In vitro activity of quinupristin/dalfopristin, linezolid, telithromycin and comparator antimicrobial agents against 13 species of coagulase-negative staphylococci

M. A. John1,2, C. Pletch1 and Z. Hussain1,2,*

1 Department of Microbiology & Infection Control, London Health Sciences Centre; 2 University of Western Ontario, London, Ontario, Canada

Received 18 January 2002; returned 17 July 2002; revised 28 August 2002; accepted 10 September 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: To determine in vitro susceptibilities of a large series of speciated coagulase-negative staphylococci (CNS) against three new antibiotics, linezolid, quinupristin/dalfopristin and telithromycin.

Methods: Susceptibilities to three new antibiotics and oxacillin, vancomycin, clindamycin and erythromycin were determined by the agar dilution method, as described by the NCCLS.

Results: Resistance to linezolid was not observed in any isolates, although MIC90 values varied between species. Fifteen of 658 (2.3%) isolates were resistant to quinupristin/dalfopristin, but <1% of the clinically most important isolates of Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus hominis demonstrated resistance to this agent. Susceptibility to clindamycin correlated with susceptibility to quinupristin/dalfopristin; however, resistance to clindamycin did not predict quinupristin/dalfopristin resistance. Telithromycin was the least active of the new agents tested, showing activity similar to that of clindamycin. Susceptibility and resistance to clindamycin were predictive of susceptibility and resistance to telithromycin.

Conclusion: Clindamycin susceptibility can be used as a surrogate marker for susceptibility to quinupristin/dalfopristin and telithromycin. Quinupristin/dalfopristin and linezolid show good activity against both mecA-positive and -negative CNS.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Over the last decades, the incidence of nosocomially acquired Gram-positive infections has increased, and coagulase-negative staphylococci (CNS) are now a major cause of hospital-acquired bloodstream infections.1,2 They are the most common cause of infections associated with the presence of intravascular catheters, cerebrospinal fluid shunts, prosthetic valves, orthopaedic devices, pacemakers, dialysis catheters and vascular grafts. Typically between 50% and 80% of CNS, depending on the species, are mecA positive.2,3 Antimicrobial resistance in these organisms has complicated treatment of infections and vancomycin has become the first line agent for these infections.4,5

The purpose of this study was to determine the in vitro activity of three new antimicrobials, linezolid, quinupristin/dalfopristin and telithromycin, against a collection of speciated CNS. For the purpose of comparison, the MICs of clindamycin, erythromycin, oxacillin and vancomycin were determined.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 658 non-duplicate clinical isolates of CNS were collected from patients at the University and Victoria Campuses of the London Health Sciences Centre, London, Ontario, Canada. All isolates were speciated using conventional biochemical tests and cellular fatty acid profiles determined by gas–liquid chromatography.6 The presence or absence of the mecA gene was determined using multiplex PCR.3

Thirteen species were represented amongst the isolates: Staphylococcus auricularis (five), Staphylococcus capitis (29), Staphylococcus caprae (34), Staphylococcus cohnii (31), Staphylococcus epidermidis (186), Staphylococcus haemolyticus (39), Staphylococcus hominis (76), Staphylococcus lugdunensis (51), Staphylococcus saprophyticus (38), Staphylococcus schleiferi (45), Staphylococcus simulans (39), Staphylococcus warneri (43) and Staphylococcus xylosus (42). In addition to susceptibilities to linezolid, quinupristin/dalfopristin and telithromycin, MICs of erythromycin, clindamycin, oxacillin and vancomycin were determined. Linezolid, and quinupristin/dalfopristin and telithromycin reference powders were kindly provided by Pharmacia & Upjohn, Inc. (Kalamazoo, MI, USA) and Aventis Pharma (Bridgewater, NJ, USA), respectively. All other reference antibiotic powders were obtained from Sigma Chemical Co. (Indianapolis, IN, USA). Agar dilution MIC testing was carried out by the procedures advocated by the NCCLS.7 In addition to test isolates, the NCCLS-recommended control strains Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and Enterococcus faecium ATCC 19434 were included with each test batch.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A summary of data is presented in Table 1. Two hundred and eleven of 658 isolates tested (32%) were mecA positive. Interestingly, 221/447 mecA-negative isolates had an oxacillin MIC of >0.5 mg/L. Therefore, these were phenotypically resistant to oxacillin, using the NCCLS breakpoints for oxacillin susceptibility and resistance for CNS.8


View this table:
[in this window]
[in a new window]
 
Table 1.  In vitro susceptibilities to quinupristin/dalfopristin, linezolid, telithromycin and comparator antimicrobial agents of 17 species of CNS
 
Quinupristin/dalfopristin was more active than clindamycin, and only 15/658 (2.3%) isolates were resistant. S. capitis, S. epidermidis, S. lugdunensis, S. schleiferi, S. simulans and S. warneri were most susceptible, with MIC90s of 0.5 or 1 mg/L. Approximately 29% of S. cohnii isolates were resistant to quinupristin/dalfopristin. Susceptibility to clindamycin was associated with susceptibility to quinupristin/dalfopristin; however, resistance to clindamycin did not indicate quinupristin/dalfopristin resistance. Of 522 isolates that were susceptible to clindamycin, 410 (78.5%) were susceptible and 102 (19.5%) were classified in the intermediate category (for a total of 98.0%) for quinupristin/dalfopristin. On the other hand, 95.5% of 136 clindamycin-resistant strains were susceptible to quinupristin/dalfopristin.

Linezolid demonstrated good activity against all CNS and resistance to it was not observed. S. caprae was most susceptible with an MIC90 of 1 mg/L. S. capitis, S. hominis, S. lugdunensis, S. haemolyticus, S. simulans and S. warneri had MIC90s of 2 mg/L. All the remaining species had an MIC90 of 4 mg/L. Resistance to oxacillin, clindamycin or any other agent did not affect susceptibility to linezolid.

The activity of telithromycin against CNS was similar to that of clindamycin. Susceptibility and resistance to clindamycin were predictive of telithromycin MICs of <2 or >4 g/L. Of 522 clindamycin-susceptible isolates, 98.1% had MICs of <2 g/L, and of 136 clindamycin-resistant strains, 123 (90.4%) had MICs of telithromycin > 4 g/L. Overall, activity of telithromycin against CNS was better than that of erythromycin, with resistance rates of 34.6% for erythromycin and 20.2% for telithromycin.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The CNS are a heterogeneous group of organisms made up of approximately 15 species known to cause infections in man. They are important causes of infection, particularly in the presence of foreign bodies. Most clinical laboratories do not routinely speciate the CNS, and not all species are equally represented in infections. More than 90% of blood culture isolates belong to three species, S. epidermidis, S. haemolyticus and S. hominis.2 The activity of oxacillin against different species of CNS is quite variable, as demonstrated previously.3

Marked increases in multidrug-resistant Gram-positive bacteria have compromised the selection of agents available for therapy.4 Emergence of vancomycin-resistant enterococci raised the concern that this resistance could be transferred to staphylococci, and recently a vancomycin-resistant S. aureus was isolated from a patient with a catheter exit-site infection.9 New classes of antibiotics with novel mechanisms of action are highly desirable. Quinupristin/dalfopristin, linezolid, and to certain extent telithromycin, are such antibiotics.

Quinupristin/dalfopristin had good activity against most species of CNS regardless of the presence of the mecA gene. More than 97% of isolates had MICs of <4 g/L. Amongst the three most commonly occurring species, S. epidermidis, S. haemolyticus and S. hominis, resistance rates were <1.0%. Overall susceptibility results of this study are similar to those published previously.1012 However, species-specific rates of resistance in the present study differed significantly from those reported from Taiwan.10

Susceptibility to clindamycin was found to be predictive of susceptibility to quinupristin/dalfopristin; a similar correlation has been reported for S. aureus.13 Quinupristin/dalfopristin, unlike other macrolides and lincosamides, is bactericidal and has a prolonged post-antibiotic effect, so that the potential for development of resistance is low.14 Its use is complicated by a number of drug incompatibilities and its metabolism by the P450 cytochromes leads to numerous drug interactions. Resistance to quinupristin/dalfopristin has already been reported, both in E. faecium and staphylococci. Several mechanisms of resistance have been identified.15

Linezolid, along with vancomycin, was the most active agent against the CNS isolates, both mecA positive and negative. A report from Taiwan documented non-susceptibility to linezolid in 2% of CNS isolates from that country.10 Although clinical data are lacking, linezolid may prove to be a useful agent in treating CNS infections owing to its excellent oral bioavailability. There have been reports of reversible myelosuppression with longer-term use of linezolid, and further experience is needed on the use of this agent in infections requiring long-term therapy (such as prosthetic valve endocarditis or orthopaedic device infections).16

In our study, telithromycin showed superior activity against mecA-positive and -negative CNS when compared with erythromycin. This observation has also been reported previously.1719 Activity was, however, no better than that of clindamycin. In the present study, susceptibility and resistance to clindamycin were predictive of susceptibility and resistance to telithromycin. A similar correlation was noted by Jamijian et al.20 between clindamycin and another ketolide (RU-64004).


    Acknowledgements
 
The authors wish to thank Aventis Pharma (Laval, Quebec) and Pharmacia & Upjohn Inc. (Kalamazoo, MI, USA) for financial support for this study.


    Footnotes
 
* Corresponding author. Tel: +1-519-685-8149; Fax: +1-519-685-8203; E-mail: Zafar.hussain{at}lhsc.on.ca Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Emori, T. G. & Gaynes, R. P. (1993). An overview of nosocomial infections, including the role of the microbiology laboratory. Clinical Microbiology Reviews 6, 428–42.[Abstract]

2 . Marshall, S. A., Wilke, W. W., Pfaller, M. A. & Jones, R. N. (1998). Staphylococcus aureus and coagulase-negative staphylococci from blood stream infections: frequency of occurrence, antimicrobial susceptibility, and molecular (mecA) characterization of oxacillin resistance in the SCOPE program. Diagnostic Microbiology and Infectious Disease 30, 205–14.[ISI][Medline]

3 . Hussain, Z., Stoakes, L., Massey, V., Diagre, D., Fitzgerald, V., Elsayed, S. et al. (2000). Correlation of oxacillin MIC with mecA gene carriage in coagulase-negative staphylococci. Journal of Clinical Microbiology 38, 752–4.[Abstract/Free Full Text]

4 . Tomasz, A. (1994). Multiple-antibiotic-resistant bacteria—report on the Rockefeller University workshop. New England Journal of Medicine 330, 1247–51.[Free Full Text]

5 . Carbon, C. (1999). Cost of treating infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci. Journal of Antimicrobial Chemotherapy 44, 31–6.[Abstract/Free Full Text]

6 . Stoakes, L., John, M. A., Lannigan, R., Schieven, B. C., Ramos, M., Harley, D. et al. (1994). Chromatography of cellular fatty acids for identification of staphylococci. Journal of Clinical Microbiology 323, 1908–10.

7 . 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, USA.

8 . National Committee for Clinical Laboratory Standards. (1999). Performance Standards for Antimicrobial Susceptibility Testing—Ninth Informational Supplement: NCCLS Document M100-S9. NCCLS, Wayne, PA, USA.

9 . Morbidity and Mortality Weekly Report. (2002). Staphylococcus aureus resistant to vancomycin—United States. Morbidity and Mortality Weekly Report 51, 565–7.[Medline]

10 . Luh, K. T., Hsueh, L. J., Pan, H. J., Chen, Y. C. & Lu, J. (2000). Quinupristin-dalfopristin resistance among Gram-positive bacteria in Taiwan. Antimicrobial Agents and Chemotherapy 44, 3374–80.[Abstract/Free Full Text]

11 . Jones, R. N., Ballow, C., Biedenbach, D. J., Deinhart, J. A. & Schentag, J. J. (1998). Antimicrobial activity of quinpristin-dalfopristin (RP 59500, Synercid®) tested against 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. Diagnostic Microbiology and Infectious Disease 30, 437–51.

12 . Dowzicky, M., Nadler, H. L., Fegner, C., Talbot, G., Bompa, F. & Pease, M. (1998). Evaluation of in-vitro activity of quinupristin/dalfopristin and comparator antimicrobial agents against worldwide clinical trial and other laboratory isolates. American Journal of Medicine 104, 34S–42S.[Medline]

13 . Fuchs, P. C., Barry, A. L. & Brown, S. D. (2000). Bactericidal activity of quinupristin-dalfopristin against Staphylococcus aureus: clindamycin susceptibility as a surrogate indicator. Antimicrobial Agents and Chemotherapy 44, 2880–2.[Abstract/Free Full Text]

14 . Vannuffel, P. & Cocito, C. (1996). Mechanism of action of streptogramins and macrolides. Drugs 51, Suppl. 1, 20–30.[ISI][Medline]

15 . Thal, L. A. & Zervos, M. J. (1997). Occurrence and epidemiology of resistance to virginiamycin and streptogramins. Antimicrobial Agents and Chemotherapy 43, 171–6.

16 . Green, S. L., Maddox, J. C. & Huttenbach, E. D. (2001). Linezolid and reversible myelosuppression. Journal of the American Medical Association 285, 1291.[Free Full Text]

17 . Barry, A. L., Fuchs, P. C. & Brown, S. D. (1998). In vitro activities of ketolides HMR 3647 against Gram-positive clinical isolates and Haemophilus influenzae. Antimicrobial Agents and Chemotherapy 42, 2138–40.[Abstract/Free Full Text]

18 . Boswell, F. J., Andrews, J. M., Ashby, J. P., Fogarty, C., Brenwald, N. P. & Wise, R. (1998). In-vitro activity of HMR 3647, a new ketolide antimicrobial agent. Journal of Antimicrobial Chemotherapy 42, 703–9.[Abstract]

19 . Jones, R. N. & Biedenbach, D. J. (1997). Antimicrobial activity of RU-66647, a new ketolide. Diagnostic Microbiology and Infectious Disease 27, 7–12.[ISI][Medline]

20 . Jamijian, C., Biedenbach, D. J. & Jones, R. N. (1997). In-vitro evaluation of a novel ketolide antimicrobial agent, RU-64004. Antimicrobial Agents and Chemotherapy 41, 454–9.[Abstract]





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
50/6/933    most recent
dkf241v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (3)
Disclaimer
Request Permissions
Google Scholar
Articles by John, M. A.
Articles by Hussain, Z.
PubMed
PubMed Citation
Articles by John, M. A.
Articles by Hussain, Z.