This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hoban, D. J.
Right arrow Articles by Zhanel, G. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hoban, D. J.
Right arrow Articles by Zhanel, G. G.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2001, p. 2147-2150, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2147-2150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Macrolide-Resistant Streptococcus pneumoniae in Canada during 1998-1999: Prevalence of mef(A) and erm(B) and Susceptibilities to Ketolides

Daryl J. Hoban,1,2 Aleksandra K. Wierzbowski,1 Kim Nichol,1 and George G. Zhanel1,2,3,4,*

Department of Medical Microbiology, Faculty of Medicine1 and Faculty of Pharmacy,3 University of Manitoba, and Departments of Medicine4 and Clinical Microbiology,2 Health Sciences Centre, Winnipeg, Manitoba, Canada

Received 22 January 2001/Returned for modification 2 March 2001/Accepted 9 April 2001


    ABSTRACT
Top
Abstract
Text
References

In this study (1998-1999), we collected 215 macrolide-resistant Streptococcus pneumoniae isolates from an ongoing Canadian Respiratory Organism Surveillance Study involving 23 centers representing all regions of Canada. The prevalence of erythromycin-resistant S. pneumoniae was 8% (215 of 2,688). Of the 215 isolates, 48.8% (105 of 215) were PCR positive for mef(A) and 46.5% (100 of 215) were PCR positive for erm(B). The ketolides telithromycin and ABT-773 demonstrated excellent activity against both mef(A) (MIC for 90% of strains [MIC90], 0.06 and 0.03 µg/ml, respectively) and erm(B) (MIC90, 0.06 and 0.03 µg/ml, respectively) strains of S. pneumoniae.


    TEXT
Top
Abstract
Text
References

Macrolides, especially the newer agents (azithromycin and clarithromycin) are used extensively for the treatment of respiratory infections due to their broad-spectrum activity against both typical and atypical respiratory pathogens (5, 25). However, emergence of erythromycin resistance (Ery-R) in Streptococcus pneumoniae is a growing concern because of the importance of this pathogen in infections of the respiratory tract (6, 13, 15, 25). Although the prevalence of resistant strains varies geographically and temporally, antimicrobial resistance is widespread (6, 9, 10, 26). Macrolide resistance in S. pneumoniae has increased during the 1990s to the extent that over 30% of clinical isolates are now resistant in some communities (2, 3, 21, 23, 27).

Macrolide resistance in S. pneumoniae may be encoded by the erm(B) gene, which reduces the binding affinity of all macrolides for the 23s rRNA (domain V) and leads to cross-resistance to macrolides, lincosamides, and streptogramin B (MLSB) (16, 19, 27). Cross-resistance occurs as a result of methylation of the adenine residue (A2058) within the overlapping binding sites for the three chemically distinct antimicrobial classes (16, 21, 23, 27). S. pneumoniae strains possessing the erm(B) gene have an MLSB phenotype and usually express high-level resistance (MIC for 90% of strains [MIC90], >= 64 µg/ml) to MLSB antibiotics (23, 27). The second macrolide resistance mechanism in S. pneumoniae is the efflux of the antibiotic (22). S. pneumoniae strains with this type of resistance mechanism are classified as possessing an M-phenotype. An efflux pump encoded by the mef(A) gene in S. pneumoniae pumps out 14- and 15-membered macrolides only (20; K. Gay and D. S. Stephens, Program Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., 2000, abstr. 1929). S. pneumoniae with an M-phenotype express low-level resistance (MIC90, <= 4 µg/ml) to macrolides but demonstrate no cross-resistance to lincosamides and streptogramin B (20, 22).

The prevalence of the MLSB and M-phenotypes varies both geographically and temporally (9, 10, 13, 21). In the United States and Canada, where macrolide resistance in S. pneumoniae is 20 and 9%, respectively, the M-phenotype [product of the mef(A) gene] predominates (9; J. A. Karlowsky, D. J. Hoban, and G. G. Zhanel, Program Abstr. 5th Int. Conf. Macrolides, Azalides, Streptogramins, 2000, abstr. 7.11, p. 65). In Europe the prevalence of macrolide resistance varies from low (<5%) to high (>30%) but the MLSB phenotype [product of the erm(B) gene] is the more prevalent in comparison to the M-phenotype (10, 13; Karlowsky et al., abstr. 7.11).

Ketolides are third-generation, semisynthetic macrolides derived from clarithromycin (12). These 14-membered antibiotics are made by the replacement of the cladinose at C-3 with a keto group (12). This semisynthetic alteration of the natural erythromycin A molecule renders the drug more stable in acidic environments and reduces the induction of MLSB resistance phenotype (7, 8, 12). Ketolides have activity against a broad range of respiratory tract pathogens, including S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma species, Legionella species, and some anaerobic bacteria (4, 7, 12). Previous work has demonstrated that ketolides are active against macrolide-resistant S. pneumoniae, whether possessing the erm(B) or mef(A) genotype (12). Ketolides bind to domain II as well as domain V of 23s rRNA (13). In addition to the additional ribosomal contact, the potency of ketolides may also be due to slow dissociation from the ribosome (11). The purpose of this study was to determine the incidence of erm(B) and mef(A) among erythromycin-resistant S. pneumoniae isolated in Canada (1998-1999) during an ongoing national respiratory surveillance program. Second, the activity of telithromycin and ABT-773, two new ketolides, was assessed against erm(B) and mef(A) S. pneumoniae.

S. pneumoniae isolates were collected between 1998 and 1999 from an ongoing national surveillance study (Canadian Respiratory Organism Susceptibility Study [CROSS] [28]). Specifically, isolates were obtained from 23 medical centers in 9 of 10 Canadian provinces (26). Consecutive isolates, one per patient, were collected from respiratory tract specimens only. Isolates were identified by conventional methodology and deemed to be respiratory pathogens by individual laboratory protocols. All isolates were shipped to a central laboratory (Health Sciences Centre, Winnipeg, Manitoba) on Amies charcoal swabs. The identity of each S. pneumoniae was confirmed by the central reference laboratory, and it was then stored in skim milk and stored at -80°C (26).

Antibiotics for this study were supplied by the manufacturers: erythromycin (Hoechst Marion Rousell, Romainville, France), ABT-773 (Abbott, Abbott Park, Ill.), telithromycin (Hoechst Marion Rousell, Romainville, France) and clindamycin (Pharmacia and Upjohn, Mich.). Antibiotics were reconstituted according to National Committee for Clinical Laboratory Standards (NCCLS) guidelines (18). Susceptibility to erythromycin, clindamycin, telithromycin, and ABT-773 was determined using the NCCLS M7-A4 broth microdilution method (20). Each final-panel well volume was 100 µl, with a bacterial inoculum of 5 × 105 CFU/ml. Panels were read following 20 to 24 h of incubation at 35°C in ambient air. The MIC was defined as the lowest concentration of antibiotic inhibiting visible growth. Colony counts were performed periodically to confirm inocula.

S. pneumoniae cultures were grown overnight on Trypticase soy agar with 5% sheep blood, and two to five colonies were resuspended in 1 ml of sterile saline. Following centrifugation at 13,000 rpm for 10 min, supernatants were removed, and the resulting bacterial pellet was resuspended in 300 µl of lysis buffer containing 0.1 M NaOH, 2.0 M NaCl, and 0.5% sodium dodecyl sulfate (SDS). Cell suspensions were then boiled for 15 min, and 200 µl of 0.1 M Tris-HCl (pH 8.0) was added. For extraction of genomic DNA, 500 µl of phenol-chloroform-isoamyl alcohol (25:24:1) was added, and the mixture was centrifuged at 13,000 rpm for 10 min; 1 ml of cold (-20°C) anhydrous alcohol was then added, and DNA was precipitated at -80°C for a minimum of 30 min. The precipitated DNA was collected by centrifugation at 13,000 rpm for 15 min at 4°C, and the pellets were allowed to air dry for no less than half an hour. Pellets containing the purified DNA were subsequently resuspended in sterile distilled water and used as the DNA template (26).

DNA was amplified in a total volume of 50 µl containing 5 µl of template DNA, 5 µl of 40 mM MgCl2-10× PCR buffer, 1.25 mM each of dCTP, dGTP, dATP, and dTTP (Amersham Pharmacia Biotech), 100 mM each primer (Gibco-BRL), 2.5 U of Taq DNA polymerase (Amersham Pharmacia Biotech), and 30.5 µl of sterile distilled water. Primers used for amplification of erm(B) and mef(A) were 5'-GAAAAGGTACTAAACCAAATA-3' and 5'-AGTAACGGTACTTAAATTGTTTAC-3' (PCR product, 616 bp) and 5'-ACTATCATTAATCACTAGTGC-3' and 5'-TTCTTCTGGTACTAAAAGTGG-3' (PCR product, 346 bp), respectively (16). Amplification of erm(B) and mef(A) was performed using a Perkin-Elmer GeneAmp PCR system 9700 and consisted of initial denaturation at 95°C for 2 min, 30 cycles at 95, 52, and 72°C for 1 min each, and a final extension at 72°C for 10 min. Amplified DNA fragments were analyzed by electrophoresis through 2% agarose gels containing ethidium bromide and visualized under UV transillumination. S. pneumoniae ATCC 49619 and a mef(A) or erm(B) strain were consistently included as negative and positive controls, respectively.

An ongoing national surveillance study representing all regions in Canada (CROSS) was initiated in 1997 (26). In 1998-1999, 2,688 S. pneumoniae isolates from respiratory tract specimens were prospectively collected from 23 different medical centers throughout Canada, and 215 of these isolates were identified as being resistant to erythromycin. Thus, the national macrolide resistance rate in S. pneumoniae in Canada was approximately 8%. The incidence of macrolide-resistant S. pneumoniae from 1997 to 2000 has consistently remained at approximately 8% over the 3 years of the study (26; Karlowsky et al., abstr. 7.11). The 215 macrolide-resistant S. pneumoniae isolates were screened for the presence of mef(A) and erm(B), the two major macrolide resistance genes described in S. pneumoniae. The results of the PCR amplification studies for mef(A) and erm(B) are displayed in Table 1.

                              
View this table:
[in this window]
[in a new window]
  		TABLE 1.   Genotypic and phenotypic results for macrolide-resistant S. pneumoniae

The quality control strains tested [ATCC 49619, mef(A) positive, and erm(B) positive] were in control (data not shown). As shown in Table 1, 48.8% of macrolide-resistant S. pneumoniae were PCR positive for mef(A), demonstrating the presence of a macrolide efflux pump. The erythromycin MICs for these strains ranged from 1 to >= 64 µg/ml; however, the majority of these isolates had erythromycin MICs of 1 to 4 µg/ml (see Table 3). None of the mef(A)-positive strains were resistant to clindamycin, and 46.5% of all macrolide-resistant S. pneumoniae were PCR positive for erm(B). Erythromycin MICs for erm(B)-positive strains ranged from 1 to >= 64 µg/ml; however, the majority of the isolates demonstrated very high erythromycin MICs of >= 32 µg/ml (See Table 3). The majority of erm(B)-positive S. pneumoniae were resistant to clindamycin. A small number (2.8%) of macrolide-resistant S. pneumoniae were erm(B) and mef(A). All of these strains had high MICs to erythromycin, and the majority were concomitantly resistant to clindamycin (Tables 2 and 3); 1.9% of strains were both mef(A) and erm(B) negative, generally displayed very low MICs to erythromycin, and were susceptible to clindamycin.

                              
View this table:
[in this window]
[in a new window]
  		TABLE 2.   MIC distribution data for erythromycin-resistant S. pneumoniae

Table 1 describes the susceptibility of macrolide-resistant S. pneumoniae to both telithromycin and ABT-773. As can be seen from Table 1, telithromycin was very active against both mef(A)-positive and erm(B)-positive S. pneumoniae, with MIC90s of 0.06 µg/ml. Telithromycin was not as active against mef(A)-positive or erm(B)-positive strains as it was against macrolide-susceptible controls, which demonstrated MIC90s of 0.008 µg/ml. Telithromycin was very active against erm(B)-positive and mef(A)-positive strains, as well as macrolide-resistant S. pneumoniae that were both mef(A) and erm(B) negative. ABT-773 was also very active against both mef(A)-positive and erm(B)-positive macrolide-resistant S. pneumoniae, with MIC90s of 0.03 µg/ml. Like telithromycin, ABT-773 was not as active against mef(A) or erm(B) strains as it was against macrolide-sensitive S. pneumoniae, which demonstrated MIC90s of 0.004 µg/ml. ABT-773 was very active against erm(B)-positive and mef(A)-positive strains, as well as macrolide-resistant S. pneumoniae that were both mef(A) and erm(B) negative.

Table 3 describes the telithromycin and ABT-773 distributions with macrolide-susceptible and -resistant S. pneumoniae. As can be seen, the majority of telithromycin MICs against erm(B)-positive S. pneumoniae clustered between 0.004 and 0.008 µg/ml. Telithromycin MICs for mef(A)-positive strains were more disparate, 0.004 to 0.06 µg/ml (Table 3). Occasional erm(B)-positive or mef(A)-positive strains demonstrated higher MICs to telithromycin, with two strains as high as 1 µg/ml. With ABT-773, the majority of MICs against erm(B)-positive S. pneumoniae ranged from 0.002 to 0.008; however, occasional strains demonstrated higher MICs, including one strain as high as 0.5 µg/ml. Against mef(A)-positive S. pneumoniae, the majority of ABT-773 MICs ranged from 0.002 to 0.015 µg/ml.

                              
View this table:
[in this window]
[in a new window]
  		TABLE 3.   Telithromycin and ABT-773 MIC distributions with S. pneumoniaea

Presently the prevalence of macrolide resistance in Canada is low at approximately 8%. Since 1997, in our ongoing national surveillance program, which assesses macrolide resistance in over 1,000 respiratory isolates of S. pneumoniae per year from all regions of Canada, macrolide resistance has been approximately 8% and appears to have remained stable over the last 3 years (26; Karlowsky et al., abstr. 7.11). The low and stable incidence of macrolide-resistant S. pneumoniae in Canada has occurred despite large increases (29.5% over 1995 to 1998) in macrolide use in all regions of Canada, especially with the new macrolides, such as azithromycin and clarithromycin (5). Perhaps the reason why macrolide resistance is stable in Canada despite large increases in use of newer macrolides may be that total antibiotic use (total number of prescriptions for all antibiotics per year) is decreasing in Canada (14%) over the last 5 years (1995 to 1999) (G. G. Zhanel, A. Carrie, L. Hoban, K. Weiss, D. E. Low, and A. S. Gin, 40th ICAAC, p. 508).

Presently, 48.8% of macrolide-resistant S. pneumoniae in Canada harbor mef(A), while 46.5% of macrolide-resistant S. pneumoniae harbor erm(B). These data are consistent with previous Canadian and U.S. data and suggest that approximately 50% of macrolide-resistant S. pneumoniae possess a macrolide efflux pump and this has not changed over the last 7-year period (13, 21; Karlowsky et al., abstr. 7.11). The importance of knowing whether macrolide-resistant S. pneumoniae have mef(A) or erm(B) is that low-level macrolide resistance might be cured by drug concentrations that are clinically achievable in tissues (1). On the other hand, strains demonstrating high MICs to erythromycin may lead to microbiological and clinical failure with macrolides in patients with community-acquired pneumonia (14).

In this study we demonstrated that both telithromycin and ABT-773 had excellent activity against macrolide-resistant S. pneumoniae possessing the mef(A) or erm(B) phenotype. In light of their excellent activity against macrolide-resistant S. pneumoniae, ketolides may be an attractive alternative for the treatment of respiratory tract infections caused by this important pathogen.


    ACKNOWLEDGMENTS

We thank the participating centers, investigators, and laboratory site staff for their continued support. The technical support of L. Palatnick, B. Weshnoweski, and T. Bellyou and the secretarial assistance of M. Wegrzyn are appreciated.

The financial support of Abbott Laboratories Ltd., Aventis Pharma, Bayer Inc., Bristol-Myers Squibb Pharmaceutical Group, Glaxo Wellcome Inc., Janssen-Ortho, Merck Frosst Canada & Co., Pharmacia Upjohn, and SmithKline Beecham Pharma Inc. is gratefully acknowledged.


    FOOTNOTES

* Corresponding author. Mailing address: Department of Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada. Phone: (204) 787-4902. Fax: (204) 787-4699. E-mail: ggzhanel{at}pcs.mb.ca.


    REFERENCES
Top
Abstract
Text
References

1. Amsden, G. W. 1999. Pneumococcal macrolide resistance: myth or reality? J. Antimicrob. Chemother. 44:1-6[Free Full Text].
2. Baquero, F. 1999. Evolving resistance patterns of S. pneumoniae: a link with long-acting macrolide consumption? J. Chemother. 11(Suppl. 1):35-43.
3. Baquero, F., J. A. Garcia-Rodriguez, J. Garcia de Lomas, and L. Aguilar. 1999. Antimicrobial resistance of 1,113 Streptococcus pneumoniae isolates from patients with respiratory tract infections in Spain: results of 1-year (1996-1997) multi-center surveillance study. The Spanish Surveillance Group for Respiratory Pathogens. Antimicrob. Agents Chemother. 43:357-359[Abstract/Free Full Text].
4. Brueggemann, A. B., G. V. Doern, H. K. Huynh, E. M. Wingret, and P. R. Rhomberg. 2000. In vitro activity of ABT-773, a new ketolide, against recent clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob. Agents Chemother. 44:447-449[Abstract/Free Full Text].
5. Carrie, A. G., and G. G. Zhanel. 2000. Antibiotic use in a Canadian province 1995-1998. Ann. Pharmacother. 34:459-464[Abstract].
6. Dagan, R. 2000. Clinical significance of resistant organisms in otitis media. Pediatr. Infect. Dis. J. 19:378-382[CrossRef][Medline].
7. Davies, T. A., B. E. Dewasse, M. R. Jacobs, and P. C. Appelbaum. 2000. In vitro development of resistance to telithromycin (HMR 3647), four macrolides, clindamycin, and pristinamycin in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44:414-417[Abstract/Free Full Text].
8. Davies, T. A., L. M. Ednie, D. M. Hoellman, M. R. Jacobs, and P. C. Appelbaum. 2000. Antipneumococcal activity of ABT-773 compared to those of 10 other agents. Antimicrob. Agents Chemother. 44:1894-1899[Abstract/Free Full Text].
9. Doern, G. V., M. A. Pfaller, K. Kugler, J. Freeman, and R. N. Jones. 1998. Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North Ameerica: 1997 results from the SENTRY Antimicrobial Surveillance Program. Clin. Infect. Dis. 27:764-770[Medline].
10. Felmingham, D., R. N. Grunberg, and the Alexander Project Group. 1996. A multicentre collaborative study of the antimicrobial susceptibility of community acquired lower respiratory tract pathogens. J. Antimicrob. Chemother. 38(Suppl. A):1-57[Free Full Text].
11. Flamm, R. K. 2000. The new antibacterial class: the ketolides. Clin. Microbiol. News 22:129-133.
12. Hoban, D. J., G. G. Zhanel, and J. A. Karlowsky. 1999. In vitro activity of the novel ketolide HMR 3647 and comparative oral antibiotics against Canadian respiratory isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Diagn. Microb. Infect. Dis. 35:37-44[CrossRef][Medline].
13. Johnston, N. J., J. C. De Azavedo, J. D. Kellner, and D. E. Low. 1998. Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 42:2425-2426[Abstract/Free Full Text].
14. Kelley, M. A., D. J. Weber, P. Gilligan, and M. S. Cohen. 2000. Breakthrough pneumococcal bacteremia in patients being treated with azithromycin and clarithromycin. Clin. Infect. Dis. 31:1008-1011[CrossRef][Medline].
15. Klein, J. O. 1998. Clinical implications of antibiotic resistance for management of acute otitis media. Pediatr. Infect. Dis. J. 17:1084-1089[CrossRef][Medline].
16. Klugman, K. P., T. Capper, C. A. Widdowson, H. J. Koornhof, and W. Moser. 1998. Increased activity of 16-membered lactone ring macrolides against erythromycin-resistant Streptococcus pyogenes and Streptococcus pneumoniae: characterization of South African isolates. J. Antimicrob. Chemother. 42:729-734[Abstract/Free Full Text].
17. National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa.
18. National Committee for Clinical Laboratory Standards. 1999. Performance standards for antimicrobial susceptibility testing; eighth informational supplement, vol. 19, no. 1. National Committee for Clinical Laboratory Standards, Wayne, Pa.
19. Roberts, M. C., J. Sutcliffe, P. Courvalin, L. B. Jensen, J. Rood, and H. Seppala. 1999. Nomenclature for macrolide and macrolide-lincosamide-streptogramin B resistance determinants. Antimicrob. Agents Chemother. 43:2823-2830[Free Full Text].
20. Santagati, M., F. Iannelli, M. R. Oggioni, S. Stefani, and G. Pozzi. 2000. Characterization of a genetic element carrying the IV efflux gene mefA in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44:2585-2587[Abstract/Free Full Text].
21. Shortridge, V. D., G. V. Doern, A. B. Brueggemann, J. M. Beyer, and R. K. Flamm. 1999. Prevalence of macrolide resistance mechanisms in Streptococcus pneumoniae isolates from a multicenter antibiotic resistance surveillance study conducted in the United States in 1994-1995. Clin. Infect. Dis. 29:1186-1188[CrossRef][Medline].
22. Sutcliffe, J., A. Kamradt-Tait, and L. Wondrack. 1996. Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system. Antimicrob. Agents Chemother. 40:1817-1824[Abstract].
23. Waites, K., C. Johnson, B. Gray, K. Edwards, M. Crain, and B. William, Jr. 2000. Use of clindamycin disks to detect macrolide resistance mediated by erm(B)erm(B) and mefE in Streptococcus pneumoniae isolates from adults and children. J. Clin. Microbiol. 38:1731-1734[Abstract/Free Full Text].
24. Wilson, R., and R. Grossman. 2000. Introduction: the role of bacterial infection in chronic bronchitis. Semin. Respir. Infect. 15:1-6[Medline].
25. Zhanel, G. G., M. Dueck, L. Vercaigne, J. A. Karlowsky, A. Gin, J. Embil, and D. J. Hoban. 2000. Review of macrolides/ketolides: focus on respiratory infections. Drugs 61:443-498.
26. Zhanel, G. G., J. A. Karlowsky, L. Palatnick, L. Vercaigne, D. E. Low, the Canadian Respiratory Infection Study Group, and D. Hoban. 1999. Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study. Antimicrob. Agents Chemother. 43:2504-2509[Abstract/Free Full Text].
27. Zhong, P., C. Zhenshenh, R. Hammond, Y. Chen, J. Beyer, V. D. Shortridge, L. Y. Phan, S. Pratt, J. Capobianco, A. Reich, and R. K. Flamm. 1999. Induction of ribosome methylation in MLS-resistant Streptococcus pneumoniae by macrolides and ketolides. Microb. Drug Resist. 5:183-188[Medline].

Antimicrobial Agents and Chemotherapy, July 2001, p. 2147-2150, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2147-2150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Jiang, L.-J., Wang, M., Or, Y. S. (2009). Pharmacokinetics of EDP-420 after Ascending Single Oral Doses in Healthy Adult Volunteers. Antimicrob. Agents Chemother. 53: 1786-1792 [Abstract] [Full Text]  
  • Del Grosso, M., Northwood, J. G. E., Farrell, D. J., Pantosti, A. (2007). The Macrolide Resistance Genes erm(B) and mef(E) Are Carried by Tn2010 in Dual-Gene Streptococcus pneumoniae Isolates Belonging to Clonal Complex CC271. Antimicrob. Agents Chemother. 51: 4184-4186 [Abstract] [Full Text]  
  • Wierzbowski, A. K., Nichol, K., Laing, N., Hisanaga, T., Nikulin, A., Karlowsky, J. A., Hoban, D. J., Zhanel, G. G. (2007). Macrolide resistance mechanisms among Streptococcus pneumoniae isolated over 6 years of Canadian Respiratory Organism Susceptibility Study (CROSS) (1998 2004). J Antimicrob Chemother 60: 733-740 [Abstract] [Full Text]  
  • Hawkyard, C. V., Koerner, R. J. (2007). The use of erythromycin as a gastrointestinal prokinetic agent in adult critical care: benefits versus risks. J Antimicrob Chemother 59: 347-358 [Abstract] [Full Text]  
  • Farrell, D. J., File, T. M., Jenkins, S. G. (2007). Prevalence and Antibacterial Susceptibility of mef(A)-Positive Macrolide-Resistant Streptococcus pneumoniae over 4 Years (2000 to 2004) of the PROTEKT US Study. J. Clin. Microbiol. 45: 290-293 [Abstract] [Full Text]  
  • Del Grosso, M., Camilli, R., Iannelli, F., Pozzi, G., Pantosti, A. (2006). The mef(E)-Carrying Genetic Element (mega) of Streptococcus pneumoniae: Insertion Sites and Association with Other Genetic Elements.. Antimicrob. Agents Chemother. 50: 3361-3366 [Abstract] [Full Text]  
  • Azoulay-Dupuis, E., Mohler, J., Bedos, J. P., Barau, C., Fantin, B. (2006). Efficacy of Cethromycin, a New Ketolide, against Streptococcus pneumoniae Susceptible or Resistant to Erythromycin in a Murine Pneumonia Model.. Antimicrob. Agents Chemother. 50: 3033-3038 [Abstract] [Full Text]  
  • Sevillano, D., Alou, L., Aguilar, L., Echevarria, O., Gimenez, M.-J., Prieto, J. (2006). Azithromycin iv pharmacodynamic parameters predicting Streptococcus pneumoniae killing in epithelial lining fluid versus serum: an in vitro pharmacodynamic simulation. J Antimicrob Chemother 57: 1128-1133 [Abstract] [Full Text]  
  • Wierzbowski, A. K., Boyd, D., Mulvey, M., Hoban, D. J., Zhanel, G. G. (2005). Expression of the mef(E) Gene Encoding the Macrolide Efflux Pump Protein Increases in Streptococcus pneumoniae with Increasing Resistance to Macrolides. Antimicrob. Agents Chemother. 49: 4635-4640 [Abstract] [Full Text]  
  • Rantala, M., Huikko, S., Huovinen, P., Jalava, J., the Finnish Study Group for Antimicrobial Resistan, (2005). Prevalence and Molecular Genetics of Macrolide Resistance among Streptococcus pneumoniae Isolates Collected in Finland in 2002. Antimicrob. Agents Chemother. 49: 4180-4184 [Abstract] [Full Text]  
  • Zhanel, G. G., Johanson, C., Laing, N., Hisanaga, T., Wierzbowski, A., Hoban, D. J. (2005). Pharmacodynamic Activity of Telithromycin at Simulated Clinically Achievable Free-Drug Concentrations in Serum and Epithelial Lining Fluid against Efflux (mefE)-Producing Macrolide- Resistant Streptococcus pneumoniae for Which Telithromycin MICs Vary. Antimicrob. Agents Chemother. 49: 1943-1948 [Abstract] [Full Text]  
  • Kasbekar, N., Acharya, P. S. (2005). Telithromycin: The first ketolide for the treatment of respiratory infections. Am J Health Syst Pharm 62: 905-916 [Abstract] [Full Text]  
  • Klaassen, C. H. W., Mouton, J. W. (2005). Molecular Detection of the Macrolide Efflux Gene: To Discriminate or Not To Discriminate between mef(A) and mef(E). Antimicrob. Agents Chemother. 49: 1271-1278 [Full Text]  
  • Wierzbowski, A. K., Swedlo, D., Boyd, D., Mulvey, M., Nichol, K. A., Hoban, D. J., Zhanel, G. G. (2005). Molecular Epidemiology and Prevalence of Macrolide Efflux Genes mef(A) and mef(E) in Streptococcus pneumoniae Obtained in Canada from 1997 to 2002. Antimicrob. Agents Chemother. 49: 1257-1261 [Abstract] [Full Text]  
  • Zhanel, G. G., Johanson, C., Hisanaga, T., Mendoza, C., Laing, N., Noreddin, A., Wierzbowski, A., Hoban, D. J. (2004). Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations. J Antimicrob Chemother 54: 1072-1077 [Abstract] [Full Text]  
  • Novotny, G. W., Jakobsen, L., Andersen, N. M., Poehlsgaard, J., Douthwaite, S. (2004). Ketolide Antimicrobial Activity Persists after Disruption of Interactions with Domain II of 23S rRNA. Antimicrob. Agents Chemother. 48: 3677-3683 [Abstract] [Full Text]  
  • Kresken, M., Henrichfreise, B., Bagel, S., Brauers, J., Wiedemann, B. (2004). High Prevalence of the ermB Gene among Erythromycin-Resistant Streptococcus pneumoniae Isolates in Germany during the Winter of 2000-2001 and In Vitro Activity of Telithromycin. Antimicrob. Agents Chemother. 48: 3193-3195 [Abstract] [Full Text]  
  • Daly, M. M., Doktor, S., Flamm, R., Shortridge, D. (2004). Characterization and Prevalence of MefA, MefE, and the Associated msr(D) Gene in Streptococcus pneumoniae Clinical Isolates. J. Clin. Microbiol. 42: 3570-3574 [Abstract] [Full Text]  
  • Del Grosso, M., Scotto d'Abusco, A., Iannelli, F., Pozzi, G., Pantosti, A. (2004). Tn2009, a Tn916-Like Element Containing mef(E) in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 48: 2037-2042 [Abstract] [Full Text]  
  • Dandliker, P. J., Pratt, S. D., Nilius, A. M., Black-Schaefer, C., Ruan, X., Towne, D. L., Clark, R. F., Englund, E. E., Wagner, R., Weitzberg, M., Chovan, L. E., Hickman, R. K., Daly, M. M., Kakavas, S., Zhong, P., Cao, Z., David, C. A., Xuei, X., Lerner, C. G., Soni, N. B., Bui, M., Shen, L. L., Cai, Y., Merta, P. J., Saiki, A. Y. C., Beutel, B. A. (2003). Novel Antibacterial Class. Antimicrob. Agents Chemother. 47: 3831-3839 [Abstract] [Full Text]  
  • Clark, J. P., Langston, E. (2003). Ketolides: A New Class of Antibacterial Agents for Treatment of Community-Acquired Respiratory Tract Infections in a Primary Care Setting. Mayo Clin Proc. 78: 1113-1124 [Abstract]  
  • Zhanel, G. G., DeCorby, M., Noreddin, A., Mendoza, C., Cumming, A., Nichol, K., Wierzbowski, A., Hoban, D. J. (2003). Pharmacodynamic activity of azithromycin against macrolide-susceptible and -resistant Streptococcus pneumoniae simulating clinically achievable free serum, epithelial lining fluid and middle ear fluid concentrations. J Antimicrob Chemother 52: 83-88 [Abstract] [Full Text]  
  • Zhanel, G. G., Palatnick, L., Nichol, K. A., Bellyou, T., Low, D. E., Hoban, D. J. (2003). Antimicrobial Resistance in Respiratory Tract Streptococcus pneumoniae Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob. Agents Chemother. 47: 1867-1874 [Abstract] [Full Text]  
  • Reinert, R. R., Lutticken, R., Bryskier, A., Al-Lahham, A. (2003). Macrolide-Resistant Streptococcus pneumoniae and Streptococcus pyogenes in the Pediatric Population in Germany during 2000-2001. Antimicrob. Agents Chemother. 47: 489-493 [Abstract] [Full Text]  
  • Mason, E. O. Jr., Lamberth, L. B., Wald, E. R., Bradley, J. S., Barson, W. J., Kaplan, S. L. (2003). In Vitro Activities of Cethromycin (ABT-773), a New Ketolide, against Streptococcus pneumoniae Strains That Are Not Susceptible to Penicillin or Macrolides. Antimicrob. Agents Chemother. 47: 166-169 [Abstract] [Full Text]  
  • Montanari, M. P., Mingoia, M., Cochetti, I., Varaldo, P. E. (2003). Phenotypes and Genotypes of Erythromycin-Resistant Pneumococci in Italy. J. Clin. Microbiol. 41: 428-431 [Abstract] [Full Text]  
  • Noreddin, A. M., Roberts, D., Nichol, K., Wierzbowski, A., Hoban, D. J., Zhanel, G. G. (2002). Pharmacodynamic Modeling of Clarithromycin against Macrolide-Resistant [PCR-Positive mef(A) or erm(B)] Streptococcus pneumoniae Simulating Clinically Achievable Serum and Epithelial Lining Fluid Free-Drug Concentrations. Antimicrob. Agents Chemother. 46: 4029-4034 [Abstract] [Full Text]  
  • Hamilton-Miller, J. M. T., Shah, S. (2002). Activity of ketolide ABT-773 (cethromycin) against erythromycin-resistant Streptococcus pneumoniae: correlation with extended MLSK phenotypes. J Antimicrob Chemother 50: 907-913 [Abstract] [Full Text]  
  • Low, D. E., de Azavedo, J., Weiss, K., Mazzulli, T., Kuhn, M., Church, D., Forward, K., Zhanel, G., Simor, A., McGeer, A. (2002). Antimicrobial Resistance among Clinical Isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob. Agents Chemother. 46: 1295-1301 [Abstract] [Full Text]  
  • Fuchs, P. C., Barry, A. L., Brown, S. D. (2002). In vitro activity of telithromycin against Streptococcus pneumoniae resistant to other antibiotics, including cefotaxime. J Antimicrob Chemother 49: 399-401 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hoban, D. J.
Right arrow Articles by Zhanel, G. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hoban, D. J.
Right arrow Articles by Zhanel, G. G.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»