COMMENTARY

Carbapenem Resistance in the United States: What Should Clinicians Do?

Arjun Srinivasan, MD; Alexander J. Kallen, MD, MPH

Disclosures

December 06, 2010

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Arjun Srinivasan, MD: Hi, I'm Dr. Arjun Srinivasan. I'm the Associate Director for Healthcare-Associated Infection Prevention Programs here at the Centers for Disease Control and Prevention (CDC). We're here today for this Medscape Peer-to-Peer discussion on carbapenem-resistant Enterobacteriaceae (CRE). I'm joined by my colleague, Dr. Alex Kallen, a medical epidemiologist in the Division of Healthcare Quality Promotion.

Alex, why don't you get us started? There has been a lot in the press lately about carbapenem-resistant Enterobacteriaceae, in particular the NDM-1 (New Delhi metallo-beta-lactamase) resistance mechanism. Can you say a few words about these new resistance mechanisms that people are hearing so much about?

Alexander J. Kallen, MD, MPH: Sure, I'd be happy to. As most people are probably aware, we've recognized a number of NDM-1s in the United States since about April of 2009. So far that number stands at 5 from 4 different states. All the cases that we've identified so far have been associated with medical care in either India or Pakistan. Most of these involved inpatient stays, although there is 1 case that was in a patient who had a chronic medical device and several comorbidities but wasn't actually admitted to the hospital.

It's important to point out that none of these cases were associated with medical tourism. We've seen these isolates in a number of different species including Escherichia coli Enterobacteriaceae and Klebsiella pneumoniae, and these have been identified from both urine and respiratory specimens.

Interestingly, we've also recognized several other metallo-beta-lactamases besides the NDM-1. So far we've seen 5 of these in the United States, beginning in about November of 2009. Two of these cases were associated with medical care in other countries, 1 from Italy and 1 from Greece, all have been Klebsiella pneumoniae and most have been from urine, with 1 from blood. It is important to point out, however, that systematic surveillance is not being conducted on these organisms, and these are likely underestimates of the true prevalence of these organisms. Most of these strains that I mentioned have been sensitive to a number of antibiotics, including tigecycline and colistin, but at least 1 of these isolates was nonsusceptible to all known antimicrobials.

However, as you know, these 10 cases now are really just a drop in the bucket when it comes to CRE in the US. Can you elaborate?

Dr. Srinivasan: Yes, absolutely, Alex, I think that's a good point and I think a take-home message from this is that there is a lot of attention focused on these new resistance mechanisms, the NDM-1 and the VIM and the IMP, but in the United States right now, the Klebsiella pneumoniae carbapenemase (KPC enzyme), is far and away the most common mechanism by which these Enterobacteriaceae bacteria, like E. coli and Klebsiella, are becoming resistant to carbapenems. The KPC enzyme, unlike some of the other ones that are thought to be more common in other countries and imported into the United States, was first identified here in the US back in 2000, and since that time, [it] has increased in frequency and become more widespread.

For example, we know that in infections reported to CDC in healthcare-associated infections for Klebsiella, 8% of the Klebsiella now reported to us are resistant to carbapenems, and we think that almost all of those are resistant because they have acquired this KPC enzyme.

We've seen reports that the KPC-containing organisms have spread from North Carolina to 35 different states. We also have a better understanding of the mortality of these KPC infections, and it's a very serious infection. In a study in New York, which is some of the most systematic information [available] on these KPC infections, there was about a 40% mortality attributable to these infections, so they're very serious infections.

As you've pointed out, there are a variety of different ways that these organisms can become resistant, but ultimately knowing which enzyme the organism had is really not that important from a clinical standpoint. They all functionally, we think, behave the same way with respect to the need for infection control and the treatment difficulties that they pose. It is most important to take a step back and view the totality of carbapenem-resistant Enterobacteriaceae, taken altogether, and not worry so much about the specific method by which the organism is resistant.

When we think about carbapenem-resistant Enterobacteriaceae, it's important to emphasize a few key points about them. First of all, we've seen that these organisms really have a propensity to spread in healthcare settings, and we've seen that in this country, we've seen that in other countries, and you can say a few words about that when you talk about some of the outbreak investigations that we've done.

The other issue that gives us cause for concern is that the Enterobacteriaceae organisms can cause both healthcare and community types of infections. Right now all of our experience with these carbapenem-resistant Enterobacteriaceae is related to healthcare in this country, but we have begun to see some of these infections outside of hospitals, in long-term care facilities, and so there is concern about community-based pathogens acquiring this resistance mechanism.

The last thing that emphasizes the need to try and prevent and control these infections is the fact that they're very difficult to treat as you mentioned, some of them are truly resistant to all the antibiotics that we have, and we know that there are not going to be new drugs to treat these types of infections coming any time soon.

So, let me turn it back over to you. You've led a number of outbreak investigations of these carbapenem-resistant Enterobacteriaceae, and the experience from those investigations really helps inform how we can prevent and control these infections. Can you say a few words about the investigations that you've done and what you've learned from them?

Dr. Kallen: Sure. We're lucky here at CDC in that we have the opportunity to work with lots of different hospitals during outbreaks, and we learn something every time we do an outbreak investigation. One of the main things that I've taken away from a lot of these investigations is that it's best to intervene with CRE early to prevent them from becoming endemic, when you're just seeing the first few cases, when they're relatively uncommon. When these organisms become endemic, not only does it potentially change the approach to these organisms, it also makes it more difficult to control them.

Another important thing that we've seen is that sometimes these organisms are not being recognized as epidemiologically important organisms. The example I'll give is an investigation that we did when we were asked to come and help control an outbreak that the facility thought had been going on a relatively short period of time, but when we actually looked back at their records, they had had cases for a very long period of time that had just not been recognized.

It's important to recognize how serious this organism is, for the reasons that you mentioned, and also to make sure there are mechanisms in place for the laboratory to notify infection prevention personnel when these are first recognized.

In addition, we're also seeing the importance of long-term care as a reservoir for these infections. Obviously these infections can be transmitted in long-term or acute healthcare, but we are seeing a lot of these cases being concentrated or manifesting themselves in patients in long-term care, especially long-term acute care.

It speaks to the importance of approaching this organism across the spectrum of healthcare. It certainly requires aggressive communication between acute and long-term care when these patients are being transferred, so that appropriate interventions can take place in both settings.

Lastly, a point that often gets overlooked is that outbreaks of these organisms can be controlled. It's certainly not easy, but it is possible. In addition, we have learned a lot, and these lessons help us develop the guidance that we've released to help others with these organisms. Arjun, of course, you were 1 of the primary authors of the CDC/HICPAC Guidelines for control of these organisms in acute care settings. What should facilities be doing to prevent the spread of these organisms?

Dr. Srinivasan: When you boil it down to what people need to do, it actually ends up being fairly simple, and the tools that we need people to implement are ones that they already have access to. One of the most important things we've seen, as you were pointing out, is the issue of recognition. It's knowing that these organisms are in your facility and that you need to be taking steps to control them, because we are in a situation in this country where it is still early; we hope that we can contain them now. We can act now to control the transmission of carbapenem-resistant Enterobacteriaceae.

There are some facilities where they aren't encountering these organisms and that's fantastic. What we want is for people to be aware of the situation, so if you're not seeing it, that's fantastic, but there are some circumstances where people think they haven't seen it, but in fact those isolates have been seen by the microbiology lab, but have not been communicated to infection control.

One of the things we ask people to do as a first step is to go and talk with your microbiology lab. Go back and look at 6 months or a year of information on your Enterobacteriaceae and look to see if you've ever had any carbapenem-resistant Enterobacteriaceae in your hospital. If you have not, that's fantastic. Make sure that the lab knows that infection control really wants to know about these organisms. Set up a mechanism so that the microbiology lab can alert them right away if they encounter one of these.

If your facility has seen these pathogens in the past and you didn't know about them at the time, one of the things that we encourage people to do is to think about actively trying to look to see if these organisms are currently present in your facility. One of the best ways to do that is through what we call a point prevalence survey, where you go and do surveillance cultures on people who were in a unit where the organisms were previously (a lot of these are high-risk units like intensive care units or transplant areas, where there's a lot of antibiotic use) and simply do a point prevalence survey. Studies have shown that rectal cultures are a fairly good way of detecting these organisms and you can do a point prevalence and that helps you understand whether you're still seeing these organisms, or if the one you saw 3 months ago really was the one that you've had in your facility.

If you go back and you don't see any cases, or if you're at the type of facility that is not encountering this with great regularity, the other prevention step that we'd like people to take is to think about doing active surveillance cultures when you see cases of carbapenem-resistant Enterobacteriaceae. Essentially what we're encouraging with these guidelines is that if you are in a facility where these organisms are rare, that you treat each case like an outbreak. It's not something that's normally supposed to be there, and so you treat it like an outbreak, like an occurrence that's not supposed to happen, and you do some surveillance cultures on the patients who have epidemiologic links to the case patient who had the carbapenem-resistant Enterobacteriaceae.

The point of these surveillance cultures is to look for transmission that you didn't know about. It's to look and see if your infection control measures are being effective, and that all fits in the context of recognition, because recognition is obviously a critical step in preventing transmission. Once you can recognize the cases, the steps that you take to prevent transmission are the same steps that everybody already knows about. They're already doing them to prevent transmission of organisms like MRSA [methicillin-resistant Staphylococcus aureus] and other drug-resistant infections.

It is good attention to basic infection control, in particular hand hygiene, and making sure that patients with these resistant organisms are on contact precautions.

Dr. Kallen: Arjun, in addition to the things you just mentioned, people often describe a role for antimicrobial stewardship in the prevention of infections through transmission of these organisms. Do you think that's true and how should it be applied?

Dr. Srinivasan: Yes, absolutely, and ultimately that's a key area; it's an under-addressed area, in which we need to see a lot more activity. The advantage is that improving the use of antibiotics will help address the root cause of these carbapenem-resistant infections.

You know, the study out of New York showed that exposure to a carbapenem antibiotic increases a patient's risk of getting an infection with a carbapenem-resistant strain (in that study, Klebsiella) by 15 times. So, if we can improve the use of antibiotics, we really have an opportunity to not just address the transmission of these organisms but to prevent them from developing in the first place.

I think that there are 3 key steps that people could follow right now that would really improve the use of antibiotics in inpatient settings. The first step is to ensure that whenever we write orders for antibiotics in hospitals and other inpatient facilities that we make sure the orders come with a dose, a duration, and an indication.

We've heard from people in the field that without a duration and an indication, it becomes very hard for other clinicians who are taking care of a patient to stop or change the antibiotics that the patient is on because they don't know why the patient was on antibiotics in the first place and don't know how long they were supposed to be continued.

The second thing that we can all make sure we are doing is getting the right cultures before we start therapy. That's incredibly important when you're talking about these drug-resistant infections, where the choice of antibiotics can be very difficult and it becomes impossible to guide the therapy if you don't have some susceptibility information to help you do that.

The last thing that we really encourage people to do is apply the concept of a time-out in healthcare, which has become fairly common now, to the idea of antibiotic use, and what we'd like people to do is, after about 24 to 48 hours of therapy, take that antibiotic time-out to reassess your therapy. Often, information has come to light in the first day or 2 of hospitalization that really can inform optimal use of antibiotics. It's a good time to look at the information and, first of all, decide whether an antibiotic is even necessary in the first place -- does this patient really have an infection?

If they do need an antibiotic, that's a great time to look at the susceptibility results and determine if the therapy could be narrowed in spectrum or altered in some way, and I think that's also a great time to make a decision on a diagnosis and put down a duration of therapy, so that if you know the patient has, for example, a urinary tract infection, you can specify the right amount of therapy and specify that duration so the antibiotics will stop when they're supposed to.

I'd like to thank you all for joining us today for this Medscape Peer-to-Peer discussion on carbapenem-resistant Enterobacteriaceae, and I thank my colleague, Dr. Alex Kallen, for joining us for this discussion.

Related Resources

Three Steps to Antibiotic Stewardship

Don't Give In and Give Those Antibiotics

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