Endoprosthetic reconstruction with a modular megaprosthesis has provided important versatility to orthopedic oncology surgeons for the reconstruction of critical bone defects after bone tumor resection.1 However, the infection rate is high for endoprosthetic reconstruction, ranging from 3% to more than 30% for primary operations and up to 60% for revision operations.2–5 The high infection rate related to endoprosthetic reconstruction is attributed to large soft tissue defects, large implants, increased operative time, immunosuppression from cancer itself, and adjuvant treatments.6–10 Diagnosis and treatment of endoprosthetic reconstruction infections is challenging.11,12 Although surgical debridement remains the mainstay of treatment, identification of the bacterial isolate is necessary for diagnosis of the infection and optimum administration of antibiotics.11,13 Isolation of the pathogens by tissue cultures is the gold standard14,15; however, cultures may have a false-negative result in up to 30% of cases.16,17 To improve the diagnosis of prosthetic joint infections of standard arthroplasties, several techniques for the detection of biofilm-related infections, such as sonication and treatment of the removed implant with dithiothreitol, have recently been developed.15,18,19 In addition, prolonged incubation (for as long as 2 weeks) has been proposed for tissue cultures to detect slow-growing fastidious pathogens such as Propionibacterium acnes.12,20,21 Sonication fluid cultures of the removed implants were shown to be more sensitive than tissue cultures, especially in patients treated with antibiotics preoperatively15,16,22; however, most of the related information is available from series of patients treated for prosthetic joint infections of standard arthroplasties for non-oncological cases.22–25
Limited data are currently available for patients with tumors with infected endoprosthetic reconstructions.26 In these patients, the infection of the endoprosthetic reconstruction leads to severe consequences because of the need for long hospital stays, expensive treatments, multiple reoperations, and possible amputation and dismal quality of remaining life.8–10 To enhance the literature, the authors reviewed their patients with tumors treated with resection and endoprosthetic reconstruction and studied those with a clinical and laboratory diagnosis of infected endoprosthetic reconstruction. The primary goal was to evaluate whether sonication was effective for the diagnosis of the infection. The secondary goal was to compare sonication fluid cultures with tissue cultures.
Materials and Methods
The authors retrospectively studied the files of 58 patients with a clinical and laboratory diagnosis of late-onset infected endoprosthetic reconstruction who underwent revision surgery with removal of the megaprosthesis at the authors' institutions from April 2015 to July 2017. There were 32 male and 26 female patients with a mean age of 36 years (range, 13–78 years). Information regarding the type of megaprosthesis, clinical presentation, erythrocyte sedimentation rate, C-reactive protein level, white blood cell count, and detailed leukocyte parameters was available for all of the patients (Table 1). The mean follow-up was 17 months (range, 9–35 months); no patient was lost to follow-up. All data were retrieved from the patients' files. Patients or their relatives gave written informed consent for the data to be included in this study.
Patient Characteristics at Baseline
Patients were considered to have an infected endoprosthetic reconstruction (1) if a fistula communicating with the implant was observed or (2) if, in the absence of a fistula, laboratory examination revealed an erythrocyte sedimentation rate greater than 30 mm/h, C-reactive protein level greater than 1 mg/dL, and leukocyte count greater than 3000/µL with greater than 80% neutrophils in joint aspiration fluid.13 All patients had revision surgery with removal of their endoprosthetic reconstruction and tissue debridement. All patients had stopped treatment with antibiotics for at least 3 weeks before revision surgery and were not administered antibiotics intraoperatively until tissue samples were obtained and megaprosthesis removal was completed. At least 5 tissue samples were obtained from different areas of periprosthetic tissues. All endoprosthetic reconstruction components were removed, placed in a sterile, wide-mouth, airtight, polypropylene container, and transferred immediately to the microbiology laboratory for sonication.
Tissue samples were processed in a Class II cabinet. Homogenization was performed in the original container, and vortexing of the specimen was done in 3 mL of Tryptic Soy Broth (Biolife Italiana, Milan, Italy).17 Each homogenate was inoculated into sheep blood agar, Thiogly-collate Broth Medium (Biolife Italiana), and Tryptic Soy Broth. All media were incubated at 36°±1°C for 7 days and examined daily for evidence of bacterial growth. For isolation of individual colonies, aliquots from enrichment broth tubes were spread using a sterile loop onto Columbia CNA Blood agar (Biolife Italiana), mannitol salt agar, MacConkey agar, and chocolate agar, incubated at 36°±1°C under aerobic conditions for 24 hours, and subcultured onto chocolate agar under anaerobic conditions at 36°±1°C for another 72 hours. Identification and antimicrobial susceptibility testing were performed with the MicroScan WalkAway system (Beckman Coulter, Sacramento, California). Thioglycollate Broth Medium and Tryptic Soy Broth cultures with negative results were re-incubated at 36°±1°C for up to 14 days and examined daily for evidence of growth; terminal subcultures were performed.
Sonication was performed as previously described.15 The container was filled with sterile saline until submersion of the implant, carefully sealed, vortexed, and sonicated in an ultrasound bath (Cortex mixer; VWR, Milan, Italy) with a frequency of 40 kHz at room temperature for 5 minutes. The obtained fluid was collected in sterile tubes and centrifuged at 3000 rpm at room temperature for 10 minutes. The pellet was suspended in a volume of 2 mL of the same solution. Next, 100 µL of each sample was plated onto chocolate agar and sheep blood agar and inoculated into Tryptic Soy Broth and Thioglycollate Broth Medium. Sheep blood agar was incubated aerobically, whereas chocolate agar was incubated in a 5% carbon dioxide atmosphere at 36°±1°C for 7 days. Broths were incubated at 36°±1°C for 7 days, and if negative results were found, the incubation was extended to 14 days and they were examined daily for evidence of growth; terminal subcultures were performed.18 Sonication fluid cultures were considered to have positive results if at least 5 colonies grew on agar plates at 24 hours to 7 days or if a bacterial growth was observed during broth enrichment.
In the definition of infection according to the Musculoskeletal Infection Society criteria,13 sonication fluid cultures were considered together with tissue cultures. Both cultures were considered to have positive results if at least 1 culture showed growth of a pathogen (Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae species) or if 2 cultures yielded a skin commensal microorganism (coagulase-negative staphylococci or Propionibacterium acnes).11,27 The results of tissue cultures and sonication fluid cultures were compared. The sensitivity, specificity, positive predictive value, and negative predictive value of tissue cultures and sonication fluid cultures were calculated and compared. The Student's t test was used for comparisons. P<.05 was considered significant. All analyses were completed using the Statistical Package for the Social Sciences (SPSS Statistics for Windows, version 22.0; IBM Corporation, Armonk, New York).
Overall, tissue cultures and sonication fluid cultures confirmed an endoprosthetic reconstruction infection in 42 of the 58 patients; the remaining 16 patients were therefore considered to have aseptic loosening of their megaprostheses. Infections were most commonly mono-microbial from gram-positive pathogens (coagulase-negative staphylococci and S aureus). Multipathogen infections were diagnosed in 4 patients: 1 patient had a methicillin-resistant S aureus and methicillin-sensitive coagulase-negative staphylococci infection, another patient had a methicillin-resistant S aureus and Enterococcus species infection, and 2 patients had a methicillin-sensitive S aureus and methicillin-resistant coagulase-negative staphylococci infection. All multipathogen infections were detected in both tissue cultures and sonication fluid cultures.
In 36 of the 42 infected endoprosthetic reconstructions, tissue cultures and sonication fluid cultures identified the same bacterial isolate. In all of these cases, cultures had positive results within 7 days of incubation. In 5 cases, a bacterial isolate was identified only in sonication fluid cultures; in 1 case, a bacterial isolate was identified only in tissue cultures. The sensitivity and negative predictive value of sonication fluid cultures were statistically significantly better than those of tissue cultures (P<.001), whereas specificity and positive predictive value were not different between tissue cultures and sonication fluid cultures (P=.347 and P=.879, respectively) (Table 2).
Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value of Tissue Cultures and Sonication Fluid Cultures of the 42 Patients With Infected Endoprosthetic Reconstructions
The incidence of endoprosthetic reconstruction infections, ranging from 3% to 60%, is higher than that of prosthetic joint infections.2–5 Diagnosis of infection is often challenging because a clinically assessed and analytically valid technique that could serve as a reference for this diagnosis has not been developed.9,28 Periprosthetic tissue cultures have been considered the gold standard for the diagnosis of infection and the isolation of the bacterial pathogens. However, tissue cultures lack optimal sensitivity and specificity for the diagnosis of the infection, having sensitivity ranging from 70% to 90% and specificity ranging from 67% to 91%.14,29,30 Sonication fluid cultures of removed prostheses were shown to be more sensitive than tissue cultures, especially for patients treated with antibiotics preoperatively; however, most related studies reporting on the diagnostic performance of sonication have involved patients with standard arthroplasties.15,16,22 Studies involving patients with tumors with infected endoprosthetic reconstructions are lacking.31 Therefore, the authors performed this study to evaluate the sensitivity, specificity, negative predictive value, and positive predictive value of tissue cultures and sonication fluid cultures. The key hypothesis was that sonication should be considered an adjunct to the criteria of the Musculoskeletal Infection Society for the diagnosis of infected endoprosthetic reconstructions. The results confirmed this hypothesis: for the diagnosis of endoprosthetic reconstruction infections, sensitivity and negative predictive value were better for sonication fluid cultures and specificity and positive predictive value were similar for tissue cultures and sonication fluid cultures. The authors believe that their results would be useful for physicians treating patients with tumors with possible endoprosthetic reconstruction infections.
The authors acknowledge 2 limitations of this series. First, the follow-up period was short. However, the purpose was not to study the outcome of patients with infected endoprosthetic reconstructions but rather to evaluate the diagnostic value of sonication. Additionally, long-term follow-up studies are difficult in patients with tumors because of the effect of the primary disease on patients' survival. Second, the number of patients with infected endoprosthetic reconstructions included in this series was relatively small. Further, the sample was heterogeneous for the type of megaprosthesis used, the site of endoprosthetic reconstruction, and adjuvant treatments. However, the authors opted to include all of their patients with infected endoprosthetic reconstructions, aiming to increase the sample and the power of the study.
Previous studies of prosthetic joint infections and sonication in standard arthroplasties reported sensitivity ranging from 85% to 97% and specificity ranging from 90% to 97%.15,19,31,32 Compared with these studies, the current study found similar performance for sonication fluid cultures15,17,19 but a higher sensitivity for tissue cultures.14,29 This may be explained by the methodology used in this study and the authors' practice of always discontinuing treatment with antibiotics for at least 3 weeks before tissue cultures to increase the diagnostic accuracy of the cultures.33 In a previous study of 31 patients with tumors with infected endoprosthetic reconstructions, sonication was reported to have a sensitivity of 91.3% and a specificity of 100%.34 Compared with that study, the current study found improved diagnosis of the infection with a higher sensitivity and negative predictive value for sonication fluid cultures compared with tissue cultures. Additionally, the authors reported a higher prevalence of high virulence bacteria such as S aureus and Enterobacteriaceae33,35–37 and of methicillin-resisitant bacteria compared with series involving prosthetic joint infections.38–40 These findings could probably be explained by the higher susceptibility to infection of patients with tumors.41–43 Furthermore, high virulence bacteria have been associated with poorer infection control and outcome.41 These underline the importance of a rapid and accurate microbiologic diagnosis for patients with tumors. In these patients, because prognosis is often dismal and survival is short, early diagnosis of the infection and appropriate management with a 1- or 2-stage endoprosthetic reconstruction revision surgery is paramount.
Compared with tissue cultures for the diagnosis of infected endoprosthetic reconstructions in patients with tumors, sonication fluid cultures are associated with better sensitivity and negative predictive value and similar specificity and positive predictive value. Therefore, sonication should be considered a useful adjunct for the optimal diagnosis and management of these patients.
- Calori GM, Colombo M, Ripamonti C, et al. Megaprosthesis in large bone defects: opportunity or chimaera?Injury. 2014;45(2):388–393. doi:10.1016/j.injury.2013.09.015 [CrossRef]
- Flint MN, Griffin AM, Bell RS, Wunder JS, Ferguson PC. Two-stage revision of infected uncemented lower extremity tumor endoprostheses. J Arthroplasty. 2007;22(6):859–865. doi:10.1016/j.arth.2006.11.003 [CrossRef]
- Gosheger G, Gebert C, Ahrens H, Streitbuerger A, Winkelmann W, Hardes J. Endoprosthetic reconstruction in 250 patients with sarcoma. Clin Orthop Relat Res. 2006;450:164–171. doi:10.1097/01.blo.0000223978.36831.39 [CrossRef]
- Henderson ER, O'Connor MI, Ruggieri P, et al. Classification of failure of limb salvage after reconstructive surgery for bone tumours: a modified system including biological and expandable reconstructions. Bone Joint J. 2014;96-B(11):1436–1440. doi:10.1302/0301-620X.96B11.34747 [CrossRef]
- Jeys LM, Grimer RJ, Carter SR, Tillman RM. Periprosthetic infection in patients treated for an orthopaedic oncological condition. J Bone Joint Surg Am. 2005;87(4):842–849. doi:10.2106/JBJS.C.01222 [CrossRef]
- Grimer RJ, Carter SR, Tillman RM, et al. Endoprosthetic replacement of the proximal tibia. J Bone Joint Surg Br. 1999;81(3):488–494. doi:10.1302/0301-620X.81B3.9234 [CrossRef]
- McDonald DJ, Capanna R, Gherlinzoni F, et al. Influence of chemotherapy on perioperative complications in limb salvage surgery for bone tumors. Cancer. 1990;65(7):1509–1516. doi:10.1002/1097-0142(19900401)65:7<1509::AID-CNCR2820650710>3.0.CO;2-I [CrossRef]
- Kurtz SM, Lau E, Watson H, Schmier JK, Parvizi J. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty. 2012;27(8)(suppl):61–65. doi:10.1016/j.arth.2012.02.022 [CrossRef]
- Neut D, van Horn JR, van Kooten TG, van der Mei HC, Busscher HJ. Detection of biomaterial-associated infections in orthopaedic joint implants. Clin Orthop Relat Res. 2003;413:261–268. doi:10.1097/01.blo.0000073345.50837.84 [CrossRef]
- Ercolano LB, Christensen T, McGough R, Weiss K. Treatment solutions are unclear for perimegaprosthetic infections. Clin Orthop Relat Res. 2013;471(10):3204–3213. doi:10.1007/s11999-013-2852-7 [CrossRef]
- Osmon DR, Berbari EF, Berendt AR, et al. Infectious Diseases Society of America. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1–e25. doi:10.1093/cid/cis803 [CrossRef]
- Del Pozo JL, Patel R. Clinical practice: infection associated with prosthetic joints. N Engl J Med. 2009;361(8):787–794. doi:10.1056/NEJMcp0905029 [CrossRef]
- Parvizi J, Gehrke TInternational Consensus Group on Periprosthetic Joint Infection. Definition of periprosthetic joint infection. J Arthroplasty. 2014;29(7):1331. doi:10.1016/j.arth.2014.03.009 [CrossRef]
- Achermann Y, Vogt M, Leunig M, Wüst J, Trampuz A. Improved diagnosis of periprosthetic joint infection by multiplex PCR of sonication fluid from removed implants. J Clin Microbiol. 2010;48(4):1208–1214. doi:10.1128/JCM.00006-10 [CrossRef]
- Trampuz A, Piper KE, Jacobson MJ, et al. Sonication of removed hip and knee prostheses for diagnosis of infection. N Engl J Med. 2007;357(7):654–663. doi:10.1056/NEJMoa061588 [CrossRef]
- Portillo ME, Salvadó M, Alier A, et al. Advantages of sonication fluid culture for the diagnosis of prosthetic joint infection. J Infect. 2014;69(1):35–41. doi:10.1016/j.jinf.2014.03.002 [CrossRef]
- Piper KE, Jacobson MJ, Cofield RH, et al. Microbiologic diagnosis of prosthetic shoulder infection by use of implant sonication. J Clin Microbiol. 2009;47(6):1878–1884. doi:10.1128/JCM.01686-08 [CrossRef]
- Drago L, Signori V, De Vecchi E, et al. Use of dithiothreitol to improve the diagnosis of prosthetic joint infections. J Orthop Res. 2013;31(11):1694–1699.
- Sambri A, Cadossi M, Giannini S, et al. Is treatment with dithiothreitol more effective than sonication for the diagnosis of prosthetic joint infection?Clin Orthop Relat Res.2018;476(1):137–145. doi:10.1007/s11999.0000000000000060 [CrossRef]
- Geipel U. Pathogenic organisms in hip joint infections. Int J Med Sci. 2009;6(5):234–240. doi:10.7150/ijms.6.234 [CrossRef]
- Schäfer P, Fink B, Sandow D, Margull A, Berger I, Frommelt L. Prolonged bacterial culture to identify late periprosthetic joint infection: a promising strategy. Clin Infect Dis. 2008;47(11):1403–1409. doi:10.1086/592973 [CrossRef]
- Puig-Verdié L, Alentorn-Geli E, González-Cuevas A, et al. Implant sonication increases the diagnostic accuracy of infection in patients with delayed, but not early, orthopaedic implant failure. Bone Joint J. 2013;95-B(2):244–249. doi:10.1302/0301-620X.95B2.30486 [CrossRef]
- Portillo ME, Salvadó M, Trampuz A, et al. Sonication versus vortexing of implants for diagnosis of prosthetic joint infection. J Clin Microbiol. 2013;51(2):591–594. doi:10.1128/JCM.02482-12 [CrossRef]
- Portillo ME, Salvadó M, Trampuz A, et al. Improved diagnosis of orthopedic implant-associated infection by inoculation of sonication fluid into blood culture bottles. J Clin Microbiol. 2015;53(5):1622–1627. doi:10.1128/JCM.03683-14 [CrossRef]
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Patient Characteristics at Baseline
|Age, mean (range), y||36 (13–78)|
|Erythrocyte sedimentation rate, mean (range), mm/h||83 (22–146)|
|C-reactive protein, mean (range), mg/dL||1.15 (0.47–28.00)|
| Distal femur||28|
| Proximal tibia||18|
| Proximal femur||9|
| Total femur||3|
|Diagnosis (histology of tumor), No.|
| Ewing sarcoma||7|
| Soft tissue sarcoma||7|
| Metastatic carcinoma||6|
|Time from endoprosthetic reconstruction to infection, mean (range), mo||37 (5–127)|
Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value of Tissue Cultures and Sonication Fluid Cultures of the 42 Patients With Infected Endoprosthetic Reconstructions
|Parameter||Culture (No./Total No.)||P|
|Sensitivity||85.7% (36/42)||97.6% (41/42)||<.001|
|Specificity||100% (16/16)||93.7% (15/16)||.347|
|Positive predictive value||100% (36/36)||97.6% (41/42)||.879|
|Negative predictive value||72.7% (16/22)||93.7% (15/16)||<.001|