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Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery

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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotics Use and Antimicrobial Stewardship".

Deadline for manuscript submissions: closed (15 March 2025) | Viewed by 15055

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Prof. Dr. Christian O. Fölsch

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Guest Editor

1. Universitätsklinikum Gießen und Marburg, Gießen, Germany
2. Klinik für Orthopädie und Orthopädische Chirurgie, Klinikstraße 33, Gießen, Germany
Interests: biomaterials; arthroplasty; antibiotics in revision surgery

Prof. Dr. Klaus Dieter Kühn

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Guest Editor

Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
Interests: antibiotics

Special Issue Information

Dear Colleagues,

The increasing number of joint replacements worldwide leads to more infections of implants. Biofilm and antibiotic resistance still make the prevention and treatment of implant-associated infections challenging. The improvement of diagnostic procedures for the early detection of infections is important to improve outcomes and avoid the removal of implants.

Depending on the clinical situation and the bacterial detection, the treatment of choice might be the primary change of an implant, or a two-stage procedure is performed. Different regimes of antibiotic treatment are proposed, since the duration and choice of antibiotic application remain controversial.

Immediate antibiotic treatment is necessary to prevent biofilm formation. A combined systemic antibiotic treatment as well as the local application of antibiotics and antibacterial substances might improve the outcomes of infected implants. For two-stage revisions of joint replacements, the application of a cement spacer, including antibiotics, is established. The combination of several antibiotics and the dose applied are relevant for the antimicrobial effect, since their influence on the mechanic stability of the cement has to be considered. The duration of antibiotic treatment should be performed individually.

Prof. Dr. Christian O. Fölsch
Prof. Dr. Klaus Dieter Kühn
Guest Editors

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Keywords

biofilm
antibiotic resistance
implant-associated infections
local antibiotic application
cement spacer
antibacterial substances
antibiotic carrier

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Published Papers (9 papers)

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Research

18 pages, 2298 KiB

Open AccessArticle

High and Low Dosage of Vancomycin in Polymethylmethacrylate Cements: Efficacy and Mechanical Properties

by Jeffrey W. Kwong, Michael Abramowicz, Klaus Dieter Kühn, Christian Foelsch and Erik N. Hansen

Antibiotics 2024, 13(9), 818; https://doi.org/10.3390/antibiotics13090818 - 28 Aug 2024

Cited by 3 | Viewed by 1286

Abstract

Introduction: Prosthetic joint infections (PJIs) are difficult to treat and represent a significant burden to the healthcare system. Two-stage revision surgery with placement of an antibiotic-loaded cement spacer is currently the gold standard for treatment in the United States for late-onset infections. We evaluate the efficacy of varying doses of vancomycin added to antibiotic-containing acrylic cement spacers and discuss the biomechanical and antimicrobial properties of using high versus low doses of vancomycin in cement spacers in the hip and knee. Materials and Methods: Commercially available Copal cement containing either gentamicin and clindamycin (G + C) or gentamicin and vancomycin (G + V) was prepared with the manual addition of low (2 g) and high (6 g) doses of vancomycin. In vitro mechanical testing was then carried out according to ISO 5833 and DIN 53435, as well as inhibition zone assays against common PJI pathogens. Additionally, inhibition zone assays were conducted on two commercially available prefabricated spacers containing gentamicin: Copal Exchange G and Cemex Spacer-K. Results: In biomechanical testing, Copal G + V with the addition of 6 g of vancomycin failed to meet the ISO standard. Copal G + C and Copal G + V with low and high dosages of vancomycin were all effective against the tested pathogens and displayed constant efficacy for a duration of 42 days. High doses of vancomycin showed significantly lower mechanical stability. Moreover, Copal Exchange G showed significantly larger inhibition zones across 42 days. Discussion: While higher concentrations of vancomycin appear to improve the antimicrobial efficacy of cement, they also reduce its mechanical stability. Despite its smoother surface, the Copal Exchange G spacer exhibits large inhibition zones after 1 day and maintains consistently large inhibition zones over 6 weeks. Thus, it may be preferred for use in two-stage revision surgery. Conclusion: Copal Exchange G is more effective than Cemex Spacer K against S. aureus and E. coli. The manual addition of vancomycin to cement containing double antibiotics is very effective. The influence on ISO compression is low, the ISO bending modulus is increased, and ISO bending, DIN bending, and DIN impact, are reduced. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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12 pages, 5776 KiB

Open AccessArticle

Cemented Calcar-Guided Short-Stem Prostheses in Geriatric Patients: Short-Term Results from a Prospective Observational Study

by Bertram Regenbrecht, Ahmed Yaseen, Gideon Wagener and Michael Wild

Antibiotics 2024, 13(8), 739; https://doi.org/10.3390/antibiotics13080739 - 6 Aug 2024

Cited by 1 | Viewed by 1248

Abstract

Both cementless and cemented stems have exhibited favorable long-term outcomes in total hip arthroplasty. Nonetheless, in elderly patients, cemented hips offer an advantage due to their reduced risk of periprosthetic fractures. This study aimed to assess the initial outcomes of 28 patients who underwent unilateral cemented total hip arthroplasty utilizing a calcar-guided A2 stem (ARTIQO GmbH, Lüdinghausen, Germany). Various types of antibiotic-loaded bone cement were employed. During follow-up, we recorded demographic data and comorbidities and employed standardized clinical assessment tools, including the Harris Hip Score. Radiographic assessments included preoperative, postoperative, and follow-up imaging to evaluate subsidence, osteolysis, and bone resorption. The results indicated that among the 28 patients, 5 withdrew consent and 2 patients passed away from unrelated causes. Additionally, one prosthesis was explanted due to the undersizing of the cement stopper, which resulted in an inadequate cement mantle. As a result, 20 patients underwent a 1-year follow-up, revealing noteworthy enhancements in clinical scores, with no instances of radiolucent lines or osteolysis. No infections were detected. In summary, our short-term experience with this particular cemented short-stem design yielded promising results, exhibiting excellent functional outcomes, no aseptic loosening attributable to the stem, and no infections. Further clinical studies and registry data are essential to corroborate these findings. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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12 pages, 3002 KiB

Open AccessArticle

Impact of Manual Addition of Vancomycin to Polymethylmethacrylate (PMMA) Cements

by Clemens Kittinger, Michael Eder-Halbedl and Klaus Dieter Kühn

Antibiotics 2024, 13(8), 721; https://doi.org/10.3390/antibiotics13080721 - 1 Aug 2024

Viewed by 1116

Abstract

(1) Background: The addition of antibiotics to bone cements is a common practice in the treatment of periprosthetic joint infections. In revision cases, the amount and type of antibiotic is often insufficient and additional antibiotics must be added. The addition, however, changes the product itself, and the surgeon becomes the “manufacturer” of the bone cement. PMMAe wished to clarify whether the admixture of antibiotics changes the mechanical stability of the bone cements used and if the added antibiotics were still functional and released in sufficient quantities. (2) Methods: We compared two industrially manufactured vancomycin-containing PMMA cements; the low-viscous VancogenX^® (TECRES, Sommacampagna, Italy) and the high-viscous Copal^® G+V (Heraeus Medical GmbH, Wehrheim, Germany), with two PMMA cements loaded with aminoglycosides, to which 2.0 g of vancomycin (Hexal CT1631) were manually added—the high-viscous Smartset^® GHV and the medium-viscous Antibiotic Simplex with Tobramycin (antibiotic Simplex^® T). Test specimens of the bone cements were used to determine mechanical stability (bending strength and bending module), and the release of the antibiotics was determined by HLPC and modified Kirby–Bauer assays. (3) Results: All tested bone cements showed an initial high release within the first hours. Repeated testing after 24 h showed a reduced efficacy of VancogenX^® and Smartset^® GHV in Kirby–Bauer assays. Long-time release over days showed a release of functional antimicrobial active ingredients over this period of time in anti-microbial assays, but no activity of VancogenX^® from day 21 onward. No significant differences in the ISO bending modules could be detected, but in contrast to the bending module, the ISO bending strength was substantially reduced by 10–15 mPal in comparison to both cements of the reference group. The Simplex^®T met just the ISO 5833; the Smartset^® GHV did not after adding vancomycin. (4) Conclusions: In conclusion, the manual addition of 2 g of vancomycin to 40 g of PMMA powder is recommended for the treatment of methicillin-resistant staphylococci. Vancomycin is released over a period of 42 days with concentrations above the MIC for typical staphylococci. The mechanical properties of the PMMA just met, or did not fulfill, ISO mechanical specification. Copal^® G+V showed a better elution than VancogenX^® over time. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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14 pages, 3106 KiB

Open AccessEditor’s ChoiceArticle

Development of a Galleria mellonella Infection Model to Evaluate the Efficacy of Antibiotic-Loaded Polymethyl Methacrylate (PMMA) Bone Cement

by You Zhao, Gopala Krishna Mannala, Raphaëlle Youf, Markus Rupp, Volker Alt and Martijn Riool

Antibiotics 2024, 13(8), 692; https://doi.org/10.3390/antibiotics13080692 - 25 Jul 2024

Viewed by 1499

Abstract

Prosthetic joint infections (PJIs) can have disastrous consequences for patient health, including removal of the device, and placement of cemented implants is often required during surgery to eradicate PJIs. In translational research, in vivo models are widely used to assess the biocompatibility and antimicrobial efficacy of antimicrobial coatings and compounds. Here, we aim to utilize Galleria mellonella implant infection models to assess the antimicrobial activity of antibiotic-loaded bone cement (ALBC) implants. Therefore, we used commercially available bone cement loaded with either gentamicin alone (PALACOS R+G) or with a combination of gentamicin and vancomycin (COPAL G+V), compared to bone cement without antibiotics (PALACOS R). Firstly, the in vitro antimicrobial activity of ALBC was determined against Staphylococcus aureus. Next, the efficacy of ALBC implants was analyzed in both the G. mellonella hematogenous and early-stage biofilm implant infection model, by monitoring the survival of larvae over time. After 24 h, the number of bacteria on the implant surface and in the tissue was determined. Larvae receiving dual-loaded COPAL G+V implants showed higher survival rates compared to implants loaded with only gentamicin (PALACOS R+G) and the control implants without antibiotics (PALACOS R). In conclusion, G. mellonella larvae infection models with antibiotic-loaded bone cements are an excellent option to study (novel) antimicrobial approaches. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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21 pages, 6485 KiB

Open AccessArticle

Plasmid-Mediated Spread of Carbapenem Resistance in Enterobacterales: A Three-Year Genome-Based Survey

by Yancheng Yao, Can Imirzalioglu, Linda Falgenhauer, Jane Falgenhauer, Petra Heinmüller, Eugen Domann and Trinad Chakraborty

Antibiotics 2024, 13(8), 682; https://doi.org/10.3390/antibiotics13080682 - 23 Jul 2024

Cited by 5 | Viewed by 1675

Abstract

The worldwide emergence and dissemination of carbapenem-resistant Gram-negative bacteria (CRGNB) is a challenging problem of antimicrobial resistance today. Outbreaks with CRGNB have severe consequences for both the affected healthcare settings as well as the patients with infection. Thus, bloodstream infections caused by metallo-ß-lactamase-producing Enterobacterales can often have clinical implications, resulting in high mortality rates due to delays in administering effective treatment and the limited availability of treatment options. The overall threat of CRGNB is substantial because carbapenems are used to treat infections caused by ESBL-producing Enterobacterales which also exist with high frequency within the same geographical regions. A genome-based surveillance of 589 CRGNB from 61 hospitals across the federal state Hesse in Germany was implemented using next-generation sequencing (NGS) technology to obtain a high-resolution landscape of carbapenem-resistant isolates over a three-year period (2017–2019). The study examined all reportable CRGNB isolates submitted by participating hospitals. This included isolates carrying known carbapenemases (435) together with carbapenem-resistant non-carbapenemase producers (154). Predominant carbapenemase producers included Klebsiella pneumoniae, Escherichia coli, Citrobacter freundii and Acinetobacter baumannii. Over 80% of 375 carbapenem-resistant determinants including KPC-, NDM-, VIM- and OXA-48-like ones detected in 520 Enterobacterales were plasmid-encoded, and half of these were dominated by a few incompatibility (Inc) types, viz., IncN, IncL/M, IncFII and IncF(K). Our results revealed that plasmids play an extraordinary role in the dissemination of carbapenem resistance in the heterogeneous CRGNB population. The plasmids were also associated with several multispecies dissemination events and local outbreaks throughout the study period, indicating the substantial role of horizontal gene transfer in carbapenemase spread. Furthermore, due to vertical and horizontal plasmid transfer, this can have an impact on implant-associated infections and is therefore important for antibiotic-loaded bone cement and drug-containing devices in orthopedic surgery. Future genomic surveillance projects should increase their focus on plasmid characterization. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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16 pages, 2592 KiB

Open AccessArticle

Do High Doses of Multiple Antibiotics Loaded into Bone Cement Spacers Improve the Success Rate in Staphylococcal Periprosthetic Joint Infection When Rifampicin Cannot Be Employed?

by Lourdes Prats-Peinado, Tanya Fernández-Fernández, Miguel Márquez-Gómez, José Antonio Matas-Diaz, Mar Sánchez-Somolinos, Sofía de la Villa-Martínez, Javier Vaquero-Martín and Pablo Sanz-Ruiz

Antibiotics 2024, 13(6), 538; https://doi.org/10.3390/antibiotics13060538 - 10 Jun 2024

Viewed by 2023

Abstract

Rifampicin is one of the mainstays in treating staphylococcal prosthetic joint infection (PJI). However, discontinuation due to intolerance, drug interactions, and adverse events is common. Two-stage revision surgery remains the gold standard, with the number of revision arthroplasties steadily increasing. This study aims to evaluate the effectiveness and safety of a novel two-stage revision protocol for staphylococcal prosthetic joint infection (PJI) utilizing bone cement spacers loaded with multiple high doses of antibiotics. Additionally, it seeks to analyze outcomes in patients ineligible for rifampicin treatment. A retrospective review of 43 cases of staphylococcal hip and knee prosthetic joint infections (PJIs) from 2012 to 2020 was conducted. In all instances, a commercial cement containing 1 g of gentamicin and 1 g of clindamycin, augmented with 4 g of vancomycin and 2 g of ceftazidime, was employed to cast a spacer manually after thorough surgical debridement. We report an eradication rate of 82%, with no significant differences observed (p = 0.673) between patients treated with (84%, n = 19) and without rifampicin (79%, n = 24). There were no disparities in positive culture rates (7%), spacer replacement (18%), or survival analysis (p = 0.514) after an average follow-up of 68 months (range 10–147) in the absence of systemic toxicity and surgical complications superimposable to those previously reported. In conclusion, two-stage revision with local high doses of ceftazidime, vancomycin, gentamicin, and clindamycin demonstrates high effectiveness in treating staphylococcal PJIs. Notably, systemic rifampicin does not influence the outcomes. This protocol, with multiple high doses of antibiotics loaded into the bone cement spacer, is presented as a viable and safe alternative for patients unsuitable for rifampicin treatment. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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15 pages, 641 KiB

Open AccessArticle

Effect of Multiantibiotic-Loaded Bone Cement on the Treatment of Periprosthetic Joint Infections of Hip and Knee Arthroplasties—A Single-Center Retrospective Study

by Benedikt Paul Blersch, Florian Hubert Sax, Moritz Mederake, Sebastian Benda, Philipp Schuster and Bernd Fink

Antibiotics 2024, 13(6), 524; https://doi.org/10.3390/antibiotics13060524 - 3 Jun 2024

Cited by 2 | Viewed by 1655

Abstract

Background: Two-stage septic revision is the prevailing method for addressing late periprosthetic infections. Using at least dual-antibiotic-impregnated bone cement leads to synergistic effects with a more efficient elution of individual antibiotics. Recent data on the success rates of multiantibiotic cement spacers in two-stage revisions are rare. Methods: We conducted a retrospective follow-up single-center study involving 250 patients with late periprosthetic hip infections and 95 patients with prosthetic knee infections who underwent septic two-stage prosthesis revision surgery between 2017 and 2021. In accordance with the antibiotic susceptibility profile of the microorganisms, a specific mixture of antibiotics within the cement spacer was used, complemented by systemic antibiotic treatment. All patients underwent preoperative assessments and subsequent evaluations at 3, 6, 9, 12, 18, and 24 months post operation and at the most recent follow-up. Results: During the observation period, the survival rate after two-step septic revision was 90.7%. Although survival rates tended to be slightly lower for difficult-to-treat (DTT) microorganism, there was no difference between the pathogen groups (easy-to-treat (ETT) pathogens, methicillin-resistant staphylococci (MRS), and difficult-to-treat (DTT) pathogens). Furthermore, there were no differences between monomicrobial and polymicrobial infections. No difference in the survival rate was observed between patients with dual-antibiotic-loaded bone cement without an additional admixture (Copal^® G+C and Copal^® G+V) and patients with an additional admixture of antibiotics to proprietary cement. Conclusion: Employing multiple antibiotics within spacer cement, tailored to pathogen susceptibility, appears to provide reproducibly favorable success rates, even in instances of infections with DTT pathogens and polymicrobial infections. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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24 pages, 3326 KiB

Open AccessArticle

Impact of Anti-Mycotic Drugs on the Osteogenic Response of Bone Marrow Mesenchymal Stem Cells In Vitro

by Tim Niklas Bewersdorf, Jakob Hofmann, Sebastian Findeisen, Christian Schamberger, Thomas Lingner, Ulrike Sommer, Gerhard Schmidmaier and Tobias Grossner

Antibiotics 2024, 13(2), 186; https://doi.org/10.3390/antibiotics13020186 - 15 Feb 2024

Viewed by 1825

Abstract

The treatment of fungal bone infections and infected non-unions is a huge challenge in modern trauma and orthopedics, which normally contain the local and systemic administration of anti-fungal drugs. Although frequently used, little is known about the impact of systemic and locally administered fungicides on the osteogenic regenerative capabilities of infected bone tissue, especially upon the osteogenesis of human bone marrow mesenchymal stem cells (BM-hMSCs). This study evaluates the effects of the three most common fungicides for the systemic treatment of bone infections, Voriconazole (VOR), liposomal Amphotericin B (LAMB), and Fluconazole (FLU), as well as the effects of VOR and LAMB-loaded Polymethylmethacrylate (PMMA) cement chips in different concentrations upon the osteogenic response of BM-hMSCs in vitro. Within this study, we compared the ability of BM-hMSC to differentiate into osteoblast-like cells and synthesize hydroxyapatite as assessed by radioactive ^99mTechnetium-Hydroxydiphosphonate (^99mTc-HDP) labeling, cell proliferation, and analyses of supernatants upon various osteogenic parameters. Our results revealed that VOR added to the cell culture medium affects the osteogenic potential of BM-hMSC negatively, while there were no detectable effects of LAMB and FLU. Moreover, we showed dose-dependent negative effects of high- and extended-dose fungicide-loaded PMMA cement due to cytotoxicity, with a higher cytotoxic potential of VOR than LAMB, while low-dose fungicide-loaded PMMA had no significant effect on the osteogenic potential of BM-hMSC in vitro. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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14 pages, 3390 KiB

Open AccessArticle

Impact of Antibiotic-Loaded PMMA Spacers on the Osteogenic Potential of hMSCs

by Jakob Hofmann, Tim Niklas Bewersdorf, Ulrike Sommer, Thomas Lingner, Sebastian Findeisen, Christian Schamberger, Gerhard Schmidmaier and Tobias Großner

Antibiotics 2024, 13(1), 44; https://doi.org/10.3390/antibiotics13010044 - 3 Jan 2024

Cited by 7 | Viewed by 1756

Abstract

Antibiotic-loaded PMMA bone cement is frequently used in modern trauma and orthopedic surgery. Although many of the antibiotics routinely applied are described to have cytotoxic effects in the literature, clinical experience shows no adverse effects for bone healing. To determine the effects of antibiotic-loaded PMMA spacers on osteogenesis in vitro, we cultivated human bone marrow mesenchymal stem cells (BM-hMSCs) in the presence of PMMA spacers containing Gentamicin, Vancomycin, Gentamicin + Clindamycin as well as Gentamicin + Vancomycin in addition to a blank control (agarose) and PMMA containing no antibiotics. The cell number was assessed with DAPI staining, and the osteogenic potential was evaluated by directly measuring the amount of hydroxyapatite synthesized using radioactive ^99mTc-HDP labelling as well as measuring the concentration of calcium and phosphate in the cell culture medium supernatant. The results showed that Gentamicin and Vancomycin as well as their combination show a certain amount of cytotoxicity but no negative effect on osteogenic potential. The combination of Gentamicin and Clindamycin, on the other hand, led to a drastic reduction in both the cell count and the osteogenic potential. Full article

(This article belongs to the Special Issue Local Antibiotics: Antibiotic Loaded Bone Cement and Drug Containing Medical Devices in Orthopaedic Surgery)

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