New Antimicrobial Agents

In Vitro Activity of Cefpodoxime, a New Oral Cephalosporin, Compared with that of Nine Other Antimicrobial Agents M. Sheppard, A. King*, I. Phillips

The in vitro activity of the compound RU-51746, the sodium salt of cefpodoxime (which is administered orally as the ester cefpodoxime proxetil) was compared with that of other commonly used oral antibiotics against a selection of clinical isolates of c o m m o n bacteria from patients with urinary tract, soft tissue and respiratory tract infections. RU-51746 was found to inhibit 90 % of Enterobacteriaceae at < 1 mg/I; pneumococci, pyogenic streptococci (Lancefield groups A, C and G) and Streptococcus agalactiae were almost all inhibited by concentrations of < 0.06 mg/I; Haemophilus in3ffuenzae (including beta-lactamase producers) were inhibited by < 1 mg/l; 90 % ofBranhamella catarrhalis were inhibited at < 2 mg/I. Activity against Acinetobacter spp. and staphylococci was variable and enterococci were all resistant.

RU-51476 is the sodium salt of the active metabolite, eefpodoxime, of a new oral cephalosporin cefpodoxime proxetil. This agent is a pro-drug ester, which is hydrolysed into the active metabolite before absorption. We compared the in vitro activity of cefpodoxime with that of other commonly used oral agents against a variety of bacteria recently isolated from clinical specimens at St. Thomas' Hospital, which were responsible for urinary tract, soft tissue and respiratory infections.

Materials' and Methods'. The organisms tested were randomly collected from recent clinical specimens associated with urinary tract, soft tissue and respiratory tract infections. A small number of isolates known to produce a variety of beta-lactamases were also included. Anaerobes and pseudomonads were not tested as previous work has shown cefpodoxime to be inactive against most of them (1). Department of Microbiology, United Medical and Dental Schools, St. Thomas' Hospital, Lambeth Palace Rd., London SEt 7EH, UK.

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The antimicrobial agents tested, gifts of their manufacturers supplied as powders of known potency, included cefaclor (Eli Lilly, UK), cefadroxil (Brystol Myers, UK) and cefuroxime (Glaxo, UK); amoxieillin alone and in combination with clavulanate (Smith Kline Beecham, UK) in a ratio of 2:1 (referred to for convenience as amoxicillin/CA); trimethoprim, co-trimoxazole tested in the ratio 20/1 sulphamethoxazole/ trimethoprim (Wellcome, UK), ciprofloxacin (Bayer, Germany), and erythromycin (Eli Lilly) which was not tested against Enterobacteriaceae or Acinetobacter spp. All powders were stored at -20 °C and fresh stock solutions were prepared according to the manufacturers' instructions. Minimum inhibitory concentrations (MICs) were determined for all agents by standard agar-dilution techniques, as described previously (2). The agar used was Diagnostic Sensitivity Test Agar (CM 261, Oxoid, UK) supplemented with 5 % saponin-lysed horse blood for fastidious organisms (and also with 10 rag/1 nicotinamide adenine dinucleotide for Haemophilus influenzae), and with 25 mg/l para-nitrophenyl glycerol for Proteus spp. to prevent swarming. Lysed blood (5 %) was also added in all tests involving trimethoprim or co-trimoxazole. Organisms were inoculated from overnight growth in nutrient broth (Enterobacteriaceae and Acinetobacterspp.) or Brain-Heart Infusion broth (staphylococci), diluted to produce an inoculum of approximately 104 organisms. Branhamellae, streptococci and haemophili were grown overnight on solid medium, then suspensions were made in nutrient broth and diluted as above. A multi-point inoculator was used to inoculate all plates, and at least one control organism was included in each batch of plates. The results were accepted only if the MIC of the antibiotic for the control organism was within one doubling dilution of the expected value. Inoculated plates were incubated overnight at 37 °C in air for all organisms except haemophilus, which was incubated in an atmosphere of 5 % CO2. The MIC was taken as the lowest concentration of antibiotic at which no visible growth, or less than five individual colonies, were seen. Breakpoints used were as stated in the report of a Working Party for the British Society of Antimicrobial Chemotherapy (3) or calculated by the formula given for those antibiotics not included in the report (Table 1). Where low and high breakpoints have been included, results equal to or below the low breakpoint have been designated sensitive, those above

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Eur. J. Clin. Microbiol. Infect. Dis.

the high b r e a k p o i n t as resistant and those between as intermediate. T h e b e t a - l a c t a m antibiotics were also tested against a higher inoculum (about 106) of Staphylococcus aureus, to assess the effect of inoculum on MIC, and hence the relative stability to staphylococcal b e t a - l a c t a m a s e of the agents tested. Results" and Discussion. In Enterobacteriaceae (Table 2) amoxicillin resistance, especially in hospital isolates, has long been a problem, and resistance to oral cephalosporins is not uncommon. The balance of isolates tested within this group does not reflect the normal distribution but was selected to include representatives of each species and hence is heavily weighted with betalactamase-producing organisms. Despite this, cefp o d o x i m e p r o v e d to be a very active compound. T h e m e m b e r s of this group of organisms most c o m m o n l y causing disease are Escherichia coli, Klebsiella spp. and Proteus mirabilis, all as causative agents of uncomplicated urinary tract infections, and it would be reasonable to use the high b r e a k p o i n t for resistance for these organisms. Our results for these species illustrate the high incidence of resistance to amoxicillin; of 120 isolates, 73 were resistant ( 6 1 % ) . T h e susceptible p r o p o r t i o n was increased by use of a beta-lactamase inhibitor (clavulanic acid) so that only 19 (16 % ) were resistant to amoxicillin/CA. With respect to the oral cephalosporins, the resistance rates in this group were 16 % for cefaclor and 9 % for cefadroxil. T h e r e was only one isolate for which the M I C s of c e f p o d o x i m e and cefuroxime were above the high breakpoint. Amoxicillin resistant organisms were invariably highly resistant ( M I C > 128 mg/l), whereas the M I C s for organisms resistant to other beta-lactams were just

a b o v e the b r e a k p o i n t in the majority of cases. The n u m b e r s in this group with M I C s four-fold higher or m o r e than the high b r e a k p o i n t w e r e 70 for amoxicillin, 4 for amoxicillin/CA, 6 for cefaclor, 3 for cefadroxil and none for cefuroxime or cefpodoxime. T h e remaining species of Enterobacteriaceae and Acinetobacter spp. (Table 2) are often associated with m o r e complicated infections in which tissue levels m a y be m o r e i m p o r t a n t and for this reason we felt the low b r e a k p o i n t should be used. O u r results for these organisms c o m b i n e d give rates for intermediate sensitivity and resistance of 87 % for amoxicillin, 67 % for amoxicillin/CA, 90 % for cefaclor, 87 % for cefadroxil, 47 % for cefuroxime, and 18 % for cefpodoxime. In cases in which the high b r e a k p o i n t was relevant, the resistance rates were 72 % for cefaclor, 65 % for cefadroxil, 22 % for cefuroxime and 7 % for cefpodoxime. T h e numbers of organisms with M I C s m o r e than fourfold higher than the low breakpoint were 65 for amoxicillin, 36 for amoxicillin/CA, 73 for cefaclor, 73 for cefadroxil, 20 for cefuroxime and 5 for cefpodoxime. T h e s e findings substantiate recent work which shows that cefp o d o x i m e is stable to beta-lactamases f r o m m a n y organisms (4). O u r results show that c e f p o d o x i m e is active against some organisms that are clearly resistant to cefuroxime. Against the Enterobacteriaceae ciprofloxacin was the most active of the n o n - b e t a - l a c t a m agents tested; one isolate of Providencia stuartii was of only intermediate sensitivity and all o t h e r isolates were sensitive. Co-trimoxazole was active against most isolates but there was some resistance in Es'cherichia coli, Klebsiella spp., Citrobacterfreundii, Proteus mirabilis and Providencia stuartii. T h e ac-

Table 1: Breakpoints often antibiotics (rag/l). Antibiotic

Ccfpodoximc Cefaclor Cefadmxil Cefuroximc b Amoxicillin/CA Amoxicillin Co-trimoxazole Trimcthoprim Ciprofloxacin Erythromycin

Low breakpoint for for othcr Enterobacteriaceae organisms" 1 2 4 4 8 8 32 0.5 t -

High breakpoint for Enterobacteriaceae

1 2 4 4 1 1 32 0.5 1 0.5

a Staphylococci, streptococci, Bran/lanwlla catarrhalis and Haemophilus influcnzae. bBre~lkpoints relate to parcnteral administration.

4 8 16 16 2 4 -

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575

Table 2: In vitro activity of nine antibiotics against Enterobacteriaceaeand A cinetobacter species. Organism (n)

MIC (mg/l) Compound Lowest

Highest

cefpodoxime cefaclor cefadroxil cefuroxlme amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.12 0.5 8 1 4 4 0.25 0.008 0.008

16 128 128 32 64 128 128 128 1

ccfpodoxime cefaclor eefadroxil cefuroxime amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.03 O.25 4 0.12 1 1 0.12 0.03 0.004

1 128 16 8 64 > 128 > 128 > 128 0.5

Citrobacter freundii

cefpodoximc cefaclor cefadroxil cefuroxim¢ amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.25 4 4 2 1).5 8 0.25 0.03 0.008

8 > 128 128 4 128 > 128 > 128 > 128 0.03

Citrobacter koseri

cefpodoxime cefaclor cefadroxil cefuroxime amoxicillin/CA anaoxieillin co-trimoxazole trimethopriln ciprofloxacin

0.12 0.5 4 2 2 64 I).5 0.06 0.002

cefpodoximc cefaclor cefadroxiI cefuroxime amoxicillin/CA alnoxicillin co-trimoxazole trimethoprim eiprofloxacin

I).5 8 8 4 2 4 0.12 0.03 I}.008

cefpodoximc cefaclor cefadroxil cefm'oxime amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.12 4 8 2 8 16 0.5 0.12 0.016

Escherichia coli (4O)

Klebsiella spp. (40)

(1o)

(10)

EtJterobacter cloacae

(1o)

Enterobacter aerogenes

(10)

>

> > >

0.25 8 8 8 16 > 128 2 0.25 0.008 128 > 128 > 128 > 128 128 > 128 2 0.5 0.1}3 1 64 64 8 128 > 128 2 1 0.016

MIC50 O.5 2 8 4 8 8 1 0.12 0.016 0.06 1 8 1 4 128 1 0.25 0.03

MIC90 1 32 32 8 32 > 128 64 4 0.06 0.25 8 8 4 16 > 128 > 128 > 128 0.12

1 8 32 2 64 > 128 0.5 0.12 0.008

4 16 128 4 128 > 128 > 128 > 128 0.008

0.25 4 8 2 2 128 0.5 0.12 0.008

0.25 4 8 4 4 > 128 1 0.12 0.008

1 128 > 128 8 64 > 128 0.5 0.12 0.016

32 > 128 > 128 > 128 128 > 128 1 0.25 0.016

0.5 16 16 4 32 128 1 0.25 0.016

1 32 64 8 128 128 1 0.5 0.016

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Eur. J. Clin. Microbiol. Infect. Dis.

Table 2 continued Organism (n)

Serratia spp. 00)

Proteus mirabil& (40)

Proteus vulgaris (10)

Providencia alcalifaciens (10)

Providenciu stuartii

(lO)

Providencia rettgeri (10)

MIC (mg/l) Compound

cefpodoxime cefaclor cefadroxil cefuroximc amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

Lowest

Highest

MIC50

0.5 8 8 16 1 1 2 0.12 0.03

0.5 > 128 > 128 128 128 128 8 4 0.25

0.5 16 128 16 64 32 2 1 0.06

0.5 32 > 128 32 128 64 8 2 0.06

0.5 64 32 8 16 > 128 > 128 > 128 0,5

0.06 8 16 1 2 4 1 0.25 0.03

0.12 16 16 2 8 > 128 > 128 > 128 0.06

cefpodoxime cefaclor cefadroxi[ cefuroxlme amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.03 2 8 0.5 0.25 0.5 0.]2 0,016 0.004

cefpodoxime cefaclor cefadroxil cefuroxlmc amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.06 64 64 8 2 64 0.25 0,06 0.004

0.25 > 128 > 128 > 128 4 > 128 1 0.5 0.03

0.12 128 64 128 2 > 128 0.5 (I.25 0.016

cefpodoxime cefaclor ccfadroxil cefuroxime amoxieillin/CA amoxieillin co-trimoxazole trimethoprim ciprofloxacin

0.002 0.25 0.5 0.016 0.25 0.12 0.25 0.06 0.004

1 16 8 0.5 128 > 128 4 1 0.(36

0.008 2 2 0.25 32 8 1 0.25 0.016

cefpodoxime cefaclor cefadroxil ecfuroxime amoxicillin/CA amoxicillin co-trimoxazolc trimethoprim ciprofloxacin

0.016 4 4 (3.25 32 64 2 1 O.O3

cefpodoxime cefaclor cefadroxi[ cefuroxlme amoxicillin/CA amoxicillin co-trimoxazolc trimethoprim ciprofloxacin

0.002 0.5 1

0,016 8 16 0.5 0.12 0.008

4 > 128 > 128 128 128 > 128 > 128 > 128 2 0.5 > 128 > 128 64 > 128 > 128 16 2 0.25

0.12 128 64 4 128 > 128 16 8 0.12 0.008 4 16 0.5 128 64 1 {3.5 0.03

MIC90

0.12 > 128 > 128 > 128 4 > 128 1 0.5 0.016 0.5 16 2 0.5 128 128 1 1 0.06 2 > 128 > 128 32 128 > 128 > 128 > 128 1 0.06 > 128 > 128 16 128 > 128 16 2 0,12

Vol. 10, 1991

577

Table 2 continued Organism (n)

MIC (mg/l) Compound Lowest

Highest

cefaclor cefadroxil cefuroxime amoxicillin/CA amoxicil|in co-trimoxazole trimethoprim ciprofloxacin

0.12 32 64 4 64 64 1 0.12 0.008

32 > 128 > 128 128 > 128 > 128 2

cefpodoximc cefaelor cefadroxi[ cefuroxime amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.5 4 8 1 4 8 1 0.25 0.004

cefpodoxime cefaelor cefadroxi[ cefuroxime amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin

0.06 0.25 2 0.12 0,12 0.25 1 0.25 0.008

Morganellamorganii cefpodoxime (10)

Hafitia a l v e i (10)

Acinetobactcrspp, (10)

tivity of trimethoprim also varied between species, more than 10 % of Escherichia coli, Klebsiella spp. and Proteus mirabilis being resistant and the results for many of the Proteae being in the intermediate range. Overall, 1 1 % of the Enterobacteriaceae tested were resistant to cotrimoxazole and 15 % were resistant to trimethoprim, with a further 13 % in the intermediate range for trimethoprim. Of the 10 strains of Acinetobacterspp. tested seven Were sensitive to cefpodoxime and six were sensitive to cefuroxime and amoxicillin but only two Were sensitive to cefaclor and cefadroxil. All were sensitive to amoxicillin/CA but at least some of this sensitivity was due to the activity of clavulanate alone. All were sensitive to ciprofloxacin and co-trimoxazole but only three of the isolates were sensitive to trimethoprim with a further four in the intermediate range. Cefpodoxime was at least as active as the other cephalosporins tested against the respiratory pathogens Haemophilus influenzae and Branhamella catarrhalis (Table 3). Cefpodoxime and

MIC50 0.12

128 > 128 16 128 128 1

MIC90 8 > 128 > 128 64 > 128 > 128 2

1

0.5

1

0.016

0.016

0.016

2 128 128 16 64 128 2 0.5 0.016

2 32 64 2 64 64 1 0.25 0.004

2 128 128 8 64 64 2 0.5 0.008

64 > 128 > 128 > 128 8 32 8 16 1

1 16 64 1 1 4 1 1 0.03

16 > 128 128 32 8 16 4 4 0.5

cefuroxilne both showed little variation between results for beta-lactamase positive and negative isolates of Haemophilus influenzae and, although tile beta-lactamase-producing Branhamella catarrtmlis were less sensitive than the non-beta-lactamase producers they were still within the sensitive range - further evidence of the stability of these agents to these enzymes. The results quoted for erythromycin tested against Haemophilus influenzae may be misleading if these breakpoints are used, as the tests were p e r f o r m e d in an atmosphere of 5 % CO2. This would have the effect of lowering the pH in the medium and reducing the activity of efythromycin. Branhamella catarrhalis strains producing beta-lactamase were sometimes apparently sensitive to beta-lactams susceptible to beta-lactamases, which emphasises the need to test for beta-lactamase production rather than determine MICs for organisms like Branhamella catarHmlis, Neisseria gonorrhoeae and Haemo-

philus inJluenzae. The activity of the agents tested against grampositive organisms is shown in Table 4. For most of

578

Eur. J. Clin. Microbiol. Infect. Dis.

the s t a p h y l o c o c c i tested the c e f p o d o x i m e M I C s w e r e at or close to the b r e a k p o i n t a n d it is d o u b t f u l if it w o u l d b e a useful a g e n t for t r e a t i n g i n f e c t i o n s c a u s e d by these o r g a n i s m s except for Staphylococcus saprophyticus u r i n a r y tract i n f e c t i o n s w h e r e levels m a y b e a d e q u a t e . T h e effect of i n c r e a s e d i n o c u l u m size was also inv e s t i g a t e d for Staphylococcus aureus a n d b e t a lactams. T h e M I C was m o s t affected in the case of a m o x i c i l l i n , rising b y b e t w e e n 1 a n d 5 ( m e a n 3.2) d o u b l i n g d i l u t i o n s . C e f a c l o r a n d cefadroxil w e r e n e x t m o s t affected, the M I C s rising by b e t w e e n 1 a n d 3 d o u b l i n g d i l u t i o n s ( m e a n 1.9). F o r c e f u r o xime the m e a n i n c r e a s e in M I C at a h i g h e r ino c u l u m was 0.6 d o u b l i n g d i l u t i o n s , a n d for cefp o d o x i m e t h e r e was n o s i g n i f i c a n t c h a n g e in M I C

at a h i g h e r i n o c u l u m . T h e s e c h a n g e s w e r e m o s t m a r k e d with m e t h i c i l l i n - r e s i s t a n t o r g a n i s m s , a n d n o t seen with p e n i c i l l i n - s e n s i t i v e o r g a n i s m s . A l l the b e t a - h a e m o l y t i c s t r e p t o c o c c i t e s t e d w e r e highly sensitive to c e f p o d o x i m e a n d o n a w e i g h t for-weight basis it was e i t h e r e q u a l to or m o r e active t h a n a m o x i c i l l i n . O f t h e p n e u m o c o c c i , all except o n e were highly s u s c e p t i b l e to all b e t a - l a c t a m agents. T h e c e f p o d o x i m e M I C for this isolate was also m u c h h i g h e r a n d a l t h o u g h it was l o w e r t h a n the b r e a k p o i n t for c e f u r o x i m e it is d o u b t f u l w h e t h e r this a g e n t w o u l d b e effective clinically. O u r results for e n t e r o c o c c i were also i n t e r e s t i n g in that f o r a few isolates c e f u r o x i m e a n d cefp o d o x i m e h a d M I C s close to the b r e a k p o i n t , u n -

Table 3: In vitro activity of ten antibiotics against Branhamella catarrhalis and Haemophilus influenzae. MIC (mg/l) Compound

Bcta-lactamasc production

Lowest

Highest

MIC50

MIC90

+ + + + + +

0.12 0.25 0.25 0.5 0.5 1 0.12 (.1.25 0,008 0.03 0.008 0.5 (.1.25 8 0.002 0.06

0.12 2 0.5 4 2 4 0.25 4 (I.03 0.25 (.1.(/3 4 4 64 (.1.03 (I.5

0.12 1 (.I.5 2 2 2 0.25 1 (.1.016 0.06 0.016 2 2 16 0.016 0.12

0.12 1 0.5 4 2 4 0.25 2 0.03 0.25 0.03 2 2 32 (.1.(.13 0.12

+ + + + + +

(.1.(.13 0.03 4 8 32 64 0.5 (.1.5 0.25 0.5 0.25 4 0.25 0.06 0.004 2

0.5 0.25 128 32 > 128 > 128 2 2 1 1 2 > 128 1 0.5 0.25 16

0.12 0.12 16 32 64 64 1 1 0.5 (I.5 0.5 16 0.25 0.12 0.016 4

0.12 0.25 32 32 128 128 2 1 1 1 1 128 0,5 0.25 0,016 8

Branhan~elht catarrhalis (n = 20) Ccfpodoximc Ccfaclor Ccfadroxil Cefuroxime Amoxicillin/CA Amoxicillin Co-trimoxazolc Trimcthoprim Ciprofloxacin Erythromycin

Haemophihts infhtenzae (n = 40) Ccfpodoximc Ccfaclor Cc fadroxil Ccfuroximc Amoxicillin/CA Amoxicillin Co-trimoxazolc Trimcthoprim Ciprofloxacin Erythromycin

Vo1.10,1991

579

Table 4: In vitro activity of ten antibiotics against 190 gram-positive cocci, Organism (n)

M I C (rag/l) Compound Lowest

Penicillin-sensitive

Staphylococcus aureus (10)

Penicillin-resistant

Staphylococcus attreus (20)

Methieillin-rcsistant

Staphylococcus aureus (10)

Staphylococcus saprolJhyticus (20)

O t h e r coagulasenegative penicillinsensitive Staphylococci (7)

Highest 2 32 4 2 0.25 0.25 1 0,25 2 0.25

MIC50

MIC90

cefpodoximc cefaclor ce fad roxil ccfuroxime amoxicillin/CA amoxicillin co-trimoxazole trimcthoprim ciprofloxacin crythromycin

1 4 1 0.5 0.12 0,06 0.25 0.25 0.12 0.25

cefpodoxime cefaclor cefadroxil cefuroxime amoxicillin/CA amoxicil[in co-trimoxaz61c trimethoprim ciprofloxacin crythromyein

1 2 1 0.12 0.12 0.06 0,25 0.12 0,12 0,12

4 64 16 2 1 4 8 8 1 > 32

2 8 2 1 0.5 0.5 0.5 0.25 0.25 0.25

0.5 0.5 > 32

cefpodoxime ccfaclor cefadroxil ccfuroxime amoxicillin/CA amoxicillin co-trimoxazolc trimethoprim ciprofloxacin crythromycin

4 32 8 2 1 2 0.5 0.03 0.12 0.12

> 128 > 128 128 64 16 32 4 0.25 0.5 > 32

64 32 64 16 2 8 2 O.25 0.5 4

> 128 > 128 128 64 8 16 4 0.25 0.5 > 32

cefpodoximc cefaclor ccfadroxi[ ccfuroxime amoxicillin/CA amoxicillin co-trimoxazolc trimcthoprim ciprofloxacin crythromycin

1 1 0.5 0,5 0.12 0.06 0.5 0.03 0.25 0.06

8 8 4 4 0.5 0.5 1 0.25 0,5 0.25

8 8 4 2 0.5 0.5 1 0.12 0.5 0.12

8 8 4 4 0.5 0.5 1 0,25 0.5 0.25

ccfpodoxilne cc faclor cehldroxil cefuroxime amoxicillin/CA amoxicillin co-trimoxazolc trimethoprim ciprtffloxacin crythromycin

0.5 0.5 {).5 0.25 0.03 0.03 0.5 0.25 0.12 0.12

2 4 2 1 0.25 0.25 8 32 0.5 > 32

0.5 2 2 0.5 0.12 0.12

2 4 2 1 0.25 0.25 8 32 0.5 >32

2 8 2 1 0.12 .0.12 0.5 0.25 0.25 0.25

1

0,25 0,25 0.25

2 8 4 1 0.25 0.25 1 0.25 1

0.25 4 16 4 2 1 1 1

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Eur. J, Clin. Microbiol. Infect. Dis.

Table 4 continued Organism

M I C (mg/l)

(n)

Compound

O t h e r coagulasenegative penicillinresistant staphylococci

cefpodoxime cefaclor cefadroxil cefuroxime amoxicillin/CA amoxicillin co-trimoxazolc trimethoprim ciprofloxacin erythromycin

0.5 1 1 0.25 0.06 0.5 0.5 0.12 0.06 0.06

16 64 64 16 8 32 64 > 128 1 > 32

4 8 2 2 0.5 2 4 0.5 0.25 8

cefpodoxime cefaclor cefadroxil cefuroxime amoxicillin/CA amoxicillin co-trimoxazole trimethoprim ciprofloxacin erythromycin

0.004 0.25 0.12 0.004 0.(304 0.004 0.5 {3.12 {3.5 0.{)16

2 32 32 2 1 1 32 64 2 > 32

0.016 0.5 0.5 0.{316 0.008 0.008 1 1 1 0.06

Enteroeocci (25)

cefpodoxime cefaclor cefadroxil cefuroxime amoxicillin/CA amoxicillin co-trimoxazolc trimcthoprim eiprofloxacin erythromycin

2 128 32 4 0.12 0.12 0.25 {).016 0.5 0.25

Streptococclts agalactiae

ccfpodoxime cefaclor cefadroxil ccfuroximc amoxicillin/CA amoxicillin co-trimoxazolc trimethoprim ciprofloxacin erythromycin

0.008 0.5 0.25 0.03 0.016 0.03 0.12 0.06 0.5 0.016

0.03 2 1 0,06 {).06 0.06 2 1 2 0.03

0.016 1 1 0.03 0.03 0.03 1 (1.5 1 (3.(33

0.016 2 1 0.03 0.03 0.{)6 1 0.5 2 0.03

cefpodoxime cefaclor cefa d rox i I cefuroxime amoxiciilin/CA amoxicillin eo-trimoxazole trimethoprim ciprofloxacin erythromycin

0.002 0.06 (3.06 0.004 0.002 0.004 (3.12 0.06 {).25 0.008

0.016 0.5 0.12 0.016 0.016 0.016 4 {).5 4 2

0,008 0,12 0.12 0.008 0.008 0.008 1 0.25 0.5 (3.03

0.016 0.25 0.12 0,016 0.016 0.008 1 0.25 1 0.06

03)

Streptococcus lmeumoniae (20)

(25)

Haemolyticstreptococci (Lancefield groups A, C, G) (40)

Lowest

Highest

> > > >

128 128 128 128 16 16 > 128 32 4 > 32

MIC50

> 128 > 128 64 > 128 0.5 0.5 0.5 0.03 1 1

MIC90 16 64 32 8 4 8 64 128 0.5 > 32 0.03 2 1 0.03 0.03 0.016 16 8 2 0.06 > > > >

128 128 128 128 8 8 4 {),5 2 2

Vo1.10,1991

like the other cephalosporins to which these organisms were all highly resistant. However, in general neither agent can be considered to have any useful activity against these species. Overall, our results show that on the basis of its in vitro activity cefpodoxime could be appropriate for the empirical therapy of urinary tract, respiratory tract and many soft tissue infections. Clinical trials will be needed to demonstrate that this in vitro activity is matched by clinical efficacy and safety.

References 1. Jones R, Barry A: Antimicrobial activity and disc diffusion susceptibility testing of U-76, 235A (R-3746), the active metabolite of the new ccphalosporin ester, U-76,252 (CS-807). Antimicrobial Agents and Chemotherapy 1988, 32: 443-449. 2. King A, Warren C, Shannon K, Phillips h The in vitro antibacterial activity of eefotaxime compared with that of cefuroxime and cefoxitin. Journal of Antimicrobial Chemotherapy 1980, 6: 479-494. 3. Working Party of the British Society for Anlimierohial Chemotherapy: Breakpoints in in vitro antibiotic sensitivity testing. Journal of Antimicrobial Chemotherapy 1988, 21: 701-710. 4. Chin NX, Neu H: In vitro activity of an oral iminomethoxy aminothiazolyl eephalosporin, R-3746. Antimicrobial Agents and Chemotherapy 1988, 32: 671-677.

In Vitro Activity of Cefpodoxime against Bacterial Isolates Obtained from Patients with Cancer K.V.I. R o l s t o n * , M. Messer, H . N g u y e n , D. H o , B. L e B l a n c , G.R B o d e y

The in vitro activity of cefpodoxime, an oral cephalosporin ester, against 792 bacterial isolates representing 36 species was evaluated in comparison to that of ciprofloxacin and trimethoprinff sulfamethoxazole (TMP/SMX). Cefpodoxime inhibited the majority of Streptococcus spp., Haemophilus influenzae and Proteus mirabilis Sectionof InfectiousDiseases, Department of MedicalSpecialties, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

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at a concentration of < 0.12/ag/ml. It was also active against Citrobacter diversus, Escherichia coil, Klebsiella spp., Proteus vulgaris, Serratia marcescens and methicillin-susceptible Staphylococcus aureus isolates. Overall, cefpodoxime appeared to be less active than ciprofloxacin and T M P / S M X against many pathogens c o m m o n in cancer patients.

Cefpodoxime proxetil (U-76, 252; CS-807) is an oral cephalosporin ester, which in the intestine is de-esterified to its active metabolite cefpodoxime (1). Cefpodoxime has a relatively broad antimicrobial spectrum and has been shown to be active in vitro against Streptococcus spp., methicillin-susceptible Staphylococcus spp., Haemophilus

influenzae, Branhamella catarrhalis, Neisseria spp., Escherichia coli, Klebsiella spp. and indolepositive and -negative Proteus spp. (2-5). The availability of oral broad-spectrum agents has in recent years enabled clinicians to treat a variety of infections without admitting patients to hospital. Patients with serious infections that require parenteral therapy initially are being switched to oral therapy after 5 to 7 days, thereby simplifying antimicrobial administration and making possible earlier discharge of patients from the hospital. These approaches are being evaluated in cancer patients at our institution. T h e purpose of this study was to evaluate the in vitro activity of cefpodoxime against clinical isolates from cancer patients and to compare its activity to that of ciprofloxacin and trimethoprim/sulfamethoxazole (TMP/SMX), the two most commonly used oral agents at our institution.

Materials and Methods. The organisms studied included 792 bacterial strains (representing 36 bacterial species) isolated from cancer patients admitted to the University of Texas M.D. Anderson Cancer Center. M o r e than 90 % of these isolates were from blood culture specimens. T h e antimicrobials were obtained from their respective manufacturers: cefpodoxime from Upjohn, USA, ciprofloxacin from Miles Pharmaceuticals, USA, and TMP/SMX from H o f f m a n - L a R o c h e , USA. Standard laboratory powders of known potency were used and were stored at -70 °C until use. Susceptibility testing was performed using a previously described microtiter broth dilution method in accordance with the guidelines established by the National C o m m i t t e e for Clinical Laboratory Standards (6, 7). Briefly, antimicrobial solutions were prepared manually and serial