Mixed data prompt questions on antibiotic bone cement

Practicing good stewardship with antibiotics may reduce resistance, cement weakening.

Musculoskeletal and infection professionals from 98 countries convened July 25-27, 2018 at the International Consensus Meeting on Musculoskeletal Infection in Philadelphia to discuss how to improve the prevention and treatment of musculoskeletal infections. Of the topics presented, delegates strongly debated whether antibiotic-loaded bone cement should be used in primary total joint arthroplasty to prevent periprosthetic joint infection.

Although antibiotic-loaded bone cement has been used since the 1970s, some sources who spoke with Orthopedics Today for this Cover Story said worldwide registry data on this topic vary when it comes to reporting outcomes and revision rates for primary TJA performed with antibiotic-loaded cement.

“Longitudinal data from Scandinavia, particularly the Norwegian Arthroplasty Registry, would indicate there is a significant benefit for both septic and aseptic revision rates if you use antibiotic-impregnated cement in hips,” Michael J. Dunbar, MD, FRCSC, PhD, professor of surgery at Dalhousie University and chair of arthroplasty outcomes at QEII Health Sciences Centre, told Orthopedics Today.

In contrast, Dunbar noted data from the Canadian Joint Replacement Registry showed no beneficial effect of antibiotic-loaded bone cement in primary total knee arthroplasty.

Source: Christina Sanchez

Likewise, this result was found in registry data from Australia, according to Thorsten Gehrke, MD, director of the Helios Endo-Klinik Hamburg in Hamburg, Germany.

“Then in New Zealand, they have seen ... that the infection rate was a little bit higher when they used antibiotics in the bone cement,” Gehrke said.

Randomized controlled studies

Despite the extent of registry data available on the use of antibiotic-loaded bone cement, Javad Parvizi, MD, FRCS, professor of orthopedic surgery at Rothman Orthopaedic Institute and Sydney Kimmel Medical School, Thomas Jefferson University, noted such data lack detailed information about the patient and the metrics, such as the synovial cell counts, serology tests and the microbiology data, which are important to diagnosing prosthetic joint infection (PJI). Therefore, he said, registry data should not be used in studies related to infection. Some registries also collect data on total hip arthroplasty, which Parvizi said is not relevant to U.S. surgeons because cement is not used much in THA performed in the United States.

“The majority of the data from the Scandinavian registry relate to the hip and not the knee and that is of no relevance to us in the United States because we do not use cemented hips,” Parvizi, an Orthopedics Today Editorial Board Member, said. “We use cemented knees, and you cannot just extrapolate hip data to the knee.”

Conducting randomized, controlled trials may help answer questions related to the effect of antibiotics on the in vivo biomechanical properties of cement, efficacy, antibiotic resistance and the time it takes for antibiotics to elute from the cement, Louis M. Kwong, MD, FACS, said. However, he said, when it comes to infection management, the type of studies that are needed to answer key questions like these are difficult to perform and, therefore, may never be done.

“We are likely going to be dependent for some time on large databases, like national registries or consensus opinions, because of the challenges associated with obtaining level-1 data looking at the impact of the different strategies, like the use of antibiotics in cement for primary total joint,” Kwong, professor and chairman of the department of orthopedic surgery and chief of the joint replacement service at Harbor-UCLA Medical Center, told Orthopedics Today.

High-risk patients

Perhaps due to the mixed results and lack of evidence found among registries, orthopedic surgeons also have mixed beliefs on when antibiotic-loaded bone cement should be used in TJA.

Sources interviewed said antibiotic-loaded bone cement should only be used in patients undergoing primary TJA who are at a higher risk of PJI. This includes patients with diabetes, anemia, sickle cell anemia, autoimmune diseases or compromised immune systems, as well as patients who previously had an infection.

“I think a lot of surgeons, even those who do not use antibiotic-impregnated cement, would tip in favor of applying it in those cases because the risk of infection is several times higher, two- to three-times higher in some of these groups,” Dunbar said.

On the other hand, Keith R. Berend, MD, an Orthopedics Today Editorial Board Member, contends antibiotic-loaded bone cement should be used regularly in all patients regardless of whether they are stratified as high risk.

“My interpretation of the data, whether it is from studies or from registries, is there is increased survivorship both septic and aseptic. Our own internal data that we have looked at demonstrate a lower infection risk,” Berend, who is a senior partner at Joint Implant Surgeons, told Orthopedics Today. “One of the harder things is trying to use it in what I would define as a high-risk patient. Then you end up getting a random infection in a low-risk patient.”

Identify comorbidities

Whether deciding to use antibiotic-loaded bone cement routinely or only in patients at high risk for PJI after primary TJA, it is important to assess patients on an individual basis and identify for them whether the benefits outweigh the risks, according to Kwong.

Surgeons should be aware of the patient’s allergy history, so they do not use an antibiotic to which the patient may be allergic. Although it is uncommon, certain antibiotics, such as gentamicin, have been associated with an increase in acute renal failure, he said.

“Look at the renal function of the patient because there can be measurable levels of antibiotics, like aminoglycosides, in the systemic circulation. This can have a potentially serious adverse effect on kidney function for patients who have chronic renal failure or pre-existing renal disease,” Kwong said.

More directly defining who has a higher risk for infection will also help surgeons identify the best patients to receive antibiotic-loaded bone cement, Gehrke said.

“Is the definition [of high-risk patient] BMI more than 30 or BMI more than 40 or smoking or drinking or diabetes mellitus, and so on?” Gehrke said.

Differences in antibiotics

Not all antibiotic-loaded bone cements are equal. Different types and dosages of antibiotics are used in bone cement, depending on the manufacturer, Parvizi said. As most infections that occur in the United States are due to Staphylococcus aureus, he said he prefers to use vancomycin, but tobramycin and gentamicin are also commonly used in bone cement.

“Gentamicin and tobramycin are effective against many gram-negative organisms, but also have anti-gram-positive activity,” Kwong said. “Vancomycin, of course, is effective against gram-positive pathogens and MRSA. It is not effective against most gram-negative bacteria. Investigations in vitro suggest that when you combine an aminoglycoside with vancomycin, the elution of both antibiotics is better when the two of them are together.”

Patients at high risk for infection may also receive a combination of gentamicin and clindamycin, according to Gehrke, who said this combination has also shown better elution properties.

“It is a good combination because clindamycin and gentamicin have some synergistic effect,” Gehrke said. “That means the gentamicin is strengthening or increasing the effects of clindamycin in the bone cement, so that is a good combination.”

Hand-mixed vs premixed antibiotics

If an orthopedic surgeon chooses to hand-mix antibiotics into bone cement instead of buying commercially manufactured antibiotic-loaded bone cement, he or she must be sure the antibiotics are bactericidal and bacteriostatic, and they are heat stable and can be sterilized, Berend said.

Despite the benefits of control and customization that are associated with hand-mixing antibiotics into bone cement, Dunbar said surgeons should not feel the need to hand-mix the antibiotics in primary TJA unless it is an “exceptional case, with, say, a fungal infection previously or some extraordinary circumstance, where you want to add a specific agent.”

There are also lingering questions in the research and among surgeons about whether the stability of the cement is affected to a greater extent when the antibiotics are hand-mixed.

There is evidence that the stability and mechanical properties in commercially produced antibiotic-loaded bone cement are better due to a “more uniform distribution of the antibiotic within the cement,” Kwong said.

Berend said he has found little evidence of aseptic loosening that occurred due to bone cement with antibiotics onboard.

“There is discussion about the biomechanical properties of cement being reduced or decreased by adding antibiotics, but we have been doing it for 20-plus years and have an incredibly low rate of aseptic loosening, so we only see benefit and no drawback,” he said.

Variable cement prices, usage

Cost is another factor when it comes to whether orthopedic surgeons should use industrially manufactured or hand-mixed bone cement with antibiotics. Cost analyses have shown one pack of manufactured antibiotic-loaded bone cement could cost about $300, according to Parvizi.

“We usually use two packs,” Parvizi told Orthopedics Today. “If you are doing 700,000 primary total knee replacements in the United States and ... spending $600 per case, you can see this is an immense cost to the society.”

The price can be reduced, however, if surgeons hand-mix the antibiotics into the bone cement themselves, he noted.

Parvizi said for hand-mixed cement prices are about $48 per pack with $40 of that cost for a pack of cement and $8 for a gram of antibiotics.

The cost of antibiotic-loaded bone cement indeed raises questions, but its benefits may speak for themselves pricewise, according to Kwong.

Spending $400 to $600 per case to add antibiotics to the cement may outweigh the $40,000 to $50,000 it costs to eradicate a single infection after primary TJA, he said.

Dunbar said, “If it reduces the infection rate even by a small percentage, that is a huge advantage because infections are probably one of the most—if not the most—devastating complications you can have after arthroplasty because of the burden to the patient, importantly, but also, secondarily, the burden to the health care system.”

Less is more

Several sources said orthopedic surgeons who decide to use antibiotic-loaded bone cement in primary TJA should exercise good stewardship of antibiotics to reduce the risk of patients becoming antibiotic resistant.

“We have little in the way of new antibiotics that are being developed, due to the cost. Antibiotics like vancomycin represent one of our most valuable tools against infection,” Kwong said. “The concerns always are if we begin routinely using this in cement, might this in the long run be a detriment by fostering increasing antibiotic resistance to one of the few tools that we have?”

Gehrke said the amount of antibiotic used should not exceed 2 g to 40 g of packaged cement.

“The one package is usually 40 g bone cement. If you add ... not more than 2 g to 40 g bone cement, then it is okay. Then the mechanical properties are not weakened too much,” Gehrke told Orthopedics Today.

Although 2 g antibiotics is ideal, he said 4 g antibiotics is the maximum being used at his institution for treating patients with PJI. The antibiotic dosage, however, may be higher than that when the cement is used in a two-stage exchange.

“A completely different story is if you treat periprosthetic infection in a two-stage exchange where you use a [temporary] spacer ... then you can add almost as much as you want,” Gehrke said. “You can go up to 8 [g] and then, in some cases, even 10 g because the spacers are only there for 6 to 8 weeks and then they are going to be removed.”

Like the issue of whether antibiotics weaken the strength of bone cement, Berend noted large-scale utilization of antibiotic-loaded bone cement should be reviewed to see if antibiotic resistance is indeed one the risks associated with this material.

“There is the question of resistance, meaning that if you use this in all patients could you create a resistance environment,” Dunbar said. “I do not think there is any evidence to support that, particularly looking at the Scandinavian registries which have been using it long term.”

Options for infection reduction

More than anything, Dunbar said the discussion about antibiotic-loaded bone cement may be a distraction from the bigger discussion that needs to be had about practices that maintain high standards of hygiene inside the OR, some of which may ultimately be more cost-effective.

“Sometimes, because we do more arthroplasties, it may become a bit like a commodity,” Dunbar said. “We lose some of the emphasis on the basic free things that would make a difference on our infection rates.”

He said for Sir John Charnley, the Charnley tent and other steps taken in the OR helped whittle down his original infection rates of 8% to about 2% with TJA, which was viewed as super-specialized surgery at the time. Now that TJA is done more routinely, it is important that surgeons remember the basic tenets of surgical hygiene, like surgical masks and limiting the number of times the OR door swings open or closed.

According to Kwong, other examples include reducing the duration of the surgery and traffic in and out of the OR, both of which can positively impact infection risk.

“We use prophylactic antibiotics that are administered IV, make sure we administer it at the appropriate time and in the appropriate dose, which is fairly universally well-practiced by orthopedic surgeons throughout the country,” he said.

Although it only has lower-level scientific evidence, dilute betadine solution appears to have a positive benefit in reducing infection risk, Kwong said.

“There are many tools that we have in our armamentarium that can be used use in addition to antibiotics in higher-risk individuals so that we can have a positive impact on reducing infection risk and likely reserve the use of antibiotic-loaded cement to selected individuals,” Kwong said. – by Casey Tingle

• Reference:
• Delegates seek better care of patients with orthopedic infections through discussion, consensus. Available at: www.healio.com/orthopedics/infection/news/online/%7b6d371757-1a17-4f0c-aeea-e6cc6006c77c%7d/delegates-seek-better-care-of-patients-with-orthopedic-infections-through-discussion-consensus. Accessed Sept. 5, 2018.

• For more information:
• Keith R. Berend, MD, can be reached at 7277 Smith’s Mill Road, #200, New Albany, OH 43054; email: berendkr@joint-surgeons.com.
• Michael J. Dunbar, MD, FRCSC, PhD, can be reached at 1796 Summer St., 4th Fl., Ortho Clinic, Halifax, Nova Scotia, B3H 3A6, Canada; email: michael.dunbar@dal.ca.
• Thorsten Gehrke, MD, can be reached at Holstenstrasse 2, 22767 Hamburg, Germany; email: tagehrke@gmail.com.
• Louis M. Kwong, MD, FACS, can be reached at 1000 W. Carson St., Box 422, Torrance, CA 90509; email: lkwong@dhs.lacounty.gov.
• Javad Parvizi, MD, FRCS, can be reached at 925 Chestnut St., 5th Fl., Philadelphia, PA 19107; email: javadparvizi@gmail.com.

Disclosures: Dunbar reports he is a consultant for and receives royalties from Stryker. Kwong reports he is a consultant and implant designer for Zimmer Biomet. Berend, Gehrke and Parvizi report no relevant financial disclosures.

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