Abstract
-
Orthopaedic and trauma device-related infection (ODRI) remains one of the major complications in modern trauma and orthopaedic surgery.
-
Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, leading to infections that negatively impact clinical outcome and significantly increase healthcare expenditure.
-
The following review summarises the microbiological profile of modern ODRI, the impact antibiotic resistance has on treatment outcomes, and some of the principles and weaknesses of the current systemic and local antibiotic delivery strategies.
-
The emerging novel strategies aimed at preventing or treating ODRI will be reviewed. Particular attention will be paid to the potential for clinical impact in the coming decades, when such interventions are likely to be critically important.
-
The review focuses on this problem from an interdisciplinary perspective, including basic science innovations and best practice in infectious disease.
Cite this article: Moriarty TF, Kuehl R, Coenye T, et al. Orthopaedic device related infection: current and future interventions for improved prevention and treatment. EFORT Open Rev 2016;1:89-99. DOI: 10.1302/2058-5241.1.000037.
Introduction
Orthopaedic and trauma device-related infection (ODRI) remains a major complication in modern trauma and orthopaedic surgery. 1 Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, and can lead to infections that negatively impact clinical outcome and significantly increase healthcare expenditure. 2 Pre-operative and correctly-timed prophylactic antibiotic intervention is mandatory for a majority of orthopaedic procedures. However, despite this, the incidence of infection following elective orthopaedic surgery is in the range of 0.7% to 4.2%, 3 -7 while the incidence can be much higher in trauma cases where infection rates range from approximately 1% after operative fixation of closed low-energy fractures, to more than 30% in complex open tibia fractures. 8,9 Treatment success rates vary, with between 57% and 88% often reported. 10 -12 Current curative approaches (radical debridement, revision surgery and prolonged antibiotic therapy) often result in significant socioeconomic costs, not to mention the risk of life-long functional impairment for the patient. Against this background, and with the increasing issue of antibiotic-resistant bacteria, the problem of ODRI is set to continue to pose a challenge for practising clinicians in the coming decades.
The clinical and microbiological challenges of modern device-related infections
The most prevalent species in ODRIs are Staphylococci. 13 -17 Staphylococcus (S.) aureus accounts for between 20% and 30% of cases of infection after fracture fixation and prosthetic joint infections (PJI), with coagulase-negative staphylococci (CoNS) accounting for 20%–40% of cases, 13 -16 including small colony variants. 18 Other Gram-positive cocci including Streptococci (1%–10%) and Enterococci (3%–7%) are less frequently encountered. Infections caused by Gram-negative bacilli, including Pseudomonas aeruginosa and Enterobacteriaceae account for approximately 6%–17%, 13 -17 and anaerobes (including Propionibacteria and Peptostreptococci) are comparatively rare at approximately 4%–5%. 13 -17 Shoulder ODRIs, however, may have higher Propionibacterium (P.) acnes prevalence, at up to 38%. 19 Recently, more attention has been focussed upon polymicrobial infections, which may account for 10%-20% of cases. 13,14,17 Furthermore, studies using molecular diagnostic techniques indicate that, in addition, there is a significant proportion (5%-34%) of culture-negative infections. 13,20,21
Antibiotic resistance
Infections caused by antibiotic-resistant pathogens are a major public health concern, and their treatment can be challenging. 22 With reference to ODRI, bacteria resistant to the few antibiotics with proven anti-biofilm activity (Rifampicin-resistant staphylococci and ciprofloxacin-resistant Gram-negatives) are among the most difficult pathogens to treat. Methicillin-resistant S. aureus (MRSA) has also emerged as a significant threat in both the hospital and community environment. 23 Within the healthcare setting alone, MRSA infections are estimated to affect more than 150 000 patients annually in the European Union (EU), resulting in additional in-hospital costs of EUR 380 million for EU healthcare systems. 24 Between 25% and 32% of infections after fracture fixation in the United States are caused by MRSA, 25,26 but this is highly dependent on the local epidemiology, with lower rates also observed. With limited treatment options, MRSA infections are associated with a higher mortality and increased financial costs relative to sensitive equivalents. 10,27 -30 However, this has not been a universal finding. 31 Recent publications on PJIs stated that treatment decisions should focus more on the identified pathogen, and not merely on its methicillin resistance. 32
The rise of antimicrobial resistance is one of the major challenges in the treatment of ODRIs; however, there are also many other challenges (Table 1).
Biggest challenges in the diagnosis and treatment of ODRI
| 1. Proof of infection and detection of disease-causing pathogen |
| A considerable number of infections are ‘culture-negative’ despite being clinically apparent.
20,21
In some cases, the causative bacteria are difficult to grow because they exist in a metabolically less active state as a biofilm. Bacteria may also be difficult to culture when the patient has been empirically treated with antibiotics.
21
In such cases, cessation of all antibiotic therapy for at least two weeks, followed by open biopsy of tissue and sonication of the device, may offer additional opportunity to culture the organism.
21
This raises the question: can we do better with diagnosis? Establishing the correct diagnosis with a new test would represent a major breakthrough in the field. Similarly, rapid, non-invasive diagnostics and those offering pre-operative diagnostics have the potential to change medical and surgical treatment without requiring invasive biopsies. |
| 2. Antimicrobial resistance |
| Multi drug-resistant organisms are becoming increasingly challenging to treat over time. Many reports now exist of pan drug-resistant organisms and extensively drug-resistant pathogens such as vancomycin-resistant S. aureus and Enterococcus spp. |
| 3. Persistence and recurrence of infection |
| One of the major challenges with treatment of a device-associated infection is the reimplantation of the device, which in most cases is required for the function of the patient. The issue is that organisms frequently reside in a biofilm state that is not usually completely eradicated or resected during the explantation phase. The biofilm tends to be harboured on tiny fragments of necrotic bone known as sequestra, and may also reside within the cortical bone itself. During reimplantation, the biofilm-residing bacteria may be liberated and re-enter their planktonic growth phase, resulting in reinfection. This remains one of the great challenges in infection surgery. |
State-of-the-art treatment for orthopaedic device-related infection
Systemic antibiotic therapy
The goal of any medical strategy for the treatment of ODRI should consist of the long-term elimination of pain, restoration of function of the affected joint and, in trauma cases, consolidation of the fracture with prevention of osteomyelitis. Usually this includes a therapeutic approach aiming for definite eradication of the micro-organisms causing infection, but in some circumstances can entail long-term suppressive antibiotic therapy. Hence, each treatment must be tailored to the needs and the medical conditions of the individual patient.
To date, a curative therapy always includes surgery, since antibiotics alone are not capable of eradicating biofilm infections. The surgical approach varies from debridement with retention of the prosthesis to one-stage or two-stage exchange procedures. In fracture care, the chosen operative intervention often depends on the grade of fracture healing. An algorithm for choosing the optimal procedure has been proposed, 6,33 but there are still substantial differences in procedural preferences between countries and institutions. Nevertheless, the therapeutic approach should always be decided by an interdisciplinary team comprised of orthopaedic surgeons and infectious disease specialists and/or microbiologists.
High-quality evidence on the choice of antibiotics is scarce. Therefore, therapeutic decisions are often based on retrospective data, on pharmacokinetic/pharmacodynamic principles and on results from animal models. The optimal antibiotic should reach high bactericidal concentrations in the organic and inorganic bone tissue, on the surface of the device and in intracellular compartments. It should be active against slow-growing biofilms and against the metabolically quiescent small colony variants. It should have a low propensity to induce bacterial resistance and low toxicity towards the patient. In each case, it is essential to know which bacteria are responsible for the infection. Hence, antibiotics should be withheld until appropriate diagnostics have been performed. Mounting evidence shows that routine susceptibility tests that determine the minimal inhibitory concentration (MIC) do not reflect the real-life susceptibility of the biofilm-embedded bacteria on the surface of the device; antibiotic susceptibility in biofilms can be reduced a thousand-fold. 34 Therefore, even when bacteria are reported as sensitive to an antibiotic, clinicians should be aware that this does not reflect the ability of the antibiotic to kill the same bacteria when growing in a biofilm.
The best evidence for antibiotic selection is available for staphylococci. For other bacteria (such as streptococci, enterococci, Gram-negatives) the evidence for antibiotic selection is less clear. Rifampicin is of critical importance in the treatment of staphylococci as an anti-staphylococcal biofilm antibiotic, and has been associated with a higher rate of treatment success. 35 -37 Rifampicin should never be administered by itself due to rapid development of resistance. The initial partner antibiotic most often consists of a beta-lactam and later switched to a quinolone (historically ciprofloxacin, nowadays often levofloxacin). 38 In case of quinolone resistance, various other antibiotic partners have been used such as fusidic acid, 39,40 cotrimoxazole, 41 linezolid, 42 clindamycin or minocycline. 31,43 In the case of rifampicin resistance, alternative antibiotics are chosen, with one study showing good results with moxifloxacin monotherapy. 44 Alternatives to beta-lactams, for example in the case of methicillin-resistant staphylococci, are vancomycin or daptomycin, 45 both of which are generally well-tolerated.
Great variability in total duration and the time point of the switch 46 from intravenous to oral antibiotics exists between different countries and hospitals. Guidelines recommend between two and six weeks of initial intravenous therapy, according to the circumstances. 33 An early switch to oral antibiotics does not seem to be associated with a worse outcome. 47 The total duration of therapy is usually between three and six months. Nevertheless, a duration of six weeks may be sufficient. 48 -50 Long-term suppression therapy is used alternatively in cases of inoperable patients, multi drug-resistant bacteria, 51 but also in specific fracture cases where consolidation of the fracture has not yet occurred and the surgical treatment consistent of debridement with implant retention. 52 On the other hand, successful experiences from single centres with a very short duration of systemic antibiotic therapy of less than one week, or solely intra-articular application of antibiotics, have been reported. 46,53
There are still a lot of open questions to be answered (Table 2) and high-level evidence studies are urgently needed to overcome these gaps in knowledge.
Summary of targets required for improvement of treatment outcomes in ODRI
| Systemic antibiotic therapy | Local antibiotic therapy |
|---|---|
| • Improved diagnostic methods to predict bactericidal activity against biofilm-embedded bacteria | • Introduction of guidelines for local delivery (antibiotic agent selection made on a species and resistance status) |
| • Evidence for timing of antibiotic switching (parenteral vs oral) and duration of treatment | • Establishment of pharmacodynamic principles applicable to local delivery |
| • New antibiotics with increased anti-biofilm activity | • Design of local delivery vehicles that attain pharmacodynamic principles |
| • Better oral formulations and drugs with less toxicity | • Biomaterials that can accommodate a wider range of antibiotics |
Local antibiotic delivery
The use of biomaterials as carriers, or vehicles, for the delivery of antibiotic agents to the site of infection has become a regular adjunct in the treatment of ODRIs. 54,55 Local delivery has numerous theoretical advantages over systemic delivery, which can offer the potential for significant supportive antimicrobial action. Since the antibiotic is placed directly at the site of interest, an intact vascular system is not required to reach the surgical site, which may be particularly beneficial in trauma patients. Local delivery can also achieve local concentrations exceeding those achievable systemically, while requiring a lower total drug amount, thereby not only improving the local concentration, but simultaneously reducing the risk of systemic toxicity. Interestingly, the local application of antibiotics has even been shown in preclinical in vivo studies to offer protection against bacteria that are resistant to the applied antibiotic, 56 indicating that local delivery may offer some hope for further improvements in antibiotic therapy in the face of bacteria resistant to conventional, systemic dosing regimens.
The local application of antibiotics in orthopaedic medicine has been described since the 1970s, when gentamicin-loaded bone cement was first tested in humans. 57 Bone cement was a convenient vehicle for antibiotic delivery, as it was routinely applied in cemented arthroplasties. Gentamicin was identified as a suitable antibiotic due to the fact that it was found to withstand the elevated temperatures of curing bone cement, and was considered to offer an acceptable profile against the most common pathogens associated with ODRI. Antibiotic-loaded bone cements have been shown to improve ODRI outcomes. 58,59 Bone cement, however, was not designed in the first instance as an antibiotic delivery vehicle. Therefore, the usual pharmacodynamic principles governing systemic antibiotic therapy were not part of the equation in the advent of antibiotic-loaded bone cements. Unfortunately, despite the passage of more than four decades since the first use of antibiotic-loaded bone cements, pharmacodynamic principles are still not established specifically for use in this way. Therefore, it is perhaps not surprising that resistance against gentamicin has emerged secondary to gentamicin use in local delivery vehicles. 60,61 The reason for the development of resistance is probably the prolonged release of antibiotics at sub-therapeutic levels from local delivery vehicles, which is in direct opposition to ideal release kinetics for a concentration dependent antibiotic such as gentamicin. 62
There are antimicrobial-loaded device surfaces and coatings which have passed through the regulatory approval process, have been described in clinical studies, 63 -65 and may be expected to emerge in greater numbers in future. However, a number of critical issues must be resolved prior to achieving the maximum benefit of local antibiotic delivery vehicles (Table 2).
New approaches for prevention and treatment
Active and passive vaccines
Based on its cost-effectiveness, which is unparalleled by any other medical intervention, vaccination is an obvious approach to prevent, treat and potentially eradicate ODRIs. Unfortunately, all efforts to develop an effective vaccine against S. aureus, the primary pathogen involved in ODRI, have failed for a number of reasons (Table 3). 66 -68 The most prominent reason is that, in contrast to successful bacterial vaccines, which to date have exclusively been against transient flora, S. aureus has co-evolved with mammalian hosts to become a human commensal. Thus, all patients have some level of acquired immunity against S. aureus prior to surgery. However, the protective versus susceptible nature of an individual’s immune response against S. aureus at this time is virtually unknown. Therefore, a major research focus in targeting the immune response is understanding the functional role of specific T cells (cellular immunity) and antibodies (humoral immunity) in S. aureus infections. To this end of vaccine development, several groups have described anti-S. aureus immune responses in physiological and pathological situations, 69 -75 in order to elucidate the immune proteome of S. aureus. 76 Recently, a multiplex immunoassay for characterising a patient’s immune response was developed against 14 known S. aureus antigens, which was then used to determine if certain antigens dominate humoral immunity in a pilot study of patients with osteomyelitis versus uninfected controls. 75 Measurement of the immune response against S. aureus may help guide future prophylaxis and therapy in an era of personalised medicine, and follow-up research is ongoing.
Outline status of novel interventional strategies targeting ODRI
| Ionic silver | Active and passive immunisation for S. aureus | Antimicrobial peptides and immunomodulatory peptides | Quorum sensing inhibitors and biofilm degrading enzymes |
|---|---|---|---|
| Research status and gaps in the knowledge | |||
| • Widely-studied antimicrobial, particularly in the experimental preclinical phase • Comparative studies against conventional antibiotic agents are required • A full understanding of the risk factors for the emergence of silver resistance is required |
• Has been the focus of industrial research strategies for decades • Needs full understanding of the immune response against S. aureus to make real progress • Needs full understanding of the nature of the S. aureus antigen(s) and antibody response • Needs to identify appropriate patient populations for evaluating vaccine efficacy |
• Thousands of peptides described from a wide range of sources • Potential target for antibiotic-resistant infections • Toxicity at high concentrations a concern |
• Require advancement through the preclinical translational research pathway • In vitro and early in vivo studies show promise • Debate over whether resistance against these compounds can develop is still ongoing |
| Current clinical application and future outlook | |||
| • Currently available for limited number of orthopaedic devices • Clinical data promising, with specific application in the most challenging cases • Outlook: Role in antibiotic-resistant cases, or for coverage of multiple species |
• Numerous clinical trials ongoing • To date, no trial shown efficacy in terms of reduced incidence • Outlook: Great potential for treating most challenging cases, where even optimal antimicrobial strategies have high failure rate |
• Not yet applied in orthopaedic setting • Currently only available for topical application • Outlook: Future role for antibiotic-resistant isolates |
• Not yet clinically applied • Still early stage of translation • Outlook: Potential novel approach, particularly important for resistant biofilm infections |
S. aureus is primarily an extracellular pathogen. Thus, its clearance from within mammalian hosts is largely dependent on neutrophils. 77 Importantly for vaccine development, this innate immune mechanism has been modeled by the opsonophagocytic activity assay (OPA), which has been used to quantify S. aureus killing in vitro. 78 However, antigen-specific T-helper cells are critically involved in antibody responses, and it is known that Th17 cells enhance neutrophil function and bacterial clearance. 79 Thus, although the role of adaptive immunity for protection against S. aureus remains controversial, there is a rationale for a human vaccine. For the most part, the molecular targets of S. aureus vaccines that have been developed so far have been pathogenic determinants (i.e. clumping factor A, ClfA 80 ) and virulence factors (i.e. alpha-toxin 81 and coagulases 82 ). Unfortunately, this strategy is limited by great redundancy, as S. aureus contains a multitude of factors with similar pathogenic function. Thus, neutralising all of them to decrease pathogenicity seems unlikely. Alternatively, interests have focussed on S. aureus autolysin (Atl), which comprises highly conserved aminidase (Amd) and glucosaminidase (Gmd) subunits. Functionally, Atl is known to be essential for cell wall biosynthesis and degradation during binary fission. 83 -85 . Atl also functions as an adhesin, 86 a biofilm enzyme, 87 which was identified as a potential molecular target of vancomycin 88 and has been reported to interfere with the production of antibodies in mice. 89 Moreover, Amd and Gmd are immune-dominant antigens in mice and humans, 75,90 and pre-clinical vaccine studies have demonstrated significant efficacy. 91,92
The most common vaccines involve ‘active’ immunisation of the host with purified molecular constituents of the pathogen, and require the host to evolve protective adaptive immunity for this non-virulent challenge. An advantage of active vaccines is the robustness of the resulting immunity, which includes both cellular and humoral immunity, and the potential of life-long immunity from the generation of protective memory T cells and B cells. However, the greatest limitation of active vaccination is its unpredictability in individual patients, particularly immune-compromised individuals from those with established comorbidities (i.e. ageing, autoimmunity, obesity and diabetes). 93 -96 Thus, it is not surprising that the two most recent large clinical trials with active S. aureus vaccines (StaphVAX (polysaccharide capsular antigens CP5 and CP8), 97 and V710 (IsdB) 98 ) failed to meet their primary endpoints. However, what was very surprising was that V710 vaccination was associated with increased sepsis, multi-organ failure and death in patients undergoing heart valve replacement who developed S. aureus infections, 98 which is consistent with the finding that high titres of anti-IsdB antibodies are associated with these adverse events in total joint arthroplasty patients. 75 This observation raises a new concern that some anti-S. aureus immune responses exacerbate infection and/or its sequelae, and that additional pre-clinical testing is needed to confirm a vaccine’s mechanism of action. It also supports transfusion of purified functional anti-S. aureus antibodies as a passive immunisation, which is a safer and more predictable vaccine approach. However, it should be noted that passive S. aureus vaccines such as Altastaph, 99 Veronate, 100,101 Aurexis, 80,102 Aurograb 103-104 and Pagibaximab, 105,106 have also failed in clinical trials.
Silver
The significant difficulties involved in the treatment of established biofilms prompted research on engineering device surfaces that could resist microbial colonisation. Silver is a potent candidate for coating devices, as it provides a broad spectrum of antibacterial activity against planktonic and sessile, Gram-positive and Gram-negative, and also multi drug-resistant bacteria. 107 Moreover, it demonstrates bactericidal efficacy at a low concentration, with limited toxicity towards human cells. Silver attacks a broad range of bacterial targets by interfering with thiol and amino groups of proteins, with nucleic acids and cell membranes. The disruption of iron-sulphur clusters seems to be particularly detrimental for the affected organism, producing reactive oxygen species and inhibiting the respiratory chain. 108 -110
Silver has been used as a disinfectant for many centuries. 111 From the 19th century onwards, silver was employed, among other uses, in the prevention of gonorrhoeal ophthalmia (Crédé prophylaxis), as suture material, or as ointment to treat wound infections. 111,112 Currently, technological advances have created many new formulations of silver, which are either still under development, or already deployed for commercial and medical purposes. Silver is used in its metallic form as a nanoparticle, or silver-containing polymers and composites. 113,114 For orthopaedic applications, silver has been introduced into hydroxyapatite and bone cement, and as a coating for trauma devices. 115 Most formulations exert good antimicrobial properties. Nevertheless, the heterogeneity of materials and methods make direct comparison of the antimicrobial effect difficult. Recently, new compounds called silver oxynitrate (Ag(Ag3O4)2NO3 or Ag7NO11) showed a better effect against bacterial biofilms than other formulations (Ag2SO4, AgNO3, silver sulfadiazine (AgSD), AgO, Ag2O). 116
Primary clinical studies are promising, demonstrating a trend in reducing infection with silver-coated central venous catheters, 117 urinary catheters 118 and ventilator endotracheal tubes. 119 Similar results were achieved with silver-coated external fixation pins, 120 proximal femur or tibia megaprostheses 64 and tumour prostheses. 121
One of the major concerns associated with the use of an antimicrobial substance is the development and spread of resistant mutants. Indeed, development of resistance to silver was reported in relation to P. aeruginosa as early as 1966. 122 Thereafter, many publications have demonstrated widespread occurrence of silver resistance in Enterobacteriaceae, but interestingly never in Gram-positive bacteria. These data strengthen the notion that the concerted action against intracellular silver is so far neither known to be inherent nor inducible for Gram-positive bacteria, which makes silver coatings controversial for clinical use.
The toxicity of silver to eukaryotic cells has been another concern. 112 However, the health risk in exposed humans seems to be low, and consists mostly of a discolouration of the skin and eyes due to silver deposition called argyria and argyrosis, respectively. 123 -125 Nevertheless, few case reports exist of neural or other systemic toxicity after high exposure to silver. 126,127 In this context, the potent new silver formulations should be tested in solid in vitro and in vivo toxicity studies. Accordingly, the potential of osseointegration of silver-coated prostheses needs further exploration. However, the available evidence in this respect is encouraging. 128 Finally, one of the biggest hurdles in designing a silver-coated surface is the controlled release of silver. Data on silver release kinetics are mostly lacking, but crucial for defining the optimal clinical application. With further development, knowledge and optimisation of formulations, silver seems a promising addition to our antibacterial arsenal in the fight against device infection.
Antimicrobial and anti-biofilm peptides
Antimicrobial peptides (AMPs) are innate defence molecules of animals, plants and microorganisms, with a broad spectrum of antimicrobial activity and low risk of resistance development in general. 129,130 The low risk of resistance development is due to the fact that AMPs interact with microbial membranes, resulting in membrane depolarisation, destabilisation and/or disruption leading to rapid cell death, or passing of the membrane to reach intracellular targets. 131 Native AMPs have been used as design templates for a large variety of synthetic AMPs, some of which have now reached the stage of phase 2 and 3 clinical trials. 132
Several AMPs also have the capacity to prevent biofilm formation. A recent study by Mansour et al 133 demonstrated that a synthetic peptide (named 1018) inhibited biofilm formation by S. aureus and multiple other species by blocking (p)ppGpp, an important signal in biofilm development, at concentrations that did not affect bacterial growth. A peptide derived from CRAMP (the mouse homologue of the human defence peptide LL-37 (cathelicidin), showed inhibition of biofilm formation of the yeast Candida albicans, and also prevented biofilm formation by different bacterial species. 134 Many more examples of AMPs with anti-biofilm activity have recently been listed in the specialised biofilm-active antimicrobial peptides (BaAMPs) database. 135
Application of AMPs to biomaterials
Immobilisation of AMPs on surfaces has been performed with a variety of peptides, and many different chemistries. A good overview of immobilisation strategies has been published by Costa et al. 136 For peptides to be effective after immobilisation, they should retain the structural characteristics important for their antimicrobial activity. Other decisive factors for success are length, flexibility, and kind of spacer connecting the peptide to the surface, the AMP surface density and the orientation of the immobilised peptides. 136 Although peptides are considered to be active through insertion into the microbial membranes, even short surface-attached peptides, which are unlikely to have a free interaction with the membrane, have antimicrobial activity. 137 This activity is thought to be due to destabilisation of the membrane by displacement of positively charged counter-ions, changing bacterial surface electrostatics and activating autolytic enzymes or disrupting the ionic balance. 137
Chemical procedures of tethering AMPs to surfaces may cause a strong decrease in their antimicrobial activity or even inactivation, 138,139 depending on the combination of peptides and immobilisation technology. A recent, novel approach of attaching peptides to hydrogels used for surface coating is the application of thiol-ene chemistry allowing a fast, single-step immobilisation strategy. 140 Using this strategy, mimics of the HHC-10 peptide 141 with optimal plasma stability were attached to a polymer surface. These surfaces killed inocula of S. aureus, S taphylococcus epidermidis and Escherichia coli with high efficiency in vitro. 140
Controlled release coatings for orthopaedic and trauma devices, for example, are designed to provide a burst release of an antimicrobial agent during the first days after implantation, preferably followed by a continuous release providing local protective levels during several weeks after implantation. The incorporation of AMPs in such coatings has not yet been extensively developed. In a recent study, a polymer lipid encapsulation matrix (PLEX) coating designed for doxycycline release from a bone filler 142 was tailored to such a preferred release profile. The doxycycline-PLEX coating prevented osteomyelitis caused by S. aureus in a rabbit model. 56 Based on these studies, PLEX coatings containing the novel AMPs were recently developed successfully. These coatings show potent antimicrobial activity, prevent biofilm formation and prevent S. aureus infection of subcutaneous implants in mice (Zaat et al 143 ).
Quorum-sensing inhibitors and biofilm-degrading enzymes
Quorum sensing (QS) is a mechanism that many microorganisms use to coordinate gene expression in populations in response to local conditions, including cell density. 144 The canonical QS system consists of one or more proteins involved in producing and transporting the signalling molecule, the actual signalling molecule, a receptor for the signalling molecule and, in some QS systems, additional regulatory proteins. 144 The most-studied systems are those that use N-acyl homoserine lactones (AHL) as signalling molecules (present in many Gram-negative bacteria, including P. aeruginosa) and the QS system in S. aureus in which auto-inducing peptides (AIP) are used as signalling molecules. 144 In many organisms, biofilm formation is (co-)regulated by QS, making the latter process an interesting target for novel approaches to antimicrobial chemotherapy in biofilm infections such as ODRI. 144,145 In addition, it is well-known from early work in this field that, in at least some microorganisms, QS is involved in tolerance to antimicrobial agents and the immune system. 146,147 These observations suggested that combining a conventional antimicrobial agent with a quorum-sensing inhibitor (QSI) might circumvent the problem of biofilm tolerance.
Experimental evidence for this approach has been provided in several studies in which it was shown that combining antibiotics with QSI increased the success of treatment in different model systems. This was true for various organisms (including S. aureus and P. aeruginosa) and for different antibiotic/QSI combinations (including the combination vancomycin/hamamelitannin against S. aureus and tobramycin/furanone C-30 against P. aeruginosa). 148,149 While the QSI described in the literature are extremely diverse in structure, they can be grouped according to their target. A first approach to inhibit QS is the enzymatic degradation of the AHL signalling molecules, by using specific AHL lactonases or acylases produced by bacteria. 145 Also paraoxonases found in human serum and expressed in various cell types can degrade AHLs. 145 A second group of QSIs target the synthesis of the signal molecule. From studies investigating the role of QS-related genes in biofilm formation, we know that mutant strains in which genes involved in the synthesis of the signalling molecule(s) are inactivated, are affected in biofilm formation. This is, for example, the case in Burkholderia cenocepacia cepI and cciI mutants (both CepI and CciI are AHL-synthases) 150 and in S. aureus mutants that are defective in producing AIP. 151 Considering the biosynthesis pathway of AHLs, inhibitors of S-adenosylmethionine and fatty acid biosynthesis (including sinefungin and 5-methylthioadenosine) may be used as QSIs. 145 Less is known about QSI targeting AIP synthesis, although inhibitors of the type-I signal peptidase SpsB that reduce AIP production have been described. 151 Finally, compounds targeting the QS receptors and/or signal analogues can act as QSI. Many AHL analogues (with modifications in the acyl side chain, the central amide moiety, and/or the lactone ring) have been synthesised and tested, and many of these interfere with the process of biofilm formation. For example, application of AHL in which the central amide moiety was replaced by triazolylhydrofuranones resulted both in biofilm inhibition and biofilm eradication in a number of Gram-negative pathogens, including P. aeruginosa. 152 One of the most-studied QSIs with activity against S. aureus also targets the QS receptor: the RNAIII-inhibiting peptide (RIP), several of its analogues and the non-peptide analogue hamamelitannin are thought to interfere with the RAP/TRAP QS system in S. aureus, and by doing so to affect biofilm formation and increase biofilm susceptibility towards antibiotics. 148,151 So far most of the studies on QSIs as anti-biofilm agents have been carried out using in vitro model systems, or in simple in vivo models. 148,153 In a limited number of studies, QSIs were tested using animal models, for example in a mouse model for pulmonary infection (with B. cenocepacia) 148 or for skin infection (with S. aureus). 154 However, to our knowledge, testing of QSIs in an appropriate animal model for orthopaedic device-associated biofilm infections has not yet been done, although several foreign body models mimicking biofilm infections on prosthetic devices are available. 155,156
A second innovative anti-biofilm strategy depends on the use of biofilm-degrading enzymes, and both deoxyribonuclease I (DNase I) and exopolysaccharide-degrading dispersin B (DspB), which could have applications in the prevention or treatment of biofilm infections associated with orthopaedic devices. 157,158 Extracellular DNA (eDNA) is a key component of many microbial biofilms, and the use of DNase I leads to the disruption of pre-existing biofilms in many species, as well as an increased susceptibility to antimicrobial agents. 159 In addition, biofilm formation is inhibited in some species by the presence of DNase I. 159 However, this is not the case for all bacteria tested, and the effect on pre-existing biofilms is also species and biofilm age-dependent. 159 DspB is a β-hexosaminidase capable of degrading poly-(β-1,6)-N-acetylglucosamine, an exopolysaccharide that is an important component of the biofilm matrix in various organisms. 157,158 Application of DspB resulted in biofilm dispersal and detachment, and when combined with conventional antimicrobial agent, DspB showed synergism. 157,158,160 In the context of PJIs, it is interesting to see that DspB overall has good activity against staphylococcal biofilms 157,158 and that its activity is maintained in vivo (at least in a subcutaneous implant model for S. aureus infections in a rabbit). 160 In addition, DspB-loaded coatings were shown to inhibit S. epidermidis biofilm formation in vitro, without affecting the attachment or growth of cultured human osteoblasts, suggesting that such coatings hold promise for developing medical devices with anti-biofilm properties. 161
Summary and outlook
ODRI remains one of the most challenging complications in orthopaedics. A wide range of treatment options are available, although the established guidelines and algorithms have improved standardisation and outcomes. However, improvements in preventative and therapeutic strategies are required, as current practices are not completely effective. This is particularly critical considering the increasing challenge of antibiotic-resistant bacteria.
Emerging technologies and interventions may be expected to improve treatment success in the future (Table 3). Crucially, research strategies have focussed on antibiotic resistance and biofilm formation as targets for future interventional strategies. These interventions have the potential to reduce infection rates and improve treatment outcomes, if and when these interventions make it to clinical practice. Few regulatory body-approved antibiotic-functionalised orthopaedic and trauma devices are currently available; however this may yet grow in the coming decades, provided they pass a robust preclinical evaluation and emerge onto the market with a proven ability to improve outcome in the prevention and treatment of ODRIs.
ES, FM, GR and SK acknowledge the AOTrauma Clinical priority program on Bone Infection.
FM, MR, NK, RK and SZ would like to acknowledge networking support by the COST Action TD1305.
BZ, MR, FM acknowledge funding by the EU, FP7-HEALTH-2011 grant 278890, BALI – Biofilm Alliance.
TC acknowledges funding by the Fund for Scientific Research – Flanders (FWO-Vlaanderen), by the Institute for the Promotion of Innovation through Science & Technology in Flanders (IWT, SBO program) and the Interuniversity Attraction Pole Program supported by the Belgian Science Policy Office.
NK is supported by the Swiss National Foundation (grant PZ00P3_142403I).
Conflict of Interest
None declared.
Funding
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
References
- 1↑
Tsaras G , , Osmon DR , , Mabry T , et al.. Incidence, secular trends, and outcomes of prosthetic joint infection: a population-based study, olmsted county, Minnesota, 1969-2007. Infect Control Hosp Epidemiol 2012;33:1207-12.
- 2↑
Poultsides LA , , Liaropoulos LL , , Malizos KN . The socioeconomic impact of musculoskeletal infections. J Bone Joint Surgery [Am] 2010;92:e13.
- 3↑
Bauer TW , , Schils J . The pathology of total joint arthroplasty. I. Mechanisms of implant fixation. Skeletal Radiol 1999;28:423-32.
- 4↑
Bauer TW , , Schils J . The pathology of total joint arthroplasty.II. Mechanisms of implant failure. Skeletal Radiol 1999;28:483-97.
- 5↑
Sugarman B , , Young EJ . Infections associated with prosthetic devices: magnitude of the problem. Infect Dis Clin North Am 1989;3:187-98.
- 6↑
Zimmerli W , , Trampuz A , , Ochsner PE . Prosthetic-joint infections. N Engl J Med 2004;351:1645-54.
- 7↑
Kurtz SM , , Lau E , , Schmier J , et al.. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty 2008;23:984-91.
- 8↑
Patzakis MJ , , Wilkins J . Factors influencing infection rate in open fracture wounds. Clin Orthop Relat Res 1989;(243):36-40.
- 9↑
Boxma H , , Broekhuizen T , , Patka P , , Oosting H . Randomised controlled trial of single-dose antibiotic prophylaxis in surgical treatment of closed fractures: the Dutch Trauma Trial. Lancet 1996;347:1133-7.
- 10↑
Teterycz D , , Ferry T , , Lew D , et al.. Outcome of orthopedic implant infections due to different staphylococci. Int J Infect Dis 2010;14:e913-8.
- 11↑
Beswick AD , , Elvers KT , , Smith AJ , et al.. What is the evidence base to guide surgical treatment of infected hip prostheses? Systematic review of longitudinal studies in unselected patients. BMC Med 2012;10:18.
- 12↑
Kapadia BH , , Berg RA , , Daley JA , et al.. Periprosthetic joint infection. Lancet. 2016;387:386-94.
- 13↑
Corvec S , , Portillo ME , , Pasticci BM , , Borens O , , Trampuz A . Epidemiology and new developments in the diagnosis of prosthetic joint infection. Int J Artif Organs 2012;35:923-34.
- 14↑
Del Pozo JL , , Patel R . Clinical practice. Infection associated with prosthetic joints. N Engl J Med 2009;361:787-94.
- 15↑
Montanaro L , , Speziale P , , Campoccia D , et al.. Scenery of Staphylococcus implant infections in orthopedics. Future Microbiol 2011;6:1329-49.
- 16↑
Trampuz A , , Zimmerli W . Diagnosis and treatment of infections associated with fracture-fixation devices. Injury 2006;37 Suppl 2:S59-66.
- 18↑
Tande AJ , , Osmon DR , , Greenwood-Quaintance KE , et al.. Clinical characteristics and outcomes of prosthetic joint infection caused by small colony variant staphylococci. MBio 2014;5:e01910-14.
- 19↑
Achermann Y , , Sahin F , , Schwyzer HK , et al.. Characteristics and outcome of 16 periprosthetic shoulder joint infections. Infection 2013;41:613-20.
- 20↑
Hoiby N , , Bjarnsholt T , , Moser C , et al.. ESCMID guideline for the diagnosis and treatment of biofilm infections 2014. Clin Microbiol Infect 2015;21 Suppl 1:S1-25.
- 21↑
Parvizi J , , Erkocak OF , , Della Valle CJ . Culture-negative periprosthetic joint infection. J Bone Joint Surg [Am] 2014;96:430-6.
- 22↑
Vergidis P , , Schmidt-Malan SM , , Mandrekar JN , , Steckelberg JM , , Patel R . Comparative activities of vancomycin, tigecycline and rifampin in a rat model of methicillin-resistant Staphylococcus aureus osteomyelitis. J Infect 2015;70:609-15.
- 23↑
Boucher HW , , Corey GR . Epidemiology of methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008;46 Suppl 5:S344-9.
- 24↑
Kock R , , Becker K , , Cookson B , et al.. Methicillin-resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe. Euro Surveill 2010;15:19688.
- 25↑
Chen AF , , Schreiber VM , , Washington W , , Rao N , , Evans AR . What is the rate of methicillin-resistant Staphylococcus aureus and Gram-negative infections in open fractures? Clin Orthop Relat Res 2013;471:3135-40.
- 26↑
Torbert JT , , Joshi M , , Moraff A , et al.. Current bacterial speciation and antibiotic resistance in deep infections after operative fixation of fractures. J Orthop Trauma 2015;29:7-17.
- 27↑
Haddadin AS , , Fappiano SA , , Lipsett PA . Methicillin resistant Staphylococcus aureus (MRSA) in the intensive care unit. Postgrad Med J 2002;78:385-92.
- 28↑
Klein E , , Smith DL , , Laxminarayan R . Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis 2007;13:1840-6.
- 29↑
Cordero-Ampuero J , , Esteban J , , Garcia-Rey E . Results after late polymicrobial, gram-negative, and methicillin-resistant infections in knee arthroplasty. Clin Orthop Relat Res 2010;468:1229-36.
- 30↑
Salgado CD , , Dash S , , Cantey JR , , Marculescu CE . Higher risk of failure of methicillin-resistant Staphylococcus aureus prosthetic joint infections. Clin Orthop Relat Res 2007;461:48-53.
- 31↑
Lora-Tamayo J , , Murillo O , , Iribarren JA , et al.. A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention. Clin Infect Dis 2013;56:182-94.
- 32↑
Zurcher-Pfund L , , Uckay I , , Legout L , et al.. Pathogen-driven decision for implant retention in the management of infected total knee prostheses. Int Orthop 2013;37:1471-5.
- 33↑
Osmon DR , , Berbari EF , , Berendt AR , et al.. Executive summary: diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1-10.
- 34↑
Hoiby N , , Bjarnsholt T , , Givskov M , , Molin S , , Ciofu O . Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010;35:322-32.
- 35↑
El Helou OC , , Berbari EF , , Lahr BD , et al.. Efficacy and safety of rifampin containing regimen for staphylococcal prosthetic joint infections treated with debridement and retention. Eur J Clin Microbiol Infect Dis 2010;29:961-7.
- 36↑
Holmberg A , , Thorhallsdottir VG , , Robertsson O A WD , , Stefansdottir A . 75% success rate after open debridement, exchange of tibial insert, and antibiotics in knee prosthetic joint infections. Acta Orthop 2015;86:457-62.
- 37↑
Zimmerli W , , Widmer AF , , Blatter M , , Frei R , , Ochsner PE . Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 1998;279:1537-41.
- 38↑
Nguyen S , , Robineau O , , Titecat M , et al.. Influence of daily dosage and frequency of administration of rifampicin–levofloxacin therapy on tolerance and effectiveness in 154 patients treated for prosthetic joint infections. Eur J Clin Microbiol Infect Dis 2015;34:1675-82.
- 39↑
Peel TN , , Buising KL , , Dowsey MM , et al.. Outcome of debridement and retention in prosthetic joint infections by methicillin-resistant staphylococci, with special reference to rifampin and fusidic acid combination therapy. Antimicrob Agents Chemother 2013;57:350-5.
- 40↑
Aboltins CA , , Page MA , , Buising KL , et al.. Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid. Clin Microbiol Infect 2007;13:586-91.
- 41↑
Nguyen S , , Pasquet A , , Legout L , et al.. Efficacy and tolerance of rifampicin-linezolid compared with rifampicin-cotrimoxazole combinations in prolonged oral therapy for bone and joint infections. Clin Microbiol Infect 2009;15:1163-9.
- 42↑
Gomez J , , Canovas E , , Banos V , et al.. Linezolid plus rifampin as a salvage therapy in prosthetic joint infections treated without removing the implant. Antimicrob Agents Chemother 2011;55:4308-10.
- 43↑
Sendi P , , Zimmerli W . Antimicrobial treatment concepts for orthopaedic device-related infection. Clin Microbiol Infect 2012;18:1176-84.
- 44↑
San Juan R , , Garcia-Reyne A , , Caba P , et al.. Safety and efficacy of moxifloxacin monotherapy for treatment of orthopedic implant-related staphylococcal infections. Antimicrob Agents Chemother 2010;54:5161-6.
- 45↑
Byren I , , Rege S , , Campanaro E , et al.. Randomized controlled trial of the safety and efficacy of Daptomycin versus standard-of-care therapy for management of patients with osteomyelitis associated with prosthetic devices undergoing two-stage revision arthroplasty. Antimicrob Agents Chemother 2012;56:5626-32.
- 46↑
McKenna PB , , O’Shea K , , Masterson EL . Two-stage revision of infected hip arthroplasty using a shortened post-operative course of antibiotics. Arch Orthop Trauma Surg 2009;129:489-94.
- 47↑
Daver NG , , Shelburne SA , , Atmar RL , et al.. Oral step-down therapy is comparable to intravenous therapy for Staphylococcus aureus osteomyelitis. J Infect 2007;54:539-44.
- 48↑
Farhad R , , Roger PM , , Albert C , et al.. Six weeks antibiotic therapy for all bone infections: results of a cohort study. Eur J Clin Microbiol Infect Dis 2010;29:217-22.
- 49↑
Puhto AP , , Puhto T , , Syrjala H . Short-course antibiotics for prosthetic joint infections treated with prosthesis retention. Clin Microbiol Infect 2012;18:1143-8.
- 50↑
Bernard L , , Legout L , , Zurcher-Pfund L , et al.. Six weeks of antibiotic treatment is sufficient following surgery for septic arthroplasty. J Infect 2010;61:125-32.
- 51↑
Siqueira MB , , Saleh A , , Klika AK , et al.. Chronic suppression of periprosthetic joint infections with oral antibiotics increases infection-free survivorship. J Bone Joint Surg [Am] 2015;97:1220-32.
- 52↑
Trebse R , , Pisot V , , Trampuz A . Treatment of infected retained implants. J Bone Joint Surg [Br] 2005;87:249-56.
- 53↑
Antony SJ , , Westbrook RS , , Jackson JS , , Heydemann JS , , Nelson JL . Efficacy of single-stage revision with aggressive debridement using intra-articular antibiotics in the treatment of infected joint prosthesis. Infect Dis (Auckl) 2015;8:17-23.
- 54↑
Hake ME , , Young H , , Hak DJ , et al.. Local antibiotic therapy strategies in orthopaedic trauma: Practical tips and tricks and review of the literature. Injury 2015;46:1447-56.
- 55↑
ter Boo GJ , , Grijpma DW , , Moriarty TF , , Richards RG , , Eglin D . Antimicrobial delivery systems for local infection prophylaxis in orthopedic- and trauma surgery. Biomaterials 2015;52:113-25.
- 56↑
Metsemakers WJ , , Emanuel N , , Cohen O , et al.. A doxycycline-loaded polymer-lipid encapsulation matrix coating for the prevention of implant-related osteomyelitis due to doxycycline-resistant methicillin-resistant Staphylococcus aureus. J Control Release 2015;209:47-56.
- 57↑
Buchholz HW , , Engelbrecht H . [Depot effects of various antibiotics mixed with Palacos resins]. Chirurg 1970;41:511-5.
- 58↑
Lynch M , , Esser MP , , Shelley P , , Wroblewski BM . Deep infection in Charnley low-friction arthroplasty. Comparison of plain and gentamicin-loaded cement. J Bone Joint Surg [Br] 1987;69:355-60.
- 59↑
Engesaeter LB , , Lie SA , , Espehaug B , et al.. Antibiotic prophylaxis in total hip arthroplasty: effects of antibiotic prophylaxis systemically and in bone cement on the revision rate of 22,170 primary hip replacements followed 0-14 years in the Norwegian Arthroplasty Register. Acta Orthop Scand 2003;74:644-51.
- 60↑
Thomes B , , Murray P , , Bouchier-Hayes D . Development of resistant strains of Staphylococcus epidermidis on gentamicin-loaded bone cement in vivo. J Bone Joint Surg [Br] 2002;84:758-60.
- 61↑
Anagnostakos K , , Hitzler P , , Pape D , , Kohn D , , Kelm J . Persistence of bacterial growth on antibiotic-loaded beads: is it actually a problem? Acta Orthop 2008;79:302-7.
- 62↑
Balint L , , Koos Z , , Horvath G , , Szabo G . Detection of gentamicin emission from bone cement in the early postoperative period following total hip arthroplasty. Orthopedics 2006;29:432-6.
- 63↑
Fuchs T , , Stange R , , Schmidmaier G , , Raschke MJ . The use of gentamicin-coated nails in the tibia: preliminary results of a prospective study. Arch Orthop Trauma Surg 2011;131:1419-25.
- 64↑
Hardes J , , von Eiff C , , Streitbuerger A , et al.. Reduction of periprosthetic infection with silver-coated megaprostheses in patients with bone sarcoma. J Surg Oncol 2010;101:389-95.
- 65↑
Brooks B , , Brooks A , , Grainger D . Antimicrobial medical devices in preclinical development and clinical use. In: Moriarty TF , , Zaat SAJ , , Busscher HJ , eds. Biomaterials Associated Infection. New York: Springer, 2013:307-54.
- 67↑
Proctor RA . Challenges for a universal Staphylococcus aureus vaccine. Clin Infect Dis 2012;54:1179-86.
- 68↑
Jansen KU , , Girgenti DQ , , Scully IL , , Anderson AS . Vaccine review: “Staphyloccocus aureus vaccines: problems and prospects”. Vaccine 2013;31:2723-30.
- 69↑
den Reijer PM , , Lemmens-den Toom N , , Kant S , et al.. Characterization of the humoral immune response during Staphylococcus aureus bacteremia and global gene expression by Staphylococcus aureus in human blood. PLoS One 2013;8:e53391.
- 70↑
Dryla A , , Prustomersky S , , Gelbmann D , et al.. Comparison of antibody repertoires against Staphylococcus aureus in healthy individuals and in acutely infected patients. Clin Diagn Lab Immunol 2005;12:387-98.
- 71↑
Royan S , , Sharp L , , Nair SP , et al.. Identification of the secreted macromolecular immunogens of Staphylococcus aureus by analysis of serum. FEMS Immunol Med Microbiol 2000;29:315-21.
- 72↑
Verkaik NJ , , de Vogel CP , , Boelens HA , et al.. Anti-staphylococcal humoral immune response in persistent nasal carriers and noncarriers of Staphylococcus aureus. J Infect Dis 2009;199:625-32.
- 74↑
Gedbjerg N , , LaRosa R , , Hunter JG , et al.. Anti-glucosaminidase IgG in sera as a biomarker of host immunity against Staphylococcus aureus in orthopaedic surgery patients. J Bone Joint Surg [Am] 2013;95:e171.
- 75↑
Nishitani K , , Beck CA , , Rosenberg AF , et al.. A diagnostic serum antibody test for patients with Staphylococcus aureus osteomyelitis. Clin Orthop Relat Res 2015;473:2735-49.
- 76↑
Holtfreter S , , Kolata J , , Broker BM . Towards the immune proteome of Staphylococcus aureus - The anti-S. aureus antibody response. Int J Med Microbiol 2010;300:176-92.
- 77↑
Mayer-Scholl A , , Averhoff P , , Zychlinsky A . How do neutrophils and pathogens interact? Curr Opin Microbiol 2004;7:62-6.
- 78↑
Nanra JS , , Buitrago SM , , Crawford S , et al.. Capsular polysaccharides are an important immune evasion mechanism for Staphylococcus aureus. Hum Vaccin Immunother 2013;9:480-7.
- 79↑
Joshi A , , Pancari G , , Cope L , et al.. Immunization with Staphylococcus aureus iron regulated surface determinant B (IsdB) confers protection via Th17/IL17 pathway in a murine sepsis model. Hum Vaccin Immunother 2012;8:336-46.
- 80↑
Patti JM . A humanized monoclonal antibody targeting Staphylococcus aureus. Vaccine 2004;22 Suppl 1:S39-43.
- 81↑
Tkaczyk C , , Hua L , , Varkey R , et al.. Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency. Clin Vaccine Immunol 2012;19:377-85.
- 82↑
Cheng AG , , McAdow M , , Kim HK , et al.. Contribution of coagulases towards Staphylococcus aureus disease and protective immunity. PLoS Pathog 2010;6:e1001036.
- 83↑
Oshida T , , Sugai M , , Komatsuzawa H , et al.. A Staphylococcus aureus autolysin that has an N-acetylmuramoyl-L-alanine amidase domain and an endo-beta-N-acetylglucosaminidase domain: cloning, sequence analysis, and characterization. Proc Natl Acad Sci U S A 1995;92:285-9.
- 84↑
Sugai M , , Komatsuzawa H , , Akiyama T , et al.. Identification of endo-beta-N-acetylglucosaminidase and N-acetylmuramyl-L-alanine amidase as cluster-dispersing enzymes in Staphylococcus aureus. J Bacteriol 1995;177:1491-6.
- 85↑
Yamada S , , Sugai M , , Komatsuzawa H , et al.. An autolysin ring associated with cell separation of Staphylococcus aureus. J Bacteriol 1996;178:1565-71.
- 86↑
Heilmann C , , Hartleib J , , Hussain MS , , Peters G . The multifunctional Staphylococcus aureus autolysin aaa mediates adherence to immobilized fibrinogen and fibronectin. Infect Immun 2005;73:4793-802.
- 87↑
Brady RA , , Leid JG , , Camper AK , , Costerton JW , , Shirtliff ME . Identification of Staphylococcus aureus proteins recognized by the antibody-mediated immune response to a biofilm infection. Infect Immun 2006;74:3415-26.
- 88↑
Eirich J , , Orth R , , Sieber SA . Unraveling the protein targets of vancomycin in living S. aureus and E. faecalis cells. J Am Chem Soc 2011;133:12144-53.
- 89↑
Valisena S , , Varaldo PE , , Satta G . Staphylococcal endo-beta-N-acetylglucosaminidase inhibits response of human lymphocytes to mitogens and interferes with production of antibodies in mice. J Clin Invest 1991;87:1969-76.
- 90↑
Gedbjerg N , , Larosa R , , Hunter JG , et al.. Anti-glucosaminidase IgG in sera as a biomarker of host immunity against Staphylococcus aureus in orthopaedic surgery patients. J Bone Joint Surg [Am] 2013;95:e1711-9.
- 91↑
Brady RA , , O’May GA , , Leid JG , et al.. Resolution of Staphylococcus aureus biofilm infection using vaccination and antibiotic treatment. Infect Immun 2011;79:1797-803.
- 92↑
Varrone JJ , , de Mesy Bentley KL , , Bello-Irizarry SN , et al.. Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis of Staphylococcus aureus megaclusters. J Orthop Res 2014;32:1389-96.
- 93↑
Bongartz T , , Halligan CS , , Osmon DR , et al.. Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis. Arthritis Rheum 2008;59:1713-20.
- 94↑
Berbari EF , , Osmon DR , , Lahr B , et al.. The Mayo prosthetic joint infection risk score: implication for surgical site infection reporting and risk stratification. Infect Control Hosp Epidemiol 2012;33:774-81.
- 95↑
Dowsey MM , , Choong PF . Obesity is a major risk factor for prosthetic infection after primary hip arthroplasty. Clin Orthop Relat Res 2008;466:153-8.
- 96↑
Aggarwal VK , , Tischler EH , , Lautenbach C , et al.. Mitigation and education. J Orthop Res 2014;32 Suppl 1:S16-25.
- 97↑
Shinefield H , , Black S , , Fattom A , et al.. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N Engl J Med 2002;346:491-6.
- 98↑
Fowler VG , , Allen KB , , Moreira ED , et al.. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA 2013;309:1368-78.
- 99↑
Benjamin DK , , Schelonka R , , White R , et al.. A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin. J Perinatol 2006;26:290-5.
- 100↑
Bloom B , , Schelonka R , , Kueser T , et al.. Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants. Pediatr Infect Dis J 2005;24:858-66.
- 101↑
Capparelli EV , , Bloom BT , , Kueser TJ , et al.. Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants. Antimicrob Agents Chemother 2005;49:4121-7.
- 102↑
Hetherington S , , Texter M , , Wenzel E , et al.. Phase I dose escalation study to evaluate the safety and pharmacokinetic profile of tefibazumab in subjects with end-stage renal disease requiring hemodialysis. Antimicrob Agents Chemother 2006;50:3499-500.
- 103↑
Burnie JP , , Matthews RC , , Carter T , et al.. Identification of an immunodominant ABC transporter in methicillin-resistant Staphylococcus aureus infections. Infect Immun 2000;68:3200-9.
- 104↑
Schaffer AC , , Lee JC . Vaccination and passive immunisation against Staphylococcus aureus. Int J Antimicrob Agents 2008;32 Suppl 1:S71-8.
- 105↑
Weisman LE , , Fischer G , , Mandy G , et al.. Safety and pharmacokinetics of an anti-lipoteichoic acid humanized mouse chimeric monoclonal antibody in health adults. Baltimore, MD: Pediatric Academic Societies Meeting, 2002.
- 106↑
Weisman LE , , Fischer GW , , Thackray HM , et al.. Safety and pharmacokinetics of a chimerized anti-lipoteichoic acid monoclonal antibody in healthy adults. Int Immunopharmacol 2009;9:639-44.
- 107↑
Percival SL , , Slone W , , Linton S , et al.. The antimicrobial efficacy of a silver alginate dressing against a broad spectrum of clinically relevant wound isolates. Int Wound J 2011;8:237-43.
- 108↑
Gordon O , , Vig Slenters T , , Brunetto PS , et al.. Silver coordination polymers for prevention of implant infection: thiol interaction, impact on respiratory chain enzymes, and hydroxyl radical induction. Antimicrob Agents Chemother 2010;54:4208-18.
- 109↑
Semeykina AL , , Skulachev VP . Submicromolar Ag+ increases passive Na+ permeability and inhibits the respiration-supported formation of Na+ gradient in bacillus Ftu vesicles. Febs Lett 1990;269:69-72.
- 110↑
Lemire JA , , Harrison JJ , , Turner RJ . Antimicrobial activity of metals: mechanisms, molecular targets and applications. Nat Rev Microbiol 2013;11:371-84.
- 112↑
Maillard JY , , Hartemann P . Silver as an antimicrobial: facts and gaps in knowledge. Crit Rev Microbiol 2013;39:373-83.
- 113↑
Eckhardt S , , Brunetto PS , , Gagnon J , et al.. Nanobio silver: its interactions with peptides and bacteria, and its uses in medicine. Chem Rev 2013;113:4708-54.
- 114↑
Fromm KM . Silver coordination compounds with antimicrobial properties. Appl Organomet Chem 2013;27:683-7.
- 115↑
Brennan SA , , Ni Fhoglu C , , Devitt BM , et al.. Silver nanoparticles and their orthopaedic applications. Bone Joint J 2015;97B:582-9.
- 116↑
Lemire JA , , Kalan L , , Bradu A , , Turner RJ . Silver oxynitrate, an unexplored silver compound with antimicrobial and antibiofilm activity. Antimicrob Agents Chemother 2015;59:4031-9.
- 117↑
Rupp ME , , Lisco SJ , , Lipsett PA , et al.. Effect of a second-generation venous catheter impregnated with chlorhexidine and silver sulfadiazine on central catheter - Related infections - A randomized, controlled trial. Ann Intern Med 2005;143:570-80.
- 118↑
Saint S , , Elmore JG , , Sullivan SD , , Emerson SS , , Koepsell TD . The efficacy of silver alloy-coated urinary catheters in preventing urinary tract infection: A meta-analysis. Am J Med 1998;105:236-41.
- 119↑
Kollef MH , , Afessa B , , Anzueto A , et al.. Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia - The NASCENT Randomized Trial. JAMA 2008;300:805-13.
- 120↑
Masse A , , Bruno A , , Bosetti M , et al.. Prevention of pin track infection in external fixation with silver coated pins: Clinical and microbiological results. J Biomed Mater Res 2000;53:600-4.
- 121↑
Wafa H , , Grimer RJ , , Reddy K , et al.. Retrospective evaluation of the incidence of early periprosthetic infection with silver-treated endoprostheses in high-risk patients: case-control study. Bone Joint J 2015;97B:252-7.
- 122↑
Cason JS , , Jackson DM , , Lowbury EJ , , Ricketts CR . Antiseptic and aseptic prophylaxis for burns: use of silver nitrate and of isolators. Br Med J 1966;2:1288-94.
- 123↑
Lansdown AB . A pharmacological and toxicological profile of silver as an antimicrobial agent in medical devices. Adv Pharmacol Sci 2010;2010:910686.
- 124↑
Mijnendonckx K , , Leys N , , Mahillon J , , Silver S , , Van Houdt R . Antimicrobial silver: uses, toxicity and potential for resistance. Biometals 2013;26:609-21.
- 125↑
Drake PL , , Hazelwood KJ . Exposure-related health effects of silver and silver compounds: a review. Ann Occup Hyg 2005;49:575-85.
- 126↑
Vik H , , Andersen KJ , , Julshamn K , , Todnem K . Neuropathy caused by silver absorption from arthroplasty cement. Lancet 1985;1:872.
- 127↑
Mirsattari SM , , Hammond RR , , Sharpe MD , , Leung FY , , Young GB . Myoclonic status epilepticus following repeated oral ingestion of colloidal silver. Neurology 2004;62:1408-10.
- 128↑
Zheng Z , , Yin W , , Zara JN , et al.. The use of BMP-2 coupled - Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects. Biomaterials 2010;31:9293-300.
- 129↑
Hancock RE , , Sahl HG . Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 2006;24:1551-7.
- 131↑
Pasupuleti M , , Schmidtchen A , , Malmsten M . Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol 2012;32:143-71.
- 133↑
Mansour SC , , de la Fuente-Nunez C , , Hancock RE . Peptide IDR-1018: modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections. J Pept Sci 2015;21:323-9.
- 134↑
De Brucker K , , Delattin N , , Robijns S , et al.. Derivatives of the mouse cathelicidin-related antimicrobial peptide (CRAMP) inhibit fungal and bacterial biofilm formation. Antimicrob Agents Chemother 2014;58:5395-404.
- 135↑
Di Luca M , , Maccari G , , Maisetta G , , Batoni G . BaAMPs: the database of biofilm-active antimicrobial peptides. Biofouling 2015;31:193-9.
- 136↑
Costa F , , Carvalho IF , , Montelaro RC , , Gomes P , , Martins MC . Covalent immobilization of antimicrobial peptides (AMPs) onto biomaterial surfaces. Acta Biomater 2011;7:1431-40.
- 137↑
Hilpert K , , Elliott M , , Jenssen H , et al.. Screening and characterization of surface-tethered cationic peptides for antimicrobial activity. Chem Biol 2009;16:58-69.
- 138↑
Bagheri M , , Beyermann M , , Dathe M . Immobilization reduces the activity of surface-bound cationic antimicrobial peptides with no influence upon the activity spectrum. Antimicrob Agents Chemother 2009;53:1132-41.
- 139↑
Onaizi SA , , Leong SS . Tethering antimicrobial peptides: current status and potential challenges. Biotechnol Adv 2011;29:67-74.
- 140↑
Cleophas RTC , , Riool M , , van Ufford HCQ , et al.. Convenient preparation of bactericidal hydrogels by covalent attachment of stabilized antimicrobial peptides using thiol-ene click chemistry. Acs Macro Lett 2014;3:477-80.
- 141↑
Cherkasov A , , Hilpert K , , Jenssen H , et al.. Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs. ACS Chem Biol 2009;4:65-74.
- 142↑
Emanuel N , , Rosenfeld Y , , Cohen O , et al.. A lipid-and-polymer-based novel local drug delivery system–BonyPid: from physicochemical aspects to therapy of bacterially infected bones. J Control Release 2012;160:353-61.
- 144↑
LaSarre B , , Federle MJ . Exploiting quorum sensing to confuse bacterial pathogens. Microbiol Mol Biol Rev 2013;77:73-111.
- 145↑
Brackman G , , Coenye T . Quorum sensing inhibitors as anti-biofilm agents. Curr Pharm Des 2015;21:5-11.
- 146↑
Bjarnsholt T , , Jensen PO , , Burmolle M , et al.. Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent. Microbiology 2005;151:373-83.
- 147↑
Hassett DJ , , Ma JF , , Elkins JG , et al.. Quorum sensing in Pseudomonas aeruginosa controls expression of catalase and superoxide dismutase genes and mediates biofilm susceptibility to hydrogen peroxide. Mol Microbiol 1999;34:1082-93.
- 148↑
Brackman G , , Cos P , , Maes L , , Nelis HJ , , Coenye T . Quorum sensing inhibitors increase the susceptibility of bacterial biofilms to antibiotics in vitro and in vivo. Antimicrob Agents Chemother 2011;55:2655-61.
- 149↑
Christensen LD , , van Gennip M , , Jakobsen TH , et al.. Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model. J Antimicrob Chemother 2012;67:1198-206.
- 150↑
Udine C , , Brackman G , , Bazzini S , et al.. Phenotypic and genotypic characterisation of Burkholderia cenocepacia J2315 mutants affected in homoserine lactone and diffusible signal factor-based quorum sensing systems suggests interplay between both types of systems. PLoS One 2013;8:e55112.
- 151↑
Brackman G , , Coenye T . Inhibition of quorum sensing in Staphylococcus spp. Curr Pharm Des 2015;21:2101-8.
- 152↑
Brackman G , , Risseeuw M , , Celen S , et al.. Synthesis and evaluation of the quorum sensing inhibitory effect of substituted triazolyldihydrofuranones. Bioorg Med Chem 2012;20:4737-43.
- 153↑
O’Loughlin CT , , Miller LC , , Siryaporn A , et al.. A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc Natl Acad Sci U S A 2013;110:17981-6.
- 154↑
Sully EK , , Malachowa N , , Elmore BO , et al.. Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathog 2014;10:e1004174.
- 155↑
Coenye T , , Nelis HJ . In vitro and in vivo model systems to study microbial biofilm formation. J Microbiol Methods 2010;83:89-105.
- 156↑
Calabro L , , Lutton C , , Din A , , Richards RG , , Moriarty TF . Animal models of orthopedic implant-related infection. In: Moriarty TF , , Zaat SAJ , , Busscher HJ , eds. Biomaterials Associated Infection. New York: Springer, 2013:273-304.
- 157↑
Arciola CR , , Montanaro L , , Costerton JW . New trends in diagnosis and control strategies for implant infections. Int J Artif Organs 2011;34:727-36.
- 158↑
Kaplan JB . Therapeutic potential of biofilm-dispersing enzymes. Int J Artif Organs 2009;32:545-54.
- 159↑
Okshevsky M , , Regina VR , , Meyer RL . Extracellular DNA as a target for biofilm control. Curr Opin Biotechnol 2015;33:73-80.
- 160↑
Darouiche RO , , Mansouri MD , , Gawande PV , , Madhyastha S . Antimicrobial and antibiofilm efficacy of triclosan and DispersinB combination. J Antimicrob Chemother 2009;64:88-93.
- 161↑
Pavlukhina SV , , Kaplan JB , , Xu L , et al.. Noneluting enzymatic antibiofilm coatings. ACS Appl Mater Interfaces 2012;4:4708-16.