This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Watanabe, Y.
Right arrow Articles by Hiramatsu, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watanabe, Y.
Right arrow Articles by Hiramatsu, K.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2008, p. 4207-4208, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00676-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Improved Antimicrobial Activity of Linezolid against Vancomycin-Intermediate Staphylococcus aureus{triangledown}


arrow
LETTER
 
Linezolid (LZD) has been used for the treatment of nosocomial and community-acquired pneumonia, as well as complicated skin and soft-tissue infection caused by methicillin-resistant Staphylococcus aureus (MRSA), including vancomycin (VCM)-intermediate S. aureus (VISA) (5, 10, 12). Since the first report of a VISA strain in 1997, VISA infection has been reported in many countries (2, 7). Because VISA tends to exhibit cross-resistance to some anti-MRSA agents, such as teicoplanin and daptomycin (4, 9, 11), we evaluated the in vitro activity of LZD toward VISA strains isolated from various countries of the world. During the susceptibility tests, quite unexpectedly, we noticed that the LZD MIC was relatively low for VISA clinical strains compared to that for VCM-susceptible S. aureus (VSSA). To confirm this phenomenon, we compared VCM and LZD MICs for clinical VSSA and VISA strains, with a total number of 47 VSSA strains and 43 VISA strains (3), including 28 VISA strains from the network on antimicrobial resistance in S. aureus (http://www.narsa.net/content/default.jsp). To evaluate VCM and LZD susceptibilities more precisely, the MICs were also determined using Etest strips (AB Biodisk, Sweden). The test confirmed a significant inverse relationship of VCM and LZD susceptibilities between VSSA and VISA. The MICs of VCM for VSSA and VISA were 1.65 ± 0.38 and 5.16 ± 1.42 mg/liter, and those of LZD for VSSA and VISA were 2.14 ± 0.81 and 1.46 ± 0.51 mg/liter, respectively (Student's t test; P < 0.01 for VISA results versus VSSA results for both VCM and LZD).

To further confirm the phenomenon, we evaluated the VCM and LZD MICs for 15 isogenic sets of clinical VISA strains, their passage-derived VCM-susceptible strains, and VISA phenotypic revertant strains using Etest strips (3, 4). An inverse relationship between VCM and LZD susceptibilities was again observed in most of these isogenic triple sets of VISA and their derivatives (Table 1). Regression analysis with the above 15 triple sets confirmed the existence of a negative correlation between VCM and LZD MICs, with a correlation coefficient of –0.628 (P < 0.01).


View this table:
[in this window]
[in a new window]

  		TABLE 1. VCM and LZD susceptibility profiles for VISA strains and their derivativesa

Finally, to further confirm this negative correlation, we generated another set of isogenic strains from the VCM-susceptible laboratory strain N315LR5-P1 (VCM MIC = 0.75 mg/liter). The strain is a heterogeneously methicillin-resistant derivative of N315 with its mecI gene inactivated and its penicillinase plasmid eliminated (1, 8). The strain was cultivated in gradual increments of VCM concentrations, and isogenic resistant mutants were selected from ascending VCM concentrations of 1, 2, 3, and 4 mg/liter. This set of isogenic laboratory-derived strains with gradual increments of VCM resistance was subjected to LZD MIC determination. Consistent with results of the first two investigations, we found that the derivative strains with higher VCM resistance had greater susceptibility to LZD and vice versa (Table 2). Analysis of resistant subpopulations (population analysis [6]) of the derivative strains also showed an inverse relationship between VCM and LZD susceptibilities (Fig. 1), indicating that N315LR5-P1 becomes more susceptible to LZD as it acquires VCM resistance. We carried out the same experiment using chloramphenicol, clindamycin, azithromycin, and quinupristin-dalfopristin. Unlike the case with LZD, there was no clear correlation between results for VCM and those for the above antibiotics. Taken together, the results presented here show a curious negative correlation between VCM and LZD susceptibilities in MRSA. The phenomenon seems to reveal a weakness of VISA posed by its vancomycin resistance mechanism, which might provide a hint for developing a new strategy in the treatment of VISA infection.


View this table:
[in this window]
[in a new window]

  		TABLE 2. VCM and LZD MICs for N315-LR5-P1 and its derivatives


Figure 1
View larger version (20K):
[in this window]
[in a new window]

  		FIG. 1. Antibiotic-resistant subpopulation profiles of N315LR5-P1 and its vancomycin-resistant derivatives. Note that the order of their antibiotic resistance patterns for vancomycin (left) and linezolid (right) is inverted.


arrow
ACKNOWLEDGMENTS
 
This work was supported by a Grant-in-Aid for 21st Century COE Research and a Grant-in-Aid for Scientific Research on Priority Areas (13226114 and 18590438) from the Ministry of Education, Science, Sports, Culture and Technology of Japan.


arrow
FOOTNOTES
 
{triangledown} Published ahead of print on 18 August 2008. Back


arrow
REFERENCES
 
    1
  1. Asada, K., Y. Inaba, E. Tateda-Suzuki, K. Kuwahara-Arai, T. Ito, and K. Hiramatsu. 1995. Evolution and resistance expression of MRSA. Evaluation of beta-lactam antibiotics against a set of isogenic strains with different types of phenotypic expression. Acta Biochim. Pol. 42:517-524.[Medline]
    2. 2
  2. Cui, L., and K. Hiramatsu. 2003. Vancomycin-resistant Staphylococcus aureus, p. 187-212. In A. C. Fluit and F. J. Schmitz (ed.), MRSA: current perspectives. Caister Academic Press, Norfolk, England.
    3. 3
  3. Cui, L., X. Ma, K. Sato, K. Okuma, F. C. Tenover, E. M. Mamizuka, C. G. Gemmell, M. N. Kim, M. C. Ploy, N. El-Solh, V. Ferraz, and K. Hiramatsu. 2003. Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J. Clin. Microbiol. 41:5-14.[Abstract/Free Full Text]
    4. 4
  4. Cui, L., E. Tominaga, H. M. Neoh, and K. Hiramatsu. 2006. Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob. Agents Chemother. 50:1079-1082.[Abstract/Free Full Text]
    5. 5
  5. Diekema, D. J., and R. N. Jones. 2001. Oxazolidinone antibiotics. Lancet 358:1975-1982.[CrossRef][Medline]
    6. 6
  6. Hiramatsu, K., N. Aritaka, H. Hanaki, S. Kawasaki, Y. Hosoda, S. Hori, Y. Fukuchi, and I. Kobayashi. 1997. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 350:1670-1673.[CrossRef][Medline]
    7. 7
  7. Hiramatsu, K., M. Kapi, Y. Tajima, L. Cui, S. Trakulsomboon, and T. Iso. 2004. Advances in vancomycin resistance: research in Staphylococcus aureus, p. 289-298. In M. Alekshun, P. McDermott, and D. White (ed.), Frontiers in antibiotic resistance: a tribute to Stuart B. Levy. ASM Press, Washington, DC.
    8. 8
  8. Kuroda, M., T. Ohta, I. Uchiyama, T. Baba, H. Yuzawa, I. Kobayashi, L. Cui, A. Oguchi, K. Aoki, Y. Nagai, J. Lian, T. Ito, M. Kanamori, H. Matsumaru, A. Maruyama, H. Murakami, A. Hosoyama, Y. Mizutani-Ui, N. K. Takahashi, T. Sawano, R. Inoue, C. Kaito, K. Sekimizu, H. Hirakawa, S. Kuhara, S. Goto, J. Yabuzaki, M. Kanehisa, A. Yamashita, K. Oshima, K. Furuya, C. Yoshino, T. Shiba, M. Hattori, N. Ogasawara, H. Hayashi, and K. Hiramatsu. 2001. Whole genome sequencing of methicillin-resistant Staphylococcus aureus. Lancet 357:1225-1240.[CrossRef][Medline]
    9. 9
  9. Patel, J. B., L. A. Jevitt, J. Hageman, L. C. McDonald, and F. Tenover. 2006. An association between reduced susceptibility to daptomycin and reduced susceptibility to vancomycin in Staphylococcus aureus. Clin. Infect. Dis. 42:1652-1653.[CrossRef][Medline]
    10. 10
  10. Ruef, C. 2004. Epidemiology and clinical impact of glycopeptide resistance in Staphylococcus aureus. Infection 32:315-327.[CrossRef][Medline]
    11. 11
  11. Sakoulas, G., J. Alder, C. Thauvin-Eliopoulos, R. C. Moellering, Jr., and G. M. Eliopoulos. 2006. Induction of daptomycin heterogeneous susceptibility in Staphylococcus aureus by exposure to vancomycin. Antimicrob. Agents Chemother. 50:1581-1585.[Abstract/Free Full Text]
    12. 12
  12. Wunderink, R., J. Rello, S. Cammarata, R. Croos-Dabrera, and M. Kollef. 2003. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 124:1789-1797.[CrossRef][Medline]
Yukiko Watanabe
Hui-min Neoh
Longzhu Cui
Keiichi Hiramatsu*
Department of Bacteriology
Faculty of Medicine
Juntendo University
2-1-1 Hongo, Bunkyo-Ku
Tokyo, Japan 113-8421

* Phone: 81 (03) 5802-1040, Fax: 81-3-5684-7830, E-mail: khiram06{at}med.juntendo.ac.jp

Antimicrobial Agents and Chemotherapy, November 2008, p. 4207-4208, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00676-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Watanabe, Y.
Right arrow Articles by Hiramatsu, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Watanabe, Y.
Right arrow Articles by Hiramatsu, K.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»