In vitro evaluation of AZD2563, a new oxazolidinone, tested against ß-haemolytic and viridans group streptococci

Tamara R. Anderegg1, Douglas J. Biedenbach1 and Ronald N. Jones1,2,*

1The Jones Group/JMI Laboratories, North Liberty, IA; 2Tufts University School of Medicine, Boston, MA, USA

Received 25 October 2001; returned 21 January 2002; revised 21 February 2001; accepted 26 February 2002.


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Linezolid was the first clinically applied agent from the oxazolidinone class, and AZD2563, a new agent, is described here. Five hundred and twenty-five streptococcal isolates were tested, including ß-haemolytic (266) and viridans group (259) species. MIC50/MIC90/% susceptible (susceptibility breakpoint <2 mg/L of AZD2563) results were, for ß-haemolytic species: AZD2563 (1/2/100), linezolid (1/2/100), quinupristin–dalfopristin (0.25/0.25/100), vancomycin (0.25/0.5/100) and levofloxacin (0.5/1/99); for viridans group species: AZD2563 (0.5/1/100), linezolid (1/1/100), quinupristin–dalfopristin (0.5/1/99), vancomycin (0.5/0.5/100) and levofloxacin (1/1/98). The modal MICs of AZD2563 and linezolid were 0.5 or 1 mg/L and 1 mg/L, respectively. AZD2563 activity screening against these non-pneumococcal streptococci indicated a slightly greater potency of AZD2563 when compared with linezolid. All AZD2563 MICs were <2 mg/L.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Resistance to antimicrobials among Streptococcus species has been reported with great regularity over the last 10–15 years.14 Use of macrolides has been associated with susceptibility changes among streptococcal species including ß-haemolytic strains.4 Like the pneumococci, viridans group streptococcal species have acquired high rates of resistance to penicillin and other ß-lactams, often attributed to altered penicillin binding protein targets.2 These threats to contemporary streptococcal infection chemotherapy have fostered the development of new classes of antimicrobial agents (everninomicins, oxazolidinones, streptogramins, lipopeptides, etc.) that have been focused toward these Gram-positive pathogens.5,6 This study examined the in vitro characteristics of AZD2563,7,8 a new once-daily oxazolidinone, tested by reference susceptibility test methods against Streptococcus species other than Streptococcus pneumoniae.9


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Antimicrobial agents

The comparator drugs tested were obtained from the United States manufacturers and AZD2563 was provided by AstraZeneca (Macclesfield, UK). The antimicrobials included: linezolid,6 quinupristin–dalfopristin, vancomycin, erythromycin, clindamycin, gentamicin, levofloxacin and penicillin.

Bacterial isolates

The 525 strains tested were from various North American surveillance collections processed in the last 12 months by the JMI Laboratories (North Liberty, IA, USA). These strains included: viridans group streptococci (259 strains) and ß-haemolytic streptococci (five serogroups, 266 strains). Each strain was identified by two or more laboratories and represented isolates derived from recent clinical cases. For 126 viridans group streptococci, high confidence identification (>=85%) to species level could not be made; these strains were classified as viridans group, NOS (not otherwise speciated). The remaining strains were identified as follows: Streptococcus anginosis (four strains), Streptococcus constellatus (four strains), Streptococcus equinus (one strain), Streptococcus equisimilus (one strain), Streptococcus gordonii (one strain), Streptococcus intermedius (14 strains), Streptococcus milleri (17 strains), Streptococcus mitis (48 strains), Streptococcus mutans (one strain), Streptococcus oralis (15 strains), Streptococcus salvarius (six strains), Streptococcus sanguis (20 strains), Streptococcus uberis (one strain), and ß-haemolytic streptococci from groups A (112 strains), B (132 strains), C (11 strains), F (one strain) and G (10 strains). All viridans group strains were isolated from bloodstream infections, and the ß-haemolytic isolates came from cultures of blood, wounds and the upper airway.

Susceptibility testing

All strains were tested by the NCCLS broth microdilution method.9 Broth microdilution trays were prepared in frozen form by Trek Diagnostics (Westlake, OH, USA) and stored at –80°C until used. Antimicrobials were diluted in Mueller–Hinton broth with 5% lysed horse blood and the final inoculum was 5 x 105 cfu/mL, confirmed by regular colony counts. Quality control (QC) strains included fastidious (S. pneumoniae ATCC 49619) and rapidly growing species (Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212). All QC results were within control ranges published by the NCCLS10 or product manufacturer (AstraZeneca).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Table 1 shows the antimicrobial activity of AZD2563 compared with the eight other antimicrobials tested, against the 259 isolates of viridans group streptococci. When evaluating the oxazolidinones, AZD2563 (MIC90 1 mg/L) had a similar activity to that of linezolid (MIC90 1 mg/L; 100.0% susceptible). Other antimicrobials with comparable activity to the oxazolidinones against the viridans group streptococci included: quinupristin–dalfopristin (MIC90 1 mg/L; 99.2% susceptible), vancomycin (MIC90 0.5 mg/L; 100.0% susceptible) and levofloxacin (MIC90 1 mg/L; 98.1% susceptible). The rate of resistance among these strains to the antimicrobials cited ranged from nil to only 0.8%. The rates of resistance to the other antimicrobial agents tested (erythromycin, clindamycin, gentamicin, penicillin) were significantly higher, 9.6–50.0%, thus characterizing the challenge collection.


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Table 1.  In vitro activity of AZD2563 compared with that of eight other antimicrobial agents tested against 259 strains of viridans group streptococci and 266 strains of ß-haemolytic streptococci
 
Table 1 also shows the antimicrobial activity of the nine antimicrobial agents tested against the 266 ß-haemolytic streptococci. The oxazolidinones, AZD2563 and linezolid, again showed equal potency (MIC90 2 mg/L). Among the ß-haemolytic streptococci, only 1.5% of isolates were penicillin resistant, but 16.9% were resistant to erythromycin. Clindamycin and levofloxacin were active against >=93.6%.

When analysing all 525 streptococcal isolates tested, AZD2563 and linezolid had nearly identical MIC ranges (0.06–2 mg/L of AZD2563 compared with 0.12–2 mg/L of linezolid) as well as MIC50 and MIC90 results. However, Figure 1 demonstrates that AZD2563 had a slight potency advantage for some streptococcal strains when compared with linezolid.



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Figure 1. MIC distributions of AZD2563 (open bars) and linezolid (filled bars) tested for 525 strains of non-pneumococcal Streptococcus spp.

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Linezolid has established the clinical utility of the oxazolidinone class for the therapy of problematic Gram-positive infections.6 The spectrum of the oxazolidinones remains nearly complete, with only very rare occurrences of resistant S. aureus or enterococci being seen following long-term treatment with linezolid.6 AZD2563 compared favourably with linezolid when tested against streptococci (viridans group and ß-haemolytic species)7,8 and the early results from pharmacodynamic studies indicate the potential for once-daily dosing schedules.11 We eagerly await the results of in vivo clinical trials and expanded pharmacokinetic data.


    Acknowledgements
 
The co-authors express their gratitude to the following persons for support in technical areas and in the preparation of the manuscript: K. Meyer, M. A. Pfaller, W. Howard, J. Jones, L. Deshpande and M. Beach. This study was supported by an educational/research grant from AstraZeneca. These results were presented in part at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, December 2001, abstract F-1030.


    Footnotes
 
* Correspondence address. JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: ronald-jones{at}jmilabs.com Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Hoban, D. J., Doern, G. V., Fluit, A. C., Roussel-Delvallez, M. & Jones, R. N. (2001). Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clinical Infectious Diseases 32, Suppl. 2, 81–93.

2 . Jones, R. N. & Pfaller, M. A. (2000). Potencies of newer fluoroquinolones against viridans group streptococci isolated in 637 cases of bloodstream infection in the SENTRY Antimicrobial Surveillance Program (1997 to 1999): Beyond Canada! Antimicrobial Agents and Chemotherapy 44, 2922–3.[Free Full Text]

3 . Morales, W. J., Dickey, S. S., Bornick, P. & Lim, D. V. (1999). Change in antibiotic resistance of group B streptococcus: Impact on intrapartum management. American Journal of Obstetrics and Gynecology 181, 310–4.[ISI][Medline]

4 . Seppala, H., Klaukka, T., Vuopio-Varkila, J., Muotiala, A., Helenius, H., Lager, K. et al. (1997). The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. New England Journal of Medicine 337, 441–6.[Abstract/Free Full Text]

5 . Bryskier, A. (2000). Novelties in the field of anti-infective compounds in 1999. Clinical Infectious Diseases 31, 1423–66.[ISI][Medline]

6 . Diekema, D. J. & Jones, R. N. (2001). Oxazolidinone antibiotics. Lancet 358, 1975–82.[ISI][Medline]

7 . Johnson, A. P., Warner, M., Parsons, T. & Livermore, D. M. (2001). In vitro activity of a novel oxazolidinone, AZD2563, against Gram-positive cocci, including diverse multi-resistant isolates. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1026, p. 223. American Society for Microbiology, Washington, DC.

8 . Turner, P. J., Wookey, A., Greenhalgh, J. M., Eastwood, M. & Clarke, J. (2001). Investigations into the antibacterial spectrum of the new oxazolidinone, AZD2563, against recent clinical isolates from North America and Europe. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1024, p. 222. American Society for Microbiology, Washington, DC.

9 . National Committee for Clinical Laboratory Standards. (2000). Performance Standard for Antimicrobial Susceptibility Testing—Seventh Edition: Approved Standard M2-A7. NCCLS, Wayne, PA.

10 . National Committee for Clinical Laboratory Standards. (2002). Performance Standard for Antimicrobial Susceptibility Testing. Document M100-S12. NCCLS, Wayne, PA.

11 . Craig, W. A. & Andes, D. R. (2001). Pharmacodynamic characteristics of AZD2563, the new oxazolidinone, in a murine thigh-infection model. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract 1037, p. 226. American Society for Microbiology, Washington, DC.