylori und Anaerobier (Ausnahme BAY 3522) ist nur schwach. Bordetella pertussis bleibt gegen alle resorbierbaren Cephalosporine resistent. Der Fortschritt in der antibakteriellen Aktivit/it oraler Cephalosporine wurde gegen Enterobacteriaceae und anspruchsvoUe Erreger haupts/ichlich durch Cefpodoxim, Certain, Cefdinir, Cefetamet und Ceftibuten erlangt, gegen Staphylokokken und Streptokokken (aul3er Enterokokken) durch Cefdinir, BAY 3522, Cefprozil und Cefpodoxim.
Vergleichrnitanderen oralen Cephalosporinen. Die neuen oralen Cephalosporine Cefpodoxim, Cef'trdm, Cefdinir, Cefetamet und Ceftibuten zeigen eine verst/irkte Aktivit/it auch gegen solche Enterobacteriaceae, die gegen etablierte Substanzen empfindlich sind (z.B. Cefuroxim, Cefaclor, Cefadroxil). Zus/itzlich schlieBt das Spektrum von Cefpodoxim, Cefixim, Cefdinir, Cefetamet und Ceftibuten Spezies ein, die gegen die bisherigen oralen Cephalosporine resistent waren (Proteus vulgaris, Providencia spp., Yersinia enterocolitica). Daneben zeigt die Mehrheit der neuen Substanzen erh6hte Aktivit/it (MHKs0 < 2 mg/1) gegen Enterobacter spp., Citrobacter freundii, Serratia spp. und MorganeUa morganii. Gegen die meisten Enterobacteriaceae ist Ceftibuten das wirksamste orale Cephalosporin. Non-Fermenter (Acinetobacter spp., Pseudomonas spp.) bleiben gegeniJber oralen Cephalosporinen vollst/indig resistent (mit Ausnahme einiger Acinetobacter-Spezies gegen Cefdinir und Pseudomonas cepacia gegen Ceftibuten). Die Antistaphylokokken-Aktivit/it oraler Cephalosporine ist am h6chsten bei Cefdinir, gefolgt von BAY 3522, Cefprozil, Cefuroxim und Cefpodoxim. Loracarbef, Cefaclor und Cefadroxil sind etwa gleich aktiv, w/ihrend die anderen Substanzen nur schwach aktiv (Cefixim) oder inaktiv sind (Cefetamet, Ceftibuten). Enterokokken sind gegeniiber der neuen Generation oraler Cephalosporine ebenso unempfindlich wie gegeniiber den
Prof. Dr. A. Bauernfeind, R. Jungwirth, Max-von-Pettenkofer-Institut, Pettenkoferstr. 9a, W-8000 Mfinchen 2, Germany. * Supported by Luitpold-Werk, a company of the Sankyo group.
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, M6nchen 1991
353 / 63
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime Introduction
Oral cephalosporins established their role in therapy of infections of the respiratory tract, skin and skin structure, urinary tract and bone infections. The use of the established compounds (e.g. cephalexin, cefadroxil, cefaclor) is limited by their restricted activity against Haemophilus, Moraxella, Neisseria, alpha-hemolytic streptococci (Streptococcus miUeri group, Streptococcus mitior) and most species among Enterobacteriaceae except Escherichia coli, Klebsiella, Proteus mirabilis [1-3]. However, beta-lactamases hydrolyzing established cephalosporins are emerging in Escherichia coli and Klebsiella [4]. These limitations as well as the short serum half-life (between 30 and 90 rain) necessitating frequent dosing and limited chemical stability (e.g. of cefaclor) of established oral cephalosporins initiated the development o f absorbable cephalosporins with improved characteristics. The new compounds are structural derivatives of ancestor cephalosporins: 1. of the aminothiazole-methoximino type (e.g. cefdinir, ceftibuten, cefetamet (pivoxil-ester), cefpodoxime (proxetil-ester); 2. of the glycyl-cephalosporin type (e.g. loracarbef, cefprozil, BAY 3522); 3. of the furanyl-methoximino-cephalosporin type (e.g. cefuroxime-axetil). Progress achieved by the new compounds in comparison with established oral cephalosporins as to their in vitro activity against a broad spectrum of human pathogens is presented in this investigation. Materials and Methods
erythrocytes and 2% horse serum) were incubated in a candle jar for growth of Haemophilus spp., Neisseria gonorrhoeae and Bordetella pertussis. Helicobacter pylori was grown on Columbia-Agar (Oxoid, supplemented by 5% human blood) in a microaerophilic atmosphere produced by the gas generating kit BR 56 (Oxoid). Wilkins-Chalgren-Agar (Oxoid), supplemented by 10% sheep blood frozen and thawed twice prior to addition as used for anaerobes together with the oxoid gas generating kit BR 38. E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923 were used as MIC reference strains. Results
Enterobacteriaceae The activity of established cephalosporins (e.g. cefuroxime, cefaclor, cefadroxil) against Enterobacteriaceae was mainly restricted to the majority of isolates of E. coli, Klebsiella spp., Enterobacter sakazakii, P. mirabilis, Salmonella spp. and Shigella spp. This holds true as well for loracarbef, cefprozil and BAY 3522 among the newer compounds (Table 1). Cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten are, however, more potent against these pathogens, in particular cefixime and ceftibuten against P. mirabilis. In addition, cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten expand the antibacterial spectrum of oral cephalosporins within Enterobacteriaceae to include species hitherto resistant to oral cephalosporins, namely Proteus vulgaris (except cefdinir), Providencia spp., Yersinia enterocolitica (except cefixime). Besides cefpodoxime, cefixime, cefdinir, cefetamet and ceftibuten demonstrate remarkable activity (MICs0 equal to or below 2 mg/1) against Enterobacter cloacae (except cefpodoxime and cefdinir), Enterobacter aerogenes, Hafnia alvei (only cefdinir and ceftibuten), Citrobacter freundii, Serratia marcescens (except cefpodoxime and cefdinir), Serratia liquefaciens (except cefdinir) and Morganella morganii (except cefdinir and cefetamet). The enhanced activity against these pathogens indicates improved stability of the new compounds against the chromosomal cephalosporinases produced by the majority of these organisms. This effect is most impressive for ceftibuten, the most potent among the oral cephalosporins against Enterobacteriaceae except for Proteus spp., whereas cefixime is one log 2 more active.
Antibiotics compared in this investigation were cefpodoxime (Sankyo Europe), cefixime (Merck), cefdinir (Fujisawa), cefetamet (Hoffmann- LaRoche Inc.), ceftibuten (ScheringPlough Corporation), cefuroxime (Hoechst AG), loracarbef and cefaclor (Eli Lilly and Co.), cefprozil and cefadroxil (Bristol-Myers) and BAY 3522 (Bayer AG). These compounds were obtained from the manufacturers as powders with stated potency. Determination of minimal inhibitory concentrations (MICs): Minimal inhibitory concentrations (MICs) were determined by agar dilution technique. An inoculum of 104 CFU per spot (105 CFU per spot for anaerobes) was delivered by a multipoint inoculator (Denley) to a series of agar plates which obtained the antibiotic in twofold dilutions. Incubation was usually for t6 h (24 h for methicillin resistant staphylococci, 48 h for anaerobes, Bordetella pertussis and Helicobacter pylori). Incubation tempe- Non-Fermentative Bacilli (NFB) rature was at 35°C except for methicillin resistant staphylococci (32°C). The MIC was determined as the lowest concentration of Taxonomy within the genus Acinetobacter has changed antibiotic at which no visible growth or growth -- 64 8 > 64
0.06> 64 2 > 64
0.25> 64
0.25> 64
Escherichia coli AMP-S (20)
Range MICso MICgo
0.5
1
1
2
0.54 2 4
0.030.25 0.06 0.13
0.52 0.5 1
).58 4 8
164 2 32
18 2 8
0.516 0.5 8
816 8 16
0.061 0.13 0.5
0.030.25 [).06 9.13
0.52 0.5 2
).516 4 8
132 2 16
18 2 8
0.251 0.5 1
8
0.13> 64 16 > 64
0.25, 64 1 - 64
9.03,64 0.5 ,64
1> 54 > 54 > 54
864 64 64
254 54 54
4> 64 16 > 64
2> 64 > 64 > 64
0.25>64 0.5 32
0.25,64 0.5 64
1> 54 32 > 54
1664 64 64
864
32 64
Klebsiella pneumoniae (20)
Range MICso MICgo
Klebsiella oxytoca (20)
Range MICso MICgo
8 8
Enterobacter cloacae (66)
Range MIC5o MICgo
4> 54 > 54 > 54
Enterobacter aerogenes (13)
Range MICso MICgo
1
1
64
> 64
0.5>64 1 > 64
0.131 0.25 0.5
0.0160.5 0.06 0.25
0.034 0.5 1
0.132 0.25 0.5
.0160.13 0.03 0.06
0.516 1 2
18 2 4
232 16 32
1> 64 4 > 64
0.5> 64 4 32
0.2564 2 32
0.13> 64 8 64
0.1316 0.5 8
2> 64 64 > 64
864 64 64
64 64 64
0.2532 1 8
0.1364 1 8
0.13> 64 0.5 16
0.138 1 2
0.0632 0.5 4
1> 64 8 32
464 64 64
0.5> 64 4 64
0.25> 64 1 16
2> 64 8 > 64
0.25> 64 2 64
0.068 0.25 2
32> 64 > 64 > 64
6464 64 64
. 64 .64 .64 .64
0.25> 64 2 > 64
0.2532 2 32
0.5> 64 4 > 64
0.2516 0.5 16
0.138 !> 0.25 8 >
0.060.13 0.06 0.13
0.0160.06 0.016 0.06
0.138 0.13 0.5
0.060.13 0.06 0.13
2-
> 64 8 > 64
8-
> 64 > 64 > 64
8-
> 54 > 54 > 54
Enterobacter sakazakii (11)
Range MICso MICgo
0.516 2 8
116 4 8
0 131 0 25 t.5
Hafnia alvei (15)
Range MICso MIC9o
8-
1-
4-
8-
> 64 4 > 64
> 64 16 > 64
> M > 54 > 54
2> 64
4> 64 32 > 64
4> 64 64 > 64
32> 64 > 64 > 64
16> 64 > 64 > 64
32> 64 > 64 > 64
16> 64 64
> 64
32> 64 > 64 > 64
Citrobacter freundii (38)
Range MICso MIC9o
2,64
64 . 64
4 64
Serratia marcescens (38)
Range MICso MIC9o
Serratia liquefaciens (15)
Range MICso MIC9o
1664 64 64
64
• 64
64 64
• 64 • 64
14 2 2
416 8 16
> 64
> 64 > 64
Proteus mirabilis (20)
Range MICso MICgo
Infection 19 (1991) No. 5
0.03 0.03 0.03
© M M V Mcdizin Verlag G m b H Miinchen, Mtinchen 1991
14 2 4
18 4 4
14 4 4
416 8 8
355 / 65
A. B a u e r n f e i n d , R. Jungwirth: Comparative Antibacterial Activity of C e f p o d o x i m e
Table 1 (continued) ......................
N~
ii i!INIiNNi!iilINNNNiiNN:NII iiiiiili?il!iiNi?iii! i ! i i! !iliN iii iiiiliiN!? ?i! N ii!i i!il!Nll iiNiiiiNiiii!i!;!i!iiiiiiiigNii!iiiiiiiiiiiiiiiiiiiii:ii!iiiiiiii!;iii
~i~!~:~ ~
I~!ii~it~'iii;!ii!ii
~~i i ~
...........................
iilill:!gl!ii~;iI
Nil
64> 64 > 64 > 64
> 64 > 64 > 64
16> 64 > 64 > 64
6i4 i4 i4
1. . . . i4 > 64 i4 > 64 i4 > 64
Proteus vulgar& Range
(36)
MICso MICgo
0.0162 0.13 1
0.0040,06 0.016 0.03
164 8 32
0
4)8- I )6 > 64
0 0
)3 )6
0.0028 0.06 0.5
0.0024 0.016 0.13
0.0088 0.06 0.5
0
)2- I 1[3 > 64 )8 64 [3 > 64
2> 64 16 > 64
1> 64 64 > 64
0.03> 64 2 8
0.030.5 0.06 0.5
0.0080.25 0.016 0.13
0.038 0.06 2
0.1
)8- I 1[3 >64 [6 32 16 > 64
4>64 64 > 64
4> 64 32 64
116 2 4
4i4 i4 ;,4
,,-E > 64 I 32 I > 64 I
0.1364 0.5 64
0.2564 2 64
0.532 16 32
)6- I 1~2 > 64 ~.5 32 ~2 > 64
32> 64 > 64 > 64
4-> 64 > 64 > 64
16> 64 > 64 > 64
i4i4 i4 i4
16> 64 > 64 > 64
I I I I
0.132 0.25 0.5
0.030.13 0.03 0.13
0.031 0.13 0.5
C
t6- 1 )6 )3 )6
0.52 0.5 1
0.251 0.5 1
0.532 4 32
0.516 8 16
L3)2 2 8
0.2516 x x
I I I i
0.250.5 0.25 0.25
14 2 2
0.060.25 0.13 0.25
£
)6-! ~5 13 25
0.51 0.5 1
28 2 8
24 2 4
24 2 4
12 1 1
0.5 2 1 2
28 4 8
0.51 0.5 1
(
361.5 13 25
4> 64 16 64
1632 16 32
16> 64 32 > 64
28 4 4
> 64 > 64
32> b4 >64 >64
I t I I
Providencia rettgeri Range
(51)
MICso MICgo
0 0
I I I
Providencia stuartii Range
(20)
MICso MIC~
0
Morganella morganii Range
(20)
MIC5o MICgo
Salmonella spp. Range
(12)
MICso MICgo
Salmonella Salmonella Salmonella Salmonella Salmonella Shigella spp.
typhimurium enteritidis brandenburg angona mendocina
(22)
Range MICs0 MICro
,*--, " ~ , ~
Yersinia enterocolitica (15)
Range MICso MICro
and Acinetobacter lwoffi (MIC50 1 rag/I) (Table 2). Pseudomonas species remain resistant to the new oral cephalosporins as they have been to the established compounds. Minor improvements were made in activity against Pseudomonas stutzeri. The activity of ceftibuten against Pseudomonas cepacia (MICs0 2 mg/1) could be of therapeutic concern due to the resistance of this organism to the majority of antibiotics.
(
16 16 I6
m- I 32 1 16 32
3522, cefprozil, cefuroxime and cefpodoxime (Table 3). Loracarbef, cefaclor and cefadroxil are about equally active against the majority of staphylococcal species. Cefixime demonstrates only low antistaphylococcal activity, while cefetamet and ceftibuten are inactive. The methicillin resistant strains are insensitive to the oral cephalosporins of all generations.
Enterococci Staphylococci Cefdinir was found to be the most active oral cephalosporin against staphylococci, followed by BAY 66 / 356
Enterococci are insensitive to oral cephalosporins. Minor activity was found for cefdinir, cefprozil and BAY 3522 (Table 4).
Infection 19 (1991) No. 5
© MMV Medizin Verlag GmbH Miinchen, Mfinchen 1991
A. B a u e r n f e i n d ,
Table 2: Comparative
R. J u n g w l r t h : C o m p a r a t i v e A n t i b a c t e r i a l A c t i v i t y o f C e f p o d o x i m e
invitro
activity of cefpodoxime against non-fermentative bacilli.
iiiiiiii!;i;i;.i;.i~.i.;i;.i;i.;i~.iiiiiiiii.i~ii!iiiiiiiiiii ..i;i.;i.~.i~.i .!i;i.;!i;.ii'~'' ~.i.i;~.i;i.;li.i~i.~.il.~!i.!l;.~.i.!~. ........................................ ;!iiiiiiii!~iiMiiiiiil ::==:= .......................
ii
iiiliiiil)iiiiiiiiiiiiiiiiiiiiiNi4iiii l
Acinetobacter baumannii Range
(20)
0.5 -
8-
1-
32
16 4 4
32 16 32
2-
1-
> 64 32 32
8-
> 64 > 64 > 64
4> 64 > 64 > 64
2> 64 > 64 > 64
2> 64 32 64
> 64
2> 64 > 64 > 64
MICso MICgo
16 32
> 64 16 32
Range
0.516 4 8
2> 64 8 16
0.54 1 2
0.532 2 8
0.0364 1 16
0.2516 0.5 4
264 4 16
164 1 16
416 4 8
16- I > 64 32 64
432 16 32
3264 32 64
28 4 8
832 16 32
832 16 32
32> 64 64 > 64
16> 64 > 64 > 64
8> 64 64 > 64
864 32 64
64- I 32> 64 > 64 > 64 > 64 > 64 > 64
0.532 4 16
264 8 32
0.258 0.5 4
0.532 2 16
0.516 2 8
0.134 2 4
232 8 16
232 8 32
264 4 32
2> 64 2 > 64
8> 64 8 > 64
0.5.16 I 16
2> 64 2 64
4> 64 64 > 64
0.5> 64 4 64
0.564 8 16
2> 64 32 64
0.2516 2 4
0.5> 64 8 16
32> 64 64 > 64
24 2 4
28 8 8
0.252 0.5 1
0.54 2 4
> 64 > 64
Acinetobacter lwoffi (20)
MICso MIC9o
264 8 8
Acinetobacter catcoaceticus (12)
Range MICsa MICgo
Acinetobacter johnsonii (12)
Range MICso MIC9o
4-1 64 8 32
264 8 32
Acinetobacter strain 84 (7)
Range MIC5o MICgo
32 >64
>64 64 >64
>64 4 >64
4-1 4>64 >64 8 16 >64 >64
8> 64 64 > 64
32>64 >64 >64
32>64 >64 >64
2>64 32 64
32- I 64>64 >64 >64 >64 >64 >64
28 4 8
032 1 2
416 8 16
432 8 32
28 4 8
16> 64 64 > 64
> 64
>64
>64
>64
>64
>64
> 64 > 64
>64 > 64
>64 > 64
>64 > 64
>64 > 64
>64 > 64
32> 64 > 64 > 64
> 64
>64
>64
>64
>64
>64
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
> 64
>64
>64
>64
>64
! >64
> 64 > 64
> 64 >64
> 64 >64
> 64 >64
> 64 >64
> 64 >64
8->64 64 > 64
>64
>64
> 64 > 64
> 64 > 64
>64
>64
>64 >64
>64 >64
8>64
4-
4-
Acinetobacter genospecies 3 (9)
Range MICso MICgo
Acinetobacter genospecies 12 (6)
Range MICso MICgo
4- I 16 8 16
432 16 32
Pseudomonas aeruginosa (30)
Range
> 64
> 64
> 64
> 64
MICso MICgo
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
Range
> 64
> 64
> 64
MICso MICgo
> 64 > 64
8> 64 > 64 > 64
> 64 > 64
> 64 > 64
Range
> 64
> 64
> 64
MICro MICgo
> 64 > 64
32>64 > 64 > 64
> 64 > 64
> 64 > 64
Range
8> 64 32 64
16> 64 64 > 64
4> 64 > 64 > 64
1664 32 64
832 16 32
> 64
>64
>64
> 64 > 64
> 64 > 64
> 64 > 64
8>64 64 > 64
1>64 8 > 64
8>64 32 64
0.25>64 2 64
> 64
>64
>64
MICro MICgo
2>64 8 64
> 64 > 64
>64 >64
>64 >64
4> 64 16 >64
Range
> 64
> 64
> 64
> 64
> 64
>64
>64
>64
>64
>64
MICso MIC9o
> 64 > 64
> 64 > 64
> 64 > 64
> 64 > 64
16> 64 > 64 > 64
> 64 > 64
>64 >64
>64 >64
>64 >64
>64 >64
>64 >64
Pseudomonas fluorescens (20)
Pseudomonas putida (20)
32>64 > 64 > 64
Pseudomonas stutzeri (8)
MIC5o MICgo
Pseudomonas cepacia (24)
Range
Pseudomonas maltophilia (20)
Infection 19 (1991) NO. 5
© M M V Medizin Verlag G m b H Miinchen, MiJnchen 1991
357 / 67
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime
Table 3: Comparativein vitro activity of cefpodoxime against staphylococci.
Staphylococcus aureus MET-R (20)
Range
4- I
16- I
MICso MICro
32 16 32
1>64 > 64 > 64
Range
0.5- I 0.25-
8-
1>64 I > 64 > 64
> 64
I > 64
> 64 > 64
> 64 > 64
Staphylococcus aureus PEN-R (20)
MICro MIC~
4t 1 4
1-
X I 0.5 1
2-
28
4 2 2
16
8
12
4
?
1 2
4
4
Staphylococcus aureus PEN-S (20)
Range MICso MICgo
0.25- I 0.1311o.5 f 0.5 0,5
0.25 0.5
Staphylococcus epidermidis MET-R (20)
Range
4-1 64
4-1 I
32
MIC5o MICgo
16 32
Range
0.5- I 0.13-
MIC5o MICgo
32 0.5 32
Range
0.5- I 0 . 1 3 - I
I
8 16
564 4 64
g~
> 64 16 64
4--
> 64 64 > 64
I
Staphylococcus epidermidis PEN-R (8)
I
1 0.25 1
0.25I
2 0.5 2
Staphylococcus epidermidis PEN-S (19)
0.25-
1
1 0.25
1
MICso MICgo
0.5 0,5
0.13 0.13
0.5 1
Range
> 64
MICso MICgo
> 64 > 64
16I > 64 64 > 64
64> 64 > 64 > 64
Staphylococcus haemolyticus MET-R (5)
Staphylococcus haemolyticus MET-S (19)
Range
0.25-I
0.13-
21o.5
MICso MICgo
0.5 2
0.25 0.5
0.5-
I
2
1 2
0.25-I
1-
1
2
; 44
Staphylococcus simulans (14)
Range MICso MICgo
0.25- I o.~31 0.5 0.5
10.25 0.13 0.25
o.13I
1 0.5 1
Staphylococcus hominis (12)
Range MICso MICgo
0.25-1 0-°6-I 0.252 I 0.5 1
0.13 10.25
2
0.5
1
Staphylococcus cohnii (10)
Range
0.25- ] 0.252 I 1 2 1 2 1
0.54 2 4
0.25- I
1-
4
8
Range
0.25-I
2-
MICro MICgo
1
2
Range
1-
2-
MICro MICgo
2
2
MICro MICgo
Staphylococcus saprophyticus (9)
; 44
Staphylococcus wameri (4)
68 / 358
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1991
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity o f C e f p o d o x i m e
Table 4: Comparative in vitro activity of cefpodoxime against streptococci.
Will/lira
Enterococcus faecalis (20)
Range
> 64
> 64
MICso MIC90
> 64 >64
> 64 > 64
Range
> 64
> 64
432 8 16
64
> 64
> 64
64 64
> 64 >64
> 64 >64
64
> 64
>64
®®
i~i!i~ii~!iiiii!~ilii~i~ ..........................................
416 8 8
> 64
64
> 64 > 64
64 64
3264 64 64
Enterocococcus faecium (17)
416 8 16
MICs0 MICg0
>64 > 64
> 64 > 64
Range
> 64
64>64 ! >64 >64 i
1 64 64
> 64 > 64
> 64 > 64
64
>64
>64
1
416 16 16
> 64 > 64 > 64
64> 64 64 > 64
> 64 > 64 > 64
Enterococcus liquefaciens (13)
MICso MICg0
>64 >64
28 4 8
1 64 64
>64 >64
>64 >64
1
416 4 8
> 64 > 64 > 64
1664 32 64
1664 32 64
Streptococcus pneumoniae PEN-R (15) (MIC PEN 1-4 mg/l)
Range MICs0 MIC9o
0.54 2 4
1664 32 64
3264 64 64
1664 32 64
16> 64 64 > 64
,062 1 1
48 4 4
14 2 2
0.0
6 6
18 2 4
0.58 2 4
64> 64 > 64 > 64
16> 64 > 64 > 64
0.060.25 0.06 0.13
0.0160.06 0.03 0.03
14 2 2
216 4 16
0.03 0.5 0.06 0.5
0.030.5 0.13 0.25
216 8 16
216 4 16
0.06 0.25 0.13 0.25
0.030.13 0.03 0.06
216 4 16
216 4 16
i
Streptococcus pneumoniae PEN-S (20)
i 0.25! 8 i 2 [ 4
Range MICso MICgo
0.0160.13 0.03 0.06
0.5-10.0080.25 0.5 I 0,06 ~ I 0.13
0. 0.
Streptococcus milleri group (11)
Range MICso MICgo
0.0160.25 0.06 0.13
0.134 1 4
i0.016[ 0.25 i 0.06 ! 0.25
116 2 16
464 16 64
0.54 2 4
0.1
0.0160.13 0.06 0.13
0.134 0.5 4
0.0160.25 0.03 0.25
~.516 2 16
264 32 64
0.54 1 4
0.1
0.016-0.06 0.03 0.06
0.130.5 0.13 0.25
0.0080.06 0.016 0.03
.031 .06 .25
0.254 1 1
0.060.5 0.13 0.13
0.0t 0.1 0.( 0.(
0.03 0.13 0.06 0.13
0.0160.25 0.03 0.06
0.060.5 0.13 0.25
0.060.25 0.13 0.25
0.030.25 0.06 0.25
0.52 1 2
0.0080.03 0.016 0.03
.251 0.5 1
16 16 16
0.060.5 0.06 0.5
0.01 0A 0.( 0.(
0.03 0,13 0.13 0.13
0.030.13 0.06 0.13
0,016-0.25 0.06 0.25
0.060.25 0.25 0.25
0.030.5 0.5 0.5
0.251 0.5 1
0.0080.016 0.008 0.016
.030.5 .13 0.5
0.51 1 1
0.060.13 0.06 0.13
0.01 01 0.01 0.(
0.016 0.13 0.03 0.13
0.0161 1 1
0.0160.13 0.03 0.13
0.060.13 0.06 0.13
0.0160.06 0.03 0.06
0.130.5 0.13 0.25
0.0080.03 0.016 0.016
.03'.25 .13 0.5
0.51 1 1
0.060.25 0.13 0.13
0.01 0.1 0.( O.I
0.0160.13 0.03 0.06
0.060:25 0.13 0.13
0.060.25 0.13 0.25
0.2
Streptococcus mitior (7)
Range MICs0 MICgo
Hemolytic streptococci group A (19)
Range MICso MIC90
Hemolytic streptococci group B (16)
Range MIC50 MICgo
Hemolytic streptococci group C (5)
Range MIC50 MICg0
Hemolytic streptococci group G (21)
Range MICs0 MICgo
Non-Enterococcal Hemolytic Streptococci Non-enterococcal hemolytic streptococci are about equally susceptible to all oral cephalosporins (except Infection 19 (1991) No, 5
0.2
0.030.13 0.06 0.13
ceftibuten against hemolytic streptococci group B), cefdinir and cefprozil being the most potent compounds (Table 4).
© MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1991
359 / 69
A. Bauernfeind, R. J u n g w i r t h : Comparative Antibacterial Activity of Cefpodoxime
Table 5: Comparative in vitro activity of cefpodoxime against Listeria, Haemoph#us, Moraxella, Neisseria, Brucella, Bordetella.
MICro
> 64
>64 > 64 >64 > 64
28 4 8
2>64 32 >64
64>64 >64 >64
18 4 8
18 2 8
0.252 1 2
1>64 32 >64
16>64 32 >64
1632 32 32
Hemophilus influenzae AMP-R (21) (MIC AMP 16-64 rag/l)
Range
0.030.25 0.06 0.13
L0160.25 0.03 0.13
0.131 0.25 0.5
0.060.5 0.13 0.25
0.030.25 0.06 0.25
0.251 0.5 1
432 8 16
0.25 1 0.5 1
0.52 1 1
432 8 32
864 16 32
0.030.13 0.06 0.13
0.030.5 0.13 0.25
0.130.5 0.25 0.5
0.060.5 0.13 0.25
0.030.13 0.03 0.06
0.250.5 0.5 0.5
432 8 16
0.251 0.5 1
0.251 1 1
216 8 16
832 16 32
0,060.13 0.06 0.13
0.030.06 0.03 0.06
0.130.25 0.25 0.25
0.060.5 0.13 0.5
0.030.06 0.06 0.06
0.251 1 1
0.54 2 4
0.251 1 1
0.131 0.5 1
416 8 16
416 8 16
0.060.5 0.25 0.5
0.060.5 0.13 0.5
0.130.5 0.25 0.5
0.060.5 0.13 0.5
0.54 1 4
0.51 0.5 1
14 1 4
0.50.254 2 2 i 0.5 4 2
0.54 4 4
12 1 2
0,0040.13 0.03 0.06
).0020.06 ).016 0.03
0.0040.06 0.0:16 0.06
).0080.13 0.03 0.06
0.030.5 0.13 0.5
0,254 1 4
8> 64 16 > 64
232 8 32
0.031 0.25 1
2> 64 > 16 > 64
464 16 64
MICro MICgo
0.0040.06 0.008 0.03
).002).016 ).008 ).016
0.0020.03 0.008 0.03
).0040.13 ).016 0.06
0.0080.25 0.06 0.25
0.132 0.5 2
164 8 32
18 4 8
0.0160.13 0.06 0.13
0.2564 8 32
164 8 64
Range
0.25
MICro MICgo
0.25 0.25
0.062 0.5 2
0.130,25 0.25 0.25
0.251 0.5 1
0.138 1 8
0.251 1
Range
8> 64 32 > 64
MICro MICro
Haemophilus influenzae AMP-S (35)
Range MICro MIC90
Haemophilus parainfluenzae (6)
Range MICs0 MICg0
MoraxeUa catarrhalis (13)
Range MIC50 MICgo
i
Neisseria gonorrhoeae PEN-R (20) (MIC PEN 16-64 nag/l)
Range MIC50 MICg0
Neisseria gonorrhoeae PEN-S (24)
Range
Brucella spp. (5)
2
8
2 2
8 8
MICro MICgo
2> 64 32 > 64
4> 64 32 > 64
Streptococcus pneumoniae
4
4
4 !
4
48 4
4
8
!
Bordetella pertussis (7)
1
4
64> 64 > 64 > 64
64> 64 64 > 64
16- > 6 4 64 >64 64 64 [ > 6 4
3264 64 64
cefuroxime and compounds.
I
BAY
3522
8-,I
> 64
64-
>64
i > 64
>64
L>64
>64
>64
r>64
>64
are the most potent
S. pneumoniae is most susceptible to cefpodoxime, cefdinir, cefuroxime and BAY 3522 (MIC90 between 0.03 and 0.13 mg/1). However, the MICs of penicillin resistant pneumococci are between 32 and 128 times above the MICs of penicillin susceptible strains (Table 4). The lowest MIC90 were 4 mg/l indicating resistance to all oral cephalosporins. S. milleri and S. mitior are less susceptible than the other non-enterococcal streptococci; however, against these two cefpodoxime, cefdinir, 70 / 3 6 0
Fastidious Pathogens
Haemophilus spp., Moraxella catarrhalis, N. gonorrhoeae are more susceptible to cefpodoxime, cefdinir, cefetamet and ceftibuten than the other oral cephalosporins included (Table 5). Loracarbef is more active than cefaclor against the TEM producing strains of E. coli,
Haemophilus influenzae, M. catarrhalis, N. gonorrhoeae,
Infection 19 (1991) No. 5
© MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1991
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime
Table 6: Comparative in vitro activity of cefpodoxime against anaerobes, Helicobacter pylori.
~N®i~ !i~ii~iiii ~iiii!il~i i~iiiiii~i!~~iii~Nii~i!iiilii~i®~i Niii2iMN:?i!jii iiiiiNi~Jiii!il;ii IiNi~iNi'i~ii
Clostridium difficile (12)
Range MICs0 MICg0
64> 64 > 64 > 64
> i4
64
>64
64
• 64 > >
0.5.
1
64> 64 > 64 > 64
16 32 16 32
0.130.5 0.25 0.5
).54 2 4
4 16 4 16
).5> 64 16 64
8 16 16 16
6
>6
i4 i4
64 64
>64 > 64
64 64
0.5 1
64 > 6
1
3.54 2 4
4 > 64 4 >64
1 64 4 64
32
3.516
64 64 64 64
& 64 64 64
16
0.5, > 64 I 0.5 ~>64
64 64 64 64
16 32 32 32
16 8 16
0.250.5 0.25 0.5
14 2 4
8' 16 16 16
0.06 4 2 4
0 258
0.516
Clostridium spp. (5)
Range MIC~0 MICg0
0 2516 8 16
i4
1 i4
16 32 32
16
Bacteroides spp. (11)
Range MICs0 MICg0
1
0 25> 64 ).5 > 64
1
1
L6
16
64 > 64 >64 >64
i4
64 >64 > 64 >64 4 16 16 16
[6
16
8
Peptococcus magnus (4)
Range MICs0 MICg0
832 8 32
> i4 > i4
4 16 8 16
0.54 2 4
.5 8 1 4
).N 2 ).5 2
>
Helicobacter pylori (16)
Range MIC~0 MICg0
Progress in activity is less pronounced for Brucella spp. (except for cefpodoxime, cefdinir and loracarbef). Listeria spp. are only moderately susceptible to some of the oral cephalosporins (BAY 3522, cefprozil, loracarbef, cefdinir), while B. pertussisis resistant to all oral cephalosporins [5], however, susceptible to parenteral cephalosporins, namely cefotaxime, cefepime and cefpirome [6]. The in vitro activity of the oral cephalosporins is low against anaerobes except for BAY 3522 (Table 6). H. pylori is moderately susceptible to the majority of the oral cephalosporins, cefdinir, loracarbef and cefaclor being the most active. Discussion The antibacterial activity of established oral cephalosporins 'is restricted to a limited number of pathogens. Some of the gaps in the activity spectrum of established cephalosporins remain open for most of the new compounds of this group as well (no or only moderate activity against Enterobacter spp., Morganella, Listeria (except BAY 3522), Pseudomonas and Acinetobacter, methicillin resistant staphylococci, Enterococcus spp., penicillin resistant pneumococci and anaerobes (except BAY 3522). The resistance mechanisms - inadequate binding affinity of PBPs, incomplete penetration or
.252 0.5 2
0.2
1
8
4
16
instability against [3-1actamases - remain effective against the majority of the new compounds as well. On the other hand, therapeutically significant progress was made against various other species both in activity and spectrum. Thus, for example, cefpodoxime exceeds the activity of cefaclor against Klebsiella pneumoniae 16-fold, against Haemophilus spp. 128- to 256-fold, against gonococci 1024-fold. Furthermore, new compounds (cefpodoxime, cefixime, cefdinir, cefetamet, ceftibuten) extend the spectrum of oral cephalosporins within. Enterobacteriaceae (including Citrobacter with cefetamet and ceftibuten [7]; Proteus, Providencia rettgeri with cefpodoxime, cefixime, cefetamet, ceftibuten). The compounds with enhanced antibacterial activity are structurally related to parenteral cephalosporins of the aminothiazole type. Activity in the magnitude of parenteral third generation cephalosporins is reached by some of the new absorbable compounds. Improvements in in vitro activity against staphylococci by new oral cephalosporins are confined to cefdinir, BAY 3522 and cefprozil. Among the new cephalosporins, ceftibuten, cefetamet and cefixime have no therapeutically significant antistaphylococcal activity, whereas the antistaphylococcal efficacy of cefpodoxime and loracarbef corresponds to that of cefuroxime, cefaclor and cefadroxil [8]. The oral cephalosporins with the broadest antibacterial spectrum are cefpodoxime and cefdinir.
Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, Miinchen t991
361 / 71
A. Bauernfeind, R. Jungwirth: Comparative Antibacterial Activity of Cefpodoxime
New oral cephalosporins signify an advance in therapy with pathogens which are also susceptible to established
oral cephalosporins, and especially of infections caused by pathogens resistant to established oral cephalosporins.
References
5. Hoppe, J. E., Miiller, J.: In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to six new oral cephalosporins. Antimicrob. Agents Chemother. 34 (1990) 1442-1443. 6. Bauernfeind, A.: In vitro activity and stability against novel beta-lactamases of flomoxef in comparison with latamoxef, SCE 2787, cefpirome, cefepime, cefotaxime, piperacillin and piperacillin plus tazobactam. Infection (in press). 7. Bauernfeind, A.: Comparative antimicrobial spectrum and activity of ceftibuten against clinical isolates from West Germany. Diagnost. Microbiol. Infect. Dis. 4 (1991) 63-74. 8. Banernfeind, A., Przyklenk, B., Matthias, C., Jungwirth, R., Bertele, R. M., Harms, IL: Selection of antibiotics for treatment and prophylaxis of staphylococcal infections in cystic fibrosis patients. Infection t8 (1990) 126-130.
1. Neu, H. C., Fu, K. P.: Cefaclor: In vitro spectrum of activity and beta-lactamase stability. Antimicrob. Agents Chemother. 13 (1978) 584- 588. 2. Grimm, H.- Bakteriologische in vitro Untersuchungen mit Cefaclor. Infection 7 Suppl. 6 (1979) 540-542. 3. Mittermayer, H.: In vitro activity of cefetamet (Ro 15-8074) Eur. J. Clin. Microbiol. 5 (1986) 530-534. 4. Mabilat, C., Conrvalin, P.: Development of "oligotyping" for characterization and molecular epidemiology of TEM [5-1actamasesin members of the family Enterobacteriaceae. Antimicrob. Agents Chemother. 34 (I990) 2210-2216.
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Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, M~inchen 1991
