In vitro activity of cefpodoxime and ten other cephalosporins against gram-positive cocci, Enterobacteriaceae and Pseudomonas aeruginosa, including beta-lactamase producers.

B. W i e d e m a n n , E. L u h m e r , M. T. Z t i h l s d o r f

In Vitro Activity of Cefpodoxime and Ten Other Cephalosporins against Gram-Positive Cocci, Enterobacteriaceae and Pseudomonas aeruginosa, Including [5-Lactamase Producers Summary: Cefpodoxime, the deesterified part of the orally available cefpodoxime proxetil, is active against most Enterobacteriaceae with MICs0 of 0.06 to 2 rng/l. Only Enterobacter cloacae and Citrobacter freundii strains show MICs0 of 4 mg/l. Coagulase negative staphylococci have a MICs0 of 2, while Staphylococcus aureus strains have a MIC of 4 mg/l. In comparison to other orally available cephalosporins cefpodoxime is slightly less active than cefixime and cefotiam against gram-negative bacteria but more active than cefuroxime, cefaclor, and cephalexin. Against staphylococci the activity of cefpodoxime is comparable to that of cefotiam and cefuroxime and superior to cefaclor and cephalexin, while cefixime does not have sufficient activity against these species. Like all cephalosporins cefpodoxime has no activity against enterococci. Zusammenfassung: In-vitro-Aktivitiit yon Cefpodoxim und zehn anderen Cephalosporinen gegen grampositire Kokken, Enterobacteriaceae und Pseudomonas aeruginosa einschliefllich ~-Laktamase-Bildnern. Cefpodoxim entsteht durch Spaltung des Esters aus dem resorbierbaren Cefpodoxim-Proxetil und ist gegen die meisten Enterobacteriaceae mit MHKs0-Werten von 0,06 bis 2 mg/l aktiv. Nur St/imme von Enterobacter cloacae und Citrobacter freundii zeigen MHKs0-Werte von 4 mg/l. Coagulase negative Staphylokokken haben eine MHKs0 von 2, w/ihrend Staphylococcus aureus-Stftmme eine MHK von 4 mg/1 aufweisen. Im Vergleich mit anderen oral verfiigbaren Cephalosporinen ist Cefpodoxim gegen gramnegative Bakterien etwas weniger aktiv als Cefixim und Cefotiam, aber aktiver als Cefuroxim, Cefaclor und Cephalexin. Gegen Staphylokokken ist die Aktivit/it von Cefpodoxim mit der von Cefotiam und Cefuroxim vergleichbar und der von Cefaclor und Cephalexin fiberlegen, wahrend Cefixim keine ausreichende Aktivitfit gegen diese Spezies hat. Wie alle Cephalosporine weist Cefpodoxim keine Aktivit/it gegen Enterokokken auf. Introduction In the last two decades, the pharmacodynamic and pharmacokinetic properties of parenteral cephalosporins have been improved dramatically, by modification at the 3-position and the 7-position of the cephem nucleus. Recently there has been intense activity in the

development of orally absorbable cephalosporins. Cefpodoxime proxetil (U-76,252; CS-807) is one of those which must be enzymatically cleaved into their active forms after absorption [1]. The drug is deesterified to its active metabolite cefpodoxime (U-76,253; R- 3763). Cefpodoxime is active against a great variety of gram-negative and gram-positive bacteria [2-4]. The objective of this study was to compare the in vitro activities of the sodium salt of cefpodoxime (CFP) with other newly developed orally available [Mactams, with established orally available cephalosporins, and with established third generation cephalosporins. These drugs were tested against randomly isolated pathogens and strains which produce known [Mactamases. Materials and Methods Antibacterial agents: All antibacterial agents were kindly supplied by the following manufacturers: cefpodoxime (CFP) (Sankyo, Dtisseldorf, FRG), cephalexin (CEX), cefaclor (CEC) and loracarbef (LOC) (Lilly, Bad Homburg, FRG), ceftazidime (CAZ) and cefuroxime (CXM) (Glaxo, Greenford, UK), ceftibuten (CFB) (Schering Plough, USA), cefetamet (CTF) (Hoffmann-La Roche, Basel, Switzerland), cefotiam (CTM) (Takeda, Aachen, FRG), cefotaxime (CTX) (Hoechst AG, Frankfurt, FRG), cefixime (CFX) (Merck, Darmstadt, FRG). Organisms: The majority of strains examined in this study were obtained from clinical material examined during a multicentre study in 30 different centers in the Federal Republic of Germany, Austria, and Switzerland, thus representing a non selected collection of strains avoiding repetitive isolates and hospital or unit specific material. The bacteria were identified by conventional methods and in addition with API20E, API20NE, and API20Strep (API BioM6rieux, Niirtingen, FRG). Bacteria producing I]-lactamases were from our own laboratory collection. Determination of the minimal inhibitory concentrations: The MICs were determined by the microdilution technique with Mfiller-Hinton broth (Difco, USA) according to the recommendations of the NCCLS [5], with an inoculum of 105 cfu per ml. Results Sensitivity of Cefpodoxime In total 1,018 strains were examined. In Table 1 the range of MICs, MICs0, and MIC90 for cefpodoxime in comparison with other orally available cephalosporins, loracarbef (an orally available carbapenem), and third Prof. Dr. B. Wiedemann, Elisabeth Luhmer, M. 7'. Ziihlsdorf, Pharmazeutische Mikrobiologie der Universitfit Bonn, An der Immenburg 4, W-5300Bonn 1, Germany.

Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1991

363 / 73

B. Wiedemann

et al.: Cefpodoxime:

Table 1 : T h e in vitro activity of

Escherichia coli (98)

Comparative

in Vitro Activity

cefpodoxime in comparison with other drugs against gram-positive and gram-negative bacteria.

Cefaclor Cefetamet Cefixime Cefotaxime Cefotiarn Cefpodoxime Ceftazidime Ceftibuten Cefuroxime Cephalexin Loracarbef

32 0.03 8 0.06 32 0.5 16 2 - 256 0.2564

4 0.13 0.13 -< 0.03 0.06 1 0.13 0.25 2 4 0.5

8 0.25 0.5 0.06 0.25 2 0.5 1 4 8 1

2 0.25 0.13 0.06 0.13 0.5 0.25 0.25 4 4 0.5

2 0.25 0.13 0.13 0.25 1 0.5 0.5 4 4 0.5

32 1 2 O. 13 0.5 2 0.5 0.5 4 32 4

-> 512 -> 64 -> 64 16 -> 64 -> 32 16 2 -> 128 256 - 512

Salmonella spp. (44)

Cefaclor Cefetamet Cefixime Cefotaxime Cefotiam Cefpodoxime Ceftazidime Ceftibuten Cefuroxime Cephalexin Loracarbef

Citrobacter fr eundii (42)


1 --> 0 . 0 6 - -> -< 0 . 0 3 - - > 0.03 0.03 - -> 0.25-- > 0.06 0.06 - -> 1 - -> 2 0.5 - - >

Klebsiella oxytoca (5 t )

Cefaclor Cefetamet Cefixime Cefotaxirne Cefotiam Cefpodoxime Ceftazidime Ceftibuten Cefuroxime Cephalexin Loracarbef

1 - --> 5 1 2 < 0.030.25 -< 0 . 0 3 0.25 0.03 2 0.03 32 0.13 16 0.06 1 0.03 0.25 0.5 - -> 128 2 128 --< 0 . 2 5 512

2 0.06 -< 0.03 0.03 0.13 0.25 0.13 0.06 2 4 0.5

8 0.06 0.06 0.13 1 1 0.5 0.06 4 8 4

Ktebsiella pneumoniae (94)


0.5 -< 0 . 0 3 -< 0 . 0 3 0.03 0.03 0.13 0.03 -< 0 . 0 3 0.5 2 -< 0 . 2 5 -

2 0.06 0.06 0.03 O. 13 0.25 0.25 -< 0.03 1 4 0.5

32 0.25 0.13 0.13 1 2 1 0.13 4 8 4

74 / 364

I n f e c t i o n 19 (1991) N o . 5

1 O. 13 0.06 0.03 0.13 0.25 0.03 0.13 0.5 2 < 0.25-

-

16 0.5 0.25 0.25 0.5 1 0.5 0.5 8 16 0.5

512 64 64 64 64 32 64 64 128 256 512

128 0.5 0.5 4 16 16 8 0.5 16 64 32

© M M V M e d i z i n V e r l a g G m b H M i i n c h e n , M i i n c h e n 1991

B. W i e d e m a n n e t al.: C e f p o d o x i m e : C o m p a r a t i v e in V i t r o A c t i v i t y

Table 1 continued

Enterobacter aerogenes (22)


Enterobacter cloacae (51)

Cefaclor Cefetamet Cef'Lxime Cefotaxime Cefotiam Cefpodoxime Ceftazidime Ceftibuten Cefuroxime Cephalexin Loracarbef

Serratia spp. (46)


Proteus mirabilis (98)


0.030.03 0.03 0.03 - -> -< 0 . 0 3 0.015 --< 0 . 0 3 0.25 ---> 4 -2 --->

Proteus vulgaris (49)

Infection 19 (1991) No. 5

© MMV Medizin Verlag G m b H Miinchen, Miinchen 1991

2 --> 0.06--> 0.06-- > 0.03 0.I3 - -> 0.5 - -> 0.13 0.06 - -> 1 --> 4 0.5 -

512 64 64 16 64 32 64 64 128 256 512

256 0.25 0.5 0.13 0.5 2 0.5 0.25 4 128 16

-> 512 -> 64 -> 64 16 -> 64 -> 32 32 -> 64 -> 128 256 256

1 - - > 512 < 0.03 - --> 64 --< 0 . 0 3 - - -> 64 0.03 64 0 . 0 3 - - > 64 0.13 - -> 32 0.06 32 0.03 - -> 64 0.5 - - > 128 2 256 < 0 . 2 5 - -> 512

128 0.5 1 0.25 0.5 4 0.25 0.5 8 128 16

-> 512 32 -> 64 16 -> 64 -> 32 4 32 -> 128 256 -> 512

-> 512 0.5 0.5 0.25 8 1 0.25 0.5 64 256 128

-> 512 4 4 4 -> 64 8 0.5 2 -> 128 -> 256 512

64 0.25 0.06 0.06 1 0.5 0.03 0.25 8 32 2

-< -
--> -

512 16 16 16 64 32 2 16 128 256 512

1 256 0.03 0.5 0.030.25 0.03 0.13 0.06 2 0 . 0 3 - - > 32 0.03 0.25 0.03 0.5 0.5 8 4 256 0.5 32

512 2 0.5 0.5 64 2 0.5 2 128 128 512

4 0.06 -< 0.03 0.03 0.25 0.13 0.13 0.06 1 8 0.5

4 0.06 -< 0.03 0.03 0.5 0.5 0.13 0.06 2 16 2

-> 512 0.06 -< 0.03 0.03 1 0.25 0.06 0.06 --> 128 ----- 128 --> 512

-> 512 0.25 0.06 0.03 -> 64 2 0.13 0.t3 -> 128 --> 128 --> 512

365 / 75

B. W i e d e m a n n e t al.: C e f p o d o x i m e : C o m p a r a t i v e in V i t r o A c t i v i t y

Table 1 continued

Providencia spp. (19)

Cefaclor Cefetamet Cefixime Cefotaxime Cefotiam Cefpodoxime Ceftazidime Ceftibuten Cefuroxime Cephatexin Loracarbef

Morganella morganii (48)


Pseudomonas aemginosa (100)


1 --> --. 0.03 -< 0.03 0,03 0.03 -< 0.03 -< 0 . 0 1 5 -< 0,03 0.03 2 ->-< 0.25 -

512 2 0.5 0,25 0.5 1 0.25 2 128 128 64

32 -< 0.03 -< 0,03 0.03 0,13 < 0.03 0.13 -< 0.03 0.5 32 1

-> 512 0,5 0.25 0,13 0.5 1 0,25 0.13 16 -> 128 32

>-- 512 2 0.25 0.03 0.5 2 0,13 2 16 256 32

-> 512 >-- 64 16 2 16 -> 32 2 -> 64 --> 128 256 256

64 64 64

> 512 _> 64 32 16

--> 512 >- 64 -> 64 64

64 - - > 64 - - > 128 ---> 128 ---> 512

----- 32 2 -> 64 >- 128 -> 128 --> 512

--> 32 4 -> 64 -> 128 -> 128 --> 512

2 ->0.06 - --> -< 0.03 - >0.03 0.13 0.25--> 0.03 0.06 - --> 1 --> 8 0.5 >-- 512 4 16 0.25 nd >-- 32 0.5 4 4 8 256

512 64 64 16 64 32 16 64 128 256 512

- >- -> - >

Staphylococcus aureus (100)


2 - 256 32 - - > 64 8 - -> 64 1 32 0,5 8 2 4 2 32 32 - > - 64 0.25 128 2 - 256 -< 0 . 2 5 - 256

Staphylococcus coagulase negative (58)


0,06 - 16 nd nd 0.13- 4 nd 0.25 - 16 0,25 - 32 nd -< 0 . 0 6 - 4 nd -< 0 . 2 5 - 8

Enterococcus f aecalis (98)

76 / 3 6 6



64 - >-32--> 32--> 4--> nd 64 >- 64 32--> 8--> 128 8-

8 -> 64 16 2 0.5 4 16 32 1 4 2

16 -> 64 32 2 1 4 16 --> 64 2 8 4

2

8

2

4

2 8

8 32

1

2

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512 64 64 64

_> _> ->

256 64 64 64

64 128 256 256

64 -> 64 >- 64 -> 128 128 128

-> -> ->

256 64 64 64

64 -> 64 -> 64 -> 128 256 128

© MMV Medizin Verlag G m b H Mfinchen, Miinchen 1991

B. Wiedemann et al.: Cefpodoxime: Comparative in Vitro Activity

C.freundii

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0.015 0.06 0.25 1 4 16 64 MIC [mg/I] Cefpodoxime Figure 1A: Cefpodoxime-MIC distribution for most common bacteria. ~-Iactamase producers which impair the activity of cefpodoxime are seen on the right-hand side of the normal sensitive distribution constituting the maximum of strains.

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0.0080.03 0.13 0.5 2 8 32 128 512 0.015 0.06 0.25 1 4 16 64 256 MIC [mg/I] Figure 1C: Distribution of M ICs of Citrobacter freundii for orally available cephalosporins. All antibiotics show similar bimodal distributions with comparably high proportion of resistant strains (right-hand side distribution) due to chromosomally mediated ~-Iactamases.

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t0-V! ~ l i = = ~ = = ' ~ ~ . ~ ' / - / - / - / C e ~ x i m e i ~_./_././/~./././././_/Cefetamet o V / ~ / , , w , , w / , , " ,/,,",,",///Cefotiam 0.008 0.03 0,13 0.5 2 8 32 128 512 0.0150.060.25 1 4 16 64 256 MIC [rng/I]

Figure 1B: Distributions of MICs of Escherichia coil for orally available cephalosporins. Nearly an equal number of [3lactamase producers (approx. 2%) appear on the right-hand side of the "sensitive bacteria" for all antibiotics. The reason is a chromosomally mediated [3-1actamase. Cefpodoxime takes a position between the older cephalosporins and the very modern ones, which all show about fourfold lower MICs.

generation cephalosporins are listed. The drugs are given in alphabetical order. The MIC50 of cefpodoxime, a value which usually indicates the maximum of strains in one species showing an MIC around this value, was less or equal to 1 mgh for Escherichia coti, Salmonella, Klebsielta oxytoca, KlebsieUa pneumoniae, Serratia spp., Proteus mirabilis, Proteus vulgaris, and Providencia spp. A MIC50 of 2 to 4 mg/l was found for Citrobacterfreundii, Enterobacter

"~ " z 1 0 [ ~ ~

~ ~ _ ~ , ~ j ~~/f///,/Cefpodoxime l~E~'/~v~'/~'//////Cef°t'arn ll~__~_~.._J/////~Cefetamet

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" ~/ff//(/(//,/Cefixime 0.0080.030.130.5 2 8 32 126 612

0

0.0150.060.25 1 4 MIC [mg/I]

16 64 256

Figure 1D: Distribution of MICs of Klebsiella pneumoniae for orally available cephalosporins. The decreasing influence of {]-Iactamases from the older to the newer drugs is evident from the right to the left-hand side.

aerogenes, Enterobacter cloacae, Morganella morganii, coagulase negative Staphylococcus aureus, and staphylococci. Pseudomonas aeruginosa and Enterobacter faecalis need much higher concentrations to be inhibited. An overview of the antibacterial activity of cefpodoxime is shown in Figure 1A. Figures 1 B to F demonstrate the MIC distribution for orally available cephalosporins tested. All strains of E. coli seem to be distributed symmetrically

Infection 19 (1991) No. 5 © MMV MedizinVerlag GmbH Mfinchen,Miinchen 1991

367 / 77

B. W i e d e m a n n et al.: C e f p o d o x i m e : C o m p a r a t i v e in V i t r o A c t i v i t y

S.aureus

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"~1 ~ ~ ~ce~uroxime o~---a~'~A~c~/,/,/ "/W Cefot~.~ 0.06 0.25 1 4 16 64 256 0,13 0.5 2 8 32 128 512 MIC [mg~]

//ce~me

0.0080.030.130.5 2 8 32 128 512 0.015 0.06 0.25 1 4 16 64 256 MIC [rag/I] Figure 1 E: Distribution of MICs of Proteus mirabilis strains for orally available cephalosporins. Cefpodoxime is a 16-fold more active drug than cefaclor and eight times less active than cefixime, which is the most active drug.

Figure 1F: Distribution of MICs of Staphylococcus aureus strains. The comparison of orally available cephalosporins demonstrates that those drugs with specially high activity against gram-negative bacteria (cefetamet, cefixime) have no activity against staphylococci. Cefpodoxime has an intermediate position.

except for very few, which produce a higher level of chromosomally mediated [~-lactamase than usual. Except for cefuroxime these strains appear outside the normal distribution of MICs for all drugs. The difference in the MIC, as compared with normal strains, varies from drug to drug. It ranges from about seven dilution steps (factor 128) for cefixime to about four dilution steps (factor 8) for cefpodoxime. Within the C. freundii and K. pneumoniae strains again the

Table 2: MIC of cefpodoxime with standard strains.

Escherichia coil Staphylococcus aureus Staphylococcus aureus Enterococcus faecalis Pseudomonas aeruginosa

25922 25923 29213 29212 27853

l 2 2 > 32 > 32

0.5- 2 2 - 4 2 - 4 > 32 > 32

Table 3: Susceptibility of organisms with plasmid mediated 13-1actamases.

Escherichia coli Escherichia coli Escherichia coli Escherichia coli Escherichia coli Pseudomonas aeruginosa

TEM-1 TEM-2 SHV-1 SHV-2 HMS-1 LCR-1

4 8 2 32 8 1

1 1 1 2 1 1

1 1 1 4 1 1

2 1 1 16 1 1

8 8 2 8 8 1

1 1 1 16 1 1

1 1 1 8 2 1

1 1 1 1 1 1

1 1 1 1 1 1

1 1 1 32 1 1

1 2 1 32 4 1

Escherichia coli Escherichia coli Escherichia coli Escherichia coli Escherichia coli Pseudomonas aeruginosa Escherichia coti Pseudomonas aeruginosa

OXA-1 OXA-2 OXA-3 OXA-4 OXA-5 OXA-6 OXA-7 OXA-8

2 4 4 2 4 1 128 1

2 1 1 2 4 1 1 1

1 1 1 2 8 1 1 1

2 1 1 2 2 1 4 1

4 16 8 4 64 1 256 1

2 1 1 1 1 1 1 1

1 2 4 1 2 1 2 1

1 1 1 1 2 1 1 1

2 1 1 1 4 1 4 1

1 1 1 1 2 1 2 1

1 1 1 1 2 1 32 1

Pseudornonas aeruginosa Pseudomonas aeruginosa Pseudomonas aeruginosa

CARB-1 CARB-2 CARB-4

1 1 1

1 1 1

i 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

Escherichia coli Pseudomonas aeruginosa Klebsiella oxytoca

TLE-1 NPS-1 LXA-1

2 1 32

1 1 1

1 1 1

1 1 1

2 1 16

1 1 2

1 1 1

1 1 1

1 1 2

1 1 1

1 1 16

N u m b e r s indicate t h e factor by which the M I C increased as compared with the host strain without plasmid mediated 13-1actamase.

78 / 368


© M M V Medizin Verlag G m b H Miinehen, Mtinchen 1991

B, Wiedemann et al.: Cefpodoxime: Comparative in Vitro Activity

Table 4: Increase of MIC due to hyperproduction of chromosomally-mediated IMactamases (numbers indicate the factor by which the MIC was increased as compared with the MIC for the parent strain).

I Enterobacter cloacae 149 Enterobacter cloacae 150 Enterobacter cloacae 314 Enterobacter cloacae 352 I Enterobacter cloacae 352 II Enterobacter cloacae 988 Citrobacterfreundii

-> 32 + + -> 8 -> 8 + -> 64

-> 256 >-- 4 -> 128 4 128 128 -> 128

--> 8 >- 16 --> 16 4 --> 128 --> 64 -> 64

>-- 4 + + --> 8 --> 8 --> 4 -> 32

64 4 8 2 32 16 64

->

2 + nd --> 256 64 --> 128 -> 128

+ + + >-- 4 -> 4 + -> 8

--> 2 + --> 2 64 128 2 -> 8

+ MIC of the wild type was already outside the tested MIC range.

13-1actamase producers with impaired sensitivity are separated from the biologically homogenous group of fully sensitive strains. Again cefuroxime is the only exception (Figures 1G a n d ]D). A bimodal distribution characterizes the MICs of the older cephalosporins for Proteus strains (Figure 1E). Comparing the activity of all antibiotics tested against S. aureus it becomes obvious that the most recently developed compounds such as cefibuten, cefixime, and cefetamet need higher antibiotic concentrations for inhibition. The activity of cefpodoxime against S. aureus is comparable to that of cephalexin, loracarbef, and cefuroxime. The sensitivity of standard strains is given in Table 2.

Influence of 13-Lactamases Cefpodoxime, like the other newly developed 13-1actams, seems stable towards the most commonly found plasmid mediated 13-1actamases (Table 3). SHV-2, however, reduces the activity of this compound. The influence of chromosomally determined 13-1actamases is depicted in Table 4. Although the increase of the MICs for cefpodoxime seems to be marginal as compared to the other 13-1actams, the activity against 13-1actamase producing Enterobacter and Citrobacter strains is extremely limited. Discussion

This new orally available cephalosporin cefpodoxime is active against Enterobacteriaceae. There are, however, resistant strains due to the production of chromosomally mediated 13-1actamases in E. coli, M. morganii, Serratia, References i. Fujimoto, K., Ishihara, S., Yanagisawa, H., Ide, J., Nakayama, E., Nakao, H., Sugawara, S., Wata, M.: Studies on orally active

cephalosporin esters. J. Antibiot. 40 (1987) 370-384. 2. Jones, R. N., BarD", A. L.: Antimicrobial activity and disk diffusion

susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester U-76,252 (CS-807). Antimicrob. Agents Chemother. 32 (1988) 443-449. 3. Knapp, C. C., Sierra-Madero, J., Washington, J. A.: Antibacterial activities of cefpodoxime, cefixime, and ceftriaxone. Antimicrob. Agents Chemother. 32 (1988) 1896-1898.

Enterobacter, and Citrobacter spp. Especially so-called derepressed [3-1actamases in E. cloacae and C. freundii render these strains cefpodoxime resistant. Cefpodoxime is slightly less active against staphylococci. No activity is seen against P. aeruginosa and E. faecalis. Our results are in accordance with those of earlier investigators [1, 3, 4]. Knapp et al. [3] found substantially higher MICs0 than Jones and Barry [2] and Utsui et al. [4] for C. freundii, E. aerogenes, and E. cloacae. Our data for C. freundii and E. aerogenes are nearly identical with those of Knapp et al. [3]. O u r MICs0 value for E. cloacae, however, is m o r e than fourfold below the one of Knapp et al. [3]. These authors attribute the differences to incorrect inoculum sizes and differences in the n u m b e r of mutants with derepressed class I 13-1actamases. The M I C distributions (Figure 1) illustrate that our MIC50 value is identical with the median value, which is a more reliable measure of the activity as it cannot be influenced b y only a few abnormal strains. Similar data from the other authors are unfortunately not available. Sanders et al. [6] explained differences in antimicrobial spectrum and potency among oral cephalosporins with data on 13-1actamase stability, permeation of the drugs, and induction of 13-1actamases. Although we did not. check all these parameters, from the data available on cefpodoxime it can be deduced that the good stability of cefpodoxime towards 13- lactamases of plasmid origin is the reason for the broad spectrum of activity. Furthermore, the affinity to the target enzymes seems not to be limited to gram-negative species, as staphylococci are inhibited as well. This feature discriminates cefpodoxime from other recently developed cephalosporins with resistance to staphylococci like cefetamet, ceftibuten, and cefixime. 4. Utsui, Y., Inoue, M., Mitsuhashi, S.: In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin. Antimicrob. Agents Chemother. 31 (1987) 1085-1092. 5. National Committee for Clinical Laboratory Standards: Methods for

dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A. National Committee for Clinical Laboratory Standards, Villanova, Pa. 1985. 6. Sanders, C. C.: 13-1aetamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance. Antimicrob. Agents Chemother. 33 (1989) 1313- 1317.

Infection 19 (1991) No. 5 © MMV Medizin Verlag GmbH Mtinchen, M0nchen 1991

369 / 79

Synergy between ticarcillin and tobramycin against Pseudomonas aeruginosa and Enterobacteriaceae in vitro and in vivo.

In vitro activity of piperacillin compared with that of carbenicillin, ticarcillin, ampicillin, cephalothin, and cefamandole against Pseudomonas aeruginosa and Enterobacteriaceae.

Comparative activity of netilmicin, gentamicin, amikacin, and tobramycin against Pseudomonas aeruginosa and Enterobacteriaceae.

Activity of ceftazidime-avibactam against fluoroquinolone-resistant Enterobacteriaceae and Pseudomonas aeruginosa.

Activity of cephazolin and other cephalosporins against Bacteroides fragilis.

Comparative in-vitro activities of newer cephalosporins cefclidin, cefepime, and cefpirome against ceftazidime- or imipenem-resistant Pseudomonas aeruginosa.

Activity of antibiotics against resistant Pseudomonas aeruginosa.

In Vitro Activity of Oral Cephalosporins (Cefprozil and Cefixime) Against Ciprofloxacin-Resistant Enterobacteriaceae from Community-Acquired Urinary-Tract Infections.

In vitro susceptibility of gentamicin-resistant Enterobacteriaceae and Pseudomonas aeruginosa to netilmicin and selected aminoglycoside antibiotics.

Comparative in vitro activity of piribenicillin, ticarcillin, and carbenicillin against Pseudomonas aeruginosa.

Dissemination of carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa in Romania.

Comparison of the antibacterial activity of nine cephalosporins against Enterobacteriaceae and nonfermentative gram-negative bacilli.

Comparative in vitro activity of newer cephalosporins against anaerobic bacteria.

Comparative in vitro activity of five cephalosporins against Lactobacilli.

[Carbapenem-resistance in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii].

In-vitro activity of azlocillin against Pseudomonas.

In vitro activity of E1040 against imipenem-resistant Pseudomonas aeruginosa strains.

In vitro activity of josamycin against aerobic gram-positive cocci and anaerobes.

Enterobacteriaceae and Pseudomonas aeruginosa recovered from vegetable salads.

In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa.

Activity of cefamandole and other cephalosporins against aerobic and anaerobic bacteria.

Vitamin D3 enhances bactericidal activity of macrophage against Pseudomonas aeruginosa.

In vitro activity and beta-lactamase stability of BL-S786 compared with those of other cephalosporins.

In vitro activity of ciprofloxacin in combination with ceftazidime, aztreonam, and azlocillin against multiresistant isolates of Pseudomonas aeruginosa.