In vitro activity of telithromycin against Streptococcus pneumoniae resistant to other antibiotics, including cefotaxime

Peter C. Fuchs,*, Arthur L. Barry and Steven D. Brown

The Clinical Microbiology Institute, 9725 SW Commerce Circle, Wilsonville, OR 97070, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
A total of 407 isolates of Streptococcus pneumoniae, most of which were resistant to one or more antibiotics, were tested for susceptibility to telithromycin and four other agents. Telithromycin was the most active agent tested, with 98% of isolates susceptible to <=1.0 mg/L. For strains resistant to the other antibiotics, susceptibility to telithromycin ranged from 98.6% for strains resistant to trimethoprim/sulfamethoxazole to 94.4% for strains resistant to cefotaxime.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
Pneumococcal resistance to penicillin and macrolides is now a worldwide problem.1 The current mainstay of therapy of serious pneumococcal infections such as meningitis is an expanded-spectrum cephalosporin such as ceftriaxone or cefotaxime. However, recent surveys have indicated that in vitro pneumococcal resistance to these expanded-spectrum cephalosporins is also increasing.2,3 Furthermore, cefotaxime treatment (MIC 4.0 mg/L) of serious infections caused by pneumococci has failed.4,5

Telithromycin is a ketolide with potent in vitro antimicrobial activity against Streptococcus pneumoniae, including penicillin-resistant and macrolide-resistant strains.6,7 It is rapidly bactericidal for pneumococci, both extracellular and intracellular organisms.8 In this study we evaluated the in vitro antimicrobial activity of telithromycin against a large number of pneumococcal isolates, most of which were not susceptible to cefotaxime (MIC >= 1.0 mg/L) and many of which were resistant to other agents.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
The 407 isolates of S. pneumoniae that were selected to provide a high proportion of resistant strains comprised 321 recent North American clinical isolates and 86 European isolates.

Telithromycin was provided as standardized powder by Aventis Pharmaceuticals (Romainville, France). Cefotaxime, erythromycin, penicillin and trimethoprim/sulfamethoxazole (SXT) were obtained from commercial sources. MICs were determined by the broth microdilution method, following the procedure outlined by the National Committee for Clinical Laboratory Standards.9 Microdilution trays were prepared with serial two-fold antibiotic dilutions in cation-adjusted Mueller–Hinton broth supplemented with 3% lysed horse blood. Drug concentrations ranged from 4.0 to 0.008 mg/L for telithromycin, 2.0 to 0.06 mg/L for erythromycin, 16 to 0.03 mg/L for penicillin, 16 to 0.12 mg/L for cefotaxime and 4.0/76 to 0.5/9.5 mg/L for SXT. The quality-control strain S. pneumoniae ATCC 49619 was also tested on each day of testing, and all results were within the acceptable range.


    Results and discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
Because of the selection process, a disproportionate percentage of this population of 407 strains of S. pneumoniae was resistant to many of the antibiotics tested in this study: 73% were resistant to penicillin (MICs >= 2.0 mg/L), 62% were resistant to erythromycin (MICs >= 1.0 mg/L), 70% were resistant to SXT (MICs >= 4.0/76 mg/L) and 22% were resistant to cefotaxime (MICs >= 2.0 mg/L). Over half of the strains had an intermediate cefotaxime MIC of 1.0 mg/L. The cumulative percentage of strains inhibited by increasing drug concentration is shown in the FigureGo.



View larger version (14K):
[in this window]
[in a new window]
 
Figure. In vitro activity of telithromycin ({blacksquare}), erythromycin ({blacktriangleup}), cefotaxime (x), penicillin ({diamond}) and SXT (•) against 407 strains of S. pneumoniae selected because of their resistance to one or more antimicrobial agents.

 
The geometric mean telithromycin MICs were significantly higher for isolates resistant to any of the other antibiotics tested than for isolates susceptible to those drugs. These ranged from three times higher for SXT-resistant isolates to nearly 14 times higher for erythromycin-resistant strains (TableGo). The activity of telithromycin against macrolide-resistant strains in this study was consistent with the experience reported from Canada.10 More than 94% of isolates resistant to the other drugs tested were susceptible to <=1.0 mg/L telithromycin. The lowest percentage of antibiotic-resistant strains susceptible to <=1.0 mg/L telithromycin was 94.4% for cefotaxime-resistant strains.


View this table:
[in this window]
[in a new window]
 
Table. Susceptibility of 407 S. pneumoniae strains to telithromycin
 
Pending the results of clinical trials, telithromycin appears to be a viable alternative for the treatment of serious pneumococcal infections, including those caused by strains currently resistant to cefotaxime and those resistant to the macrolides.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
This study was supported in part by a grant from Aventis Pharmaceuticals, Research and Development, Romainville, France.


    Notes
 
* Corresponding author. Tel: +1-503-682-3232; Fax: +1-503-682-2065; E-mail: cmi{at}hevanet.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Acknowledgements
 References
 
1 . Centers for Disease Control and Prevention. (1996). Defining the public health impact of drug-resistant Streptococcus pneumoniae. Morbidity and Mortality Weekly Report 45, Suppl. RR-1, 1–20.[Medline]

2 . Jones, R. N., Jenkins, S. G., Hoban, D. J., Pfaller, M. A. & Ramphal, R. (2000). In vitro activity of selected cephalosporins and erythromycin against staphylococci and pneumococci isolated at 38 North American medical centers participating in the SENTRY antimicrobial surveillance program, 1997–1998. Diagnostic Microbiology and Infectious Disease 37, 93–8.[ISI][Medline]

3 . Zhanel, G. G., Karlowsky, J. A., Palatnick, L., Vercaigne, L., Low, D. E., The Canadian Respiratory Infection Study Group et al. (1999). Prevalence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian national surveillance study. Antimicrobial Agents and Chemotherapy 43, 2504–9.[Abstract/Free Full Text]

4 . Brett, M. S. (2001). Emergence of a high-level cefotaximeresistant Streptococcus pneumoniae strain in New Zealand. Journal of Medical Microbiology 50, 173–6.[Abstract/Free Full Text]

5 . Wong, S. S., Woo, P. C., Ho, P. L., Cheng, V. C. & Yuen, K. Y. (1999). Emergence of Streptococcus pneumoniae with high-level resistance to cefotaxime in Hong Kong. Hong Kong Medical Journal 5, 406–9.[Medline]

6 . Barry, A. L., Fuchs, P. C. & Brown, S. D. (1998). Antipneumococcal activities of a ketolide (HMR 3647), a streptogramin (quinupristin-dalfopristin), a macrolide (erythromycin), and a lincosamide (clindamycin). Antimicrobial Agents and Chemotherapy 42, 945–6.[Abstract/Free Full Text]

7 . Pankuch, G. A., Visalli, M. A., Jacobs, M. R. & Appelbaum, P. C. (1998). Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with the susceptibilities to 17 other agents. Antimicrobial Agents and Chemotherapy 42, 624–30.[Abstract/Free Full Text]

8 . Mandell, G. L. & Coleman, E. J. (2000). Activities of antimicrobial agents against intracellular pneumococci. Antimicrobial Agents and Chemotherapy 44, 2561–3.[Abstract/Free Full Text]

9 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA.

10 . Hoban, D. J., Wierzbowski, A. K., Nichol, K. & Zhanel, G. G. (2001). Macrolide-resistant Streptococcus pneumoniae in Canada during 1998–1999: prevalence of mef(A) and erm(B) and susceptibilities to ketolides. Antimicrobial Agents and Chemotherapy 45, 2147–50.[Abstract/Free Full Text]

Received 30 May 2001; returned 22 August 2001; revised 8 October 2001; accepted 6 November 2001