Paper of the week: Orthopedic Implant-Associated Infection by Multidrug-Resistant Enterobacteriaceae.

Paper of the week: Orthopedic Implant-Associated Infection by Multidrug Resistant Enterobacteriaceae. Pfang BG, García-Cañete J, García-Lasheras J, Blanco A, Auñón Á, Parron-Cambero R, Macías-Valcayo A, Esteban J. J Clin Med. 2019 Feb 8;8(2). pii: E220. doi: 10.3390/jcm8020220.

Summary and Editorial by Sreeram Penna

This is a retrospective observational study from a single institution. Researchers reviewed all cases of orthopaedic implant-associated multidrug-resistant Enterobacteriaceae (MDREB). The overall incidence of MDREB was 6.4% (31/482). Six patients were excluded, and twenty-five patients are included in the study. Patients included ten prosthetic joints, seven osteosyntheses, six combination of prosthetic joint and osteosynthesis, and two spacers. MDREB is defined as any enterobacteria resistant to three or more antibacterial classes. Bacteria in this cohort was 12 extended spectrum beta-lactamase producing Escherichia coli, 3 OXA-48-carbapenamase producing Klebsiella pneumoniae, nine extended-spectrum beta-lactamase producing Proteus mirabilis and ten cases were polymicrobial infections. Overall 16 patients (64%) underwent implant removal. This included 7 cases of resection arthroplasty and 3 cases of Amputation. All patients with implant removal achieved 100% infection clearance. Only 33% of patients with retained implants had infection clearance. Four patients died within one year of diagnosis.

Literature review shows an increase in multidrug-resistant Gram-negative bacterial joint infections.[1] These multidrug-resistant Gram-negative bacterial infections are often difficult to control and require special antibiotics combinations to treat and also to prevent further development of antibiotic resistance.[2] Surgical procedures require implant removal for infection clearance.[3] This study provides further insights into MDREB orthopaedic implant infections and clearly shows how dangerous these are.


[1] Murillo O, Grau I, Lora-Tamayo J, Gomez-Junyent J, Ribera A, Tubau F, et al. The changing epidemiology of bacteraemic osteoarticular infections in the early 21st century. Clin Microbiol Infect 2015;21:254.e1-8. doi:10.1016/j.cmi.2014.09.007.
[2] Hawkey PM, Warren RE, Livermore DM, McNulty CAM, Enoch DA, Otter JA, et al. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother 2018;73:iii2–78. doi:10.1093/jac/dky027.
[3] Papadopoulos A, Ribera A, Mavrogenis AF, Rodriguez-Pardo D, Bonnet E, Salles MJ, et al. Multidrug-resistant and extensively drug-resistant Gram-negative prosthetic joint infections: Role of surgery and impact of colistin administration. Int J Antimicrob Agents 2018. doi:10.1016/j.ijantimicag.2018.10.018.



Paper of the week: In vivo analysis of a first-in-class tri-alkyl norspermidine-biaryl antibiotic in an active release coating to reduce the risk of implant-related infection.

Paper of the week: In vivo analysis of a first-in-class tri-alkyl norspermidine-biaryl antibiotic in an active release coating to reduce the risk of implant-related infection. Williams DL, Epperson RT, Ashton NN, Taylor NB, Kawaguchi B, Olsen RE, Haussener TJ, Sebahar PR, Allyn G, Looper RE. Acta Biomater. 2019 Jan 31. pii: S1742-7061(19)30077-7. doi: 10.1016/j.actbio.2019.01.055.

Summary and Editorial by Sreeram Penna

This study in a sheep model of joint space infection was conducted to assess antibacterial properties of compound CZ-01127 as the active release agent in a silicone (Si)-based implant coating to prevent periprosthetic joint infection. Researchers also studied the impact of silicone-based coating and compound CZ-01127 on bone ingrowth and integration. Bone ingrowth was studied using implanting simulated total joint replacement device with regions of porous-coated titanium and adjacent silicone polymer with and without CZ-01127. To understand ability of CZ-01127 to reduce bioburden total joint replacement devices with a silicon-based coating with the above compound was used and compared against controls without compound. And sheep were inoculated with bacteria (MRSA) during implantation procedure after that sheep was monitored to assess outcome, especially infection.

Results of the study show that the CZ-01127 coating reduced bioburden near the total joint replacement device. It also appeared to provide some protection to the joint space and synovium. However joint space ultimately succumbed and was susceptible to infection following bacterial challenge. Bone ingrowth assessment showed that both Titanium and Silicone coated surfaces had decent osseointegration at 24 weeks post procedure. Coating with CZ-01127 resulted in initial bone resorption followed by regrowth, remodeling, and recovery by 8 weeks.

Implant-related infection is associated with significant morbidity and mortality.[1] To prevent this costly complication various methods are actively researched one of this is the development of active release coatings to implants that reduce bioburden and inhibit biofilm production.[2] Antibiotics are considered as compounds for active release. However, researchers in this study identified concerns using antibiotics as it is noted that these coatings loose activity over time and there is concern over the development of antibiotic resistance due to subminimum inhibitory concentrations reached at the site of implants. They suggested using novel substances which reduce the risk of resistance. Researchers identified CZ compounds as they have broad-spectrum activity against planktonic and biofilm bacteria.[3–5] This study assesses the use of newer compound CZ-01127 with silicone polymer to create an effective active release implant to combat implant-related infection.


[1]   Parvizi J, Zmistowski B, Adeli B. Periprosthetic joint infection: treatment options. Orthopedics 2010;33:659. doi:10.3928/01477447-20100722-42.
[2]   Hetrick EM, Schoenfisch MH. Reducing implant-related infections: active release strategies. Chem Soc Rev 2006;35:780–9. doi:10.1039/b515219b.
[3]   Haussener TJ, Sebahar PR, Reddy HRK, Williams DL, Looper RE. A practical synthesis of N-alkyl- and N,N′-dialkyl-polyamines This work is dedicated to the memory of our dear colleague and friend Mr. Charles Edward Price. Tetrahedron Letters 2016;57:2845–8. doi:10.1016/j.tetlet.2016.05.034.
[4]   Looper R, Williams D, Jeyapalina S, Haussener T, Sebahar PR, Reddy HK. Compositions comprising a biocidal polyamine. US8853278B1, 2014.
[5]   Williams D, Looper R, Jeyapalina S, Haussener T, Sebahar PR, Reddy HK. Methods of use for compositions comprising a biocidal polyamine. US9034927B2, 2015.



Paper of the week: Oral versus Intravenous Antibiotics for Bone and Joint Infection

Paper of the Week: Oral versus Intravenous Antibiotics for Bone and Joint Infection. Ho-Kwong Li, M.R.C.P., Ines Rombach, D.Phil., Rhea Zambellas, M.Sc., A. Sarah Walker, Ph.D., Martin A. McNally, F.R.C.S.(Orth.), Bridget L. Atkins, F.R.C.P., Benjamin A. Lipsky, M.D., Harriet C. Hughes, M.A.(Cantab.), Deepa Bose, F.R.C.S., Michelle Kümin, Ph.D., Claire Scarborough, M.R.C.P., Philippa C. Matthews, D.Phil., et al., for the OVIVA Trial Collaborators. N Engl J Med 2019; 380:425-436. DOI: 10.1056/NEJMoa1710926

Summary and editorial by Dr. Katherine Belden, MD

The standard of care for the management of prosthetic joint infection, in particular, staphylococcal infection, includes surgery if indicated and extended parenteral antimicrobial therapy.1,2 Parenteral therapy is used with the goal of achieving optimal plasma drug concentration in the shortest period of time and has traditionally been considered superior to oral therapy for the treatment of most bone and joint infections. Parenteral therapy requires an intravenous vascular access line that can be associated with infection and thromboembolic disease.3 Oral antimicrobial therapy is less invasive for patients, lowers costs and reduces hospital length of stay. Management of PJI with an initial short course of parenteral therapy followed by oral therapy to complete the course has been shown to be effective in observational studies.4–6  Additionally, a 2013 meta-analysis of patients with chronic osteomyelitis showed no difference in outcome with parenteral or oral therapy.7

The Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial, published in the New England Journal of Medicine on January 31, 2019, evaluated standard parenteral therapy compared with an early switch to oral therapy for the treatment of bone and joint infections, 60% involving hardware including prosthetic joints. 1054 patients were enrolled from 26 UK centers with the majority having a staphylococcal infection. Therapy was tailored for each patient by Infectious Diseases physicians and the primary composite endpoint was definite treatment failure at one year. Extended therapy after an initial 6-week course was allowed and the duration of therapy included a median of 78 days in the intravenous group and 71 days in the oral group. Adjunctive rifampin was used in 41% of parenteral regimens and 55.7% of oral regimens. Treatment failure occurred in 14.6% of the intravenous group and 13.2% of those in the oral group; oral therapy was found to be non-inferior to parenteral therapy when used during the first 6 weeks for treatment of bone and joint infection and was associated with decreased length of hospital stay.8

The OVIVA trial supports the use of oral antimicrobial therapy in select patients with PJI and osteomyelitis, challenging the standard of care. While specific pathogens and antibiotics were not compared and analysis according to surgical procedure was limited, the generalized findings of this study suggest that oral therapy has a role. There were no significant differences between groups in the incidence of serious adverse events including Clostridium difficile infection, highlighting the need for close monitoring of patients receiving both extended intravenous and oral therapy for PJI. New concerns as to the safety of fluoroquinolone antibiotics, known to have excellent bioavailability and the most common class of oral antibiotics used in this study, pose risk-benefit questions in antimicrobial selection.9 Given the advantages of oral rather than parenteral therapy to the patient, health care system and antimicrobial stewardship, the OVIVA study is an important contribution to the literature and our understanding of how to optimize antimicrobial selection for PJI. Additional well-designed studies will hopefully continue to shed light on this important topic.


  1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: Clinical practice guidelines by the infectious diseases Society of America. Clin Infect Dis. 2013;56(1):1-10.
  2. Esposito S, Leone S, Bassetti M, et al. Italian guidelines for the diagnosis and infectious disease management of osteomyelitis and prosthetic joint infections in adults. Infection. 2009;37(6):478-496.
  3. Norris AH, Shrestha NK, Allison GM, et al. 2018 IDSA Clinical Practice Guideline for the Management of OPAT. Clinical Infectious Diseases 2019;68(1):e1-35.
  4. Darley ESR, Bannister GC, Blom AW, Macgowan AP, Jacobson SK, Alfouzan W. Role of early intravenous to oral antibiotic switch therapy in the management of prosthetic hip infection treated with one- or two-stage replacement. J Antimicrob Chemother. 2011;66(10):2405-2408.
  5. Ascione T, Pagliano P, Balato G, Mariconda M, Rotondo R, Esposito S. Oral Therapy, Microbiological Findings, and Comorbidity Influence the Outcome of Prosthetic Joint Infections Undergoing 2-Stage Exchange. J Arthroplasty. 2017;32(7):2239-2243.
  6. Cordero-Ampuero J, Esteban J, García-Cimbrelo E, Munuera L, Escobar R. Low relapse with oral antibiotics and two-stage exchange for late arthroplasty infections in 40 patients after 2-9 years. Acta Orthop. 2007;78(4):511-519.
  7. Conterno LO, Da Silva Filho CR, Lo C. Antibiotics for treating chronic osteomyelitis in adults ( Review ). Cochrane Database Syst Rev. 2013;(9):CD004439.
  8. Li H-K, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019;380(5):425-436.
  9. FDA warns about increase risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. fda.gov. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm. 12/20/18.



2018 ICM book updates

Dear Delegates many of you are still waiting to receive a hard copy of the ICM book. The 5000 copies we had are all accounted for at this point. We are planning to have 300-400 copies of the book for distribution at the AAOS either in some of our industry partners’ booth or during off-site activities like the ICM symposium that will be held on Thursday evening at Venetian. In addition, some copies will be distributed in European meetings this month. We hope you will be able to get your hands on a copy soon.

Very sorry if we were unable to get you a copy. We distributed the books on first come first served basis and have ran out of the hard copies at this point. We may consider a second print run in the future.

Please note that the entire document (and the soon to come translations) are available on the App (ICMPhilly) and also the website (www.icmphilly.com).


Paper of the week: Continuous Antibiotic Therapy Can Reduce Recurrence of Prosthetic Joint Infection in Patients Undergoing 2-Stage Exchange.

Paper of the week: Continuous Antibiotic Therapy Can Reduce Recurrence of Prosthetic Joint Infection in Patients Undergoing 2-Stage Exchange. Ascione T, Balato G, Mariconda M, Rotondo R, Baldini A, Pagliano P. J Arthroplasty. 2018 Dec 20. pii: S0883-5403(18)31218-X. doi: 10.1016/j.arth.2018.12.017

Summary and editorial by Sreeram Penna

The main aim of this observational cohort study is to compare infection recurrence in patients who had continuous antibiotic therapy versus antibiotic holiday period prior to reimplantation following two-stage revision for periprosthetic joint infection (PJI). Researchers also analyzed factors associated with poor outcome in patients undergoing two-stage revision procedure who had normalization of serum markers and improvement of symptoms prior to reimplantation. All patients in the study had two weeks of intravenous antibiotics followed by six weeks targeted oral antibiotics.

A total of 196 patients were included in the study. 110 patients had continuous antibiotic therapy prior to reimplantation, and 82 patients had an antibiotic holiday. Overall 169 (86%) patients had a favorable outcome, and 14% had PJI recurrence. In the group that had continuous antibiotics, the cure rate was 91% (104/110) versus 79% (65/82) in patients who had antibiotic holiday prior to reimplantation, and this result was statistically significant (p=0.029). Further analysis revealed that the cure rate was significantly (p=0.02) better in immunocompromised patients receiving continuous antibiotics (41/46, 89%) versus patients who had an antibiotic holiday (20/31, 65%). Immunocompromised patients included those with diabetes, liver cirrhosis, autoimmune disease, and those who were on immunosuppressive medication.

The study also found that serum markers, body mass index, and positive microbiology at reimplantation did not affect the overall outcome. Immunocompromised patients and culture-negative cases were associated with poor outcome following a two-stage procedure. Of the culture positive cases, patients with Gram-positive cultures had a better outcome compared to Gram-negative cases. In another study done by Herman et al., researchers found that CRP and other classic markers like synovial white cell count and PMN % performed poorly in identifying residual infection prior to reimplantation.[1] In addition as researchers noted in this study that antibiotic holiday was shown to have poor outcomes especially in immunocompromised patients, as conditions for bacterial regrowth are still present. This paper puts forth an important argument to continue antibiotic treatment until reimplantation. However further research is needed to identify the optimal time and predictive factors to calculate the success of reimplantation.


[1] Herman A, Albers A, Garbuz DS, Duncan CP, Masri BA. Classic Markers for Infection Perform Poorly in Predicting Residual Infection Prior to Reimplantation. Orthopedics 2019;42:34–40. doi:10.3928/01477447-20190103-03.