Systemic Percutaneous Irrigation and Delivery Experimental Resource (SPIDER)

Septic Arthritis & Wound Healing

Brief Summary

In the United States, the yearly cost of antibiotic resistance exceeds $20 billion. Of particular concern is septic arthritis of both native and replaced joints. Each year, over 13 000 patients are diagnosed with septic arthritis, at a cost of more than $750 million. Current evidence is limited as to the best therapy; however, minimally invasive arthroscopic approach with irrigation is effective if caught early. Further, the adjunct of light therapies could accelerate healing and reduce infectious burden. Such a device is had in the SPIDER, a mobile irrigation and light delivery system with the potential to improve recovery and function of infected joints and tissue.

Detailed Summary

Septic arthritis (SA) is a costly problems and the best treatment is uncertain. Greater than 13 000 cases a year of SA are diagnosis in the USA, amounting to a cost of > $750 million (Singh 2017). Complicating this often are resistant organisms. The CDC estimates nearly 2 million patients in the USA are affected by antibiotic resistant organisms; with excess health costs and lost productivity annually ranging $20-35 billion (CDC 2013, Hampton 2013). 25% of SA patients are discharged to a skilled nursing facility or with home health aides, after a week or more in the hospital. Of treated SA cases, nearly 12% fail initial therapy (Wirtz 2001). 1% of all arthroscopic procedures, most commonly with cruciate ligament reconstruction, develop SA (Bauer 2015). In patients undergoing total joint arthroplasty (TJA), with a history of prior SA in the same joint, the risk of SA is 8% within 2 years (Sultan 2019). Finally, complications are common. In the case of native knee SA, 90 day mortality is 7.05% increasing to 22.69% in patients > 79 years old (Abram 2020). 8.76% of survivors will require a TJA within 15 years, 6x the general population.

A paucity of high quality evidence exists to base management decisions from (Mathews 2007). The initial diagnosis is often a challenge as early symptoms may mimic an uncomplicated arthroscopy (Bauer 2015). Although diagnosis depends on analysis of synovial fluid and culture, and initial antibiotic choices on patient demographics and local biogram, duration of therapy and mechanism of delivery remain uncertain. Early, aggressive care is critical for successful management of SA (Esterhai 1991, Stutz 2000, Vispo 2002, Lungershausen 1998). Initial treatment often involves lavage, synovectomy, and > 6 weeks of antibiotics, with response in 85% of cases (Bauer 2015). However, even with early and appropriate intervention, suboptimal results still occur in nearly 1/7^th of cases (Lungershausen 1998, Stutz 2000, Bynum 1982). Further, cartilage dystrophy as a result of prolonged joint immobility necessitate continuous passive motion of the post-operative/ post procedure joint often complicated by pain from larger procedures ( Salter 1981, Stutz 2000, Draijer 1994, Wirtz 2001, Thiery 1989).

A recent comparison of the 30-day complications and adverse outcomes between arthroscopic irrigation or debridement of SA of the knee vs. arthrotomy with open irrigation and debridement demonstrated a 9.8% absolute risk reduction of bleeding necessitating transfusion, 12.5% absolute increased likelihood to discharge to home, and 15% absolute harm reduction, all favoring arthroscopy (Faour 2019). Similar findings are noted with SA of the native shoulder (Khazi 2020). However, the development of biofilms, polymicrobial communities of often resistant organisms causing persistent infection, remain a concern (Sousa 2018). Total joint arthroscopic irrigation with the distension-irrigation technique can reduce these (Ateschrang 2011, Jackson 1985, Jackson 1973, Riel 1994, Sousa 2018).

As stated, early intervention with antibiotics and irrigation may be insufficient. A novel intervention is photodynamic therapy (PDT). PDT uses light to influence tissue function influencings a desired outcome, depending on the wavelength. Near infrared light between 630-1000nm at 4J/cm2 promotes accelerated wound healing, resistance to ischemia, and improved mitochondria function via a process known as photobiomodulation (PBM) (Desmet 2006). Antimicrobial blue light (ABL), 405-470 nm delivered at a variety of energy densities excites endogenous photosensitive chromophores in microbes, resulting in reactive oxygen species that promote infectious organism death without damage to human tissue (Dai 2012, Ahmed 2018, Ramakrishnan 2014, McDonald 2013, Kleinpenning 2010).

ABL has demonstrated efficacy against gram positive and negative bacteria, mycobacterium, mold, yeast, dermatophytes, and some viruses (Wang 2017). Animal studies have demonstrated wounds inoculated with bacteria, treated at 460nm, and a density of 120J/cm2 resulted in significantly reduced infectious burden, accelerated wound healing, and 100% survival of the animal group compared to 50% of untreated controls (Yang 2017). Other work as found similar findings (Zhu 2017). Human cell cultures inoculated with bacteria and treated with 405nm ABL at < 216J/cm2 demonstrated reduced bacterial load without loss of human keratinocytes (Ferrer-Espada 2019). Further, infectious biologic fluids treated at 405nm at 144 J/cm2 had a 99.9% reduction in bacterial load (Maclean 2016). Clinical work in dental plaques has demonstrated 25-56% reduction in bacterial load at 455nm at a density of 8.4J/cm2 (Soukos 2015).

Mobility to mitigate cartilage dystrophy, a platform to minimize iatrogenic tissue injury, use of PDT, and ability to remove infectious tissue and flush with antibiotics is all offered with the patented SPIDER. A number of its functions have been demonstrated effective and safe at the pre-clinical and clinical level. Beyond SA, applications could include soft-tissue and boney abscesses treatment, ventriculitis, and peritonitis.

Focus

This device has the potential for a number of intervention avenues. In this introductory stage, focus on immediate applications are most prudent. Currently a working prototype exists. Production of an ISO certified product capable to animal testing then clinical applications with early focus on use in SA of the knee is this group’s goal. With approval, progress can then be made expanding the application of this platform to other sites of infection, and use in restorative medicine.

References

Zhu H, Kochevar IE, Behlau I, Zhao J, Wang F, Wang Y, Sun X, Hamblin MR, Dai T. Antimicrobial Blue Light Therapy for Infectious Keratitis: Ex Vivo and In Vivo Studies. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):586-593. doi: 10.1167/iovs.16-20272. PubMed [citation] PMID: 28129422, PMCID: PMC5283079

Yang P, Wang N, Wang C, Yao Y, Fu X, Yu W, Cai R, Yao M. 460nm visible light irradiation eradicates MRSA via inducing prophage activation. J PhotochemPhotobiol B. 2017 Jan;166:311-322. doi: 10.1016/j.jphotobiol.2016.12.001. Epub 2016 Dec 18. PubMed [citation] PMID: 28024282

Wirtz DC, Marth M, Miltner O, Schneider U, Zilkens KW. Septic arthritis of the knee in adults: treatment by arthroscopy or arthrotomy. Int Orthop. 2001;25(4):239-41. PubMed [citation] PMID: 11561499, PMCID: PMC3620826

Wang Y, Wang Y, Wang Y, Murray CK, Hamblin MR, Hooper DC, Dai T. Antimicrobial blue light inactivation of pathogenic microbes: State of the art. Drug Resist Updat. 2017 Nov;33-35:1-22. doi: 10.1016/j.drup.2017.10.002. Epub 2017 Oct 13. Review. PubMed [citation] PMID: 29145971, PMCID: PMC5699711

Vispo Seara JL, Barthel T, Schmitz H, Eulert J. Arthroscopic treatment of septic joints: prognostic factors. Arch Orthop Trauma Surg. 2002 May;122(4):204-11. Epub 2002 Apr 6. PubMed [citation] PMID: 12029509

Sultan AA, Mahmood B, Samuel LT, George J, Faour M, Pelt CE, Anderson MB, Klika AK, Higuera CA. Patients with a History of Treated Septic Arthritis are at High Risk of Periprosthetic Joint Infection after Total Joint Arthroplasty. Clin Orthop Relat Res. 2019 Jul;477(7):1605-1612. doi: 10.1097/CORR.0000000000000688. PubMed [citation] PMID: 30913112, PMCID: PMC6999997

Stutz G, Kuster MS, Kleinstück F, Gächter A. Arthroscopic management of septic arthritis: stages of infection and results. Knee Surg Sports Traumatol Arthrosc. 2000;8(5):270-4. PubMed [citation] PMID: 11061294

Sousa R, Abreu MA. Treatment of Prosthetic Joint Infection with Debridement, Antibiotics and Irrigation with Implant Retention – a Narrative Review. J Bone Jt Infect. 2018 Jun 8;3(3):108-117. doi: 10.7150/jbji.24285. eCollection 2018. Review. PubMed [citation] PMID: 30013891, PMCID: PMC6043472

Soukos NS, Stultz J, Abernethy AD, Goodson JM. Phototargeting human periodontal pathogens in vivo. Lasers Med Sci. 2015 Apr;30(3):943-52. doi: 10.1007/s10103-013-1497-9. Epub 2013 Dec 18. PubMed [citation] PMID: 24346334

Singh JA, Yu S. The burden of septic arthritis on the U.S. inpatient care: A national study. PLoS One. 2017 Aug 15;12(8):e0182577. doi: 10.1371/journal.pone.0182577. eCollection 2017. PubMed [citation] PMID: 28809954,PMCID: PMC5557487

Salter RB, Bell RS, Keeley FW. The protective effect of continuous passive motion in living articular cartilage in acute septic arthritis: an experimental investigation in the rabbit. Clin Orthop Relat Res. 1981 Sep;(159):223-47. No abstract available. PubMed [citation] PMID: 7285461

Riel KA, Primbs J, Bernett P. [Arthroscopic distension irrigation in acute postoperative infection of the knee joint–long-term follow-up]. Chirurg. 1994 Nov;65(11):1023-7. German. PubMed [citation] PMID: 7821061

Ramakrishnan P, Maclean M, MacGregor SJ, Anderson JG, Grant MH. Differential sensitivity of osteoblasts and bacterial pathogens to 405-nm light highlighting potential for decontamination applications in orthopedic surgery. J Biomed Opt. 2014;19(10):105001. doi: 10.1117/1.JBO.19.10.105001. PubMed [citation] PMID: 25277146

McDonald RS, Gupta S, Maclean M, Ramakrishnan P, Anderson JG, MacGregor SJ, Meek RM, Grant MH. 405 nm Light exposure of osteoblasts and inactivation of bacterial isolates from arthroplasty patients: potential for new disinfection applications? Eur Cell Mater. 2013 Mar 7;25:204-14. PubMed [citation] PMID: 23471732

Mathews CJ, Kingsley G, Field M, Jones A, Weston VC, Phillips M, Walker D, Coakley G. Management of septic arthritis: a systematic review. Ann Rheum Dis. 2007 Apr;66(4):440-5. Epub 2007 Jan 12. Review. PubMed [citation] PMID: 17223664, PMCID: PMC1856038

Maclean M, Anderson JG, MacGregor SJ, White T, Atreya CD. A New Proof of Concept in Bacterial Reduction: Antimicrobial Action of Violet-Blue Light (405 nm) in Ex Vivo Stored Plasma. J Blood Transfus. 2016;2016:2920514. Epub 2016 Sep 28. PubMed [citation] PMID: 27774337, PMCID: PMC5059568

Lungershausen W, Markgraf E, Dorow C, Winterstein K. [Joint empyema]. Chirurg. 1998 Aug;69(8):828-35. Review. German. PubMed [citation] PMID: 9782399

Kleinpenning MM, Smits T, Frunt MH, van Erp PE, van de Kerkhof PC, Gerritsen RM. Clinical and histological effects of blue light on normal skin. Photodermatol Photoimmunol Photomed. 2010 Feb;26(1):16-21. doi: 10.1111/j.1600-0781.2009.00474.x. PubMed [citation] PMID: 20070834

Khazi ZM, Cates WT, Shamrock AG, An Q, Duchman KR, Westermann RW, Wolf BR. Arthroscopic débridement has similar 30-day complications compared with open arthrotomy for the treatment of native shoulder septic arthritis: a population-based study. J Shoulder Elbow Surg. 2020 Jun;29(6):1121-1126. doi: 10.1016/j.jse.2019.11.007. Epub 2020 Feb 10. PubMed [citation] PMID: 32057658

Jackson RW, Parsons CJ. Distension-irrigation treatment of major joint sepsis. Clin Orthop Relat Res. 1973 Oct;(96):160-4. No abstract available. PubMed [citation] PMID: 4749813

Jackson RW. The septic knee–arthroscopic treatment. Arthroscopy. 1985;1(3):194-7. PubMed [citation] PMID: 4096770

Hampton T. Report reveals scope of US antibiotic resistance threat. JAMA. 2013 Oct 23;310(16):1661-3. doi: 10.1001/jama.2013.280695. No abstract available. PubMed [citation] PMID: 24150445

Ferrer-Espada R, Liu X, Goh XS, Dai T. Antimicrobial Blue Light Inactivation of Polymicrobial Biofilms. Front Microbiol. 2019 Apr 9;10:721. doi: 10.3389/fmicb.2019.00721. eCollection 2019. PubMed [citation] PMID: 31024499, PMCID: PMC6467927

Faour M, Sultan AA, George J, Samuel LT, Curtis GL, Molloy R, Higuera CA, Mont MA. Arthroscopic irrigation and debridement is associated with favourable short-term outcomes vs. open management: an ACS-NSQIP database analysis. Knee Surg Sports Traumatol Arthrosc. 2019 Oct;27(10):3304-3310. doi: 10.1007/s00167-018-5328-1. Epub 2019 Jan 2. PubMed [citation] PMID: 30604252

Esterhai JL Jr, Gelb I. Adult septic arthritis. Orthop Clin North Am. 1991 Jul;22(3):503-14. Review. No abstract available. PubMed [citation] PMID: 1852426

Draijer F, Lorentzen T, Nissen R, Havemann D. [Functional treatment of surgically treated empyema of the knee joint]. Unfallchirurg. 1994 May;97(5):273-7. German. PubMed [citation] PMID: 8052866

Desmet KD, Paz DA, Corry JJ, Eells JT, Wong-Riley MT, Henry MM, Buchmann EV, Connelly MP, Dovi JV, Liang HL, Henshel DS, Yeager RL, Millsap DS, Lim J, Gould LJ, Das R, Jett M, Hodgson BD, Margolis D, Whelan HT. Clinical and experimental applications of NIR-LED photobiomodulation. Photomed Laser Surg. 2006 Apr;24(2):121-8. Review. PubMed [citation] PMID: 16706690

Dai T, Gupta A, Murray CK, Vrahas MS, Tegos GP, Hamblin MR. Blue light for infectious diseases: Propionibacterium acnes, Helicobacter pylori, and beyond? Drug Resist Updat. 2012 Aug;15(4):223-36. doi: 10.1016/j.drup.2012.07.001. Epub 2012 Jul 28. Review. PubMed [citation] PMID: 22846406, PMCID: PMC3438385

Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. Available at: https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf

Bynum DK Jr, Nunley JA, Goldner JL, Martinez S. Pyogenic arthritis: emphasis on the need for surgical drainage of the infected joint. South Med J. 1982 Oct;75(10):1232-5, 1238. PubMed [citation] PMID: 7123295

Bauer T, Boisrenoult P, Jenny JY. Post-arthroscopy septic arthritis: Current data and practical recommendations. Orthop Traumatol Surg Res. 2015 Dec;101(8 Suppl):S347-50. doi: 10.1016/j.otsr.2015.09.004. Epub 2015 Sep 26. Review. PubMed [citation] PMID: 26412207

Ateschrang A, Albrecht D, Schröter S, Hirt B, Weise K, Dolderer JH. Septic arthritis of the knee: presentation of a novel irrigation-suction system tested in a cadaver study. BMC Musculoskelet Disord. 2011 Aug 7;12:180. doi: 10.1186/1471-2474-12-180. PubMed [citation] PMID: 21819619, PMCID: PMC3173402

Ahmed I, Fang Y, Lu M, Yan Q, El-Hussein A, Hamblin MR, Dai T. Recent Patents on Light-Based Anti-Infective Approaches. Recent Pat Antiinfect Drug Discov. 2018;13(1):70-88. doi: 10.2174/1872213X11666171108104104. Review. PubMed [citation] PMID: 29119936, PMCID: PMC5938159

Abram SGF, Alvand A, Judge A, Beard DJ, Price AJ. Mortality and adverse joint outcomes following septic arthritis of the native knee: a longitudinal cohort study of patients receiving arthroscopic washout. Lancet Infect Dis. 2020 Mar;20(3):341-349. doi: 10.1016/S1473-3099(19)30419-0. Epub 2019 Dec 17. PubMed [citation] PMID: 31862240