Archive ScienceWatch



March 2008

Professor Keiichi Hiramatsu
From the Special Topic of Methicillin-Resistant Staphylococcus aureus (MRSA)

In our March 2008 Special Topic on MRSA, the scientist ranked at #1 is Professor Keiichi Hiramatsu, with 51 papers, cited a total of 3,598 times. Three of his papers have also made the list of the top 20 papers published in the past decade. In Essential Science IndicatorsSM from Thomson Scientific, Professor Hiramatsu is in the top 1% of researchers in both Clinical Medicine and Microbiology.

Professor Hiramatsu graduated from Tokyo University Medical School in 1975, and earned a doctorate in Medical Science in 1981 from Tokyo University. After stints in a variety of fields, including immune system genetics at MIT and human retrovirology at Tokyo University and Tokyo Medical Dental University, he joined the staff of Juntendo University in 1988, where he concentrated on the fields of bacteriology and chemotherapy. He is currently Professor of Bacteriology and Director of the Department of Bacteriology at Juntendo, as well as the Director and Professor of the newly founded Center of Excellence (COE) for Infection Control Science at the Juntendo University Postgraduate School.

Professor Hiramatsu has served on the editorial and advisory boards of several journals, including The Lancet, The Lancet Infectious Diseases, Drug Resistance Updates, Journal of Infection and Chemotherapy, Journal of Antimicrobial Chemotherapy, and the International Journal of Antimicrobial Agents. He is also a Visiting Professor at the Tokyo Medical Dental University. His studies on MRSA won him the Japan Medical Association Medical Award in 2002.

In the interview below, Professor Hiramatsu talks with about his highly cited work on MRSA.

What sparked your interest in MRSA in particular?

I started studying MRSA because Takeshi Yokota, former Professor of the Juntendo Bacteriology Department, was studying it. At that time, little was known about the mechanism of resistance of MRSA. I applied my discipline in molecular cloning (which I learned at Susumu Tonegawa's Lab at MIT) to the study of MRSA.

Molecular genetic methodology was still rare in the field of hospital infection and antimicrobial chemotherapy; it was fun to expand my view into the genetic makeup of MRSA, which culminated in the whole-genome sequence determination of two MRSA strains in 2001.

One of your seminal papers is the 1997 Journal of Antimicrobial Chemotherapy paper, "Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility." Would you please sum up the findings from this paper for our readers, as well as talk about its impact on the research community?

This is a short paper which I had a hard time getting published. The paper was rejected by some authoritative journals. I finally asked the late Prof. John David Williams to introduce this paper to the Journal of Antimicrobial Chemotherapy. The publisher decided to publish the paper, which announced the first discovery in Japan of a clinical MRSA strain which resisted vancomycin therapy.

"In this world of resistant bacteria, it is also important to think out the way to treat infectious diseases using strategies other than antibiotics."

The paper stirred up an international sensation because it was the first report of vancomycin-resistant MRSA. At that time I called it Vancomycin-resistant S. aureus, but now it is designated Vancomycin-intermediate S. aureus (VISA). The paper warned that the threat of hospital infection caused by multidrug-resistant pathogens has reached its final stage.

What has happened in this line of research since the 1997 paper?

The news prompted the researchers of the world to screen many clinical MRSA strains and report the identification of similar strains from their countries, which confirmed that the emergence of VISA is a worldwide phenomenon.

My paper's report that vancomycin therapeutic failure occurs with such a low level of resistance (minimum inhibitory concentration[MIC] of 8 mg/L) stirred up a discussion about the effectiveness of vancomycin chemotherapy, which eventually led to the change of the breakpoint for susceptibility from 4 to 2 mg/L, and resistance from 32 to 16 mg/L.

Pharmaceutical companies rekindled their efforts to develop new antibiotics against MRSA, which is becoming a hot field of pharmacology in the 21st century.

Some of your more recent papers address new agents to treat MRSA, such as DX-619 and cloned lysin. Would you talk a little about these agents (and any others) and how they work? 

DX-619 is a unique quinolone agent which has a very strong activity against MRSA. This is the outcome of the trial to raise a narrow-spectrum antibiotic, which has never been a popular idea among the world's pharmaceutical companies. Obviously the antibiotics with a broad spectrum are more liked and used by the clinicians, because they are more versatile. On the other hand, narrow-spectrum antibiotics can be used only for a limited number of patients whose infections are caused by certain bacterial species for which the antibiotics are effective.

However, narrow-spectrum antibiotics are more important in this historical stage of antimicrobial chemotherapy. We have to focus on each of the resistant pathogens and raise novel antimicrobial agents specific to the bug. Such a drug is much stronger and does not select resistant bacteria easily.

In this world of resistant bacteria, it is also important to think out the way to treat infectious diseases using strategies other than antibiotics. Lysis therapy is one of the examples, and I am also engaged in the development of antibody therapy for infection. Finally, vaccination is also an important trial for MRSA infection.

What are your predictions for our ability to keep up with MRSA's evolution and spread?

It is evident that MRSA cannot be overcome by only raising a new antibiotic against it. Our half-century of experience clearly testifies that whatever measure we take, staphylococci will never cease to be our natural flora. However, it is not an easy task for the staphylococci to be resistant to all of the antibiotics. The cost of multidrug resistance is a slowed growth rate. Therefore, we should take advantage of it, and control our use of antibiotics.

If we wisely restrain from using antibiotics as long as the MRSA resident in the patient's body does not cause infection, it may be diluted out by the growth of antibiotic-susceptible staphylococcus strain. To do this we should get the information on the MRSA carriage by hospital patients and even in healthy people in the community. The PCR method for rapid identification of the MRSA carriage would become the critical first step to control MRSA. If we know it is there, we can clean it off by using effective antiseptics.

If patients are diagnosed with severe infection, we definitely need effective antibiotics. In this case, development of novel antibiotics is desirable, but it would be also helpful to develop a rapid test method for quickly revealing the antibiotic susceptibility pattern of the causative MRSA strain. Even if it is multidrug resistant, each MRSA strain tends to have a few antibiotics to which it is susceptible, such as rifampin, co-trimoxazole, and chloramphenicol. If we observe MRSA carefully and treat it properly (without continually threatening it with antibiotics), it would not be difficult to control it. It should be noted that antibiotic resistance emerges because we use antibiotics.

Professor Keiichi Hiramatsu
Juntendo University
Tokyo, Japan

Professor Keiichi Hiramatsu's most-cited paper with 534 cites to date:
Kuroda M, et al., “Whole-genome sequencing of meticillin-resistant Staphylococcus aureus,” Lancet 357(9264): 1225-40, 21 April 2001. Source: Essential Science Indicators from Thomson Scientific.

Special Topics : Methicillin-Resistant Staphylococcus aureus (MRSA) : Professor Keiichi Hiramatsu - Special Topic of MRSA