Biomedical Implant-associated Infections

Biomedical implant-associated infections (BIAIs) are a relatively rare yet potentially life-threatening complication generally considered to be untreatable. BIAIs can occur postoperatively in patients who received a biomedical implant such as a vascular graft, pacemaker, stent, or artificial joint, and the consequences often include long-term antibiotic use with concomitant risk of developing antimicrobial resistance (AMR), the need for repeat surgery, increased healthcare costs and patient burden, and an increased risk of mortality.[1-7] More importantly, some types of biomedical implants such as prosthetic vascular grafts cannot be replaced without causing a serious risk of amputation, organ damage, or death; indeed, the mortality rate for some patients with an aortic BIAI is as high as 70-100%, a prognosis comparable to the most aggressive forms of cancer.

 

Strikingly, among healthcare-associated infections, which affect approximately 4% of all patients in acute care settings, BIAIs account for approximately 25% of all healthcare-associated bacterial infections,[8] with Staphylococcus aureus (S. aureus) as a common underlying cause.[1,9–14] The prevalence, clinical consequences, and associated costs of various BIAIs are summarised in Fig. 1.[1-3]

Figure 1.png

Bacterial Antimicrobial Resistance and Tolerance

Figure 2.png

Bacterial antimicrobial resistance (AMR) is one of the largest socio-economic and medical challenges currently facing humanity. In 2019, an estimated 1.27 million deaths were attributed directly to AMR, with an additional 4.95 million deaths attributed indirectly to AMR.[15] Moreover, the annual number of AMR-related deaths is expected to reach 10 million by 2050, with corresponding costs projected to total $100 trillion.[16]

 

In addition to AMR, bacteria can develop antibiotic tolerance, in which they slow their cellular activity and growth, enabling them to escape treatment with existing antibiotics, even at extremely high doses. These slow-growing “persister” bacteria occur primarily in infections associated with biomedical implants such as vascular implants, mechanical heart valves, and artificial joints.

 

In a biomedical implant-associated infection (BIAI), a biofilm composed of extracellular matrix and bacteria forms on the implant’s surface, protecting the cells from the host’s immune system (Fig. 2).[17] Although rapidly growing bacteria (but not persisters) can be cleared by antibiotics, after the antibiotic treatment stops, the persisters can resume their normal growth rate, re-establishing the infection and increasing the risk of AMR.

Current Treatment

The current treatment for a BIAI is long-term antibiotic therapy and/or explantation. Antibiotic therapy can require the use of highly potent antibiotics administered intravenously, which can have severe side effects and an increased risk of developing AMR. In the case of S. aureus, many clinical isolates are either methicillin-resistant or multiple-drug resistant, which limits the treatment options based on currently available antibiotics.

 

Explantation requires an additional surgical procedure as well as a prolonged course of postoperative antibiotics. In addition, the risk of re-infection following placement of an implant is many times larger than the original risk of infection. More importantly, some types of biomedical implants such as prosthetic vascular grafts cannot be replaced without causing a serious risk of amputation, organ damage, or death. Efforts to prevent the occurrence of a BIAI in the first place (for example, applying an antimicrobial coating to the implant) have not had any meaningful clinical impact on infection rates nor have they had commercial success.

 

Given these challenges, a paradigm shift is urgently needed in order to successfully treat BIAIs. Current antibiotics are generally ineffective at treating BIAIs because they only eliminate the active bacteria and fail to target the antibiotic-tolerant bacteria that reside in the biofilm. After antibiotic treatment, these persister cells can then resume their normal growth rate, re-establishing the infection. Currently the only solution is to place the patient on long-term antibiotic therapy, increasing the risk of AMR.  

 

Although antibiotic resistance can be managed ‒ at least in principle ‒ by switching to a different antibiotic, no currently available antibiotics are able to target persister cells. Therefore, a novel treatment that targets both actively growing and dormant, persister cells is urgently needed.

Our Solution

At Pincer Biotech, the ultimate goal is to develop a new class of therapeutic compounds that address the critical issue of targeting the antibiotic-tolerant persister cells residing in the biofilm, thus overcoming the limitation that plagues all known antibiotics.

 

A major shortcoming of all existing antibiotics is that they only eliminate actively growing bacteria but have virtually no effect on slow-growing bacteria. We therefore develop molecules that: 1) penetrate the biofilm to reach the bacteria, 2) target and kill antibiotic-tolerant persisters, and 3) overcome the antibiotic resistance of methicillin-resistant S. aureus (MRSA). These molecules will act rapidly during a brief treatment period in order to minimise the risk of the bacteria becoming antibiotic-resistant.

 

The research is conducted in collaboration with leading experts in infection medicine, molecular biology and organic chemistry at Aarhus University and other top class universities in Europe and the US.

Literature References

[1] Smeds MR, Duncan AA, Harlander-Locke MP, Lawrence PF, Lyden S, Fatima J, et al. Treatment and outcomes of aortic endograft infection. Journal of Vascular Surgery 2016;63:332–40. https://doi.org/10.1016/J.JVS.2015.08.113.

[2] Darouiche RO. Treatment of infections associated with surgical implants. New England Journal of Medicine 2004;350:1422–9. https://doi.org/10.1056/NEJMRA035415.

[3] Lalani T, Chu VH, Park LP, Cecchi E, Corey GR, Durante-Mangoni E, et al. In-hospital and 1-year mortality in patients undergoing early surgery for prosthetic valve endocarditis. JAMA Internal Medicine 2013;173:1495–504.

https://doi.org/10.1001/JAMAINTERNMED.2013.8203.

[4] Duwayri Y, Goss J, Knechtle W, Veeraswamy RK, Arya S, Rajani RR, et al. The readmission event after vascular surgery: causes and costs. Annals of Vascular Surgery 2016;36:7–12. https://doi.org/10.1016/J.AVSG.2016.02.024.

[5] Shiraev T, Barrett S, Heywood S, Mirza W, Hunter-Dickson M, Bradshaw C, et al. Incidence, management, and outcomes of aortic graft infection. Annals of Vascular Surgery 2019;59:73–83. https://doi.org/10.1016/J.AVSG.2019.01.027.

[6] Haddad FS, Ngu A, Negus JJ. Prosthetic joint infections and cost analysis?Advances in Experimental Medicine and Biology 2017;971:93–100.

https://doi.org/10.1007/5584_2016_155.

[7] Pabinger C, Lothaller H, Geissler A. Utilization rates of knee-arthroplasty in OECD countries. Osteoarthritis and Cartilage 2015;23:1664–73.

https://doi.org/10.1016/J.JOCA.2015.05.008.

[8] Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Multistate point-prevalence survey of health care–associated infections. New England Journal of Medicine 2014;370:1198–208.

https://doi.org/10.1056/NEJMOA1306801/SUPPL_FILE/NEJMOA1306801_DISCL OSURES.PDF.

[9] Arciola CR, Campoccia D, Montanaro L. Implant infections: adhesion, biofilm formation and immune evasion. Nature Reviews Microbiology 2018;

16:397–409. https://doi.org/10.1038/S41579-018-0019-Y.

[10] Khairy TF, Lupien M-A, Nava S, Baez FV, Ovalle FS, Ochoa NEL, et al. Infections associated with resterilized pacemakers and defibrillators. New England Journal of Medicine 2020;382:1823–31. https://doi.org/10.1056/NEJMOA1813876.

[11] Zhang JL, Zou H, Wang HW, Cai CL, Ma HM, Zhang N, et al. Incidence, bacterial spectrum and predictive risk factors for stent associated respiratory tract infection. Chinese Journal of Tuberculosis and Respiratory Diseases 2016;

39:368–71. https://doi.org/10.3760/CMA.J.ISSN.1001-0939.2016.05.007.

[12] Dhanoa A, Ajit Singh V, Elbahri H. Deep infections after endoprosthetic replacement operations in orthopedic oncology patients. Surgical Infections 2015; 16:323–32. https://doi.org/10.1089/SUR.2014.049.

[13] Costerton JW, Montanaro L, Arciola CR. Biofilm in implant infections: its production and regulation. International Journal of Artificial Organs 2005;

28:1062–8. https://doi.org/10.1177/039139880502801103.

[14] Li HL, Chan YC, Cheng SW. Current evidence on management of aortic stent-graft infection: a systematic review and meta-analysis. Annals of Vascular Surgery 2018;51:306–13. https://doi.org/10.1016/J.AVSG.2018.02.038.

[15] Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022;399:629–55.

https://doi.org/10.1016/S0140-6736(21)02724-0/ATTACHMENT/B227DEB3-FF04-497F-82AC-637D8AB7F679/MMC1.PDF.

[16] Review on Antimicrobial Resistance. Tackling drug-resistant infection globally: final report and recommendations. The Review on Antimicrobial Resistance chaired by Jim O’Neill. London: 2016.

https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf

[17] Gristina AG, Costerton JW. Bacterial adherence to biomaterials and tissue. The significance of its role in clinical sepsis. Journal of Bone and Joint Surgery 1985;67:264–73. https://doi.org/10.2106/00004623-198567020-00014.