Infection a major clinical challenge

Infection is the invasion of body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agent (e.g. bacteria, viruses, fungi, or parasites).
An infection is commonly caused by bacteria entering the body after injury or during or after surgical intervention and it can manifest in hard tissue (bone), soft tissues (skin, muscle), or as a biofilm-layer on an implant surface (hip, pacemaker, stent).
The discovery of penicillin by Alexander Flemming in 1928 marked the advent of the age of antibiotics, an era where previously deadly bacterial infectious diseases could be cured in days. These antibiotics revolutionized medicine in the second half of the 20th century. 
Over time, the success of antibiotics may be completely cancelled out by their combative counterparts: bacteria that are resistant to the majority of antibiotics commonly used in clinical practice (AMR). This will result in a less optimal treatment outcome, a large amount of deaths, and a tremendous increase in healthcare costs.
The current incidence of bacterial-related surgical infections in hard tissues ranges from 1% (hip replacement) up to 55% (open fractures) 1-2. Incidence of bacterial infections in soft tissue ranges such as skin, fat or muscle ranges between 12-29% 3.

Regardless of the nature of the infection and the infected tissue, infection in hard- or soft tissue is always treated with systemic and local antibiotics. Current antibiotic therapies aim to elevate local antibiotic load as high as possible without causing toxicity for host cells. Concentrations of probably 100 times the Minimal Inhibitory Concentration (MIC; the dose needed to kill the bacteria) in the first 1-2 days are desirable 4-6.
When the antibiotic dose becomes too low, bacteria can develop resistance to the antibiotic and are no longer susceptible to it. When bacteria become resistance to antibiotics it greatly complicates and lengthens the treatment, dramatically increasing the incidence of further complications or even, ultimately, death.

AMR: the problem worsens even further

With frequent use, microorganisms acquire antibiotic resistance. This is due to chromosomal DNA mutations and horizontal transfer of genetic material leading to a change in bacterial proteins 7.
AMR is a rapidly increasing problem with devastating consequences on quality of life worldwide. It is associated with unfavourable clinical outcomes often result in amputation or death and associated with high healthcare costs.
The threat of AMR is substantiated in a multitude of World Health Organization (WHO) and government reports 8-12. It is estimated that already now, 1.5 million people die every year as a result of AMR. A recent published paper report determined that within the USA alone in 2010 at least 153.000 people died and 2.1 million people sustained illness due to AMR. Predictive models described in a recent WHO report estimate that in 2050 10 million people worldwide (USA 700.000) will die every year due to AMR. At that time, AMR will have surpassed cancer, cardiovascular disease, and diabetes combined as the leading cause of death 13-14.
AMR will also lead to increased infection rates and worsened treatment results in most surgical interventions and cancer treatments, and potentially other diseases as well 13-14. To avoid the situation that in the near future mortality due to infection will reach unacceptable rates, we urgently need to develop new antimicrobial/bactericidal technologies that do not employ antibiotics, and in addition develop technologies that enhance the therapeutic efficacy of current antibiotics.

Challenge of the biofilm on implant surfaces

Biofilm formation on an implant surface adds to the complexity of infection treatment. A biofilm is a complex structure comprised of microorganisms entangled in macromolecules of glycocalyx and extracellular DNA and it interferes with the ability of antibiotics to penetrate the biofilm and reach individual bacteria.
In contrast to a defined infection in hard tissue or soft tissue, the treatment of choice in acute postoperative Prosthetic Joint Infection (PJI) or implant infection has been a combination of irrigation and surgical debridement to diminish local bacterial load with exchange of implant components in combination with local and systemic antibiotic therapy 4-5.
Moreover, in a biofilm, bacteria are often in a dormant state and therefore not or less susceptible to most antibiotics, resulting in inadequate antibiotic treatment 7-8

Literature references

1. Hogan A et al. Osteomyelitis. Archives of Orthopaedic and Trauma Surgery, 2013 vol. 133, no. 9: 1183–1196.

2. Trampuz A. and Widmer AF. Infections associated with orthopedic implants. Current Opinion in Infectious Diseases, 2006 vol. 19, no. 4, pp. 349–356.

3. Esposito S, Noviello S, Leone S. Epidemiology and microbiology of skin and soft tissue infections. Curr Opin Infect Dis. 2016 Apr;29(2):109-15.

4. Parsons P. and Strauss E. Surgical management of chronic osteomyelitis. The American Journal of Surgery, 2004, vol. 188, no. 1, supplement 1, pp. 57–66.

5. Geurts J et al. Bone graft substitutes in active or suspected infection. Contraindicated or not?. Injury, 2011, vol. 42, supplement 2, pp. S82–S86.

6. Walenkamp GH et al. Gentamicin-PMMA beads. Pharmacokinetic and nephrotoxicological study Clinical Orthopaedics and Related Research, 1986, vol. 205, pp. 171–183.

7. Zhivich A. Fighting antimicrobial resistance: approaches, challenges, and opportunities in the search for new antibiotics. Mir journal 2017 Vol 4 (1):31-51.

8. Report: The evolving threat of antimicrobial resistance. Options for action. World Health Organization 2012. ISBN 978 92 4 150318 1.

9. Burnham JP, Olsen MA, Kollef MH. Re-estimating annual deaths due to multidrug-resistant organism infections. Infect Control Hosp Epidemiol. 2019 Jan;40(1):112-113.

10. Report: Annual epidemiological report antimicrobial resistance and healthcare-associated infections 2014. EARS-net. www.ecdc.europa.eu

11. Report: CDC. Antibiotic Use in the United States, 2017: Progress and Opportunities. Atlanta, GA: US Department of Health and Human Services, CDC; 2017.

12. O'Neill J. Review on Antimicrobial Resistance Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. London: Review on Antimicrobial Resistance; 2014.

13. Teillant A et al. Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: A literature review and modeling study. Lancet Infect Dis 2015. 15(12): 1429-37

14. Report: Global action plan on antimicrobial resistance. World Health Organization 2015 ISBN 978 92 4 150976 3.

The DARTBAC project will prepare the Netherlands for the time when antibiotics are much less effective in the prevention and eradication of infection due to AntiMicrobial Resistance (AMR)
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