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Antimicrobial Agents and Chemotherapy, September 1998, p. 2365-2370, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Pharmacodynamic Studies of L-749,345 in
Comparison with Imipenem and Ceftriaxone against Gram-Positive and
Gram-Negative Bacteria
Inga
Odenholt,*
Elisabeth
Löwdin, and
Otto
Cars
Antibiotic Research Unit, Department of
Infectious Diseases and Clinical Microbiology, University Hospital,
Uppsala, Sweden
Received 16 April 1997/Returned for modification 18 December
1997/Accepted 10 June 1998
 |
ABSTRACT |
L-749,345 is a new parenteral carbapenem with a very
long half-life similar to that of ceftriaxone. The aim of the present study was to investigate different pharmacodynamic parameters of
L-749,345 in comparison with those of ceftriaxone and imipenem. The following studies were performed: (i) comparative studies of the
MICs of L-749,345, imipenem, and ceftriaxone for 70 strains of
gram-positive and gram-negative bacteria; (ii) comparative studies of
the rate of killing of gram-positive and gram-negative bacteria by
L-749,345, imipenem, and ceftriaxone; (iii) studies of the
postantibiotic effects of L-749,345, imipenem, and ceftriaxone; and (iv) studies of the postantibiotic sub-MIC effects of L-749,345, imipenem, and ceftriaxone. Significantly lower MICs of
L-749,345 compared with those of ceftriaxone were found for all
gram-negative organisms except Haemophilus influenzae. The
MICs of L-749,345 were similar to those of imipenem for all
organisms except Pseudomonas aeruginosa and
methicillin-resistant Staphylococcus aureus, for which the
MICs of L-749,345 were higher. A concentration-dependent killing of
methicillin-resistant S. aureus but not
methicillin-susceptible strains was noted for both L-749,345 and
imipenem. All three of the investigated drugs exhibited a
postantibiotic effect against the gram-positive strains but exhibited
no postantibiotic effect against the gram-negative strains.
| |
INTRODUCTION |
The carbapenems are
broad-spectrum agents with excellent in vitro activities against
gram-positive and gram-negative bacteria including strictly anaerobic
bacteria. Imipenem and meropenem, which are registered on
the market, are both highly resistant to hydrolysis by 
-lactamases,
with a few exceptions, such as the -lactamases of
Stenotrophomonas maltophilia and some Aeromonas strains (6, 7, 11). The carbapenems have been
shown to exhibit a postantibiotic effect (PAE) against gram-positive
bacteria and also against some gram-negative strains (3, 4, 12, 16, 19). Imipenem is less stable than meropenem
against human dehydropeptidase and must therefore be administered with
cilastatin. Both drugs have half-lives of approximately 1 h
(1).
L-749,345 is a new parenteral broad-spectrum carbapenem
that is resistant to most -lactamases and which is also stable
against human dehydropeptidase. Pharmacokinetic studies with
rats and rhesus monkeys indicate that L-749,345 has a long
half-life comparable to that of ceftriaxone. The level of protein
binding of L-749,345 in human plasma is estimated to be 95%
(10a).
The aim of the present study was to compare the in vitro
pharmacodynamic properties of L-749,345 with those of imipenem
and ceftriaxone. In the study the following experiments were
performed: (i) comparative studies of the MICs of L-749,345,
imipenem, and ceftriaxone for reference strains and clinical
isolates of gram-positive and gram-negative bacteria; (ii) comparative
studies of the rate and extent of killing of reference strains of
methicillin-sensitive Staphylococcus aureus (MSSA) and
methicillin-resistant S. aureus (MRSA) and reference
strains of the family Enterobacteriaceae by
L-749,345, imipenem, and ceftriaxone at five different
concentrations (L-749,345 and ceftriaxone were also investigated
against three clinical isolates of MSSA, MRSA, and
Enterobacter cloacae); and (iii) studies of the
PAEs and (iv) studies of the postantibiotic sub-MIC effects (PA-SME) of
L-749,345, imipenem, and ceftriaxone against gram-positive and
gram-negative strains.
(This material was presented in part at the 36th Interscience
Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La.,
15 to 18 September 1996.)
| |
MATERIALS AND METHODS |
Antibiotics.
L-749,345 and imipenem were provided by
Merck Sharp & Dohme, Starnberg, Germany, and ceftriaxone was provided
by Roche, Stockholm, Sweden. The antibiotics were obtained as reference
powders with known potencies. L-749,345 was diluted in distilled water,
and ceftriaxone was diluted in Sörensens buffer (pH 7.0).
Dilutions were made on the same day that the experiments were
performed.
Bacterial strains and media.
The strains used in the MIC
studies are listed in Table
1. The
strains used in the second study were S. aureus ATCC
29213 (MSSA) and three clinical isolates of the same species (strains 2005, 1003, 3028), S. aureus Col 1841 (MRSA) and three
clinical isolates of MRSA (strains 6010, 2007, 1011), and E. cloacae EN 20 and three clinical isolates of E. cloacae
(strains 1012, 4006, 3025). The strains used in the third and fourth
studies were S. aureus ATCC 29213, Streptococcus
pneumoniae ATCC 6306, Haemophilus influenzae NTCC
(National Type Culture Collection) 8468, Escherichia coli
ATCC 25922, and E. cloacae EN 20. The clinical strains were obtained from the Clinical Microbiological Laboratory, Uppsala, Sweden.
All the gram-negative strains except H. influenzae were grown in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) supplemented with 50 mg of Ca2+ per liter and 25 mg of
Mg2+ per liter for 6 h at 37°C, yielding an initial
inoculum of approximately 109 CFU/ml. H. influenzae was cultured in Progressive Diagnostics Manufacturers
broth (Biodisk, Solna, Sweden) supplemented with 30 mg of hemin per
liter and 1% IsoVitaleX for 6 h at 37°C, resulting in
approximately 109 CFU/ml. The gram-positive strains were
grown in Todd-Hewitt broth for 6 h at 37°C, resulting in
approximately 109 CFU/ml.
Determination of MICs.
The MICs for the investigated strains
were determined in fluid media by a macrodilution technique in
triplicate on different occasions by the methods recommended by the
National Committee for Clinical Laboratory Standards. Twofold serial
dilutions of the antibiotics were added to broth, and the broth was
inoculated with a final inoculum of approximately 105 CFU
of the test strain per ml and incubated at 37°C for 24 h. The
MIC was defined as the lowest concentration of the antibiotic allowing
no visible growth. At the end of the experiments in which S. aureus ATCC 29213 and S. aureus Col 1841 were
exposed to different concentrations of imipenem, the MICs for
bacteria exposed to 4 and 16× the MIC, respectively, were
reinvestigated by the same method described above.
Determination of the rate and extent of killing at different
concentrations.
In the second study, different concentrations of
L-749,345, imipenem, and ceftriaxone were used. Tubes
containing 4 ml of the same media described above to which one of the
antibiotics had been added at 2, 4, 8, 16, and 32× the MIC were
inoculated with a suspension of the test strain, giving a final
bacterial count of approximately 5 × 105 CFU/ml. The
tubes were incubated at 37°C, and samples were withdrawn at 0, 3, 6, 9, 12, and 24 h and, if necessary, diluted in phosphate-buffered saline. Three dilutions of each sample were spread onto blood agar
plates (Columbia agar base with 5% horse blood), the plates were
incubated at 37°C, and the colonies were counted after 24 h.
Only the colonies on plates with 50 to 500 colonies were counted. The
activity of L-749,345 was tested against MSSA ATCC 29213, 2005, 1003, and 3028; MRSA Col 1841, 6010, 2007, and 1011; and E. cloacae EN 20, 1012, 4006, and 3025. The activity of
imipenem was tested against MSSA ATCC 29213, MRSA Col 1841, and
E. cloacae EN 20. Due to very high MICs for MRSA and
E. cloacae, the activity of ceftriaxone was investigated
only against MSSA. Three experiments were performed for each of the
reference strains, and one experiment was performed for each of the
clinical strains.
Determination of the PAEs of L-749,345, imipenem, and
ceftriaxone in the BioScreen C.
The PAEs of L-749,345,
imipenem, and ceftriaxone against S. aureus
ATCC 29213, S. pneumoniae ATCC 6306, H. influenzae NTCC 8468, and E. coli ATCC 25922 were
investigated. The PAEs of L-749,345 and imipenem against
E. cloacae EN 20 were also studied. All antibiotic-bacterium combinations were investigated in triplicate. After incubation for
6 h at 37°C, all strains were diluted 1:10 in order to obtain an
inoculum of approximately 5 × 107 CFU/ml at the
beginning of the experiments. The strains were then exposed to 10× the
MIC of the antibiotic for 2 h at 37°C. To eliminate the
antibiotic, the cultures were washed three times, after each wash
centrifuged at 1,400 × g for 5 min. Depending on the
rate of killing, some of the cultures were thereafter diluted 1:10. The
unexposed control strains were washed similarly but were also diluted
10
2, 103, 104, and
105 in order to obtain an inoculum as close to that of
the exposed strains as possible. Both the exposed strains and the
different dilutions of the controls were then diluted 1:10 and
inoculated in microtiter wells of 400 µl and incubated in the
BioScreen C (Lab Systems). BioScreen C is a computerized incubator
which provides automatic serial dilutions of bacteria and antibiotics.
It also incubates the bacteria, measures growth continuously by
vertical photometry (optical density) at a wavelength of 540 nm,
processes the data, and provides a printout of the results. Earlier
experimental studies have revealed that the shape of the control growth
curves were independent of the inoculum and that 1 log10
difference in the initial inoculum corresponded to a constant delay in
growth. A control curve for each strain and experiment could therefore be constructed by interpolation of the curve for the controls with the
growth curve for an inoculum nearest that of the experimental culture.
The PAE was calculated as the difference in time for the exposed
cultures and the corresponding control to grow up to a defined point
(A50) on the absorbance curve, where
A50 was defined as 50% of the maximal
absorbance of the control. A50 was chosen, since
this point represented growth of approximately 1 log10 CFU
(9, 16, 19). Since killing cannot be measured in BioScreen
C, viable counts were used to measure the initial level of killing of
the exposed cultures and after the washing. Viable counts of the
controls were also measured at the start of the experiments and before
and after washing at 2 h.
Determination of the PA-SMEs of L-749,345, imipenem,
and ceftriaxone.
The PA-SMEs of L-749,345, imipenem,
and ceftriaxone for the same strains used in the third experiment were
determined on three different occasions. The postantibiotic phase was
induced as described above, and the controls were diluted
(102, 103, 104,
105) in the same way as in the PAE experiments. Viable
counts were also used as described above. The strains in the
postantibiotic phase and the different dilutions of the controls were
then exposed to 0.1, 0.2, 0.3, 0.4, and 0.5× the MICs of
L-749,345, imipenem, and ceftriaxone and were incubated in
BioScreen C. Growth curves were monitored automatically for 20 h.
The PA-SME was defined as the difference in time for the cultures in
the postantibiotic phase and then later exposed to the drugs at
sub-MICs and the corresponding controls with the same initial inoculum
as the preexposed culture to reach the A50
(defined as described above) (9, 16, 19).
| |
RESULTS |
MICs.
The MICs of L-749,345, imipenem, and
ceftriaxone for the strains studied are presented in Table 1.
L-749,345 had the lowest MICs for E. coli (both
TEM-1-producing and non-TEM-1-producing strains),
Klebsiella pneumoniae, E. cloacae
(ceftazidime susceptible), Serratia marcescens,
and Citrobacter freundii. Imipenem was 4- to
8-fold more active than L-749,345 against Pseudomonas
aeruginosa and E. cloacae (ceftazidime resistant)
and was 100-fold more active than L-749,345 against MSSA. However,
L-749,345 was fourfold more active than ceftriaxone
against MSSA. For MRSA, L-749,345 MICs ranged from 2 to 8 mg/liter,
values which were lower than those of ceftriaxone but higher than those
of imipenem. The MICs of all drugs for
penicillin-sensitive S. pneumoniae were similar, but
imipenem had the lowest MICs for penicillin-resistant
S. pneumoniae. Ceftriaxone had the lowest MICs
for both -lactamase-producing and
non--lactamase-producing strains of H. influenzae.
Rate and extent of killing at different concentrations.
No
concentration-dependent killing of MSSA and E. cloacae by
L-749,345, imipenem, and ceftriaxone was noted (Fig.
1). A tendency toward a paradoxical
effect against MSSA could be noted, with the fastest killing occurring
at the lowest concentration (Fig. 2).
Against the MRSA, 3 to 4 log10 CFU better killing was noted for both L-749,345 and imipenem at 32× the MIC compared to
that at 2× the MIC (Fig. 3). At 24 h regrowth was seen for three of the four strains tested with
L-749,345 and for the MRSA strain tested with imipenem. At
the end of the experiments, determination of the MICs of
imipenem for S. aureus Col 1841 revealed the
emergence of resistant strains, with an increase in the MICs from 0.5 to 64 mg/liter. When S. aureus ATCC 29213 was
investigated in the same manner, no increase in MICs was seen.
PAEs and PA-SMEs of L-749,345, imipenem, and
ceftriaxone.
The PAEs and PA-SMEs of L-749,345, ceftriaxone,
and imipenem are presented in Tables
2, 3, and
4, respectively. L-749,345 and
imipenem had almost identical PAEs. L-749,345,
imipenem, and ceftriaxone had similar PAEs against
S. pneumoniae (2.4, 2.4, and 2.6 h, respectively)
but no PAE or a negative PAE against the gram-negative strains.
L-749,345 and imipenem had slightly longer PAEs against
S. aureus compared with that of ceftriaxone. The
PA-SMEs of L-749,345 at 0.3× the MIC were 2.9 h against
S. aureus, 6.9 h against S. pneumoniae and H. influenzae, 1.0 h against E. coli, and 5.0 h against E. cloacae.
Imipenem had PA-SMEs similar to those of L-749,345 with the
exception of that against E. coli; for imipenem at
0.3× the MIC the PA-SME was substantially longer (13.9 h) than that of
L-749,345. Ceftriaxone had PA-SMEs against S. aureus and S. pneumoniae similar to those of
L-749,345 but had no PA-SME against H. influenzae.
| |
DISCUSSION |
Several pharmacodynamic parameters such as the MICs, the rate and
extent of bacterial killing, and PAEs have been recognized as important
factors that may influence the optimal antibiotic dosing regimens
(4, 8, 21, 23). In the present study, we have studied the
pharmacodynamic parameters mentioned above for L-749,345,
imipenem, and ceftriaxone. In comparison with the MICs of
ceftriaxone, the MICs of L-749,345 for all the gram-negative strains except H. influenzae were lower. Compared with
the MICs of imipenem, the MICs of L-749,345 for P. aeruginosa, MSSA, MRSA, and penicillin-resistant strains of
S. pneumoniae were higher. Ceftazidime-resistant
strains of E. cloacae were sensitive to both L-749,345
and imipenem but were highly resistant to ceftriaxone. A
pronounced concentration-dependent killing was seen against the
reference strain of MRSA for both L-749,345 and imipenem, and for L-749,345 this was also seen when clinical strains were tested. In contrast, no concentration-dependent killing of the methicillin-sensitive strains was seen for any of the three drugs tested. The MICs for S. aureus Col 1841 after exposure
to imipenem for 24 h revealed the emergence of resistant
strains, probably due to the presence of a heterogeneous population.
When S. aureus ATCC 29213 was investigated in the same
manner, no increases in the MICs were seen, which implies that this
strain is homogeneously sensitive to the -lactams investigated. No
concentration-dependent killing of E. cloacae was seen for
L-749,345 or imipenem.
A pharmacodynamic factor that has attracted great interest during the
last 10 years is the PAE, i.e., the inhibition of bacterial growth
after a short exposure to antibiotics (2, 4, 5, 10, 22, 24).
In general, all -lactam antibiotics except carbapenems induce a
PAE against gram-positive bacteria but no PAE or a negative PAE against
gram-negative bacteria; carbapenems may produce a PAE
against some gram-negative organisms, depending on the method used
(3, 4, 12, 13, 16, 19). The negative PAEs occasionally seen
have been explained by the formation of filamentous bacteria during the
exposure to the antibiotic. At the time of drug removal and in the
postantibiotic phase, cell division occurs, yielding a more rapid
increase in the number of bacterial cells than the rate for the control
culture (4). Why the carbapenems produce a PAE
against some gram-negative bacteria is not clear. It has, however, been
speculated that, at least with imipenem, its failure to bind to
PBP 3 would prevent the formation of filamentous bacteria, and because
of this a short PAE may be seen against some bacterial species. In this
study, the PAEs of L-749,345, imipenem, and ceftriaxone
were investigated by the optical density method. All three antibiotics
produced a PAE against H. influenzae and E. coli
but no PAE or a negative PAE against the gram-negative strains; the two
carbapenems, however, produced a short PAE against E. cloacae. The PAE results are in agreement with those from earlier
studies of imipenem, meropenem, and BO-2727
(12, 16, 19).
When the PAE is determined, the bacteria are exposed to the antibiotic
for a limited period of time at a given constant concentration, followed by removal of the antibiotic. This is in contrast to the
clinical situation, in which the bacteria are exposed to
suprainhibitory concentrations followed by subinhibitory levels
(sub-MICs). We have earlier studied the influence of the effect of
sub-MICs on bacteria in the postantibiotic phase and have found a very
long delay in bacterial regrowth for many antibiotic classes and
different bacterial species (14, 15, 17-20). In the present
study, we showed that L-749,345 at 0.3× the MIC produces a PA-SME
of 5 to 7 h against S. pneumoniae, H. influenzae, and E. cloacae. Shorter PA-SMEs were noted
against S. aureus and E. coli. The
relatively long PA-SME of L-749,345 at 0.3× the MIC against
H. influenzae, even though it had no PAE, is explained
by the direct effects of subinhibitory concentrations (sub-MIC effect
[SME]) (17, 18). The SME of L-749,345 at 0.3× the MIC
was 5.7 h. Imipenem had similar PA-SMEs against S. pneumoniae and H. influenzae but longer values
against S. aureus and E. coli compared to
those of L-749,345. Ceftriaxone had a PA-SME of 5 to 7 h
against S. aureus and S. pneumoniae but
a short PA-SME against H. influenzae.
In conclusion, L-749,345 is a new carbapenem with
pharmacodynamic properties similar to those of other
carbapenems, e.g., fast but non-concentration-dependent
killing of gram-negative bacteria; a slower, almost paradoxical killing
of S. aureus MSSA; and a concentration-dependent
killing of MRSA. The MICs of L-749,345 for all of the gram-negative
strains tested except P. aeruginosa were lower than those of
imipenem. However, imipenem had more favorable activity
against the gram-positive strains. In comparison with the MICs of
ceftriaxone, L-749,345 had significantly lower MICs for all
gram-negative strains investigated except H. influenzae. All three antibiotics investigated in the present
study, L-749,345, imipenem, and ceftriaxone, induced a PAE
against the gram-positive strains but not against the gram-negative
strains; the two carbapenems, however, produced a short PAE
against E. cloacae.
| |
ACKNOWLEDGMENT |
This study was supported by a grant from Merck & Co., Rahway,
N.J.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Infectious Diseases, University Hospital, S-751 85 Uppsala, Sweden.
Phone: (46)-18-665651. Fax: (46)-18-665650. E-mail:
Inga.Odenholt{at}infektion.uas.se.
| |
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Antimicrobial Agents and Chemotherapy, September 1998, p. 2365-2370, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
