Antibiotic-Laden Cement Lowers TKA-Revision Rates in US Veterans
We recently celebrated Veteran’s Day with the annual tradition of rightfully honoring the men and women who have served in the Armed Forces. After their active duty ends, servicemembers are eligible for care in Veterans Health Administration (VHA) hospitals around the nation. The VHA is a “closed” medical system that affords ample opportunity for population-based research.
In the November 18, 2020 issue of The Journal, Bendich et al. utilized VHA data to compare revision rates after primary total knee arthroplasty (TKA) among veterans treated with antibiotic-laden bone cement (ALBC) or plain cement. Although results of similarly designed studies focused on this question have been equivocal, antibiotic-laden cement seems to be especially effective at preventing infection in higher-risk populations, which is what the US veteran population is considered to be.
The researchers identified 15,972 primary TKAs that were implanted using Palacos bone cement between 2007 and 2015. Approximately 70% (11,231) of those cases used cement mixed with gentamicin, while 30% (4,741) utilized plain bone cement. The authors found similar patient demographics among patients treated with ALBC and those treated with plain cement, but ALBC was used more frequently in patients with higher comorbidity scores.
Overall, utilization of ALBC increased from 50.6% of the cases in 2007 to 69.4% in 2015. At a follow-up of 5 years, ALBC TKAs had a lower all-cause revision rate (5.3%) than plain-cement TKAs (6.7%) and a lower rate of revision for infection (1.9% compared to 2.6%). Even after multivariable adjustments to account for patient, surgical, and hospital factors, these revision-rate differences remained.
Bendich et al. also found that 71 TKAs needed to be implanted with ALBC to avoid 1 revision TKA. With a cost differential of $240 per case for ALBC, I think spending $17,040 ($240 × 71) is more cost-effective than 1 revision TKA, although a formal cost analysis is warranted.
In the interest of full disclosure, as an active-duty US Air Force officer, I am inherently biased, but I feel that no cost is too great to improve the health of our veterans. The authors review arguments against using ALBC, such as a theoretical risk of poor cement mechanical properties and systemic toxicity, but the findings of this study suggest that cement with antibiotics enhances treatment outcomes among these US heroes.
Click here to view the “Author Insight” interview about this study with co-author Alfred Kuo, MD, PhD.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
Balancing Antibiotic Perfusion and Tourniquet Usage
Antibiotics are an integral part of infection prophylaxis in orthopaedic surgery, and tourniquets are widely used during many of those same surgeries. The timing of antibiotic administration in relation to tourniquet use has long been debated. Hanberg et al. explore this “balancing act” in the November 4, 2020 issue of The Journal in a carefully performed animal study.
The researchers anesthetized 24 female pigs and surgically exposed both of their hind calcanei. They then placed microdialysis catheters through drill holes in each calcaneus and also into the subcutaneous adipose tissue in the hind feet. Tourniquets were applied to one hind leg on each animal, and each pig was then randomized into 1 of 3 groups, based on when the animal received 1.5 gm of cefuroxime intravenously:
- Group A –15 minutes prior to tourniquet inflation
- Group B – 45 minutes prior to tourniquet inflation
- Group C – At the time of tourniquet release
Hanberg et al. inflated the tourniquets for 90 minutes in all 3 groups, and then they measured the concentrations of cefuroxime and ischemic markers at regular intervals between the time of tourniquet inflation and up to 480 minutes afterward.
The authors found that in both Groups A and B, cefuroxime concentrations were maintained above the minimum inhibitory concentration (MIC) for Staphylococcus aureus in cancellous bone and adipose tissue throughout the 90 minutes of tourniquet inflation. In addition, injecting cefuroxime at the time of tourniquet deflation (Group C) kept the tissue-antibiotic levels above the MIC on the tourniquet side for 3.5 hours after tourniquet release.
There were no differences in the time above MIC in bone or adipose tissue between the 3 groups, but the researchers noted a trend toward shorter time above MIC in bone in Group A vs. Group C (p=0.08). There was also a tendency toward higher time above MIC in bone on the tourniquet side compared to no-tourniquet side in Group B (p=0.08) and Group C (p=0.06). The researchers also found that, in all the animals, tissue ischemia persisted for 2.5 hours after tourniquet deflation in bone, while the adipose tissue recovered immediately.
This animal study provides useful data and prompts us to ponder ideas for further investigation regarding the interplay between tourniquets and antibiotic perfusion. For example, I think the prolonged ischemia in cancellous bone is a topic that warrants further investigation, and I am also curious whether adding antibiotics at the time of tourniquet release might help combat the potentially negative effects of that ischemia.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
Revision Shoulder Arthroplasty: IV or Oral Antibiotics?
Surgeons performing revision shoulder arthroplasty typically order postoperative antibiotics to be administered while they wait for results from intraoperative cultures. Based on their index of suspicion from preoperative exams and intraoperative observations, they order either intravenous (high suspicion of infection) or oral (low suspicion) antibiotics during the waiting period. In the June 3, 2020 issue of JBJS, Yao et al. report on a retrospective review of 175 patients who underwent revision shoulder arthroplasty, finding that surgeons’ presumptive choice of antibiotic type matched the culture results in 75% of the cases.
Among the 175 patients in the study, IV antibiotics were initiated in 62, while 113 patients received oral antibiotics. Cultures from 49 of the 62 patients started on IV antibiotics came back positive, and cultures from 83 of the 113 patients started on oral antibiotics came back negative. Treatment of patients whose initial antibiotic regimen did not match culture results was modified accordingly.
After multivariate analysis Yao et al. found that male sex, prior ipsilateral infection, and intraoperative presence of a humeral membrane were 3 independent predictors of surgeons initiating IV antibiotics. Antibiotic-related adverse events (including GI, dermatologic, and allergic reactions) occurred in 19% of the patients. Not surprisingly, the rate of these complications was highest among those receiving IV antibiotics.
Although the surgeons’ empirical initiation of antibiotic administration route was “correct” 75% of the time, that still left 25% of the patients needing modification of therapy based on culture results. While the authors observe that their study was not designed “to report the relative effectiveness of the 2 antibiotic protocols in minimizing the risk of recurrent infection,” their findings confirm that preoperative and intraoperative observations can help surgeons select the “right” type of antibiotic without culture results—and that is heartening.
Stop Adding Antibiotics to Irrigation Solutions
The rate of adoption of knowledge gleaned from multiple well-done randomized clinical trials into medical practice is disappointingly slow. This has been well-documented in cardiovascular medicine, and the examples in orthopaedic surgery are embarrassingly similar. A corollary phenomenon exists with the slow rate of transfer of information from basic science studies to orthopaedic clinical practice.
These “disconnects” occur largely because we tend to adopt the practices of our residency faculty, often without any rational inquiry. Having been an oral examiner for the Part II ABOS Oral Boards, I frequently asked, “Why did you decide on that approach to the patient’s problem?” And I often heard in response, “That’s the way it was done in my residency.”
In the September 18, 2019 issue of The Journal, Goswami et al,. report findings from a well-designed in vitro study demonstrating that the common practice of adding the antibiotics polymyxin and bacitracin to irrigation solution to lower the risk of infection is not based on sound evidence. While adding antibiotics might make intuitive sense, according to these authors, it is “a futile exercise.”
After testing 8 different irrigation solutions for efficacy against S. aureus and E. coli and for toxicity to musculoskeletal cells, Goswami et al. concluded that “our results provide further support for the use of dilute povidone-iodine because of its bactericidal properties, relatively limited toxicity,… and modest cost.” They go on to say that their findings bring into question the widespread usage of polymyxin-bacitracin.
Certainly, we need to assemble more evidence from additional research to identify the optimal irrigation solution for orthopaedic surgery, but in the interim, we should probably stop using polymyxin-bacitracin. Doing so would have the added benefits of lowering costs and not exacerbating the serious problem of antimicrobial resistance. There are many areas of clinical practice where we have no evidence either for against a particular approach. But when we do have solid evidence, even if it’s from an in vitro study, we should work together to improve the rates of adoption into clinical practice.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Rabbit Study Suggests Antibiotic-Releasing Implant Coating Could Cut Infection Risk
A study by Miller et al. in the February 20, 2019 issue of JBJS provides preclinical proof of concept that antibiotic-loaded coatings on orthopaedic implants could eventually reduce the incidence of implant-associated infection.
The researchers used in vivo bioluminescence imaging (BLI) and ex vivo analysis of colony-forming units (CFUs) to show the efficacy of an implant coating that released linezolid-rifampin over a 7-day period. Through a parapatellar arthrotomy, researchers reamed the femoral canal of 12 rabbits and inoculated the canals with a bioluminescent strain of MRSA. They then inserted a surgical grade titanium peg into each canal. All of the pegs were coated with a nanofiber coating; 6 of the pegs were loaded with the antibiotic coating and 6 were not.
Implants coated without antibiotics were associated with significantly increased in vivo BLI signals and significantly increased knee width, relative to implants with the antibiotic-releasing coatings. The animals were killed on day 7, and ex vivo analysis of CFUs isolated from soft tissue, bone, and implant specimens showed significantly increased CFUs in the specimens without the antibiotic-releasing coating, while CFUs were undetectable in the implants with antibiotics.
This larger-animal model to assess bacterial burden employed a clinically used orthopaedic implant and replicated a medial parapatellar arthrotomy in humans. According to the authors, the coating used is “highly versatile, and the polymers or drug concentrations could be modified for more rapid or longer release.” This rabbit model should be amenable to studying additional antibiotic-releasing strategies for possible translation to clinical research in humans.
Musculoskeletal Infections: Oral Antibiotics Not Inferior to IV
OrthoBuzz occasionally receives posts from guest bloggers. In response to a recent New England Journal of Medicine study, the following commentary comes from Daniel Leas, MD and Joseph R. Hsu, MD.
Deep infections continue to be one of the most resource-intensive problems that orthopaedic surgeons face. Long-standing dogma has favored 6 or more weeks of intravenous (IV) antibiotics, resulting in increased healthcare costs during both the inpatient and outpatient treatment periods.
To explore the possibility of utilizing targeted oral antibiotics as an alternative, effective treatment for musculoskeletal infections, the OVIVA (Oral versus Intravenous Antibiotics) multicenter research collaboration conducted a prospective, randomized controlled trial. A total of 1,054 patients with deep musculoskeletal infections were randomized to oral or IV arms for 6 weeks of antibiotic treatment and followed for 1 year to determine treatment efficacy. The primary end point was treatment failure within 1 year, defined as the presence of predefined clinical symptoms of deep infection, microbiologic evidence of continued infection, or histologic presence of microorganisms or inflammatory tissue. Secondary outcomes included catheter-associated complications, discontinuation of therapy, and Clostridium difficile diarrhea.
Of the 1,054 patients enrolled, 909 patients were included in the final analysis. Treatment failure occurred in 14.6% of patients treated with IV antibiotics and 13.2% of patients in the oral-therapy group. This -1.4% difference indicated noninferiority based on the predetermined 7.5% noninferiority margin. Secondary outcomes between the groups differed only in catheter-related complications being more common in the IV group (9.4% vs 1.0% in the oral group).
These findings and conclusions should challenge us to re-evaluate the basis for extended IV antibiotics to treat complex musculoskeletal infections, and to consider a greater role for oral antibiotics for such infections. Further study of this question focused on patients with retained hardware is warranted.
Daniel P. Leas, MD is a PGY-5 orthopaedic resident at Carolinas Medical Center.
Joseph R. Hsu, MD is a Professor of Orthopaedic Trauma and Vice Chair of Quality at the Atrium Health Musculoskeletal Institute.
Surgical Infection Prevention: Local Antibiotic Powders Beat IV Agents in Rats
When it comes to preventing infections associated with orthopaedic procedures, the question of which antibiotic to use is only one of several concerns. How and where to administer antibiotics is another relevant question, not only in terms of infection-fighting effectiveness but also in terms of combatting the proliferation of antibiotic-resistant microbes.
In the September 19, 2018 issue of The Journal of Bone & Joint Surgery, Sweet et al. report on findings from a study in rats that compared the infection-prevention efficacy of intravenous (IV) cefazolin (n = 20) and IV vancomycin (n = 20) with local application of 4 antimicrobials—vancomycin powder (n = 20), cefazolin powder (n = 20), tobramycin powder (n = 20), and dilute Betadine lavage (n = 20).
The researchers induced infection by surgically implanting a polytetrafluoroethylene vascular graft near each rat’s thoracic spine and inoculating it with methicillin-sensitive Staphylococcus aureus (MSSA). After 7 days, all of the rats in each of the IV cefazolin, IV vancomycin, and Betadine lavage groups had grossly positive cultures for MSSA, “with bacterial colonies too numerous to count.” Ninety percent of the rats in the local cefazolin-powder group also had positive cultures, but the infection rates with vancomycin and tobramycin powder were much lower than those with the other four approaches (p <0.000001).
In addition to the main “disclaimer” about this study (namely, that its findings cannot be extrapolated to clinical practice in humans), the authors caution that “the effect of locally applied antibiotics on the emergence of resistant organisms is unknown,” while citing evidence that systemic administration of antibiotics is “associated with the emergence of resistant organisms at an alarming rate.”
Sweet et al. say they plan to follow up this study with a similar model to investigate the efficacy of local antimicrobials against the more problematic methicillin-resistant Staphylococcus aureus (MRSA)—and they suggest further that “clinical studies should be considered to determine the relative clinical efficacy of local versus systemic antibiotics for surgical infection prophylaxis in humans.”
Use Data, Guidelines, and Intuition to Manage Infection after Toe/Forefoot Amputation
The number of articles published each year in orthopaedics that evaluate infections seems to approach, if not exceed, 1,000. Yet, despite all of these publications, consensus statements, and guidelines, we seem to have very few concrete recommendations about which every surgeon will say, “This is what needs to be done.” So we send out samples, run cultures, sonicate implants, and sometimes even perform DNA sequencing, and then we mix the data with selected recommendations and intuition to make our final treatment decisions. Foolproof? No, but it is the best we can do in many situations.
The article by Mijuskovic et al. in the September 5, 2018 edition of The Journal helps simplify this type of decision making in the setting of residual osteomyelitis after toe or forefoot amputation. The authors evaluated 51 consecutive patients with gangrene and/or infection who underwent either digit or partial foot amputations. They found that, after surgery, 41% of the patients without histological evidence of osteomyelitis (which the authors considered the reference, “true positive” analysis) had a positive culture from the same sample. In addition, only 12 patients (24%) had both positive histological findings and positive cultures, the criteria set forth by the Infectious Disease Society of America for the definitive diagnosis of osteomyelitis.
As interesting as the main findings of the study are, some of the “minor” results are even more curious. The decision regarding which patients received antibiotics after amputation seemed largely arbitrary, with 10 of the 14 patients who had a positive histological result not receiving any postoperative antibiotics. (Five of those patients ended up needing a secondary procedure.) In addition, because of the need for decalcification prior to analysis, the median time to receiving histological results was almost a week. Based on the findings in this study, in many instances patients are sent home or to a rehabilitation facility with antibiotics based only on the results of a potentially “false-positive” culture.
The authors conclude that their results “cast doubt on the strategy of relying solely on culture of bone biopsy specimens when deciding whether antibiotic treatment for osteomyelitis is necessary after toe or forefoot amputation.” But this paper also highlights the fact that we are still looking for definitive answers about which data to use and which to disregard when it comes to the detection and treatment of post-amputation osteomyelitis. We surgeons decide on which side to err, and we need to appreciate all three facets—data, guidelines, and patient factors—when discussing treatment options with patients.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
What’s New in Musculoskeletal Infection
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, Arvind Nana, MD, co-author of the July 19, 2017 Specialty Update on musculoskeletal infection, selected the five most compelling findings from among the more than 120 studies cited in the Specialty Update.
Periprosthetic Joint Infection
–Much of the discussion around treating periprosthetic joint infections (PJIs) centers around comparing one-stage versus two-stage exchange arthroplasty. Two-stage exchange arthroplasty requires the use of a temporary cement spacer, and one study1 found that debris from articulating spacers may induce CD3, CD20, CD11(c), and IL-17 changes, raising the possibility of associated immune modulation.
–When performing debridement to treat a PJI, instead of an irrigation solution containing antibiotics, a 20-minute antiseptic soak with 0.19% vol/vol acetic acid reduced the risk of reinfection.2
Spine
–Four studies helped bolster evidence that surgical-site infections are the leading cause of reoperations after spine surgery, both early (within 30 days)3, 4 and late (after 2 years).5, 6
Trauma
–A 100-patient prospective cohort study found that posttraumatic osteomyelitis treated with a 1-stage protocol and host optimization in Type B hosts resulted in 96% infection-free outcomes.7
Shoulder
–As in lower-extremity procedures, the risk of infection after shoulder arthroplasty and arthroscopy is higher when the surgeries are performed less than 3 months after a corticosteroid injection. This finding suggests elective shoulder procedures should be delayed for at least 90 days after such injections.8
References
- Singh G, Deutloff N, Maertens N, Meyer H, Awiszus F, Feuerstein B, Roessner A, Lohmann CH. Articulating polymethylmethacrylate (PMMA) spacers may have an immunomodulating effect on synovial tissue. Bone Joint J. 2016 ;98-B(8):1062–8.
- Williams RL, Ayre WN, Khan WS, Mehta A, Morgan-Jones R. Acetic acid as part of a debridement protocol during revision total knee arthroplasty. J Arthroplasty. 2017 ;32(3):953–7. Epub 2016 Sep 28.
- Medvedev G, Wang C, Cyriac M, Amdur R, O’Brien J. Complications, readmissions, and reoperations in posterior cervical fusion. Spine (Phila Pa 1976). 2016 ;41(19):1477–83.
- Hijas-Gómez AI, Egea-Gámez RM, Martínez-Martín J, González-Díaz RC, Losada-Viñas JI, Rodríguez-Caravaca G. Surgical wound infection rates and risk factors in spinal fusion in a university teaching hospital in Madrid, Spain. Spine. November 2016.
- Ohya J, Chikuda H, Takeshi O, Kato S, Matsui H, Horiguchi H, Tanaka S, Yasunaga H. Seasonal variations in the risk of reoperation for surgical site infection following elective spinal fusion surgery: a retrospective study using the Japanese diagnosis procedure combination database. Spine (Phila Pa 1976). 2016 . Epub 2016 Nov 22.
- Ahmed SI, Bastrom TP, Yaszay B, Newton PO; Harms Study Group. 5-year reoperation risk and causes for revision after idiopathic scoliosis surgery. Spine (Phila Pa 1976). 2016 . Epub 2016 Nov 9.
- McNally MA, Ferguson JY, Lau ACK, Diefenbeck M, Scarborough M, Ramsden AJ, Atkins BL. Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases. Bone Joint J. 2016 ;98-B(9):1289–96.
- Werner BC, Cancienne JM, Burrus MT, Griffin JW, Gwathmey FW, Brockmeier SF. The timing of elective shoulder surgery after shoulder injection affects postoperative infection risk in Medicare patients. J Shoulder Elbow Surg. 2016 ;25(3):390–7. Epub 2015 Nov 30.
What’s New in Musculoskeletal Infection: Update on Biofilms
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, Arvind Nana, MD, co-author of the July 20, 2016 Specialty Update on musculoskeletal infection, selected the three most compelling discoveries from among the more than 100 studies cited in the Specialty Update, which focused on biofilms.
Dr. Nana and his co-authors provide a concise primer on the biology of biofilms, the network of microorganisms that adhere to implant surfaces and form a complex structure surrounded by a self-generated extracellular polymeric matrix. This matrix not only anchors bacteria to orthopaedic implants, but also provides a nearly impenetrable defense mechanism against the host immune system. Staphylococci are the most common biofilm-forming bacteria found in orthopaedics.
Persister Cells in Biofilms
So-called persister cells have an inherent tolerance to antimicrobial agents. Misconceptions about persisters have permeated the literature. The authors provide clarification about persisters:
- Persister cells CAN be reliably killed when the antimicrobial concentration is high enough. The minimum biofilm eradication concentration (MBEC) is lower when antimicrobial exposure is continuous and prolonged.1
- Decreasing the number of microorganisms with antimicrobial intervention is NOT good enough. Cure requires the total elimination of all viable microbes.
Biofilm in Orthopaedic Trauma
Biofilm formation in the setting of open fractures is concerning because biofilm can develop on bone and in soft tissues in a matter of hours. The assumption is that appropriate surgical techniques for open fractures, including therapeutic antibiotic administration, can decrease bioburden and provide fracture stability, thus modulating the acute, local inflammatory response and minimizing biofilm formation.2 However, current technology does not enable noninvasive quantification of biofilm activity and presence in a stable open fracture following wound closure.
Biofilm in Total Joint Arthroplasty
Traditionally, prosthesis-related biofilm infections in the US have been treated by a 2-stage exchange arthroplasty. Although biofilm from the implant is removed by extraction of the components, the potential exists for persistence of biofilm in the surrounding soft tissues. Most patients treated for periprosthetic joint infections also receive intravenous antibiotics, but a recent in vitro study demonstrated that administering cefazolin even at increased concentrations still resulted in persistent Staphylococcus biofilm on cobalt-chromium, polymethylmethacrylate, and polyethylene,3 which supports the need for explantation.
There is still room to develop novel treatment methods for eradicating biofilm in periprosthetic joint infections. Future novel treatment methods for eradicating implant biofilm will help minimize the morbidity associated with current accepted periprosthetic joint infection treatment options.
References
- Castaneda P, McLaren A, Tavaziva G, Overstreet D. Biofilm antimicrobial susceptibility increases with antimicrobial exposure time. Clin Orthop Relat Res. 2016 Jan 21.
- Pfeifer R, Darwiche S, Kohut L, Billiar TR, Pape HC. Cumulative effects of bone and soft tissue injury on systemic inflammation: a pilot study. Clin Orthop Relat Res. 2013 Sep;471(9):2815-21.
- Urish KL, DeMuth PW, Kwan BW, Craft DW, Ma D, Haider H, Tuan RS, Wood TK, Davis CM 3rd..Antibiotic-tolerant Staphylococcus aureus biofilm persists on arthroplasty materials. Clin Orthop Relat Res.2016 Feb 1.
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