Translate this page into:
Outcomes and safety of antibiotic-loaded calcium sulfate beads in orthopaedics: A systematic review and meta-analysis
, Vishwa Suravaramb, Victor Yan Zhe Luc, Armando Hocha, Patrick O. Zingga, Octavian Andronica
⁎Corresponding author: Alberto Pedrazzini. alberto.pedrazzini@balgrist.ch
-
Received: ,
Accepted: ,
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Abstract
Calcium sulfate (CS) has emerged as a local antibiotic delivery system, offering biodegradability, osteoconductive properties and sustained antibiotic release. The aim was to evaluate the clinical outcomes and safety of antibiotic-loaded CS beads as an adjunct in the management and prevention of orthopaedic infections.
The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies reporting outcomes on the use of antibiotic-loaded CS beads in orthopaedics were considered eligible. Risk of bias assessment was performed using the methodological index for non-randomized studies (MINORS) criteria. Evaluated outcomes included rates of infection eradication or incidence, bone union, CS resorption, complications and reinterventions. Exploratory meta-analyses used a random-effects model, with heterogeneity assessed via the I2 statistic.
The systematic search included 41 studies. No randomized controlled trials were identified. Twenty-three studies examined patients with osteomyelitis, yielding a pooled infection eradication rate of 88% (95% CI: 85 to 90%; I2 = 19%). Among patients with infected nonunion, the pooled bone union rate was 93% (95% CI: 85 to 97%; I2 = 36%). In patients with periprosthetic joint infections (PJI), the pooled infection eradication rate reached 88% (95% CI: 76 to 95%; I2 = 87%). Wound-related complications were documented in 17% (189/1086) of osteomyelitis cases, compared to 8% (23/277) of PJI cases. PJI treatment was associated with minimal complications, including 12 cases of hypercalcemia (12/277, 4%) and nine cases of heterotopic ossification (9/262, 3%).
Current evidence describes favorable infection eradication rates when antibiotic-loaded CS beads are used as an adjunct in orthopaedic infection management and prevention, but the absence of comparative trials precludes conclusions regarding independent efficacy. All studies showed complete CS resorption. Wound-related complications were substantial in osteomyelitis cases, while other adverse events were rare. Higher-quality comparative studies are required before routine adoption.
Keywords
Calcium sulfate
Antibiotic beads
Infection
Osteomyelitis
Periprosthetic joint infection
Prevention
1 Introduction
Infections in orthopaedic and trauma surgery, ranging from superficial soft tissue infections to osteomyelitis and periprosthetic joint infections (PJI), constitute major causes of morbidity and healthcare burden.1,2 Recent epidemiological data revealed a growing trend in osteomyelitis prevalence.3 At the same time, the increasing volume of arthroplasty procedures, particularly total hip arthroplasty (THA) and total knee arthroplasty (TKA), has contributed to a corresponding rise of PJI.4 The emergence of resistant bacteria further complicates treatment,5 underscoring the need for innovative treatment strategies.
The management of osteomyelitis has historically relied on surgical debridement and antibiotic therapy.6 PJI treatment includes complete prosthesis revision, either as one- or two-staged procedure, or debridement with exchange of modular components accompanied by appropriate antibiotic therapy, usually referred to as DAIR (Debridement, Antibiotics and Implant Retention). Despite technical advances, considerable failure rates have been reported.7,8 Systemic antibiotics face limitations due to poor vascularity in affected areas, biofilm formation, difficulty achieving adequate local concentrations and potential systemic side effects.9
Local antibiotic delivery systems have emerged as an important treatment option. Polymethyl methacrylate (PMMA) cement is commonly used but presents limitations, including rapid antibiotic elution, after which it may act as a nidus for bacterial proliferation and require surgical removal.10,11 These drawbacks have directed attention towards biodegradable materials for local antibiotic delivery. Calcium sulfate (CS) is fully biodegradable and possesses osteoconductive properties, eliminating the need for surgical removal while simultaneously enhancing dead space management by providing a scaffold for bone regeneration.12 Additionally, CS can be combined with all water-soluble antibiotics and demonstrated superior elution characteristics compared to PMMA, maintaining effective concentrations over up to six weeks.10,13,14
Despite these favorable characteristics, concerns exist regarding prolonged wound discharge, heterotopic ossification (HO), symptomatic hypercalcemia, acute renal failure, and potential implant damage 15–18.
Previous systematic reviews focused on single indications and incorporated relatively few studies 11,19–24. Moreover, no previous literature review has addressed infection prevention. The aim of this systematic review was to perform an updated evaluation of the evidence regarding the clinical outcomes and safety profile of CS in orthopaedics.
2 Methods
2.1 Strategy of the systematic search
The systematic review followed The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines25 and was registered in the International Prospective Register for Systematic Reviews and Meta-analyses (PROSPERO) under the registration number: CRD42023489317. Ethics approval was waived as this study analyzed only previously published data. The systematic search strategy for peer-reviewed original articles evaluating the effectiveness of antibiotic-loaded CS beads in orthopaedic surgery covered multiple databases including MEDLINE, Web of Science, Scopus, and ProQuest. All studies published from the inception of the databases to December 31st, 2024 were included. The following keywords were used combined using the Boolean terms AND and OR: "calcium sulfate beads" OR "local antibiotics" AND "prevention" OR "prophylaxis" OR "treatment" OR "therapy" AND "prosthetic joint infections" OR "bone infections" OR "osteomyelitis" OR "soft tissue infections".
2.2 Selection process and data extraction
After duplicates removal, screening of studies based on titles and abstracts was performed by two authors in a blinded and independent process. Discrepancies were resolved through consensus or consultation with the senior author. Selected studies were assessed for eligibility by evaluating full texts according to the predefined inclusion and exclusion criteria (Table 1). This systematic review focused exclusively on pure CS products, such as OsteoSet® and Stimulan®, while excluding composite formulations of CS with other materials (e.g. Cerament ®, Herafill ®, PerOssal ®), thereby reducing heterogeneity of data. Extracted patient characteristics included sample size, gender distribution, mean age, anatomical site involved, and follow-up duration. Documentation also covered etiology or treatment indication, Cierny-Mader classification,26 identified pathogens, and details regarding CS beads (commercial product, antibiotic selection, and placement). Additionally, data on concurrent systemic antibiotic therapy and surgical procedures, clinical outcomes, complication and reintervention rates were collected.
| Inclusion criteria | Exclusion criteria |
| Antibiotic-loaded calcium sulfate beads for prevention and treatment of orthopaedic infection | Non-English articles |
| Publication between from database inception to December 31st, 2024 | Reviews, hypothesis articles, surgical techniques, cadaveric or animal studies, case reports |
| Oxford Centre of Evidence-Based Medicine 2011 Levels of Evidence: I–IV | Abstract or full text not accessible |
| Insufficient or inadequate data for extraction | |
| Diabetic foot infection related osteomyelitis | |
| Studies focusing on paediatric patient population | |
| Use of carrier materials other than pure calcium sulfate | |
| Use of calcium sulfate in spine surgery |
Primary outcomes were infection eradication rate for studies evaluating osteomyelitis treatment, bone union rate for infected nonunions, and infection eradication rate for studies evaluating PJI treatment. Secondary outcomes included CS resorption, time to resorption, complications and reinterventions.
2.3 Risk of bias assessment
The methodological index for non-randomized studies (MINORS) criteria were used to assess risk of bias.27 MINORS evaluates eight items for noncomparative studies and an additional four for comparative studies, with each item scored 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate), yielding maximum scores of 16 and 24, respectively.
2.4 Statistical analysis
Meta-analysis was carried out using R version 4.2.1, for three primary outcome measures: infection eradication rate for osteomyelitis, bone union rate for infected nonunions, and infection eradication rate for PJI. Secondary outcomes were reported descriptively due to heterogeneous definitions and reporting. Since heterogeneity within the dataset was predicted, a random effects model was used. Effect sizes were pooled using the inverse-variance weighting method. The Paule-Mandel model was used to calculate the variance of distribution of effect sizes (τ2).28 Higgins and Thompson's I2 statistic was used to illustrate heterogeneity. Heterogeneity values above 40% were considered moderate, and those above 75% were considered highly heterogeneous.29 Prediction intervals were included to suggest a range into which other studies' effect size may fall.30,31 A P-value of <0.05 was used to determine statistical significance.
3 Results
3.1 Database search
The initial database search identified 2999 records. After duplicate removal and screening, 77 studies underwent full-text review, of which 41 were ultimately included (Fig. 1). 15,32–71. Studies comprised two prospective cohort studies35,66 (level II), 13 retrospective cohort studies 34,41,50,52–55,59,60,65,68,69,71 and one historically controlled prospective study57 (level III), as well as 20 retrospective case series 33,36–40,42–44,47–49,51,56,58,61,62,64,67,70 and five prospective case series15,32,45,46,63 (level IV). Notably, no randomized controlled trials were identified. Studies were categorized according to the indication for CS application: 23 studies examined CS in osteomyelitis treatment 32–35,37,38,41,43,45,47–51,55,56,59,61–64,66,67, 11 investigated PJI management,39,40,46,52,53,57,58,60,65,69,71 while two studies focused on PJI prophylaxis.54,68 Five studies reported combined cohorts encompassing more than one clinical indication for CS use without separate reporting, precluding allocation to a single category. These were classified as mixed indications.15,36,42,44,70
MINORS score ranged from 31 to 75%, with consistent limitations including lack of prospective sample size calculation and incomplete follow-up reporting.
3.2 Demographics and infection profile
3.2.1 Osteomyelitis treatment
Studies on osteomyelitis treatment included 1205 patients (1208 extremities) with a weighted mean follow-up of 32.9 months (range, 6 to 85.2). The tibia was most frequently affected (531/1,078, 49%) and Staphylococcus aureus was the most common pathogen (311/932, 33%). Demographics and treatment characteristics are detailed in Tables 2 and 3.
| First Author | Year | Level of Evidence | Number of patients (extremities) | Sex | Mean age, years (range) | Bone/joint involved (n) | Mean follow-up, months (range) | MINORS score (%) |
| Osteomyelitis treatment | ||||||||
| McKee | 2002 | II | 25 | 15 M, 10 W | 43 (27 to 69) | Tibia (15),Femur (6),Humerus (1),Radius/ulna (3) | 28 (20 to 38) | 75 |
| Gitelis | 2002 | IV | 6 | 3 M, 3 W | 50 (26 to 85) | Tibia (3),Femur (3) | 28 (18 to 40) | 38 |
| Chang | 2007 | III | 25 | NA | NA | NA | >36 | 46 |
| McKee | 2010 | II | 15 | 10 M, 5 W | 44.1 (16 to 86) | Tibia (8),Femur (4),Humerus (2),Radius/ulna (1) | >24 | 75 |
| Humm | 2014 | IV | 21 | 18 M, 3 W | 49 (26 to 88) | Tibia (21) | 16 (6 to 25) | 32 |
| Ferguson | 2014 | III | 193 (195) | 150 M, 43 W | 46.1 (16.1 to 82.0) | Tibia (88),Femur (73),Humerus (10),Radius/ulna (6),Pelvis (4),Foot/ankle (10),Knee (4) | 44.4 (15.6 to 85.2) | 75 |
| Ferrando | 2017 | IV | 13 | 9 M, 4 W | 48 (17 to 67) | Tibia (6),Femur (2),Humerus (1),Foot/ankle (4) | 22 (16 to 29) | 63 |
| Masrouha | 2018 | IV | 13 | 13 M | 35 (18 to 63) | Tibia (9),Femur (2),Humerus (2) | 24 | 44 |
| Badie | 2019 | IV | 30 | 25 M, 5 W | 26.2 (17 to 53) | Tibia (14),Femur (11),Humerus (2),Radius/ulna (3) | >12 | 44 |
| Qin | 2020 | IV | 33 | 27 M, 6 W | 44.5 (17 to 67) | Foot/ankle (33) | 35.9 (12 to 75) | 44 |
| Zhou | 2020 | IV | 42 (43) | 24 M, 19 W | 43.7 (23 to 74) | Tibia (43) | 42.8 (12.8 to 77.5) | 44 |
| Jiang | 2020 | IV | 34 | 27 M, 7 W | 41 (3 to 67) | Foot/ankle (34) | 26 (12 to 68) | 44 |
| Zhao | 2020 | III | 10 | 10 M | 48.2 (SD 19.2) | Tibia (5),Femur (5) | 20 (SD 5.4) | 63 |
| Ruan | 2021 | IV | 35 | 25 M, 10 W | 54 (34 to 82) | Tibia (35) | 38 (24 to 60) | 44 |
| Xu | 2022 | III | 41 | 30 M, 11 W | 47.3 (SD 16.2) | Foot/ankle (41) | >22 | 63 |
| Patel | 2023 | IV | 13 | 10 M, 3 W | 38 (22 to 66) | Tibia (10),Femur (3) | 19.7 (12 to 28) | 56 |
| McKee | 2023 | III | 106 | 68 M, 38 W | 44.2 (SD 14.2) | NA | NA | 46 |
| Du | 2023 | IV | 145 | 128 M, 17 W | 49.6 (20 to 84) | Tibia (78),Femur (41),Foot/ankle (15),Knee (5),Elbow (6) | NA | 31 |
| Casiraghi | 2023 | IV | 7 | 4 M, 3 W | 38.7 (16 to 53) | Pelvis (7) | 9 (6 to 16) | 38 |
| Mereddy | 2023 | II | 106 | 67 M, 33 W | 50 (11 to 79) | Tibia (28),Femur (46),Humerus (4),Radius/ulna (14)Foot/ankle (6),Hip (5),Knee (2),Shoulder (2)∗ | 20 (12 to 30) | 63 |
| Selvaratnam | 2023 | IV | 34 | 24 M, 10 W | 46.8 (20 to 67) | Tibia (16),Femur (14),Humerus (3),Radius/ulna (1) | 30 (16.8 to 79.2) | 50 |
| Palo | 2024 | II | 95 | 59 M, 36 W | 27.1 (SD 5.8) | Tibia (61),Femur (15),Humerus (19) | >12 | 75 |
| Su | 2024 | IV | 163 | 136 M, 27 W | 51 (18 to 85) | Tibia (91),Femur (39),Humerus (6),Radius/ulna (2)Foot/ankle (15),Knee (10) | >12 | 56 |
| Summary | 1205 (1208) | 882 M (75%),298 W (25%) | 45.1∗∗ (3 to 88) | Tibia (531, 49%),Femur (264, 24%),Humerus (50, 5%),Radius/ulna (30, 3%),Foot/ankle (158, 15%),Pelvis (11, 1%),Hip (2, 0.2%),Knee (24, 2%),Shoulder (2, 0.2%),Elbow (6, 0.6%)∗ | 32.9∗∗ (6 to 85.2) | 31 to 75 | ||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | ||||||||
| PJI treatment | ||||||||
| Kallala | 2015 | IV | 15 | 8 M, 7 W | 64.8 (41 to 83) | THA (7),Hip resurfacing (2)TKA (6) | 16 (12 to 22) | 50 |
| Flierl | 2017 | IV | 32 (33) | 22 M, 11 W | 62 (32 to 88) | THA (6),TKA (27) | 13 (3 to 30) | 31 |
| Sandiford | 2020 | IV | 29 | 13 M, 16 W | 67 (36 to 94) | THA (29) | 1.5 | 56 |
| Tarity | 2022 | III | 20 | 12 M, 8 W | 72.1 (SD 11.8) | THA (8),TKA (12) | >24 | 58 |
| Piovan | 2022 | III | 17 | 10 M, 7 W | 64.2 (SD 8.7) | TKA (17) | 16.1 (12 to 37) | 63 |
| Reinisch | 2022 | III | 27 | 16 M, 11 W | 71.3 (34.6 to 91.9) | THA (27) | >12 | 63 |
| Iorio | 2023 | III | 20 | 12 M, 8 W | 76 (SD 10.75) | TKA (20) | >12 | 54 |
| Indelli | 2023 | IV | 62 | 57 M, 5 W | 71 (62 to 77) | THA (19),TKA (37),TSA (6) | >24 (24 to 84) | 50 |
| De Meo | 2023 | III | 7 | 4 M, 3 W | 66.9 (SD 7.7) | THA (3),TKA (4) | 7.7 (SD 1.8) | 54 |
| Dimofte | 2024 | III | 45 | 30 M, 15 W | 66.7 (SD 11.9) | THA (45) | NA | 46 |
| Sigmund | 2024 | III | 102 | 42 M, 60 W | 76 (67 to 83) | THA (36),TKA (66) | 39 (23-57) | 63 |
| Summary | 376 (377) | 226 M (60%),151 W (40%) | 70.5∗∗ (32 to 94) | THA (182, 48%),TKA (189, 50%),TSA (6, 2%) | 24.8∗∗ (1.5 to 84) | 31 to 63 | ||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | ||||||||
| PJI prophylaxis | ||||||||
| Mohamed | 2022 | III | 48 | 28 M, 20 W | 62.2 (SD 12.6) | THA (48) | >24 | 63 |
| Zhang | 2024 | III | 35 | 9 M, 26 W | 64.0 (SD 7.9) | TKA (35) | 3 | 50 |
| Summary | 83 | 37 M (45%),46 W (55%) | 63.0∗∗ | THA (48, 58%),TKA (35, 42%) | 3∗∗ (3 to 24) | 50 to 63 | ||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | ||||||||
| Mixed indications | ||||||||
| McPherson | 2013 | IV | 250 | NA | NA | THA (108),TKA (142) | >3 | 38 |
| Menon | 2018 | IV | 39 | 28 M, 11 W | 51 (10 to 79) | NA | 25.7 (6 to 49) | 38 |
| Kallala | 2018 | IV | 755 | 374 M, 381 W | 63 (30 to 94) | THA (299),TKA (456) | 35 (0 to 78) | 50 |
| Lum | 2018 | IV | 56 | NA | NA | THA (30),TKA (26) | NA | 31 |
| Vallon | 2022 | IV | 215 | 138 M, 77 W | 69 (5 to 90) | NA | >12 | 56 |
| Summary | 1315 | 540 M (54%)469 W (46%) | 63.8∗∗ (10 to 94) | THA (437, 41%),TKA (624, 59%) | 34.5∗∗ (0 to 78) | 31 to 56 | ||
| First Author | Year | Etiology (n) | Cierny-Mader classification (n) | Isolated bacteria (n) | Calcium sulfate | Mean duration of Antibiotic Treatment, weeks (range) | Additional procedures (n) | ||
| Product | Antibiotics (n) | Placement | |||||||
| Osteomyelitis treatment | |||||||||
| McKee | 2002 | Posttraumatic (25) | I (1)III (6)IV (18)A (4)B (21) | S. aureus (9),S. epidermidis (4),P. aeruginosa (2)Polymicrobial (10) | OsteoSet-T | Tobramycin (25) | Defect | 7.2 (6 to 12) | Fixation (15),Soft tissue reconstruction (6) |
| Gitelis | 2002 | NA | NA | S. aureus (5),Polymicrobial (1) | OsteoSet-BVF | Tobramycin (5),Tobramycin + Vancomycin (1) | Intracavitary | 6 | - |
| Chang | 2007 | NA | NA | NA | OsteoSet | Tobramycin (19),Vancomycin (6) | Intracavitary | ≥2 | - |
| McKee | 2010 | Posttraumatic (14),Other (1) | I (5)III (4)IV (6)A (3)B (12) | S. aureus (3),S. epidermidis (3),Other (3)Polymicrobial (6) | OsteoSet-T | Tobramycin (15) | Intracavitary | 4.6 | - |
| Humm | 2014 | Posttraumatic (21) | III (7)IV (14)A (19)B (2) | S. aureus (4),CoNS (4),Other (6),Polymicrobial (4),Culture negative (3) | OsteoSet-T | Tobramycin (21) | Defect/intramedullary | (6 to 26.1) | Fixation (9),Soft tissue reconstruction (7) |
| Ferguson | 2014 | Hematogenous (57),Posttraumatic (110),Postoperative (23),Other (5) | I (12)II (1)III (144)IV (38)A (69)B (125)C (1) | S. aureus (49),MRSA (7),CoNS (10),P. aeruginosa (9),K. pneumoniae (1),E. coli (4),E. cloacae (3),Other (13)Polymicrobial (31),Culture negative (68) | OsteoSet-T | Tobramycin (195) | Defect | ≥6 (most patients) | Fixation (49),Soft tissue reconstruction (46) |
| Ferrando | 2017 | Posttraumatic (2),Postoperative (11) | NA | S. aureus (5),MRSA (2),P. aeruginosa (1),E. coli (1),E. cloacae (1),Other (2),Polymicrobial (1) | Stimulan | Vancomycin + Gentamicin (13) | Intracavitary | 8.9 (SD 1.7) | Soft tissue reconstruction (1) |
| Masrouha | 2018 | Posttraumatic (13) | IV (13) | S. aureus (2),CoNS (5),E. coli (2),E. cloacae (1),Polymicrobial (3) | Stimulan | Vancomycin + Gentamicin (13) | Defect | (0.4 to 0.7) | Fixation (13) |
| Badie | 2019 | Hematogenous (17),Posttraumatic (13) | NA | S. aureus (15),MRSA (3),K. pneumoniae (2),E. coli (2),Other (4),Polymicrobial (2),Culture negative (2) | Stimulan | Vancomycin + Gentamicin (30) | Defect | 6 | NA |
| Qin | 2020 | Posttraumatic (30),Other (3) | NA | S. aureus (7),P. aeruginosa (5),E. coli (1)E. faecalis (1),E. cloacae (2),Other (4),Polymicrobial (3),Culture negative (10) | Stimulan | NA | Defect | ≤2 | Soft tissue reconstruction (3) |
| Zhou | 2020 | Hematogenous (10),Posttraumatic (31),Other (2) | III (43),A (36),B (7) | S. aureus (11),P. aeruginosa (2),K. pneumoniae (1),E. coli (1),E. faecalis (1),E. cloacae (1),Other (3),Polymicrobial (1),Culture negative (22) | Stimulan | Vancomycin + Gentamicin (43) | Defect | ≤2 | Fixation (13),Soft tissue reconstruction (2) |
| Jiang | 2020 | Hematogenous (4),Posttraumatic (30) | III (34)A (3)B (31) | S. aureus (2),P. aeruginosa (5),E. coli (1),E. cloacae (2),Other (2),Polymicrobial (2),Culture negative (20) | Stimulan | Vancomycin + Gentamicin (34) | Defect | 6 | Soft tissue reconstruction (3) |
| Zhao | 2020 | Hematogenous (4),Posttraumatic (6) | NA | S. aureus (5),E. cloacae (1),Culture negative (4) | OsteoSet | Vancomycin (10) | Defect | 6.5 (SD 1.3) | Fixation (2),Soft tissue reconstruction (0) |
| Ruan | 2021 | Posttraumatic (35) | III (35)A (20)B (15) | S. aureus (4),S. epidermidis (1),P. aeruginosa (1),K. pneumoniae (2),E. coli (1),E. faecalis (1),Other (3),Polymicrobial (1),Culture negative (21) | OsteoSet | Vancomycin + Gentamicin (35) | Defect | 6 | Fixation (4, change from internal to external fixation),Soft tissue reconstruction (35) |
| Xu | 2022 | Posttraumatic (35),Other (6) | NA | S. aureus (9),P. aeruginosa (5),K. pneumoniae (1),E. coli (1),E. faecalis (2),E. cloacae (2),Other (8),Culture negative (13) | NA | NA | Defect | NA | NA |
| Patel | 2023 | Posttraumatic (13) | NA | S. aureus (5),MRSA (1),S. epidermidis (1),E. coli (1),Other (2),Culture negative (3) | Stimulan | Vancomycin + Gentamicin (13) | Intramedullary | 6.3 (2 to 12) | Fixation (3),Soft tissue reconstruction (2) |
| McKee | 2023 | NA | NA | NA | OsteoSet | NA | NA | NA | NA |
| Du | 2023 | NA | NA | NA | NA | Vancomycin (44),Gentamicin (39)Other (62) | Defect | NA | Soft tissue reconstruction (35) |
| Casiraghi | 2023 | Posttraumatic (5),Postoperative (2) | NA | S. aureus (2),K. pneumoniae (1),E. faecalis (1),Other (1),Culture negative (2) | Stimulan | Vancomycin + Gentamicin (7) | Near implant | 12 | NA |
| Mereddy | 2023 | Hematogenous (28),Postoperative (78) | I (8)II (4)III (82)IV (6)A (40)B (44)C (16) | S. aureus (28),MRSA (2),S. epidermidis (1),P. aeruginosa (5),K. pneumoniae (13),E. coli (5),E. faecalis (5),Other (7),Polymicrobial (8),Culture negative (27)∗ | Stimulan | NA | NA | NA | Soft tissue reconstruction (1) |
| Selvaratnam | 2023 | Hematogenous (6),Postoperative (28) | I (21)III (13)A (30)B (4) | S. aureus (18),MRSA (1),CoNS (6),P. aeruginosa (1),Other (4),Polymicrobial (10),Culture negative (4)∗ | Stimulan | Gentamicin (34) | NA | 6 | Soft tissue reconstruction (2) |
| Palo | 2024 | NA | NA | S. aureus (46),MRSA (28),S. epidermidis (9),P. aeruginosa (8),K. pneumoniae (4) | Stimulan | Vancomycin + Gentamicin (32),Other (63) | Defect | (4 to 6) | NA |
| Su | 2024 | Posttraumatic (91),Postoperative (32),Other (40) | III (163) | S. aureus (82),MRSA (22),S. epidermidis (11),P. aeruginosa (34),E. coli (8),Culture negative (6) | NA | NA | Defect | NA | Soft tissue reconstruction (45) |
| Summary | Hematogenous (98, 12%),Posttraumatic (474, 57%),Postoperative (174, 21%),Other (85, 10%) | I (47, 7%),II (5, 1%),III (531, 78%),IV (95, 14%),A (224, 45%),B (261, 52%),C (17, 3%) | S. aureus (311, 33%),MRSA (66, 7%),CoNS (25, 3%),S. epidermidis (30, 3%),P. aeruginosa (78, 8%),K. pneumoniae (25, 3%),E. coli (28, 3%),E. faecalis (11, 1%),E. cloacae (13, 1%),Other (62, 7%),Polymicrobial (83, 9%),Culture negative (205, 22%)∗ | Osteoset (9 studies, 45%; 438 procedures, 51%),Stimulan (11 studies, 55%; 421 procedures, 49%) | Tobramycin (280, 37%),Vancomycin (60, 8%),Gentamicin (73, 10%),Vancomycin + Gentamicin (220, 29%),Other (126, 17%) | 6.4∗∗ (0.4 to 26.1) | Fixation (108, 28%),Soft tissue reconstruction (188, 21%) | ||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | |||||||||
| PJI treatment | |||||||||
| Kallala | 2015 | NA | NA | S. aureus (3),S. epidermidis (4),P aeruginosa (1),E. faecalis (1),Other (3),Polymicrobial (3) | Stimulan | Vancomycin + Gentamicin (15) | Around joint | 6 | Hip resurfacing to THA (2),THA revision (7),TKA revision (6) |
| Flierl | 2017 | Hematogenous (19),Postoperative (14) | NA | S. aureus (13),MRSA (3),S. epidermidis (4),E. coli (1),Other (8),Polymicrobial (1),Culture negative (3) | Stimulan | Tobramycin + Vancomycin (33) | Deep wound | ≥6 | DAIR (33) |
| Sandiford | 2020 | NA | NA | NA | Stimulan | NA | Intracapsular | ≥6 | 1-stage (7),First-stage (4),Second stage (9),DAIR (6),Excision arthroplasty (1),Periprosthetic fracture (2) |
| Tarity | 2022 | NA | NA | S. aureus (7),MRSA (4),S. epidermidis (2),E. coli (1),E. cloacae (1),Other (3),Culture negative (2) | NA | Tobramycin + Vancomycin (18),NA (2) | Intracapsular | ≥6 | DAIR (20) |
| Piovan | 2022 | Hematogenous (5),Postoperative (12) | NA | S. aureus (1),CoNS (6),K. pneumoniae (1),E. coli (1),C. acnes (1),Other (4),Polymicrobial (1),Culture negative (2) | Stimulan | Tobramycin + Vancomycin (4),Vancomycin + Gentamicin (13) | Intracapsular | 11.6 (8 to 14) | DAIR (17) |
| Reinisch | 2022 | NA | NA | S. aureus (5),CoNS (10),P. aeruginosa (2),E. coli (2),C. acnes (1),Other (11)Polymicrobial (2),Culture negative (2)∗ | Osteoset | Tobramycin (2),Vancomycin (23),Other (2) | Intracapsular | 12 | DAIR (27) |
| Iorio | 2023 | NA | NA | S. aureus (7),MRSA (6),CoNS (4),Other (3) | Stimulan | NA | NA | 7.1 (SD 1.8) | First stage of 2-stage revision with implantation of antibiotic-loaded cement spacer (20) |
| Indelli | 2023 | NA | NA | NA | Stimulan | NA | Intracapsular | ≥12 | DAIR (62) |
| De Meo | 2023 | Hematogenous (4),Postoperative (3) | NA | S. aureus (2),CoNS (1),P. aeruginosa (1),E. coli (1), Polymicrobial (1),Culture negative (1) | Stimulan | Vancomycin + Gentamicin (6),Other (1) | Intracapsular | 12 | DAIR (7) |
| Dimofte | 2024 | NA | NA | NA | Stimulan | Vancomycin + Gentamicin (45) | Intracapsular | 6 | DAIR (26),First stage of 2-stage revision (19) |
| Sigmund | 2024 | Hematogenous (28),Postoperative (30),Chronic (44) | NA | S. aureus (30),CoNS (15),P. aeruginosa (2),Other (23),Polymicrobial (26),Culture negative (6) | Stimulan | Vancomycin + Gentamicin (99),Other (3) | Intracapsular | (12 to 24) | DAIR (102) |
| Summary | Hematogenous (56, 35%),Postoperative (59, 37%),Chronic (44, 28%) | S. aureus (68, 28%),MRSA (13, 5%),CoNS (36, 15%),S. epidermidis (10, 4%),P. aeruginosa (6, 2%),K. pneumoniae (1, 0.4%),E. coli (6, 2%),E. faecalis (1, 0.4%),E. cloacae (1, 0.4%),C. acnes (2, 1%),Other (55, 23%),Polymicrobial (34, 14%),Culture negative (16, 7%) | Osteoset (1 study, 10%, 27 procedures, 8%),Stimulan (9 studies, 90%; 330 procedures, 92%) | Tobramycin (2, 1%),Vancomycin (23, 9%),Tobramycin + Vancomycin (55, 21%),Vancomycin + Gentamicin (178, 67%),Other (6, 2%) | 8.5∗∗ (6 to 24) | DAIR (300, 80%),Infected revision TJA (77, 20%) | |||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | |||||||||
| PJI prophylaxis | |||||||||
| Mohamed | 2022 | PJI prophylaxis (48) | NA | NA | Stimulan | Tobramycin + Vancomycin (48) | Intracapsular | NA | 1-stage aseptic revision (48) |
| Zhang | 2024 | PJI prophylaxis (35) | NA | NA | Stimulan | Vancomycin (35) | Intramedullary (femur) | 0.3 | Primary TKA (35) |
| Summary | PJI prophylaxis (83, 100%) | Stimulan (2 studies, 100%; 83 patients, 100%) | Tobramycin + Vancomycin (48, 58%),Vancomycin (35, 42%) | 0.3 | Primary TJA (35, 42%),Revision TJA (48, 58%) | ||||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | |||||||||
| Mixed indications | |||||||||
| McPherson | 2013 | PJI (126),PJI prophylaxis (124) | NA | NA | Stimulan | Tobramycin + Vancomycin (250) | Intracapsular/around joint | NA | Aseptic revision THA (58),DAIR THA (8),Resection THA (24),Reimplantation THA (18),Aseptic revision TKA (66),DAIR TKA (16),Resection TKA (35),Reimplantation TKA (25) |
| Menon | 2018 | Posttraumatic (17),Infection, other (19),PJI (3) | NA | S. aureus (16),CoNS (2),P. aeruginosa (5),E. coli (7),Other (3),Polymicrobial (5),Culture negative (7)∗ | Stimulan | Vancomycin (17),Vancomycin + Gentamicin (4),Other (19)∗ | NA | 6 | Soft tissue reconstruction (6) |
| Kallala | 2018 | PJI (387),PJI prophylaxis (368) | NA | NA | Stimulan | Tobramycin + Vancomycin (755) | Intracapsular | NA | Aseptic revision TJA (368),DAIR (68),First stage of 2-stage revision (176),Second stage of 2-stage revision (143) |
| Lum | 2018 | PJI (14),PJI prophylaxis (42) | NA | NA | Stimulan | Tobramycin + Vancomycin + Cefazolin (56) | Wound | NA | Primary THA (5),Aseptic revision THA (19),Infected revision THA (6),Primary TKA (6),Aseptic revision TKA (12),Infected revision TKA (8) |
| Vallon | 2022 | PJI (127),Infection, other (88) | NA | NA | Osteoset | NA | NA | NA | NA |
| Summary | Infection, posttraumatic (17, 1%),Infection, other (107, 8%),PJI (657, 50%),PJI prophylaxis (534, 41%) | S. aureus (16, 36%),CoNS (2, 4%),P. aeruginosa (5, 11%),E. coli (7, 16%),Other (3, 7%),Polymicrobial (5, 11%),Culture negative (7, 16%)∗ | Osteoset (1 study, 20%; 215 procedures, 16%)Stimulan (4 studies, 80%;1100 procedures, 84%) | Vancomycin (17, 2%),Tobramycin + Vancomycin (1005, 91%),Vancomycin + Gentamicin (4, 0.4%),Other (75, 7%)∗ | 6∗∗ | Soft tissue reconstruction (6, 0.5%),Primary TJA (11, 1%)Aseptic revision TJA (523, 48%)DAIR (92, 8%)Infected revision TJA 435, 40%) | |||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | |||||||||
3.2.2 PJI treatment
The analysis included 11 studies with a total of 376 patients (377 arthroplasties) and a weighted mean follow-up of 24.8 months (range, 1.5 to 84). Affected arthroplasties included TKA in 50% (189/377) and THA in 48% (182/377) of cases (Table 2). The most commonly isolated bacteria were S. aureus (68/241, 28%) and coagulase negative staphylococci (36/241, 15%). CS was implanted for DAIR procedures in 80% (300/377) and infected revisions of total joint arthroplasty (TJA) in 20% (77/377) of cases. All studies administered antibiotics postoperatively for a weighted mean of 8.5 weeks (range, 6 to 24) (Table 3).
3.2.3 PJI prophylaxis
Prophylactic CS use in aseptic procedures to reduce PJI incidence was reported in only two studies with a total of 83 patients and a weighted mean follow-up of 3 months (Table 2). Cases were distributed between revisions (48/83, 58%) and primary TJA (35/83, 42%) (Table 3).
3.2.4 Mixed indications
Five studies encompassed 1315 patients with a weighted mean follow-up duration of 34.5 months (range, 0 to 78) (Table 2). Patients received CS for PJI treatment in 50% (657/1315) of cases, while 41% (534/1315) had CS for PJI prophylaxis (Table 3).
3.3 Outcomes
3.3.1 Osteomyelitis treatment
The pooled infection eradication rate for osteomyelitis was 88% (95% CI: 85 to 90%; 21 studies, n = 950) with low data heterogeneity (I2 = 19%, P = 0.24) (Fig. 2). Pooled bone union rate for infected nonunions was 93% (95% CI: 85 to 97%; 6 studies, n = 85; I2 = 36%, P = 0.21) (Fig. 3). Complete CS resorption occurred in all cases after a weighted mean of 2.4 months. Wound-related complications occurred in 17% (189/1086) of cases. Reintervention was required in 13% (120/931) of patients, primarily for infection recurrence (65/87, 75%) (Table 4).
| Osteomyelitis treatment | |||||||||
| First Author | Year | Infection eradication, n/N (%) | Bone union, n/N (%) | Time to bone union (months) | CS beads resorption, n/N (%) | Time to CS beads resorption (months) | Complications | Reintervention, n/N (%) | |
| Wound discharge and related complication, n/N (%) | Other (n) | ||||||||
| McKee | 2002 | 23/25 (92) | 14/16 (88) | 6.9 | 25/25 (100) | 2.7 | 8/25 (32) | Fracture (3) | 4/25 (16) |
| Gitelis | 2002 | 6/6 (100) | NA | NA | 6/6 (100) | NA | 0/6 (0) | Fracture (0) | 0/6 (0) |
| Chang | 2007 | 20/25 (80) | NA | NA | 25/25 (100) | NA | NA | Fracture (0),Death (0) | 3/25 (12) |
| McKee | 2010 | 12/14 (86) | 8/8 (100) | 9 | 14/14 (100) | 2 | 3/14 (21) | Fracture (2),Death (1, unrelated)Wound infection (1),Knee stiffness (1),Tibial nerve neuropraxia (1) | 5/14 (36) |
| Humm | 2014 | 20/21 (95) | NA | NA | NA | NA | 7/21 (33) | AKI (1) | 2/21 (10) |
| Ferguson | 2014 | 177/195 (91) | NA | NA | NA | NA | 36/195 (18) | Fracture (9),Fluid collection (9),Death (7, unrelated) | 21/195 (11) |
| Ferrando | 2017 | 12/13 (92) | NA | NA | NA | NA | NA | Hematoma/Seroma (2) | 1/13 (8) |
| Masrouha | 2018 | 13/13 (100) | 13/13 (100) | 5.5 | NA | NA | NA | NA | NA |
| Badie | 2019 | 23/30 (77) | NA | NA | 30/30 (100) | 2.4 | NA | Fracture (1) | NA |
| Qin | 2020 | 27/33 (82) | NA | NA | NA | NA | 13/33 (39) | Death (1, unrelated),Fracture (0) | 5/33 (15) |
| Zhou | 2020 | 38/43 (88) | NA | NA | NA | NA | 13/43 (30) | Pain (4),Weakness (4),Scarring (2)Joint stiffness (1),Claudication (1),Fracture (0) | 8/43 (19) |
| Jiang | 2020 | 29/34 (85) | NA | NA | NA | NA | 11/34 (32) | Death (1, unrelated),Fracture (0) | 6/34 (18) |
| Zhao | 2020 | 8/10 (80) | NA | NA | 10/10 (100) | NA | 3/10 (30) | NA | 2/10 (20) |
| Ruan | 2021 | 33/35 (94) | 34/35 (97) | 6.2 | NA | NA | 1/35 (3) | Iliac anterolateral numbness (5),Iliac hematocele (2) | 3/35 (9) |
| Xu | 2022 | 35/41 (85) | NA | NA | NA | NA | 11/41 (27) | Pain (29),Transient fever (7)Lameness (1),Fracture (0) | NA |
| Patel | 2023 | 13/13 (100) | 6/6 (100) | 8 | NA | NA | 0/13 (0) | Deformity (1) | 1/13 (8) |
| McKee | 2023 | NA | NA | NA | NA | NA | 31/106 (29) | NA | 33/106 (31) |
| Du | 2023 | NA | NA | NA | NA | NA | 27/145 (19) | NA | NA |
| Casiraghi | 2023 | 7/7 (100) | 7/7 (100) | 4.3 | NA | NA | 2/7 (29) | Hypercalcemia (0),HO (0) | NA |
| Mereddy | 2023 | 95/100 (95) | NA | NA | NA | NA | 8/100 (8) | Nonunion (4),Death (6, sepsis),Fracture (0) | 4/100 (4) |
| Selvaratnam | 2023 | 32/34 (94) | NA | NA | NA | NA | NA | NA | NA |
| Palo | 2024 | 95/95 (100) | NA | NA | 95/95 (100) | 2.4 | 2/95 (2) | NA | 2/95 (2) |
| Su | 2024 | 138/163 (85) | NA | NA | NA | NA | 13/163 (8) | NA | 20/163 (12) |
| Summary | 88% (95% CI: 85 to 90%) | 93% (95% CI: 85 to 97%) | 6.5∗∗ | 205/205 (100) | 2.4∗∗ | 189/1086 (17) | Fracture (15/546, 3%) | 120/931 (13) | |
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | |||||||||
| PJI treatment | |||||||||
| Kallala | 2015 | 14/15 (93) | NA | NA | 15/15 (100) | 1 | 0/15 (0) | Hypercalcemia (3, 1 symptomatic) | NA |
| Flierl | 2017 | 17/33 (52) | NA | NA | NA | NA | NA | NA | 7/33 (21) |
| Sandiford | 2020 | NA | NA | NA | 29/29 (100) | 1.5 | 1/29 (3) | Hypercalcemia (0),HO (0) | 1/29 (3) |
| Tarity | 2022 | 11/20 (55) | NA | NA | NA | NA | NA | NA | NA |
| Piovan | 2022 | 15/17 (88) | NA | NA | NA | NA | 0/17 (0) | Hypercalcemia (0),HO (0) | NA |
| Reinisch | 2022 | 23/27 (85) | NA | NA | NA | NA | NA | NA | 4/27 (15) |
| Iorio | 2023 | 20/20 (100) | NA | NA | NA | NA | NA | NA | 0/20 (0) |
| Indelli | 2023 | 48/62 (77) | NA | NA | NA | NA | 4/62 (6) | HO (1),Hypercalcemia (0) | 14/62 (23) |
| De Meo | 2023 | 7/7 (100) | NA | NA | NA | NA | 0/7 (0) | Hypercalcemia (0),HO (0) | 0/7 (0) |
| Dimofte | 2024 | 42/45 (93) | NA | NA | NA | NA | 1/45 (2) | Hypercalcemia (0),HO (0) | NA |
| Sigmund | 2024 | 65/102 (64) | NA | NA | NA | NA | 17/102 (17) | Hypercalcemia (9, 1 symptomatic),HO (8),Death (19, 3 due to PJI) | 35/102 (34) |
| Summary | 88% (95% CI: 76 to 95%)DAIR: 269/360 (75);Two-stage revision, first stage: 191/196 (97);Two-stage revision, second stage: 168/186 (90);Resection arthroplasty: 57/59 (97) | 44/44 (100) | 1.3∗∗ | 23/277 (8) | Hypercalcemia (12/277, 4%),HO (9/262, 3%) | 61/280 (22) | |||
| Summary data excludes studies with no reported data. Meta-analysis result for infection eradication includes above studies plus PJI eradication data from studies with mixed indications (McPherson 2013, Kallala 2018, Lum 2018; see Table 4, “Mixed indications” section).∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data) | |||||||||
| PJI prophylaxis | |||||||||
| Mohamed | 2022 | 3/48 (6) (incidence) | NA | NA | NA | NA | NA | NA | NA |
| Zhang | 2024 | 0/35 (0) (incidence) | NA | NA | NA | NA | NA | NA | NA |
| Summary | 3/83 (4)16/617 (3)◊ | ||||||||
| Summary data excludes studies with no reported data.∗Inconsistent report, ∗∗weighted mean (excluding studies with no reported data), ◊descriptive summary includes above studies plus PJI incidence data from studies with mixed indications (McPherson 2013, Kallala 2018, Lum 2018; see Table 4, “Mixed indications” section). | |||||||||
| Mixed indications | |||||||||
| McPherson | 2013 | 119/126 (94, eradication) ‡,6/124 (5, incidence) ◊ | NA | NA | NA | NA | 8/250 (3) | AKI (2),HO (3),Fracture (1),Death (4, unspecified) | 20/250 (8) |
| Menon | 2018 | 34/39 (87, eradication) | 7/8 (88) | NA | 39/39 (100) | 1.2 | 8/39 (21) | Death (2, sepsis) | 7/39 (18) |
| Kallala | 2018 | 360/387 (93, eradication) ‡,7/368 (2, incidence) ◊ | NA | NA | NA | NA | 32/755 (4) | Hypercalcemia (41, 2 symptomatic),HO (13),Death (14, unspecified) | 59/755 (8) |
| Lum | 2018 | 14/14 (100, eradication) ‡0/42 (0, incidence) ◊ | NA | NA | 56/56 (100) | NA | 1/56 (2) | HO (1) | 1/56 (2) |
| Vallon | 2022 | NA | NA | NA | NA | NA | NA | Hypercalcemia (2) | NA |
| Summary | 7/8 (88) | 95/95 (100) | 1.2∗∗ | 49/1100 (4) | Hypercalcemia (4/970, 0.4%)HO (17/1061, 2%) | 87/1100 (8) | |||
3.3.2 PJI treatment
The pooled PJI eradication rate was 88% (95% CI: 76 to 95 %; 13 studies, n = 875) with substantial data heterogeneity (I2 = 87%, P < 0.01) (Fig. 4). When analyzed by procedure type, eradication rates varied considerably: DAIR procedure achieved a 75% (269/360) success rate, two-stage revisions showed success rates of 97% (191/196) and 90% (168/186) for first and second stages respectively, while resection arthroplasty had a 97% (57/59) eradication rate. Complete CS resorption was observed in all cases after a weighted mean of 1.3 months. Wound discharge was documented in 8% (23/277) of cases. Additional complications included HO in nine cases (9/262, 3%) and hypercalcemia in 12 cases (12/277, 4%). Symptomatic hypercalcemia requiring treatment occurred in two cases. The reintervention rate was 22% (61/280), with infection recurrence accounting for 95% (21/22) of cases in which the cause for reoperation was documented (Table 4).
3.3.3 PJI prophylaxis and mixed indications
Incidence of PJI when CS was used for infection prophylaxis was reported in five studies.15,36,44,54,68 The overall infection incidence rate was 3% (16/617). Resorption of CS was achieved in all cases. Wound-related complications were observed in 4% (49/1100) of cases, while HO occurred in 17 cases (17/1,061, 2%). Symptomatic hypercalcemia requiring treatment consisting of a combination of hydration, intravenous bisphosphonates and subcutaneous calcitonin was reported in four cases. Reintervention was necessary in 8% (87/1100) of patients. The most common indication was infection recurrence, occurring in 44% (38/87) of reinterventions. New infections in prophylaxis cases accounted for 15% of reinterventions (13/87), while 16% (14/87) were caused by prosthetic instability (Table 4).
4 Discussion
This systematic review of 41 studies evaluated the outcomes and safety of antibiotic-loaded CS beads as an adjunct in orthopaedic surgery. Treatment protocols incorporating CS were associated with a pooled infection eradication rate of 88% (95% CI: 85 to 90%) in osteomyelitis across 21 studies, while the pooled bone union rate reached 93% (95% CI: 85 to 97%) among 85 patients with infected nonunion in six studies. For PJI treatment, the pooled infection eradication rate was 88 % (95% CI: 76 to 95%) across 13 studies, though accompanied by considerable data heterogeneity (I2 = 87%, P < 0.01), driven in part by two studies reporting markedly low infection eradication rates.40,52
These two studies encompassed 53 patients who received CS combined predominantly with tobramycin and vancomycin during DAIR procedures for acute early PJI, followed by a minimum of six weeks of intravenous antibiotics. The underlying reason for this discrepancy with the literature is not entirely clear. Both Flierl et al.40 and Tarity et al.52 lacked specification of symptoms duration and procedure timing, factors affecting biofilm formation. Additionally, Tarity et al.52 omitted modular component exchange in 40% of cases, potentially resulting in inadequate debridement. The high S. aureus isolation rates in both studies (48 to 55%)40,52 may partially explain their lower success rates, as S. aureus is associated with increased DAIR failure.72 Similarly, Sigmund et al.71 reported an infection eradication rate of 64% (65/102) in the largest DAIR cohort with CS beads to date, with a median follow-up of 39 months. Notably, 43% of cases were chronic PJI, which carried a substantially higher reinfection rate compared with early postoperative infections. The longer follow-up and high proportion of chronic cases likely contributed to the lower observed eradication rate in this cohort.
The pooled bone union rate of 93% (95% CI: 85 to 97%) for infected nonunions is consistent with rates reported for conventional approaches,73,74 though the osteoconductive properties of CS may provide additional benefit as a scaffold for bone regeneration.
Evidence for PJI prophylaxis remains limited. Five studies reported an overall infection rate of 3% (16/617) when CS was used for prophylactic purposes, primarily in aseptic revision arthroplasties (571/617, 93%). However, these results must be interpreted with caution. First, distinguishing between persisting occult infections and new infections in revision arthroplasty remains challenging, particularly given that negative preoperative or perioperative aspiration was documented only in 172 of 571 (30%) aseptic revision procedures. Second, the lack of high-quality data precluded meaningful statistical pooling of prophylaxis outcomes. Furthermore, both studies analyzing exclusively aseptic procedures54,68 found no statistically significant differences in infection incidence between CS and controls.
Overall, the interpretation of these pooled estimates requires considerable caution. The outcomes reported above reflect the combined effect of multimodal treatment protocols – including patient selection, thoroughness of surgical debridement, and systemic antibiotic regimens – rather than the isolated contribution of CS beads. In the absence of controlled comparisons, it remains undetermined whether the observed eradication and union rates would have differed without local CS application. The pooled proportions presented should therefore be understood as descriptive summaries of outcomes within CS-augmented protocols, not as evidence of independent therapeutic efficacy.
Despite these interpretative constraints, certain material properties of CS can be assessed independently of comparative efficacy data. Complete CS resorption was consistently achieved, representing a major advantage over non-absorbable antibiotic carriers such as PMMA. This eliminates the need for secondary surgical procedures to remove foreign material and minimizes complications from permanent implants.
Wound-related complications occurred in 17% (189/1086) of osteomyelitis cases. This phenomenon constitutes one of the primary concerns regarding CS use in surgical applications.15 A systematic review of comparative studies21 found higher wound leakage rates with CS in the management of osteomyelitis compared to other methods (wound irrigation-suction, PMMA beads or spacer, bioactive glass S53P4), though the difference did not reach statistical significance. Various factors have been discussed as possibly contributing to prolonged wound discharge, including CS composition and implanted amount.36 Du et al.61 investigated risk factors for serous exudation following treatment of fracture-related infections with additional antibiotic-loaded CS beads, identifying CS amount, combined flap surgery, and thinner soft tissue coverage as statistically significant predictors of serous exudation. In contrast, PJI treatment with CS demonstrated a markedly lower wound complication rate of only 8% (23/277), with most cases coming from a single study.71 PJI procedures allow intracapsular CS placement beneath a substantially thicker soft tissue envelope. Conversely, osteomyelitis cases, particularly those involving subcutaneous bone such as the tibia, have inherently limited soft tissue coverage and may demonstrate increased susceptibility to wound discharge.
Despite this substantial incidence, particularly in osteomyelitis cases, the clinical relevance of exudation following CS implantation requires careful interpretation. Authors advocated conservative management through frequent sterile dressing changes, with spontaneous resolution reported in most cases.32,48,49,55,63 Ferguson et al.38 demonstrated that postoperative wound leakage was not predictive of treatment failure, further supporting a conservative approach. Therefore, wound exudation should be evaluated in conjunction with additional clinical parameters rather than interpreted as definitive evidence of treatment failure or recurrent infection.
Beyond wound-related issues, CS demonstrated a favorable safety profile. Hypercalcemia occurred in 4% of PJI cases, though the majority were asymptomatic. A systematic review by Tarar et al.20 reported a hypercalcemia rate of 4.2% (44/1049), with only 0.3% (3/1049) of patients requiring treatment. Due to the low incidence and limited reporting of patient-specific risk factors for hypercalcemia, the optimal screening protocol to identify high-risk patients remains undefined. However, Kallala et al.15 observed that patients who developed hypercalcemia received larger beads volumes compared to those without complications, suggesting a dose-dependent relationship. These findings indicate that while hypercalcemia represents a recognized complication, the incidence of symptomatic hypercalcemia requiring therapeutic intervention remains low. Similarly, isolated cases of HO were documented in the reviewed literature. Given the substantially higher rates of HO reported in THA literature,75 there is no evidence to suggest that CS contributes to HO formation.
Several systematic reviews have previously examined antibiotic-loaded CS in orthopaedic infections, though each with a narrower scope. Abosala and Ali19 focused exclusively on PJI, synthesizing five studies, while Sheridan et al.21 conducted a meta-analysis limited to comparative studies on chronic osteomyelitis, also including five studies. Other reviews similarly concentrated on either osteomyelitis or infected nonunion and fracture-related infections.22,24 Notably, none of these reviews evaluated the use of CS for infection prophylaxis in aseptic procedures, which represents a growing area of clinical interest given the increasing volume of revision arthroplasty. The present review consolidates outcomes across the full spectrum of CS indications – osteomyelitis, infected nonunion, PJI treatment, and prophylaxis – within a single analysis of 41 studies, providing the most comprehensive overview of both efficacy and safety to date.
The following limitations should be considered when interpreting the current findings. Most studies were observational and of retrospective design with small constituent sample size despite the rather large overall sample size. Critically, no randomized controlled trials comparing the use of CS beads with alternative treatments and only two level II studies were identified, precluding causal inference regarding efficacy. Methodological inconsistencies and reporting deficiencies were frequent, as shown by the MINORS score results, and should be considered when interpreting the pooled estimates. Publication bias was not formally assessed through funnel plot analysis or statistical tests for small-study effects, which may have influenced the pooled estimates. The substantial variation in follow-up duration may have influenced reported infection eradication rates, as longer follow-up periods allow detection of late recurrence events that would be missed in shorter-term studies. Primary outcome definitions, particularly for infection eradication, varied across studies. For example, some studies defined eradication as absence of clinical signs of infection at final follow-up, while others required additional normalization of inflammatory markers. This variability necessitated reliance on individual authors’ criteria rather than standardized definitions. Substantial data heterogeneity was found in terms of clinical scenario, CS volume, surgical delivery site, choice of combined antibiotic/antifungal substance and additional systemic antibiotic therapy, which limited the feasibility of more detailed meta-analysis and precluded meaningful subgroup analysis. Additionally, no quantitative data on cost-effectiveness was reported.
5 Conclusion
Current evidence describes favorable infection eradication rates when antibiotic-loaded CS beads are used as an adjunct in orthopaedic infection management and prevention. However, the absence of randomized comparative trials precludes conclusions regarding independent efficacy. All studies showed complete CS resorption. The incidence of wound-related complications was substantial in osteomyelitis cases, while other adverse events were rare. Higher-quality comparative studies with standardized outcome definitions are required to better define the clinical role of CS as a biodegradable antibiotic delivery system and to determine whether routine adoption can be recommended.
Guardian/patient's consent
Not applicable.
CRediT authorship contribution statement
Alberto Pedrazzini: Writing — original draft, Writing — review & editing, Software, Resources, Project administration, Methodology, Investigation. Vishwa Suravaram: Writing — review & editing, Visualization, Validation, Supervision, Software, Resources, Data curation. Victor Yan Zhe Lu: Writing — review & editing, Visualization, Software, Resources, Project administration, Investigation, Formal analysis. Armando Hoch: Writing — review & editing, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Data curation. Patrick O. Zingg: Writing — review & editing, Visualization, Resources, Project administration, Methodology, Investigation. Octavian Andronic: Writing — review & editing, Supervision, Software, Resources, Project administration, Methodology, Formal analysis.
Ethics approval and consent to participate
Not applicable. This systematic review analyzed previously published data and did not involve direct patient contact or new data collection from human participants.
Availability of data and materials
All study associated data are stored on a local storage in the institutional database and are password-protected. These data can be accessed and reused. Requests should be forwarded to the corresponding author.
Ethics approval and consent to participate
Not applicable. This systematic review analyzed previously published data and did not involve direct patient contact or new data collection from human participants.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References
- Chronic osteomyelitis: results obtained by an integrated team approach to management. Conn Med. Apr 2005;69(4):195-202.
- [Google Scholar]
- Projected economic burden of periprosthetic joint infection of the hip and knee in the United States. J Arthroplast. May 2021;36(5):1484-1489.e3.
- [Google Scholar]
- What is the burden of osteomyelitis in Germany? An analysis of inpatient data from 2008 through 2018. BMC Infect Dis. Jun 10 2021;21(1):550.
- [Google Scholar]
- Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. Apr 2007;89(4):780-785.
- [Google Scholar]
- Bacteria drug resistance profile affects knee and hip periprosthetic joint infection outcome with debridement, antibiotics and implant retention. BMC Musculoskelet Disord. Aug 24 2020;21(1):574.
- [Google Scholar]
- Surgical treatment of osteomyelitis. Plast Reconstr Surg. Jan 2011;127(Suppl 1):190s-204s.
- [Google Scholar]
- A systematic review of the single-stage treatment of chronic osteomyelitis. J Orthop Surg Res. Nov 28 2019;14(1):393.
- [Google Scholar]
- Debridement, antibiotics, and implant retention (DAIR) for the early prosthetic joint infection of total knee and hip arthroplasties: a systematic review. J isakos. Feb 2024;9(1):62-70.
- [Google Scholar]
- The role of microbial biofilms in prosthetic joint infections. Acta Orthop. Apr 2015;86(2):147-158.
- [Google Scholar]
- Comparing PMMA and calcium sulfate as carriers for the local delivery of antibiotics to infected surgical sites. J Biomed Mater Res B Appl Biomater. May 2015;103(4):870-877.
- [Google Scholar]
- Review of calcium-sulphate-based ceramics and synthetic bone substitutes used for antibiotic delivery in PJI and osteomyelitis treatment. EFORT Open Rev. May 2021;6(5):297-304.
- [Google Scholar]
- The use of osteoconductive bone graft substitutes in orthopaedic trauma. J Am Acad Orthop Surg. Sep 2007;15(9):525-536.
- [Google Scholar]
- Elution profiles of tobramycin and vancomycin from high-purity calcium sulphate beads incubated in a range of simulated body fluids. J Biomater Appl. Sep 2016;31(3):357-365.
- [Google Scholar]
- Treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with a synthetic carrier of calcium sulphate (Stimulan) releasing moxifloxacin. Int J Antimicrob Agents. Apr 2009;33(4):354-359.
- [Google Scholar]
- Use of Stimulan absorbable calcium sulphate beads in revision lower limb arthroplasty: safety profile and complication rates. Bone Joint Res. Oct 2018;7(10):570-579.
- [Google Scholar]
- A case of hypercalcemia and antibiotic-related acute kidney injury following implantation of antibiotic impregnated calcium sulfate beads. Ann Lab Med. 2019;5:507-508.
- [Google Scholar]
- The effect of absorbable calcium sulfate on wear rates in ultra-high-molecular-weight polyethylene: potential implications for its use in treating arthroplasty infections. J Am Acad Orthop Surg. Jun 2017;25(6):e114-e120.
- [Google Scholar]
- The use of calcium sulphate beads in Periprosthetic joint infection, a systematic review. J Bone Jt Infect. 2020;5(1):43-49.
- [Google Scholar]
- The risk of iatrogenic hypercalcemia in patients undergoing calcium sulphate beads implantation in prosthetic joint surgery: a systematic review. Cureus. Oct 2021;13(10)
- [Google Scholar]
- Calcium sulfate in the management of osteomyelitis: a systematic review and meta-analysis of comparative studies. Medicine (Baltim). Nov 11 2022;101(45)
- [Google Scholar]
- Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: a systematic review and meta-analysis. J Orthop Surg Res. Feb 19 2022;17(1):104.
- [Google Scholar]
- The use of calcium sulphate beads in the management of osteomyelitis of femur and Tibia: a systematic review. Arch Bone Jt Surg. Apr 2022;10(4):320-327.
- [Google Scholar]
- The efficacy of antibiotic-impregnated calcium sulfate (AICS) in the treatment of infected non-union and fracture-related infection: a systematic review. J Bone Jt Infect. 2023;8(2):91-97.
- [Google Scholar]
- The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. Mar 29 2021;372
- [Google Scholar]
- A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res. Sep 2003;414:7-24.
- [Google Scholar]
- Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. Sep 2003;73(9):712-716.
- [Google Scholar]
- Consensus values, regressions, and weighting factors. J Res Natl Inst Stand Technol. May-Jun 1989;94(3):197-203.
- [Google Scholar]
- Quantifying heterogeneity in a meta-analysis. Stat Med. Jun 15 2002;21(11):1539-1558.
- [Google Scholar]
- Misunderstandings about Q and 'Cochran's Q test' in meta-analysis. Stat Med. Feb 20 2016;35(4):485-495.
- [Google Scholar]
- Basics of meta-analysis: I2 is not an absolute measure of heterogeneity. Res Synth Methods. 2017;8(1):5-18.
- [Google Scholar]
- The use of an antibiotic-impregnated, osteoconductive, bioabsorbable bone substitute in the treatment of infected long bone defects: early results of a prospective trial. J Orthop Trauma. Oct 2002;16(9):622-627.
- [Google Scholar]
- The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant. J Orthop Surg. Jun 2002;10(1):53-60.
- [Google Scholar]
- Adult osteomyelitis: debridement versus debridement plus Osteoset T pellets. Acta Orthop Belg. Apr 2007;73(2):238-243.
- [Google Scholar]
- A prospective, randomized clinical trial comparing an antibiotic-impregnated bioabsorbable bone substitute with standard antibiotic-impregnated cement beads in the treatment of chronic osteomyelitis and infected nonunion. J Orthop Trauma. Aug 2010;24(8):483-490.
- [Google Scholar]
- Dissolvable antibiotic beads in treatment of periprosthetic joint infection and revision arthroplasty - the use of synthetic pure calcium sulfate (Stimulan®) impregnated with Vancomycin & Tobramycin. Reconstructive Review. 2013;3
- [Google Scholar]
- Adjuvant treatment of chronic osteomyelitis of the tibia following exogenous trauma using OSTEOSET(®)-T: a review of 21 patients in a regional trauma centre. Strategies Trauma Limb Reconstr. Nov 2014;9(3):157-161.
- [Google Scholar]
- The use of a biodegradable antibiotic-loaded calcium sulphate carrier containing tobramycin for the treatment of chronic osteomyelitis: a series of 195 cases. Bone Joint J. Jun 2014;96-b(6):829-836.
- [Google Scholar]
- Hypercalcaemia following the use of antibiotic-eluting absorbable calcium sulphate beads in revision arthroplasty for infection. Bone Joint J. Sep 2015;97-b(9):1237-1241.
- [Google Scholar]
- Poor outcomes of irrigation and debridement in acute periprosthetic joint infection with antibiotic-impregnated calcium sulfate beads. J Arthroplast. Aug 2017;32(8):2505-2507.
- [Google Scholar]
- Treatment of cavitary bone defects in chronic osteomyelitis: bioactive glass S53P4 vs. calcium sulphate antibiotic beads. J Bone Jt Infect. 2017;2(4):194-201.
- [Google Scholar]
- Careful interpretation of the wound status is needed with use of antibiotic impregnated biodegradable synthetic pure calcium sulfate beads: series of 39 cases. J Bone Jt Infect. 2018;3(2):87-93.
- [Google Scholar]
- A novel treatment approach to infected nonunion of long bones without systemic antibiotics. Strategies Trauma Limb Reconstr. Apr 2018;13(1):13-18.
- [Google Scholar]
- Local bio-absorbable antibiotic delivery in calcium sulfate beads in hip and knee arthroplasty. J Orthop. Jun 2018;15(2):676-678.
- [Google Scholar]
- One-stage surgery for adult chronic osteomyelitis: concomitant use of antibiotic-loaded calcium sulphate and bone marrow aspirate. Int Orthop. May 2019;43(5):1061-1070.
- [Google Scholar]
- Complication rates are low with the use of Stimulan calcium sulphate based antibiotic delivery system in the management of patients with hip-related PJI: early results of a consecutive case series. Hip Int. Sep 2020;30(1_suppl):3-6.
- [Google Scholar]
- Extensive eggshell-like debridement technique plus antibiotic-loaded calcium sulphate for one-stage treatment of chronic calcaneal osteomyelitis. Foot Ankle Surg. Aug 2020;26(6):644-649.
- [Google Scholar]
- Single-stage treatment of chronic localized tibial osteomyelitis with local debridement and antibiotic-loaded calcium sulfate implantation: a retrospective study of 42 patients. J Orthop Surg Res. Jun 1 2020;15(1):201.
- [Google Scholar]
- Single-stage debridement with implantation of antibiotic-loaded calcium sulphate in 34 cases of localized calcaneal osteomyelitis. Acta Orthop. Jun 2020;91(3):353-359.
- [Google Scholar]
- The effect of calcium sulfate/calcium phosphate composite for the treatment of chronic osteomyelitis compared with calcium sulfate. Ann Palliat Med. Jul 2020;9(4):1821-1833.
- [Google Scholar]
- Gastrocnemius muscle flap with vancomycin/gentamicin-calcium sulfate and autogenous iliac bone graft for the phase I treatment of localized osteomyelitis after tibial plateau fracture surgery. J Orthop Surg Res. May 27 2021;16(1):341.
- [Google Scholar]
- Do antibiotic-loaded calcium sulfate beads improve outcomes after debridement, antibiotics, and implant retention? A matched cohort Study. Arthroplast Today. Apr 2022;14:90-95.
- [Google Scholar]
- The role of antibiotic calcium sulfate beads in acute periprosthetic knee infection: a retrospective cohort study. Arthroplasty. Sep 6 2022;4(1):42.
- [Google Scholar]
- Utilisation of calcium sulphate beads in one-stage aseptic revision total hip arthroplasty. Hip Int. Sep 2022;32(5):656-660.
- [Google Scholar]
- Antibiotic-Impregnated calcium sulfate vs. wound irrigation-suction to treat chronic calcaneal osteomyelitis. Foot Ankle Int. Mar 2022;43(3):331-342.
- [Google Scholar]
- Intramedullary application of local antibiotic bullets for the treatment of long bone fracture related infection. Eur J Orthop Surg Traumatol. Feb 2023;33(2):385-391.
- [Google Scholar]
- A modified technique for two-stage revision in knee PJI treatment. J Clin Med. Nov 26 2023;12(23)
- [Google Scholar]
- Debridement, antibiotic pearls, and retention of the implant (DAPRI) in the treatment of early periprosthetic joint infections: a consecutive series. Pathogens. Apr 16 2023;12(4)
- [Google Scholar]
- Chitosan sponges are associated with higher rates of wound complications compared to calcium sulfate beads. Cureus. May 2023;15(5)
- [Google Scholar]
- Hydrogel coating versus calcium sulphate beads as a local antibiotic carrier for debridement procedures in acute periprosthetic joint infection: a preliminary Study. Gels. Sep 18 2023;9(9)
- [Google Scholar]
- Analysis of risk factors for serous exudation of biodegradable material calcium sulfate in the treatment of fracture-related infections. Front Bioeng Biotechnol. 2023;11
- [Google Scholar]
- Implant retention with serial debridement and use of antibiotic-loaded calcium sulfate beads in acute fracture-related infection (FRI) after pelvic ring or acetabular fractures: a retrospective case series of 7 cases. Injury. Apr 2023;54(4):1082-1087.
- [Google Scholar]
- The use of Stimulan in bone and joint infections. Bone Jt Open. Jul 10 2023;4(7):516-522.
- [Google Scholar]
- Effectiveness of an antibiotic-impregnated bioabsorbable carrier for the treatment of chronic intramedullary and diffuse osteomyelitis. Strategies Trauma Limb Reconstr. Sep-Dec 2023;18(3):148-154.
- [Google Scholar]
- The efficacy of antibiotic-loaded calcium sulfate beads (Stimulan) in patients with hip arthroplasty infections. J Clin Med. Jul 9 2024;13(14)
- [Google Scholar]
- Role of STIMULAN in chronic osteomyelitis-A randomised blinded study on 95 patients comparing 3 antibiotic compositions, bead quality, forming & absorption time. J Clin Orthop Trauma. May 2024;52
- [Google Scholar]
- Analysis of risk factors for the recurrence of osteomyelitis of the limb after treatment with antibiotic-loaded calcium sulfate and autologous bone graft. Front Bioeng Biotechnol. 2024;12
- [Google Scholar]
- Inflammatory marker changes following total knee arthroplasty for rheumatoid arthritis with vancomycin-loaded calcium sulfate bone filling. J Knee Surg. Jan 2025;38(1):13-21.
- [Google Scholar]
- Local antibiotic treatment with calcium sulfate as carrier material improves the outcome of debridement, antibiotics, and implant retention procedures for periprosthetic joint infections after hip arthroplasty - a retrospective study. J Bone Jt Infect. 2022;7(1):11-21.
- [Google Scholar]
- The incidence of severe hypercalcaemia-induced mental status changes in patients treated with antibiotic-loaded calcium sulphate depot for orthopaedic infections. J Clin Med. Aug 20 2022;11(16)
- [Google Scholar]
- The use of antibiotic-loaded calcium sulphate beads in debridement, antibiotics, and implant retention (DAIR) for periprosthetic infections: a retrospective comparative cohort on outcome. Acta Orthop. Nov 29 2024;95:707-714.
- [Google Scholar]
- Efficacy of DAIR (Debridement, antibiotics, and implant retention) in total hip and knee arthroplasty: a systematic review and meta-analysis. J Arthroplast Jun 4 2025
- [Google Scholar]
- Septic tibial nonunions on proximal and distal Metaphysis-A systematic narrative review. Biomedicines. Jun 8 2023;11(6)
- [Google Scholar]
- Prospective randomised comparison of ring versus rail fixator in infected gap nonunion of tibia treated with distraction osteogenesis. Bone Joint J. Oct 2016;98-b(10):1399-1405.
- [Google Scholar]
- Incidence of heterotopic ossification following total hip arthroplasty by approach: a systematic review. Eur J Orthop Surg Traumatol. May 2024;34(4):2089-2098.
- [Google Scholar]