Drug stewardship: A failure to de-escalate

Physician leadership needed

Robert RappRobert Rapp, PharmD, professor of pharmacy at the University of Kentucky Chandler Medical Center, is an outspoken advocate for antibiotic stewardship to preserve the efficacy of our remaining antibiotics against rising drug resistance. He sat down with Hospital Infection Control & Preventionfor a few questions on the subject.

HIC: What is causing this growing drug resistance in gram negative infections — microevolution and/or antibiotic pressure to select resistant strains?

Rapp: Well, all the beta-lactamases have gone through an evolution. When the gram negative penicillins were marketed — like ampicillin and omoxicillin — then the first thing the bacteria like E. coli and Klebsiella pneumoniae did is produce penicillinases. So those were beta-lactamases that hydrolyzed penicillins – destroyed penicillins. After losing the penicillins, the pharmaceutical industry developed cephalosporins and penicillin beta-lacatamase inhibitor combinations. Then shortly after the cephalosporins were marketed the bacteria learned how to produce enzymes that could now destroy the cephalosporins and the penicillins.

So as the industry developed new classes of beta-lactam antibiotics the bacteria were able to mutate their previous enzymes to new enzymes that could now hydrolyze the newer drugs. That evolution has continued all the way now to the carbapenems. In many hospitals, carbapenems are sort of the drugs of last resort. In other words, when your patient is dying and your back is against the wall, more than likely most physicians — including infectious disease physicians — will probably place the patient on a carbapenem. As a result of that, now we are starting to lose the carbapenems.

Q. What can be done through infection control and antibiotic stewardship?

A. Hospitals need to do everything they possibly can to try to spare their carbapenem class of antibiotics, because — folks, we ain't got any new ones coming down the road. It's all coming down to two things: better infection control — and I don't think I have to tell you that we are not very good in the United States at infection control — and secondly, antimicrobial stewardship. In other words, using the antibiotics we have in a much better way and using less of them. We just use way too many antibiotics and we let them go way too long. We don't do the things we are supposed to do and that is the whole purpose for our antibiotic stewardship initiative that's ongoing. If you don't have any new drugs and you're losing the old drugs, the only thing you've got is better infection control and stewardship."

Q. What can you do when you are down to these drugs of last resort?

A. The first thing you have to do is evaluate your resistance patterns using a properly constructed antibiogram. That will allow you to see what exactly is going on in your hospital with resistant gram positive and gram negative bacteria. That needs to be evaluated, and based on that you need to decide what your empiric therapy is going to be for various common infections that are treated in the hospital — ventilator-associated pneumonia, community-acquired pneumonia, urinary tract infections, etc.

In most case these days, it's going to take a minimum of three antibiotics for empiric therapy. The important thing then is that when you get your cultures back — and obviously you must do your cultures in a timely, correct manner — you either have to de-escalate or stop the antibiotics based on the cultures. The single biggest failing in the United States and throughout the world is the failure to de-escalate based on cultures. We start three or four antibiotics and unfortunately, even when we get the cultures back — we either don't believe them or don't pay any attention to them — we keep [the drugs] going. At the end of three days, when we get our cultures back, everything needs to be reevaluated and we just don't do a very good job of that at the present time. As far as I am concerned, where the rubber hits the road in antimicrobial stewardships is day three de-escalation and discontinuation. "

Q. Do we need rapid culture molecular epidemiology to do antibiograms?

A. "Most hospitals are still dependent upon culture and susceptibility reports, but those bacteria are all easy to culture. They grow well — they are not something that are fastidious and difficult to grow. Consequently, generally they are going to grow and we are going to know. That's when we need to de-escalate and/or discontinue [drugs], particularly if the cultures are negative. But what happens right now is that we get the cultures back and [for example], you've started a carbapenem, an aminoglycoside and a drug for MRSA. So you have started three drugs for your patient's infection. You get the cultures back and it happens to be susceptible to a narrow spectrum agent like ampicillin. Then you need to de-escalate to ampicillin and stop the other three. We frequently don't do that. We too frequently just say, 'I'm not sure I believe the culture at this point, my patient is doing a little better, I'm just going to go with what I have.' Frankly, that's killing us. Even if the cultures are negative and we have a chance to actually stop [drug administration] very seldom is it actually done. "

Q. What is needed to address this problem?

A. Physician leadership. We simply have to have physician leaders in our hospitals working with pharmacy and infection control that understand that this stuff isn't going away. If our physicians aren't cooperating we are going to be in big trouble. Physician leadership, from the chief of staff, from whoever is in charge of the medical staff, is such a key component that I don't think you can overestimate it. Unfortunately, there are a lot of hospitals that do not have this at the present time. You know as well as I do, that infection control and antimicrobial stewardship costs money. But doggone it, having patients in your hospital with resistant infections costs a lot of money too. We simply all have to get on board and get together with this. In many institutions today, it is still being ignored."

Q. This stewardship presumably goes hand in hand with infection control. What else can infection preventionists do?

A. One of the things that we are doing and I think that everybody needs to do is not only involve your own hospital, but involve your major referring facilities. For example, if you have a 400-bed nursing home down the road that refers you a lot of patients with resistant bacteria, you are not going to be very successful in your hospital unless you can work with that nursing home to get them to improve what they do. So reach out to your primary referring nursing homes, your primary referring general hospitals, your long-term acute care kinds of hospitals. It is very important to work together both with antibiotic use and infection control with those institutions.

Q. Why aren't there more drugs in the pipeline for these gram-negative infections?

A. "You can't make money developing antibiotics. That's a problem. I think something like 70% of major pharmaceutical companies are now out of the infectious disease research area. So, consequently there is nobody out there developing antibiotics in a big way. There are a few on the horizon, but most of them are for gram positives. I see a couple of new MRSA drugs coming down the road. But on the gram negative side there are very few things that look real promising at least in the next five to 10 years. And it may be 15 years. We have a real problem. Can the federal government, the CDC, do something to put some kind of initiatives back in the area of antibiotic development? I'm not sure anybody is listening right now.