Rethinking the role of antibiotics in bone cement

Issue: August 2016

ByJavad Parvizi, MD, FRCS

ByAndrew N. Fleischman, MD

H.W. Buchholz, MD, is credited as the first clinician to add antibiotics to polymethylmethacrylate cement. He thought the antibiotic would elute from cement and accumulate in the local environment of the joint.

Since this concept was first introduced in 1970, orthopedic surgeons have continued to use antibiotic-laden bone cement (ALBC) in cement spacers for the treatment of periprosthetic joint infection (PJI) and, in recent years, for fixation in primary joint arthroplasty. Despite widespread use, a recent publication by the FDA questioned the role of ALBC spacers for treatment of PJI. They correctly posited there have been no randomized prospective studies to prove the suspected beneficial role of ALBC spacers.

The scientific evidence to support the efficacy of ALBC used in primary arthroplasty is weaker. Initial interest in Europe was sparked by favorable outcomes in national joint registries. The Norwegian Joint Registry demonstrated a small but significant increase in the rate of infection-free survival for primary total hip arthroplasty patients receiving ALBC. Similar results were observed for primary total knee arthroplasty in Finland while no difference was seen in Canada. Registry data is observational, however, and results often most reflect an interaction with confounding variables. The most definitive evidence comes from a large randomized trial that found erythromycin and colistin cement to be no more effective than simple bone cement. Unfortunately, the use of erythromycin has now largely been superseded by tobramycin and gentamicin.

Javad Parvizi

Adverse effects

There are few clinically relevant adverse effects with the use of ALBC. The addition of antibiotic to polymethylmethacrylate (PMMA) causes a dose-dependent reduction in both compressive and tensile strength. However, low-dose antibiotic (about 1 gram of antibiotic per 40-gram bag of cement) does not appear to affect the mechanical survival of prosthesis fixation. While high local antibiotic concentrations are maintained beyond 48 hours, systemic absorption is minimal. There have been no reports of systemic aminoglycoside toxicity with low-dose ALBC. Reports of acute renal failure have been limited to high-dose antibiotics in cement spacers. High concentrations necessary to impact osteoblast replication or cause cell death are not likely achieved with low-dose ALBC.

Resistance, cost

There is no direct evidence the routine use of ALBC in primary total joint arthroplasty (TJA) increases risk for the development of resistant bacteria. However, prolonged exposure to the sub-inhibitory systemic antibiotic levels that occurs with the use of ALBC is particularly concerning. While some have suggested exposure with low-dose ALBC is insufficient to promote resistance, an increase in aminoglycoside-resistant bacteria has been reported in some institutions. The practice of antibiotic stewardship is warranted and should be a cooperative effort reflected in national guidelines.

One of the most prominent concerns with the routine use of ALBC is its considerable cost. At our institution, commercially available PMMA containing tobramycin costs an additional $420 per case. In order to be cost-effective, the addition of ALBC would need to prevent one infection for every 100 TJA performed. A lower cost formulation achieved with hand mixing does not have equivalent mechanical and elution properties. From an economic point of view, the use of commercial ALBC is clearly unjustified and its funding could be redirected to methods or services that provide a clearer benefit.

Big picture

With considerable uncertainty as to its benefit, we cannot recommend the routine “off-label” use of ALBC for primary joint prophylaxis. Perhaps primary prevention with ALBC should be focused on high-risk patients for whom the potential benefit is greatest. This may include patients with morbid obesity, diabetes, local or systemic immunocompromise, or a previous history of infection. The potential for benefit also likely outweighs the risks for patients undergoing revision or conversion arthroplasty. These populations should be the focus of future multicenter clinical trials.

References:
Bohm E, et al. Clin Orthop Relat Res. 2014;doi: 10.1007/s11999-013-3186-1.
Buchholz HW, et al. Chirurg. 1970;41:511-515.
Dunne NJ, et al. Proc Inst Mech Eng H. 2008 Apr;222(3):355-365.
Engesaeter LB, et al. Acta Orthop. 2006;77:351-358.
Hinarejos P, et al. J Bone Joint Surg Am. 2013;doi: 10.2106/JBJS.L.00901.
Iarikov D, et al. Clin Infect Dis. 2012;doi:10.1093/cid/cis735.
Jämsen E, et al. J Bone Joint Surg Am. 2009;doi: 10.2106/JBJS.G.01686.
Miclau T, et al. J Orthop Trauma. 1995;9:401-406.

For more information:
Andrew N. Fleischman, MD, and Javad Parvizi, MD, FRCS, can be reached at The Rothman Institute at Thomas Jefferson University Hospital, Sheridan Building, Suite 1000, 125 S. 9th St., Philadelphia, PA 19107; Fleishman’s email: anfleischman@gmail.com; Parvizi’s email: parvj@aol.com.

Disclosures: Parvizi reports he is a consultant to Zimmer Biomet, Ceramtec, Convatec and TissueGene; and has ownership in CD Diagnostics, Hip Innovation Technology, ForMD, Alphaeon and Joint Purification Systems. Fleischman reports no relevant financial disclosures.