DIAGN MICROBIOLINFECT DIS 1991;14:89-92
89
Ceftibuten and Bactericidal Kinetics Comparative in vitro Activity Against Enterobacteriaceae Producing Extended Spectrum -Lactamases A. Bauernfeind
Ceftibuten, compared to cefixime, cefetamet, cefpodoxime, loracarbef, cefprozil, cefuroxime, cefaclor, and cefadroxil, was the most active oral cephalosporin derivative against Enterobacteriaceae producing plasmid-encoded broad spectrum ~-lacta-
mases. In a pharmacodynamic model, ceftibuten was bactericidal for Haemophilus influenzae and Streptococcus pneumoniae at concentrations simulating human serum levels following 200 rag, p.o., b.i.d.
INTRODUCTION
~-lactam antibiotics. The widespread use of broad spectrum cephalosporins and penicillins in some locations has been correlated with the appearance of transmissible plasmid-encoded extended spectrum f3-1actamases (reviewed by Philippon et al., 1989, and Jacoby and Carreras, 1990). These enzymes are responsible for resistance of Enterobacteriaceae to cefotaxime, ceftazidime, and to other broad-spectrum cephalosporins as well as monobactams, and, more recently, cephamycins (Bauernfeind et al., 1989). The first part of this report is on an investigation carried out to study the activity of ceftibuten and comparative newer oral cephalosporin derivatives against bacterial strains producing the extended spectrum ~-lactamases. The second part of this report discusses an investigation carried out to study the bactericidal kinetics of ceftibuten for H. influenzae and pneumococcus in a pharmacodynamic model at variable concentrations simulating those obtained in human serum following oral administration.
Ceftibuten (7432-S; SCH 39720) is a new oral cephem antibiotic with an extended spectrum and improved activity against Gram-negative bacteria (Hamashima et al., 1987, Jones and Barry, 1988a-d; Nagata et al., 1989; Shawar et al., 1989; Bauernfeind, 1990). With few exceptions, the minimal bactericidal concentrations (MBCs) for ceftibuten are within fourfold of the minimum inhibition concentration (MIC). However, occasional clinical isolates, including two Haemophilus influenzae isolates, have been reported tolerant to ceftibuten as well as to cefixime (Jones and Barry, 1988a; Mendelman et al., 1989). Several studies have also shown that ceftibuten has increased stability to widespread ~-lactamases (Jones and Barry, 1988d), excellent bactericidal activity (Jones and Barry, 1988a), and improved pharmacokinetics following oral administration compared to other oral cephalosporins (Nakashima et al., 1988). B-Lactamase-mediated resistance in bacteria has evolved concurrently with the development of newer From the Max von Pettenkofer Institute, Munich, Federal Republic of Germany. Address reprint requests to: Dr. A. Bauernfeind, Max von Pettenkofer Institute, Pettenkoferstrol3e9A, 8000Miinchen 2, Federal Republicof Germany. ReceivedMay 10, 1990; accepted and revised August 13, 1990. © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/91/$3.50
MATERIALS AND METHODS
All of the compounds used in these studies were obtained from the manufacturers as powders with stated potency. These included ceftibuten (Schering Plough), cefixime (Fujisawa), cefetamet (HoffmanLa Roche), cefpodoxime (Sankyo Europe), cefaclor and loracarbef (Eli Lilly), cefprozil (Bristol-Myers), cefuroxime and cefotaxime (Hoechst AG), cefadroxil
90
TABLE 1.
A. Bauernfeind
In v i t r o A c t i v i t y of C e f t i b u t e n a n d C o m p a r a t i v e C e p h a l o s p o r i n D e r i v a t i v e s A g a i n s t Strains P r o d u c i n g E x t e n d e d S p e c t r u m ~-Lactamases
Cephalosporins Organism/lBLactamase
K. pneumoniae
Ceftibuten
0.25
Cefixime
8
Cefetamet
Cefpodoxime
Loracarbef
Cefprozil
Cefuroxime
Cefaclor
Cefadroxil
Ceftazidime
Cefotaxime
Cefoxitin
0.5
32
16
64
:>64
32
16
32
32
16
32
32
:>64
2
16
TEM-3 {CTX-1) E. coli TEM-5
1
32
2
16
64
64
16
E. coli TEM-6
1
2
4
16
4
16
16
8
16
:>64
E. coli TEM-7
0.12
0.5
0.5
16
2
16
8
4
8
32
K. pneumoniae
0.25
0.25
0.5
64
1
8
16
16
:>64
16
32
8
(CAZ-1) 2
4
0.25
8
SHV-2 K. pneumoniae
8
:>64
4
64
:>64
:>64
64
:>64
:>64
32
ND
8
8
2>64
8
64
>-64
:>64
64
:>64
:>64
32
32
8
:>64
:>64
:>64
:>64
:>64
:>64
:>64
:>64
:>64
4
:>64
:>64
1
16
32
64
:>64
:>64
:>64
:>64
:>64
4
:>64
4
SHV-4 K. pneumoniae SHV-5 K. pneumoniae CMY-1 E. coli CTX-M
(Ciba Geigy), ceftazidime (Glaxo Pharm.), and cefoxitin (Merch Sharp and Dohme). The fB-lactamase type strains included clinical isolates of Escherichia coli and Klebsiella species, which produced TEM-3 (Chanal et al., 1988), TEM-5 (Chanal et al., 1988), TEM-6 (Bauernfeind and Hoerl, 1987). TEM-7 (Gutmann et al., 1988), SHV-2 (Shah et al., 1983; Bauernfeind et al., 1984; Jarlier et al., 1988), SHV-4 (Burg et al., 1988), SHV-5 (Gutmann et al., 1989), CMY-1 (Bauernfeind et al., 1989), and CTXM (Bauernfeind et al., 1990), a new plasmidic cefotaximase in a clinical isolate of Escherichia coli. The minimum inhibitory concentrations of each of the compounds were determined by standard agar dilution tests on Mueller-Hinton agar (NCCLS, 1990). Using a multipoint inoculator, a 104 colony-forming units (CFU)/spot inoculum was delivered to agar plates containing twofold dilutions of the compounds at 0.004-64 ~g/ml. The ampicillin-resistant H. influenzae strains and the Streptococcus pneumoniae strains used for the bactericidal kinetic studies were clinical isolates. An in vitro model (Bauernfeind et al., 1982) simulating the human serum concentrations obtained following oral dosing was chosen to study the bactericidal kinetics of ceftibuten. The concentration of ceftibuten in the organism cultures, 106 CFU/ml, was adjusted to the concentration in h u m a n serum at regular intervals of 1 or 2 hr over 12-hr dosing intervals. Viable cell counts were obtained following incubation at 37°C and prior to adjustment of the ceftibuten concentration.
RESULTS When compared with other oral cephalosporin derivatives and ceftazidime, cefotaxime, and cefoxitin as reference compounds for parenteral cephalospofins, ceftibuten was the most active cephalosporin against the Enterobacteriaceae strains producing extended spectrum {B-lactamases (Table 1). All of the strains with novel plasmid-encoded ~-lactamases related to TEM-1 or TEM-2, and SHV-1 were susceptible to ceftibuten; the MIC breakpoint for susceptibility being 48 ~g/ml (Barry and Jones, 1990). Most of the strains were also susceptible to cefetamet (44.0 p,g/ml). All of the compounds were less active against the strains carrying SHV-derived ~-lactamases than they were against strains carrying TEM-derived enzymes. Ceftibuten was the only oral cephalosporin to which E. coli GRI (CTX-M) was susceptible. This strain was also susceptible to ceftazidime and cefoxitin. None of the oral cephalosporins were active against K. pneumoniae CHO (CMY-1). This strain was only susceptible to ceftazidime. Data on the bactericidal activity of antibacterial compounds are usually based upon in vitro tests in which the test strains are exposed to a constant concentration of the drug. These include MBC determinations as well as time-killing curves that neglect differences in pharmacokinetics of individual agents. So we reproduced the serum pharmacokinetics of different dosages of ceftibuten in broth cultures of Haemophilus influenzae and Streptococcus pneumoniae.
Ceftibuten/Novel 13-Lactamases/Cidal Kinetics
91
resented 90%, 99%, 99.9%, 99.99%, and 99.999% killing at each time calculated. At concentrations corresponding to higher ceftibuten dosages (400 mg and 800 mg p.o. twice daily), killing occurred more rapidly. A 90% reduction in CFU/ml was achieved in approximately 6 and 4 hr, 99% in 8 and 7 hr, 99.9% in 10 and 9 hr, 99.99% in 13 and 12 hr, and 99.999% in 18 and 16 hr for the 400-mg and 800-mg dosages, respectively. At concentrations corresponding to 200 mg p.o. twice daily, the number of CFUs of S. pneumoniae were reduced to 105 CFU/ml (90% killing) in only 2 hr and 104 CFU/ml (99% killing) in approximately 5 hr. At concentrations corresponding to the cited higher doses, a 90% reduction in CFU/ml was achieved in 2 and 1 hr, 99% in 3 and 2.5 hr and 99.9% in 8 and 7 hr for the respective dosages.
A
io~_
to.
io'
S
O Control
• Ceftibuten
I 0°
10 s
o 104
I
102 99.9 %
101 I
E= t0
I
B
I
I
I
I I
I
I
[
I
I
[
1.o z=o o
0 0.1
]
I
I
I
I
I
I
12 Time ( Hours )
I
I
I
I
I
24
FIGURE I (A) Bactericidal kinetics during exposure of ampiciUin-resistant H. influenzae(ceftibuten MIC, 0.06 t~g/ml) to ceftibuten at levels obtained in serum following 200 mg p.o., b.i.d. (B) Human serum pharmacokinetics of ceftibuten following 200 mg p.o., b.i.d. The bactericidal kinetics of ceftibuten against H. influenzae and S. pneumoniae were expressed as the reduction in the initial inoculum concentration over time following exposure of 106 CFU/ml to variable concentrations of ceftibuten. Two strains, H. influenzae 27 and H. influenzae 257, both resistant to ampicillin and both with a ceftibuten MIC = 0.06 txg/ml, showed similar CFU/ml reductions under conditions simulating ceftibuten serum levels following an oral dose of 200 mg twice daily (Fig. 1). The organisms were reduced to 105 CFU/ml, 104 CFU/ml, 103 CFU/ml, 102 CFU/ml, and 101 CFU/ml in approximately 7, 9, 12, 15, and 25 hr, respectively. These reductions rep-
DISCUSSION The ongoing emergence of new, broader spectrum plasmid-encoded transmissible f3-1actamases presents a continuing therapeutic challenge. Of the oral cephalosporins tested, including the newer ones still in development, ceftibuten was the most active against the ~3-1actamase-producing strains. Ceftibuten and cefetamet were still active against strains producing new TEM-derived f3-1actamases. All of the strains producing SHV-derived ~-lactamases were also susceptible to ceftibuten, but not to cefetamet. Ceftibuten had potent activity against multiplyresistant Enterobacteriaceae and H. influenzae strains. In vitro simulation of serum pharmacokinetics in bacterial cultures indicated, by both the rate and the extent of killing, that a twice-daily 200-mg dose is highly bactericidal against ampicillin-resistant H. influenzae. Killing of S. pneumoniae was less extensive under conditions simulating a 200-mg dose b.i.d., but ceftibuten was highly bactericidal at increased doses. This was probably due to the elevated MIC of ceftibuten for this species, for example, MIC90 = 4 txg/ml compared to MICg0 = 0.12 txg/ml for H. influenzae. Treatment of infections caused by S. pneumoniae might require higher doses. Based upon its superior f3-1actamase stability, compared to other oral cephalosporins and its efficient bactericidal activity, ceftibuten warrants further clinical investigation.
REFERENCES
Barry AL, Jones RN, and the Collaborative Antimicrobial Susceptibility Testing Group (1990) Interpretive criteria and quality control limits for ceftibuten disk susceptibility tests. J Clin Microbiol 28:605-607. Bauernfeind A, Jungwirth R, Petermiiller C (1982) Simi-
lation of serum pharmacokinetics of two drugs in a liquid culture of Pseudomonas aeruginosa and analysis of their inactivating activity. Chemotherapy 28:334-340. Bauernfeind A, Shah P, Petermtiller C, Motz M (1984) Plasmid-determined resistance to third generation
92
cephalosporins in Enterobacteriaceae. IV Mediterranean Congress of Chemotherapy, Proceedings 30-31. Bauernfeind A, Hoerl G (1987) Novel R-factor borne J3lactamase of Escherichia coli conferring resistance to cephalosporins. Infection 15:257-259. Bauernfeind A, Chong Y, Schweighart S (1989) Extended broad spectrum ~-lactamases in Klebsiella pneumoniae including resistance to cephamycins. Infection 17:316321. Bauernfeind A (1990) Comparative antimicrobial spectrum and activity of ceftibuten against clinical isolates from West Germany. Diagn Microbiol Infect Dis 14:63-73 [this issue]. Bauernfeind A, Grimm H, Schweighart S (1990) A new plasmidic cefotaximase in the clinical isolate of Escherichia coil Infection 18:294-298. Bur6 A, Legrand P, Arlet G, Jarlier V, Paul G, Philippon A (1988) Dissemination in five French hospitals of Klebsiella pneumoniae serotype K25 harboring a new transferable enzymatic resistance to third generation cephalosporins and aztreonam. Eur J Clin Microbiol 7:780782. Chanal CM, Sirot, DL, Labia, R, Petit A, Morand A, Sirot JL, Cluzel RA (1988) Comparative study of a novel plasmid-mediated f3-1actamase, CAZ-2, and the CTX-1 and CAZ-1 enzymes conferring resistance to broad-spectrum cephalosporins. Antimicrob Agents Chemother 32:1660-1665. Gutmann L, Ferr6 B, Goldstein FW, Rizk N, Pinto-Schuster E, Acar JF, Collatz E (1989) SHV-5, a novel SHVtype ~-lactamase that hydrolyzes broad-spectrum cephalosporins and monobactams. Antimicrob Agents Chemother 33:951-956. Gutmann L, Kitzis MD, Billot-Klein D, et al. (1988) Plasmid-mediated ~-lactamase (TEM-7) involved in resistance to ceftazidime and aztreonam. Rev Infect Dis 10:860866. Hamashima Y, Kubota T, Minami K, et al. (1987) Synthesis and biological properties of 7 beta[(Z)-2-(2-amino-4thiazolyl)-4-carboxy-2obutenoylamino]-3-cephem-4carboxylic acid (7432-S), a new oral cephem antibiotic. J Antibiotics 40:1468-1470. Jacoby GA, Carreras I (1990) Activities of f~-lactam antibiotics against Escherichia coli strains producing extended-spectrum ~-lactamases. Antimicrob Agents Chemother 34:858-862. Jarlier V, Nicolas M-H, Fournier G, Philippon A (1988)
A. Bauernfeind
Extended broad-spectrum ~-lactamases conferring transferable resistance to newer f~-lactam agents in Enterobacteriaceae: hospital prevalence and susceptibility patterns. Rev Infect Dis 10:867-878. 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, and the Collaborative Antimicrobial Susceptibility Testing Group (1988d) Ceftibuten (7432S, 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. Mendelman PM, Henritzy LL, Chaffin DO, Lent K, Smith AL, Stull TL, Wiley EA (1989) In vitro activities and targets of three cephem antibiotics against Haemophilus influenzae. Antimicrob Agents Chemother 33:1878-1882. Nagata H, Kameda Y, Motokawa K, et al. (1989) In vitro antibacterial activity of 7432-S, a new oral cephem antibiotic. Chemotherapy 37:701-22. Nakashima M, Uematsu T, Takiguchi Y, et al. (1988) Phase I clinical studies of 7432-S, a new oral cephalosporin: safety and pharmacokinetics. J Clin Pharmacol 28:246252. 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. Philippon A, Labia R, Jacoby G (1989) Extended-spectrum ~3-1actamases. Antimicrob Agents Chemother 33:1131-1136. Shawar R, LaRocco M, Cleary TG (1989) Comparative in vitro activity of ceftibuten (SCH 39720) against bacterial enteropathogens. Antimicrob Agents Chemother 33:781784. Shah P, Stille W (1983) Escherichia coli and Klebsiella pneumoniae strains more susceptible to cefoxitin than to third generation cephalosporins. JAntimicrob Chemother11:597601.
89
Ceftibuten and Bactericidal Kinetics Comparative in vitro Activity Against Enterobacteriaceae Producing Extended Spectrum -Lactamases A. Bauernfeind
Ceftibuten, compared to cefixime, cefetamet, cefpodoxime, loracarbef, cefprozil, cefuroxime, cefaclor, and cefadroxil, was the most active oral cephalosporin derivative against Enterobacteriaceae producing plasmid-encoded broad spectrum ~-lacta-
mases. In a pharmacodynamic model, ceftibuten was bactericidal for Haemophilus influenzae and Streptococcus pneumoniae at concentrations simulating human serum levels following 200 rag, p.o., b.i.d.
INTRODUCTION
~-lactam antibiotics. The widespread use of broad spectrum cephalosporins and penicillins in some locations has been correlated with the appearance of transmissible plasmid-encoded extended spectrum f3-1actamases (reviewed by Philippon et al., 1989, and Jacoby and Carreras, 1990). These enzymes are responsible for resistance of Enterobacteriaceae to cefotaxime, ceftazidime, and to other broad-spectrum cephalosporins as well as monobactams, and, more recently, cephamycins (Bauernfeind et al., 1989). The first part of this report is on an investigation carried out to study the activity of ceftibuten and comparative newer oral cephalosporin derivatives against bacterial strains producing the extended spectrum ~-lactamases. The second part of this report discusses an investigation carried out to study the bactericidal kinetics of ceftibuten for H. influenzae and pneumococcus in a pharmacodynamic model at variable concentrations simulating those obtained in human serum following oral administration.
Ceftibuten (7432-S; SCH 39720) is a new oral cephem antibiotic with an extended spectrum and improved activity against Gram-negative bacteria (Hamashima et al., 1987, Jones and Barry, 1988a-d; Nagata et al., 1989; Shawar et al., 1989; Bauernfeind, 1990). With few exceptions, the minimal bactericidal concentrations (MBCs) for ceftibuten are within fourfold of the minimum inhibition concentration (MIC). However, occasional clinical isolates, including two Haemophilus influenzae isolates, have been reported tolerant to ceftibuten as well as to cefixime (Jones and Barry, 1988a; Mendelman et al., 1989). Several studies have also shown that ceftibuten has increased stability to widespread ~-lactamases (Jones and Barry, 1988d), excellent bactericidal activity (Jones and Barry, 1988a), and improved pharmacokinetics following oral administration compared to other oral cephalosporins (Nakashima et al., 1988). B-Lactamase-mediated resistance in bacteria has evolved concurrently with the development of newer From the Max von Pettenkofer Institute, Munich, Federal Republic of Germany. Address reprint requests to: Dr. A. Bauernfeind, Max von Pettenkofer Institute, Pettenkoferstrol3e9A, 8000Miinchen 2, Federal Republicof Germany. ReceivedMay 10, 1990; accepted and revised August 13, 1990. © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/91/$3.50
MATERIALS AND METHODS
All of the compounds used in these studies were obtained from the manufacturers as powders with stated potency. These included ceftibuten (Schering Plough), cefixime (Fujisawa), cefetamet (HoffmanLa Roche), cefpodoxime (Sankyo Europe), cefaclor and loracarbef (Eli Lilly), cefprozil (Bristol-Myers), cefuroxime and cefotaxime (Hoechst AG), cefadroxil
90
TABLE 1.
A. Bauernfeind
In v i t r o A c t i v i t y of C e f t i b u t e n a n d C o m p a r a t i v e C e p h a l o s p o r i n D e r i v a t i v e s A g a i n s t Strains P r o d u c i n g E x t e n d e d S p e c t r u m ~-Lactamases
Cephalosporins Organism/lBLactamase
K. pneumoniae
Ceftibuten
0.25
Cefixime
8
Cefetamet
Cefpodoxime
Loracarbef
Cefprozil
Cefuroxime
Cefaclor
Cefadroxil
Ceftazidime
Cefotaxime
Cefoxitin
0.5
32
16
64
:>64
32
16
32
32
16
32
32
:>64
2
16
TEM-3 {CTX-1) E. coli TEM-5
1
32
2
16
64
64
16
E. coli TEM-6
1
2
4
16
4
16
16
8
16
:>64
E. coli TEM-7
0.12
0.5
0.5
16
2
16
8
4
8
32
K. pneumoniae
0.25
0.25
0.5
64
1
8
16
16
:>64
16
32
8
(CAZ-1) 2
4
0.25
8
SHV-2 K. pneumoniae
8
:>64
4
64
:>64
:>64
64
:>64
:>64
32
ND
8
8
2>64
8
64
>-64
:>64
64
:>64
:>64
32
32
8
:>64
:>64
:>64
:>64
:>64
:>64
:>64
:>64
:>64
4
:>64
:>64
1
16
32
64
:>64
:>64
:>64
:>64
:>64
4
:>64
4
SHV-4 K. pneumoniae SHV-5 K. pneumoniae CMY-1 E. coli CTX-M
(Ciba Geigy), ceftazidime (Glaxo Pharm.), and cefoxitin (Merch Sharp and Dohme). The fB-lactamase type strains included clinical isolates of Escherichia coli and Klebsiella species, which produced TEM-3 (Chanal et al., 1988), TEM-5 (Chanal et al., 1988), TEM-6 (Bauernfeind and Hoerl, 1987). TEM-7 (Gutmann et al., 1988), SHV-2 (Shah et al., 1983; Bauernfeind et al., 1984; Jarlier et al., 1988), SHV-4 (Burg et al., 1988), SHV-5 (Gutmann et al., 1989), CMY-1 (Bauernfeind et al., 1989), and CTXM (Bauernfeind et al., 1990), a new plasmidic cefotaximase in a clinical isolate of Escherichia coli. The minimum inhibitory concentrations of each of the compounds were determined by standard agar dilution tests on Mueller-Hinton agar (NCCLS, 1990). Using a multipoint inoculator, a 104 colony-forming units (CFU)/spot inoculum was delivered to agar plates containing twofold dilutions of the compounds at 0.004-64 ~g/ml. The ampicillin-resistant H. influenzae strains and the Streptococcus pneumoniae strains used for the bactericidal kinetic studies were clinical isolates. An in vitro model (Bauernfeind et al., 1982) simulating the human serum concentrations obtained following oral dosing was chosen to study the bactericidal kinetics of ceftibuten. The concentration of ceftibuten in the organism cultures, 106 CFU/ml, was adjusted to the concentration in h u m a n serum at regular intervals of 1 or 2 hr over 12-hr dosing intervals. Viable cell counts were obtained following incubation at 37°C and prior to adjustment of the ceftibuten concentration.
RESULTS When compared with other oral cephalosporin derivatives and ceftazidime, cefotaxime, and cefoxitin as reference compounds for parenteral cephalospofins, ceftibuten was the most active cephalosporin against the Enterobacteriaceae strains producing extended spectrum {B-lactamases (Table 1). All of the strains with novel plasmid-encoded ~-lactamases related to TEM-1 or TEM-2, and SHV-1 were susceptible to ceftibuten; the MIC breakpoint for susceptibility being 48 ~g/ml (Barry and Jones, 1990). Most of the strains were also susceptible to cefetamet (44.0 p,g/ml). All of the compounds were less active against the strains carrying SHV-derived ~-lactamases than they were against strains carrying TEM-derived enzymes. Ceftibuten was the only oral cephalosporin to which E. coli GRI (CTX-M) was susceptible. This strain was also susceptible to ceftazidime and cefoxitin. None of the oral cephalosporins were active against K. pneumoniae CHO (CMY-1). This strain was only susceptible to ceftazidime. Data on the bactericidal activity of antibacterial compounds are usually based upon in vitro tests in which the test strains are exposed to a constant concentration of the drug. These include MBC determinations as well as time-killing curves that neglect differences in pharmacokinetics of individual agents. So we reproduced the serum pharmacokinetics of different dosages of ceftibuten in broth cultures of Haemophilus influenzae and Streptococcus pneumoniae.
Ceftibuten/Novel 13-Lactamases/Cidal Kinetics
91
resented 90%, 99%, 99.9%, 99.99%, and 99.999% killing at each time calculated. At concentrations corresponding to higher ceftibuten dosages (400 mg and 800 mg p.o. twice daily), killing occurred more rapidly. A 90% reduction in CFU/ml was achieved in approximately 6 and 4 hr, 99% in 8 and 7 hr, 99.9% in 10 and 9 hr, 99.99% in 13 and 12 hr, and 99.999% in 18 and 16 hr for the 400-mg and 800-mg dosages, respectively. At concentrations corresponding to 200 mg p.o. twice daily, the number of CFUs of S. pneumoniae were reduced to 105 CFU/ml (90% killing) in only 2 hr and 104 CFU/ml (99% killing) in approximately 5 hr. At concentrations corresponding to the cited higher doses, a 90% reduction in CFU/ml was achieved in 2 and 1 hr, 99% in 3 and 2.5 hr and 99.9% in 8 and 7 hr for the respective dosages.
A
io~_
to.
io'
S
O Control
• Ceftibuten
I 0°
10 s
o 104
I
102 99.9 %
101 I
E= t0
I
B
I
I
I
I I
I
I
[
I
I
[
1.o z=o o
0 0.1
]
I
I
I
I
I
I
12 Time ( Hours )
I
I
I
I
I
24
FIGURE I (A) Bactericidal kinetics during exposure of ampiciUin-resistant H. influenzae(ceftibuten MIC, 0.06 t~g/ml) to ceftibuten at levels obtained in serum following 200 mg p.o., b.i.d. (B) Human serum pharmacokinetics of ceftibuten following 200 mg p.o., b.i.d. The bactericidal kinetics of ceftibuten against H. influenzae and S. pneumoniae were expressed as the reduction in the initial inoculum concentration over time following exposure of 106 CFU/ml to variable concentrations of ceftibuten. Two strains, H. influenzae 27 and H. influenzae 257, both resistant to ampicillin and both with a ceftibuten MIC = 0.06 txg/ml, showed similar CFU/ml reductions under conditions simulating ceftibuten serum levels following an oral dose of 200 mg twice daily (Fig. 1). The organisms were reduced to 105 CFU/ml, 104 CFU/ml, 103 CFU/ml, 102 CFU/ml, and 101 CFU/ml in approximately 7, 9, 12, 15, and 25 hr, respectively. These reductions rep-
DISCUSSION The ongoing emergence of new, broader spectrum plasmid-encoded transmissible f3-1actamases presents a continuing therapeutic challenge. Of the oral cephalosporins tested, including the newer ones still in development, ceftibuten was the most active against the ~3-1actamase-producing strains. Ceftibuten and cefetamet were still active against strains producing new TEM-derived f3-1actamases. All of the strains producing SHV-derived ~-lactamases were also susceptible to ceftibuten, but not to cefetamet. Ceftibuten had potent activity against multiplyresistant Enterobacteriaceae and H. influenzae strains. In vitro simulation of serum pharmacokinetics in bacterial cultures indicated, by both the rate and the extent of killing, that a twice-daily 200-mg dose is highly bactericidal against ampicillin-resistant H. influenzae. Killing of S. pneumoniae was less extensive under conditions simulating a 200-mg dose b.i.d., but ceftibuten was highly bactericidal at increased doses. This was probably due to the elevated MIC of ceftibuten for this species, for example, MIC90 = 4 txg/ml compared to MICg0 = 0.12 txg/ml for H. influenzae. Treatment of infections caused by S. pneumoniae might require higher doses. Based upon its superior f3-1actamase stability, compared to other oral cephalosporins and its efficient bactericidal activity, ceftibuten warrants further clinical investigation.
REFERENCES
Barry AL, Jones RN, and the Collaborative Antimicrobial Susceptibility Testing Group (1990) Interpretive criteria and quality control limits for ceftibuten disk susceptibility tests. J Clin Microbiol 28:605-607. Bauernfeind A, Jungwirth R, Petermiiller C (1982) Simi-
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