Journal of Antimicrobial Chemotherapy (2001) 48, 407-409
© 2001 The British Society for Antimicrobial Chemotherapy
Brief report |
In vitro activity of a novel ketolide ABT-773 against invasive strains of Streptococcus pneumoniae
a Hôpital Maisonneuve-Rosemont, University of Montreal, 5415 L’Assomption, Montreal, Quebec H1T 2M4; b Mount Sinai Hospital, University of Toronto, Toronto; c Montreal Children's Hospital, McGill University, Montreal; d Hôpital de l’Enfant-Jesus, Laval University, Quebec City, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResults and discussionAcknowledgementsReferences |
|---|
New ketolides such as ABT-773 are a promising group of antibiotics in an era of increasing antibiotic resistance. We tested 704 invasive strains of Streptococcus pneumoniae collected from 1990 to 1998. Overall resistance was 8.3, 4.6, 4.5 and 3.6% for penicillin, cefuroxime, erythromycin and clarithromycin, respectively. By using a recommended breakpoint for susceptibility of <0.5 mg/L, no strains showed reduced susceptibility to ABT-773. ABT-773 was very active against all penicillin-resistant strains (MIC > 2 mg/L, with a mean geometric mean <0.06 mg/L), and against all 33 erythromycin-resistant strains, irrespective of the mode of resistance [mef- or erm(B)-mediated]. ABT-773 is a very active and promising agent against invasive strains of S. pneumoniae, including multiresistant strains.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionAcknowledgementsReferences |
|---|
Increasing resistance of Streptococcus pneumoniae to penicillins, cephalosporins, quinolones and macrolides constitutes a growing challenge. Bacteraemia caused by S. pneumoniae remain a major cause of morbidity and mortality, particularly in the elderly. The worldwide prevalence of macrolide resistance varies considerably, being high in Japan, Italy (42%) and France (47.3%), intermediate in the USA (23.3%) and UK (18.4%), and lower in Canada (12%).1,2 New ketolides are a promising group of antibiotics against penicillin- and macrolide-resistant strains of S. pneumoniae. Macrolide resistance in S. pneumoniae occurs either by target modification through erm genes, which encode 23S rRNA methylases, and which is associated with a high-level resistance, or through an efflux pump encoded by the mef(E) gene. Recently, insertions in the L4 ribosomal protein of a Canadian S. pneumoniae isolate were found to be associated with reduced susceptibility to the ketolide telithromycin.3 The objective of this study was to evaluate the in vitro activity of the new ketolide ABT-773 against invasive strains of S. pneumoniae.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionAcknowledgementsReferences |
|---|
Strains
From 1990 to 1998, all strains of S. pneumoniae isolated from sterile sites (blood, CSF, pleural or articular fluids) were stored and frozen at –70°C. Three large teaching tertiary care hospitals (two adult: Hôpital Maisonneuve-Rosemont, Montreal, and Hôpital de l’Enfant-Jesus, Quebec City; and one paediatric: The Montreal Children's Hospital, Montreal) participated in the study. A total of 704 single clinical isolates of S. pneumoniae were included in this survey (634 blood, 51 CSF, 19 other). Patients comprised 390 males (55.3%) and 314 females (44.7%) with an age range of 0.1–102 years and a median age of 33.2 years.
Strains were identified using standard procedures: Gram's stain, optochin susceptibility test and bile solubility test.
Antibiotics and susceptibility testing
Penicillin, cefuroxime and erythromycin were purchased from Nucrotechnics (Scarborough, Ontario, Canada). Clarithromycin and ABT-773 were provided by Abbott Canada (Montreal, Quebec, Canada). The isolates were tested against the following antibiotics at the following concentrations (mg/L): penicillin, 0.03–4; cefuroxime, 0.06–8; erythromycin, 0.06–8; clarithromycin, 0.06–8; and ABT-773, 0.06–8.
MICs were determined using a broth microdilution method according to NCCLS recommendations.4 A 0.5 McFarland equivalent suspension was prepared from an overnight sheep blood agar culture of S. pneumoniae. This solution was then diluted 1:10 to yield 107 cfu/mL. Five microlitres of this suspension was added to a cation-adjusted Mueller–Hinton supplemented with 5% lysed horse blood in order to reach a final concentration of 5 x 104 cfu/well. Trays were incubated at 35°C for 24 h in ambient air. The lowest concentration of antibiotic showing no growth was recorded as the MIC. Quality control was assessed by testing S. pneumoniae ATCC 49619.
For ABT-773, a recommended breakpoint for susceptibility of 
0.5 mg/L was used.5
Determination of macrolide-resistance mechanisms
The macrolide-resistance mechanism was determined for 28 erythromycin-resistant S. pneumonia strains by PCR using specific primers as described previously.6
|
Results and discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionAcknowledgementsReferences |
|---|
High levels of in vitro resistance to ß-lactams and macrolides in S. pneumoniae have been reported throughout the world. However, in many instances the differences in resistance patterns between invasive strains, considered to be always clinically significant, and non-invasive strains have not been clearly established. Some published data indicate that resistance is higher among non-invasive strains, notably those isolated from the respiratory tract or eye specimens.2 In our study, 8.3% of the strains were resistant to penicillin, 4.7% to cefuroxime, 4.5% to erythromycin, 3.6% to clarithromycin and none to ABT-773 (Table 1
). There were no significant differences between paediatric and adult isolates. Although still low, there was an important increase in the level of resistance to all antibiotics except ABT-773 when comparing the 1990–1994 and 1995–1998 periods. ABT-773 was found to be highly active against all macrolide-resistant strains irrespective of the mode of resistance [erm(B) or mef]. Among the erythromycin-resistant stains, 18 were characterized as erm(B) positive and 10 as mef positive. ABT-773 was also very active against all penicillin non-susceptible (PNSP) strains, with a geometric mean MIC < 0.06 mg/L (Table 2). For ABT-773, the highest recorded MIC was 0.125 mg/L (Table 2). The two strains with an MIC of 0.125 mg/L were both harbouring the mef determinant. Only 22% (13/59) of PNSP were also resistant to erythromycin. All the penicillin-resistant strains were also resistant to cefuroxime; however, none showed reduced susceptibility to ABT-773 using a tentative breakpoint of 0.5 mg/L.
|
|
ABT-773 has been shown to be very active against other respiratory pathogens such as Haemophilus influenzae and Moraxella catarrhalis.7 It also has excellent activity against intracellular Legionella spp., and against Chlamydia pneumoniae.8 Experimental data have demonstrated that it binds to ribosomes isolated from either susceptible or resistant S. pneumoniae 10- to 100-fold more strongly than erythromycin.9 In this study, ABT-773 showed excellent in vitro activity against a large number of clinically significant S. pneumoniae strains, irrespective of their resistance patterns. Preliminary data have shown ABT-773 to be bactericidal for S. pneumoniae in vitro, making it a promising new agent against S. pneumoniae infections.10 In addition, a plasma Cmax of 0.6 mg/L has been reported after a single 400 mg oral dose, which is four times the highest MIC recorded in this study. This compound may become an option for invasive S. pneumoniae infections in adults and children, and may represent an interesting alternative to the newer quinolones which are targeted towards treatment of Gram-positive infections.
|
Acknowledgements |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionAcknowledgementsReferences |
|---|
This study was partially funded by a grant from Abbott Canada.
|
Notes |
|---|
* Corresponding author. Tel: +1-514-252-3817; Fax: +1-514-252-3898; E-mail: weisscan{at}aol.com
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionAcknowledgementsReferences |
|---|
1 . Schito, G. C., Debbia, E. A. & Marchese, A. (2000). The evolving threat of antibiotic resistance in Europe: new data from the Alexander project. Journal of Antimicrobial Chemotherapy 46, Topic T1, 3–9.
2
.
Thornsberry, C., Ogilvie, P. T., Holley, H. P. & Sahm, D. F. (1999). Survey of susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates to 26 antimicrobial agents: a prospective US study. Antimicrobial Agents and Chemotherapy 43, 2612–23.
3
.
Tait-Kamradt, A., Davies, T., Appelbaum, P. C., Depardieu, F., Courvalin, P., Petitpas, J. et al. (2000). Two new mechanisms of macrolide resistance in clinical strains of Streptococcus pneumoniae from eastern Europe and North America. Antimicrobial Agents and Chemotherapy 44, 3395–401.
4 . 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, Villanova, PA.
5 . Barry, A. L., Fuchs, P. C. & Brown, S. D. (1999). Comparative in vitro antimicrobial activity of ABT-773 and tentative disk interpretive criteria. In Program and Abstracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1999. Abstract 2144, p. 348. American Society for Microbiology, Washington, DC.
6
.
Johnston, N. J., De Azavedo, J. C., Kellner, J. D. & Low, D. E. (1998). Prevalence and characterization of the mechanisms of macrolides, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 42, 2425–6.
7
.
Brueggemann, A. B., Doern, G. V., Huynh, H. K., Wingert, E. M. & Rhomberg, P. R. (2000). In vitro activity of ABT-773, a new ketolide, against recent clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Antimicrobial Agents and Chemotherapy 44, 447–9.
8
.
Strigl, S., Roblin, P. M., Reznik, T. & Hammerschlag, M. (2000). In vitro activity of ABT-773, a new ketolide antibiotic, against Chlamydia pneumoniae. Antimicrobial Agents and Chemotherapy 44, 1112–3.
9
.
Capobianco, J. O., Cao, Z., Shortridge, V. D., Ma, Z., Flamm, R. K. & Zhong, P. (2000). Studies of the novel ketolide ABT-773: transport, binding to ribosomes, and inhibition of protein synthesis in Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 44, 1562–67.
10 . Neuhauser, M. M., Prause, J. L., Li, D. H. et al. (1999). In vitro bactericidal activity of ABT-773, a new ketolide, versus clarithromycin, azithromycin, ciprofloxacin, amoxicillin/clavulanate against penicillin/erythromycin sensitive and resistant Streptococcus pneumoniae and Haemophilus influenzae. In Program and Abtracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1999. Abstract 2139, p. 347 American Society for Microbiology, Washington, DC.
Received 28 March 2001; returned 14 June 2001; revised 25 June 2001; accepted 4 July 2001
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Weiss and G. S. Tillotson The Controversy of Combination vs Monotherapy in the Treatment of Hospitalized Community-Acquired Pneumonia Chest, August 1, 2005; 128(2): 940 - 946. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||