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Antimicrobial Agents and Chemotherapy, January 2005, p. 309-315, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.309-315.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of Novel 2-Fluoro-Naphthyridine-Containing Ketolides

Darren Abbanat,^1* Glenda Webb,¹ Barbara Foleno,¹ Y. Li,² Mark Macielag,¹ Deborah Montenegro,¹ Ellyn Wira,¹ and Karen Bush¹

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey,¹ Kosan Biosciences, Hayward, California²

Received 5 May 2004/ Returned for modification 1 June 2004/ Accepted 20 September 2004

Top Abstract Introduction Materials and Methods Results Discussion References

 
In vitro activities of erythromycin A, telithromycin, and two investigational ketolides, JNJ-17155437 and JNJ-17155528, were evaluated against clinical bacterial strains, including selected common respiratory tract pathogens. Against 46 macrolide-susceptible and -resistant Streptococcus pneumoniae strains, the MIC₉₀ (MIC at which 90% of the isolates tested were inhibited) of the investigational ketolides was 0.25 µg/ml, twofold lower than that of telithromycin and at least 64-fold lower than that of erythromycin A. Against erm(B)-containing pneumococci, the MIC₉₀ of all the ketolides was 0.06 µg/ml. The MIC₉₀ of the investigational ketolides against mef(A)-containing pneumococci or pneumococci with both mef(A) and erm(B) was 0.25 µg/ml, two-and fourfold lower, respectively, than that of telithromycin. In contrast, the MICs of the investigational ketolides against macrolide-resistant S. pneumoniae strains with ribosomal mutations were similar to or, in some cases, as much as eightfold higher than those of telithromycin. Against Haemophilus influenzae, MICs of all the ketolides were 2 µg/ml. Against three Moraxella catarrhalis isolates, the MIC of the ketolides was 0.25 µg/ml. The ketolides inhibited in vitro protein synthesis, with 50% inhibitory concentrations ranging from 0.23 to 0.27 µM. In time-kill studies against macrolide-susceptible and erm- or mef-containing pneumococci, the ketolides were bacteriostatic to slowly bactericidal, with 24-h log₁₀ decreases ranging from 2.0 to 4.1 CFU. Intervals of postantibiotic effects for the ketolides against macrolide-susceptible and -resistant S. pneumoniae were 3.0 to 8.1 h.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Respiratory tract infections, including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), acute bacterial sinusitis (ABS), and pharyngitis, are a frequent cause of illness and, for CAP, a substantial cause of mortality (3, 22). Streptococcus pneumoniae and Haemophilus influenzae are responsible for a majority of the cases of CAP, AECB, and ABS, while Streptococcus pyogenes is the primary causal agent for pharyngitis (5, 23). Macrolides efficacious against S. pneumoniae and H. influenzae are first-line agents for the treatment of CAP (10, 16, 28) and are second-line agents for the treatment of AECB (1). With ABS (2, 26) and pharyngitis (5, 25), macrolides are an important treatment option where intolerance to penicillins is a concern.

Macrolide resistance in pneumococci has been increasing since the early 1980s, with worldwide resistance levels of clinical isolates currently at approximately 25% in some studies (19, 34). In the United States, macrolide nonsusceptibility varies by region from 17 to 36% (34), while nonsusceptibility outside the United States ranges from 1.5% in the Czech Republic to 80% in Hong Kong (19). Clinical macrolide resistance results primarily from the expression of the erm(B) dimethylase or the mef(A) efflux gene. The proportion of macrolide-resistant strains expressing the erm or mef phenotypes differs by region and by country. In the United States, resistance results from mef(A) in approximately 64% of resistant isolates, from erm(B) in approximately 23% of cases, and a combination of erm(B) and mef(A) in 12% of resistant isolates (14). Outside the United States, the distribution of resistance varies from 0% mef(A) and 100% erm(B) in Belgium to 83% mef(A) and 17% erm(B) in Argentina. Worldwide, erm(B) is the predominant mechanism of resistance, accounting for 56% of macrolide-resistant strains, while mef(A) accounts for 35%; strains with both mechanisms comprise most of the remainder (14). Other clinically relevant but less frequent mechanisms of macrolide resistance include mutations in the L4 and L22 ribosomal proteins and mutations in domain V of the 23S rRNA (approximately 2% of macrolide-resistant pneumococci) (11, 14, 30). With the proportion of penicillin-nonsusceptible pneumococci concomitantly reaching 37% in the United States and ranging from 4% (The Netherlands) to 74% (Hong Kong) outside the United States (19), the need for new agents to treat respiratory tract infections is increasingly important.

Recent efforts to identify new agents with activity against macrolide-resistant respiratory tract pathogens resulted in the development of the ketolide telithromycin (32), a member of a new class of antibiotics structurally related to macrolides. Telithromycin, with demonstrated clinical efficacy against H. influenzae, macrolide-susceptible and -resistant strains of S. pneumoniae, and S. pyogenes (8, 23, 36), is being used for the treatment of CAP, AECB, ABS, and tonsillitis/pharyngitis.

To date, most attempts to produce new ketolides have utilized traditional macrolide cores such as erythromycin A as starting material in synthetic schemes. In contrast, in the studies outlined in this report, novel ketolides were synthesized from unique macrolides produced biosynthetically from genetically altered actinomycete strains (9, 20); these unnatural macrolide core molecules were produced as part of a program to yield novel ketolides with potent in vitro and in vivo activities. This is the first publication describing the in vitro antibacterial activities of ketolides derived from bioengineered macrolide core molecules. Herein, the in vitro activities of two naphthyridine-containing ketolides derived from 15-methylerythromycin A are described.

(Portions of the data were previously presented [D. Abbanat, G. Webb, G. Ashley, B. Foleno, H. Fu, Y. Li, P. Licari, M. Macielag, D. Montenegro, E. Wira, and K. Bush, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1663, 2002].)

Top Abstract Introduction Materials and Methods Results Discussion References

 
Antibiotics and microorganisms. JNJ-17155437 (JNJ 1) and JNJ-17155528 (JNJ 2) were synthesized by Kosan Biosciences. Telithromycin was purchased from Aventis, and ampicillin and erythromycin A were obtained from Sigma. Except where indicated, bacterial strains used in these studies were clinical isolates.

Bacterial susceptibility testing. MICs of reference and test compounds were determined in Mueller-Hinton broth (BBL) by the broth microdilution method according to NCCLS guidelines (27). The panel of representative clinical isolates described herein was shown to be predictive for activity against expanded panels of macrolide-susceptible and -resistant gram-positive clinical strains, when tested using telithromycin and other selected ketolides.

Time-kill studies. Experiments were performed with the following S. pneumoniae strains: macrolide-susceptible ATCC 6301 and OC4409, macrolide-resistant [erm(B)] OC4444 and OC4430, and macrolide-resistant [mef(A)] OC4568 and OC4427. Early-log-phase broth cultures stored overnight (4°C) were used to inoculate cation-adjusted Mueller-Hinton broth (CAMHB; BBL) supplemented with 5% lysed horse blood (HB), with or without telithromycin, JNJ 1, or JNJ 2, at 4x the MIC. Cultures were incubated (35°C), and CFU were determined at indicated time points by plating on Trypticase soy agar supplemented with 5% sheep blood (Northeast Laboratories). Values for each graph were averaged from at least three determinations.

Postantibiotic effect (PAE) determinations. Studies were performed according to methods described by Loewdin et al. (21). Briefly, colonies of the indicated S. pneumoniae strains were resuspended in CAMHB with HB to 0.5 McFarland standard and cultured in the absence or presence of antibiotic (4x the MIC) for 2 h. Cells were washed twice through centrifugation with an equal volume of medium, resuspended, and diluted 10-fold in CAMHB with 2% HB (one to three serial dilutions). Dilutions were plated for CFU determinations on Trypticase soy agar with 5% sheep blood and incubated in triplicate in 100-well Bioscreen plates (200 µl per well), in a Thermo Labsystems Bioscreen C microbiology workstation at 35°C. The absorbance of each well in a Bioscreen plate was measured every 10 min at 600 nm; plates were briefly shaken immediately prior to this measurement. A standard curve for each strain without antibiotic was created relating the times required to achieve maximum growth for each starting cell density. The PAE for each strain-antibiotic combination was calculated by taking the difference between the actual time required to achieve 50% of the maximum optical density and the time predicted for that starting cell concentration in the absence of drug.

Synthesis of JNJ 1 and JNJ 2. Biosynthesis of 15-methylerythromycin A (the substrate used in the synthesis of the naphthyridine-containing ketolides) was performed using sequential fermentations with genetically modified Streptomyces coelicolor and Saccharopolyspora erythraea strains (9, 20). Purified 15-methylerythromycin A was used as the starting material for the synthesis of the ketolides JNJ 1 and JNJ 2 (Fig. 1). (Synthesis was detailed in the work of Macielag et al. [M. Macielag, D. Abbanat, G. Ashley, B. Foleno, H. Fu, Y. Li, E. Wira, and K. Bush, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-1662, 2002].)

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FIG. 1. Macrolide and ketolide structures.

Transcription-translation assay. Inhibition of protein synthesis was evaluated in an in vitro-coupled transcription-translation assay containing an Escherichia coli S30 extract system optimized for circular DNA (Promega, Madison, Wis.), with a plasmid encoding ß-galactosidase as the DNA template (33). In vitro synthesis of ß-galactosidase was monitored spectrophotometrically by using o-nitrophenyl-ß-D-galactopyranoside (ONPG). The concentration of compound resulting in 50% inhibition of ß-galactosidase synthesis (IC₅₀) was determined graphically.

Top Abstract Introduction Materials and Methods Results Discussion References

 
MIC determinations. In vitro MICs of JNJ 1 and JNJ 2 were compared to those of erythromycin A and telithromycin against a panel of gram-positive and gram-negative clinical isolates, including key respiratory tract pathogens (Table 1). As expected, erythromycin A was poorly active against macrolide-resistant pneumococci with erm(B), mef(A), or mutations in 23S rRNA or L4 genes. Against S. pneumoniae (including macrolide-susceptible and -resistant strains), the investigational ketolides demonstrated antimicrobial activities similar to those of telithromycin. The MIC₉₀s (MICs at which 90% of the isolates tested were inhibited) of JNJ 1 and JNJ 2 against erm(B)-containing pneumococci were equivalent to that of telithromycin, while MIC₉₀s of the investigational ketolides against mef(A)-containing strains were twofold lower than that of telithromycin. Against strains containing both erm(B) and mef(A) genes, the MIC₉₀ of JNJ 1 and JNJ 2 was fourfold lower than that of telithromycin. In contrast, the JNJ ketolides were somewhat less active than telithromycin against strains carrying mutations in the 23S rRNA gene, with a MIC₉₀ twofold higher than that of telithromycin; notably, against one isolate, JNJ 1 and JNJ 2 had a MIC of 4 µg/ml while telithromycin had a MIC of 0.5 µg/ml. MICs of telithromycin against S. pneumoniae strains with L4 and L22 mutations were about fourfold lower than those of JNJ 1 and JNJ 2. Against the gram-negative respiratory tract pathogens H. influenzae and Moraxella catarrhalis, the MICs of the investigational ketolides and telithromycin were equivalent.

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TABLE 1. Antibacterial activities of erythromycin A, telithromycin, JNJ 1, and JNJ 2

Against methicillin-susceptible and -resistant staphylococci, including isolates with inducibly regulated expression of the erm methylase and isolates containing the msr efflux gene, MICs of JNJ 1, JNJ 2, and telithromycin were 0.5 µg/ml (Table 1). Erythromycin A and the ketolides tested at concentrations as high as 16 µg/ml did not inhibit growth of staphylococci expressing the erm gene constitutively. All three ketolides were active against non-erm(B)-producing enterococci (Enterococcus faecium and Enterococcus faecalis isolates) including vancomycin-resistant strains, with ketolide MICs of 0.25 µg/ml. Enterococci expressing the erm methylase were resistant to the ketolides.

MICs of the ketolides were 8 µg/ml when tested against two E. coli strains. Relatively low MICs were noted against a lipopolysaccharide (LPS)-deficient E. coli laboratory strain, possibly due to changes in envelope permeability or efflux in this strain.

Inhibition of protein synthesis. JNJ 1, JNJ 2, and telithromycin affected ribosomal activity similarly, inhibiting protein synthesis with IC₅₀s of approximately 0.25 µM (Table 2). Notably, the ketolide IC₅₀s were similar to MICs identified for most of the staphylococci, enterococci, and the LPS-deficient E. coli strain and were two- to threefold lower than that of erythromycin A. As expected, ampicillin, an inhibitor of cell wall biosynthesis, was inactive in this assay.

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TABLE 2. Inhibition of protein synthesis by erythromycin A, telithromycin, JNJ 1, JNJ 2, and ampicillin

Time-kill studies. Against the erm- or mef-containing pneumococci, viable cell counts with telithromycin-, JNJ 1-, and JNJ 2-treated broth cultures decreased by at least 3 log₁₀ CFU over 24 h, indicating that, against these isolates, the ketolides were bactericidal over this time period (Table 3). Against the macrolide-susceptible S. pneumoniae strain ATCC 6301, the ketolides were bacteriostatic, with bacterial cell counts decreasing by 2.0 to 2.3 log₁₀ CFU over 24 h. Against the macrolide-susceptible strain OC4409, telithromycin and JNJ 1 were bacteriostatic over 24 h, while JNJ 2, with a log₁₀ decrease in CFU of 3.1, was technically bactericidal. Following shorter antibiotic exposure times of 4 or 8 h, the ketolides were bacteriostatic against all strains, with log₁₀ decreases ranging from 0.3 to 2.9 CFU.

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TABLE 3. Decrease in bacterial counts of macrolide-susceptible and -resistant pneumococci after treatment with telithromycin, JNJ 1, or JNJ 2

PAE studies. As previously noted for telithromycin (6, 18), prolonged PAE intervals were observed for the investigational ketolides. PAEs for telithromycin, JNJ 1, and JNJ 2 were similar against the macrolide-susceptible and -resistant pneumococci (Table 4), ranging from 3 to 4 h for the strain OC4409 (macrolide susceptible), to 5 to 6 h for strains OC4430 (erm) and OC4427 (mef), to 6 to 8 h for strains ATCC 6301 (macrolide susceptible), OC4444 (erm), and OC4568 (mef).

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TABLE 4. PAE of telithromycin, JNJ 1, and JNJ 2 on S. pneumoniae isolates

Top Abstract Introduction Materials and Methods Results Discussion References

 
With the recent introduction of telithromycin into clinical practice, advances in macrolide chemistry have provided an important new class of agents for the treatment of macrolide-resistant respiratory tract infections. Yet, telithromycin and other competitive ketolides synthesized to date have been conceived through traditional medicinal chemistry approaches. A new approach, described herein, utilizes genetic engineering to produce a biologically modified macrolide core. When combined with synthetic chemistry, this strategy has produced novel ketolides with activity against macrolide-susceptible and -resistant respiratory tract pathogens. It is anticipated that these modifications to the macrolide core, hitherto inaccessible through traditional chemistry routes, may contribute unique biological properties to resulting ketolides. JNJ 1 and JNJ 2 are the first published examples of ketolides produced in this program. JNJ 1 and JNJ 2 were selected for further study from a series of related structures based on their potent in vitro activities. Among members of the 15-methyl-6-heteroarylalkenyl ketolide series, JNJ 1 and JNJ 2 displayed the most potent and consistent activity against susceptible and resistant strains of S. pneumoniae and H. influenzae. In particular, fluorination at C-2 improved activity against erythromycin-resistant pneumococci, while incorporation of the 1,5- and 1,8-naphthyridine side chains conferred improved activity against S. pneumoniae with erm(B) compared to ketolides with other heterocycles (Macielag et al., 42nd ICAAC).

In vitro MICs of JNJ 1 and JNJ 2 were similar to those of telithromycin against clinical strains of the key respiratory pathogens S. pneumoniae, H. influenzae, and M. catarrhalis, with values ranging from 0.008 to 4 µg/ml. Except for one strain with a 23S rRNA mutation, antipneumococcal activity of JNJ 1 and JNJ 2 was maintained regardless of the mechanism of resistance (erm, mef, or ribosomal mutations), a characteristic important for the empirical treatment of community-acquired lower respiratory tract infections. In contrast, with staphylococci, the MIC of JNJ 1 or JNJ 2 was 0.25 µg/ml with strains containing inducibly expressed methylase but increased at least 64-fold with constitutive erm(C)-containing isolates. Furthermore, reports indicate that mutants with constitutively regulated erm(A) can be readily selected from an S. aureus strain with inducible erm(A) regulation through exposure to inhibitory concentrations of telithromycin or cethromycin (31). Thus, the in vitro spectrum of activity of JNJ 1 and JNJ 2 is similar to that reported for other ketolides such as telithromycin and cethromycin, which have demonstrated efficacy for the treatment of respiratory tract infections but show inconsistent activity against erm-containing staphylococci that precludes their empirical use for staphylococcal infections.

Although the MICs of JNJ 1 and JNJ 2 were equivalent to those of telithromycin against the erm-containing pneumococci, MICs of the investigational ketolides against mef- or mef-erm-containing pneumococci were frequently two- to fourfold lower than that of telithromycin. With the majority of pneumococcal macrolide resistance in the United States resulting from mef efflux (14), this improved activity against mef-containing strains ultimately may help distinguish compounds such as these clinically from telithromycin. With one exception, against macrolide-resistant S. pneumoniae strains with ribosomal mutations, MICs of the JNJ ketolides were 0.5 µg/ml; interestingly, against these strains, JNJ 1 and JNJ 2 were often two- to fourfold less active than telithromycin, suggesting that ribosomal mutations may selectively affect the binding affinity of the JNJ ketolides.

Comparisons of the three ketolides in an in vitro protein synthesis assay demonstrated that the IC₅₀s of all the ketolides were similar and approximately threefold lower than that of erythromycin A. These results are consistent with reports indicating that telithromycin and cethromycin bind to the ribosome with greater affinity than erythromycin A does (12, 15), possibly reflecting the additional binding site of ketolides in domain II of the ribosome (4, 13, 17, 35). Together with the structural similarities shared among cethromycin and JNJ 1 and JNJ 2, these results suggest that the investigational ketolides may also have increased ribosomal affinity.

The characterization of antibiotics with respect to their bacteriostatic or bactericidal activity may be important for dosing, for interpretation of pharmacodynamic parameters, and ultimately for clinical utility. Macrolides and ketolides may be classified as bacteriostatic agents, with slow bactericidal activity observed at higher concentrations against selected clinical pathogens (7, 24, 29). Consistent with these reports, in our study, telithromycin was slowly bactericidal against four of the six pneumococci evaluated in this study, requiring 24 h to achieve a 3-log₁₀ decrease in CFU with these strains. Against the remaining two strains, telithromycin was bacteriostatic. The bactericidal-bacteriostatic activities of JNJ 1 and JNJ 2 were similar to that of telithromycin. However, it should be noted that data generated at 24-h time points for pneumococci may overestimate bactericidality, due to the slow autolysis observed with some strains in drug-free medium (37).

The PAE of antibiotics is thought to be relevant to in vivo dosing, potentially permitting less frequent dosing through continued growth suppression of the pathogen as plasma drug concentrations decrease below the MIC. Against pneumococci, reported PAE values for telithromycin range from 1.3 to 7 h when tested at 4x the MIC and 1.5 to 8.2 h at 10x the MIC (6, 18). In this study, the PAE values observed for telithromycin at 4x the MIC against the six pneumococcal strains tested ranged from 3.0 to 8.1 h, consistent with the literature values described above. PAE values for JNJ 1 and JNJ 2 were similar, with values ranging from 3.7 to 6.7 h. There was no relationship noted between the length of the PAE for telithromycin, JNJ 1, and JNJ 2 and the macrolide resistance genotype of the strains tested in this study.

These results indicate that utilization of the unique biologically derived 15-methylerythromycin A core to form JNJ 1 and JNJ 2 yielded ketolides with potent in vitro activities against key respiratory tract pathogens, similar to those of telithromycin. Thus, ketolides with similar microbiological properties may be candidates for further development.

 
We kindly thank Todd Davies for providing S. pneumoniae strains with characterized L4 and 23S rRNA mutations, Marilyn Roberts for two pneumococci with a macrolide resistance mutation in the L4 ribosomal protein, and Ronald Jones for two pneumococci with a macrolide resistance mutation in the L22 ribosomal protein. We also thank G. Ashley and P. Licari of Kosan Biosciences for their scientific contributions to the overall project.

 
* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ 08869. Phone: (908) 704-4421. Fax: (908) 707-3501. E-mail: dabbanat{at}prdus.jnj.com.

Top Abstract Introduction Materials and Methods Results Discussion References

 

1
1. Akalin, H. E. 2001. The place of antibiotic therapy in the management of chronic acute exacerbations of chronic bronchitis. Int. J. Antimicrob. Agents 18:S49-S55.
2
2. American Academy of Pediatrics. 2001. Clinical practice guideline: management of sinusitis. Pediatrics 108:798-808.[Abstract/Free Full Text]
3
3. Bartlett, J. G., S. F. Dowell, L. A. Mandell, T. M. File, Jr., D. M. Musher, and M. J. Fine. 2000. Practice guidelines for the management of community-acquired pneumonia in adults. Clin. Infect. Dis. 31:347-382.[CrossRef][Medline]
4
4. Berisio, R., J. Harms, F. Schluenzen, R. Zarivach, A. S. Hansen Harly, P. Fucini, and A. Yonath. 2003. Structural insight into the antibiotic action of telithromycin against resistant mutants. J. Bacteriol. 185:4276-4279.[Abstract/Free Full Text]
5
5. Bisno, A. L., M. A. Gerber, J. M. Gwaltney, Jr., E. L. Kaplan, and R. H. Schwartz. 2002. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin. Infect. Dis. 35:113-125.[CrossRef][Medline]
6
6. Boswell, F. J., J. M. Andrews, and R. Wise. 1998. Pharmacodynamic properties of HMR 3647, a novel ketolide, on respiratory pathogens, enterococci and Bacteroides fragilis demonstrated by studies of time-kill kinetics and postantibiotic effect. J. Antimicrob. Chemother. 41:149-153.[Abstract/Free Full Text]
7
7. Boswell, F. J., and R. Wise. 2000. Linking pharmacodynamics with pharmacokinetics (including comments on CO₂ and susceptibility testing). Infect. Dis. Ther. 23:3-24.
8
8. Carbon, C. 2003. A pooled analysis of telithromycin in the treatment of community-acquired respiratory tract infections in adults. Infection 31:308-317.[Medline]
9
9. Carreras, C., S. Frykman, S. Ou, L. Cadapan, S. Zavala, E. Woo, T. Leaf, J. Carney, M. Burlingame, S. Patel, G. Ashley, and P. Licari. 2002. Saccharopolyspora erythraea-catalyzed bioconversion of 6-deoxyerythronolide B analogs for production of novel erythromycins. J. Biotechnol. 92:217-228.[CrossRef][Medline]
10
10. Dalhoff, K. 2001. Worldwide guidelines for respiratory tract infections: community-acquired pneumonia. Int. J. Antimicrob. Agents 18:S39-S44.
11
11. Doktor, S. Z., V. D. Shortridge, J. M. Beyer, and R. K. Flamm. 2004. Epidemiology of macrolide and/or lincosamide resistant Streptococcus pneumoniae clinical isolates with ribosomal mutations. Diagn. Microbiol. Infect. Dis. 49:47-52.[CrossRef][Medline]
12
12. Douthwaite, S. 2001. Structure-activity relationships of ketolides vs. macrolides. Clin. Microbiol. Infect. 7:11-17.[CrossRef]
13
13. Douthwaite, S., L. H. Hansen, and P. Mauvais. 2000. Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA. Mol. Microbiol. 36:183-193.[CrossRef][Medline]
14
14. Farrell, D. J., I. Morrissey, S. Bakker, and D. Felmingham. 2002. Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999-2000 study. J. Antimicrob. Chemother. 50:39-47.[Abstract]
15
15. Garza-Ramos, G., L. Xiong, P. Zhong, and A. Mankin. 2001. Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA. J. Bacteriol. 183:6898-6907.[Abstract/Free Full Text]
16
16. Guthrie, R. 2001. Community-acquired lower respiratory tract infections: etiology and treatment. Chest 120:2021-2034.[Abstract/Free Full Text]
17
17. Hansen, L. H., P. Mauvais, and S. Douthwaite. 1999. The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA. Mol. Microbiol. 31:623-631.[CrossRef][Medline]
18
18. Jacobs, M. R., S. Bajaksouzian, and P. C. Appelbaum. 2003. Telithromycin post-antibiotic and post-antibiotic sub-MIC effects for 10 Gram-positive cocci. J. Antimicrob. Chemother. 52:809-812.[Abstract/Free Full Text]
19
19. Jacobs, M. R., D. Felmingham, P. C. Appelbaum, R. N. Gruneberg, and The Alexander Project Group. 2003. The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J. Antimicrob. Chemother. 52:229-246.[Abstract/Free Full Text]
20
20. Leaf, T., L. Cadapan, C. Carreras, R. Regentin, S. Ou, E. Woo, G. Ashley, and P. Licari. 2000. Precursor-directed biosynthesis of 6-deoxyerythronolide B analogs in Streptomyces coelicolor: understanding precursor effects. Biotechnol. Prog. 16:553-556.[CrossRef][Medline]
21
21. Loewdin, E., I. Odenholt-Tornqvist, S. Bengtsson, and O. Cars. 1993. A new method to determine postantibiotic effect and effects of subinhibitory antibiotic concentrations. Antimicrob. Agents Chemother. 37:2200-2205.[Abstract/Free Full Text]
22
22. Lonks, J. R. 2004. What is the clinical impact of macrolide resistance? Curr. Infect. Dis. Rep. 6:7-12.[Medline]
23
23. Low, D. E., S. Brown, and D. Felmingham. 2004. Clinical and bacteriological efficacy of the ketolide telithromycin against isolates of key respiratory pathogens: a pooled analysis of phase III studies. Clin. Microbiol. Infect. 10:27-36.[CrossRef][Medline]
24
24. Malathum, K., T. M. Coque, K. V. Singh, and B. E. Murray. 1999. In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria. Antimicrob. Agents Chemother. 43:930-936.[Abstract/Free Full Text]
25
25. Malbruny, B., K. Nagai, M. Coquemont, B. Bozdogan, A. T. Andrasevic, H. Hupkova, R. Leclercq, and P. C. Appelbaum. 2002. Resistance to macrolides in clinical isolates of Streptococcus pyogenes due to ribosomal mutations. J. Antimicrob. Chemother. 49:935-939.[Abstract/Free Full Text]
26
26. McCracken, G. H. 2001. Clinical practice guidelines for the diagnosis and treatment of respiratory tract infections. Am. J. Managed Care 7:S183-S191.[Medline]
27
27. NCCLS. 2003 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 5th ed. Approved standard M7-A5. NCCLS, Wayne, Pa.
28
28. Niederman, M. S. 2001. Guidelines for the management of community-acquired pneumonia: current recommendations and antibiotic selection issues. Med. Clin. N. Am. 85:1493-1509.[CrossRef][Medline]
29
29. Pankuch, G. A., M. A. Visalli, M. R. Jacobs, and P. C. Appelbaum. 1998. Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents. Antimicrob. Agents Chemother. 42:624-630.[Abstract/Free Full Text]
30
30. Reinert, R. R., A. Wild, P. Appelbaum, R. Lutticken, M. Y. Cil, and A. Al-Lahham. 2003. Ribosomal mutations conferring resistance to macrolides in Streptococcus pneumoniae clinical strains isolated in Germany. Antimicrob. Agents Chemother. 47:2319-2322.[Abstract/Free Full Text]
31
31. Schmitz, F.-J., J. Petridou, H. Jagusch, N. Astfalk, S. Scheuring, and S. Schwarz. 2002. Molecular characterization of ketolide-resistant erm(A)-carrying Staphylococcus aureus isolates selected in vitro by telithromycin, ABT-773, quinupristin and clindamycin. J. Antimicrob. Chemother. 49:611-617.[Abstract/Free Full Text]
32
32. Shain, C. S., and G. W. Amsden. 2002. Telithromycin: the first of the ketolides. Ann. Pharmacother. 36:452-464.[Abstract]
33
33. Shinabarger, D. L., K. R. Marotti, R. W. Murray, A. H. Lin, E. P. Melchior, S. M. Swaney, D. S. Dunyak, W. F. Demyan, and J. M. Buysse. 1997. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob. Agents Chemother. 41:2132-2136.[Abstract]
34
34. Thornsberry, C., D. F. Sahm, L. J. Kelly, I. A. Critchley, M. E. Jones, A. T. Evangelista, and J. A. Karlowsky. 2002. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999-2000. Clin. Infect. Dis. 34:S4-S16.
35
35. Xiong, L., S. Shah, P. Mauvais, and A. S. Mankin. 1999. A ketolide resistance mutation in domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase centre. Mol. Microbiol. 31:633-639.[CrossRef][Medline]
36
36. Zhanel, G. G., M. Walters, A. Noreddin, L. M. Vercaigne, A. Wierzbowski, J. M. Embil, A. S. Gin, S. Douthwaite, and D. J. Hoban. 2002. The ketolides: a critical review. Drugs 62:1771-1804.[CrossRef][Medline]
37
37. Zurenko, G. E., B. H. Yagi, R. D. Schaadt, J. W. Allison, J. O. Kilburn, S. E. Glickman, D. K. Hutchinson, M. R. Barbachyn, and S. J. Brickner. 1996. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents Chemother. 40:839-845.[Abstract]

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Antimicrobial Agents and Chemotherapy, January 2005, p. 309-315, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.309-315.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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