DIAGN MICROBIOLINFECTDIS 1991;14:63-74
63
Comparative Antimicrobial Spectrum and Activity of Ceftibuten Against Clinical Isolates from West Germany A. Bauernfeind
The in vitro activity of a new oral cephalosporin, ceftibuten, was determined against 837 clinical isolates by agar dilution technique and compared with that of the oral cephalosporins, cefaclor, cefuroxime, cefixime, cefpodoxime, and cefprozil. Against Enterobacteriaceae, ceftibuten was the most active of the compounds. Ceftibuten MIC9os were ~0.25 t~g/ml for most members of the family Enterobacteriaceae, 0.13 i~g/ml for Haemophilus influenzae, 4 I~g/ml for Moraxella catarrhalis, and 0.5 I.Lg/mlfor Neisseria gonorrhoeae. Ceftibuten also was active against AS-haemolytic streptococci (serogroups A, C, and G) and penicillin-susceptible strains of
Streptococcus pneumoniae (MICgo, 4 I~g/ml), but was not active against Staphylococcus spp. or the anaerobic bacteria studied. Cefpodoxime and cefuroxime were the most active of the cephalosporins against nonenteric streptococci; cefprozil and cefuroxime were the most active against staphylococci, and cefaclor demonstrated the greatest activity against some Bacteroides spp. Most strains of Acinetobacter baumanii, Pseudomonas spp., and methicillin-resistant staphylococci, as well as all strains of Clostridium difficile, were resistant to each of the cephalosporins tested.
INTRODUCTION
The new oral cephem antibiotic, ceftibuten, typifies such cephalosporin derivatives. Ceftibuten has the formula 7 ~-[(Z)-2-(2-amino-4thiazolyl)-4-carboxy-2-butenoylamino]-3-cephem-1carboxylic acid (Hamashima et al., 1987). To date, research demonstrates potent activity and an extended spectrum of activity against Gram-negative bacteria, including many microorganisms of Enterobacteriaceae, Moraxella catarrhalis, Haemophilus influenzae, and pathogenic strains of Neisseria spp. (Hamashima et al., 1987; Jones and Barry, 1988a-d; Nagata et al., 1989; Shawar et al., 1989). Moreover, Grampositive bacteria are within ceftibuten's spectrum of activity: B-hemolytic streptococci, serogroups A, C, and G; and Streptococcus pneumoniae (Jones and Barry, 1988a-c; Nagata et al., 1989). Ceftibuten demonstrates stability to bacterial f~-lactamase activity (Jones and Barry, 1988a, d). Further, favorable pharmacokinetic properties have been observed following oral administration. A 100-mg dose provides mean peak serum concentrations of 5.6 p~g/ml and has a serum half-life of 1.5 hr (Nakashima et al., 1988). Ceftibuten is tolerated well, based on objective and subjective evaluation of the safety of 100- and 200-mg doses administered twice daily to volunteers for 7-14 consecutive days (Nakashima et al., 1988). Overall, these
The continual development of new antimicrobial agents has been necessitated by the emergence of bacterial pathogens that are resistant to presently available antibiotics. Although new compounds have b e e n introduced within all classes of antibiotics, it is within the cephalosporin class that one sees especially rapid development of new therapeutic agents (Lafong and Murphy, 1986). This development has been spurred not only by an increase in bacterial resistance to early antimicrobial compounds, but by the comparative safety of the cephalosporin antibiotics, as well (Lafong and Murphy, 1986). Research has been directed, in particular, at the development of cephalosporin derivatives that offer improvements with respect to potency, stability to bacterial ~-lactamases, pharmacokinetic properties, and safety. From the Max von PettenkoferInstitute, Munich, Federal Republic of Germany. Address reprint requests to: Dr. A. Bauernfeind,Max von Pettenkofer Institut, Pettenkoferstra~e 9A, 8000M~inchen2, Federal Republicof Germany. ReceivedMay 25, 1990; revised and acceptedJuly 23, 1990. © 1991 ElsevierSciencePublishing Co., Inc. 655 Avenue of the Americas,New York, NY 10010 0732-8893/91/$3.50
64
A. Bauernfeind
findings suggest that ultimately ceftibuten may prove to be highly useful in the clinical setting. In this in vitro study, the antimicrobial activity of ceftibuten versus that of the early generation oral cephalosporins (cefaclor and cefuroxime) and the recently released or investigational oral cephalosporins, cefixime, cefpodoxime and cefprozil, was determined against a wide variety of clinical isolates from West Germany.
MATERIALS AND METHODS Antimicrobial Agents Among the antibiotics compared in this investigation were ceftibuten, cefaclor, cefixime, cefpodoxime, cefprozil, and cefuroxime. These compounds were obtained from the manufacturers as powders with stated potency and were prepared as stock solutions.
Microorganisms Bacterial isolates were collected from six hospitals in West Germany, most of which were in the Munich area. The isolates were cultured from specimens of blood, sputum, and urine, and from swabs of wound sites, ears, noses, and throats. Only one isolate was accepted from each patient. At the conclusion of approximately I year, 837 microorganisms of 76 genera had been obtained. These 837 isolates were distributed as follows: Acinetobacter spp. (40 strains), Brucella spp. (five strains), Enterobacteriaceae (297 strains), H. influenzae (40 strains), Haemophilus parainfluenzae (six strains), Helicobacter pylori (16 strains), M. catarrhalis (10 strains), Neisseria gonorrhoeae (14 strains), Pseudomonas aeruginosa (30 strains), other Pseudomonas spp. (56 strains), Enterococcus spp. (50 strains), Listeria spp. (13 strains), Staphylococcus spp. (143 strains), Streptococcus spp. (82 strains), Bacteroides spp. (11 strains), Clostridium spp. including Clostridium difficile (17 strains), and Peptococcus magnus (four strains).
Susceptibility Testing All isolates were tested by agar dilution technique using Mueller-Hinton agar (Difco Laboratories, Detroit, Michigan) or other acceptable media (NCCLS, 1990). For fastidious microorganisms, appropriate supplements were added to the Mueller-Hinton base. For anaerobes, Wilkins-Chalgren medium was supplemented with 5% sheep blood. An inoculum of 104 colony-forming units (CFU)/spot was delivered by a multipoint inoculator to agar plates that contained twofold antibiotic dilutions ranging from 0.004 to 64 ~g/ml. Most plates were incubated for 16 hr in ambient air at 35°C. Those containing methicillinresistant staphylococci were incubated for a 24-hr period at 32°C and supplemented by 2% NaC1. After incubation, plates were examined for colony development, and the minimum inhibitory concentration (MIC) of each antibiotic was determined. The MIC was defined as the lowest concentration of antibiotic at which no visible growth or growth of 43 colonies was observed.
RESULTS Activity Against Gram-Negative Microorganisms Ceftibuten was the most active of the agents studied against members of the family Enterobacteriaceae (Table 1). At a concentration of 48 ~g/ml, ceftibuten inhibited at least 90% of strains of Citrobacter freundii, Enterobacter sakazakii, Escherichia coli, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Salmonella spp., Serratia spp., Shigella spp., and Yersinia enterocolitica. In fact, the MICg0 for most of these species was 40.25 ~g/ml. Against the remaining species of enteric bacilli (Enterobacter aerogenes, Enterobacter cloacae, and Morganella morganii), ceftibuten MIC50s were 41 i~g/ml, but MICg0 were ~32 tzg/ml. In general, cefixime and cefpodoxime were nearly as active as ceftibuten against most species groups of enterobacteria, and cefprozil and cefuroxime were the least active of the agents against these isolates.
TABLE 1. Comparative Activity of Ceftibuten MIC in ~,g/ml Microorganism (no. of isolates)
Citrobacter freundii (20)
Antibiotic
Range
50%
Ceftibuten Cefaclor Cefixime Cefpodoxime
0.06-64 8->64 0.254 0.5-8
0.5 32 1 1
90% 1 >64 2 4
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
65
Continued MIC in tzg,/ml
Microorganism (no. of isolates)
Antibiotic Cefprozil Cefuroxlme
Range 8->64 4->64
50%
90%
64 4
>64 64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25->64 8->64 0.5->64 0.25->64 16->64 2->64
0.5 >64
8
64 >64 >64 64 >64 >64
Enterobacter cloacae (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
O.13->64 2->64 O.13->64 0.03->64 8->64 4->64
1 >64 8 1 >64 4
>64 >64 >64 >64 >64 >64
Enterobacter sakazakii (11)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlme
0.015-0.13 1-16 0.015-0.5 0.13-1 1-8 0.5-16
0.03 4 0.06 0.25 2 2
0.06 8 0.25 0.5 4 8
Escherichia coli Ampicillin susceptible (17)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurox~me
0.03-0.5 0.25-4 0.06-0.5 0.13-0.5 0.5-4 2-4
0.13 1 0.25 0.25 1 2
0.25 2 0.5 0.5 2 4
Ampicillin resistant, ceftazidime susceptible (8)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.06-0.25 0.5-2 0.13-0.5 0.13-0.25 1-8 2-8
0.13 1 0.25 0.5 2 4
Ampicillin resistant, ceftazidime resistant (3)a
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
1 4-8 2 16-32 8-16 16
Hafnia alvei (5)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-1 8-16 1-4 1-4 8-32 2-16
Klebsiella oxytoca Ceftazidime susceptible (19)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurordme
0.03-0.25 0.25-1 0.015-0.5 0.06-2 0.5-16 1-8
Enterobacter aerogenes (10)
1 1
>64
1 4 2 16 8 16 0.5 8 1 2 16 2 0.06 0.5 0.03 0.13 4 2
0.13 1 0.13 0.5 8 8
66
A. B a u e m f e i n d
TABLE 1.
Continued MIC in ~g/ml
Microorganism (no. of isolates)
Antibiotic
Range
50%
90%
Ceftibuten Cefaclor Cefixime Cefpodoxlme Cefprozil Cefuroxime
0.13 1 2 2 4 4
0.13 1 2 2 4 4
Ceftibuten Cefaclor Cefixlme Cefpodoxime Cefprozil Cefuroxime
0.03-0.25 0.5-16 0.03-0.25 0.03-4 0.5-8 1-8
0.06 0.5 0.06 0.13 4 2
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-0.5 2-32 0.25-8 8-64 8-64 8->64
0.25 8 0.5 16 16 8
Morganella morganii (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
0.06-32 64->64 0.25-64 0.13-64 32->64 16->64
0.25 >64 2 0.5 >64 64
Proteus mirabilis (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlme
0.03 14 0.015-0.06 0.06-0.13 4-16 1-8
Proteus vulgaris (15)
Ceftibuten Cefaclor Cefixlme Cefpodoxime Cefprozil Cefuroxlme
0.03-0.06 16->64 0.015-0.03 0.06-0.5 64->64 16->64
0.03 >64 0.03 0.13 >64 >64
0.06 >64 0.03 0.25 >64 >64
Providencia rettgeri (20)
Ceftibuten Cefaclor Cefixlme Cefpodoxime Cefprozil Cefuroxime
0.03-0.13 1->64 0.015-8 0.008-2 2->64 0.5-64
0.03 4 0.03 0.13 8 2
0.13 >64 0.25 0.5 >64 8
Providencia stuartii (6)
Ceftibuten Cefaclor Cefixlme Cefpodoxlme Cefprozil Cefuroxlme
0.16-0.6 4->64 0.015-0.25 0.06-0.5 4->64 1-4
0.03 32 0.015 0.13 16 1
Ceftibuten Cefaclor Cefixime Cefpodoxime
0.03 0.13-0.5 0.03-0.13 0.13-0.5
0.03 0.25 0.13 0.25
Ceftazidime resistant
(2)
Klebsiella pneumoniae Ceftazidime susceptible (16)
Ceftazidime resistant
(4)
Salmonella spp. b (5)
0.03 4 0.015 0.06 8 4
m
m
m
0.13 8 0.25 0.5 8 8
32 >64 64 64 >64 >64 0.03 4 0.06 0.13 16 4
m
m
m
m
m
m
m
m
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
67
Continued MIC in ~g/rnl
Microorganism (no. of isolates)
Antibiotic
Range
50%
90%
Cefprozil Cefuroxime
0.25-1 0.5-4
Serratia spp. c (29)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxirne
0.06-8 16->64 0.25->64 0.25->64 64->64 16->64
0.25 >64 0.5 2 >64 >64
Shigella spp. a (22)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
0.06-0.25 1-2 1-4 0.25-0.5 2-8 2-4
0.13 1 2 0.25 2 2
0.25 1 2 0.25 8 4
Yersinia enterocolitica
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlrne
0.06-0.5 16 2-8 0.5-2 16-32 2-8
0.13 16 4 1 16 4
0.25 16 8 2 32 4
(15)
0.5 4 8 >64 32 64 >64 >64
Acinetobacter baumanii (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxarne
1->64 >64 8->64 0.5-32 4->64 2->64
32 >64 16 16 >64 32
32 >64 32 32 >64 64
Acinetobacter lwoffii (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlrne
0.03-64 16->64 2->64 0.5-16 2-64 4-16
1
32 8 4 4 4
16 64 16 8 16 8
Ceftibuten Cefaclor Cefixame Cefpodoxime Cefprozil Cefuroxarne
16->64 >64 >64 >64 >64 >64
64 >64 >64 >64 >64 >64
>64 >64 >64 >64 >64 >64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxarne
0.25->64 >64 32->64 4->64 >64 8->64
2 >64 64 >64 16
>64 >64 >64 64 >64 >64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlrne
8->64 >64 8->64 8->64 >64 8->64
>64 >64 >64 >64 >64 >64
>64 >64 >64 >64 >64 >64
Pseudomonas aeruginosa e (30)
Pseudomonas cepacia (14)
Pseudomonas spp/(22)
8
68
A. Bauernfeind
TABLE 1.
Continued MIC in ~g/ml
Microorganism (no. of isolates)
Xanthomonas maltophilia
Antibiotic
Range
50%
90%
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
16->64 >64 >64 >64 >64 >64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.03-0.25 2-16 0.03-0.13 0.03-0.5 4-32 0.5-2
0.06 8 0.06 0.06 8 1
0.13 16 0.13 0.25 16 2
Ampicillin resistant (16)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlme
0.03-0.13 4-16 0.13-0.5 0.03-1 4-32 1-4
0.06 8 0.5 0.06 8 2
0.13 16 0.5 0.5 16 2
Haemophilus parainfluenzae
Ceftibuten Cefaclor Cefixime Cefpodoxlme Cefprozil Cefuroxlme
0.03-0.06 4-16 0.03-0.06 0.06-0.13 0.5-4 0.13-1
0.06 8 0.03 0.06 2 0.5
Moraxella catarrhalis (13)
Ceftibuten Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxlme
0.5-4 0.5-4 0.06-0.5 0.06-0.5 1-4 0.25-2
1 4 0.13 0.25 1 0.5
Neisseria gonorrhoeaeg (14)
Ceftibuten Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxime
0.015-0.5 2-32 0.004-0.06 0.004-0.06 1->32 0.03-0.5
0.13 8 0.015 0.015 32 0.06
Brucella spp. h (5)
Ceftibuten Cefaclor Cefixirne Cefpodoxime Cefprozil Cefuroxlme
8 4 0.06-2 0.25 0.13-8 4
8 4 0.5 0.25 1 4
Helicobacter pylori (16)
Ceftibuten Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxlme
2-8 0.13-2 0.5-8 0.5-4 0.25-8 0.25-8
4 1 1 2 2 1
8 2 4 4 8 4
Staphylococcus aureus,
Ceftibuten Cefaclor Cefixime Cefpodoxlme
>64 >64 >64 >64
>64 >64 >64 >64
(2O)
Haemophilus influenzae, Ampicillin susceptible (24)
(6)
Methicillin resistant (11)
>64 >64 >64 16->64
>64 >64 >64 >64 >64 >64
>64 >64 >64 >64 >64 >64
4 4 0.5 0.5 4 2 0.5 16 0.06 0.06 >32 0.25
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
69
Continued MIC in p,g/ml
Microorganism (no. of isolates)
Antibiotic Cefprozil Cefuroxime
Range 4-32 8->64
Penicillin susceptible (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
32->64 2-4 8-64 24 0.25-1 1-2
Penicillin resistant (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
32->64 2-16 8-32 2-8 0.5-4 1-4
Staphylococcus epidermidis,
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
16->64 1-8 1-16 0.5-4 0.5-32 0.25-2
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
>64 8--64 32->64 4->64 8-64 0.5->32
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
8->64 0.25-4 2-32 1-4 0.25-2 0.5-2
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
>64 64->64 >64 >64 >64 >64
Staphylococcus simulans (10)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurorame
16->64 0.5-2 4-16 0.5-2 0.25-1 0.25-1
Staphylococcus hominis (8)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurorame
8->64 0.5-4 2-8 0.5-2 0.25-2 0.25-1
Staphylococcus cohnii (5)
Ceftibuten
Methicillin susceptible / (24)
Methicillin resistant (11)
Staphylococcus haemolyticus, Methicillin susceptible (13)
Methicillin resistant (5)
>64
50%
90%
16 >64
32 >64
>64 2 16 2 0.5 1
>64 4 32 4 0.5 2
>64 8 16 4 1 2
>64 16 32 4 4 2
16 1 2 1 0.5 0.5 >64 32 64 4 16 4 64 1 16 2 0.5 1
32 2 4 2 1 1 >64 64 64 >64 32 >32 >64 2 32 4 2 2
>64 >64 >64 >64 >64 >64 64 1 8 1 0.5 0.5 8 0.5 4 1 1 0.25 >64
>64 1 16 2 0.5 1
70
A. Bauernfeind
TABLE 1.
Continued MIC in Ixg/ml
Microorganism (no. of isolates
Antibiotic
Range
Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-8 8->64 2-8 0.25-2 0.5-4
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
64->64 0.25-2 16-64 2-8 0.5-1 1-4
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
8-32 1-4 2-8 0.5-1 0.5-2 0.25-0.5
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-1 0.06-0.25 0.25-2 0.008-0.5 0.015-0.06 0.015-0.25
gr. B (16)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
16 0.5-4 0.5-2 0.03-0.25 0.015-0.13 0.03-0.13
gr. C (5)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.5-1 0.015-0.13 0.13-0.25 0.015-0.03 0.015-0.03 0.015-0.03
1 0.03 0.13 0.015 0.03 0.015
gr. G (8)
Ceftibuten Cefaclor Cefixime Cefpodoxzme Cefprozil Cefuroxime
0.5-1 0.03-0.25 0.25-2 0.015-0.06 0.015-0.03 0.03-0.06
0.5 0.06 0.25 0.015 0.015 0.03
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
4-64 2-16 0.134 0.015-0.25 0.13-4 0.03-0.5
Staphylococcus saprophyticus (6)
Staphylococcus warnerz (4)
Streptococci, hemolytic gr. A (9)
Streptococcus milleri gr. (11)
Streptococcus mitior (7)
Ceftibuten Cefaclor Cefixime Cefpodoxime
2-64 2-16 0.13-4
0.015-0.13
50%
90%
4
64 8 2 2 >64 1
32 4 1
2 16 2 2 1 1 0.25 1 0.06 1 0.015 0.03 0.03 16 2 1 0.06 0.03 0.06
16 8 1 0.06 0.25 0.13 32 4 0.5 0.06
16 4 2 0.25 0.06 0.13
64 16 4 0.13 2 0.25
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
71
Continued MIC in t~g/ml
Microorganism (no. of isolates)
Antibiotic Cefprozil Cefuroxime
Streptococcus pneumoniae, Penicillin susceptible (20)
Penicillin resistant (6)
Range
50%
0.13-2 0.03-0.13
0.25 0.03
Ceffibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
4-8 1-4 0.5-1 0.015-0.13 0.03-1 0.015-0.06
4 2 0.5 0.03 0.5 0.03
Ceffibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
32-64 64->64 16-64 2-4 4-64 2-8
90% m
m
4 2 1 0.06 0.5 0.03
32 >64 32 2 8 2
Enterococcus faecalis (20)
Ceftibuten Cefaclor Cefiximc Cefpodoxime Cefprozil Cefuroxime
>64 64 >64 >64 8 >64
>64 64 >64 >64 8 >64
>64 64 >64 >64 8 >64
Enterococcus faecium (17)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
>64 64->64 >64 >64 4-16 >64
>64 64 >64 >64 8 >64
>64 >64 >64 >64 16 >64
Enterococcus liquefaciens
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
>64 16-64 64->64 >64 4-16 >64
>64 32 >64 >64 8 >64
>64 64 >64 >64 16 >64
Listeria spp. j (13)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
64->64 16->64 >64 2->64 1-8 1->64
>64 32 >64 32 2 32
>64 >64 >64 >64 8 >64
Bacteroides spp. k (11)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
64->64 1-16 0.25->64 8-16 0.5->64
>64 8 1 0.5 8 16
>64 8 16 >64 16 64
Clostridium difficile (12)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
>64 32->64 >64 64->64 64->64 64->64
>64 64 >64 >64 64 >64
>64 >64 >64 >64 >64 >64
Clostridium spp. z (5)
Ceftibuten
1->64
4
(13)
8
72
A. Bauernfeind
TABLE 1.
Continued MIC in ~g/ml
Microorganism (no. of isolates)
Peptococcus magnus (4)
Antibiotic
Range
Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxime
8-32 1-64 0.25-16 1-16 0.5-4
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
64->64 8 >64 8-32 8-16 1-4
50% 8 1 8 2 2 >64 8 >64 8 8 2
90% m
m
m
m
m
m
m
m
~Bauernfeind and H6rl (1987) bIncludes two isolates of Salmonella typhimurium, one of Salmonella enteritidis, one of Salmonella Brandenburg, and one of Salmonella agona. qncludes 20 isolates of Serratia marcescens and nine of Serratia liquefaciens. qncludes 17 isolates of Shigella flexneri, three of Shigella sonnei, and two of Shigella boydii. qncludes 17 carbenicillin-susceptible isolates and 13 carbenicillin-resistant isolates. flncludes eight isolates of Pseudomonas fluorescens, nine of Pseudomonas putida, and five of Pseudomonas stutzeri. Xlncludes five penicillin-susceptible isolates and nine penicillin-resistant isolates. hlncludes three isolates of Brucella melitensis, one of Brucella abortus, and one of Brucella suis. iIncludes 16 penicillin-susceptible isolates and eight penicillin-resistant isolates. /Includes eight isolates of Listeria monocytogenes, two of Listeria inocua, one of Listeria seeligeri, one of Listeria welshemeri, and one of Listeria ivanovii. klncludes four isolates of Bacteroidesfragilis, two of Bacteroides thetaiotaomicron, one of Bacteroides distasonis, one of Bacteroides vulgatus, one of Bacteroides disiens, one of Bacteroides bivius, and one of Bacteroides ovatus. tIncludes one isolate each of Clostridium sordelli, Clostridium sporogenes, Clostridium histolyticum, Clostridium perfringens, and Clostridium ramosum.
With respect to other Gram-negative species (Table 1), ceftibuten was highly active against ampicillin-susceptible a n d ampicillin-resistant strains of H. influenzae, H. parainfluenzae, a n d penicillin-susceptible a n d penicillin-resistant strains of N. gonorrhoeae (MIC90s, 0.06-0.5 ~g/ml), and m o d e r a t e l y active against Brucella spp. and M . catarrhalis (MIC90s, 4-8 ~g/ml). Ceftibuten was the most active of the oral cephalosporins against strains of Pseudomonas cepacia; the MICs0 was 2 ~,g/ml, but the MICg0 was >64 ~g/ml. N o n e of the c o m p o u n d s h a d a n y useful activity against Acinetobacter baumanii. All strains of P. aeruginosa and P. maltophilia were resistant to each of the antibiotics studied, as w e r e the majority of isolates of other Pseudomonas spp. All tested oral cephalosporins a p p e a r e d active in vitro (MIC50, 4 8 }xg/ml) against H. pylori.
Activity Against Gram-Positive Microorganisms Overall, cefprozil a n d cefuroxime were the most active of the oral cephalosporins against strains of
Staphylococcus spp. (Table 1). In particular, cefprozil a n d cefuroxime MICg0s r a n g e d from 0.5 to 4 ~g/ml for the various species of methicillin-susceptible staphylococci studied. Cefaclor and cefpodoxime t e n d e d to be s o m e w h a t less active than cefprozil and cefuroxime against these species, and ceftibuten and cefixime had no useful activity against these isolates. For the m o s t part, methicillin-resistant staphylococci were refractory to inhibition b y all of the agents (Table 1). Against nonenteric streptococci, cefpodoxime and cefuroxime MIC90s w e r e 0.03-1 ~g/ml for all species groups, except penicillin-resistant S. pneumoniae (Table 1). Cefprozil was nearly as active against these strains. Against penicillin-resistant isolates of S. pneumoniae, cefpodoxime inhibited 100% of strains at a concentration of 4 ~g/ml; resistant-range MIC5os were r e c o r d e d for all comparative c o m p o u n d s except cefuroxime. Ceftibuten exhibited good activity against ~-haemolytic streptococci, s e r o g r o u p s A, C, and G (MIC90s, 1 ~g/ml). Also, ceftibuten was m o d erately active against penicillin-susceptible strains of S. pneumoniae (MIC100, 8 ~g/ml). Enterococci were consistently resistant to all of the c o m p o u n d s except
Ceftibuten Spectrum/Activity in West Germany
cefprozil. Further, only cefprozil exhibited any potentially useful activity against Listeria spp.
Activity Against Anaerobic Microorganisms Cefaclor was the most active of the agents against Gram-negative anaerobic bacteria; />90% of strains of Bacteroides spp. and P. magnus (Table 1) were inhibited at a concentration of 48 ~g/ml. The remaining compounds showed low activity against the anaerobic species studied. Strains of C. difficile were consistently resistant to all of the agents tested. DISCUSSION Ceftibuten is a new, orally administered cephem antibiotic. In this in vitro study, the antimicrobial spectrum and activity of ceftibuten were determined against 837 clinical isolates of 76 genera. Results were compared with those determined for several other oral cephalosporins, including the first-generation agent, cefaclor, the second-generation agent, cefuroxime, and the recently released or investigational agents, cefixime, cefpodoxime and cefprozil. Our study documents the potent activity of ceftibuten against many species of gram-negative and selected Gram-positive bacteria, as well as its broad spectrum of activity, which includes many species of Enterobacteriaceae, H. influenzae, H. parainfluenzae, N. gonorrhoeae, Brucella spp., M. catarrhalis, ~hemolytic streptococci (serogroups A, C, and G), S. pneumoniae, and H. pylori. Notably, ceftibuten was the most active of the compounds against many spe-
73
cies of enteric bacilli studied. These findings corroborate those of previous researchers (Hamashima et al., 1987; Jones and Barry, 1988a-d; Nagata et al., 1989; Shawar et al., 1989). With respect to the comparative cephalosporins, cefaclor was the most active against anaerobes, but was surpassed in activity against both Gram-negative and Gram-positive bacteria by one or more of the comparative compounds. Cefprozil and cefuroxime were the most active of the agents against Staphylococcus spp., but the least active of the agents against Enterobacteriaceae, and cefpodoxime and cefuroxime were the most active against Streptococcus spp. Only cefprozil was weakly active against enterococci and Listeria spp. Of the compounds tested, cefixime was most similar to ceftibuten with regard to potency and spectrum of activity. Nevertheless, the bioavailability of cefixime is limited, and a susceptibility breakpoint of I ~g/ml has been recommended (Fuchs et al., 1986a and b; Guay et al., 1986; NCCLS, 1990). In contrast, serum concentrations attained with ceftibuten are comparable to those achieved with presently available, early generation, oral cephalosporins, thus warranting recommendation of a ceftibuten susceptibility breakpoint of 8 ~g/ml (Jones et al., 1988d; Nakashima et al., 1988; NCCLS, 1990). Hence, ceftibuten should prove to have greater clinical utility than cefixime and similar investigational cephalosporins. In conclusion, ceftibuten seems particularly suited as therapy for patients with genital, urinary, and respiratory tract infections caused by susceptible bacteria. Clinical investigation is warranted.
REFERENCES Bauernfeind A, H6rl G (1987) Novel R-factor borne ~lactamase of Escherichia coli conferring resistance to cephalosporins. Infection 15:257-259. Fuchs PC, Barry AL, Jones RN (1986a) Cefixime disk susceptibility test criteria. J Clin Microbiol 24:647-649. Fuchs PC, Jones RN, Barry AL, Thornsberry C, Ayers LW, Gavan TL, Gerlach EH (1986b) In vitro evaluation of cefixime (FK027, FR17027, CL284,635): spectrum against recent clinical isolates, comparative antimicrobial activity, beta-lactamase stability, and preliminary susceptibility testing criteria. Diagn Microbiol Infect Dis 5:151162. Guay DR, Meatherall RC, Harding GK, Brown GR (1986) Pharmacokinetics of cefixime (CL 284,635; FK027) in healthy subjects and patients with renal insufficiency. Antimicrob Agents Chemother 30:483-490. Hamashima Y, Kubota T, Minami K, Ishikura K, Konoike T, Yoshioka M, Yoshida T, Nakashimizu H, Motokawa K (1987) Synthesis and biological properties of 7 beta[(Z)2-(2-amino-4-thiazolyl)4-carboxy-2-butenoylamino]-3cephem-4-carboxylic acid (7432-S), a new oral cephem antibiotic. J Antibiotics 40:1468-1470.
Jones RN, Barry AL (1988a) Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin. Antimicrob Agents Chemother 32:1576-1582. Jones RN, Barry AL (1988b) In-vitro antimicrobial activity of 7432-S (SCH 39720) against commonly isolated respiratory tract pathogens. J Antimicrob Chemother 22:387389. Jones RN, Barry AL (1988c) In vitro evaluation of ceftibuten (7432-S, SCH 39720), a novel orally administered cephalosporin. Chemioterapia 7:283-286. Jones RN, Barry AL, The Collaborative Antimicrobial Susceptibility Testing Group (1988d) Ceffibuten (7432-S, SCH 39720): comparative antimicrobial activity against 4735 clinical isolates, beta-lactamase stability and broth microdilution quality control guidelines. Eur J Clin Microbiol Infect Dis 7:802-807. Lafong AC, Murphy PG (1986) New antibacterial agents and their uses. J Clin Hosp Pharm 11:237-269. Nagata H, Kameda Y, Motokawa K, Miwa H, Higashiyama I, Nishikawa T, Watanabe Y, Matsuda H, Sak-
74
A. Bauernfeind
anoue M, Funai M, Komatsu Y, Yoshida T (1989) In vitro antibacterial activity of 7432-S, a new oral cephem antibiotic. Chemotherapy 37:701-722. Nakashima M, Uematsu T, Takiguchi Y, Mizuno A, Iida M, Yoshida T, Yamamoto S, Kitagawa K, Oguma T, Ishii H, Yamada H (1988) Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. J Clin Pharmacol 28:246-252.
National Committee for Clinical Laboratory Standards (NCCLS) (1990) Approved standard M7-A2. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Villanova, PA: NCCLS. Shawar R, LaRocco M, Cleary TG (1989) Comparative in vitro activity of ceftibuten (SCH 39720) against bacterial enteropathogens. Antimicrob Agents Chemother 33:781784.
63
Comparative Antimicrobial Spectrum and Activity of Ceftibuten Against Clinical Isolates from West Germany A. Bauernfeind
The in vitro activity of a new oral cephalosporin, ceftibuten, was determined against 837 clinical isolates by agar dilution technique and compared with that of the oral cephalosporins, cefaclor, cefuroxime, cefixime, cefpodoxime, and cefprozil. Against Enterobacteriaceae, ceftibuten was the most active of the compounds. Ceftibuten MIC9os were ~0.25 t~g/ml for most members of the family Enterobacteriaceae, 0.13 i~g/ml for Haemophilus influenzae, 4 I~g/ml for Moraxella catarrhalis, and 0.5 I.Lg/mlfor Neisseria gonorrhoeae. Ceftibuten also was active against AS-haemolytic streptococci (serogroups A, C, and G) and penicillin-susceptible strains of
Streptococcus pneumoniae (MICgo, 4 I~g/ml), but was not active against Staphylococcus spp. or the anaerobic bacteria studied. Cefpodoxime and cefuroxime were the most active of the cephalosporins against nonenteric streptococci; cefprozil and cefuroxime were the most active against staphylococci, and cefaclor demonstrated the greatest activity against some Bacteroides spp. Most strains of Acinetobacter baumanii, Pseudomonas spp., and methicillin-resistant staphylococci, as well as all strains of Clostridium difficile, were resistant to each of the cephalosporins tested.
INTRODUCTION
The new oral cephem antibiotic, ceftibuten, typifies such cephalosporin derivatives. Ceftibuten has the formula 7 ~-[(Z)-2-(2-amino-4thiazolyl)-4-carboxy-2-butenoylamino]-3-cephem-1carboxylic acid (Hamashima et al., 1987). To date, research demonstrates potent activity and an extended spectrum of activity against Gram-negative bacteria, including many microorganisms of Enterobacteriaceae, Moraxella catarrhalis, Haemophilus influenzae, and pathogenic strains of Neisseria spp. (Hamashima et al., 1987; Jones and Barry, 1988a-d; Nagata et al., 1989; Shawar et al., 1989). Moreover, Grampositive bacteria are within ceftibuten's spectrum of activity: B-hemolytic streptococci, serogroups A, C, and G; and Streptococcus pneumoniae (Jones and Barry, 1988a-c; Nagata et al., 1989). Ceftibuten demonstrates stability to bacterial f~-lactamase activity (Jones and Barry, 1988a, d). Further, favorable pharmacokinetic properties have been observed following oral administration. A 100-mg dose provides mean peak serum concentrations of 5.6 p~g/ml and has a serum half-life of 1.5 hr (Nakashima et al., 1988). Ceftibuten is tolerated well, based on objective and subjective evaluation of the safety of 100- and 200-mg doses administered twice daily to volunteers for 7-14 consecutive days (Nakashima et al., 1988). Overall, these
The continual development of new antimicrobial agents has been necessitated by the emergence of bacterial pathogens that are resistant to presently available antibiotics. Although new compounds have b e e n introduced within all classes of antibiotics, it is within the cephalosporin class that one sees especially rapid development of new therapeutic agents (Lafong and Murphy, 1986). This development has been spurred not only by an increase in bacterial resistance to early antimicrobial compounds, but by the comparative safety of the cephalosporin antibiotics, as well (Lafong and Murphy, 1986). Research has been directed, in particular, at the development of cephalosporin derivatives that offer improvements with respect to potency, stability to bacterial ~-lactamases, pharmacokinetic properties, and safety. From the Max von PettenkoferInstitute, Munich, Federal Republic of Germany. Address reprint requests to: Dr. A. Bauernfeind,Max von Pettenkofer Institut, Pettenkoferstra~e 9A, 8000M~inchen2, Federal Republicof Germany. ReceivedMay 25, 1990; revised and acceptedJuly 23, 1990. © 1991 ElsevierSciencePublishing Co., Inc. 655 Avenue of the Americas,New York, NY 10010 0732-8893/91/$3.50
64
A. Bauernfeind
findings suggest that ultimately ceftibuten may prove to be highly useful in the clinical setting. In this in vitro study, the antimicrobial activity of ceftibuten versus that of the early generation oral cephalosporins (cefaclor and cefuroxime) and the recently released or investigational oral cephalosporins, cefixime, cefpodoxime and cefprozil, was determined against a wide variety of clinical isolates from West Germany.
MATERIALS AND METHODS Antimicrobial Agents Among the antibiotics compared in this investigation were ceftibuten, cefaclor, cefixime, cefpodoxime, cefprozil, and cefuroxime. These compounds were obtained from the manufacturers as powders with stated potency and were prepared as stock solutions.
Microorganisms Bacterial isolates were collected from six hospitals in West Germany, most of which were in the Munich area. The isolates were cultured from specimens of blood, sputum, and urine, and from swabs of wound sites, ears, noses, and throats. Only one isolate was accepted from each patient. At the conclusion of approximately I year, 837 microorganisms of 76 genera had been obtained. These 837 isolates were distributed as follows: Acinetobacter spp. (40 strains), Brucella spp. (five strains), Enterobacteriaceae (297 strains), H. influenzae (40 strains), Haemophilus parainfluenzae (six strains), Helicobacter pylori (16 strains), M. catarrhalis (10 strains), Neisseria gonorrhoeae (14 strains), Pseudomonas aeruginosa (30 strains), other Pseudomonas spp. (56 strains), Enterococcus spp. (50 strains), Listeria spp. (13 strains), Staphylococcus spp. (143 strains), Streptococcus spp. (82 strains), Bacteroides spp. (11 strains), Clostridium spp. including Clostridium difficile (17 strains), and Peptococcus magnus (four strains).
Susceptibility Testing All isolates were tested by agar dilution technique using Mueller-Hinton agar (Difco Laboratories, Detroit, Michigan) or other acceptable media (NCCLS, 1990). For fastidious microorganisms, appropriate supplements were added to the Mueller-Hinton base. For anaerobes, Wilkins-Chalgren medium was supplemented with 5% sheep blood. An inoculum of 104 colony-forming units (CFU)/spot was delivered by a multipoint inoculator to agar plates that contained twofold antibiotic dilutions ranging from 0.004 to 64 ~g/ml. Most plates were incubated for 16 hr in ambient air at 35°C. Those containing methicillinresistant staphylococci were incubated for a 24-hr period at 32°C and supplemented by 2% NaC1. After incubation, plates were examined for colony development, and the minimum inhibitory concentration (MIC) of each antibiotic was determined. The MIC was defined as the lowest concentration of antibiotic at which no visible growth or growth of 43 colonies was observed.
RESULTS Activity Against Gram-Negative Microorganisms Ceftibuten was the most active of the agents studied against members of the family Enterobacteriaceae (Table 1). At a concentration of 48 ~g/ml, ceftibuten inhibited at least 90% of strains of Citrobacter freundii, Enterobacter sakazakii, Escherichia coli, Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Salmonella spp., Serratia spp., Shigella spp., and Yersinia enterocolitica. In fact, the MICg0 for most of these species was 40.25 ~g/ml. Against the remaining species of enteric bacilli (Enterobacter aerogenes, Enterobacter cloacae, and Morganella morganii), ceftibuten MIC50s were 41 i~g/ml, but MICg0 were ~32 tzg/ml. In general, cefixime and cefpodoxime were nearly as active as ceftibuten against most species groups of enterobacteria, and cefprozil and cefuroxime were the least active of the agents against these isolates.
TABLE 1. Comparative Activity of Ceftibuten MIC in ~,g/ml Microorganism (no. of isolates)
Citrobacter freundii (20)
Antibiotic
Range
50%
Ceftibuten Cefaclor Cefixime Cefpodoxime
0.06-64 8->64 0.254 0.5-8
0.5 32 1 1
90% 1 >64 2 4
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
65
Continued MIC in tzg,/ml
Microorganism (no. of isolates)
Antibiotic Cefprozil Cefuroxlme
Range 8->64 4->64
50%
90%
64 4
>64 64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25->64 8->64 0.5->64 0.25->64 16->64 2->64
0.5 >64
8
64 >64 >64 64 >64 >64
Enterobacter cloacae (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
O.13->64 2->64 O.13->64 0.03->64 8->64 4->64
1 >64 8 1 >64 4
>64 >64 >64 >64 >64 >64
Enterobacter sakazakii (11)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlme
0.015-0.13 1-16 0.015-0.5 0.13-1 1-8 0.5-16
0.03 4 0.06 0.25 2 2
0.06 8 0.25 0.5 4 8
Escherichia coli Ampicillin susceptible (17)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurox~me
0.03-0.5 0.25-4 0.06-0.5 0.13-0.5 0.5-4 2-4
0.13 1 0.25 0.25 1 2
0.25 2 0.5 0.5 2 4
Ampicillin resistant, ceftazidime susceptible (8)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.06-0.25 0.5-2 0.13-0.5 0.13-0.25 1-8 2-8
0.13 1 0.25 0.5 2 4
Ampicillin resistant, ceftazidime resistant (3)a
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
1 4-8 2 16-32 8-16 16
Hafnia alvei (5)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-1 8-16 1-4 1-4 8-32 2-16
Klebsiella oxytoca Ceftazidime susceptible (19)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurordme
0.03-0.25 0.25-1 0.015-0.5 0.06-2 0.5-16 1-8
Enterobacter aerogenes (10)
1 1
>64
1 4 2 16 8 16 0.5 8 1 2 16 2 0.06 0.5 0.03 0.13 4 2
0.13 1 0.13 0.5 8 8
66
A. B a u e m f e i n d
TABLE 1.
Continued MIC in ~g/ml
Microorganism (no. of isolates)
Antibiotic
Range
50%
90%
Ceftibuten Cefaclor Cefixime Cefpodoxlme Cefprozil Cefuroxime
0.13 1 2 2 4 4
0.13 1 2 2 4 4
Ceftibuten Cefaclor Cefixlme Cefpodoxime Cefprozil Cefuroxime
0.03-0.25 0.5-16 0.03-0.25 0.03-4 0.5-8 1-8
0.06 0.5 0.06 0.13 4 2
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-0.5 2-32 0.25-8 8-64 8-64 8->64
0.25 8 0.5 16 16 8
Morganella morganii (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
0.06-32 64->64 0.25-64 0.13-64 32->64 16->64
0.25 >64 2 0.5 >64 64
Proteus mirabilis (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlme
0.03 14 0.015-0.06 0.06-0.13 4-16 1-8
Proteus vulgaris (15)
Ceftibuten Cefaclor Cefixlme Cefpodoxime Cefprozil Cefuroxlme
0.03-0.06 16->64 0.015-0.03 0.06-0.5 64->64 16->64
0.03 >64 0.03 0.13 >64 >64
0.06 >64 0.03 0.25 >64 >64
Providencia rettgeri (20)
Ceftibuten Cefaclor Cefixlme Cefpodoxime Cefprozil Cefuroxime
0.03-0.13 1->64 0.015-8 0.008-2 2->64 0.5-64
0.03 4 0.03 0.13 8 2
0.13 >64 0.25 0.5 >64 8
Providencia stuartii (6)
Ceftibuten Cefaclor Cefixlme Cefpodoxlme Cefprozil Cefuroxlme
0.16-0.6 4->64 0.015-0.25 0.06-0.5 4->64 1-4
0.03 32 0.015 0.13 16 1
Ceftibuten Cefaclor Cefixime Cefpodoxime
0.03 0.13-0.5 0.03-0.13 0.13-0.5
0.03 0.25 0.13 0.25
Ceftazidime resistant
(2)
Klebsiella pneumoniae Ceftazidime susceptible (16)
Ceftazidime resistant
(4)
Salmonella spp. b (5)
0.03 4 0.015 0.06 8 4
m
m
m
0.13 8 0.25 0.5 8 8
32 >64 64 64 >64 >64 0.03 4 0.06 0.13 16 4
m
m
m
m
m
m
m
m
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
67
Continued MIC in ~g/rnl
Microorganism (no. of isolates)
Antibiotic
Range
50%
90%
Cefprozil Cefuroxime
0.25-1 0.5-4
Serratia spp. c (29)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxirne
0.06-8 16->64 0.25->64 0.25->64 64->64 16->64
0.25 >64 0.5 2 >64 >64
Shigella spp. a (22)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
0.06-0.25 1-2 1-4 0.25-0.5 2-8 2-4
0.13 1 2 0.25 2 2
0.25 1 2 0.25 8 4
Yersinia enterocolitica
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlrne
0.06-0.5 16 2-8 0.5-2 16-32 2-8
0.13 16 4 1 16 4
0.25 16 8 2 32 4
(15)
0.5 4 8 >64 32 64 >64 >64
Acinetobacter baumanii (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxarne
1->64 >64 8->64 0.5-32 4->64 2->64
32 >64 16 16 >64 32
32 >64 32 32 >64 64
Acinetobacter lwoffii (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlrne
0.03-64 16->64 2->64 0.5-16 2-64 4-16
1
32 8 4 4 4
16 64 16 8 16 8
Ceftibuten Cefaclor Cefixame Cefpodoxime Cefprozil Cefuroxarne
16->64 >64 >64 >64 >64 >64
64 >64 >64 >64 >64 >64
>64 >64 >64 >64 >64 >64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxarne
0.25->64 >64 32->64 4->64 >64 8->64
2 >64 64 >64 16
>64 >64 >64 64 >64 >64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlrne
8->64 >64 8->64 8->64 >64 8->64
>64 >64 >64 >64 >64 >64
>64 >64 >64 >64 >64 >64
Pseudomonas aeruginosa e (30)
Pseudomonas cepacia (14)
Pseudomonas spp/(22)
8
68
A. Bauernfeind
TABLE 1.
Continued MIC in ~g/ml
Microorganism (no. of isolates)
Xanthomonas maltophilia
Antibiotic
Range
50%
90%
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
16->64 >64 >64 >64 >64 >64
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.03-0.25 2-16 0.03-0.13 0.03-0.5 4-32 0.5-2
0.06 8 0.06 0.06 8 1
0.13 16 0.13 0.25 16 2
Ampicillin resistant (16)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxlme
0.03-0.13 4-16 0.13-0.5 0.03-1 4-32 1-4
0.06 8 0.5 0.06 8 2
0.13 16 0.5 0.5 16 2
Haemophilus parainfluenzae
Ceftibuten Cefaclor Cefixime Cefpodoxlme Cefprozil Cefuroxlme
0.03-0.06 4-16 0.03-0.06 0.06-0.13 0.5-4 0.13-1
0.06 8 0.03 0.06 2 0.5
Moraxella catarrhalis (13)
Ceftibuten Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxlme
0.5-4 0.5-4 0.06-0.5 0.06-0.5 1-4 0.25-2
1 4 0.13 0.25 1 0.5
Neisseria gonorrhoeaeg (14)
Ceftibuten Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxime
0.015-0.5 2-32 0.004-0.06 0.004-0.06 1->32 0.03-0.5
0.13 8 0.015 0.015 32 0.06
Brucella spp. h (5)
Ceftibuten Cefaclor Cefixirne Cefpodoxime Cefprozil Cefuroxlme
8 4 0.06-2 0.25 0.13-8 4
8 4 0.5 0.25 1 4
Helicobacter pylori (16)
Ceftibuten Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxlme
2-8 0.13-2 0.5-8 0.5-4 0.25-8 0.25-8
4 1 1 2 2 1
8 2 4 4 8 4
Staphylococcus aureus,
Ceftibuten Cefaclor Cefixime Cefpodoxlme
>64 >64 >64 >64
>64 >64 >64 >64
(2O)
Haemophilus influenzae, Ampicillin susceptible (24)
(6)
Methicillin resistant (11)
>64 >64 >64 16->64
>64 >64 >64 >64 >64 >64
>64 >64 >64 >64 >64 >64
4 4 0.5 0.5 4 2 0.5 16 0.06 0.06 >32 0.25
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
69
Continued MIC in p,g/ml
Microorganism (no. of isolates)
Antibiotic Cefprozil Cefuroxime
Range 4-32 8->64
Penicillin susceptible (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
32->64 2-4 8-64 24 0.25-1 1-2
Penicillin resistant (20)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
32->64 2-16 8-32 2-8 0.5-4 1-4
Staphylococcus epidermidis,
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
16->64 1-8 1-16 0.5-4 0.5-32 0.25-2
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
>64 8--64 32->64 4->64 8-64 0.5->32
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
8->64 0.25-4 2-32 1-4 0.25-2 0.5-2
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
>64 64->64 >64 >64 >64 >64
Staphylococcus simulans (10)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurorame
16->64 0.5-2 4-16 0.5-2 0.25-1 0.25-1
Staphylococcus hominis (8)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefurorame
8->64 0.5-4 2-8 0.5-2 0.25-2 0.25-1
Staphylococcus cohnii (5)
Ceftibuten
Methicillin susceptible / (24)
Methicillin resistant (11)
Staphylococcus haemolyticus, Methicillin susceptible (13)
Methicillin resistant (5)
>64
50%
90%
16 >64
32 >64
>64 2 16 2 0.5 1
>64 4 32 4 0.5 2
>64 8 16 4 1 2
>64 16 32 4 4 2
16 1 2 1 0.5 0.5 >64 32 64 4 16 4 64 1 16 2 0.5 1
32 2 4 2 1 1 >64 64 64 >64 32 >32 >64 2 32 4 2 2
>64 >64 >64 >64 >64 >64 64 1 8 1 0.5 0.5 8 0.5 4 1 1 0.25 >64
>64 1 16 2 0.5 1
70
A. Bauernfeind
TABLE 1.
Continued MIC in Ixg/ml
Microorganism (no. of isolates
Antibiotic
Range
Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-8 8->64 2-8 0.25-2 0.5-4
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
64->64 0.25-2 16-64 2-8 0.5-1 1-4
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
8-32 1-4 2-8 0.5-1 0.5-2 0.25-0.5
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.25-1 0.06-0.25 0.25-2 0.008-0.5 0.015-0.06 0.015-0.25
gr. B (16)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
16 0.5-4 0.5-2 0.03-0.25 0.015-0.13 0.03-0.13
gr. C (5)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
0.5-1 0.015-0.13 0.13-0.25 0.015-0.03 0.015-0.03 0.015-0.03
1 0.03 0.13 0.015 0.03 0.015
gr. G (8)
Ceftibuten Cefaclor Cefixime Cefpodoxzme Cefprozil Cefuroxime
0.5-1 0.03-0.25 0.25-2 0.015-0.06 0.015-0.03 0.03-0.06
0.5 0.06 0.25 0.015 0.015 0.03
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
4-64 2-16 0.134 0.015-0.25 0.13-4 0.03-0.5
Staphylococcus saprophyticus (6)
Staphylococcus warnerz (4)
Streptococci, hemolytic gr. A (9)
Streptococcus milleri gr. (11)
Streptococcus mitior (7)
Ceftibuten Cefaclor Cefixime Cefpodoxime
2-64 2-16 0.13-4
0.015-0.13
50%
90%
4
64 8 2 2 >64 1
32 4 1
2 16 2 2 1 1 0.25 1 0.06 1 0.015 0.03 0.03 16 2 1 0.06 0.03 0.06
16 8 1 0.06 0.25 0.13 32 4 0.5 0.06
16 4 2 0.25 0.06 0.13
64 16 4 0.13 2 0.25
Ceftibuten Spectrum/Activity in West G e r m a n y
TABLE 1.
71
Continued MIC in t~g/ml
Microorganism (no. of isolates)
Antibiotic Cefprozil Cefuroxime
Streptococcus pneumoniae, Penicillin susceptible (20)
Penicillin resistant (6)
Range
50%
0.13-2 0.03-0.13
0.25 0.03
Ceffibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
4-8 1-4 0.5-1 0.015-0.13 0.03-1 0.015-0.06
4 2 0.5 0.03 0.5 0.03
Ceffibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
32-64 64->64 16-64 2-4 4-64 2-8
90% m
m
4 2 1 0.06 0.5 0.03
32 >64 32 2 8 2
Enterococcus faecalis (20)
Ceftibuten Cefaclor Cefiximc Cefpodoxime Cefprozil Cefuroxime
>64 64 >64 >64 8 >64
>64 64 >64 >64 8 >64
>64 64 >64 >64 8 >64
Enterococcus faecium (17)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
>64 64->64 >64 >64 4-16 >64
>64 64 >64 >64 8 >64
>64 >64 >64 >64 16 >64
Enterococcus liquefaciens
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
>64 16-64 64->64 >64 4-16 >64
>64 32 >64 >64 8 >64
>64 64 >64 >64 16 >64
Listeria spp. j (13)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
64->64 16->64 >64 2->64 1-8 1->64
>64 32 >64 32 2 32
>64 >64 >64 >64 8 >64
Bacteroides spp. k (11)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
64->64 1-16 0.25->64 8-16 0.5->64
>64 8 1 0.5 8 16
>64 8 16 >64 16 64
Clostridium difficile (12)
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxame
>64 32->64 >64 64->64 64->64 64->64
>64 64 >64 >64 64 >64
>64 >64 >64 >64 >64 >64
Clostridium spp. z (5)
Ceftibuten
1->64
4
(13)
8
72
A. Bauernfeind
TABLE 1.
Continued MIC in ~g/ml
Microorganism (no. of isolates)
Peptococcus magnus (4)
Antibiotic
Range
Cefaclor Cefixime Cefpodoxirne Cefprozil Cefuroxime
8-32 1-64 0.25-16 1-16 0.5-4
Ceftibuten Cefaclor Cefixime Cefpodoxime Cefprozil Cefuroxime
64->64 8 >64 8-32 8-16 1-4
50% 8 1 8 2 2 >64 8 >64 8 8 2
90% m
m
m
m
m
m
m
m
~Bauernfeind and H6rl (1987) bIncludes two isolates of Salmonella typhimurium, one of Salmonella enteritidis, one of Salmonella Brandenburg, and one of Salmonella agona. qncludes 20 isolates of Serratia marcescens and nine of Serratia liquefaciens. qncludes 17 isolates of Shigella flexneri, three of Shigella sonnei, and two of Shigella boydii. qncludes 17 carbenicillin-susceptible isolates and 13 carbenicillin-resistant isolates. flncludes eight isolates of Pseudomonas fluorescens, nine of Pseudomonas putida, and five of Pseudomonas stutzeri. Xlncludes five penicillin-susceptible isolates and nine penicillin-resistant isolates. hlncludes three isolates of Brucella melitensis, one of Brucella abortus, and one of Brucella suis. iIncludes 16 penicillin-susceptible isolates and eight penicillin-resistant isolates. /Includes eight isolates of Listeria monocytogenes, two of Listeria inocua, one of Listeria seeligeri, one of Listeria welshemeri, and one of Listeria ivanovii. klncludes four isolates of Bacteroidesfragilis, two of Bacteroides thetaiotaomicron, one of Bacteroides distasonis, one of Bacteroides vulgatus, one of Bacteroides disiens, one of Bacteroides bivius, and one of Bacteroides ovatus. tIncludes one isolate each of Clostridium sordelli, Clostridium sporogenes, Clostridium histolyticum, Clostridium perfringens, and Clostridium ramosum.
With respect to other Gram-negative species (Table 1), ceftibuten was highly active against ampicillin-susceptible a n d ampicillin-resistant strains of H. influenzae, H. parainfluenzae, a n d penicillin-susceptible a n d penicillin-resistant strains of N. gonorrhoeae (MIC90s, 0.06-0.5 ~g/ml), and m o d e r a t e l y active against Brucella spp. and M . catarrhalis (MIC90s, 4-8 ~g/ml). Ceftibuten was the most active of the oral cephalosporins against strains of Pseudomonas cepacia; the MICs0 was 2 ~,g/ml, but the MICg0 was >64 ~g/ml. N o n e of the c o m p o u n d s h a d a n y useful activity against Acinetobacter baumanii. All strains of P. aeruginosa and P. maltophilia were resistant to each of the antibiotics studied, as w e r e the majority of isolates of other Pseudomonas spp. All tested oral cephalosporins a p p e a r e d active in vitro (MIC50, 4 8 }xg/ml) against H. pylori.
Activity Against Gram-Positive Microorganisms Overall, cefprozil a n d cefuroxime were the most active of the oral cephalosporins against strains of
Staphylococcus spp. (Table 1). In particular, cefprozil a n d cefuroxime MICg0s r a n g e d from 0.5 to 4 ~g/ml for the various species of methicillin-susceptible staphylococci studied. Cefaclor and cefpodoxime t e n d e d to be s o m e w h a t less active than cefprozil and cefuroxime against these species, and ceftibuten and cefixime had no useful activity against these isolates. For the m o s t part, methicillin-resistant staphylococci were refractory to inhibition b y all of the agents (Table 1). Against nonenteric streptococci, cefpodoxime and cefuroxime MIC90s w e r e 0.03-1 ~g/ml for all species groups, except penicillin-resistant S. pneumoniae (Table 1). Cefprozil was nearly as active against these strains. Against penicillin-resistant isolates of S. pneumoniae, cefpodoxime inhibited 100% of strains at a concentration of 4 ~g/ml; resistant-range MIC5os were r e c o r d e d for all comparative c o m p o u n d s except cefuroxime. Ceftibuten exhibited good activity against ~-haemolytic streptococci, s e r o g r o u p s A, C, and G (MIC90s, 1 ~g/ml). Also, ceftibuten was m o d erately active against penicillin-susceptible strains of S. pneumoniae (MIC100, 8 ~g/ml). Enterococci were consistently resistant to all of the c o m p o u n d s except
Ceftibuten Spectrum/Activity in West Germany
cefprozil. Further, only cefprozil exhibited any potentially useful activity against Listeria spp.
Activity Against Anaerobic Microorganisms Cefaclor was the most active of the agents against Gram-negative anaerobic bacteria; />90% of strains of Bacteroides spp. and P. magnus (Table 1) were inhibited at a concentration of 48 ~g/ml. The remaining compounds showed low activity against the anaerobic species studied. Strains of C. difficile were consistently resistant to all of the agents tested. DISCUSSION Ceftibuten is a new, orally administered cephem antibiotic. In this in vitro study, the antimicrobial spectrum and activity of ceftibuten were determined against 837 clinical isolates of 76 genera. Results were compared with those determined for several other oral cephalosporins, including the first-generation agent, cefaclor, the second-generation agent, cefuroxime, and the recently released or investigational agents, cefixime, cefpodoxime and cefprozil. Our study documents the potent activity of ceftibuten against many species of gram-negative and selected Gram-positive bacteria, as well as its broad spectrum of activity, which includes many species of Enterobacteriaceae, H. influenzae, H. parainfluenzae, N. gonorrhoeae, Brucella spp., M. catarrhalis, ~hemolytic streptococci (serogroups A, C, and G), S. pneumoniae, and H. pylori. Notably, ceftibuten was the most active of the compounds against many spe-
73
cies of enteric bacilli studied. These findings corroborate those of previous researchers (Hamashima et al., 1987; Jones and Barry, 1988a-d; Nagata et al., 1989; Shawar et al., 1989). With respect to the comparative cephalosporins, cefaclor was the most active against anaerobes, but was surpassed in activity against both Gram-negative and Gram-positive bacteria by one or more of the comparative compounds. Cefprozil and cefuroxime were the most active of the agents against Staphylococcus spp., but the least active of the agents against Enterobacteriaceae, and cefpodoxime and cefuroxime were the most active against Streptococcus spp. Only cefprozil was weakly active against enterococci and Listeria spp. Of the compounds tested, cefixime was most similar to ceftibuten with regard to potency and spectrum of activity. Nevertheless, the bioavailability of cefixime is limited, and a susceptibility breakpoint of I ~g/ml has been recommended (Fuchs et al., 1986a and b; Guay et al., 1986; NCCLS, 1990). In contrast, serum concentrations attained with ceftibuten are comparable to those achieved with presently available, early generation, oral cephalosporins, thus warranting recommendation of a ceftibuten susceptibility breakpoint of 8 ~g/ml (Jones et al., 1988d; Nakashima et al., 1988; NCCLS, 1990). Hence, ceftibuten should prove to have greater clinical utility than cefixime and similar investigational cephalosporins. In conclusion, ceftibuten seems particularly suited as therapy for patients with genital, urinary, and respiratory tract infections caused by susceptible bacteria. Clinical investigation is warranted.
REFERENCES Bauernfeind A, H6rl G (1987) Novel R-factor borne ~lactamase of Escherichia coli conferring resistance to cephalosporins. Infection 15:257-259. Fuchs PC, Barry AL, Jones RN (1986a) Cefixime disk susceptibility test criteria. J Clin Microbiol 24:647-649. Fuchs PC, Jones RN, Barry AL, Thornsberry C, Ayers LW, Gavan TL, Gerlach EH (1986b) In vitro evaluation of cefixime (FK027, FR17027, CL284,635): spectrum against recent clinical isolates, comparative antimicrobial activity, beta-lactamase stability, and preliminary susceptibility testing criteria. Diagn Microbiol Infect Dis 5:151162. Guay DR, Meatherall RC, Harding GK, Brown GR (1986) Pharmacokinetics of cefixime (CL 284,635; FK027) in healthy subjects and patients with renal insufficiency. Antimicrob Agents Chemother 30:483-490. Hamashima Y, Kubota T, Minami K, Ishikura K, Konoike T, Yoshioka M, Yoshida T, Nakashimizu H, Motokawa K (1987) Synthesis and biological properties of 7 beta[(Z)2-(2-amino-4-thiazolyl)4-carboxy-2-butenoylamino]-3cephem-4-carboxylic acid (7432-S), a new oral cephem antibiotic. J Antibiotics 40:1468-1470.
Jones RN, Barry AL (1988a) Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin. Antimicrob Agents Chemother 32:1576-1582. Jones RN, Barry AL (1988b) In-vitro antimicrobial activity of 7432-S (SCH 39720) against commonly isolated respiratory tract pathogens. J Antimicrob Chemother 22:387389. Jones RN, Barry AL (1988c) In vitro evaluation of ceftibuten (7432-S, SCH 39720), a novel orally administered cephalosporin. Chemioterapia 7:283-286. Jones RN, Barry AL, The Collaborative Antimicrobial Susceptibility Testing Group (1988d) Ceffibuten (7432-S, SCH 39720): comparative antimicrobial activity against 4735 clinical isolates, beta-lactamase stability and broth microdilution quality control guidelines. Eur J Clin Microbiol Infect Dis 7:802-807. Lafong AC, Murphy PG (1986) New antibacterial agents and their uses. J Clin Hosp Pharm 11:237-269. Nagata H, Kameda Y, Motokawa K, Miwa H, Higashiyama I, Nishikawa T, Watanabe Y, Matsuda H, Sak-
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A. Bauernfeind
anoue M, Funai M, Komatsu Y, Yoshida T (1989) In vitro antibacterial activity of 7432-S, a new oral cephem antibiotic. Chemotherapy 37:701-722. Nakashima M, Uematsu T, Takiguchi Y, Mizuno A, Iida M, Yoshida T, Yamamoto S, Kitagawa K, Oguma T, Ishii H, Yamada H (1988) Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. J Clin Pharmacol 28:246-252.
National Committee for Clinical Laboratory Standards (NCCLS) (1990) Approved standard M7-A2. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Villanova, PA: NCCLS. Shawar R, LaRocco M, Cleary TG (1989) Comparative in vitro activity of ceftibuten (SCH 39720) against bacterial enteropathogens. Antimicrob Agents Chemother 33:781784.
