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Antimicrobial Agents and Chemotherapy, January 2001, p. 67-72, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.67-72.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Susceptibilities of Haemophilus influenzae and
Moraxella catarrhalis to ABT-773 Compared to Their
Susceptibilities to 11 Other Agents
Kim L.
Credito,1
Gengrong
Lin,1
Glenn A.
Pankuch,1
Saralee
Bajaksouzian,2
Michael R.
Jacobs,2 and
Peter C.
Appelbaum1,*
Department of Pathology, Hershey Medical
Center, Hershey, Pennsylvania 17033,1 and
Department of Pathology, Case Western Reserve University,
Cleveland, Ohio 441062
Received 21 July 2000/Returned for modification 13 September
2000/Accepted 3 October 2000
 |
ABSTRACT |
The activity of the ketolide ABT-773 against
Haemophilus and Moraxella was compared to those
of 11 other agents. Against 210 Haemophilus influenzae
strains (39.0% 
-lactamase positive), microbroth dilution tests
showed that azithromycin and ABT-773 had the lowest MICs (0.5 to 4.0 and 1.0 to 8.0 µg/ml, respectively), followed by clarithromycin and
roxithromycin (4.0 to >32.0 µg/ml). Of the -lactams, ceftriaxone
had the lowest MICs (
0.004 to 0.016 µg/ml), followed by cefixime
and cefpodoxime (0.008 to 0.125 and 0.125 to 0.25 µg/ml,
respectively), amoxicillin-clavulanate (0.125 to 4.0 µg/ml), and
cefuroxime (0.25 to 8.0 µg/ml). Amoxicillin was only active against
-lactamase-negative strains, and cefprozil had the highest MICs of
all oral cephalosporins tested (0.5 to >32.0 µg/ml). Against 50 Moraxella catarrhalis strains, all of the compounds except
amoxicillin and cefprozil were active. Time-kill studies against 10 H. influenzae strains showed that ABT-773, at two times the
MIC, was bactericidal against 9 of 10 strains, with 99% killing of all
strains at the MIC after 24 h; at 12 h, ABT-773 gave 90%
killing of all strains at two times the MIC. At 3 and 6 h, killing
by ABT-773 was slower, with 99.9% killing of four strains at two times
the MIC after 6 h. Similar results were found for azithromycin,
with slightly slower killing by erythromycin, clarithromycin, and
roxithromycin, especially at earlier times. -Lactams were
bactericidal against 8 to 10 strains at two times the MIC after 24 h, with slower killing at earlier time periods. Most compounds gave
good killing of five M. catarrhalis strains, with
-lactams killing more rapidly than other drugs. ABT-773 and
azithromycin gave the longest postantibiotic effects (PAEs) of the
ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by
clarithromycin, erythromycin, and roxithromycin. -Lactam PAEs were
similar and shorter than those of the ketolide-macrolide-azalide group
for all strains tested.
| |
INTRODUCTION |
Although development of an effective
vaccine against Haemophilus influenzae type b has led to the
disappearance of the organism in many parts of the world, its place has
been taken by untypeable H. influenzae strains. These
organisms (followed by Streptococcus pneumoniae and
Moraxella catarrhalis) are now considered to be the leading
cause of acute exacerbations of chronic bronchitis and an important
cause, together with S. pneumoniae and M. catarrhalis, of acute otitis media, sinusitis, and
community-acquired respiratory tract infections (1, 8, 10, 12,
14, 23).
Current recommendations by the National Committee for Clinical
Laboratory Standards (NCCLS) for use of Haemophilus test
medium (HTM) for Haemophilus susceptibility testing
(13) have been complicated by difficulty in commercial
manufacture of this medium and its short half-life when made in house.
Reliable Haemophilus susceptibility testing with HTM
requires the use of freshly made medium within 3 weeks of manufacture
(11, 22).
ABT-773 is a new ketolide (2; A. M. Nilius, M. Bui, L. Almer, D. Hensey, J. Boor, Z. Ma, Y. S. Ar, and R. Flamm,
Abstr. 9th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. P-177,
1999; Z. Ma, R. F. Clark, and Y. Or, Abstr. 39th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 2133, 1999; Z. Cao, R. Hammond,
S. Pratt, A. Saiki, C. Lerner, and P. Zhong, Abstr. 39th Intersci.
Conf. Antimicrob. Agents Chemother., abstr. 2135, 1999). Previous
preliminary studies have shown that this compound has low MICs against
respiratory pathogens, including Haemophilus and
Moraxella (2; D. Shortridge, N. C. Ramer, J. Boor, Z. Ma, Y. Or, and R. K. Flamm, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2136, 1999). This
study further examined activity of ABT-773 against
Haemophilus and Moraxella by (i) using NCCLS
microdilution MIC methodology to test the activity of ABT-773 compared
to those of erythromycin, azithromycin, clarithromycin, roxithromycin,
amoxicillin, amoxicillin-clavulanate, cefuroxime, cefixime,
cefpodoxime, cefprozil, and ceftriaxone against 210 H. influenzae and 50 M. catarrhalis strains; (ii) testing
the kill kinetics of the above-mentioned compounds against 10 H. influenzae and 5 M. catarrhalis strains; and (iii)
testing the postantibiotic effects (PAEs) of the above-mentioned
compounds against 5 H. influenzae strains.
| |
MATERIALS AND METHODS |
Bacteria and antimicrobials.
Strains (210 H. influenzae and 50 M. catarrhalis) were isolated from
clinical specimens within the past 2 years and stored at 
70°C in
double-strength skim milk (Difco Laboratories, Detroit, Mich.) prior to
use. ABT-773 susceptibility powder was obtained from Abbott
Laboratories, Chicago, Ill. Other drugs were obtained from their
respective manufacturers.
MIC determination.
Microdilution MIC tests were performed by
the NCCLS microdilution method (13). H. influenzae strains were all untypeable organisms. Inocula were
prepared from chocolate agar plates incubated for a full 24 h by
the direct colony suspension method as follows. In a tube of
Mueller-Hinton broth (Difco), an organism suspension was made to a
density of a 0.5 McFarland standard (108 CFU/ml). The
inoculum was diluted in sterile saline such that final organism
suspensions in trays yielded colony counts of 3 × 105
to 8 × 105 CFU/ml (11).
Frozen microdilution trays were obtained from MicroMedia Systems, Inc.
(Cleveland, Ohio). Each tray contained all antimicrobials prepared in
freshly made HTM. The wells were inoculated with 5 × 105 CFU/ml and incubated in ambient air at 35°C for 20 to
24 h. The lowest drug concentration showing no growth was read as
the MIC. Clavulanate was added to amoxicillin at a ratio of 1 to 2. Standard quality control strains, including H. influenzae
ATCC 49766, H. influenzae ATCC 49247, Staphylococcus
aureus ATCC 29213, and Escherichia coli ATCC 25922 were
included with each run.
Time-kill studies.
Glass tubes containing 5 ml of HTM
(freshly made, as described above) with doubling antibiotic
concentrations were inoculated with approximately 5 × 105 CFU (5 × 105 to 5 × 106 CFU) of organism/ml and incubated at 35°C in a
shaking water bath. Antibiotic concentrations were chosen to comprise 3 doubling dilutions above and 3 dilutions below the MIC. Freshly made
batches of HTM were used for all tests. The dilutions required to
obtain the correct inoculum (approximately 5 × 105
CFU/ml) were determined by prior viability studies using each strain
(17-20).
To inoculate each tube of serially diluted antibiotic, 50 µl of
diluted inoculum was delivered by pipette beneath the surface
of the
broth and then vortexed and plated for viability counts
(zero hour).
Only tubes containing an initial inoculum within
the range of 5 × 10
5 to 5 × 10
6 CFU/ml were acceptable
(
17-20).
Viability counts of antibiotic-containing suspensions were performed at
0, 3, 6, 12, and 24 h by plating 10-fold dilutions
of 0.1-ml
aliquots from each tube in sterile HTM onto chocolate
agar plates.
Recovery plates were incubated for up to 48 h. Colony
counts were
performed on plates yielding 30 to 300 colonies (
17-20).
The lower limit of sensitivity of colony counts was 300 CFU/ml.
Time-kills were analyzed by determining the number of strains which
yielded a
log
10 CFU per milliliter of
1,
2, and
3
at 0, 3, 6, 12, and 24 h compared to counts at 0 h.
Antimicrobials
were considered bactericidal at the lowest concentration
that
reduced the original inoculum by
3 log
10 CFU/ml
(99.9%) at each
of the time points and were considered bacteriostatic
if the inoculum
was reduced by 0 to 3 log
10 CFU/ml. With
the sensitivity threshold
and inocula used in these studies, no
problems were encountered
in delineating 99.9% killing, when present.
The problem of bacterial
carryover was addressed as described
previously (
17-20).
Measurement of PAE.
PAE was determined by the viable plate
count method (4) using freshly made HTM (7,
11). The bacterial inoculum was prepared by suspending growth
from an overnight chocolate agar plate in broth. The broth was
incubated at 35°C for 2 to 4 h in a shaking water bath until the
turbidity matched a no. 1 MacFarland standard (approximately 5 × 108 CFU/ml).
For PAE experiments, 5-ml tubes of broth containing the antibiotic
concentrations to be tested at 2 times the MIC (cefprozil),
4 times the
MIC (ABT-773, erythromycin, azithromycin, clarithromycin,
roxithromycin, amoxicillin, and amoxicillin-clavulanate), and
10 times
the MIC (cefuroxime, cefixime, cefpodoxime, and ceftriaxone)
(concentrations are based upon pharmacokinetics) were inoculated
with
50 µl of inoculum to provide 5 × 10
6 CFU/ml. The
tubes were then vortexed and plated for viability
counts. Growth
controls with inoculum but no antibiotic were included
with each
experiment. The inoculated test tubes were then placed
in a shaking
water bath at 35°C for an exposure period of 1 h.
At the end of
the exposure period, the cultures were diluted 1:1,000
in prewarmed
broth to remove the antibiotic. An additional control
culture
containing bacteria and antibiotic at a concentration
of 0.01 times the
MIC was prepared to confirm that after dilution
the antibiotic was no
longer bacteriostatic (
4,
7).
Viability counts were determined before exposure and immediately after
dilution (zero hour) and then every 2 h until the turbidity
of the
tube reached a no. 1 MacFarland standard. Viability counts
were
performed by preparing 10-fold dilutions of 0.1-ml aliquots
from each
tube in HTM and plating 0.1-ml volumes onto chocolate
agar plates.
Recovery plates were inoculated for at least 72 h,
and colony
counts were performed on plates yielding 30 to 300
colonies.
The PAE was defined according to Craig and Gudmundsson (
4)
as PAE =
T C, where
T is the time
required for viability counts
of an antibiotic-exposed culture to
increase by 1 log
10 unit above
the counts observed
immediately after dilution and
C is the corresponding
time
for the growth
control.
For each experiment, viability counts, expressed as log
10
CFU per milliliter, were plotted against time. The results were
expressed as the mean of two separate
assays.
| |
RESULTS |
The results of MIC testing of H. influenzae are
presented in Table 1. Against 210 H. influenzae strains (39.0% -lactamase positive),
microbroth dilution tests showed that azithromycin and ABT-773 had the
lowest MICs (0.5 to 4.0 and 1.0 to 8.0 µg/ml, respectively), followed
by clarithromycin and roxithromycin (4.0 to >32.0 µg/ml). Of the
-lactams, ceftriaxone had the lowest MICs (0.004 to 0.016 µg/ml), followed by cefixime and cefpodoxime (0.008 to 0.125 and
0.125 to 0.25 µg/ml, respectively), amoxicillin-clavulanate (0.125 to 4.0 µg/ml) and cefuroxime (0.25 to 8.0 µg/ml). Amoxicillin was
only active against -lactamase-negative strains, and cefprozil had
the highest MICs of all oral cephalosporins tested (0.5 to >32.0
µg/ml). Against 50 M. catarrhalis strains, all compounds except amoxicillin and cefprozil were active (Table 1).
The MICs of the 15 strains tested by time-kill were similar to those
listed in Table 1. Kill kinetics results of the 10 H. influenzae strains are shown in Table
2, and those of the 5 M. catarrhalis strains are shown in Table
3. Two H. influenzae and all
five M. catarrhalis strains were -lactamase positive and were not tested by time-kill with amoxicillin. As can be seen, ABT-773,
at two times the MIC, was bactericidal (99.9% killing) against 9 of 10 strains, with 99% killing of all strains at the MIC after 24 h;
at 12 h, ABT-773 gave 90% killing of all strains at two times the
MIC. At 3 and 6 h, killing by ABT-773 was slower, with 99.9%
killing of four strains at two times the MIC after 6 h. Similar
results were found for azithromycin, with slightly slower killing by
erythromycin, clarithromycin, and roxithromycin, especially at earlier
time periods. -Lactams were bactericidal against 8 to 10 strains at
two times the MIC after 24 h, with slower killing at earlier time
periods.
Time-kill studies for the five M. catarrhalis strains (Table
3) showed that all compounds except cefprozil and ceftriaxone were
bactericidal at or above the MIC after 24 h, with other
-lactams showing more rapid killing at earlier time periods.
PAEs are presented in Table 4. As can be
seen, ABT-773 and azithromycin gave the longest PAEs of the
ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by
clarithromycin, erythromycin, and roxithromycin. -Lactam PAEs were
all similar and shorter than those of the ketolide-macrolide-azalide
group for all strains tested.
| |
DISCUSSION |
ABT-773 is a new ketolide (Ma et al., Abstr. 39th Intersci. Conf.
Antimicrob. Agents Chemother., 1999; Cao et al., Abstr. 39th Intersci.
Conf. Antimicrob. Agents Chemother., 1999) which, in preliminary
studies, has been reported to be more potent in vitro than the
macrolides against H. influenzae, M. catarrhalis, Legionella spp., Neisseria gonorrhoeae, and
Listeria monocytogenes. ABT-773 was also more potent
against macrolide-susceptible strains of S. pneumoniae,
Streptococcus pyogenes, S. aureus,
Staphylococcus epidermidis, enterococci, Helicobacter
pylori, and Mycobacterium avium complex and also
against Corynebacterium spp., Mycoplasma pneumoniae, Chlamydia trachomatis, Borrelia
burgdorferi, and Toxoplasma gondii. ABT-773 had potent
activity against macrolide-resistant streptococci and enterococci
irrespective of their macrolide resistance mechanisms but had little
detectable activity against constitutively macrolide-resistant
staphylococci and macrolide-resistant H. pylori and M. avium complex (2; Shortridge et al.,
Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother.,
1999; M. M. Neuhauser, J. L. Prause, R. Jung, N. Boyea,
J. M. Hackleman, L. H. Danziger, and S. L. Pendland, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr 2139, 1999; F. Goldstein, M. D. Kitzis, M. Miegi, and
J. F. Acar, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2142, 1999; A. L. Barry, P. C. Fuchs, and
S. D. Brown, Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 2144, 1999; S. L. Pendland, J. L. Prause,
M. M. Neuhauser, N. Boyea, J. M. Hackleman, and L. H. Danziger, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. 2145, 1999; R. Jung, D. H. Li, S. L. Pendland, and
L. H. Danziger, Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 2146, 1999; A. A. Khan, F. G. Araujo,
J. C. Craft, and J. S. Remington, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2147, 1999). ABT-773 has been shown to be effective against S. pneumoniae in a rat lung model (J. Meulbroek, M. Mitten, K. W. Mollison, P. Ewing, J. Alder, A. M. Nilius, R. K. Flamm,
Z. Ma, and Y. Or, Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 2151, 1999).
In our study, the MICs of ABT-773 against H. influenzae and
M. catarrhalis were similar to those recently reported by
others (2; J. Dubois, Abstr. 40th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 2163, 2000; T. Fujikawa, S. Miyazaki, T. Matsumoto, A. Ohno, N. Furuya, Y. Ishii, K. Tateda, and K. Yamaguchi, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. 2166, 2000), with MICs at which 90% of the strains are
inhibited (MIC90s) of 4.0 µg/ml against H. influenzae and 0.06 to 0.25 µg/ml for M. catarrhalis.
A recent study (V. Shortridge, N. Ramer, D. McDaniel, P. Johnson,
and R. K. Flamm, Abstr. 40th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 2137, 2000) has documented that, similar to our
findings, ABT-773 was bactericidal against H. influenzae at
four and eight times the MIC, with more rapid killing than erythromycin. ABT-773 was also found to have a longer PAE than erythromycin.
Previous studies have shown, similar to the findings reported here,
that azithromycin was the most potent member of the
macrolide-azalide-ketolide group by MIC and time-kill against H. influenzae strains, followed by the ketolides telithromycin,
clarithromycin, and roxithromycin (9, 15-17, 21). In the
present study, ABT-773 had kill kinetics against H. influenzae and M. catarrhalis comparable to that of azithromycin, the macrolide with the greatest overall in vitro activity
against this group (9, 17), and also had the longest PAE
of all compounds tested.
The clinical application of macrolide MICs against H. influenzae is a complex problem. Macrolides, azalides, and
ketolides all exhibit a unimodal MIC distribution against this species, and macrolide resistance mechanisms similar to ribosomal methylase and
efflux in gram-positive species have not been clearly defined. Also,
there is a question concerning the validity of established breakpoints
for macrolides and azalides against H. influenzae. Craig
(3) has suggested that breakpoints for azithromycin and clarithromycin against Haemophilus are considerably lower
than currently approved values in light of pharmacokinetic and
pharmacodynamic parameters (11) and bacteriological
outcome studies in otitis media (5, 6). Andes and Craig
(Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr.
2139, 2000) have demonstrated that ABT-773, like azithromycin and
telithromycin, exhibits pharmacodynamic properties which correlate best
with the area under the concentration-time curve/MIC ratio for S. aureus and S. pneumoniae. More detailed data on the
free area under the concentration-time curve and MIC, as well as
clinical studies, will be necessary to test the clinical validity of
the above in vitro data. Long PAEs support once-daily dosing with
ABT-773, similar to macrolides and azalides.
A tentative ABT-773 susceptibility breakpoint of 4.0 µg/ml against
H. influenzae has been proposed (G. Stone, A. Nilius, D. Hensey-Rudloff, L. Almer, J. Beyer, and R. Flamm, abstr. 40th Intersci.
Conf. Antimicrob. Agents Chemother., abstr. 2164, 2000). Other factors,
such as the increased concentration of compounds like clarithromycin in
epithelial lining fluid (11) and the known
anti-inflammatory effect of this group of agents may also play a role.
Whether this phenomenon plays a role with ABT-773 remains to be
established. Because of their low MICs, good kill kinetics, and long
PAEs, azithromycin and ABT-773 appear to be the most potent agents of
this group against H. influenzae on the basis of in vitro results.
| |
ACKNOWLEDGMENT |
This study was supported by a grant from Abbott Laboratories,
Chicago, Ill.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail:
pappelbaum{at}psu.edu.
| |
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Antimicrobial Agents and Chemotherapy, January 2001, p. 67-72, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.67-72.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
