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Antimicrobial Agents and Chemotherapy, March 1999, p. 592-597, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Synergy of an Investigational Glycopeptide,
LY333328, with Once-Daily Gentamicin against Vancomycin-Resistant
Enterococcus faecium in a Multiple-Dose, In Vitro
Pharmacodynamic Model
S. A.
Zelenitsky,1,2,*
B.
Booker,1
N.
Laing,3
J. A.
Karlowsky,1,2,3
D. J.
Hoban,2,3 and
G. G.
Zhanel1,2,3
Faculty of Pharmacy1
and Faculty of Medicine,2 University of
Manitoba, and Department of Clinical Microbiology, Health
Sciences Centre,3 Winnipeg, Manitoba, Canada
Received 10 April 1998/Returned for modification 24 August
1998/Accepted 9 December 1998
 |
ABSTRACT |
The pharmacodynamics of an investigational glycopeptide, LY333328
(LY), alone and in combination with gentamicin, against one
vancomycin-susceptible and two vancomycin-resistant Enterococcus faecium strains were studied with a multiple-dose, in vitro
pharmacodynamic model (PDM). Dose-range data for the PDM studies were
obtained from static time-kill curve studies. In PDM experiments
conducted over 48 h, peak LY concentrations of 0.1× and 1× the
MIC every 24 h and peak gentamicin concentrations of 18 µg/ml
every 24 h (Gq24h) and 6 µg/ml every 8 h (Gq8h) were
studied alone and in the four possible LY-gentamicin combinations.
Compared to either antibiotic alone, LY-gentamicin combination regimens
produced significantly higher apparent killing rates (KRs) calculated
during the initial 2 h postdosing. The mean KRs for LY or
gentamicin alone versus those for the LY-gentamicin combination
regimens were 0.35 ± 0.55 log10 CFU/ml/h (95%
confidence interval [CI95%], 0 to 0.70) and 1.46 ± 0.71 log10 CFU/ml/h (CI95%, 1.01 to 1.91),
respectively (P < 0.0001). Bacterial killing at
48 h (BK48), which was calculated by subtracting the
bacterial counts at 48 h from the initial inoculum, with a
negative value indicating net growth, was also significantly greater.
The mean BK48s were 
0.69 ± 0.44 log10
CFU/ml (CI95%, 0.41 to 0.97) and 3.72 ± 2.28 log10 CFU/ml (CI95%, 2.28 to 5.17) for LY or
gentamicin alone versus LY-gentamicin combination regimens,
respectively (P < 0.0001). None of the 12 regimens with LY or gentamicin alone but 75% (9 of 12) of the
LY-gentamicin combination regimens were bactericidal. Eighty-three
percent (10 of 12) of the LY-gentamicin combination regimens also
demonstrated synergy. No significant differences between the
pharmacodynamics of LY-gentamicin combination regimens containing Gq24h
versus those containing Gq8h were detected.
| |
INTRODUCTION |
Over the past decade, a significant
increase in the prevalence of nosocomial enterococcal infections has
been observed (11). Of greater concern has been the notable
rise in multiple-drug-resistant strains and the difficulty encountered
in the treatment of such pathogens (8, 10, 11, 19). In the
United States, the prevalence of vancomycin-resistant enterococci
(VRE), most commonly in Enterococcus faecium and frequently
in association with multiple-drug resistance, increased 20-fold from
1989 to 1995 (7). VRE are often responsible for severe
infections for which the antibiotic selection is limited for patients
with significant comorbid diseases. These factors may explain the
reported associations between vancomycin resistance and the increased
mortality rates among patients with enterococcal bacteremia (4, 5,
18).
The treatment of systemic enterococcal infections is directed by
antibiotic susceptibilities and may include single agents or
combinations of penicillins, glycopeptides, aminoglycosides, quinolones, and other antibiotics (10). As levels of
resistance continue to increase, antibiotic selection becomes more
limited, and in some cases an appropriate antibiotic is unavailable.
There is an urgent need for new antibiotics with activity against
multiple-drug-resistant Enterococcus, specifically VRE.
Preliminary susceptibility studies have demonstrated the promising
activity of a class of glycopeptide derivatives which are related to
vancomycin (9, 14, 15). Static time-kill curve studies of
one compound, LY333328 (LY), have shown that it has dose-dependent,
bactericidal activity against Enterococcus spp. including
those with high-level resistance to vancomycin (16, 21).
Only a few studies have investigated the potential for synergy between
LY and gentamicin against aminoglycoside-sensitive, vancomycin-resistant strains (12, 20). Furthermore, there are no published data regarding the use of LY in combination with gentamicin administered once daily (Gq24h) versus the use of LY in
combination with gentamicin administered thrice daily (Gq8h) against enterococcus.
The primary purpose of this research was to characterize the activity
of LY against vancomycin-resistant E. faecium with a multiple-dose, in vitro pharmacodynamic model (PDM). The research included comparisons of (i) LY or gentamicin alone versus LY-gentamicin combination regimens (i.e., synergy) and (ii) LY-gentamicin combination regimens containing Gq24h versus the same combination regimens but with
Gq8h against VRE in a PDM.
| |
MATERIALS AND METHODS |
Bacterial strains.
Three E. faecium isolates
obtained from cultures of blood were studied. The strains included a
vancomycin-susceptible strain (strain 1338), PCR-positive
vanB strain 563, and PCR-positive vanA strain
561. All strains had low-level aminoglycoside resistance.
Antibiotics and in vitro susceptibility testing.
LY (Eli
Lilly & Co., Indianapolis, Ind.), vancomycin (Eli Lilly & Co.),
teicoplanin (Merrel Dow, Laval, Quebec, Canada), and gentamicin
(Schering Corp. Ltd,. Pointe-Claire, Quebec, Canada) MICs were
determined in Mueller-Hinton broth (MHB; Difco Laboratories, Detroit,
Mich.) supplemented with 25 µg of calcium per ml and 12.5 µg of
magnesium per ml by the broth macrodilution method described by the
National Committee for Clinical Laboratory Standards (13).
Vancomycin and teicoplanin MICs were determined to confirm the
phenotypic designations of the isolates. Gentamicin MICs were determined to select isolates with low-level aminoglycoside resistance. MICs were verified in triplicate on separate occasions.
Static time-kill curve studies.
Dose-range data for the PDM
studies were obtained from static time-kill curve experiments.
Single-dose, static time-kill curve experiments were conducted over
24 h for LY alone and for LY in combination with gentamicin
against all strains (20, 21). Static time-kill curve studies
were performed in flasks containing total volumes of 10 ml. The volume
of water used from drug stock solutions was limited to 0.1 ml. The
bacteria were grown to the logarithmic phase by inoculating
cation-supplemented MHB (CSMHB) which was incubated in a shaking water
bath at 37°C for 1.5 h. One-milliliter aliquots containing
108 CFU/ml were added to 9 ml of CSMHB to yield an initial
inoculum of approximately 107 CFU/ml. This initial inoculum
was selected for all static time-kill curve and PDM experiments to
enable the detection of synergy between LY and gentamicin. LY
concentrations of 1×, 10×, 20×, 50×, and 100× the MIC were studied
alone and in combination with gentamicin concentrations of 6 µg/ml.
LY concentrations were empirically selected, whereas the gentamicin
concentration was based on the levels achieved in blood with
traditional dosage regimens (i.e., 1 to 1.5 mg/kg of body weight given
every 8 h). Samples (0.1 ml) were collected at 0, 1, 2, 4, 8, and
24 h. Samples were serially diluted in normal saline at 4°C; 10- and 100-µl aliquots were plated in duplicate onto blood agar, and the
plates were incubated at 35°C for 24 h. Viable colonies present
at between 10 and 100 per plate were counted, and a lower limit of
detection of 102 CFU/ml was used. All experiments were
performed in triplicate on separate occasions.
Residual antibiotic effects were assessed during initial experiments by
running concurrent samples which were washed twice to remove
antibiotic. Washing was performed by centrifugation at 4,000 × g for 10 min, decanting of the supernatant, and resuspension of
the pellet in CSMHB. The colony counts from unwashed and washed samples
were compared.
PDM studies.
A multiple-dose, one-compartment PDM was used
to simulate the treatment of bacteremic infections over 48 h
(6). The central chambers (690 ml) contained CSMHB which was
stirred with magnetic bars and heated to 37°C in a water bath. The
bacteria were grown to the logarithmic phase in flasks and were
injected into the central chambers to provide initial inocula of
approximately 107 CFU/ml. Bacterial growth, as confirmed by
colony counts, was permitted for 1 h following inoculation and for
another hour during equilibration of the PDM.
Antibiotic doses were injected into the central chambers at appropriate
intervals to produce the desired peak and trough concentrations.
All
antibiotic concentrations in the PDM represented steady-state,
free
levels which simulate the active antibiotic component. Free
antibiotic
concentrations in vivo, which are dependent on protein
binding and
which are proportionally related to the total concentrations
in serum,
can be calculated for antibiotics with known levels
of protein binding
(i.e., 77% for LY on the basis of data from
studies with
animals).
Because the primary purpose of the PDM studies was to investigate the
potential for synergy between LY and gentamicin, low
concentrations of
the investigational compound, LY, were used.
The static time-kill curve
experiments demonstrated maximal activity
(i.e., less than the lower
limit of detectable colonies at 24
h) for all LY-gentamicin
combination regimens containing LY at
10× the MIC, and therefore,
only the lowest LY concentration
of 1× the MIC was selected for use in
the PDM studies (
20,
21).
An even lower sub-MIC of 0.1× the
MIC was also chosen to study
potential synergy between LY and
gentamicin. On the other hand,
gentamicin is an established antibiotic
which would be used only
in combination for the treatment of
enterococcal infections. As
a result, clinically relevant gentamicin
concentrations were used
including peak levels of 18 µg/ml in
regimens containing Gq24h
and 6 µg/ml in regimens containing Gq8h.
All LY and gentamicin
dosage regimens were studied alone and in the
four possible LY-gentamicin
combinations.
When LY or gentamicin was tested alone, fresh CSMHB was pumped through
the central chambers at flow rates producing half-lives
of either
24 h for LY or 2 h for gentamicin. During studies with
the
drug combinations, fresh broth or LY-supplemented broth was
delivered
by separate computerized pumps at flow rates that concurrently
produced
the LY and gentamicin half-lives (
1). Samples (0.1
ml) were
collected at 0, 1, 2, 5 or 6, 24, 25, 26, 29 or 30, and
48 h.
During experiments with Gq8h only, samples were also collected
at 8, 10, 16, 18, 32, 34, 40, and 42 h. The samples were then
processed
as described above for the time-kill curve experiments.
The
pharmacokinetic profiles obtained in the PDM were verified
by
determining gentamicin concentrations by immunoassay (TDx;
Abbott,
Chicago, Ill.) in the samples obtained at 2, 6, and 24
h. All
experiments were performed in triplicate on separate
occasions.
For both static time-kill curve and PDM experiments, bacterial killing
curves were constructed by plotting the mean log
10 CFU per
milliliter versus time. Activity including apparent kill
rates (KRs)
during the initial 2 h postdosing, and the bacterial
killing (BK)
at 24 h (BK
24) and 48 h (BK
48) were
measured. BK
was calculated by subtracting the bacterial counts at 24 or 48
h from the initial inoculum, with negative values indicating
net
growth. Results from the PDM studies were used to compare the
activity of LY or gentamicin alone to the activities of the
LY-gentamicin
combination regimens. Bactericidal activity was defined
as a BK
of
3 log
10 CFU/ml at 24 or 48 h. Synergy was
determined from
PDM experiments and was defined as a
2
log
10 decrease in the
numbers of CFU per milliliter between
the combination and its
most active constituent at 24 and 48 h
when at least one of the
agents was present at a concentration that did
not affect the
growth curve of the test organism when the agent was
used alone
(
17). Finally, the activities of Gq24h- versus
Gq8h-containing
combination regimens were compared. Statistical
comparisons were
performed by a
t test (
= 0.05).
| |
RESULTS |
Susceptibility testing.
Vancomycin, teicoplanin, LY, and
gentamicin MICs were 0.5, 0.25, 0.06, and 16 µg/ml, respectively for
strain 1338 (vancomycin sensitive), 16, 0.5, 0.03, and 32 µg/ml,
respectively, for strain 563 (vanB), and 512, 32, 0.25, and
16 µg/ml, respectively, for strain 561 (vanA). Isolate
1338 was vancomycin and teicoplanin sensitive. Strain 563 demonstrated
low-level vancomycin resistance and teicoplanin sensitivity, whereas
strain 561 had high-level vancomycin resistance and teicoplanin
resistance. The LY MICs were similar for strain 1338 and strain 563, but the LY MIC for strain 561 was higher. All strains demonstrated
low-level aminoglycoside resistance, with MICs of either 16 or 32 µg/ml.
Static time-kill curve study results.
The colony count
variation at each time point within and between experiments was less
than 10%. In addition, no antibiotic carryover was observed, as
detected from the colony counts for unwashed samples. KR and
BK24 results from the static time-kill curve studies are
presented in Tables 1 and
2, respectively. For LY alone, the KR and
BK24 were dose dependent over the concentration range
studies for all strains. Variability in parameters was demonstrated between strains. For example, although the KR against 561 (vanA) was less than those against the other strains at 1×,
10×, and 20× the MIC, it was higher than those against the other
strains at 50× and 100× the MIC. Furthermore, LY at 20× the MIC was
bactericidal against 1338 (vancomycin susceptible) and 561 (vanA) but was not bactericidal against 563 (vanB) until the concentration was 100× the MIC.
Compared to LY alone, LY-gentamicin combination regimens produced
higher KRs; however, the difference was not statistically
significant.
The mean KRs for LY alone and the LY-gentamicin combination
regimens
were 2.1 log
10 CFU/ml/h (95% confidence interval
[CI
95%],
1.3 to 2.8) and 3.3 log
10 CFU/ml/h
(CI
95%, 2.6 to 4.1),
respectively (
P > 0.05). Compared to LY alone, LY-gentamicin combination
regimens
increased the BK
24 significantly, with mean values of
2.4 log
10 CFU/ml (CI
95%, 1.2 to 3.6) and 4.8 log
10 CFU/ml
(CI
95%, 4.5 to 5.1), respectively
(
P < 0.0001). The addition
of gentamicin lowered the
bactericidal concentrations of LY (i.e.,
the LY concentration required
to kill
3 log
10 CFU/ml) significantly
to 1× the MIC
against all
strains.
PDM study results.
The pharmacokinetic profiles in the central
chambers of the PDM were verified by gentamicin concentration
determinations. Extrapolated peak levels and calculated elimination
rates (i.e., half-lives) were within 10% of the expected values (i.e.,
peak level = 18 or 6 mg/liter and half-life = 2 h). The
colony count variation at each time point within and between
experiments was less than 10%. In addition, no antibiotic carryover
was observed, as detected from the colony counts for unwashed samples.
PDM killing curves for LY alone at 0.1× and 1× the MIC are depicted
in Fig. 1A. LY at 0.1× the MIC produced
no bacterial killing, with net growth at 24 and 48 h. Although the
first doses of LY at 1× the MIC produced modest KRs of 0.57, 0, and
0.17 log10 CFU/ml/h against strains 1338, 563 (vanB), and 561 (vanA), respectively, regrowth to
the initial inoculum occurred at 24 h. Second doses of LY had minimal KRs against all strains tested. PDM killing curves for Gq24h
and Gq8h alone are presented in Fig. 1B. The Gq8h regimen had no
activity, whereas the first doses of the Gq24h regimen produced notable
killing of all strains. Again, regrowth to the initial inoculum
occurred at 24 h.
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|
FIG. 1.
(A) BK curves for LY against E. faecium in a
multiple-dose, in vitro PDM. , growth control;  , LY at 0.1× the
MIC against strain 1338 (vancomycin sensitive); +, LY at 1× the MIC
against strain 1338 (vancomycin sensitive);  , LY at 0.1× the MIC
against strain 563 (vanB); #, LY at 1× the MIC against
strain 563 (vanB); , LY at 0.1× the MIC against strain
561 (vanA);  , LY at 1× the MIC against strain 561 (vanA). (B) BK curves for regimens with Gq24h and Gq8h
against E. faecium in a multiple-dose, in vitro PDM. ,
growth control; , Gq24h against strain 1338 (vancomycin sensitive);
+, Gq24h against strain 563 (vanB); , Gq24h against
strain 561 (vanA); #, Gq8h against strain 1338 (vancomycin
susceptible); , Gq8h against strain 563 (vanB); , Gq8h
against strain 561 (vanA).
|
|
PDM killing curves for LY-Gq24h and LY-Gq8h combination regimens are
depicted in Fig.
2A and B, respectively.
Compared to
either drug alone, the LY-gentamicin combination regimens
produced
significantly higher KRs, with mean values of 0.35 ± 0.55 log
10 CFU/ml/h (CI
95%, 0 to 0.70) and
1.46 ± 0.71 log
10 CFU/ml/h
(CI
95%, 1.01 to 1.91), respectively (
P < 0.0001). BK
48 was also significantly greater, with mean values of
0.69 ± 0.44
log
10 CFU/ml (CI
95%,
0.41 to
0.97) and
3.72 ± 2.28 log
10 CFU/ml (CI
95%, 2.28 to
5.17) for LY or gentamicin alone
versus the combination regimens,
respectively (
P < 0.0001). None
of the regimens with
LY or gentamicin alone were bactericidal,
whereas 75% (9 of 12) of the
LY-gentamicin combination regimens
were bactericidal at both 24 and
48 h. The exceptions were regimens
containing LY at 0.1× the MIC
against strain 563 (
vanB), which
had regrowth to the level
of the initial inoculum at 24 and 48
h, and the regimen with LY at
0.1× the MIC and Gq8h against strain
1338 (vancomycin susceptible),
which produced BKs of 2.41 and
2.13 log
10 CFU/ml at 24 and
48 h, respectively. Eighty-three percent
(10 of 12) of the
LY-gentamicin combination regimens were synergistic
at both 24 and
48 h. The exceptions again included the regimen
containing LY at
0.1× the MIC against strain 563 (
vanB).
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FIG. 2.
(A) BK curves for LY in combination with Gq24h against
E. faecium in a multiple-dose, in vitro PDM. , LY at
0.1× the MIC against strain 1338 (vancomycin sensitive); +, LY at 1×
the MIC against strain 1338 (vancomycin sensitive); , LY at 0.1×
the MIC against strain 563 (vanB); #, LY at 1× the MIC
against strain 563 (vanB); , LY at 0.1× the MIC against
strain 561 (vanA); , LY at 1× the MIC against strain 561 (vanA). (B) BK curves for LY in combination with Gq8h
against E. faecium in a multiple-dose, in vitro PDM. , LY
at 0.1× the MIC against strain 1338 (vancomycin sensitive); +, LY at
1× the MIC against strain 1338 (vancomycin sensitive); , LY at
0.1× the MIC against strain 563 (vanB); #, LY at 1× the
MIC against strain 563 (vanB); , LY at 0.1× the MIC
against strain 561 (vanA); , LY at 1× the MIC against
strain 561 (vanA).
|
|
There was no statistically significant difference in the
pharmacodynamic parameters of LY-gentamicin combination regimens
containing Gq24h versus those containing Gq8h. The mean KRs were
1.92 ± 0.51 log
10 CFU/ml/h (CI
95%, 1.38 to 2.46) and 1.01
± 0.59 log
10 CFU/ml/h
(CI
95%, 0.39 to 1.62) for the regimens
containing Gq24h
and Gq8h, respectively (
P > 0.05). Mean
BK
48s
were also similar, with values of 3.91 ± 2.31 log
10 CFU/ml (CI
95%,
1.48 to 6.33) and
3.54 ± 2.45 log
10 CFU/ml (CI
95%, 0.97
to
6.11) for the regimens containing Gq24h and Gq8h, respectively
(
P > 0.05).
| |
DISCUSSION |
The methodology, antibiotic concentrations, bacterial inoculum,
and measured endpoints can all influence the results of synergy testing
(2). Traditional techniques (i.e., checkerboards and static
time-kill curve studies) and the extrapolation of their results to the
in vivo situation have obvious limitations. In comparison, PDM more
closely simulates the antibiotic concentrations observed in vivo and
allows the study of multiple-dose regimens over prolonged periods. PDM
offers an alternative method for synergy testing and warrants further
investigation (2). An important consideration, however, is
the variation in PDM studies (i.e., design and analysis), with our
infection model, for example, most closely simulating the activities of
free antibiotic concentrations obtained from multiple-dose regimens
against bacteria in the blood of immunocompromised patients. As a
result, methodological standards for the use of synergy testing with
the PDM should be developed.
As was consistent with our static time-kill curve data, LY alone at the
low doses used in the PDM studies demonstrated little activity
(20, 21). In humans, LY dosage regimens and their resulting
concentrations are still being studied. In addition, there is
controversy regarding the pharmacokinetics of LY, with recent data
suggestive of a considerably longer half-life than the 24 h used
in this study (3). For reasons discussed earlier, we were
conservative in that we selected low LY concentrations (i.e., 0.1× and
1× the MIC) for use in the PDM. This, in addition to the use of a
shorter than actual half-life in our experiments, would have, if
anything, produced a situation that underestimated the activity of LY.
The significant activities of some regimens with gentamicin alone may
have been related to the peak concentrations achieved in the PDM (Fig.
1B). The regimens with Gq8h alone produced peak concentrations (i.e., 6 µg/ml) well below the MICs for the isolates (i.e., 16 to 32 µg/ml)
and were relatively inactive. In comparison, the regimens with Gq24h
alone had peak levels which approached the MICs (i.e., approximately
0.5× to 1× the MIC) and reduced bacterial counts by at least 2 log10 CFU/ml at 4 h for all strains. Despite this
initial activity, however, there was rapid regrowth which began at
5 h and which reached or exceeded the initial inoculum at 24 h. This may have been the result of declining gentamicin concentrations
in the PDM, which were approximately 3 µg/ml at 5 h and <0.3
µg/ml at 12 h. Lastly, a phenomenon more difficult to explain
was the lack of bacterial killing following administration of the
second doses for the regimen with Gq24h.
The detection of synergy between LY and gentamicin against VRE in our
study is consistent with previous results (12). Mercier et
al. (12) showed in static time-kill curve experiments that LY plus gentamicin was significantly more potent than LY alone against
a VRE strain with resistance to multiple drugs. In our study,
LY-gentamicin combination regimens produced statistically significant
increases in all pharmacodynamic parameters including KR,
BK24, and BK48. Eighty-three percent (10 of 12)
of the LY-gentamicin combination regimens were synergistic (i.e., 2
log10 decrease in the numbers of CFU per milliliter between
the combination and its most active constituent) at both 24 and 48 h. Strain variability was demonstrated by the lack of synergy with the
regimens containing LY at 0.1× the MIC against strain 563 (vanB). The concentration dependence of synergy testing was
also shown by the presence of synergy with the regimens containing LY
at 1× the MIC against the same strain. Finally, the regimens with
Gq24h alone were more active than those with Gq8h alone; however, no
statistically significant differences between the LY-gentamicin
combination regimens containing Gq24h versus those containing Gq8h were detected.
Conclusion.
LY is a new glycopeptide with activity against
vancomycin-susceptible and vancomycin-resistant E. faecium.
Synergy between LY and gentamicin against vancomycin-susceptible
E. faecium and VRE was demonstrated by PDM experiments. The
activities of combination regimens containing Gq24h were no different
from the traditional regimens containing Gq8h. Strain variability in
synergy testing was demonstrated by the consistent lack of synergy with
one LY concentration-strain combination. Since our data represent those for only three isolates, all of which demonstrated low-level resistance to gentamicin, studies that include more strains with different susceptibilities to LY and gentamicin are needed. The urgent need for
new treatments for VRE further warrants pharmacodynamic investigations of LY alone and in combination with other antibiotics.
| |
ACKNOWLEDGMENTS |
This study was supported in part by Lilly Canada and Lilly
Research Laboratories, Indianapolis, Ind. S. A. Zelenitsky was supported by an Eli Lilly Canada Postdoctoral Fellowship. J. A. Karlowsky is supported by a PMAC-HRF/MRC Postdoctoral Fellowship. G. G. Zhanel is the holder of a Merck Frosst Chair in
Pharmaceutical Microbiology.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Faculty of
Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
Phone: (204) 474-8414. Fax: (204) 474-7616. E-mail:
zelenits{at}ms.umanitoba.ca.
| |
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Antimicrobial Agents and Chemotherapy, March 1999, p. 592-597, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
