Course and medium-term outcomes of implant-associated infection caused by leading gram-negative pathogens

Introduction Implant-associated infection (IAI) caused by gram-negative pathogens is characterized by a more severe, recurrent course and higher mortality than the one caused by gram-positive ones. The main reason is growing antibiotic resistance of these pathogens and the complexity of choosing drugs for inpatient and outpatient therapy.
Purpose To evaluate the influence of various factors and compare the features of the course of implant-associated infection caused by P. aeruginosa, K. pneumoniae, A. baumannii in patients with positive and poor treatment outcomes
Methods A retrospective analysis of the medical records of 172 patients treated at the Department of Purulent Osteology between January 1, 2017 and December 31, 2022 for implant-associated infection caused by  P. aeruginosa, K. pneumoniae, A. baumannii was conducted. Based on the results of a telephone survey or examination, patients were divided into 2 groups: positive and poor treatment outcomes by Delphi criteria. The impact of various factors in the anamnesis, laboratory and microbiological analysis, features of surgical intervention, antibacterial therapy and the course of the early postoperative period on the outcomes was analyzed in the IBM SPSS STATISTICS (version 26).
Results Among patients with IAI caused by gram-negative bacteria, the rate of poor outcomes was 45 %, with fatality rate of 10 %. During the comparative study, a statistically significant effect on the development of  a  poor outcome was shown by the postoperative level of serum albumin (p = 0.002), the sensitivity of the isolated isolate to the tested antibacterial drugs (p = 0.011), the isolation of the pathogen from patients’ biomaterial in the postoperative period (p = 0.001), a more frequent need for intravenous administration of albumin and iron (p = 0.003 and p = 0.056, respectively) and the need for repeated surgical intervention in the early postoperative period (p = 0.001).
Discussion IAI caused by gram-negative bacteria is characterized by a prolonged recurrent course and high mortality, primarily associated with the overall growing antibiotic resistance of pathogens which requires an individual approach to both surgical treatment and drug therapy, as well as the development of new tactical approaches to therapy.
Conclusion The rate of poor outcomes was 45 %. Hypoalbuminemia and antibacterial resistance of isolates of P. aeruginosa, K. pneumoniae, A. baumannii, detection of the pathogens in the postoperative material, as well as the need for surgical reoperation in the early postoperative period, are risk factors for poor outcomes.

1. Singh JA, Yu S, Chen L, Cleveland JD. Rates of Total Joint Replacement in the United States: Future Projections to 2020‑2040 Using the National Inpatient Sample. J Rheumatol. 2019;46(9):1134-1140. doi: 10.3899/jrheum.170990.

2. Tubb CC, Polkowksi GG, Krause B. Diagnosis and Prevention of Periprosthetic Joint Infections. J Am Acad Orthop Surg. 2020;28(8):e340-e348. doi: 10.5435/JAAOS-D-19-00405.

3. Birt MC, Anderson DW, Bruce Toby E, Wang J. Osteomyelitis: Recent advances in pathophysiology and therapeutic strategies. J Orthop. 2016;14(1):45-52. doi: 10.1016/j.jor.2016.10.004.

4. Liukkonen RJ, Honkanen M, Reito AP, et al. Trends in Revision Hip Arthroplasty for Prosthetic Joint Infection: A SingleCenter Study of 423 Hips at a High-Volume Center Between 2008 and 2021. J Arthroplasty. 2023;38(6):1151-1159. doi: 10.1016/j.arth.2023.02.061.

5. Kasimova AR, Trufanova OS, Gordina EM, et al. Twelve-year dynamics of leading pathogens spectrum causing orthopedic infection: a retrospective study. Traumatology and Orthopedics of Russia. 2024;30(1):66-75. doi: 10.17816/2311-2905-16720.

6. Bozhkova S, Tikhilov R, Labutin D, et al. Failure of the first step of two-stage revision due to polymicrobial prosthetic joint infection of the hip. J Orthop Traumatol. 2016;17(4):369-376. doi: 10.1007/s10195-016-0417-8.

7. Tsikopoulos K, Meroni G. Periprosthetic Joint Infection Diagnosis: A Narrative Review. Antibiotics (Basel). 2023;12(10):1485. doi: 10.3390/antibiotics12101485.

8. Pfang BG, García-Cañete J, García-Lasheras J, et al. Orthopedic Implant-Associated Infection by Multidrug Resistant Enterobacteriaceae. J Clin Med. 2019;8(2):220. doi: 10.3390/jcm8020220.

9. Zmistowski B, Fedorka CJ, Sheehan E, Deirmengian G, Austin MS, Parvizi J. Prosthetic joint infection caused by gramnegative organisms. J Arthroplasty. 2011;26(6 Suppl):104-108. doi: 10.1016/j.arth.2011.03.044.

10. Kochish AA, Bozhkova SA. Modern state of problem for treating patients with recurrent hip periprosthetic joint infection (Literature review). Department of traumatology and orthopedics. 2020;(3):11-22. (In Russ.) doi: 10.17238/issn2226-2016.2020.3.11-22.

11. Jernigan JA, Hatfield KM, Wolford H, et al. Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012-2017. N Engl J Med. 2020;382(14):1309-1319. doi: 10.1056/NEJMoa1914433.

12. Gonzalez MR, Gonzalez J, Patel RV, et al. Microbiology, treatment, and postoperative outcomes of gram-negative prosthetic joint infections - a systematic review of the literature. J Am Acad Orthop Surg. 2024 Sep 5. doi: 10.5435/JAAOS-D-23-01203.

13. Fantoni M, Borrè S, Rostagno R, et al. Epidemiological and clinical features of prosthetic joint infections caused by gram-negative bacteria. Eur Rev Med Pharmacol Sci. 2019;23(2 Suppl):187-194. doi: 10.26355/eurrev_201904_17490.

14. Tufanova OS, Kasimova AR, Astakhov DI et al. Factors affecting the course and prognosis of Implant-associated Infection caused by Klebsiella spp. Traumatology and Orthopedics of Russia. 2024;30(2):40-53. doi: 10.17816/2311-2905-16719.

15. Papadopoulos A, Ribera A, Mavrogenis AF, et al. Multidrug-resistant and extensively drug-resistant Gramnegative prosthetic joint infections: Role of surgery and impact of colistin administration. Int J Antimicrob Agents. 2019;53(3):294‑301. doi: 10.1016/j.ijantimicag.2018.10.018.

16. Diaz-Ledezma C, Higuera CA, Parvizi J. Success after treatment of periprosthetic joint infection: a Delphi-based international multidisciplinary consensus. Clin Orthop Relat Res. 2013;471(7):2374-2382. doi: 10.1007/s11999-013‑2866-1.

17. Abukhalil AD, Barakat SA, Mansour A, et al. ESKAPE Pathogens: antimicrobial resistance patterns, risk factors, and outcomes a retrospective cross-sectional study of hospitalized patients in Palestine. Infect Drug Resist. 2024;17:3813-3823. doi: 10.2147/IDR.S471645.

18. Venkateswaran P, Vasudevan S, David H, et al. Revisiting ESKAPE Pathogens: virulence, resistance, and combating strategies focusing on quorum sensing. Front Cell Infect Microbiol. 2023;13:1159798. doi: 10.3389/fcimb.2023.1159798.

19. Adar A, Zayyad H, Azrad M, et al. Clinical and demographic characteristics of patients with a new diagnosis of carriage or clinical infection with carbapenemase-producing Enterobacterales: a retrospective study. Front Public Health. 2021;9:616793. doi: 10.3389/fpubh.2021.616793.

20. Lasko MJ, Nicolau DP. Carbapenem-resistant Enterobacterales: considerations for treatment in the era of new antimicrobials and evolving enzymology. Curr Infect Dis Rep. 2020;22(3):6. doi: 10.1007/s11908-020-0716-3.

21. ohnson A, McEntee L, Farrington N, et al. Pharmacodynamics of cefepime combined with the novel extendedspectrum-β-Lactamase (ESBL) inhibitor enmetazobactam for murine pneumonia caused by ESBL-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2020;64(6):e00180-20. doi: 10.1128/AAC.00180-20.

22. Sheu CC, Chang YT, Lin SY, et al. Infections caused by carbapenem-resistant Enterobacteriaceae: an update on therapeutic options. Front Microbiol. 2019;10:80. doi: 10.3389/fmicb.2019.00080.

23. Wimmer MD, Hischebeth GTR, Randau TM, et al. Difficult-to-treat pathogens significantly reduce infection resolution in periprosthetic joint infections. Diagn Microbiol Infect Dis. 2020;98(2):115114. doi: 10.1016/j.diagmicrobio.2020.115114.

24. Kalbian IL, Goswami K, Tan TL, et al. Treatment outcomes and attrition in gram-negative periprosthetic joint infection. J Arthroplasty. 2020;35(3):849-854. doi: 10.1016/j.arth.2019.09.044.

25. Artyukh VA, Bozhkova SA, Tikhilov RM, et al. Risk factors for lethal outcomes after surgical treatment of patients with chronic periprosthetic hip joint infection. Genij Ortopedii. 2021;27(5):555-561. doi: 10.18019/1028-4427-2021-27-5-555-561.

26. Grossi O, Asseray N, Bourigault C, et al. Gram-negative prosthetic joint infections managed according to a multidisciplinary standardized approach: risk factors for failure and outcome with and without fluoroquinolones. J Antimicrob Chemother. 2016;71(9):2593-2597. doi: 10.1093/jac/dkw202.

27. Hsieh PH, Lee MS, Hsu KY, et al. Gram-negative prosthetic joint infections: risk factors and outcome of treatment. Clin Infect Dis. 2009;49(7):1036-1043. doi: 10.1086/605593.

28. Scarcella NR, Mills FB, Seidelman JL, Jiranek WA. The effect of nutritional status in the treatment of periprosthetic joint infections in total hip arthroplasty. J Arthroplasty. 2024;39(9S1):S225-S228. doi: 10.1016/j.arth.2024.06.040.

29. Ulldemolins M, Roberts JA, Rello J, et al. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011;50(2):99-110. doi: 10.2165/11539220-000000000-00000.

30. Bohl DD, Shen MR, Kayupov E, et al. Is hypoalbuminemia associated with septic failure and acute infection after revision total joint arthroplasty? A study of 4517 patients from the national surgical quality improvement program. J Arthroplasty. 2016;31(5):963-967. doi: 10.1016/j.arth.2015.11.025.

31. Bozhkova SA, Liventsov VN, Tikhilov RM, et al. Protein-energy malnutrition as a predictor of early recurrent revisions after debridement surgery in patients with difficult-to-treat periprosthetic infection. Traumatology and Orthopedics of Russia. 2022;28(1):39-45. doi: 10.17816/2311-2905-1717.

32. Swenson RD, Butterfield JA, Irwin TJ, et al. Preoperative anemia is associated with failure of open debridement polyethylene exchange in acute and acute hematogenous prosthetic joint infection. J Arthroplasty. 2018;33(6):1855-1860. doi: 10.1016/j.arth.2018.01.042.

33. Winkler T, Trumpuz A, Renz N, et al. Classification and algorithm for diagnosis and treatment of hip periprosthetic infection. Traumatology and orthopedics of Russia. 2016;22(1):33-45. (In Russ.) doi: 10.21823/2311-2905-2016-0‑1‑33‑45.

34. Bernard L, Arvieux C, Brunschweiler B, et al. Antibiotic therapy for 6 or 12 weeks for prosthetic joint infection. N Engl J Med. 2021;384(21):1991-2001. doi: 10.1056/NEJMoa2020198.

35. Azamgarhi T, Scarborough M, Peter-Akhigbe V, et al. Fluoroquinolones in orthopaedic infection: balancing risks and rewards. J Antimicrob Chemother. 2024;79(10):2413-2416. doi: 10.1093/jac/dkae286.

36. Rodríguez-Pardo D, Pigrau C, Lora-Tamayo J, et al. Gram-negative prosthetic joint infection: outcome of a debridement, antibiotics and implant retention approach. A large multicentre study. Clin Microbiol Infect. 2014;20(11):O911-O919. doi: 10.1111/1469-0691.12649.

37. Tsiskarashvili AV, Melikova RE, Novozhilova EA. Analysis of six-year monitoring of common pathogens causing periprosthetic joint infection of major joints and the tendency to resistance. Genij Ortopedii. 2022;28(2):179-188. doi: 10.18019/1028-4427-2022-28-2-179-188.

38. Legout L, Senneville E, Stern R, et al. Treatment of bone and joint infections caused by Gram-negative bacilli with a cefepime-fluoroquinolone combination. Clin Microbiol Infect. 2006;12(10):1030-1033. doi: 10.1111/j.1469-0691.2006.01523.x.

39. Thabit AK, Fatani DF, Bamakhrama MS, et al. Antibiotic penetration into bone and joints: An updated review. Int J Infect Dis. 2019;81:128-136. doi: 10.1016/j.ijid.2019.02.005.

40. Bozhkova SA, Kasimova AR, Tikhilov RM, et al. Adverse trends in the etiology of orthopedic Infection: results of 6-year monitoring of the structure and resistance of leading Pathogens. Traumatology and orthopedics of Russia. 2018;24(4):20‑31. doi: 10.21823/2311-2905-2018-24-4-20-31.

41. Cisse H, Vernet-Garnier V, Hentzien M, et al. Treatment of bone and joint infections caused by Enterobacter cloacae with a fluoroquinolone-cotrimoxazole combination. Int J Antimicrob Agents. 2019;54(2):245-248. doi: 10.1016/j. ijantimicag.2019.05.010.