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Antimicrobial Agents and Chemotherapy, November 2005, p. 4816-4817, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4816-4817.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

LETTERS TO THE EDITOR

Improved Outcomes with Linezolid for Methicillin-Resistant Staphylococcus aureus Infections: Better Drug or Reduced Vancomycin Susceptibility?

Top Letter References Letter  References

 
In a recent issue of this journal, Weigelt et al. (7) reported the results of a randomized trial of linezolid versus vancomycin for complicated skin and soft tissue infections. Overall, the outcomes for patients treated with linezolid and vancomycin were equivalent; however, patients with proven methicillin-resistant Staphylococcus aureus (MRSA) infections had significantly improved outcomes if they were treated with linezolid (7). Notably, there was no difference in outcome for patients with proven methicillin-susceptible S. aureus (MSSA) infection. These results are intriguing and are similar to the results of a post hoc subgroup analysis of two prospective trials of linezolid versus vancomycin treatment for nosocomial pneumonia, which suggested improved outcome for linezolid-treated patients with proven MRSA infection but equivalent outcomes for all S. aureus infections (8). Why does linezolid appear superior to vancomycin for MRSA infection but equivalent for infections caused by MSSA?

Weigelt et al. suggest the difference may be because the severity of illness was greater in the MRSA group than the MSSA group (7), while Wunderink et al. did not really address this issue, although the APACHE II scores were no different between the MSSA and MRSA groups in the post hoc analysis (8). Both of these reports are notable because they neglect an important consideration, namely, the potential role of reduced vancomycin susceptibility in a subset of MRSA isolates leading to differences in outcome for linezolid and vancomycin.

Low-level vancomycin resistance in S. aureus is increasingly recognized as an important clinical entity (1, 4, 5). In particular, heterogenous vancomycin-intermediate S. aureus has been reported from many countries (6) but is difficult to detect using routine susceptibility testing methods, with population analysis profile testing considered necessary for accurate identification (2, 3). Although these strains have a vancomycin MIC within the susceptible range (often 2 or 4 mg/liter), they have been associated with vancomycin treatment failure (1), and therapy with agents such as linezolid has been effective in these patients (4). Reduced vancomycin susceptibility appears to be far more common in MRSA than in MSSA strains (3, 6).

The recent study by Weigelt et al. (7) does not report vancomycin susceptibility data for any S. aureus isolates; they do not appear to have considered this important issue. Thus, the apparent clinical superiority of linezolid against MRSA may only be relevant to those strains that exhibit reduced vancomycin susceptibility. Without knowing what proportion of the MRSA strains in the study (7) exhibited heterogenous resistance to vancomycin, doubt remains about the relative efficacies of linezolid and vancomycin for fully vancomycin-susceptible MRSA isolates, which in our institution still constitute over 90% of our MRSA bacteremia isolates (1).

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1. Charles, P. G. P., P. B. Ward, P. D. R. Johnson, B. P. Howden, and M. L. Grayson. 2004. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin. Infect. Dis. 38:448-451.[CrossRef][Medline]
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2. Hiramatsu, K. 2001. Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect. Dis. 1:147-155.[CrossRef][Medline]
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3. Howden, B. P., P. B. Ward, P. D. R. Johnson, P. G. P. Charles, and M. L. Grayson. 2005. Low-level vancomycin resistance in Staphylococcus aureus—an Australian perspective. Eur. J. Clin. Microbiol. Infect. Dis. 24:100-108.[CrossRef][Medline]
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4. Howden, B. P., P. B. Ward, P. G. Charles, T. M. Korman, A. Fuller, P. du Cros, E. A. Grabsch, S. A. Roberts, J. Robson, K. Read, N. Bak, J. Hurley, P. D. Johnson, A. J. Morris, B. C. Mayall, and M. L. Grayson. 2004. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin. Infect. Dis. 38:521-528.[CrossRef][Medline]
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5. Tenover, F. C., and L. C. McDonald. 2005. Vancomycin-resistant staphylococci and enterococci: epidemiology and control. Curr. Opin. Infect. Dis. 18:300-305.[Medline]
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6. Walsh, T. R., and R. A. Howe. 2002. The prevalence and mechanisms of vancomycin resistance in Staphylococcus aureus. Annu. Rev. Microbiol. 56:657-675.[CrossRef][Medline]
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7. Weigelt, J., K. Itani, D. Stevens, W. Lau, M. Dryden, C. Knirsch, and the Linezolid CSSTI Study Group. 2005. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob. Agents Chemother. 49:2260-2266.[Abstract/Free Full Text]
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8. Wunderink, R. G., J. Rello, S. K. Cammarata, R. V. Croos-Dabrera, and M. H. Kollef. 2003. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 124:1789-1797.[Abstract/Free Full Text]

						Benjamin P. Howden* Infectious Diseases Department Austin Health Studley Rd., Heidelberg Victoria, 3084 Australia Patrick G. P. Charles Paul D. R. Johnson Peter B. Ward M. Lindsay Grayson Infectious Diseases and Microbiology Departments Austin Health Melbourne, Australia
						* Phone: 61 3 9496 5000, Fax: 61 3 9496 6677, E-mail: Benjamin.Howden{at}austin.org.au

Authors' Reply

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We appreciate the thoughtful and cogent comments by Howden and colleagues in suggesting mechanisms for the observed superior results of linezolid compared to vancomycin in MRSA patients in our trial. We agree that the results could in part be related to heterogenous resistance to vancomycin. In this study, susceptibility tests were performed in local laboratories, most of which do not routinely perform the population analyses or vancomycin E-test necessary to detect heteroresistant S. aureus. The authors are to be congratulated for their outstanding work in this area and for demonstrating that in Australia, vancomycin failure in patients is clearly related to heteroresistance. This has also been noted elsewhere and has been reviewed recently (2).

However, we believe heteroresistance cannot be the only explanation for the observed difference. First, in a review of 14 studies published from 1997 to 2001, only 132/7,920 (1.67%) S. aureus strains demonstrated heteroresistance to vancomycin from geographic locations similar to the clinical trial sites in our trial and over a similar time period (1). Second, vancomycin penetrates tissue less well than linezolid, it is highly protein bound, and there are clearly questions regarding adequate dosing of vancomycin, particularly in endocarditis and ventilator-associated pneumonia. These other factors may not be important for MRSA strains that have MICs of 0.5 or even 1 µg/ml, but these become important factors when MICs are in the 2 to 4 µg/ml range or even higher.

MICs of vancomycin tend to be lower for MSSA strains than for MRSA strains. In our study, the outcomes with methicillin-susceptible S. aureus, although not statistically significant, were numerically better (84.9% linezolid versus 75.3% vancomycin, P = 0.088), providing a hint that factors other than susceptibility play roles in determining outcome. If MICs of vancomycin for MRSA strains continue to rise, then it may be important to reconsider the vancomycin breakpoints for MRSA strains and to revisit the current nomograms for vancomycin dosing. We agree with our colleagues in Australia that heteroresistance is a very important factor in the failure of vancomycin in a variety of infections caused by MRSA strains and that more information is needed on the prevalence of heteroresistant strains.

Top Letter References Letter  References

 

1
1. Liu, C., and H. F. Chambers. 2003. Staphylococcus aureus with heterogeneous resistance to vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimicrob. Agents Chemother. 47:3040-3045.
2
2. Tenover, F. C., and L. C. McDonald. 2005. Vancomycin-resistant staphylococci and enterococci: epidemiology and control. Curr. Opin. Infect. Dis. 18:300-305.

						John A. Weigelt Medical College of Wisconsin Milwaukee, Wisconsin Kamal Itani Boston VA Health Care System and Boston University Boston, Massachusetts Dennis Stevens Veterans Affairs Medical Center Boise, Idaho William Lau St. Francis Medical Center West Honolulu, Hawaii Matthew Dryden Royal Hampshire County Hospital Winchester, Hampshire, United Kingdom Charles Knirsch Pfizer World Wide Medical New York, New York

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Antimicrobial Agents and Chemotherapy, November 2005, p. 4816-4817, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4816-4817.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

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