Drugs 42 (Suppl. 3): 6-12, 1991 00 12-6667/91/0300-0006/$3. SOlO © Adis International Limited. All rights reserved. ORSUP3251
Microbiological Evaluation of Cefpodoxime Proxetil B. Wiedemann, E. Luhmer and M. T. Zuhlsdorj Department of Pharmaceutical Microbiology, University of Bonn, Bonn, Federal Republic of Germany
Summary
Cefpodoxime, the active de-esterified molecule of the orally absorbable cephalosporin cefpodoxime proxetil, inhibits streptococci, Neisseria spp., and most Enterobacteriaceae, with MICso and/or MIC90 values of ~ 2 mgJL; with regard to the latter family of bacteria, the MICso and/ or MIC90 values of cefpodoxime are consistently ~ 4 mgJL for only Enterobacter cloacae. Citrobacter freundii, Serratia marcescens, and Morganel/a morganii. The MICso of cedpodoxime for coagulase-negative staphylococci is > 2 mg/L, while the MIC for Staphylococcus aureus strains is 4 mgJL. In comparison with other orally absorbable cephalosporins, cefpodoxime is slightly less active than cefixime, cefetamet, and cefotiam against Gram-negative bacteria, but more active than cefuroxime, cefaclor, and cefalexin. Against staphylococci, the activity of cefpodoxime is comparable to that of cefotiam and cefuroxime, and superior to that of cefaclor, while cefixime and cefetamet have insufficient activity against these species. In common with other cephalosporins, cefpodoxime has no activity against enterococci. In vitro models simulating human serum cefpodoxime concentrations demonstrate that a dosage regimen of 200mg is probably sufficient to treat most infections. However, further study is needed to clarify whether infections due to bacteria such as S. aureus, with higher ccfpodoxime MICs, can be treated with this dose regimen.
While the pharmacodynamics and pharmacokinetic properties of parenteral cephalosporins have been greatly improved during recent decades by modifications at the 3-position and the 7-position of the cephem nucleus, currently available orally absorbable cephalosporins still have much less favourable properties. Cefpodoxime proxetil (U-76, 252; CS-807) is a new cephalosporin that is de-esterified into its active metabolite cefpodoxime (U76, 253; R-3763) after oral absorption. In this study we evaluated the microbiological properties of cefpodoxime using data from the literature and from our own laboratory.
1. Methods All methods used throughout the study were standard procedures. For susceptibility testing [minimum inhibitory concentration (MIC)] we used the microdilution method with Muller Hinton broth
with an inoculum of I to 5 x 105 colony-forming units/ml. The determination of viable cell counts was done with 100fold dilution in sterile saline and plating on plate count agar. Drug concentrations were measured by a bioassay. Details of the methods are given in Wiedemann and Jansen (1990) and Wiedemann et al. (1991). All microorganisms were clinical isolates or strains from our laboratory collection. The drugs used were kindly provided by the manufacturers.
2. Results and Discussion 2.1 Spectrum of Activity In figure 1 the end-points of the MICso and/or MIC90 values reported in the literature are illustrated to demonstrate the broad range of activity of cefpodoxime. The highest activity is against Gram-positive strains such as Streptococcus pneu-
Microbiological Evaluation of Cefpodoxime Proxetil
7
8
Streptococcus pyogenes
_
S. pneumoniae
_
-
Neisseria gonorrhoeae N. meningitidis
•••••• _
S. agalactiae
••••••
Haemophilus influenzae Proteus mirabilis Klebsiella pneumoniae K. o)(ytoca
0.016 0.03 0.06 0.12 0.25 0.5
1
2
4
16
32
M1Cso or MICgO (mg/L) b Providencia rettgeri Escherichia coli P. vulgaris Mora)(ella catarrhalis Yersinia enterocolitica S. viridans Clostridium perfringens Helicobacter pylori Staphylococcus aureus
0.125 0.250.5 1
2
4
8
M1CsO or MICgO (mg/L)
c S. epidermidis Enterobacter cloacae Serratia marcescens Citrobacter freundii Morganella morganii Enterococcus faecalis Bacteroides fragi/is Pseudomonas aeruginosa Acinetobacter
spp. 2
4
8
16
32
64
128
256
M1CSO or MICgo (mg/L)
Fig. 1. Activity of cefpodoxime as indicated by the end-points of the M1Cso and/or M1C90 values reported in the literature. s = MIC 0.01 to 0.5 mgfL; b = MIC 0. 125 to 32 mgfL; c = MIC 2 to 512 mgfL (after Chin & Neu 1988; Fass & Helsel 1988; Fujimoto et al. 1987; Jones & Barry 1987; Jones et al. 1988; Knapp et al. 1988; Sarubbi et al. 1989; Schaadt et al. 1990; Stobberingh et al. 1989; Utsui et al. 1987). M1Cso, M1C90 = minimum concentrations required to inhibit 50% and 90% of pathogens, respectively.
moniae and S. pyogenes. Cefpodoxime is similar to penicillin in that it is active against Gramnegative bacteria such as meningococci, Neisseria gonorrhoeae and Haemophilus injluenzae. The MICso and/or MIC90 of cefpodoxime for Gram-
negative bacteria from the family Enterobacteriaceae are mostly far below I mg/L. In common with many other cephalosporins with high activity against Gram-negative spp., activity of cefpodoxime against Staphylococcus aureus is less pro-
8
Drugs 42 (Suppl. 3) 1991
'"c:
40
.~
1;;
"0 0
z
30 20 10
8
2
0.008 0.03 0.13 0.5 0.Q15 0.06 0.25
32 16
4
128 64
MIC (mg/L) cefpodoxime 2. MIC distribution of cefpodoxime for Staphylococcus aureus. Citrobacter freundii. Escherichia coli. Klebsiella pneumoniae. and Proteus mirabilis. Resistant strains can be detected in the right hand side of the distributions for C. freundii. E. coli. K. pneumoniae. and P. mirabilis. The resistance is mainly due to chromosomally mediated ~-lactamases, which are derepressed.
Fig.
60 50
'"c:
40
.~
1;;
"0
o
z
30
Cefaclor
20 10
0.0080.03 0.13
0.5
0.015 0.06 0.25
2
8 4
32 16
128 64
512
256
MIC (mg/L) 3. MIC distributions of some orally absorbable cephalosporins for Escherichia coli. Cephalosporins are arranged by order of activity, with the most active drug in the foreground.
Fig.
Microbiological Evaluation of Cefpodoxime Proxetil
9
60 50 If)
c:
40
.~
iii 30
'0 0
z 20 10
0.008 0.03 0.13
2
0.5
8 4
0.015 0.06 0.25
32
128
16
64
512
256
MIC (mg/L)
4. MIC distributions of some orally absorbable cephalosporins for Klebsiella pneumoniae. Cephalosporins are arranged by order of activity, with the most active drug in the foreground.
Fig.
/
///
60
/ // //// // V //VV
50
/v//
70
If)
c:
.~
iii
40
'0 30 0 z
20 10 0
,III .oiIII
/V// ///V
-
-
.oiIII
-
VV~
Cefetamet ~ / /Cef ixime I.~ / /Cefacl or ~ A:J ~ / / / / ~/Cefpodox ime A:T....../ .1/ / / Cefuroxime
/
///
)".,../ /
4
0.25
0.13
W/ / /
-1
V)/v 0.06
~
-
0.5
2
/
16 8
/
64 32
/
/
/
Cefotiam
256 128
512
MIC (mg/L)
5. MIC distributions of some orally absorbable cephalosporins for Staphylococcus aureus (clinical isolate. penicillinase producing). Cephalosporins are arranged by order of activity, with the most active drug in the foreground.
Fig.
Drugs 42 (Suppl. 3) 1991
10
- - = 100mg
••..•• = 200mg
----- = 400mg
a 4
3 2
0°··
. .. . . . . . .. . . . . . . ",
0
.......... .,.,. ...
" ,"
,,'
,,.,,,
-1
~
-2
Ol
g
-3
.~ c: :::s
-4
Staphylococcus aureus
0
4
8
4
8
12
16
20
24
12
16
20
24
Ol
c:
'§
E
>c: 0
0
U
b
4 2 0 -2 -4
-6 0
Time (hours) Fig. 6. Killing kinetics in vitro after simulation of serum cefpodoxime concentrations corresponding to oral administration of 100', 200, and 400mg doses of cefpodoxime proxetil. The zero line indicates the inoculum of about 106 colony forming units/ml. (Test strain: E. coli K12, W311O.)
nounced. However, cefpodoxime is much more active than other third generation cephalosporins such as cefotaxime against S. aureus. The M1Cso of cefpodoxime for Pseudomonas aeruginosa, Acinetobacter spp., Enterococcus faecalis and Bacteroides fragilis is 32 mg/L. Thus, the spectrum of activity of cefpodoxime includes streptococci, Neisseria spp., Haemophilus spp., Moraxella (Branhamella) catarrhalis. all common Enterobacteriaceae, and staphylococci. Probably some strains of S. viridans. Clostridium perjringens. Enterobacler cloacae. and Citrobacter freundii may be resistant. E. faecalis. B. fragilis. Pseudomonas aeruginosa and Acinetobacter spp. are not included in the spectrum. The MIC distribution of cefpodoxime illustrates
a narrow range of MICs, and only a few resistant strains are indicated by the right hand peak of the bimodal distribution (fig. 2). The influence of derepression of chromosomal (j-Iactamase is evident, especially with C. freundii; the MIC for these derepressed strains is 32 or 64 mgfL. In general, however, only a few resistant strains have appeared to date. The range of MICs reported for S. aureus is extremely narrow, with the MIC for all strains being 2 or 4 mgfL. In figures 3, 4 and 5, the MIC distribution of cefpodoxime for selected species is compared with those of other orally absorbable cephalosporins. Against Gram-negative bacteria, cefaclor is always the least active drug, while cefetamet, cefixime and cefotiam are the most active. Cefetamet and cefix-
Microbiological Evaluation of Cefpodoxime Proxetil
ime, however, showed no activity against S. aureus. Cefpodoxime takes an intermediate position, with activity against both Gram-negative and Gram-positive bacteria. 2.2 Resistance to
~-Lactamases
To demonstrate the influence of ~-Iactamases, the MIC values of various orally absorbable cephalosporins were determined for different ~-Iacta rnase-producing bacteria. Cefotiam was the most dramatically affected, especially by OXA-2, OXA5 and OXA-7 enzymes. The greatest reduction in activity of cefpodoxime was observed with the SHY-2 enzyme. This enzyme, however, degrades cefaclor and cefalexin even more efficiently, and affects even cefixime and cefotiam. The most common enzymes, such as TEM-I, TEM-2, SHY-I, OXA-I and OXA-4 do not significantly destroy cefpodoxime.
11
2.3 Killing Kinetics A simple comparison of MIC values with the drug concentrations available in the patients' serum is not sufficient to calculate the potential clinical effect of the drug, because the MIC does not represent the pharmacodynamic properties of an antibiotic, such as the killing ability in vivo. Therefore, we tested cefpodoxime in an in vitro model simulating the concentration-time curves of cefpodoxime in the serum of patients following oral absorption (Grasso et al. 1978). Elimination of the E. coli strain in an inoculum of 106 cells/ml was equally efficient with all 3 doses, whereas the higher doses were required for elimination of S. aureus (fig. 6). The presence of ~-Iactamases did not change the killing of E. coli, with the exception of SHY-2, which was anticipated from data presented in table I (fig. 7). Similarly, H. inf/uenzae was effectively
Table I. Susceptibility 01 organisms with plasmid-mediated ft-Iactamases to various orally absorbable cephalosporins Host strain (enzyme)
Factor by which the MIC increased (compared with host strains without /t-Iactamase) CEC
Escherichia coli (TEM-1) E. coli (TEM-2) E. coli (SHV-1) E. coli (SHV-2) E. coli (HMS-1) Pseudomonas aeruginosa (LCR-2)
E. E. E. E. E.
coli (OXA-1) coli (OXA-2) coli (OXA-3) coli (OXA-4) coli (OXA-5) P. aeruginosa (OXA-6) E. coli (OXA-6) P. aeruginosa (OXA-1)
CFX
4 8 2 32 8
1 4
2 4 4 2 4 1 128
1 1 2 8
CTM 8 8 2 8 8 4 16 8 4
CPD
CFB
CXM
1 32
16
2
2
1 2
64
CEX
256
1 4
2
4
2
P. aeruginosa (CARB-1) P. aeruginosa (CARB-2) P. aeruginosa (CARB-4)
E. coli (TLE-1) P. aeruginosa (NPS-1) Klebsiella oxytoca (LXA-1) Abbreviations: CEC CEX = cefalexin.
= celaclor;
2 1 32 CFX
= cefixime;
16
1 1 2
CPO
= celpodoxime;
2
CTM
= cefotiam;
1 2 CFB
= ceftibuten;
CXM
= cefuroxime;
12
Drugs 42 (Suppl. 3) 1991
a
- = 4764 (Bla-)
.,.
= ROB enzyme
---
= TEM
enzyme
0 -1
-2 -3 -4
-5
Haemophilus influenzae
0 b
4
4
-
= Bla-
16
12
8
•••
= TEM
1 ---
= TEM
20 5 _.-
24
= SHY 2
Escherichia coli
4
12
8
16
20
24
Time (hours)
Fig. 7. Killing kinetics in vitro after simulation of serum cefpodoxime concentrations corresponding to oral administration of 200mgdoses of cefpodoxime proxetit. The zero line indicates an inoculum of about 106 colony forming units/mt.
killed, and ,B-Iactamases did not impair the activity of the drug (fig. 7).
References Chin NX. Neu He. In I'itro activity of an oral iminomethoxy aminothy· azolyl cephalosporin. R-3746. Antimicrobial Agents and Chemotherapy 32: 671·677. 1988 Fass RJ. Helsel V. In vitro activity of U·76.252 (CS·807). a new oral cepha· losporin. Antimicrobial Agents and Chemotherapy 32: 1082·1085. 1988 Grasso S, Meinardi G, de Caneri I. Tamassia V. New in l'ilrO model to study the effect of antibiotic concentration and rate of elimination on antibacterial activity. Antimicrobial Agents and Chemotherapy 13: 570-576. 1978 Fujimoto K. Ishihara S. Yanagisawa H. Ide J. Nakayama E. et al. Studies of orally active cephalosporin esters. Journal of Antibiotics 40: 370·384. 1987 Jones RN. Barry AL. In I'itro evaluations of U· 76.252 (CS·807): antimi· crobial spectrum. beta-Iactamase stability, and enzyme inhibition. Diagnostic Microbiology and Infectious Disease 8: 245·249. 1987 Jones RN. Barry AL. pfaller M. Allen SO. Ayers LW. et al. Antimicrobial activity of U-76.252 (CS-807). a new orally administered cephalosporin ester, induding recommendations for MIC quality control. Diagnostic Microbiology and Infectious Disease 9: 59-63. 1988 Knapp Cc. Sierra-Madero J. Washington JA. Antibacterial activities of cefpodoxime, cefixime. and ceftriaxone. Antimicrobial Agents and Chemotherapy 32: 1896-1898. 1988
Sarubbi FA. Verghese A. Caggiano C. Holtclaw-Berk S. Berk SL. In vitro activity of cefpodoxime proxetil (U-76.252: CS-807) against clinical isolates of Branhamella catarrhalis. Antimicrobial Agents and Chemotherapy 33: 113-114. 1989 Schaadt RD. Hannon Yagi B. Zurenko GE. In I'itro activity of cefpodoxime proxetil (U-76.252: CS-807) against Neisseria gonorrhoeae. Antimicrobial Agents and Chemotherapy 34: 371-372. 1990 Stobberingh EE. Houben AW. Philips JH. In I'it/'O activity of cefpodoxime. a new oral cephalosporin. European Journal of Clinical Microbiology and Infectious Diseases 8: 657-658. 1989 Utsui Y. Inoue M. Mitsuhashi S. In "itro and in 1';)'0 antibacterial activities of CS-807. a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31: 1085-1092. 1987 Wiedemann B. Jansen A. Antibacterial activity of cefpodoxime proxetil in a pharmacokinetic in l'itro model. Journal of Antimicrobial Chemotherapy 26: 71-79. 1990 Wiedemann B. Luhmer E. Zuhlsdorf MT. In l'itl'O activity of cefpodoxime and ten other cephalosporins against Gram-positive ,B-Iactamase producers. Infection 19: 363-369. 1991
Correspondence and reprints: Prof. B. Wiedemann, Department of Pharmaceutical Microbiology. University of Bonn. An der Immen burg 4. 5300 Bonn I. Federal Republic of Germany.
Microbiological Evaluation of Cefpodoxime Proxetil B. Wiedemann, E. Luhmer and M. T. Zuhlsdorj Department of Pharmaceutical Microbiology, University of Bonn, Bonn, Federal Republic of Germany
Summary
Cefpodoxime, the active de-esterified molecule of the orally absorbable cephalosporin cefpodoxime proxetil, inhibits streptococci, Neisseria spp., and most Enterobacteriaceae, with MICso and/or MIC90 values of ~ 2 mgJL; with regard to the latter family of bacteria, the MICso and/ or MIC90 values of cefpodoxime are consistently ~ 4 mgJL for only Enterobacter cloacae. Citrobacter freundii, Serratia marcescens, and Morganel/a morganii. The MICso of cedpodoxime for coagulase-negative staphylococci is > 2 mg/L, while the MIC for Staphylococcus aureus strains is 4 mgJL. In comparison with other orally absorbable cephalosporins, cefpodoxime is slightly less active than cefixime, cefetamet, and cefotiam against Gram-negative bacteria, but more active than cefuroxime, cefaclor, and cefalexin. Against staphylococci, the activity of cefpodoxime is comparable to that of cefotiam and cefuroxime, and superior to that of cefaclor, while cefixime and cefetamet have insufficient activity against these species. In common with other cephalosporins, cefpodoxime has no activity against enterococci. In vitro models simulating human serum cefpodoxime concentrations demonstrate that a dosage regimen of 200mg is probably sufficient to treat most infections. However, further study is needed to clarify whether infections due to bacteria such as S. aureus, with higher ccfpodoxime MICs, can be treated with this dose regimen.
While the pharmacodynamics and pharmacokinetic properties of parenteral cephalosporins have been greatly improved during recent decades by modifications at the 3-position and the 7-position of the cephem nucleus, currently available orally absorbable cephalosporins still have much less favourable properties. Cefpodoxime proxetil (U-76, 252; CS-807) is a new cephalosporin that is de-esterified into its active metabolite cefpodoxime (U76, 253; R-3763) after oral absorption. In this study we evaluated the microbiological properties of cefpodoxime using data from the literature and from our own laboratory.
1. Methods All methods used throughout the study were standard procedures. For susceptibility testing [minimum inhibitory concentration (MIC)] we used the microdilution method with Muller Hinton broth
with an inoculum of I to 5 x 105 colony-forming units/ml. The determination of viable cell counts was done with 100fold dilution in sterile saline and plating on plate count agar. Drug concentrations were measured by a bioassay. Details of the methods are given in Wiedemann and Jansen (1990) and Wiedemann et al. (1991). All microorganisms were clinical isolates or strains from our laboratory collection. The drugs used were kindly provided by the manufacturers.
2. Results and Discussion 2.1 Spectrum of Activity In figure 1 the end-points of the MICso and/or MIC90 values reported in the literature are illustrated to demonstrate the broad range of activity of cefpodoxime. The highest activity is against Gram-positive strains such as Streptococcus pneu-
Microbiological Evaluation of Cefpodoxime Proxetil
7
8
Streptococcus pyogenes
_
S. pneumoniae
_
-
Neisseria gonorrhoeae N. meningitidis
•••••• _
S. agalactiae
••••••
Haemophilus influenzae Proteus mirabilis Klebsiella pneumoniae K. o)(ytoca
0.016 0.03 0.06 0.12 0.25 0.5
1
2
4
16
32
M1Cso or MICgO (mg/L) b Providencia rettgeri Escherichia coli P. vulgaris Mora)(ella catarrhalis Yersinia enterocolitica S. viridans Clostridium perfringens Helicobacter pylori Staphylococcus aureus
0.125 0.250.5 1
2
4
8
M1CsO or MICgO (mg/L)
c S. epidermidis Enterobacter cloacae Serratia marcescens Citrobacter freundii Morganella morganii Enterococcus faecalis Bacteroides fragi/is Pseudomonas aeruginosa Acinetobacter
spp. 2
4
8
16
32
64
128
256
M1CSO or MICgo (mg/L)
Fig. 1. Activity of cefpodoxime as indicated by the end-points of the M1Cso and/or M1C90 values reported in the literature. s = MIC 0.01 to 0.5 mgfL; b = MIC 0. 125 to 32 mgfL; c = MIC 2 to 512 mgfL (after Chin & Neu 1988; Fass & Helsel 1988; Fujimoto et al. 1987; Jones & Barry 1987; Jones et al. 1988; Knapp et al. 1988; Sarubbi et al. 1989; Schaadt et al. 1990; Stobberingh et al. 1989; Utsui et al. 1987). M1Cso, M1C90 = minimum concentrations required to inhibit 50% and 90% of pathogens, respectively.
moniae and S. pyogenes. Cefpodoxime is similar to penicillin in that it is active against Gramnegative bacteria such as meningococci, Neisseria gonorrhoeae and Haemophilus injluenzae. The MICso and/or MIC90 of cefpodoxime for Gram-
negative bacteria from the family Enterobacteriaceae are mostly far below I mg/L. In common with many other cephalosporins with high activity against Gram-negative spp., activity of cefpodoxime against Staphylococcus aureus is less pro-
8
Drugs 42 (Suppl. 3) 1991
'"c:
40
.~
1;;
"0 0
z
30 20 10
8
2
0.008 0.03 0.13 0.5 0.Q15 0.06 0.25
32 16
4
128 64
MIC (mg/L) cefpodoxime 2. MIC distribution of cefpodoxime for Staphylococcus aureus. Citrobacter freundii. Escherichia coli. Klebsiella pneumoniae. and Proteus mirabilis. Resistant strains can be detected in the right hand side of the distributions for C. freundii. E. coli. K. pneumoniae. and P. mirabilis. The resistance is mainly due to chromosomally mediated ~-lactamases, which are derepressed.
Fig.
60 50
'"c:
40
.~
1;;
"0
o
z
30
Cefaclor
20 10
0.0080.03 0.13
0.5
0.015 0.06 0.25
2
8 4
32 16
128 64
512
256
MIC (mg/L) 3. MIC distributions of some orally absorbable cephalosporins for Escherichia coli. Cephalosporins are arranged by order of activity, with the most active drug in the foreground.
Fig.
Microbiological Evaluation of Cefpodoxime Proxetil
9
60 50 If)
c:
40
.~
iii 30
'0 0
z 20 10
0.008 0.03 0.13
2
0.5
8 4
0.015 0.06 0.25
32
128
16
64
512
256
MIC (mg/L)
4. MIC distributions of some orally absorbable cephalosporins for Klebsiella pneumoniae. Cephalosporins are arranged by order of activity, with the most active drug in the foreground.
Fig.
/
///
60
/ // //// // V //VV
50
/v//
70
If)
c:
.~
iii
40
'0 30 0 z
20 10 0
,III .oiIII
/V// ///V
-
-
.oiIII
-
VV~
Cefetamet ~ / /Cef ixime I.~ / /Cefacl or ~ A:J ~ / / / / ~/Cefpodox ime A:T....../ .1/ / / Cefuroxime
/
///
)".,../ /
4
0.25
0.13
W/ / /
-1
V)/v 0.06
~
-
0.5
2
/
16 8
/
64 32
/
/
/
Cefotiam
256 128
512
MIC (mg/L)
5. MIC distributions of some orally absorbable cephalosporins for Staphylococcus aureus (clinical isolate. penicillinase producing). Cephalosporins are arranged by order of activity, with the most active drug in the foreground.
Fig.
Drugs 42 (Suppl. 3) 1991
10
- - = 100mg
••..•• = 200mg
----- = 400mg
a 4
3 2
0°··
. .. . . . . . .. . . . . . . ",
0
.......... .,.,. ...
" ,"
,,'
,,.,,,
-1
~
-2
Ol
g
-3
.~ c: :::s
-4
Staphylococcus aureus
0
4
8
4
8
12
16
20
24
12
16
20
24
Ol
c:
'§
E
>c: 0
0
U
b
4 2 0 -2 -4
-6 0
Time (hours) Fig. 6. Killing kinetics in vitro after simulation of serum cefpodoxime concentrations corresponding to oral administration of 100', 200, and 400mg doses of cefpodoxime proxetil. The zero line indicates the inoculum of about 106 colony forming units/ml. (Test strain: E. coli K12, W311O.)
nounced. However, cefpodoxime is much more active than other third generation cephalosporins such as cefotaxime against S. aureus. The M1Cso of cefpodoxime for Pseudomonas aeruginosa, Acinetobacter spp., Enterococcus faecalis and Bacteroides fragilis is 32 mg/L. Thus, the spectrum of activity of cefpodoxime includes streptococci, Neisseria spp., Haemophilus spp., Moraxella (Branhamella) catarrhalis. all common Enterobacteriaceae, and staphylococci. Probably some strains of S. viridans. Clostridium perjringens. Enterobacler cloacae. and Citrobacter freundii may be resistant. E. faecalis. B. fragilis. Pseudomonas aeruginosa and Acinetobacter spp. are not included in the spectrum. The MIC distribution of cefpodoxime illustrates
a narrow range of MICs, and only a few resistant strains are indicated by the right hand peak of the bimodal distribution (fig. 2). The influence of derepression of chromosomal (j-Iactamase is evident, especially with C. freundii; the MIC for these derepressed strains is 32 or 64 mgfL. In general, however, only a few resistant strains have appeared to date. The range of MICs reported for S. aureus is extremely narrow, with the MIC for all strains being 2 or 4 mgfL. In figures 3, 4 and 5, the MIC distribution of cefpodoxime for selected species is compared with those of other orally absorbable cephalosporins. Against Gram-negative bacteria, cefaclor is always the least active drug, while cefetamet, cefixime and cefotiam are the most active. Cefetamet and cefix-
Microbiological Evaluation of Cefpodoxime Proxetil
ime, however, showed no activity against S. aureus. Cefpodoxime takes an intermediate position, with activity against both Gram-negative and Gram-positive bacteria. 2.2 Resistance to
~-Lactamases
To demonstrate the influence of ~-Iactamases, the MIC values of various orally absorbable cephalosporins were determined for different ~-Iacta rnase-producing bacteria. Cefotiam was the most dramatically affected, especially by OXA-2, OXA5 and OXA-7 enzymes. The greatest reduction in activity of cefpodoxime was observed with the SHY-2 enzyme. This enzyme, however, degrades cefaclor and cefalexin even more efficiently, and affects even cefixime and cefotiam. The most common enzymes, such as TEM-I, TEM-2, SHY-I, OXA-I and OXA-4 do not significantly destroy cefpodoxime.
11
2.3 Killing Kinetics A simple comparison of MIC values with the drug concentrations available in the patients' serum is not sufficient to calculate the potential clinical effect of the drug, because the MIC does not represent the pharmacodynamic properties of an antibiotic, such as the killing ability in vivo. Therefore, we tested cefpodoxime in an in vitro model simulating the concentration-time curves of cefpodoxime in the serum of patients following oral absorption (Grasso et al. 1978). Elimination of the E. coli strain in an inoculum of 106 cells/ml was equally efficient with all 3 doses, whereas the higher doses were required for elimination of S. aureus (fig. 6). The presence of ~-Iactamases did not change the killing of E. coli, with the exception of SHY-2, which was anticipated from data presented in table I (fig. 7). Similarly, H. inf/uenzae was effectively
Table I. Susceptibility 01 organisms with plasmid-mediated ft-Iactamases to various orally absorbable cephalosporins Host strain (enzyme)
Factor by which the MIC increased (compared with host strains without /t-Iactamase) CEC
Escherichia coli (TEM-1) E. coli (TEM-2) E. coli (SHV-1) E. coli (SHV-2) E. coli (HMS-1) Pseudomonas aeruginosa (LCR-2)
E. E. E. E. E.
coli (OXA-1) coli (OXA-2) coli (OXA-3) coli (OXA-4) coli (OXA-5) P. aeruginosa (OXA-6) E. coli (OXA-6) P. aeruginosa (OXA-1)
CFX
4 8 2 32 8
1 4
2 4 4 2 4 1 128
1 1 2 8
CTM 8 8 2 8 8 4 16 8 4
CPD
CFB
CXM
1 32
16
2
2
1 2
64
CEX
256
1 4
2
4
2
P. aeruginosa (CARB-1) P. aeruginosa (CARB-2) P. aeruginosa (CARB-4)
E. coli (TLE-1) P. aeruginosa (NPS-1) Klebsiella oxytoca (LXA-1) Abbreviations: CEC CEX = cefalexin.
= celaclor;
2 1 32 CFX
= cefixime;
16
1 1 2
CPO
= celpodoxime;
2
CTM
= cefotiam;
1 2 CFB
= ceftibuten;
CXM
= cefuroxime;
12
Drugs 42 (Suppl. 3) 1991
a
- = 4764 (Bla-)
.,.
= ROB enzyme
---
= TEM
enzyme
0 -1
-2 -3 -4
-5
Haemophilus influenzae
0 b
4
4
-
= Bla-
16
12
8
•••
= TEM
1 ---
= TEM
20 5 _.-
24
= SHY 2
Escherichia coli
4
12
8
16
20
24
Time (hours)
Fig. 7. Killing kinetics in vitro after simulation of serum cefpodoxime concentrations corresponding to oral administration of 200mgdoses of cefpodoxime proxetit. The zero line indicates an inoculum of about 106 colony forming units/mt.
killed, and ,B-Iactamases did not impair the activity of the drug (fig. 7).
References Chin NX. Neu He. In I'itro activity of an oral iminomethoxy aminothy· azolyl cephalosporin. R-3746. Antimicrobial Agents and Chemotherapy 32: 671·677. 1988 Fass RJ. Helsel V. In vitro activity of U·76.252 (CS·807). a new oral cepha· losporin. Antimicrobial Agents and Chemotherapy 32: 1082·1085. 1988 Grasso S, Meinardi G, de Caneri I. Tamassia V. New in l'ilrO model to study the effect of antibiotic concentration and rate of elimination on antibacterial activity. Antimicrobial Agents and Chemotherapy 13: 570-576. 1978 Fujimoto K. Ishihara S. Yanagisawa H. Ide J. Nakayama E. et al. Studies of orally active cephalosporin esters. Journal of Antibiotics 40: 370·384. 1987 Jones RN. Barry AL. In I'itro evaluations of U· 76.252 (CS·807): antimi· crobial spectrum. beta-Iactamase stability, and enzyme inhibition. Diagnostic Microbiology and Infectious Disease 8: 245·249. 1987 Jones RN. Barry AL. pfaller M. Allen SO. Ayers LW. et al. Antimicrobial activity of U-76.252 (CS-807). a new orally administered cephalosporin ester, induding recommendations for MIC quality control. Diagnostic Microbiology and Infectious Disease 9: 59-63. 1988 Knapp Cc. Sierra-Madero J. Washington JA. Antibacterial activities of cefpodoxime, cefixime. and ceftriaxone. Antimicrobial Agents and Chemotherapy 32: 1896-1898. 1988
Sarubbi FA. Verghese A. Caggiano C. Holtclaw-Berk S. Berk SL. In vitro activity of cefpodoxime proxetil (U-76.252: CS-807) against clinical isolates of Branhamella catarrhalis. Antimicrobial Agents and Chemotherapy 33: 113-114. 1989 Schaadt RD. Hannon Yagi B. Zurenko GE. In I'itro activity of cefpodoxime proxetil (U-76.252: CS-807) against Neisseria gonorrhoeae. Antimicrobial Agents and Chemotherapy 34: 371-372. 1990 Stobberingh EE. Houben AW. Philips JH. In I'it/'O activity of cefpodoxime. a new oral cephalosporin. European Journal of Clinical Microbiology and Infectious Diseases 8: 657-658. 1989 Utsui Y. Inoue M. Mitsuhashi S. In "itro and in 1';)'0 antibacterial activities of CS-807. a new oral cephalosporin. Antimicrobial Agents and Chemotherapy 31: 1085-1092. 1987 Wiedemann B. Jansen A. Antibacterial activity of cefpodoxime proxetil in a pharmacokinetic in l'itro model. Journal of Antimicrobial Chemotherapy 26: 71-79. 1990 Wiedemann B. Luhmer E. Zuhlsdorf MT. In l'itl'O activity of cefpodoxime and ten other cephalosporins against Gram-positive ,B-Iactamase producers. Infection 19: 363-369. 1991
Correspondence and reprints: Prof. B. Wiedemann, Department of Pharmaceutical Microbiology. University of Bonn. An der Immen burg 4. 5300 Bonn I. Federal Republic of Germany.
