Orthopedic Implant-related Infections Research Articles

Effectiveness of rifampicin combination therapy for orthopedic implant-related infections: A systematic review and meta-analysis

BackgroundIn vitro, animal, and clinical comparative studies have revealed that combinations of rifampicin with antibacterial agents are effective in the treatment of biofilm-associated infections. This study aimed to assess the effectiveness of rifampicin combination therapies compared with monotherapies without rifampicin in patients with orthopedic implant-related infections. Materials and MethodsThe clinical literature was comprehensively searched for studies assessing the effectiveness of rifampicin combination therapy in patients with orthopedic implant-related infection. Identified studies were screened based on the PRISMA flow diagram. The primary outcome was the cure rate and the secondary outcome was the incidence of adverse events. Subgroup analyses were performed based on causative organisms, antibacterial agents, and types of surgical intervention. ResultsTwenty-seven studies were identified, including two randomized controlled trials (RCTs) and 25 cohort studies. Rifampicin combinations were associated with significantly higher cure rates than monotherapies in cohort studies, but not in RCTs. Subgroup analyses showed that rifampicin combinations were effective in patients infected with Cutibacterium and Staphylococcus spp.; in patients who underwent debridement, antibiotics, implant retention (DAIR) procedures; and in patients with one-stage revision. Moreover, combinations of rifampicin and fluoroqinolones were more effective than fluoroquinolones alone, while combinating rifampicin with other antibacterial agents showed no significant benefit. Combination treatment did not significantly affect adverse events in either RCTs or observational studies. Risk of bias assessment and summary of findings showed that the certainty of evidence for both RCTs and observational studies was very low. ConclusionThis systematic review and meta-analysis confirmed the potential effectiveness of rifampicin combination therapy for the cure of orthopedic implant-related infection in some circumstances, although the certainty and quality of evidence were very low.

Nanotopography Influences Host-Pathogen Quorum Sensing and Facilitates Selection of Bioactive Metabolites in Mesenchymal Stromal Cells and Pseudomonas aeruginosa Co-Cultures.

Orthopedic implant-related bacterial infections and resultant antibiotic-resistant biofilms hinder implant-tissue integration and failure. Biofilm quorum sensing (QS) communication determines the pathogen colonization success. However, it remains unclear how implant modifications and host cells are influenced by, or influence, QS. High aspect ratio nanotopographies have shown to reduce biofilm formation of Pseudomonas aeruginosa, a sepsis causing pathogen with well-defined QS molecules. Producing such nanotopographies in relevant orthopedic materials (i.e., titanium) allows for probing QS using mass spectrometry-based metabolomics. However, nanotopographies can reduce host cell adhesion and regeneration. Therefore, we developed a polymer (poly(ethyl acrylate), PEA) coating that organizes extracellular matrix proteins, promoting bioactivity to host cells such as human mesenchymal stromal cells (hMSCs), maintaining biofilm reduction. This allowed us to investigate how hMSCs, after winning the race for the surface against pathogenic cells, interact with the biofilm. Our approach revealed that nanotopographies reduced major virulence pathways, such as LasR. The enhanced hMSCs support provided by the coated nanotopographies was shown to suppress virulence pathways and biofilm formation. Finally, we selected bioactive metabolites and demonstrated that these could be used as adjuncts to the nanostructured surfaces to reduce biofilm formation and enhance hMSC activity. These surfaces make excellent models to study hMSC-pathogen interactions and could be envisaged for use in novel orthopedic implants.

Bioengineering Approaches to Fight against Orthopedic Biomaterials Related-Infections.

One of the most serious complications following the implantation of orthopedic biomaterials is the development of infection. Orthopedic implant-related infections do not only entail clinical problems and patient suffering, but also cause a burden on healthcare care systems. Additionally, the ageing of the world population, in particular in developed countries, has led to an increase in the population above 60 years. This is a significantly vulnerable population segment insofar as biomaterials use is concerned. Implanted materials are highly susceptible to bacterial and fungal colonization and the consequent infection. These microorganisms are often opportunistic, taking advantage of the weakening of the body defenses at the implant surface–tissue interface to attach to tissues or implant surfaces, instigating biofilm formation and subsequent development of infection. The establishment of biofilm leads to tissue destruction, systemic dissemination of the pathogen, and dysfunction of the implant/bone joint, leading to implant failure. Moreover, the contaminated implant can be a reservoir for infection of the surrounding tissue where microorganisms are protected. Therefore, the biofilm increases the pathogenesis of infection since that structure offers protection against host defenses and antimicrobial therapies. Additionally, the rapid emergence of bacterial strains resistant to antibiotics prompted the development of new alternative approaches to prevent and control implant-related infections. Several concepts and approaches have been developed to obtain biomaterials endowed with anti-infective properties. In this review, several anti-infective strategies based on biomaterial engineering are described and discussed in terms of design and fabrication, mechanisms of action, benefits, and drawbacks for preventing and treating orthopaedic biomaterials-related infections.

High-strength biodegradable zinc alloy implants with antibacterial and osteogenic properties for the treatment of MRSA-induced rat osteomyelitis

Implant-related infections caused by drug-resistant bacteria remain a major challenge faced by orthopedic surgeons. Furthermore, ideal prevention and treatment methods are lacking in clinical practice. Here, based on the antibacterial and osteogenic properties of Zn alloys, Ag and Li were selected as alloying elements to prepare biodegradable Zn-Li-Ag ternary alloys. Li and Ag addition improved the mechanical properties of Zn-Li-Ag alloys. The Zn-0.8Li-0.5Ag alloy exhibited the highest ultimate tensile strength (>530 MPa). Zn-Li-Ag alloys showed strong bactericidal effects on methicillin-resistant Staphylococcus aureus (MRSA) in vitro. RNA sequencing revealed two MRSA-killing mechanisms exhibited by the Zn-0.8Li-0.5Ag alloy: cellular metabolism disturbance and induction of reactive oxygen species production. To verify that the therapeutic potential of the Zn-0.8Li-0.5Ag alloy is greater than that of Ti intramedullary nails, X-ray, micro-computed tomography, microbiological, and histological analyses were conducted in a rat femoral model of MRSA-induced osteomyelitis. Treatment with Zn-0.8Li-0.5Ag alloy implants resulted in remarkable infection control and favorable bone retention. The in vivo safety of this ternary alloy was confirmed by evaluating vital organ functions and pathological morphologies. We suggest that, with its good antibacterial and osteogenic properties, Zn-0.8Li-0.5Ag alloy can serve as an orthopedic implant material to prevent and treat orthopedic implant-related infections.

Bone infection site targeting nanoparticle-antibiotics delivery vehicle to enhance treatment efficacy of orthopedic implant related infection

Orthopedic implants account for 99% of orthopedic surgeries, however, orthopedic implant-related infection is one of the most serious complications owing to the potential for limb-threatening sequelae and mortality. Current antibiotic treatments still lack the capacity to target bone infection sites, thereby resulting in unsatisfactory therapeutic effects. Here, the bone infection site targeting efficacy of D6 and UBI29-41 peptides was investigated, and bone-and-bacteria dual-targeted nanoparticles (NPs) with D6 and UBI29-41 peptides were first fabricated to target bone infection site and control the release of vancomycin in bone infection site. The results of this study demonstrated that the bone-and-bacteria dual-targeted mesoporous silica NPs exhibit excellent bone and bacteria targeting efficacy, excellent biocompatibility and effective antibacterial properties in vitro. Furthermore, in a rat model of orthopedic implant-related infection with methicillin-resistant Staphylococcus aureus, the growth of bacteria was evidently inhibited without cytotoxicity, thus realizing the early treatment of implant-related infection. Hence, the bone-and-bacteria dual-targeted molecule-modified NPs may target bacteria-infected bone sites and act as ideal candidates for the therapy of orthopedic implant-related infections.

A Bone-Targeting Enoxacin Delivery System to Eradicate Staphylococcus Aureus-Related Implantation Infections and Bone Loss.

Post-operative infections in orthopaedic implants are severe complications that require urgent solutions. Although conventional antibiotics limit bacterial biofilm formation, they ignore the bone loss caused by osteoclast formation during post-operative orthopaedic implant-related infections. Fortunately, enoxacin exerts both antibacterial and osteoclast inhibitory effects, playing a role in limiting infection and preventing bone loss. However, enoxacin lacks specificity in bone tissue and low bioavailability-related adverse effects, which hinders translational practice. Here, we developed a nanosystem (Eno@MSN-D) based on enoxacin (Eno)-loaded mesoporous silica nanoparticles (MSN), decorated with the eight repeating sequences of aspartate (D-Asp8), and coated with polyethylene glycol The release results suggested that Eno@MSN-D exhibits a high sensitivity to acidic environment. Moreover, this Eno@MSN-D delivery nanosystem exhibited both antibacterial and anti-osteoclast properties in vitro. The cytotoxicity assay revealed no cytotoxicity at the low concentration (20 μg/ml) and Eno@MSN-D inhibited RANKL-induced osteoclast differentiation. Importantly, Eno@MSN-D allowed the targeted release of enoxacin in infected bone tissue. Bone morphometric analysis and histopathology assays demonstrated that Eno@MSN-D has antibacterial and antiosteoclastic effects in vivo, thereby preventing implant-related infections and bone loss. Overall, our study highlights the significance of novel biomaterials that offer new alternatives to treat and prevent orthopaedic Staphylococcus aureus-related implantation infections and bone loss.

Antimicrobial Peptides in the Battle against Orthopedic Implant-Related Infections: A Review.

Prevention of orthopedic implant-related infections is a major medical challenge, particularly due to the involvement of biofilm-encased and multidrug-resistant bacteria. Current therapies, based on antibiotic administration, have proven to be insufficient, and infection prevalence may rise due to the dissemination of antibiotic resistance. Antimicrobial peptides (AMPs) have attracted attention as promising substitutes of conventional antibiotics, owing to their broad-spectrum of activity, high efficacy at very low concentrations, and, importantly, low propensity for inducing resistance. The aim of this review is to offer an updated perspective of the development of AMPs-based preventive strategies for orthopedic and dental implant-related infections. In this regard, two major research strategies are herein addressed, namely (i) AMP-releasing systems from titanium-modified surfaces and from bone cements or beads; and (ii) AMP immobilization strategies used to graft AMPs onto titanium or other model surfaces with potential translation as coatings. In overview, releasing strategies have evolved to guarantee higher loadings, prolonged and targeted delivery periods upon infection. In addition, avant-garde self-assembling strategies or polymer brushes allowed higher immobilized peptide surface densities, overcoming bioavailability issues. Future research efforts should focus on the regulatory demands for pre-clinical and clinical validation towards clinical translation.

Development of an anti-infective coating on the surface of intraosseous implants responsive to enzymes and bacteria

BackgroundBacterial proliferation on the endosseous implants surface presents a new threat to the using of the bone implants. Unfortunately, there is no effective constructed antibacterial coating which is bacterial anti-adhesion substrate-independent or have long-term biofilm inhibition functions.MethodsDrug release effect was tested in Chymotrypsin (CMS) solution and S. aureus. We used bacterial inhibition rate assays and protein leakage experiment to analyze the in vitro antibacterial effect of (Montmorillonite/Poly-l-lysine-Chlorhexidine)10 [(MMT/PLL-CHX)10] multilayer film. We used the CCK-8 assay to analyze the effect of (MMT/PLL-CHX)10 multilayer films on the growth and proliferation of rat osteoblasts. Rat orthopaedic implant-related infections model was constructed to test the antimicrobial activity effect of (MMT/PLL-CHX)10 multilayer films in vivo.ResultsIn this study, the (MMT/PLL-CHX)10 multilayer films structure were progressively degraded and showed well concentration-dependent degradation characteristics following incubation with Staphylococcus aureus and CMS solution. Bacterial inhibition rate assays and protein leakage experiment showed high levels of bactericidal activity. While the CCK-8 analysis proved that the (MMT/PLL-CHX)10 multilayer films possess perfect biocompatibility. It is somewhat encouraging that in the in vivo antibacterial tests, the K-wires coated with (MMT/PLL-CHX)10 multilayer films showed lower infections incidence and inflammation than the unmodified group, and all parameters are close to SHAM group.Conclusion(MMT/PLL-CHX)10 multilayer films provides a potential therapeutic method for orthopaedic implant-related infections.

Orthopedic Implant-Related Biofilm Pathophysiology: A Review of the Literature.

Orthopedic implant-related infections remain a major problem even nowadays. Bacterial resistance through biofilm formation, in addition to the limited treatment options available, has resulted in an increased effort to better understand pathophysiology mechanisms. We performed a review of the literature in order to identify major biofilm formation pathways through which possible treatment strategies could arise.

An update about molecular biology techniques to detect orthopaedic implant-related infections.

Despite different criteria to diagnose a prosthetic joint infection (PJI), aetiological diagnosis of the causing microorganism remains essential to guide treatment.Molecular-biology-based PJI diagnosis is progressing (faster, higher specificity) in different techniques, from the experimental laboratory into clinical use.Multiplex polymerase chain reaction techniques (custom-made or commercial) provide satisfactory results in clinical series of cases, with specificity close to 100% and sensitivity over 70–80%.Next-generation metagenomics may increase sensitivity while maintaining high specificity.Molecular biology techniques may represent, in the next five years, a significant transformation of the currently available microbiological diagnosis in PJI.Cite this article: EFORT Open Rev 2021;6:93-100. DOI: 10.1302/2058-5241.6.200118

Antimicrobial Peptides in the Battle Against Orthopedic Implant-Related Infections – A Review

Prevention of orthopedic implant-related infections is a major medical challenge, particularly due to the involvement of biofilm-encased and multidrug-resistant bacteria. Current therapies, based on antibiotic administration, have proven to be insufficient, and infection prevalence may rise due to the dissemination of antibiotic resistance.Antimicrobial peptides (AMPs) have attracted attention as promising substitutes of conventional antibiotics, owing to their broad-spectrum of activity, high efficacy at very low concentrations, and importantly low propensity for inducing resistance. The current review focuses on the potential of using AMPs as a preventive strategy for orthopedic implant-related infections. This review addresses current progress in AMP-based approaches designed to both benefit from the key role envisioned for AMPs in the post-antibiotic era and overcome the limitations of peptides as therapeutics. Particular attention is given to application of AMPs onto titanium orthopedic and dental implants, and on encouraging achievements that pave the way for future research in this field.

In Vitro Evaluation of Gentamicin or Vancomycin Containing Bone Graft Substitute in the Prevention of Orthopedic Implant-Related Infections

In Vitro Evaluation of Gentamicin or Vancomycin Containing Bone Graft Substitute in the Prevention of Orthopedic Implant-Related Infections

In Vitro Evaluation of Gentamicin or Vancomycin Containing Bone Graft Substitute in the Prevention of Orthopedic Implant-Related Infections.

Antibiotic-loaded bone graft substitutes are attractive clinical options and have been used for years either for prophylaxis or therapy for periprosthetic and fracture-related infections. Calcium sulfate and hydroxyapatite can be combined in an injectable and moldable bone graft substitute that provides dead space management with local release of high concentrations of antibiotics in a one-stage approach. With the aim to test preventive strategies against bone infections, a commercial hydroxyapatite/calcium sulfate bone graft substitute containing either gentamicin or vancomycin was tested against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, harboring different resistance determinants. The prevention of bacterial colonization and biofilm development by selected microorganisms was investigated along with the capability of the eluted antibiotics to select for antibiotic resistance. The addition of antibiotics drastically affected the ability of the selected strains to adhere to the tested compound. Furthermore, both the antibiotics eluted by the bone graft substitutes were able to negatively impair the biofilm maturation of all the staphylococcal strains. As expected, P. aeruginosa was significantly affected only by the gentamicin containing bone graft substitutes. Finally, the prolonged exposure to antibiotic-containing sulfate/hydroxyapatite discs did not lead to any stable or transient adaptations in either of the tested bacterial strains. No signs of the development of antibiotic resistance were found, which confirms the safety of this strategy for the prevention of infection in orthopedic surgery.

Identification and Morphological Characterization of Biofilms Formed by Strains Causing Infection in Orthopedic Implants.

Objectives: For a better understanding of the mechanisms involved in biofilm formation, we performed a broad identification and characterization of the strains affecting implants by evaluating the morphology of biofilms formed in vitro in correlation with tests of the strains’ antibiotic susceptibility in planktonic form. The ability of the strains to form biofilms in vitro was evaluated by means of colony forming units counting, metabolic activity tests of biofilm cells, and scanning electron microscopy. Methods: A total of 140 strains were isolated from patients with orthopedic implant-related infections during the period of 2015 to 2018. The identification of the isolates was carried out through microbiological cultures and confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Antibiotic susceptibility rates of the isolates were accessed according to EUCAST (European Committee on Antimicrobial Susceptibility Testing). The ability of all isolates to form biofilms in vitro was evaluated by counting the colony forming units, by measuring the metabolic activity of biofilm cells, and by analyzing the morphology of the formed biofilms using scanning electron microscopy. Results: From all the isolates, 41.84% (62 strains) were Staphylococcus epidermidis and 15.60% (22 strains) were Staphylococcus aureus. A significant difference in the capacity of biofilm formation was observed among the isolates. When correlating the biofilm forming capacity of the isolates to their antibiotic susceptibility rates, we observed that not all strains that were classified as resistant were biofilm producers in vitro. In other words, bacteria that are not good biofilm formers can show increased tolerance to multiple antibiotic substances. Conclusion: From 2015 until 2018, Staphylococcus epidermidis was the strain that caused most of the orthopedic implant-related infections in our hospital. Not all strains causing infection in orthopedic implants are able to form biofilms under in vitro conditions. Differences were observed in the number of cells and morphology of the biofilms. In addition, antibiotic resistance is not directly related to the capacity of the strains to form biofilms in vitro. Further studies should consider the use of in vitro culture conditions that better reproduce the joint environment and the growth of biofilms in humans.

Bacteriophages and Lysins in Biofilm Control.

To formulate the optimal strategy of combatting bacterial biofilms, in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search for new strategies to deal with this complication. Based on recent findings, the role of bacteriophages in the prevention and elimination of biofilm-related infections has been emphasized. In vitro, ex vivo and in vivo biofilm treatment models with single bacteriophages or phage cocktails have been compared. A combined use of bacteriophages with antibiotics in vitro or in vivo confirms earlier reports of the synergistic effect of these agents in improving biofilm removal. Furthermore, studies on the application of phage-derived lysins in vitro, ex vivo or in vivo against biofilm-related infections are encouraging. The strategy of combined use of phage and antibiotics seems to be different from using lysins and antibiotics. These findings suggest that phages and lysins alone or in combination with antibiotics may be an efficient weapon against biofilm formation in vivo and ex vivo, which could be useful in formulating novel strategies to combat bacterial infections. Those findings proved to be relevant in the prevention and destruction of biofilms occurring during urinary tract infections, orthopedic implant-related infections, periodontal and peri-implant infections. In conclusion, it appears that most efficient strategy of eliminating biofilms involves phages or lysins in combination with antibiotics, but the optimal scheme of their administration requires further studies.

A noninvasive precise treatment strategy for implant-related infections based on X-ray-induced luminescent/photodynamic therapeutic multilayered device surface materials

Conventional prophylaxis and treatment of implant-related infections via devices’ surface biofilm elimination include extensive non-targeting antibiotics prescription, invasive surgical intervention, and periodic implant replacement, with their inevitable relapses being lifelong guaranteed leading to financial burdens and drug resistance risks for patients. Herein, we propose a novel, sustainable modality of noninvasive precise treatment strategy based on potential theranostic, multilayered Gd3+ (UV), Eu3+ (red) and Tb3+ (green) doped Y(PO3)3 X-ray-induced luminescent matrix surface materials cum a nanolayer coating of titanium dioxide with pH indicators on implantable medical devices, which simultaneously integrate X-ray-initiated pH-sensitive NIR luminescence for location detection of biofilm infection, and X-ray-excited, UV-triggered deep-tissue-localized antimicrobial photodynamic therapy. The Y(PO3)3 crystal composite structures allow doping of rare earth ions at rarely high concentrations and produce high emission intensity even under less-detrimental low-dose X-ray radiation. The feasibility of such precise treatment strategy has been substantiated through various pH and inactivation experiments. With the growing aging population, this work aims to provide a potentially new, patient-friendly, (i.e. surgery/antibiotics-free and lower-cost) proof-of-principle theranostic resolution for the increasing incidence of orthopaedic implant-related biofilm infections, from preventive device maintenance to precise curative eradication.

DNA extraction of microbial DNA directly from infected tissue: an optimized protocol for use in nanopore sequencing

Identification of bacteria causing tissue infections can be comprehensive and, in the cases of non- or slow-growing bacteria, near impossible with conventional methods. Performing shotgun metagenomic sequencing on bacterial DNA extracted directly from the infected tissue may improve time to diagnosis and targeted treatment considerably. However, infected tissue consists mainly of human DNA (hDNA) which hampers bacterial identification. In this proof of concept study, we present a modified version of the Ultra-Deep Microbiome Prep kit for DNA extraction procedure, removing additional human DNA. Tissue biopsies from 3 patients with orthopedic implant-related infections containing varying degrees of Staphylococcus aureus were included. Subsequent DNA shotgun metagenomic sequencing using Oxford Nanopore Technologies’ (ONT) MinION platform and ONTs EPI2ME WIMP and ARMA bioinformatic workflows for microbe and antibiotic resistance genes identification, respectively. The modified DNA extraction protocol led to an additional ~10-fold reduction of human DNA while preserving S. aureus DNA. Including the DNA sequencing and bioinformatics analyses, the presented protocol has the potential of identifying the infection-causing pathogen in infected tissue within 7 hours after biopsy. However, due to low number of S. aureus reads, positive identification of antibiotic resistance genes was not possible.

Moxifloxacin-rifampicin combination for the treatment of non-staphylococcal Gram-positive orthopedic implant-related infections

ObjectiveWe aimed to describe the effectiveness and safety of the moxifloxacin–rifampicin combination in non-staphylococcal Gram-positive orthopedic implant-related infections. MethodsPatients treated with the moxifloxacin–rifampicin combination for an implant-related infection from November 2014 to November 2016 were retrospectively identified from the database of the referral centers for bone and joint infections in Western France. ResultsTwenty-three cases of infection due to Streptococcus spp. (n=12), Cutibacteriumacnes (n=6), and Enterococcus faecalis (n=5) were included. Ten patients with hip prosthesis were included. Infection was polymicrobial in 11 cases. According to the MIC, moxifloxacin was 1.5 to 11.7 times as active as levofloxacin against non-staphylococcal Gram-positive bacteria. We reported an 81.8% success rate, and no severe adverse effect. ConclusionThe moxifloxacin–rifampicin combination is a valuable alternative for the treatment of non-staphylococcal Gram-positive implant-related infections because of the good activity of moxifloxacin against these bacteria and the potential activity on the biofilm.

Preventing S. aureus biofilm formation on titanium surfaces by the release of antimicrobial β-peptides from polyelectrolyte multilayers

Staphylococcus aureus infections represent the major cause of titanium based-orthopaedic implant failure. Current treatments for S. aureus infections involve the systemic delivery of antibiotics and additional surgeries, increasing health-care costs and affecting patient’s quality of life. As a step toward the development of new strategies that can prevent these infections, we build upon previous work demonstrating that the colonization of catheters by the fungal pathogen Candida albicans can be prevented by coating them with thin polymer multilayers composed of chitosan (CH) and hyaluronic acid (HA) designed to release a β-amino acid-based peptidomimetic of antimicrobial peptides (AMPs). We demonstrate here that this β-peptide is also potent against S. aureus (MBPC = 4 μg/mL) and characterize its selectivity toward S. aureus biofilms. We demonstrate further that β-peptide-containing CH/HA thin-films can be fabricated on the surfaces of rough planar titanium substrates in ways that allow mammalian cell attachment and permit the long-term release of β-peptide. β-Peptide loading on CH/HA thin-films was then adjusted to achieve release of β-peptide quantities that selectively prevent S. aureus biofilms on titanium substrates in vitro for up to 24 days and remained antimicrobial after being challenged sequentially five times with S. aureus inocula, while causing no significant MC3T3-E1 preosteoblast cytotoxicity compared to uncoated and film-coated controls lacking β-peptide. We conclude that these β-peptide-containing films offer a novel and promising localized delivery approach for preventing orthopaedic implant infections. The facile fabrication and loading of β-peptide-containing films reported here provides opportunities for coating other medical devices prone to biofilm-associated infections. Statement of SignificanceTitanium (Ti) and its alloys are used widely in orthopaedic devices due to their mechanical strength and long-term biocompatibility. However, these devices are susceptible to bacterial colonization and the subsequent formation of biofilms. Here we report a chitosan and hyaluronic acid polyelectrolyte multilayer-based approach for the localized delivery of helical, cationic, globally amphiphilic β-peptide mimetics of antimicrobial peptides to inhibit S. aureus colonization and biofilm formation. Our results reveal that controlled release of this β-peptide can selectively kill S. aureus cells without exhibiting toxicity toward MC3T3-E1 preosteoblast cells. Further development of this polymer-based coating could result in new strategies for preventing orthopaedic implant-related infections, improving outcomes of these titanium implants.

Evaluation of Bacteriophage Anti-Biofilm Activity for Potential Control of Orthopedic Implant-Related Infections Caused by Staphylococcus aureus.

Despite significant advancements in surgical protocols and biomaterials for orthopedics, peri-prosthetic joint infection (PJI) remains a leading cause of implant failure. Staphylococcus aureus nasal colonization is an established risk factor for PJI, with methicillin-sensitive S. aureus a leading cause of orthopedic implant-related infections. The purpose of these in vitro studies was to investigate the antibacterial activity of a tailored bacteriophage cocktail against planktonic and biofilm-associated S. aureus. The S. aureus strains (n = 30) were screened for their susceptibility to a library of S. aureus-specific bacteriophage (n = 31). Five bacteriophage preparations that demonstrated bactericidal activity against >90% of S. aureus strains tested were combined as a StaPhage cocktail and assessed for their antibacterial activity toward planktonic and biofilm-associated S. aureus, with biofilms established on three-dimensional-printed porous titanium scaffolds. StaPhage treatment immediately after bacterial inoculation inhibited growth of S. aureus by >98% in eight hour cultures when multiplicity of infection of phages to bacteria was greater than 1:1 (p < 0.01). Viable bacterial numbers within biofilms on titanium surfaces were significantly reduced (6.8 log10 to 6.2 log10 colony forming units [CFU]; p < 0.01) after exposure to the StaPhage cocktail, in vitro. No significant reduction was observed in biofilms exposed to 100 times the minimal inhibitory concentration of cefazolin (log10 6.81 CFU). Combined, these data demonstrate the in vitro efficacy of S. aureus-specific bacteriophage cocktails against S. aureus growing on porous titanium and warrant further in vivo studies in a clinically relevant animal model to evaluate the potential application of bacteriophage in the management of PJI caused by S. aureus.