J Antibiot. 2017 Jul;70(8):907-910. doi: 10.1038/ja.2017.56. 

D-cycloserine increases the effectiveness of vancomycin against vancomycin-highly resistant Staphylococcus aureus.

Tabuchi F1, Matsumoto Y2, Ishii M2,3, Tatsuno K4, Okazaki M5, Sato T4, Moriya K4, Sekimizu K2,3.

1 Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
2 Teikyo University Institute of Medical Mycology, Tokyo, Japan.
3 Genome Pharmaceuticals Institute Co. Ltd, Tokyo, Japan.
4 Faculty of Medicine, Department of Infection Control and Prevention, The University of Tokyo, Tokyo, Japan.
5 Department of Medical Technology, School of Health Sciences, Tokyo University of Technology, Tokyo, Japan.

 

Abstract

Vancomycin is a widely used clinical drug to treat for infection by methicillin-resistant Staphylococcus aureus. Some patients show a weak response to vancomycin treatment. We previously reported that β-lactams increase the susceptibility to vancomycin by vancomycin-highly resistant S. aureus (VRSA) strains obtained following repeated in vitro mutagenesis and vancomycin selection. Here we found that the susceptibility of the VRSA strains to vancomycin was remarkably increased by combined treatment with D-cycloserine. On the other hand, VRSA did not show increased susceptibility to vancomycin in combination with bacitracin, fosfomycin, erythromycin, lincomycin, gentamicin, levofloxacin or nisin. Furthermore, in an in vivo infection model with silkworms, combined treatment with vancomycin and D-cycloserine exhibited therapeutic effects, whereas treatment with each compound alone did not. These findings suggest that combined treatment with vancomycin and D-cycloserine could be therapeutically effective against infectious diseases caused by VRSA.

PMID: 28588223

 

Supplement:

Multidrug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) are isolated worldwide. Therefore, there is an urgent need to establish novel treatment strategies effective for infection caused by multidrug resistant bacteria.

 

Vancomycin-intermediate-resistant Staphylococcus aureus (VISA) strains have been clinically isolated, and medical treatment against those strains are difficult 1. We found that the combination of a β-lactam and vancomycin was effective against a vancomycin highly-resistant strains obtained from clinical isolates of MRSA strains by repeating steps of mutagenesis and vancomycin selection 2. Although these strains are resistant to β-lactam and vancomycin, the combination of a β-lactam and vancomycin is effective. The result suggests that administration of combinations of antibiotics whose clinical use was terminated due to the emergence of resistant bacteria are strategies effective for infection caused by multidrug resistant bacteria.

 

In this study, we showed that D-cycloserine increased the sensitivity of vancomycin against vancomycin highly-resistant Staphylococcus aureus (VRSA) strains. The administration of combination of D-cycloserine and vancomycin was effective against infection caused by a VRSA strain. The results suggest that D-cycloserine is a promising agent to use with vancomycin for treatment against infection caused by VRSA.

 

Based on our findings, we have proposed the concept “drug re-use” for the treatment of infectious diseases caused by multidrug resistant bacteria. Key to this concept is the combined use of antibiotics that are judged to be unsuitable to use by themselves due to the emergence of drug-resistant bacteria. Because the safety of individual antibiotics has already been established, it is advantage compared with new drug candidates that are in stage of drug development. In the development of new drugs, several years are required to gather the information about safety to use, and in many cases it cannot reach clinical application. Administration of combinations of antibiotics whose clinical use was terminated due to the emergence of resistant bacteria might be strategies in clinical effective for infection caused by multidrug resistant bacteria.

 

Silkworm infection model was used in this study for evaluation of the therapeutic effect of the combination of vancomycin and D-cycloserine against infection caused by VRSA. Since the pharmacokinetics and toxicity of drug candidates is difficult to estimate in vitro, evaluation using animal model is required 3-6. Silkworms have several advantages compared to mammals, including lower breeding costs and fewer ethical problems with regard to animal welfare. We established silkworm infection models to evaluate the therapeutic effects of antibacterial and antifungal agents 7-9. The pharmacokinetic parameters and the median effective dose (ED50) values (mg/g animal) of antibiotics are consistent between the silkworm model and mammalian models 9-11. Administration of the combination of vancomycin and D-cycloserine leads to extend the survival period of silkworms infected with VRSA. On the other hand, administration of vancomycin or D-cycloserine alone does not lead to extend. These findings suggest that silkworm infection model is useful to evaluate the therapeutic effect by the combined administration of drugs.

 

Our strategy to select drug combinations against multidrug resistant bacteria for clinical application is described below (Figure 1). The drugs are selected from antibiotics that are judged to be unsuitable to use by themselves due to the emergence of drug-resistant bacteria.

1). Screening of drugs that increase sensitivity of other antibiotics against multidrug resistant bacteria in vitro.

2). Evaluation of therapeutic activity of the combination of drugs by using silkworm infection model in vivo.

3). Determination of effective drug concentrations, which are in safety range for humans, by using silkworm infection model in vivo.

4). Application of the drug combination to human patients infected with multidrug resistant bacteria.

 

In conclusion, combination of “drug re-use” and silkworm infection models might be useful to select rapidly effective drugs for treatment of infectious diseases in human patients infected with multidrug resistant bacteria.

 


Figure 1  Outline of a strategy to select drug combinations against multidrug resistant bacteria for clinical application.

 


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