Cite this article: Bone Joint Res 2020;9(12):870–872.
The use of prophylactic systemic antibiotics in the perioperative period has been shown to reduce postoperative infections following arthroplasty procedures,1,2 tumour surgery,3 and trauma procedures.4 In open fractures, the administration of systemic broad-spectrum antibiotics has been shown to be a more important factor in minimizing the risk of infection than timing of surgical debridement.5,6 Local antibiotic prophylaxis using bone cement has been shown to reduce the risk of deep postoperative infection following arthroplasty surgery significantly.7-9 More recently a systematic review and meta-analysis found that local antibiotic prophylaxis resulted in a four-fold relative risk reduction in fracture-related infection following open limb injury.10 The World Health Organization (WHO) recommends preoperative screening and eradication in orthopaedic surgery of not only methicillin-resistant Staphylococcus aureus (MRSA) but methicillin-sensitive S. aureus (MSSA).11 Evaluation of these strategies has shown them to be both effective12-15 and acceptable to patients.16 An economic analysis estimated that national S. aureus screening programmes could potentially save up to $900 million in total treatment costs annually in the USA and UK.17
Even with therapeutic antibiotic use there has been an evolution in practice. The administration of combination therapies (local and systemic routes) has become more popular, despite the paucity of published evidence. Combination therapies are thought to work by: 1) broadening the spectrum of activity; 2) utilizing synergistic effects; 3) preventing resistance mechanisms from evolving; 4) enhancing intracellular penetration; and 5) limiting the expression of bacterial toxins and other virulence factors.18 Meta-analyses of clinical trials evaluating antibiotic combinations in periprosthetic joint infection (PJI) have reported that the available literature is currently too heterogeneous to draw any clinically useful conclusions regarding optimal regimens.19,20 Yang et al21 have compared the effectiveness of a gentamicin and vancomycin (GV)-loaded articulating spacer in two-stage revision with a vancomycin, meropenem, and amphotericin (VMA)-loaded cement spacer. It was postulated that a high percentage of gentamicin resistance within cultured isolates (22/78) was the reason the VMA combination was found to be more effective at eradicating PJI (11/62 vs 1/52). However, it should be noted that from the preoperative and intraoperative samples 20/62 and 9/52 cases were culture-negative in the full GV and in full VMA protocols, respectively, despite fulfilling the Musculoskeletal Infection Society (MSIS) criteria for PJI.22 One explanation for these culture-negative samples could be the presence of viable but non-culturable pathogens. This is a cellular state characterized by low metabolic activity and failure to grow on routine bacteriological media.23 Known inducers of the viable but non-culturable state include: starvation; non-physiological ambient temperature; osmotic stress; hypoxia; heavy metals; and antimicrobial and disinfectant challenges.24-27 A critical feature is that nutritional stimulation, known as resuscitation in this field of microbiology, can restore metabolic activity and culturability.25,28 It has been hypothesized that in vivo resuscitation of quiescent cells may be responsible for recalcitrant biomaterial infections.29 The biofilm phenotype, as often displayed by common biomaterial pathogens, is physiologically akin to the viable but non-culturable state, therefore inadequate resuscitation during laboratory culture may result in false negative results.30 The phenomenon of viable but non-culturable states should therefore be taken into account when considering whether infection has been eradicated.
The looming global crisis of antimicrobial resistance31,32 threatens to halt elective biomaterial-associated procedures.33,34 Careful antimicrobial stewardship is essential to decelerate the emergence of resistance to currently available drugs, and thus preserve their efficacy. One approach is to explore alternative bactericidal agents for the treatment of biomaterial-associated infections.35-41 A further approach is to implement antimicrobial stewardship interventions. Evaluations of these interventions have demonstrated their efficacy in reducing rates of both infection and colonization with antimicrobial-resistant bacteria.42-44 The prevalence of carbapenem (e.g. meropenem)45,46 and glycopeptides (e.g. vancomycin)47,48 resistance is increasing globally and their use should be restricted, unless absolutely necessary, to maintain their efficacy. The WHO recognizes carbapenems and glycopeptides as ‘critically important’ antimicrobials.49 Carbapenem and glycopeptide sparing, when clinically and microbiologically appropriate, is therefore a key goal of antimicrobial stewardship programmes. The injudicious use of critically important antimicrobials should be questioned.50 Their incorporation into local treatment protocols should only be implemented following a review of the institution’s bacterial epidemiology and justified by local resistance profiles as carried out by Yang et al.21
References
1. AlBuhairan B , Hind D , Hutchinson A . Antibiotic prophylaxis for wound infections in total joint arthroplasty . J Bone Joint Surg Br . 2008 ; 90-B ( 7 ): 915 – 919 . Crossref PubMed Google Scholar
2. Lidwell OM , Lowbury EJ , Whyte W , Blowers R , Stanley SJ , Lowe D . Infection and sepsis after operations for total hip or knee-joint replacement: influence of ultraclean air, prophylactic antibiotics and other factors . J Hyg . 1984 ; 93 ( 3 ): 505 – 529 . Crossref PubMed Google Scholar
3. PARITY Investigators . Prophylactic antibiotic regimens in tumour surgery (parity): a pilot multicentre randomised controlled trial . Bone Joint Res . 2015 ; 4 ( 9 ): 154 – 162 . Crossref PubMed Google Scholar
4. 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 ( 9009 ): 1133 – 1137 . Crossref PubMed Google Scholar
5. Patzakis MJ , Wilkins J . Factors influencing infection rate in open fracture wounds . Clin Orthop Relat Res . 1989 ( 243 ): 36 – 40 . PubMed Google Scholar
6. Lack WD , Karunakar MA , Angerame MR , et al. Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection . J Orthop Trauma . 2015 ; 29 ( 1 ): 1 – 6 . Crossref PubMed Google Scholar
7. Espehaug B , Engesaeter LB , Vollset SE , Havelin LI , Langeland N , Surgeon O . Antibiotic prophylaxis in total hip arthroplasty. review of 10,905 primary cemented total hip replacements reported to the Norwegian arthroplasty register, 1987 to 1995 . J Bone Joint Surg Br . 1997 ; 79-B ( 4 ): 590 – 595 . Crossref PubMed Google Scholar
8. Thierse L . [Experiences with Refobacin-Palacos with regard to deep late infections following hip-joint endoprosthesis surgery. A 4-years’ study (author’s transl)] . Z Orthop Ihre Grenzgeb . 1978 ; 116 ( 6 ): 847 – 852 . (Article in German) Google Scholar
9. Chiu F-Y , Chen C-M , Lin C-FJ , Lo W-H . Cefuroxime-impregnated cement in primary total knee arthroplasty: a prospective, randomized study of three hundred and forty knees . J Bone Joint Surg Am . 2002 ; 84-A ( 5 ): 759 – 762 . PubMed Google Scholar
10. Morgenstern M , Vallejo A , McNally MA , et al. The effect of local antibiotic prophylaxis when treating open limb fractures . Bone Joint Res . 2018 ; 7 : 447 – 456 . Crossref PubMed Google Scholar
11. Allegranzi B , Bischoff P , de Jonge S , et al. New who recommendations on preoperative measures for surgical site infection prevention: an evidence-based global perspective . Lancet Infect Dis . 2016 ; 16 ( 12 ): e276 – e287 . Crossref PubMed Google Scholar
12. Ammerlaan HSM , Kluytmans JAJW , Wertheim HFL , Nouwen JL , Bonten MJM . Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review . Clin Infect Dis . 2009 ; 48 ( 7 ): 922 – 930 . Crossref PubMed Google Scholar
13. Bode LGM , Kluytmans JAJW , Wertheim HFL , et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus . N Engl J Med . 2010 ; 362 ( 1 ): 9 – 17 . Crossref PubMed Google Scholar
14. Dancer SJ , Christison F , Eslami A , et al. Is it worth screening elective orthopaedic patients for carriage of Staphylococcus aureus? A part-retrospective case-control study in a Scottish Hospital . BMJ Open . 2016 ; 6 ( 9 ): e011642 . Crossref PubMed Google Scholar
15. Jeans E , Holleyman R , Tate D , Reed M , Malviya A . Methicillin sensitive Staphylococcus aureus screening and decolonisation in elective hip and knee arthroplasty . J Infect . 2018 ; 77 ( 5 ): 405 – 409 . Crossref PubMed Google Scholar
16. Tsang STJ , McHugh MP , Guerendiain D , et al. Evaluation of Staphylococcus aureus eradication therapy in orthopaedic surgery . J Med Microbiol . 2018 ; 67 ( 6 ): 893 – 901 . Crossref PubMed Google Scholar
17. Tsang STJ , McHugh MP , Guerendiain D , et al. Underestimation of Staphylococcus aureus (MRSA and MSSA) carriage associated with standard culturing techniques: one third of carriers missed . Bone Joint Res . 2018 ; 7 ( 1 ): 79 – 84 . Crossref PubMed Google Scholar
18. Dall GF , Tsang S-TJ , Gwynne PJ , et al. Unexpected synergistic and antagonistic antibiotic activity against Staphylococcus biofilms . J Antimicrob Chemother . 2018 ; 73 ( 7 ): 1830 – 1840 . Crossref PubMed Google Scholar
19. Stengel D , Bauwens K , Sehouli J , Ekkernkamp A , Porzsolt F . Systematic review and meta-analysis of antibiotic therapy for bone and joint infections . Lancet Infect Dis . 2001 ; 1 ( 3 ): 175 – 188 . Crossref PubMed Google Scholar
20. Iarikov D , Demian H , Rubin D , Alexander J , Nambiar S . Choice and doses of antibacterial agents for cement spacers in treatment of prosthetic joint infections: review of published studies . Clinical Infectious Diseases . 2012 ; 55 ( 11 ): 1474 – 1480 . Crossref PubMed Google Scholar
21. Yang C , Wang J , Yin Z , et al. A sophisticated antibiotic-loading protocol in articulating cement spacers for the treatment of prosthetic joint infection: a retrospective cohort study . Bone Joint Res . 2019 ; 8 ( 11 ): 526 – 534 . Crossref PubMed Google Scholar
22. Parvizi J , Zmistowski B , Berbari EF , et al. New definition for periprosthetic joint infection: from the Workgroup of the musculoskeletal infection Society . Clin Orthop Relat Res . 2011 ; 469 ( 11 ): 2992 – 2994 . Crossref PubMed Google Scholar
23. Oliver JD . The public health significance of viable but nonculturable bacteria . Nonculturable Microorganisms in the Environment . 2020 : 277 – 300 . Google Scholar
24. Oliver JD . Recent findings on the viable but nonculturable state in pathogenic bacteria . FEMS Microbiol Rev . 2010 ; 34 ( 4 ): 415 – 425 . Crossref PubMed Google Scholar
25. Kana BD , Gordhan BG , Downing KJ , et al. The resuscitation-promoting factors of Mycobacterium tuberculosis are required for virulence and resuscitation from dormancy but are collectively dispensable for growth in vitro . Mol Microbiol . 2008 ; 67 ( 3 ): 672 – 684 . Crossref PubMed Google Scholar
26. Trevors JT . Viable but non-culturable (VBNC) bacteria: gene expression in planktonic and biofilm cells . J Microbiol Methods . 2011 ; 86 ( 2 ): 266 – 273 . Crossref PubMed Google Scholar
27. Pasquaroli S , Zandri G , Vignaroli C , Vuotto C , Donelli G , Biavasco F . Antibiotic pressure can induce the viable but non-culturable state in Staphylococcus aureus growing in biofilms . J Antimicrob Chemother . 2013 ; 68 ( 8 ): 1812 – 1817 . Crossref PubMed Google Scholar
28. Dworkin J , Shah IM . Exit from dormancy in microbial organisms . Nat Rev Microbiol . 2010 ; 8 ( 12 ): 890 – 896 . Crossref PubMed Google Scholar
29. Zandri G , Pasquaroli S , Vignaroli C , et al. Detection of viable but non-culturable staphylococci in biofilms from central venous catheters negative on standard microbiological assays . Clin Microbiol Infect . 2012 ; 18 ( 7 ): E259 – E261 . Crossref PubMed Google Scholar
30. Tsang S-TJ , Eyre DW , Simpson AHRW , Simpson AHRW . Should modern molecular testing be routinely available for the diagnosis of musculoskeletal infection? Bone Joint J . 2020 ; 102-B ( 10 ): 1274 – 1276 . Crossref PubMed Google Scholar
31. World Health Organization . Surveillance of antimicrobial resistance for local and global action . 2014 . http://www.who.int/drugresistance/events/SwedenMeeting/en/. (date last accessed 1 December 2014 ). Google Scholar
32. Li B , Webster TJ . Bacteria antibiotic resistance: new challenges and opportunities for implant-associated orthopedic infections . J Orthop Res . 2018 ; 36 ( 1 ): 22 – 32 . Crossref PubMed Google Scholar
33. O’Neill J . Antimicrobial resistance: tackling a crisis for the health and wealth of nations . 2014 . https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf (date last accessed 7 December 2020 ). Google Scholar
34. Davies S . Antimicrobial resistance poses ‘catastrophic threat’, says Chief Medical Officer - GOV.UK. Department of Health and Social Care . 2013 . https://www.gov.uk/government/news/antimicrobial-resistance-poses-catastrophic-threat-says-chief-medical-officer--2. (date last accessed 11 March 2019 ). Google Scholar
35. Deng Z , Liu F , Li C . Therapeutic effect of ethylenediaminetetraacetic acid irrigation solution against wound infection with drug-resistant bacteria in a rat model: an animal study . Bone Joint Res . 2019 ; 8 ( 5 ): 189 – 198 . Crossref PubMed Google Scholar
36. Tsang STJ , Gwynne PJ , Gallagher MP , Simpson AHRW . The biofilm eradication activity of acetic acid in the management of periprosthetic joint infection . Bone Joint Res . 2018 ; 7 ( 8 517 – 523 . Crossref PubMed Google Scholar
37. Pijls BG , Sanders IMJG , Kuijper EJ , Nelissen RGHH . Segmental induction heating of orthopaedic metal implants . Bone Joint Res . 2018 ; 7 ( 11 ): 609 – 619 . Crossref PubMed Google Scholar
38. Pijls BG , Sanders IMJG , Kuijper EJ , Nelissen RGHH . Non-contact electromagnetic induction heating for eradicating bacteria and yeasts on biomaterials and possible relevance to orthopaedic implant infections . Bone Joint Res . 2017 ; 6 ( 5 ): 323 – 330 . Crossref PubMed Google Scholar
39. Hernandez P , Sager B , Fa A , Liang T , Lozano C , Khazzam M . Bactericidal efficacy of hydrogen peroxide on Cutibacterium acnes . Bone Joint Res . 2019 ; 8 ( 1 ): 3 – 10 . Crossref PubMed Google Scholar
40. Alt V , Rupp M , Lemberger K , et al. Safety assessment of microsilver-loaded poly(methyl methacrylate) (PMMA) cement spacers in patients with prosthetic hip infections: Results of a prospective cohort study . Bone Joint Res . 2019 ; 8 : 387 – 396 . Crossref PubMed Google Scholar
41. Tsang S-TJ , Morgan-Jones R , Simpson AHRW . Debridement for prosthetic joint infections: future therapies . Bone Joint Res . 2020 ; 9 ( 6 ): 311 – 313 . Crossref PubMed Google Scholar
42. Davey P , Marwick CA , Scott CL , et al. Interventions to improve antibiotic prescribing practices for hospital inpatients . Cochrane Database Syst Rev . 2017 ; 2 ( 5 ): CD003543 . Crossref PubMed Google Scholar
43. Baur D , Gladstone BP , Burkert F , et al. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis . Lancet Infect Dis . 2017 ; 17 ( 9 ): 990 – 1001 . Crossref PubMed Google Scholar
44. Russell CD , Laurenson IF , Evans MH , Mackintosh CL . Tractable targets for meropenem-sparing antimicrobial stewardship interventions . JAC Antimicrob Resist . 2019 ; 1 ( 2 ). Crossref PubMed Google Scholar
45. Livorsi DJ , Chorazy ML , Schweizer ML , et al. A systematic review of the epidemiology of carbapenem-resistant Enterobacteriaceae in the United States . Antimicrob Resist Infect Control . 2018 ; 7 ( 1 ): 55 . Crossref PubMed Google Scholar
46. van Duin D , Doi Y . The global epidemiology of carbapenemase-producing Enterobacteriaceae . Virulence . 2017 ; 8 ( 4 ): 460 – 469 . Crossref PubMed Google Scholar
47. Ruef C . Epidemiology and clinical impact of glycopeptide resistance in Staphylococcus aureus . Infection . 2004 ; 32 ( 6 ): 315 – 327 . Crossref PubMed Google Scholar
48. Faron ML , Ledeboer NA , Buchan BW . Resistance mechanisms, epidemiology, and approaches to screening for vancomycin-resistant Enterococcus in the health care setting . J Clin Microbiol . 2016 ; 54 ( 10 ): 2436 – 2447 . Crossref PubMed Google Scholar
49. World Health Organization . Critically important antimicrobials for human medicine, 6th revision : WHO , 2019 . Google Scholar
50. Stravinskas M , Nilsson M , Vitkauskiene A , Tarasevicius S , Lidgren L . Vancomycin elution from a biphasic ceramic bone substitute . Bone Joint Res . 2019 ; 8 ( 2 ): 49 – 54 . Crossref PubMed Google Scholar
Author contributions
S-T. J. Tsang: Conceptualized, co-authored, and edited the manuscript.
A. H. R. W Simpson: Conceptualized, co-authored, and edited the manuscript.
S-T. J. Tsang and A. H. R. W. Simpson are joint first authors.
Funding statement
There were no funding sources involved in the creation of this editorial. 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.
ICMJE COI statement
The authors declare that there are no conflicts of interest.
Ethical review statement
Research Ethics Committee approval was not required for this editorial.
Follow Shao-Ting Jerry Tsang @drjerrytsang
Follow A. H. R. W. Simpson @ahrwsimpson
© 2020 Author(s) et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/.
