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Tenover Dr. Fred Tenover
From the Special Topic of Methicillin-Resistant Staphylococcus aureus (MRSA)

In our March 2008 Special Topic on MRSA, the scientist ranked at #2 is Dr. Fred Tenover, with 38 papers cited a total of 2,218 times. In Essential Science IndicatorsSM from Thomson Scientific, Dr. Tenover's citation record for the period between January 1, 1997 and December 31, 2007 includes 107 papers cited a total of 4,968 times in the field of Clinical Medicine, and 26 papers cited a total of 986 times in the field of Microbiology. He has also been named as a Highly Cited researcher in Microbiology.

Dr. Tenover is the Director of the Office of Antimicrobial Resistance, part of the Coordinating Center for Infectious Diseases at the Centers for Disease Control and Prevention in Atlanta, Georgia.

In the interview below, he talks with correspondent Gary Taubes about his work with both MRSA and vancomycin-resistant Staphylococcus aureus.

 What prompted your initial interest in antibiotic resistance?

I started my Ph.D. studies in medical microbiology in 1976, and that was the year that gonococcus, the organism that causes gonorrhea, first became resistant to penicillin. That was a very exciting time in the lab—the first time that this epidemic, sexually-transmitted disease was ever known to fail therapy on a widespread basis.

The year before that, high-level penicillin resistance had also appeared in another pathogen that used to be widespread, called Haemophilus influenzae, the organism that causes bacterial meningitis and lots of ear infections in kids. The resistance gene that caused the resistance to penicillin in Haemophilus, that genetic information, was actually shared with gonococcus, and now gonococcus was becoming harder to treat around the world. Resistance was spreading.

The epidemiology of the resistant gonorrhea strains was fascinating, because it was associated primarily with sailors coming back from the Philippines and Southeast Asia, and then spreading it to little towns across the US. My job was to understand the genetic basis for the resistance in gonococcus, but also more broadly to understand resistance and how it evolves in a variety of different bacteria.

 Your most-cited paper is the 1999 New England Journal of Medicine article on the emergence of vancomycin resistance in Staphylococcus aureus (Smith TL, et al., "Emergence of vancomycin resistance in Staphylococcus aureus," 340[7]: 493-501, 18 February 1999). What prompted the research that led to that paper?

This is Theresa Smith’s paper. It has a very interesting history—it is talking about the development of resistance in Staphylococcus aureus, which is a very common infection, both in hospitals and community settings. And this resistance was something that was predicted for a long time. There is another organism that hangs out in your bowel, part of your normal flora that doesn’t cause you any harm, called Enterococcus. It’s not particularly virulent, but on occasion it can cause serious disease when it ends up in one of your heart valves.

"The bottom line is that everybody has a role in preventing the spread of this organism."

In the 1980s, the enterococci began to be resistant to commonly used drugs like ampicillin and the aminoglycosides. In 1988, we had a report from France about the first high-level vancomycin-resistant strain of Enterococcus. At that time vancomycin was the drug of last resort for these bacterial infections.

The fact that organisms like Enterococcus, which can exchange genetic information with just about any bacterial species, could become resistant to vancomycin was very notable. So there were lots of predictions that Staphylococcus aureus would also become vancomycin resistant, because we knew this genetic resistance could pass from one organism to another.

 So staphylococci becoming resistant to vancomycin seemed inevitable after Enterococcus became resistant?

Yes. Here’s the scenario: you have a relatively avirulent organism, the Enterococcus, which just happens to have lots of resistance genes in it, and one of them produces very high levels of resistance to vancomycin, which is the drug of choice for treating methicillin-resistant Staphylococcus aureus (MRSA), which at this point in time was starting to become epidemic in hospitals around the world. Everybody’s waiting for the shoe to drop. When will Staphylococcus aureus become highly resistant to vancomycin and when will we have untreatable healthcare-related infections start to run around hospitals in the US and around the world?

Lots of public health people, physicians, and researchers were investigating this, trying to figure out when it would happen. In 1992, researchers in the UK did the experiment that everybody said should not be done; they put a vancomycin-resistant Enterococcus in a test tube with the typical MRSA, and what they come up with is a highly vancomycin-resistant S. aureus. They also did that same genetic experiment on the back of a mouse and showed the resistance gene transfer could occur on skin. So now everybody knew it was feasible for Enterococcus to pass genetic information to S. aureus. The question was when would it happen in nature?

 And that’s what Theresa Smith was reporting in your NEJM article?

Well, we still have to go back one step before that paper. In 1997, we had an article in the Journal of Antimicrobial Chemotherapy (Hiramatsu K, et al., "Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility," 40[1]: 135-6, July 1997). The first author was a man named Keiichi Hiramatsu. Here’s the scoop: I had gotten an e-mail from Hiramatsu, whom I knew only by reputation. He was known to be an excellent scientist, and he had been studying resistance in staphylococci for years. He sent me an e-mail saying he had a strain of S. aureus from an infection in a young boy and it was not susceptible to vancomycin. The problem was, nobody believed it—he had submitted his data to several scientific journals and they’d all rejected him. Everybody knew that S. aureus was susceptible to vancomycin. He wanted to send me the strain and see if I got the same result he did, and we reproduced his finding.

 If everybody is expecting vancomycin-resistant MRSA, why didn’t anyone believe what Hiramatsu had found?

First, because nobody had really documented it before and his data came from a single laboratory. It hadn’t been corroborated, which is why he thought of me at the CDC. He sent me a strain; we confirmed the results and that’s what was published in the Journal of Antimicrobial Chemotherapy. But then there was a second problem: that strain of vancomycin-resistant S. aureus did not contain the resistance gene everyone was waiting for from Enterococcus. People said, "Wait a minute, we’re expecting this to happen, but not this way. Plus, it should be very highly resistant to vancomycin and this is just a little resistant. So you probably made a mistake."

But we were able to confirm it. We showed that this strain behaved differently. It had something else going on, and what it had was this enormously thick cell wall. It turned out what this organism had done was essentially make a giant vancomycin sponge on the outside of the cell, and this bound vancomycin before it could get inside the bacteria to the site where it inhibits the organism. Instead of just going out and getting a known resistance gene, the staph came up with this totally new mechanism of resistance.

Then people said, "Since it wasn’t high-level resistance, maybe it wasn’t clinically relevant. Maybe it won’t cause people to fail therapy." But the little boy from Japan, with the chest wound infection from surgery certainly failed therapy, so that wasn’t the case either. And shortly after that report appeared, there was a case in Michigan, a very similar story of a patient who failed vancomycin therapy, and from whom they isolated this vancomycin-intermediate S. aureus, or VISA, for short. The description of that patient in Michigan is what Smith’s article in the New England Journal was all about.

 The description of that one patient?


 Did the organism have the same thick wall as a defense?

Same thick cell wall, but it was a different strain. So a different strain of S. aureus evolved the same mechanism of protection. What happened was you had a patient who got a lot of vancomycin over a long period of time and had these continuing infections with S. aureus. The organism learned how to adapt and how to survive that vancomycin therapy, and it emerged with resistance in what we call the intermediate range, but it was totally unrelated to that patient in Japan. There was no link between Japan and Michigan—just an organism here in the US that figured out basically how to do the same thing. Once again it was not what everybody anticipated, that the Enterococcus resistance gene would move in and make high-level resistance in one fatal swoop.

 Did you expect it to be so highly cited?

I thought it would be highly cited, but not as high as it is. That was a surprise.

 So when does the resistance gene from Enterococcus show up? Or does it?

That happened in 2002, the event that we’d been anticipating since 1988, the first true, high-level vancomycin-resistant staph infection. That was the subject of two papers: one is the clinical description in the New England Journal of Medicine, the first author is Chang in 2003 (Chang S, et al., "Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene," 348[14]: 1342-7, 3 April 2003). The other is by Weigel in Science (Weigel LM, et al., "Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus," 302[5650]: 1569-71, 28 November 2003). The latter paper describes the genetics behind how that staph became vancomycin resistant.

 Where was that case found?

Again in Michigan; the same place where the first VISA case was noted.

 That’s strange. Not a coincidence, presumably?

It was probably not a coincidence. In fact, I just had an editorial published in Clinical Infectious Diseases discussing that ("Vancomycin-resistant Staphylococcus aureus: A perfect but geographically limited storm?" 46[5]: 675-7, 1 March 2008). It’s probably three things. One is that the Enterococcus strain that provides the resistance gene seems to be common in southeastern Michigan. Second, there are lots and lots of patients here who are diabetic and have end-stage renal disease, so there are lots of MRSA infections. And third, because you have lots of MRSA infections in the state for two decades now, there has been lots of vancomycin use. So you have the right bacterial donor, the right bacterial recipient, and the right selective pressure (vancomycin use that forces the bacteria to become resistant). That’s the hypothesis for why this happened in Michigan. In fact, seven of the nine vancomycin-resistant staph cases in the world—not just in the US, but in the world—have all come from the Detroit area.

 Is vancomycin still the drug of last resort for MRSA?

It’s still the preferred treatment, but there are two other, newer, drugs now that can be used in lieu of it.

 Where do we stand now in 2008 with vancomycin resistance?

We’ve had nine VRSA—vancomycin-resistant S. aureus—isolated from around the world; seven from Michigan, one from Pennsylvania, and one from New York. We probably have about 50 VISA strains in the United States and many more around the world. So vancomycin is clearly losing its effectiveness as one of the mainstays for treating particularly hospital-acquired S. aureus infections, which are usually MRSA.

That brings us to the third most commonly cited article on my list, the one by Okuma (Okuma K, et al., "Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community," Journal of Clinical Microbiology 40[11]: 4289-94, November 2002). Everybody thinks of MRSA as one of those classic hospital infections, which is why it has become a very huge problem around the world in hospitals and healthcare centers. But back in 1999, there were four children in Minnesota and North Dakota who all died of MRSA infections but they hadn’t been anywhere close to a hospital for over a year. They had what we call community-associated MRSA. There was no link to health care. This was a big surprise, and it was not supposed to happen.

What Okuma’s article describes is the fact that worldwide, there have been a series of these types of infections—MRSA not associated with any link to healthcare, a true biologically distinct MRSA in the community. We described strains from the US, Switzerland, France, and also some, I believe, from Australia. That article describes this new phenomenon—MRSA as a community pathogen, not just a hospital pathogen.

 How did it evolve in a non-healthcare-related setting?

It looks like what happened was that on a number of occasions, the genetic information to make an organism resistant to methicillin had moved into S. aureus strains that are typically in the community. This is not leakage of bacterial strains out of the hospital. These are very different strains of S. aureus that have acquired methicillin resistance and have been spread incredibly widely, at a very, very fast pace, particularly throughout the US.

This is a real biological success story. This all happened off the radar screen. It happened in people who don’t typically get an MRSA infection. Kids in day care, army recruits, athletes—whether in high school, college, or the pros—and Native Americans on reservations. These are groups of people who have never before been associated with MRSA infections. There have been big outbreaks of community MRSA strains in prisons. Most recently it’s been seen in men who have sex with men, also in people who get tattoos. Now the big thing is in the Netherlands, where MRSA rates in hospitals are less than one percent, but both pigs and pig farmers commonly have MRSA infections.

 Is that what your research is focusing on now?

Well, one of the things I’ve been very involved in is trying to understand how strains of S. aureus are spread, particularly MRSA. One of the problems we have in this field is that everybody calls these strains by different names. People in France would call a strain one thing; we’ll strain-type it in my lab and call it another, and people in Australia will do some strain-typing, maybe by a different method, and give it a different name.

So the question is whether we’re all taking about the same strains or different strains. The strain that caused the VISA infection in that young boy in Japan is called the Tokyo clone, and it turned out that when we exchanged a lot of strains we had a lot of the same strains in New York. So it started to be called the New York/Tokyo clone. But it was known by other names in other parts of the world. One of the problems we’ve had in the field is coming up with a system everybody could agree on, so we all know what strains we’re talking about.

 Have you managed to do so?

That’s the fourth article on the list, by Linda McDougal (McDougal LK, et al., "Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: Establishing a national database," Journal of Clinical Microbiology 41[11]: 5113-20, November 2003). We used a strain-typing technique called pulsed-field gel electrophoresis. What we did with a number of our colleagues was to look at our huge staph collection, type all of them by the same technique, and start giving them names that we think would be used throughout the US, at least.

So, for example, the New York/Tokyo clone, which turns out to be the most common strain you’ll find in US hospitals, we call USA 100. The strain of community-associated MRSA that is now widely spread across the US, and has now spread to Europe and South America, we call USA 300. We went all through the literature, gathered strains from all around the world, retested them here at the CDC, and put them together in this particular paper. So now we can all speak the same language.

 Barring something new showing up entirely, where do you see your research going in the next few years?

One of the things we’re having a hard time understanding right now is how this particular strain, USA 300, could have spread so widely in a relatively short period of time. How can one strain of S. aureus be so successful? Is it because it colonizes the nose or skin particularly well? Is it because for some reason it’s much more transmissible from person to person? Is it much less susceptible to being killed by disinfectants?

These are the sorts of things we don’t know, and which we’ll study. What we have to do as public health people is figure out how to interrupt transmission. We’ve told people the obvious things. Wash your hands. Don’t share towels, razors, etc. Don’t go to the gym and use the equipment and walk away without wiping it down. Be cautious of all these things we learned as kids about hygiene. When it comes to staph infections, all these are very important. And yet we still don’t know why this particular strain, which seems to have high virulence and can cause pretty severe disease in healthy people, has spread so successfully. And will it be replaced by something even more virulent? So the big job now is to stop its spread.

 What’s the prognosis for VRSA?

We anticipate that because vancomycin is so widely used in the United States and elsewhere, that eventually these other enterococci that have the resistance gene will be successful in passing it on to other strains of MRSA and we will see more VRSA occurring. There’s no biological reason why we should only have nine at this point. We anticipate there will be more. Fortunately, we do have some other drugs we can use in lieu of vancomycin. They’re far more expensive, but we have them.

The other thing to remember is that the VRSA problem is less an issue than the community-acquired MRSA, because that strain is very widespread and causes much more disease than the VRSA does. On the other hand, if we do get a widely disseminated community strain that becomes VRSA, then we will have a real crisis.

 What would you like to convey to the general public about your work?

Probably this: when we talk about bacteria—S. aureus or MRSA—it’s common to think about it as though it’s one organism that causes one disease. But this is a very clever organism that can cause a whole variety of diseases ranging from skin infections to bloodstream infections to food-borne diseases to pneumonia that can kill a healthy person in less than 48 hours. It’s also the same organism that causes toxic shock syndrome.

The bottom line is that everybody has a role in preventing the spread of this organism. This means washing your hands. It means not touching other people’s wounds or contaminated clothes. Just thinking healthy. It’s much better to prevent an infection in the first place than to try to treat one with antibiotics after the fact. A little bit of prevention goes a long way.

Fred C. Tenover, Ph.D. (D) A.B.M.M.
Director, Office of Antimicrobial Resistance
Coordinating Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA, USA

Dr. Fred Tenover's most-cited paper with 515 cites to date:
Smith TL, et al., “Emergence of vancomycin resistance in Staphyloccocus aureus,” N. Engl. J. Med. 340(7): 493-501, 18 February 1999. Source: Essential Science IndicatorsSM from Thomson Scientific.
Additional Information:
Dr. Fred Tenover is featured in

Relevant keywords for this interview: MRSA, vancomycin-resistant S. aureus, epidemiology, Enterococcus, community-acquired MRSA, strain-typing, pulsed-gel electrophoresis

Special Topics : Methicillin-Resistant Staphylococcus aureus (MRSA) : Dr. Fred Tenover - Special Topic of MRSA