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Antimicrobial Agents and Chemotherapy, July 2001, p. 2163-2168, Vol. 45, No. 7
Infectious Diseases Research, Abbott
Laboratories, Abbott Park, Illinois 60064-3537
Received 5 September 2000/Returned for modification 13 February
2001/Accepted 30 March 2001
The in vitro activities of ABT-773, erythromycin, clarithromycin,
and azithromycin were compared. ABT-773 was the most active compound
against macrolide-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Enterococcus
spp. and multidrug-resistant Streptococcus pneumoniae. It
also had good activity against gram-negative and atypical respiratory
tract pathogens and Helicobacter pylori.
Macrolide antibiotics are used for
treating community-acquired respiratory tract infections
(1). Ketolides, erythromycin analogs in which a ketone
functionality replaces the three-position cladinose, demonstrate in
vitro antibacterial activity and in vivo efficacy in animal models of
infection (3, 11). In addition, many ketolides retain
potency against macrolide-resistant strains of streptococci (2,
3, 11) due to dimethylation of the 23S rRNA by Erm methylases or
by macrolide-specific efflux pumps (3, 14, 15).
In addition to the ketone group at position 3, the novel ketolide
ABT-773 is modified by an O-allyl-3-quinoline at the 6 position and a cyclized carbamate group between the 11 and 12 positions (11). This study evaluated the potency and spectrum of
ABT-773. The MIC ranges and MICs inhibiting 50 (MIC50) and
90% (MIC90) of the tested strains are presented in Tables
1 and
2.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.7.2163-2168.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Comparative In Vitro Activity of ABT-773, a Novel
Antibacterial Ketolide
and
ABSTRACT
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TABLE 1.
Comparative in vitro activity of ABT-773 by agar dilution
methods
TABLE 2.
Comparative in vitro activity of ABT-773 by broth
dilution techniquesa
ABT-773, azithromycin, and clarithromycin were prepared at Abbott Laboratories, Abbott Park, Ill. Erythromycin, clindamycin, and penicillin reference powders were purchased from U.S. Pharmacopeial Convention, Inc., Rockville, Md.
Clinical isolates or reference strains obtained from the American Type Culture Collection (Manassas, Va.) were tested. The molecular mechanisms of macrolide resistance were identified by PCR amplification of the mef and erm genes (14, 15) and in Helicobacter pylori and Mycobacterium avium by DNA sequence analysis for mutations in 23S rRNA (8, 16).
MICs were determined by agar dilution or broth microdilution as described by the National Committee for Clinical Laboratory Standards (NCCLS) (9). Mueller-Hinton agar was supplemented with 5% sheep blood for testing Streptococcus pyogenes, Listeria monocytogenes, and Moraxella catarrhalis; the plates were incubated in an atmosphere containing 5% CO2 for tests of S. pyogenes and M. catarrhalis. Quality control results met NCCLS standards (9, 10). The susceptibilities of Legionella spp., M. avium, Mycoplasma pneumoniae, Borrelia burgdorferi, and Chlamydia trachomatis were determined as described previously (5, 6, 7, 13, 18).
ABT-773 was at least fourfold more potent than the three comparator
macrolides against macrolide-susceptible strains of gram-positive species, including Streptococcus pneumoniae, S. pyogenes,
Staphylococcus aureus, Staphylococcus epidermidis, L. monocytogenes, and Enterococcus spp; the strains were
inhibited by <0.06 µg of ABT-773/ml. ABT-773 was as potent as
azithromycin against the gram-negative pathogens Haemophilus
influenzae, M. catarrhalis, Legionella spp., and
Neisseria gonorrhoeae with MIC90s of
4, 0.12, 1, and 0.25 µg/ml, respectively. ABT-773 had little to no
activity against Escherichia coli, other enterobacteriaceae,
and Pseudomonas aeruginosa (MICs, 
8 µg/ml) [data not
shown]. ABT-773 was highly active against M. pneumoniae, demonstrating MICs of <0.015 µg/ml. The MIC for ABT-773 against a
single strain of C. trachomatis was 0.015 µg/ml, similar
to the activity against Chlamydia pneumoniae
(17).
The MIC90s for ABT-773 were 0.25 and 0.03 µg/ml for inducible ErmA and susceptible strains of S. aureus and S. pyogenes. In contrast, macrolide MICs were more than 100-fold higher against inducible ErmA strains than against susceptible strains. Moreover, ABT-773 did not induce resistance to clindamycin in these strains by the disk approximation test; erythromycin induced resistance to both ABT-773 and clindamycin (data not shown; 12). These results suggest that ABT-773 does not induce 23S rRNA methylation in inducible ErmA strains.
Although the macrolides and clindamycin were inactive against
constitutive ErmB strains of S. pneumoniae and S. pyogenes, the ABT-773 MIC90 for ErmB strains of
S. pneumoniae was 0.25 µg/ml, and all ErmB strains of
S. pyogenes were inhibited by 
8 µg/ml. The difference in
activity of ABT-773 was likely due to the use of agar dilution with
incubation in CO2 to test S. pyogenes and broth
microdilution to test S. pneumoniae and not to inherent species-dependent differences in susceptibility to ABT-773, since other
studies show that the MIC90s for ErmB strains of S. pneumoniae and S. pyogenes are similar when the
susceptibilities of both species are determined by broth microdilution
(V. D. Shortridge, unpublished data). The potent activity of
ABT-773 against constitutive ErmB streptococci may be due to its
affinity for methylated ribosomes, and ABT-773 may not effectively
induce higher levels of ribosome methylation in ErmB strains
(4). This may also explain the activity of ABT-773 against
other constitutive macrolide-lincosamide-streprogramin B
(MLSB) resistant species, such as
Corynebacterium spp. However, ABT little to no vitro
activity against constitutive MLSB-resistant staphylococci
and enterococci. The reason for different susceptibilities in various
species with constitutive MLSB resistance is unknown.
The MIC90s for MefA strains of S. pneumoniae and S. pyogenes were 0.06 and 0.25 µg/ml, respectively. ABT-773 accumulates rapidly in cells of S. pneumoniae containing the Mef efflux pump because the high affinity of ABT-773 for ribosomes may overcome export (4) or ABT-773 may have poor affinity for the pump.
Penicillin susceptibility had no effect on susceptibility to ABT-773
for pneumococci. For macrolide-susceptible strains, the ABT-773
MIC90 was 0.002 µg/ml for 16 penicillin-susceptible
strains and 0.002 µg/ml for 14 penicillin-nonsusceptible strains.
The ABT-773 MIC90s were 0.06, 0.06, and 0.12 µg/ml for 27 penicillin-susceptible, 19 penicillin-intermediate, and 37 penicillin-resistant strains, respectively. Each group comprised
macrolide-susceptible, MefA, and ErmB isolates. The MIC90s
of ABT-773 in a study of 1,601 pneumococci are similar: 0.008, 0.03, and 0.12 µg/ml for penicillin-susceptible, -intermediate, and
-resistant strains, respectively (2).
ABT-773 was fourfold less active than clarithromycin against macrolide-susceptible strains of H. pylori and M. avium, with MIC90s of 0.06 and 64 µg/ml, respectively. Point mutations in the 23S rRNA at residues A2058 and A2059 (E. coli numbering) reduce macrolide binding to ribosomes and result in resistance in H. pylori and M. avium (8, 16). ABT-773 was significantly less active against H. pylori strains having A2058G or A2059G mutations and against M. avium strains having mutations at A2058 than against the corresponding susceptible strains. These results confirmed the importance of A2058 and A2059 for ABT-773 binding to ribosomes (4).
Minimum bacterial concentrations (MBCs) were determined in conjunction
with broth microdilution MICs for four strains (5, 9).
ABT-773 is 87 to 96% bound to human plasma proteins. The MICs and MBCs
were also done in medium containing 50% (vol/vol) human serum
(Scantibodies Laboratory, Inc., Santee, Calif.) which had been heated
for 1 h at 56°C (Table 3). ABT-773
was bactericidal for single strains of H. influenzae, S. pneumoniae, and M. catarrhalis in medium alone or in
medium containing 50% human serum, since the MBCs were no more than
twofold higher than the corresponding MICs. In contrast, ABT-773 was
bacteriostatic for a strain of S. aureus.
|
MBC results were confirmed by time-kill analysis using ABT-773 at four
times the MIC (Fig. 1) (5).
For H. influenzae, S. pneumoniae, and M. catarrhalis in medium alone or in medium containing 50% human
serum, the number of viable cells remaining after 24 h of
incubation with ABT-773 was reduced by at least 99.9% from the number
of viable cells present in the initial inocula. For S. aureus, ABT-773 caused less than a 10-fold loss of viable cells after 24 h of incubation.
|
, drug-free control in medium;
, ABT-773 at four times the MIC in medium; 
, drug-free control in
medium containing 50% human serum, 
, ABT-773 at four times the MIC
in medium containing 50% human serum.
The overall antibacterial activity of ABT-773 was more potent and included a broader spectrum of key respiratory tract pathogens, including multidrug-resistant, atypical, and intracellular pathogens, than those of clarithromycin, azithromycin, and erythromycin. In addition, ABT-773 had comparable or improved activity against non-respiratory-tract pathogens. The improved potency is due to the greater affinity of ABT-773 to macrolide-susceptible ribosomes, resulting in rapid accumulation in bacterial cells and slower dissociation from the ribosome (4). ABT-773 retained potent antibacterial activity against macrolide-resistant pneumococcal isolates. The MIC90 for the 53 macrolide-resistant pneumococci tested was 0.12 µg/ml, and this activity derives from affinity for methylated streptococcal ribosomes, no or poor induction of ErmB, and the ability to overcome Mef efflux (4).
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FOOTNOTES |
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* Corresponding author. Mailing address: D47T, AP52, Abbott Laboratories, Abbott Park, IL 60064-3537. Phone: (847) 937-7706. Fax: (847) 935-0400. E-mail: angela.nilius{at}abbott.com.
Present address: Enanta Pharmaceuticals, Cambridge, MA 02139.
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Antimicrobial Agents and Chemotherapy, July 2001, p. 2163-2168, Vol. 45, No. 7
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.7.2163-2168.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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