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.”
Infection, whether acute, chronic, local, or systemic, is something that all surgeons respect and fear. To counter infection, tissue injury activates an acute-phase response mediated by the liver and promotes coagulation, immunity, and tissue regeneration. However, microorganisms are able to survive and disseminate throughout tissues because of virulence factors that they express. These virulence factors help to modulate and hijack the acute-phase response.
In this month’s Editor’s Choice article, An et al. discuss how an understanding of virulence strategies of musculoskeletal pathogens will help to guide clinical diagnosis and decision-making through monitoring of acute-phase markers such as C-reactive protein, the erythrocyte sedimentation rate, and fibrinogen. As pathogenic bacteria possess virulence factors that allow them to invade, persist, and disseminate within the human body, this review focuses on the pathophysiology of musculoskeletal infection and the virulence factors that enable pathogens to thrive within the context of tissue damage.
The authors demonstrate that tissue injury ruptures anatomic compartment boundaries, leading to the contamination of microenvironments that require complex physiological processes for proper temporary repair. Certain organisms, such as Staphylococcus aureus and Streptococcus pyogenes, have evolved mechanisms for evading and hijacking the hemostatic, tissue regenerative, and antimicrobial properties of the acute-phase response. Indeed, a better understanding of the virulence strategies used by pathogenic microorganisms should enhance our ability to treat infections and improve patient outcomes in the future.
Thomas A. Einhorn, MD
Editor, JBJS Reviews
Despite advances in sterile techniques and evidence-based use of perioperative antibiotics, periprosthetic joint infections still occur in 1% of primary and 3% to 7% of revision total joint arthroplasties. But a “smart” antimicrobial polymer coating, described in the July 20, 2016 Journal of Bone & Joint Surgery, has great potential to cut those percentages.
Stavrakis et al. devised a nontoxic, biodegradable polymer coating (called PEG-PPS for short) that locally delivers antibiotics (vancomycin and tigecycline in this study) both passively and actively, with the active release initiated by the presence of bacteria.
The authors tested the efficacy of the coating both in vitro and in vivo. In vitro, the release of antibiotics from the coating was enhanced in the presence of an oxidative environment, as would occur during a periprosthetic joint infection, demonstrating the coating’s “smartness.”
In vivo, using a mouse model of post-arthroplasty infection caused by Staphylococcus aureus, the authors showed radiographically that implants coated with PEG-PPS alone had a dramatic degree of periprosthetic osteolysis by postoperative day 7, compared with antibiotic-encapsulated PEG-PPS implants, which showed no detectable osteolysis. Similarly, the number of colony forming units of S. aureus cultured from implants on postoperative day 21 was significantly lower in the antibiotic-encapsulated implants than in the PEG-PPS-alone implants. (Interestingly, the tigecycline coating was more effective than the vancomycin coating in preventing bacterial colonization.)
While acknowledging that this proof-of-concept study needs to be replicated with other infectious organisms and in larger animals and humans, the authors conclude that PEG-PPS delivery of antibiotics has “great potential to minimize the incidence of postoperative infection following arthroplasty.”
Along with the sharply rising number of total hip and knee arthroplasties performed in the US comes an increasingly compelling need to prevent periprosthetic joint infections (PJIs). If a PJI occurs, guidelines recommend a two- to six-week post-revision course of pathogen-specific intravenous antibiotic therapy. However, the benefit of chronic suppression with oral antibiotics beyond that is unproven.
In the August 5 edition of The Journal of Bone & Joint Surgery, Siqueira et al. compared the infection-free prosthetic survivorship in 92 patients who underwent chronic oral antibiotic suppression for a minimum of six months with prosthetic survivorship in a matched cohort who did not receive extended antibiotic treatment. In so doing, they also attempted to determine factors associated with failure of chronic suppression with oral antibiotics.
The five-year infection-free prosthetic survival rate in the suppression group was 68.5% compared with 41.1% in the non-suppression group. Patients who benefited the most from chronic suppressive antibiotic therapy were:
- Those who underwent irrigation and debridement with polyethylene exchange. (Antibiotic suppression following two-stage procedures did not affect prosthetic survival.)
- Those with Staphylococcus aureus (Chronic antibiotic therapy did not influence infection-free survival after revisions for non-S. aureus infections.)
Suppression-group patients in whom antibiotic treatment failed had had more prior joint revisions and were more likely to have had a knee PJI than a hip infection.
Noting the benefit of suppressive therapy in patients who underwent irrigation and debridement with polyethylene exchange, the authors concluded that “persistence of a latent infection is common in patients with retained implants, and thus antibiotic suppression seems to be a reasonable alternative that avoids the need for a more invasive two-stage revision.”
Surgical site infections (SSIs) can cancel out the benefits of surgery, and they’re the number-one cause of hospital readmissions following surgery. The most prevalent pathogenic culprit is Staphylococcus aureus.
A study of patients undergoing cardiac or hip or knee arthroplasty surgery at 20 hospitals in nine states found that the following protocol reduced the rate of complex (deep incisional or organ-space) S. aureus SSIs by about 40% overall—and by about 50% among patients undergoing hip or knee arthroplasty (an absolute difference of 17 infections per 10,000 joint replacements):
- Preoperative screening of nasal samples
- Intranasal mupirocin and chlorhexidine baths for up to five days prior to surgery for patients testing positive for methicillin-resistant S. aureus (MRSA) or methicillin-susceptible S. aureus (MSSA)
- Perioperative prophylaxis with vancomycin plus cefazolin or cefuroxime for MRSA carriers and perioperative cefazolin or cefuroxime for all others
Rates of complex SSIs decreased most substantially among patients who were fully adherent to the protocol, although only 39% of the subjects experienced implementation of all the steps. Adherence rates were especially low among those who presented in urgent and emergency settings.
In an editorial accompanying the study, Preeti Malani, MD wrote that “although the absolute difference [in infections] seems modest, each complex SSI prevented is clinically meaningful.”
The treatment of periprosthetic infection remains one of the most difficult and challenging problems in orthopaedic surgery. Conventional approaches such as the use of tissue and/or fluid cultures to identify and treat organisms are not nearly as successful as they need to be in order to address these conditions. The limitations of treatment, including the inaccessibility of microorganisms at the time of irrigation and debridement, the development of resistant strains of microorganisms, and the elaboration by microorganisms of protective biofilms, have led to unsuccessful outcomes in a large number of cases.
In this issue of JBJS Reviews, Chen and Parvizi provide an update on some of the new methods that may possibly advance this field. Molecular methods such as polymerase chain reaction to amplify bacteria can improve the likelihood of identifying the pathogen in a patient with a periprosthetic joint infection. Synovial markers such as C-reactive protein, leukocyte esterase, α-defensin, human β-defensin-2 (HBD-2) and HBD-3, and cathelicidin LL-37 are known to be elevated in patients with periprosthetic joint infection and may be used as markers for diagnosing infection at the time of operative management. Serum markers such as interleukin-4 (IL-4) and IL-6, and others such as soluble intracellular adhesion molecule-1 (sICAM-1) and procalcitonin (PCT), have been shown to be elevated in patients with periprosthetic joint infection.
Molecular detection methods probably have received the most attention and interest as an advancement that may improve our ability to diagnose periprosthetic infections. The limitations of these methods, however, include their high sensitivity and an increased rate of false-positive results. Methods to reduce the number of false-positive results are currently in development and include, among other things, the measurement of 16S ribosomal RNA in the belief that targeting RNA will result in amplification of only the genetic material of live bacteria. In addition, use of the mecA gene for identifying methicillin-resistant Staphylococcus aureus (MRSA) can reduce this rate.
Although this article does not provide definitive new approaches to the problem, the review of recent advances with the development of promising biomarkers and molecular techniques provides optimism that this field is evolving in a positive way.
In a comprehensive 43-page document freely available in Clinical Infectious Diseases, the Infectious Diseases Society of America has updated its guidelines for diagnosing and managing skin and soft-tissue infections. Of special interest to orthopaedic surgeons, the guidelines include an algorithm for simpler analysis and treatment of surgical-site infections and updated approaches to treating localized purulent infections in light of concern about drug-resistant strains of Staphylococcus aureus.