Correspondence

The Effects of Vancomycin and β-Lactam Antibiotics on Vancomycin-Resistant Staphylococcus aureus

N Engl J Med 1999; 341:1624November 18, 1999

Article

To the Editor:

First Sieradzki et al.1 and then Climo et al.2 presented evidence that combinations of vancomycin and β-lactam antibiotics were synergistic in vitro and in vivo against vancomycin-resistant Staphylococcus aureus. We performed population analyses to examine the effectiveness of combinations of vancomycin and β-lactam antibiotics against S. aureus strains with various levels of vancomycin resistance: Mu 3 and Mu 50 3 (provided by Keiichi Hiramatsu, Juntendo University) and wound isolates Fu 10 and Fu 18, which were recovered from a patient receiving combination therapy with β-lactam antibiotics and vancomycin in our hospital.

Figure 1AFigure 1Results of Population Analyses of Strains of Staphylo coccus aureus with Various Levels of Resistance to Vancomycin. shows the results of the population analysis of Fu 10, Fu 18, Mu 3, and Mu 50, plus a reference strain, FDA 209P (American Type Culture Collection 6538P). Fu 10 and Mu 3 had similar levels of resistance to vancomycin, and Fu 18 had a higher level of resistance, although not as high as that of Mu 50. Figure 1B, 1C, 1D, and 1E show the effects of combinations of oxacillin and vancomycin on Fu 10, Mu 3, Fu 18, and Mu 50, respectively. The population-analysis profiles indicate that a high concentration of oxacillin (8.0 μg per milliliter) induced a reduction in the number of subpopulations resistant to vancomycin, as Sieradzki et al.1 and Climo et al.2 indicated. However, at a low concentration of oxacillin — 0.05 μg per milliliter — the number of surviving colonies increased. For example, in the presence of 8.0 μg of vancomycin per milliliter and 0.05 μg of oxacillin per milliliter, the numbers of surviving colonies of Mu 50 were about 200 times as high as those exposed to vancomycin alone. Hence, an antagonistic effect was seen (arrow in Figure 1E).

It is likely that the vancomycin concentration at which the most prominent antagonistic effect of oxacillin is observed increases in proportion to the degree of vancomycin resistance (e.g., 2.0 and 3.0 μg per milliliter for Fu 10, 4.0 and 5.0 μg per milliliter for Fu 18, and 8.0 and 9.0 μg per milliliter for Mu 50). Such antagonistic activity was also demonstrated with another β-lactam antibiotic, ceftizoxime (Figure 1F). Such low concentrations of β-lactam antibiotics are present in tissues or plasma of patients during treatment. Our data on the effect of combination therapy with vancomycin and β-lactam antibiotics on S. aureus with low or intermediate levels of resistance to vancomycin suggest that these combinations should be used with caution to avoid precipitating greater resistance to vancomycin.

Isao Haraga, M.D.
Shuichi Nomura, Ph.D.
Ariaki Nagayama, M.D.
Fukuoka University, Fukuoka 814-0180, Japan

3 References

1. 1

   Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 1999;340:517-523
   Full Text | Web of Science | Medline

2. 2

   Climo MW, Patron RL, Archer GL. Combinations of vancomycin and β-lactams are synergistic against Staphylococci with reduced susceptibilities to vancomycin. Antimicrob Agents Chemother 1999;43:1747-1753
   Web of Science | Medline

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   Hiramatsu K, Aritaka N, Hanaki H, et al. Dissemination in Japanese hospitals of strains of Staphylococcus aureus heterogeneously resistant to vancomycin. Lancet 1997;350:1670-1673
   CrossRef | Web of Science | Medline

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   Yoko Takayama, Hideaki Hanaki, Kazuhiko Irinoda, Hideya Kokubun, Kazunari Yoshida, Keisuke Sunakawa. (2003) Investigation of methicillin-resistant Staphylococcus aureus showing reduced vancomycin susceptibility isolated from a patient with infective endocarditis. International Journal of Antimicrobial Agents 22:6, 567-573
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