Gehrke v. Sculco: Routine Use of Antibiotic Bone Cement in Primary TJA is Justified

This week’s Orthopaedic Crossfire® debate was part of the 18th Annual Current Concepts in Joint Replacement® (CCJR®), Spring meeting, which took place in Las Vegas. This week’s topic is “Routine Use of Antibiotic Bone Cement in Primary TJA is Justified.” For is Thorsten Gehrke, M.D., ENDO-Klinik, Hamburg, Germany. Opposing is Thomas P. Sculco, M.D., Hospital for Special Surgery, New York, New York. Moderating is Daniel J. Berry, M.D., Mayo Clinic, Rochester, Minnesota.

Dr. Gehrke: The story of antibiotic bone cement started with Buchholz and Lodenkamper—two microbiologists who had the idea to mix antibiotic to the bone cement. Buchholz wrote a letter—almost 50 years ago—to a company that produced bone cement and asked them to mix antibiotics with their cement. The company agreed. He found that he could reduce the infection rate to 0.5%.

One of Buchholz’s good friends, Sir John Charnley, said to him in a letter ‘nothing leaks out of a stone, my dear Buchholz’. But his friend was wrong. We now know there are two kinds of antibiotic release from bone cement. First, the highest release of antibiotics out of the bone cement is within the first 10-20 minutes. And then after that is the second phenomenon of a very low, but very stable level of antibiotic leakage. During the first two hours you can reach such a high concentration that you have 1,000 times higher than MICs for staphylococci, for example.

Not every antibiotic behaves the same way. For example, vancomycin is bad regarding the release. It’s released only for the first 2-3 weeks and then it stops. It’s not the best antibiotic for the bone cement. And another issue is that the release depends on the surface properties of bone cement. Cement that incorporates water quickly is the better for antibiotic elution.

There are two kinds of industry manufactured antibiotic loaded bone cement—gentamicin and vancomycin or gentamicin and clindamycin. We did a clinical trial for both of them. The question was, “Are there any side effects if we add antibiotics to the bone cement?” We looked after 20 patients and the antibiotic concentrations. And we found that we can be really, really relax because at maximum concentrations in the serum are far below the toxic concentration.

Is there any evidence? The Norwegian registry showed that the outcome of the antibiotic loaded bone cemented stems are much better than the unloaded. If you look at a systemic review (PLOS 2013), all studies without any exception favor the antibiotic loaded bone cement.

And the Finnish registry where they looked after more than 43,000 knees, they came to the conclusion that the lack of use of antibiotic impregnated cement had a more dramatic effect than did the lack of use of intravenous antibiotics.

In Norway, again, much better results with antibiotics. That led to the fact that in the UK almost 100% of the surgeons are using antibiotic loaded bone cement routinely. Because they have seen that the cost effectiveness and the risk of infection is much, much lower.

A randomized study from Warwick, Great Britain (Sprowson AP, Bone Joint J, 2016), showed that the use of dual antibiotics in routine use significantly reduces the rate of SSI [surgical site infection] compared with standard.

Spanish investigators found (Sanz-Ruiz P, J Arthroplasty 2017), before they put antibiotics in the bone cement they had an infection rate of 4.3% for the hips and after 1.8%. This is a significant difference.

Is it evidenced based? No, it isn’t. There is still no evidence-based study. I’m coming closer to you, Tom. But despite that, in Australia and most other countries, surgeons use antibiotics in 100% of the bone cement.

The International Consensus is that antibiotic impregnated bone cement reduces the incidence of infection—but it should be selected only for patients at higher risk.

Dr. Sculco: When it comes to the use of antibiotic composites in primary joint replacement, well I think we may have a little difference of opinion.

There is no question that periprosthetic joint infection is a huge, catastrophic complication. But infection rates have definitely declined. Use of parenteral perioperative antibiotics, better surgical techniques, speed of surgery … lots of things we’ve done to reduce the incidence of infection. In the literature today, the incidence is anywhere between, in the best of centers, 0.1% to around 1%.

The other problem I see in North America is 90 – 95% of our hips are non-cemented.

No question. There is a place for it—high risk patients, as Thorsten just said—I agree with him 100%. I think you should use it in the primary knee; history of previous infection; diabetic; immunosuppressed; inflammatory arthritis. All a good place to use it. And in revision surgery—100% agree with him.

But there are some disadvantages to using it routinely. Cost is one. The emergence of resistant organisms is another. Alteration of mechanical properties is a third. If you get carried away and you use more, certainly you can impede the mechanical properties.

If you look at cost, our implant and antibiotic costs are ridiculously high. Antibiotic cement can add anywhere between $450 and $900 to a case. Under bundled payment programs, the increased cost of the antibiotic-loaded cement is not going to be reimbursed. So, it’s going to be less revenue to the institution ultimately for that event.

I did a little math here and if we do 500 knee replacements, because that’s the population I think it would apply to in the United States, and let’s say there was a 50% utilization by our surgeons, the additional cost to the system … if you look at $500 as the added cost … would be around $125 million. Now if you calculate a high infection rate for total knee replacement of 1%, for it to be cost effective, you would have to reduce the infection rate to 0.04% to be cost neutral, which would be literally impossible.

Now, what about emergent bacteria? Certainly, mutation in organisms is a problem.

Some quotes from microbiologists and people who study this: “As might be expected from Darwinian evolution antimicrobial usage exerts a selective pressure favoring the emergence of antibiotic resistant organisms.” Another economist and microbiologist: “Antimicrobial resistance is driving up healthcare costs, increasing the severity of disease and increasing the death rate from certain infections.”

An organism can, in fact, grow on these antibiotic-loaded bone cements and can be exposed at sub-inhibitory levels, which induces bacterial mutation.

Looking at revision surgery, when primary bone cement with antibiotics was used, 88% had gentamicin resistant bacteria. They mutated very quickly. By contrast, in 57 revisions where antibiotic cement was not used in the primary, only 16% had resistant organisms.

A very, very good study by the Canadian government which looked at randomized trials, meta-analysis and systematic reviews concluded that “antibiotics in cement may not confer any benefit over plain cement in total knee and total hip.”

The Norwegian registry, which was quoted, you need to reduce the infection rate 2.4-fold for it to be cost effective.

The Australian registry, which Thorsten just mentioned, 100,000 total knees, risk of revision for infection same with or without the use of antibiotics in cement.

Kaiser registry, 26,000 total knee replacements, no difference in infection rate with or without antibiotics,

So, in summary, I think the problems are that it is not cost effective, it can increase bacterial resistance (I think that is a real potential problem) and it’s primarily useful in that high risk primary or revision knee.

Moderator Berry: Thorsten, any quick rebuttal?

Dr. Gehrke: First of all, I accept, for example, your cost issue in the U.S. We don’t have it in Germany. The development of resistance of the organism was based on just two papers – again, never proven. Very low numbers. Fourteen cases. One other comment, we should differentiate between hip and knees. All Australian registry data were about knees. And the hip literature is a little bit different.

Dr. Sculco: I think you’re absolutely right, Thorsten. If you look at the registry studies that you were quoting that were used in Scandinavia and the UK, the results are better in the hips than the knee, no question.

Moderator Berry: Okay, so a couple of areas of consensus. The data are stronger for or at least some benefit of antibiotic laden cement in the hip than the knee. In North America there’s not many cemented hips done any more so it may be less clinically relevant. And it seems like the knee is less well accepted at least in terms of the literature. Would you both agree with that statement?

Dr. Gehrke: Yes.

Moderator Berry: Now I heard both of you say that you had an area of consensus and that was the high-risk patient, undergoing surgery. You both said if you’re going to use cement, that is the patient who’s got immunosuppression, complex surgery, revision surgery … you’d use antibiotic laden cement. Did I get that correct from both of you?

Dr. Sculco: Yes, definitely.

Moderator Berry: There was consensus. But let me ask you the following question. If there’s a benefit to the high-risk patient, why wouldn’t you say that there is probably some benefit to the lower risk patient?

Dr. Gehrke: Of course, it’s true. If you are seeing a very good benefit for the high-risk patient there is, of course, benefit for the low risk patient at a lower level.

Dr. Sculco: I think so, but as I said, I think the downsides to the lower risk patient are greater. And I don’t think therefore its widespread use in that population is indicated.

Moderator Berry: About this question of antibiotic resistance, Thorsten, I think you’re probably right. The data is pretty weak. Our bacteriologist tells us that the likelihood of resistance emerging in a closed environment, like the hip or the knee—closed wound—is very, very low. Is that what your microbiologists say?

Dr. Gehrke: Exactly the same.

Moderator Berry: Tom, you did a nice job of bringing out this cost effectiveness question. What about mixing the antibiotic yourself and I’ll just say that’s an off-label use, but it’s far cheaper than using the pre-mixed stuff?

Dr. Sculco: There is a question as to whether the elution properties are as good if you hand mix it than if it’s commercially done. We did a study where we looked at using liquid gentamicin and the problem is that it is detrimental to the mechanical properties, but in a spacer, you can use liquid gentamicin for $3 for a little vial.

Moderator Berry: Tom, in your high-risk patient, what are you typically using for cement? Not brand names, but just in terms of what antibiotics?

Dr. Sculco: Palacos gentamicin is the one I would ordinarily use. If it’s a particularly high-risk patient that has a previous history of infection, I’ll probably add 500mg of vancomycin to that and mix it in.

Moderator Berry: Thorsten, how about you?

Dr. Gehrke: The same, absolutely the same. And if you are operating on a patient on a high risk or who has a history, for example, of MRSA infection, we use the industrially manufactured bone cement, which contains 1g gentamicin and 1g vancomycin.

Moderator Berry: That’s my pattern as well. Please join me in thanking the two speakers for a great session.

Please visit www.CCJR.com to register for the 2018 CCJR Winter Meeting, – December 12 – 15 in Orlando.