AUTHOR COMMENTARIES - From Special Topics
From the Special Topic of
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
Science IndicatorsSM from
Scientific, Professor Hiramatsu is in the top 1% of
researchers in both Clinical Medicine and
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 ScienceWatch.com 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
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
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
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
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
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
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
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
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
Hiramatsu's most-cited paper with 534 cites
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