The incorporation of antibiotics within polymethylmethacrylate (PMMA) has been widely used over recent decades for managing infection following skeletal trauma. Early research helped to clarify which antibiotics in which formulations were potentially clinically effective, with a common application of managing “dead space” following debridement of bone and soft tissue, addressing established infection as well as preventing deep infection. As the microbiology involved in these infections evolves, along with the antibiotics available, we have need for continued research into this important area of orthopaedics.
In the September 15, 2021 issue of JBJS, Levack et al. report on their investigation into the suitability of alternative antibiotics (amikacin, meropenem, minocycline, and fosfomycin) for use in PMMA beads, with a particular focus on thermal stability and in vitro elution characteristics. Tobramycin was also used to validate the study methodology. Minimum inhibitory concentrations of the antibiotics were tested against S. aureus, E. coli, and Acinetobacter baumannii. Antibiotic-laden PMMA beads of different sizes were tested, with antibiotic elution determined using high-performance liquid chromatography with mass spectrometry.
The authors found that amikacin was comparable to tobramycin with respect to heat stability and elution. Meropenem showed favorable elution kinetics and thermal stability in the initial 7 days.
The investigators emphasize that “The data presented are intended to generate further study of these antibiotics to better identify potential areas of clinical utility,” and they rightly point out that their data are not intended for clinical decision-making, “as antibiotic dosages and in vivo applications, specifically with biofilms, have not been evaluated.” Nonetheless, these new data involving the characteristics of amikacin and meropenem are intriguing. Moreover, this study serves as a great reminder of the need to regularly reevaluate established therapies as research techniques, pharmacology, and clinical conditions (such as evolving microbial pathogens) continue to change.
Marc Swiontkowski, MD
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Matthew J. Allen, VetMB, PhD, author of the December 5, 2018 Specialty Update on Musculoskeletal Basic Science, focuses on the five most compelling findings from among the more than 60 noteworthy studies summarized in the article.
Gene Editing in Orthopaedics
–Gene-editing tools such as CRISPR-Cas9 have great potential as a means of introducing therapeutic genes into mesenchymal stem cells that can then be targeted to tissues in vivo. These researchers1 reported on genetically modified stem cells that have the potential to differentiate into chondrocytes encoding a natural inhibitor of interleukin-1, providing an opportunity for localized release of immunomodulatory factors.
Managing Orthopaedic Infections
–A novel study2 in which transmission electron microscopy was used to identify viable bacteria deep within the canalicular structure of cortical bone, remote from the site of an infected implant, suggests that effective debridement requires the removal of not just necrotic tissue, but also of adjacent, apparently unaffected bone.
Computational Modeling of Human Movement
–This report3 presented a human musculoskeletal model that provided extremely accurate predictions of ground reaction forces during simulated walking and squatting. As similar models are developed and validated, surgeons will have improved tools for evaluating patients, planning surgery, and making decisions about which procedure/implant is most appropriate for an individual patient.
–This report4 demonstrated sexually dimorphic regulation of gene-expression profiles in bone marrow osteoprogenitor cells that could partly explain clinical observations in sex differences in peak bone mass, bone remodeling, and immunomodulation.
Biological Enhancement of Ligament Healing
–Among several basic science papers focused on the optimal healing and durable fixation of tendons and ligaments, this notable work5 reported on the translation of bridge-enhanced ligament repair for the anterior cruciate ligament.
- Brunger JM, Zutshi A, Willard VP, Gersbach CA, Guilak F. CRISPR/Cas9 editing of murine induced pluripotent stem cells for engineering inflammation-resistant tissues. Arthritis Rheumatol.2017 May;69(5):1111-21. Epub 2017 Mar 31.
- de Mesy Bentley KL, Trombetta R, Nishitani K, Bello-Irizarry SN, Ninomiya M, Zhang L, Chung HL, McGrath JL, Daiss JL, Awad HA, Kates SL, Schwarz EM. Evidence of Staphylococcus aureus deformation, proliferation, and migration in canaliculi of live cortical bone in murine models of osteomyelitis. J Bone Miner Res.2017 May;32(5):985-90. Epub 2017 Jan 26.
- Jung Y, Koo YJ, Koo S. Simultaneous estimation of ground reaction force and knee contact force during walking and squatting. Int J Precis Eng Manuf.2017;18(9):1263-8.
- Kot A, Zhong ZA, Zhang H, Lay YE, Lane NE, Yao W. Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells. J Mol Endocrinol.2017 Nov;59(4):351-63. Epub 2017 Sep 4.
- Perrone GS, Proffen BL, Kiapour AM, Sieker JT, Fleming BC, Murray MM. Bench-to-bedside: bridge-enhanced anterior cruciate ligament repair. J Orthop Res.2017 Dec;35(12):2606-12. Epub 2017 Jul 9.
Nowadays, chronic deep periprosthetic joint infections (PJIs) are typically treated with 2-stage exchange arthroplasty, but what about acute PJIs? In the December 6, 2017 edition of JBJS, Bryan et al. report on a retrospective cohort study of acute infections after hip arthroplasty. The results suggest we’ve come a long way in identifying patients with early infections and that contemporary irrigation-and-debridement protocols are more successful than older methods.
The researchers studied 6-year outcomes in 90 hips that had undergone either total or hemiarthroplasty and that were determined to have either acute early postoperative infections (n=66) or acute hematogenous infections (n=24). All the infected hips were managed with either irrigation, debridement, and modular head and liner exchange (70%) or with irrigation and debridement alone (30%). The authors stratified the patients into those without comorbidities (A), those with 1 or 2 comorbidities (B), and those with >2 comorbidities (C). Postoperatively, patients were treated with broad-spectrum intravenous antibiotics, followed by targeted therapy administered by infectious disease specialists.
Of the 90 acute infections, failure—defined as uneradicated infection, subsequent removal of any component for infection, unplanned second wound debridement for ongoing infection, or infection-related mortality—occurred in 15 hips (17%). Of those 15, 9 required component removal. The chances of treatment failure were slightly higher in cases of hematogenous infection (21%), compared with acute early postoperative infection (15%), but that difference was not statistically significant. Significant comorbidity-related failure-rate differences were found: failure occurred in 8% of the grade-A patients, 16% of grade-B patients, and 44% of grade-C patients. The most common infecting organism was methicillin-sensitive Staphylococcus aureus (MSSA).
From this overall 6-year success rate of 83%, the authors conclude that “with modern inclusion criteria for acute infection, modern surgical techniques, and modern antibiotic therapy…the rate of success was higher than in most historic reports.”
This basic science tip comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
One clinical frustration following osteomyelitis debridement is poor bone healing. Impaired bone homeostasis provokes serious variations in bone remodeling that involve multiple inflammatory cytokines.
The chemokines CCL2, CCL3, and CXCL2 are known to be strong chemoattractants for neutrophils during inﬂammatory states, and they play a role during osteoclastogenesis. B cells are also activators of osteoclastognesis and are regulated, in part, by tissue inhibitor of metalloprotease 1 (TIMP-1).
Researchers drilled a 1 mm hole into the proximal tibia of 126 mice. In half of the mice (63), a dose of S. aureus was injected into the canal, while the controls had no bacteria injected. At two weeks, all proximal tibiae were debrided; cultures were taken 3 and 7 days after debridement to assure no residual infection. Cytokine assays and Western blots for CCL2, CCL3, CXCL2, TIMP-1, RANKL, and TNF-α were performed in selected mice in each group. Flow cytometry and histology were also done in selected mice in each group.
In the osteomyelitis group, Western blot analysis identified increased levels of CCL2, CCL3, and CXCL2. Histology revealed increased osteoclastogenesis after osteomyelitis debridement, with calcitonin-receptor and RANKL detection via immunohistochemical and fluorescence staining. There was diminished osteogenesis and proliferation in the osteomyelitis group, but TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Flow cytometry revealed elevated B cell activity in the osteomyelitis group, with subsequent increased osteoclast activity and accelerated bone resorption.
The researchers propose a RANKL-dependent osteoclastogenesis after debridement for osteomyelitis that is associated with elevated B cells and decreased osteogenesis. These findings could lead to new interventions to improve bone healing during the course of osteomyelitis treatment, particularly following debridement.
Wagner JM, Jaurich H, Wallner C, Abraham S, Becerikli M, Dadras M, Harati K, Duhan V, Khairnar V, Lehnhardt M, Behr B. Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity. J Orthop Res. 2017 Mar 6. doi: 10.1002/jor.23555. [Epub ahead of print] PMID: 28263017
OrthoBuzz regularly brings you a current commentary on a “classic” article from The Journal of Bone & Joint Surgery. These articles have been selected by the Editor-in-Chief and Deputy Editors of The Journal because of their long-standing significance to the orthopaedic community and the many citations they receive in the literature. Our OrthoBuzz commentators highlight the impact that these JBJS articles have had on the practice of orthopaedics. Please feel free to join the conversation about these classics by clicking on the “Leave a Comment” button in the box to the left.
From the time of Hippocrates until after the American Civil War, open fractures and other wounds prone to sepsis were fatal injuries in approximately 50% of patients, and amputation of the affected limb was recognized as lifesaving treatment. With the adoption of antisepsis and formal surgical débridement in the late 19th century, improved stabilization techniques in the 20th century, and the introduction of antibiotics, death as an outcome was virtually eliminated, but nonunion with or without infection remained challenging complications.
In the 1960s, reports concluding that in open fracture care “prophylactic antibiotics were of questionable value” created great debate and controversy among surgeons. The pioneering 1974 JBJS study by Patzakis et al., titled “The Role of Antibiotics in the Management of Open Fractures,” addressed this controversy by asking and answering three key questions:
- Is antibiotic prophylaxis worthwhile in open fractures?
- Which organisms cause the infections?
- Which antibiotics are effective?
The study demonstrated that nearly two-thirds of wounds caused by direct injury and an even higher rate of gunshot wounds were contaminated. That finding, along with the fact that several days must elapse before a culture can be considered truly sterile, makes true “prophylaxis” in open fractures practicable only if antibiotics are applied to all patients. Patzakis et al. also stressed that antibiotic treatment is not a substitute for the critically important practice of extensive surgical debridement of all devitalized tissue. Urgent surgical irrigation and debridement remain the mainstay of infection eradication, although questions persist regarding the optimal irrigation solution, volume, and delivery pressure.
I agree with the authors of this classic article that the term “prophylaxis” is not appropriate because these wounds should presumptively be considered contaminated and treated with effective antibiotics. Wound sampling has a poor predictive value in determining subsequent infections, so a first-generation cephalosporin should be administered as soon as possible, with or without coverage for gram-negative bacteria. In addition, as Lawing et al. found in a 2015 JBJS study, local aqueous aminoglycoside administration as an adjunct to systemic antibiotics may be effective in lowering infection rates in open fractures.
This classic prospective study by Patzakis et al. in the 1970s has prompted us to ask and pursue answers to many more clinical questions regarding open-fracture infections. For example, the optimal duration of antibiotic administration has not been well defined, but they should be continued for more than 24 hours. The evidence to support either extending the duration or broadening the antibiotic protocol for Gustilo type III wounds remains inconclusive, and more investigation into this question with higher-level research methods is needed.
Konstantinos Malizos, MD, PhD
JBJS Deputy Editor
Irrigation and debridement of open fractures have been standard practices since the late 1800s. However, the finer details have not been agreed upon. For example, should we use higher pressures with pulsatile lavage devices? And will adding soap to standard saline irrigation solution get better results? Answers to those two questions from lab and animal studies over the years have been limited and contradictory. The goal of the recently reported FLOW study (Fluid Lavage of Open Wounds) was to answer those questions definitively.
Initially, a pilot study with just over 100 patients suggested that using soap might yield fewer adverse events requiring a return to the OR. Little difference was noted between high and low pressures using a pulsatile lavage device. Most importantly, the pilot showed that a definitive study was feasible.
FLOW investigators, of which I was one, then began pursuing a multicenter, international, randomized, controlled study to evaluate the effects of irrigation pressure and solutions on open fractures. The US Department of Defense (DoD), the Canadian Institutes of Health Research, and others supported us in the definitive trial. From what we learned in the pilot study and from DoD input, we added a third arm to the pressure investigation and included gravity flow, which is essentially a bag of fluid run through quarter-inch tubing into the wound.
We collected data for five years from 2,447 patients at 41 sites worldwide and achieved a 90% 12-month follow-up. The results demonstrated that reoperation rates for the three different pressures were similar. But unlike the size-limited data from the pilot study, using soap in the irrigation solution resulted in a significantly higher reoperation rate than normal saline.
This second finding should convince us that saline is the irrigation solution of choice and that by avoiding soap, adverse outcomes can be diminished and costs lowered for institutions. The discrepancy between the soap findings in the pilot data and the full study may simply reflect the need for larger numbers. Intuitively, we might think that soap, which we use all the time for hand-washing, would be better because it helps remove debris and bacteria. However, the FLOW findings suggest that soap may have a negative impact on soft tissues and bone, making reoperation rates significantly higher. In regard to pressures, the use of a pulsatile lavage with high or low pressures offered no apparent benefit compared to irrigation with gravity flow. This should allow sites to avoid the cost of using pulsatile lavage devices.
Taken together, these findings should reassure institutions worldwide that do not have access to soap or pulsatile lavage devices that their wound-irrigation practices are not compromised and may indeed be the standard of care based on the FLOW data.
Kyle Jeray, MD
Greenville Health System
Vice-Chairman of Academics, Department of Orthopaedic Surgery
JBJS Associate Editor