1. Site-specific Incidence

Infection is a common and frequent complication associated with all types of biomedical materials, despite the infection rate varying greatly among different intended uses of various implantable devices (Table 1) [2-38]. Orthopedic implants, such as the ankle, hip, knee, elbow, shoulder, and finger joint prosthetics, are made of metals (titanium alloys, stainless steel, cobalt-chromium alloy, etc.) and are expected to serve long periods (>10 years) in patients’ bodies. Infections of these devices are extremely troublesome [39]. Ankle arthroplasty has higher infection rates (2.4–8.9%) than hip (0.4–2.4%) and knee (1–2%) arthroplasty, although they are normally made of the same materials (Table 1). This is remarkably related to wound dehiscence (or prolonged drainage) developed due to the frail soft tissue surrounding ankles and increased chance of delayed wound healing following ankle arthroplasty [3,40]. The infection situation will be even more serious in revision cases. For example, the incidence of infection for primary hip and knee arthroplasty is around 2% (Table 1), yet this will be possibly as high as 12% and 22% for revision hip and knee arthroplasty, respectively [41]. Moreover, the number of infection cases is expected to increase progressively because the number of arthroplasty surgeries is going to grow in the coming years. In Taiwan, China, for instance, a total of 728 hip and knee infection cases were recorded in 2013 and this number was expected to increase markedly to over 3500 by 2035 [42]. Not only these metallic implants are connected to bacterial infection, but also polymer devices are susceptible to this complication (Table 1). Examples include breast implants, vascular graft/endograft, cardiovascular electronic devices, and cochlear implants, which are made of silicone, polytetrafluoroethylene, plastics, or Teflon, and have infection incidence high up to 10.2% [9], 6% [10], 7% [14], and 8% [17], respectively. Additionally, the DAIs may occur due to the device design. As in brain stimulation implants, the battery of the pulse generator should be replaced typically every 2 years, and such multiple replacements increase the risk of DAIs [23]. Furthermore, the incidence of infection is highly determined by the site a device is placed in. As shown in Table 1, the infection rates in urinary catheters (up to 13.7 cases per 1000 catheter-days), cerebrospinal fluid shunts (27%), internal fixation devices (32%), and dental implants (47%) are high. This is because these devices are highly challenged by bacterial adhesion and biofilm formation during their insertion and the subsequent service period. For example, urinary catheters provide routes for the entry of pathogenic bacteria, increasing the risk of acquiring infections [28]. Investigations of the bacterial sources in infected shunts also demonstrate that a majority of harmful microbes gained entry from the skin of the patients themselves [43]. The risk of complications in fixation of fractures is highly in connection to the low blood supply and elder people are susceptible to infection [36]. Additionally, there are more than 500 bacterial species associated with commensals or pathogens within the oral cavity [44]. This situation makes the prevention of infections in dental implants extremely complicated. The reported incidence rates for dental implants serving of over 3 and 5 years are 9.25% and 9.6%, respectively, and this rate for implants with service periods of over 10 years is up to 26% [38]. More importantly, the prevalence of the pathogenic strains is also associated with specific anatomical locations. Although Staphylococcus spp. is the most prevalent microbe associated with all types of bacterial infections, other pathogens can be involved in specific sites. Gram-negative microbes are involved in 10-40%, 20%, and 35-55% of vertebral, trauma/fracture, and foot/ankle-related infections [45]. Additionally, 15-30%, 20-30%, and 30-80% of polymicrobial infections occur in vertebral, trauma/fracture, and foot/ankle, respectively [45]. Different bacterial strains may have different metabolisms and pathogenic mechanisms that require specifically tailored treatments. This is especially critical to cure infections involving multiple pathogenic strains; as a result, developing an all-around antibacterial solution for all medical devices is hardly possible.

Table 1. Incidence of typical device-associated infections.

* The incidence of catheter-associated urinary tract infection is typically expressed as the number of infections per 1000 urinary catheter-days [29].

2. The Unpredictable Onset

Device-associated infections become even stickier because of those host-specific, transient, or resident factors (Table 2) [46–58]. The onset of DAI is not predictable, it can onset years after implantation (Cases 1 through 6 in Table 2). The soft tissue envelope around an implant likely degenerates with aging and can be disrupted by an occasional scratch, which may have promoted the infection of an alloplastic chin implant 45 years after placement [46]. Breast implants significantly risk bacterial contamination from hematogenous spread of distant antecedent infections. It was reported that the Achromobacter xylosoxidans (lives in wet soil) from a chronic footsore and streptococcus viridans (lives in the oral cavity) from recurrent periodontitis can cause infection of breast implants even 7 and 25 years after the implantation [47]. Staphylococcus epidermidis (S. epidermidis) can colonize various biomedical implants and escape from the immune clearance and antibiotic treatments, hence possibly causing symptom-free (such as pain, redness, or fever) chronic infection lasting even for 30 years before being identified by clinical approaches [46]. Cutibacterium acnes (previously known as propionibacterium acnes), a common conjunctival inhabitant, are slow-growing, anaerobic Gram-positive rods, and can manifest several years or even decades before leading to late infections in orbital implants made of silicone or tantalum [49,50]. The sources of the pathogens of the DAIs can be host-specific (Cases 7 through 9 in Table 2). DAIs can be initiated by acute illness (e.g., diarrhea developed during a holiday journey [8]), penetration of contaminated water during participating in outdoor activities [22], or even when the patients play with their pets (bacterial contamination from zoonotic sources) [51]. Moreover, the occurrence of DAIs is commonly associated with a compromised immune system in the hosts (Cases 10 and 11 in Table 2). Methotrexate, a folate antagonist, can affect neutrophil chemotaxis and induce apoptosis of T cells and reactivation of opportunistic pathogens; hence chronic treatment of rheumatoid arthritis with this kind of drug significantly increases the risk of infections around the battery for brain stimulation [52]. Nocardia nova is a common environmental pathogen and rarely affects immunocompetent hosts; however, this species successfully colonized a tibia implant placed in an immunocompetent patient [53]. Listeria monocytogenes, a common organism associated with unpasteurized dairy products (e.g., deli meats and unpasteurized cheeses), can induce a periprosthetic joint infection in a patient with a history of diabetes mellitus, asthma, and psoriatic arthritis [54]. Anaerobiospirillum succiniciproducens, a common settler in the gastrointestinal tract of cats and dogs, can induce a prosthetic hip joint infection in an immunocompromised patient [55]. DAIs are normally initiated by bacterial seeding and as a result tissue integration will be impaired quickly; however, some cases failed to identify any organism by cultures [56,57] and tissue integration was intact after being infected [58]. These situations add difficulties to the prevention, diagnosis, and treatment of DAIs.

Table 2. Representative cases showing the latent period of DAIs.

3. Diversity of Relevant Pathogens

Infections associated with medical devices with the same intended use (the same device category) but placed in different individuals are possibly connected with different bacterial strains. As shown in Table 2, the infection of breast implants can result from achromobacter xylosoxidans (Gram-negative rod) [47], streptococcus viridans [47], and salmonella serogroup C [8], or Pasteurella canis [51]. Polymicrobial infections become more prevalent in DAIs [45,59]. Even a single infection in a specific individual often has a polymicrobial composition [60]. Multispecies including the rare Cupriavidus pauculus species were isolated in an infection associated with the generator for brain stimulation [22]. Since the bacteria associated with an infection of a medical device may have diverse morphologies and arrangements, an effective antibacterial strategy must be capable of eliminating multiple pathogenic species. Cocci cells (spherical bacteria) range from 0.5 to 2.0 µm in diameter, rods are approximate 0.5–1.0 µm in width and 1–10 µm in length, and spiral bacteria are up to 20 µm in length and 0.1–1 µm in diameter [61]. Moreover, bacterial morphology varies with the growth environments (medium, surfaces, etc.) and growth phase (normally smallest in the logarithmic phase) [62,63]. These facts add additional difficulties to developing a competent antibacterial surface for implantable devices. On account of these features of DAIs, antibacterial surfaces only have a pore-size-based cell selectivity [64], or those peptide-loaded surfaces merely have specific actions to Gram-positive or Gram-negative strains [65] and are not likely adequate to prevent infection of implantable medical devices.

4. Prevalence of Antibiotic Resistance

The uses of internal implants in humans are safer and more common since sterilization methods and techniques were established at the end of the 19th century [66], and the commercialization of antibiotics especially penicillin in the first half of the 20th century [67]. Antibiotics have become an integral component of contemporary biomedical practice, producing a serious follow-up threat: antibiotic resistance in bacteria [68,69]. Clinical cases in orthopedic practice have shown that infections of antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are closely related to high morbidity and mortality [70]. Antibiotic resistance in bacteria even multidrug-resistant (MDR) bacteria is now a worldwide challenge [70]. Antibiotic-resistant infections were frequently reported all over the world, including in both developing and developed countries (Table 3) [71-89]. During an infection, Staphylococcus aureus (S. aureus) often forms biofilms on implantable devices, which dramatically increases the ability of the species to acquire resistance via horizontal plasmid transfer [90]. This is why S. aureus has high rates of resistance. As shown by the typical cases reported in recent years (Table 3), MRSA has become the most common strain causing infections of various implantable medical devices, including cardiac devices [72,74,78,83,85], orthopedic prosthetics [75,76], cochlear implants [77], breast implants [79], laryngeal implants [80], and stent-grafts [81]. In addition, there is an alarming increase in antibiotic resistance in other strains, such as Acinetobacter baumannii [71], Mycobacterium chelonae [73], Enterobacter cloacae complex [81], S. epidermidis [83,89], Klebsiella pneumoniae [84], Staphylococcus haemolyticus [86], and Staphylococcal endophthalmitis [108], are also involved in various resistant DAIs. Those resistant DAIs impacted patients have to experience prolonged hospital stays, bear high medical costs, and risk increased mortality (references in Table 3). Antibiotic recalcitrance is a worldwide threat that likely causes substantial global economic costs ranging from USD 21,832 per individual case to over USD 3 trillion in gross domestic product (GDP) loss by 2050 [91]. In the USA alone, at least 2 million infections and 23,000 deaths per year were caused by antibiotic-resistant bacteria, costing USD 55–70 billion [69]. Currently, antibiotic-loaded materials are important complements to modular medical practices for the prevention of recurrent infections in various medical devices, such as wound dressings, bone cement, bone plates, nails, or prostheses [92-94]. However, applications of these surfaces in “uninfected tissues” to prevent DAIs should be careful and in strict guidance, because the prolonged release of prophylactic antibiotics possibly contributes to arising resistant mutants [95]. Silver-based surfaces also have attractive efficacy in the prevention of DAIs [96], improper use of this material may also pose bacterial-resistant problems [97,98]. In addition, pathogenic bacteria have many defensive actions resistant to antimicrobial challenges [70,99,100]: (a) express polymer biofilms to protect themselves from antibiotic attacks; (b) remodel their outer surface to reduce antibiotic uptake; (c) synthesize precursors to modify the target of antimicrobials; (d) produce enzymes to detoxify dangerous drugs. Therefore, antibacterial surfaces, especially those release-killing ones, should be designed to bypass these actions of bacterial cells.

Table 3. Epidemiology of antibiotic-resistant DAIs.

Because of the aforementioned clinical feature of DAIs, antibacterial designs for implantable medical devices shall conform to a specific intended use. This is crucial to choose proper routes for material synthesis, applicable parameters for material characterizations, and the right strategies for biological evaluations, enabling reproducible, comparable, and reusable results that will be consistent in clinical translation[1,96,101].

References：

1. Cao, H.; Qiao, S.; Qin, H.; Jandt, KD. Antibacterial Designs for Implantable Medical Devices: Evolutions and Challenges. Funct. Biomater. 2022, 13, 86.
2. Takakura, Y.; Tanaka, Y.; Kumai, T.; Sugimoto, K.; Ohgushi, H. Ankle arthroplasty using three generations of metal and ceramic prostheses. Orthop. Relat. Res. 2004, 424, 130-136.
3. El-Sayed, D.; Nouvong, A. Infection protocols for implants. Podiat.r Med. Surg. 2019, 36, 627–649.
4. Merola, M.; Affatato, S. Materials for hip prostheses: A review of wear and loading considerations. Materials 2019, 12, 495.
5. Henderson, R.A.; Austin, M.S. Management of periprosthetic joint infection: The more we learn, the less we know. Arthroplast. 2017, 32, 2056–2059.
6. Mihalko, W.M.; Haider, H.; Kurtz, S.; Marcolongo, M.; Urish, K. New materials for hip and knee joint replacement: what’s hip and what’s in kneed? Orthop. Res. 2020, 38, 1436–1444.
7. Perry, D.; Frame, J.D. The history and development of breast implants. R. Coll. Surg. Engl. 2020, 10, 478–482.
8. Hall, B.R.; Billue, K.L.; Sanders, S.E.; Meyer, B.R.; Johnson, P.J. Salmonella infection of breast implant associated with traveler’s diarrhea: A case report. JPRAS Open 2018, 18, 59–64.
9. Franchelli, S.; Pesce, M.; Savaia, S.; Marchese, A.; Barbieri, R.; Baldelli, I.; De Maria, A. Clinical and microbiological characterization of late breast implant infections after reconstructive breast cancer surgery. Infect. 2015, 16, 636–644.
10. Chakfé, N.; Diener, H.; Lejay, A.; Assadian, O.; Berard, X.; Caillon, J.; Fourneau, I.; Glaudemans, A.W.J.M.; Koncar, I.; Lindholt, J.; et al. Editor’s Choice—European Society for Vascular Surgery (ESVS) 2020 Clinical practice guidelines on the management of vascular graft and endograft infections. J. Vasc. Endovasc. Surg. 2020, 59, 339–384.
11. Viola, G.M.; Darouiche, R.O. Cardiovascular implantable device infections. Infect. Dis. Rep. 2011, 13, 333–342.
12. Zheng, Q.; Tang, Q.; Wang, Z.L.; Li, Z. Self-powered cardiovascular electronic devices and systems. Rev. Cardiol. 2021, 18, 7–21.
13. Zerbo, S.; Perrone, G.; Bilotta, C.; Adelfio, V.; Malta, G.; Di Pasquale, P.; Maresi, E.; Argo, A. Cardiovascular implantable electronic device infection and new insights about correlation between pro-inflammatory markers and heart failure: A systematic literature review and meta-analysis. Cardiovasc. Med. 2021, 8, 602275.
14. Tarakji, K.G.; Chan, E.J.; Cantillon, D.J.; Doonan, A.L.; Hu, T.; Schmitt, S.; Fraser, T.G.; Kim, A.; Gordon, S.M.; Wilkoff, B.L. Cardiac implantable electronic device infections: Presentation, management, and patient outcomes. Heart Rhythm. 2010, 7, 1043–1047.
15. Korkerdsup, T.; Ngarmukos, T.; Sungkanuparph, S.; Phuphuakrat, A. Cardiac implantable electronic device infection in the cardiac referral center in Thailand: Incidence, microbiology, risk factors, and outcomes. Arrhythm. 2018, 34, 632–639.
16. Stöver, T.; Lenarz, T. Biomaterials in cochlear implants. GMS Curr. Top. Otorhinolaryngol. Head Neck Surg. 2009, 8, Doc10.
17. Lodhi, F.; Coelho, D.H. Non-tuberculous mycobacterial cochlear implant infection: An emerging pathogen. Cochlear Implant. Int. 2015, 16, 237–240.
18. Sharma, S.; Gupta, A.; Bhatia, K.; Lahiri, A.K.; Singh, S. Salvaging cochlear implant after wound infection: Well worth a try. Cochlear Implant. Int. 2017, 18, 230–234.
19. Tawfik, K.O.; Golub, J.S.; Roland, J.T.; Samy, R.N. Recurrent cochlear implant infection treated with exteriorization and partial mastoid obliteration. Cochlear Implant. Int. 2016, 17, 58–61.
20. Vaid, N.; Vaid, S.; Manikoth, M. Case report-Biofilm infection of a cochlear implant. Cochlear Implant. Int. 2013, 14, 117–120.
21. Zarrintaj, P.; Saeb, M.R.; Ramakrishna, S.; Mozafari, M. Biomaterials selection for neuroprosthetics. Opin. Biomed. Eng. 2018, 6, 99–109.
22. Shenai, M.B.; Falconer, R.; Rogers, S. A cupriavidus pauculus infection in a patient with a deep brain stimulation implant. Cureus 2019, 11, e6104.
23. Wei, Z.; Gordon, C.R.; Bergey, G.K.; Sacks, J.M.; Anderson, W.S. Implant site infection and bone flap osteomyelitis associated with the neuropace responsive neurostimulation system. World Neurosurg. 2016, 88, 687.e1–e6.
24. Lawrence, E.L.; Turner, I.G. Materials for urinary catheters: A review of their history and development in the UK. Eng. Phys. 2005, 27, 443–453.
25. Huang, W.C.; Wann, S.R.; Lin, S.L.; Kunin, C.M.; Kung, M.H.; Lin, C.H.; Hsu, C.W.; Liu, C.P.; Lee, S.S.; Liu, Y.C.; et al. Catheter-associated urinary tract infections in intensive care units can be reduced by prompting physicians to remove unnecessary catheters. Control Hosp. Epidemiol. 2004, 25, 974–978.
26. Lo, E.; Nicolle, L.E.; Coffin, S.E.; Gould, C.; Maragakis, L.L.; Meddings, J.; Pegues, D.A.; Pettis, A.M.; Saint, S.; Yokoe, D.S. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals: 2014 update. Control Hosp. Epidemiol. 2014, 35, 464–479.
27. Luzum, M.; Sebolt, J.; Chopra, V. Catheter-associated urinary tract infection, clostridioides difficile colitis, central line-associated bloodstream infection, and methicillin-resistant staphylococcus aureus. Clin. North Am. 2020, 104, 663–679.
28. Li, F.; Song, M.; Xu, L.; Deng, B.; Zhu, S.; Li, X. Risk factors for catheter-associated urinary tract infection among hospitalized patients: A systematic review and meta-analysis of observational studies. Adv. Nurs. 2019, 75, 517–527.
29. Shuman, E.K.; Chenoweth, C.E. Urinary catheter-associated infections. Dis. Clin. North Am. 2018, 32, 885–897.
30. Bigio, M.R. Del. Biological reactions to cerebrospinal fluid shunt devices: A review of the cellular pathology. Neurosurgery 1998, 42, 319–326.
31. Canadian Nosocomial Infection Surveillance Program. Device-associated infections in Canadian acute-care hospitals from 2009 to 2018. Commun. Dis. Rep. 2020, 46, 387–397.
32. Shibamura-Fujiogi, M.; Ormsby, J.; Breibart, M.; Warf, B.; Priebe, G.P.; Soriano, S.G.; Sandora, T.J.; Yuki, K. Risk factors for pediatric surgical site infection following neurosurgical procedures for hydrocephalus: A retrospective single-center cohort study. BMC Anesthesiol. 2021, 21, 124.
33. Benachinmardi, K.K.; Ravikumar, R.; Indiradevi, B. Role of biofilm in cerebrospinal fluid shunt infections: A study at tertiary neurocare center from South India. Neurosci. Rural. Pract. 2017, 8, 335–341.
34. Fernández-Méndez, R.; Richards, H.K.; Seeley, H.M.; Pickard, J.D.; Joannides, A.J. UKSR collaborators, Current epidemiology of cerebrospinal fluid shunt surgery in the UK and Ireland (2004–2013). Neurol. Neurosurg. Psychiatry 2019, 90, 747–754.
35. Deshmukh, R.M.; Kulkarni, S.S. A review on biomaterials in orthopedic bone plate application. International J. Curr. Eng. Technol. 2015, 5, 2587–2591.
36. Toro-Aguilera, Á.; Zuriarrain, S.W.; Masdeu, M.G.; Sayol, R.R.; Billi, A.M.; Carrera, I.; Caso, J. de. Risk factors for infection in fixation of distal tibia fractures. Injury 2021, 52 (Suppl 4), S104–S108.
37. Guillaume, B. Dental implants: A review. Morphologie 2016, 100, 189–198.
38. Neely, A.L.; Maalhagh-Fard, A. Successful management of early peri-implant infection and bone loss using a multidisciplinary treatment approach. Adv. Periodontics 2018, 8, 5–10.
39. Arciola, C.R.; Campoccia, D.; Montanaro, L. Implant infections: Adhesion, biofilm formation and immune evasion. Rev. Microbiol. 2018, 16, 397-409.
40. Patton, D.; Kiewiet, N.; Brage, M. Infected total ankle arthroplasty: Risk factors and treatment options. Foot Ankle Int. 2015, 36, 626–634.
41. Gbejuade, H.O.; Lovering, A.M.; Webb, J.C. The role of microbial biofilms in prosthetic joint infections. Acta Orthop. 2015, 86, 147–158.
42. Chang, C.H.; Lee, S.H.; Lin, Y.C.; Wang, Y.C.; Chang, C.J.; Hsieh, P.H. Increased periprosthetic hip and knee infection projected from 2014 to 2035 in Taiwan. Infect. Public Health 2020, 13, 1768-1773.
43. Bayston, R.; Lari, J. A study of the sources of infection in colonised shunts. Med. Child Neurol.1974, 16, 16–22.
44. Reynolds-Campbell, G.; Nicholson, A.; Thoms-Rodriguez, C.A. Oral bacterial infections: Diagnosis and management. Clin. N. Am. 2017, 61, 305–318.
45. Masters, E.A.; Ricciardi, B.F.; de Mesy Bentley, K.L.; Moriarty, T.F.; Schwarz, E.M.; Muthukrishnan, G. Skeletal infections: Microbial pathogenesis, immunity and clinical management. Rev. Microbiol. 2022, 20, 385–400 https://doi.org/10.1038/s41579-022-00686-0.
46. Bain, C.J.; Odili, J. Late infection of an alloplastic chin implant masquerading as squamous cell carcinoma. Plast. Reconstr. Aesthet. Surg. 2012, 65, e151–e152.
47. Chang, J.; Lee, G.W. Late hematogenous bacterial infections of breast implants: Two case reports of unique bacterial infections. Plast. Surg. 2011, 67, 14–16.
48. Beidas, O.E.; Rabb, C.H.; Sawan, K.T.; Tan, B.K. The pseudomeningocoele that wasn’t: Case report of an adult who presented with a late infection of an implant. Plast. Reconstr. Aesthet. Surg. 2011, 64, 1228–1231.
49. Vichitvejpaisal, P.; Dalvin, L.A.; Lally, S.E.; Shields, C.L. Delayed implant infection with Cutibacterium acnes (Propionibacterium acnes) 30 years after silicone sheet orbital floor implant. Orbit 2020, 39, 139–142.
50. Coden, D.J.; Hornblass, A. Propionibacterium acnes orbital abscess. Ophthalmol. 1990, 108, 481.
51. Hannouille, J.; Belgrado, J.P.; Vankerchove, S.; Vandermeeren, L. Breast implant infection with pasteurella canis: First case-report. JPRAS Open 2019, 21, 86–88.
52. Oses, M.; Ordás, C.M.; Feliz, C.; Del Val, J.; Ayerbe, J.; García-Ruiz, P.J. Disease-modifying anti-rheumatic drugs as a risk factor for delayed DBS implant infection. Parkinsonism Relat. Disord. 2018, 55, 143–144.
53. Young, P.; Riga, A.; Brunelli, J. Nocardia nova infection of tibia tenodesis implant after anterior cruciate ligament reconstruction in an immunocompetent patient. Am. Acad. Orthop. Surg. Glob. Res. Rev. 2020, 4, e19.00167.
54. Paziuk, T.; Levicoff, E.; Tan, T.; Good, R. Periprosthetic joint infection with listeria monocytogenes: A case report. JBJS Case Connect 2020, 10, e1900489.
55. Madden, G.R.; Poulter, M.D.; Crawford, M.P.; Wilson, D.S.; Donowitz, G.R. Case report: Anaerobiospirillum prosthetic joint infection in a heart transplant recipient. BMC Musculoskelet. Disord. 2019, 20, 301.
56. Haimes, M.A.; Nelms, N J. Total knee bartonella henselae infection: An unusual manifestation of cat scratch disease: A case report. JBJS Case Connect 2019, 9, e0081.
57. Posti, J.P.; Piitulainen, J.M.; Hupa, L.; Fagerlund, S.; Frantzén, J.; Aitasalo, K.M.J.; Vuorinen, V.; Serlo, W.; Syrjänen, S.; Vallittu, P.K. A glass fiber-reinforced composite—bioactive glass cranioplasty implant: A case study of an early development stage implant removed due to a late infection. Mech. Behav. Biomed. Mater. 2016, 55, 191–200.
58. Wahl, P.; Sprecher, C.M.; Brüning, C.; Meier, C.; Milz, S.; Gautier, E.; Moriarty, T F. Successful bony integration of a porous tantalum implant despite longlasting and ongoing infection: Histologic workup of an explanted shoulder prosthesis. Biomed. Mater. Res. B Appl. Biomater. 2018, 106, 2924–2931.
59. Hurdle, J.G.; O’Neill, A.J.; Chopra, I.; Lee, R.E. Targeting bacterial membrane function: An underexploited mechanism for treating persistent infections. Rev. Microbiol. 2011, 9, 62–75.
60. Dowd, S.E.; Sun, Y.; Secor, P.R.; Rhoads, D.D.; Wolcott, B.M.; James, G.A.; Wolcott, R.D. Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol. 2008, 8, 43.
61. Ryan, K.J.; Ahmad, N.; Alspaugh, J.A.; Drew, W.L. Sherris Medical Microbiology, 7th ed.; McGraw-Hill Education: New York, NY, USA, 2018; pp. 381–
62. Männik, J.; Driessen, R.; Galajda, P.; Keymer, J.E.; Dekker, C. Bacterial growth and motility in sub-micron constrictions. Natl. Acad. Sci. USA 2009, 106, 14861–14866.
63. Pianetti, A.; Battistelli, M.; Citterio, B.; Parlani, C.; Falcieri, E.; Bruscolini, F. Morphological changes of Aeromonas hydrophila in response to osmotic stress. Micron 2009, 40, 426–433.
64. Vargas-Alfredo, N.; Santos-Coquillat, A.; Martínez-Campos, E.; Dorronsoro, A.; Cortajarena, A.L.; Del Campo, A.; Rodríguez-Hernández, J. Highly efficient antibacterial surfaces based on bacterial/cell size selective microporous supports. ACS Appl. Mater. Interfaces 2017, 9, 44270–44280.
65. Costa, F.; Carvalho, I.F.; Montelaro, R.C.; Gomes, P.; Cristina, M.; Martins, L. Covalent immobilization of antimicrobial peptides (AMPs) onto biomaterial surfaces. Acta Biomater. 2011, 7, 1431–1440.
66. Lister, J. On a new method of treating compound fracture, abscess, etc.: With observations on the conditions of suppuration. Lancet 1867, 89, 326–329.
67. Durand, G.A.; Raoult, D.; Dubourg, G. Antibiotic discovery: History, methods and perspectives. J. Antimicrob. Agents 2019, 53, 371–382.
68. Bryson, D.J.; Morris, D.L.J.; Shivji, F.S.; Rollins, K.R.; Snape, S.; Ollivere, B.J. Antibiotic prophylaxis in orthopaedic surgery: Difficult decisions in an era of evolving antibiotic resistance. Bone Joint J. 2016, 98, 1014–
69. Li, B.; Webster, T.J. Bacteria antibiotic resistance: New challenges and opportunities for implant-associated orthopedic infections. Orthop. Res. 2018, 36, 22–32.
70. Makabenta, J.M.V.; Nabawy, A.; Li, C.H.; Schmidt-Malan, S.; Patel, R.; Rotello, V.M. Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections. Rev. Microbiol. 2021, 19, 23–36.
71. Vasiliadis, A.V.; Poutoglidou, F.; Chatziravdeli, V.; Metaxiotis, D.; Beletsiotis, A. Acute periprosthetic hip joint infection caused by multidrug-resistant acinetobacter baumannii: Is debridement, antibiotics, irrigation, and implant retention a viable treatment option? Cureus 2021, 13, e13090.
72. Okada, A.; Shoda, M.; Tabata, H.; Kobayashi, H.; Shoin, W.; Okano, T.; Yoshie, K.; Kato, K.; Motoki, H.; Kuwahara, K. Simultaneous infection of abandoned leads and newly implanted leadless cardiac pacemaker: Why did this occur? Cardiol. Cases 2020, 23, 35–37.
73. Jhaveri, V.V.; Singhal, D.; Riedel, S.; Rowley, C.F.; Nathavitharana, R.R. Surgical cure of clarithromycin resistant Mycobacterium chelonae breast implant infection: A case report and review of the literature. Clin. Tuberc. Other Mycobact. Dis. 2020, 21, 100183.
74. El-Zein, R.S.; Stelzer, M.; Hatanelas, J.; Goodlive, T.W.; Amin, A.K. A ghost left behind after transvenous lead extraction: A finding to be feared. J. Case Rep. 2020, 21, e924243.
75. Palacios, L.; de Nova, A.A.; Pardo, M G. Conservative multimodal management of osteosynthesis material in surgical wounds with polymicrobial superinfection, including methicillin-resistant Staphylococcus aureus, Clinical case. Española Cirugía Ortopédica Traumatol. (Engl. Ed.) 2020, 64, 125–129.
76. Hwang, S. Oh; Chang, L.S. Salvage of an exposed cranial prosthetic implant using a transposition flap with an indwelling antibiotic irrigation system. Craniofac. Surg. 2020, 21, 73–76.
77. Fukushima, S.; Komune, N.; Kamizono, K.; Matsumoto, N.; Takaiwa, K.; Nakagawa, T.; Kadota, H. Use of negative pressure wound therapy to treat a cochlear implant infection around the auricle: A case report. Wound Care 2020, 29, 568–571.
78. Bajaj, T.; Karapetians, A.; Karapetians, N.; Duong, H.; Heidari, A. Methicillin resistant Staphylococcus aureus infective endocarditis presenting as neutrophilic meningoencephalitis. AME Case Rep. 2020, 4, 4.
79. Hisanaga, K.; Kadota, H.; Fukushima, S.; Inatomi, Y.; Shimamoto, R.; Kamizono, K.; Hanada, M.; Yoshida, S. Toxic shock syndrome caused by staphylococcal infection after breast implant surgery: A case report and literature review. Plast. Surg. 2019, 83, 359–362.
80. Meleca, J.B.; Bryson, P.C. Delayed laryngeal implant infection and laryngocutaneous fistula after medialization laryngoplasty. J. Otolaryngol. 2019, 40, 462–464.
81. Siebenbürger, G.; Grabein, B.; Schenck, T.; Kammerlander, C.; Böcker, W.; Zeckey, C. Eradication of acinetobacter baumannii/enterobacter cloacae complex in an open proximal tibial fracture and closed drop foot correction with a multidisciplinary approach using the taylor spatial frame^®: A case report. J. Med. Res. 2019, 24, 2.
82. Nozoe, M.; Yoshida, D.; Nagatomo, D.; Suematsu, N.; Kubota, T.; Okabe, M.; Yamamoto, Y. Successful percutaneous retrieval of a micra transcatheter pacing system at 8 weeks after implantation. Arrhythm. 2018, 34, 653–655.
83. Bonacker, J.; Darowski, M.; Haar, P.; Westphal, T.; Bergschmidt, P. Periprosthetic tibial fracture with nonunion and ascending prosthetic joint infection: A case report of an individual treatment strategy. Orthop. Case Rep. 2018, 8, 3–8.
84. Rico-Nieto, A.; Moreno-Ramos, F.; Fernández-Baillo, N. Lumbar arthrodesis infection by multi-resistant Klebsiella pneumoniae, successfully treated with implant retention and ceftazidime/avibactam. Española Cirugía Ortopédica Traumatol. (Engl. Ed.) 2018, 62, 471–473.
85. Vaidya, G.N.; Deam, A.G. Simultaneous suction debulking of lead vegetation prior to percutaneous lead extraction. Cardiol. Cases. 2018, 18, 17–19.
86. Sebastian, S.; Malhotra, R.; Pande, A.; Gautam, D.; Xess, I.; Dhawan, B. Staged reimplantation of a total hip prosthesis after co-infection with candida tropicalis and staphylococcus haemolyticus: A case report. Mycopathologia 2018, 183, 579–584.
87. Mahalingam, P.; Topiwalla, T.T.; Ganesan, G. Drug-resistant coagulase-negative staphylococcal endophthalmitis following dexamethasone intravitreal implant. Indian J. Ophthalmol. 2017, 65, 634–636.
88. Gharacholou, S.M.; Dworak, M.; Dababneh, A.S.; Palraj, R.V.; Roskos, M.C.; Chapman, S.C. Acute infection of viabahn stent graft in the popliteal artery. Vasc. Surg. Cases Innov. Tech. 2017, 3, 69–73.
89. Takizawa, T.; Tsutsumimoto, T.; Yui, M.; Misawa, H. Surgical site infections caused by methicillin-resistant staphylococcus epidermidis after spinal instrumentation surgery. Spine 2017, 42, 525–530.
90. Savage, V.J.; Chopra, I.; O’Neill, A.J. Staphylococcus aureus biofilms promote horizontal transfer of antibiotic resistance. Agents Chemother. 2013, 57, 1968–1970.

91. Naylor, N.R.; Atun, R.; Zhu, N.; Kulasabanathan, K.; Silva, S.; Chatterjee, A.; Knight, G.M.; Robotham, J.V. Estimating the burden of antimicrobial resistance: A systematic literature review. Resist. Infect. Control 2018, 7, 58.
92. Metsemakers, W.J.; Reul, M.; Nijs, S. The use of gentamicin-coated nails in complex open tibia fracture and revision cases: A retrospective analysis of a single centre case series and review of the literature. Injury 2015, 46, 2433–2437.
93. Zilberman, M.; Elsner, J.J. Antibiotic-eluting medical devices for various applications. Control Release 2008, 130, 202–215.
94. Freischmidt, H.; Armbruster, J.; Reiter, G.; Grützner, P.A.; Helbig, L.; Guehring, T. Individualized techniques of implant coating with an antibiotic-loaded, hydroxyapatite/calcium sulphate bone graft substitute. Clin. Risk Manag. 2020, 16, 689–694.
95. Campoccia, D.; Montanaro, L.; Speziale, P.; Arciola, C.R. Antibiotic-loaded biomaterials and the risks for the spread of antibiotic resistance following their prophylactic and therapeutic clinical use. Biomaterials 2010, 31, 6363–6377.
96. Cao, H.; Qin, H.; Li, Y.; Jandt, K.D. The action-networks of nanosilver: Bridging the gap between material and biology. Healthc. Mater. 2021, 26, e2100619.
97. Percival, S.L.; Bowler, P.G.; Russell, D. Bacterial resistance to silver in wound care. Hosp. Infect. 2005, 60, 1–7.
98. Panáček, A.; Kvítek, L.; Smékalová, M.; Večeřová, R.; Kolář, M.; Röderová, M.; Dyčka, F.; Šebela, M.; Prucek, R.; Tomanec, O.; et al. Bacterial resistance to silver nanoparticles and how to overcome it. Nanotechnol. 2018, 13, 65–71.
99. Nadeem, S.F.; Gohar, U.F.; Tahir, S.F.; Mukhtar, H.; Pornpukdeewattana, S.; Nukthamna, P.; Moula Ali, A.M.; Bavisetty, S.C.B.; Massa, S. Antimicrobial resistance: More than 70 years of war between humans and bacteria. Rev. Microbiol. 2020, 46, 578–599.
100. Ciofu, O.; Moser, C.; Jensen, P.Ø.; Høiby, N. Tolerance and resistance of microbial biofilms. Rev. Microbiol. 2022. https://doi.org/10.1038/s41579-022-00682-4.
101. Cao, H.; Dauben, T.J.; Helbing, C.; Jia, Z.; Zhang, Y.; Huang, M.; Müller, L.; Gu, S.; Zhang, X.; Qin, H.; et al. The antimicrobial effect of calcium-doped titanium is activated by fibrinogen adsorption. Horiz. 2022, 9,1962-1968.

Please Note: This entry is a part of a recent paper written by Huiliang Cao et al. J. Funct. Biomater. 2022, 13(3), 86; https://doi.org/10.3390/jfb13030086