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van Agtmaal JL, van Hoogstraten SWG, Arts JJC. Prosthetic Joint Infection Research Models in NZW Rabbits: Opportunities for Standardization-A Systematic Review. J Funct Biomater 2024; 15:307. [PMID: 39452605 PMCID: PMC11508679 DOI: 10.3390/jfb15100307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/08/2024] [Accepted: 10/10/2024] [Indexed: 10/26/2024] Open
Abstract
Prosthetic joint infection (PJI) is a major complication following total arthroplasty. Rising antimicrobial resistance (AMR) to antibiotics will further increase therapeutic insufficiency. New antibacterial technologies are being developed to prevent PJI. In vivo models are still needed to bridge the translational gap to clinical implementation. Though rabbit models have been used most frequently, there is no consensus about methodology and measured outcomes. The PubMed, Scopus, and EMBASE databases were searched for literature on PJI in rabbit models. Data extraction included bias control, experimental design, and outcome measures of the NZW rabbit models in the articles. A total of 60 articles were included in this systematic literature review. The articles were divided into six groups based on the PJI intervention: no intervention used (21%), revision surgery (14%), prevention with only antibiotics (21%), prevention with surface modifications (7%), prevention with coatings (23%), and others (14%). Despite the current availability of guidelines and recommendations regarding experimental design, bias control, and outcome measures, many articles neglect to report on these matters. Ultimately, this analysis aims to assist researchers in determining suitable clinically relevant methodologies and outcome measures for in vivo PJI models using NZW rabbits to test new antimicrobial technologies.
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Affiliation(s)
- Julia L. van Agtmaal
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Centre, 6229 Maastricht, The Netherlands; (J.L.v.A.); (S.W.G.v.H.)
| | - Sanne W. G. van Hoogstraten
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Centre, 6229 Maastricht, The Netherlands; (J.L.v.A.); (S.W.G.v.H.)
| | - Jacobus J. C. Arts
- Laboratory for Experimental Orthopaedics, Department of Orthopaedic Surgery, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Centre, 6229 Maastricht, The Netherlands; (J.L.v.A.); (S.W.G.v.H.)
- Department of Biomedical Engineering, Orthopaedic Biomechanics, Eindhoven University of Technology, 5612 Eindhoven, The Netherlands
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Jiang Y, Han P, Yin G, Wang Q, Feng J, Ruan Q, Xiao D, Zhang J. Radiosynthesis and Bioevaluation of 99mTc-Labeled Isocyanide Ubiquicidin 29-41 Derivatives as Potential Agents for Bacterial Infection Imaging. Int J Mol Sci 2024; 25:1045. [PMID: 38256119 PMCID: PMC10816394 DOI: 10.3390/ijms25021045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/08/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
To develop a novel 99mTc-labeled ubiquicidin 29-41 derivative for bacterial infection single-photon emission computed tomography (SPECT) imaging with improved target-to-nontarget ratio and lower nontarget organ uptake, a series of isocyanide ubiquicidin 29-41 derivatives (CNnUBI 29-41, n = 5-9) with different carbon linkers were designed, synthesized and radiolabeled with the [99mTc]Tc(I)+ core, [99mTc][Tc(I)(CO)3(H2O)3]+ core and [99mTc][Tc(V)N]2+ core. All the complexes are hydrophilic, maintain good stability and specifically bind Staphylococcus aureus in vitro. The biodistribution in mice with bacterial infection and sterile inflammation demonstrated that [99mTc]Tc-CN5UBI 29-41 was able to distinguish bacterial infection from sterile inflammation, which had an improved abscess uptake and a greater target-to-nontarget ratio. SPECT imaging study of [99mTc]Tc-CN5UBI 29-41 in bacterial infection mice showed that there was a clear accumulation in the infection site, suggesting that this radiotracer could be a potential radiotracer for bacterial infection imaging.
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Affiliation(s)
- Yuhao Jiang
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
| | - Peiwen Han
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
| | - Guangxing Yin
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
| | - Qianna Wang
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
| | - Junhong Feng
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
- Department of Isotopes, China Institute of Atomic Energy, P.O. Box 2108, Beijing 102413, China
| | - Qing Ruan
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
- Key Laboratory of Beam Technology of the Ministry of Education, College of Nuclear Science and Technology, Beijing Normal University, Beijing 100875, China
| | - Di Xiao
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
| | - Junbo Zhang
- Key Laboratory of Radiopharmaceuticals of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, China; (Y.J.); (P.H.); (G.Y.); (Q.W.); (J.F.); (Q.R.); (D.X.)
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Noriega-Álvarez E, Pena Pardo F, Jiménez Londoño G, García Vicente A. Molecular imaging techniques for the knee. CARTILAGE TISSUE AND KNEE JOINT BIOMECHANICS 2024:87-113. [DOI: 10.1016/b978-0-323-90597-8.00004-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Palestro CJ. Molecular Imaging of Periprosthetic Joint Infections. Semin Nucl Med 2023; 53:167-174. [PMID: 36496268 DOI: 10.1053/j.semnuclmed.2022.11.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022]
Abstract
Infection is an infrequent complication of lower extremity prosthetic joint surgery. Approximately one third develop within 3 months (early), another third within 1 year (delayed), and the remainder more than 1 year (late) after surgery. The diagnosis of periprosthetic joint infection is not always straightforward. Pain, the most common symptom, is present in 90%-100% of patients. The presence of fever is more variable, ranging from less than 5% to more than 40% of patients with infection. Erythema and joint swelling are often present in acute infections, but are less common in chronic infections. Erythrocyte sedimentation rate, C-reactive protein and interleukin-6 levels are useful "rule out" tests, while peripheral blood leukocyte count and serum tumor necrosis factor α are not helpful. The diagnosis of periprosthetic joint infection often requires a combination of blood, synovial fluid, and tissue sample tests, as well as imaging. Plain radiographs lack sensitivity and specificity. Molecular imaging is useful for evaluating painful joint replacements. Bone scintigraphy is most useful as a screening test. If it is negative then infection and aseptic loosening are unlikely. Combined labeled leukocyte/bone marrow imaging is a very specific test for diagnosing lower extremity joint arthroplasty infection; sensitivity is more variable. Despite more than two decades of investigation, there still is no consensus on the value of 18F-FDG for diagnosing periprosthetic joint infection. Differing test probabilities, an inability to discriminate between infection and inflammation secondary to physiologic reactions, and lack of standardized interpretative criteria are obstacles to incorporating 18F-FDG into the routine diagnostic imaging workup of periprosthetic joint infection. Preliminary results for gallium-68 citrate, fluorine-18, and technetium-99m labeled antimicrobial fragments are encouraging but no large scale trials with these agents have been conducted. Limited data suggest that labeled leukocyte/bone marrow SPECT/CT and 18F-FDG-PET/CT are specific but not sensitive for diagnosing periprosthetic infection of shoulder arthroplasties. There are minimal data on molecular imaging for monitoring treatment response in periprosthetic infections.
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Welling MM, Warbroek K, Khurshid C, van Oosterom MN, Rietbergen DDD, de Boer MGJ, Nelissen RGHH, van Leeuwen FWB, Pijls BG, Buckle T. A radio- and fluorescently labelled tracer for imaging and quantification of bacterial infection on orthopaedic prostheses : a proof of principle study. Bone Joint Res 2023; 12:72-79. [PMID: 36649933 PMCID: PMC9872039 DOI: 10.1302/2046-3758.121.bjr-2022-0216.r1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
AIMS Arthroplasty surgery of the knee and hip is performed in two to three million patients annually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiotics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria-specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on femoral implants using clinical-grade image guidance methods. METHODS 99mTc-UBI29-41-Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cultured on femoral prostheses using fluorescence imaging and freehand single photon emission CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria. RESULTS Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be complemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were identified using imaging, which included 500 to 2,000 viable bacteria. CONCLUSION The hybrid tracer 99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real-time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies.Cite this article: Bone Joint Res 2023;12(1):72-79.
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Affiliation(s)
- Mick M. Welling
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
| | - Kim Warbroek
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
| | - Chrow Khurshid
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
| | - Matthias N. van Oosterom
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
| | - Daphne D. D. Rietbergen
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
- Department of Radiology, Section Nuclear Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Mark G. J. de Boer
- Departments of Internal Medicine and Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | | | - Fijs W. B. van Leeuwen
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
| | - Bart G. Pijls
- Department of Orthopedics, Leiden University Medical Center, Leiden, Netherlands
| | - Tessa Buckle
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
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Signore A, Conserva M, Varani M, Galli F, Lauri C, Velikyan I, Roivainen A. PET imaging of bacteria. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00077-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Signore A, Lauri C, Micheli F, Baccini F. Gamma camera imaging of inflammatory bowel diseases. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00164-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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In Vitro and In Vivo Evaluation of 99mTc-Polymyxin B for Specific Targeting of Gram-Bacteria. Biomolecules 2021; 11:biom11020232. [PMID: 33562877 PMCID: PMC7915610 DOI: 10.3390/biom11020232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/31/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
Background: Infectious diseases are one of the main causes of morbidity and mortality worldwide. Nuclear molecular imaging would be of great help to non-invasively discriminate between septic and sterile inflammation through available radiopharmaceuticals, as none is currently available for clinical practice. Here, we describe the radiolabeling procedure and in vitro and in vivo studies of 99mTc-polymyxin B sulfate (PMB) as a new single photon emission imaging agent for the characterization of infections due to Gram-negative bacteria. Results: Labeling efficiency was 97 ± 2% with an average molar activity of 29.5 ± 0.6 MBq/nmol. The product was highly stable in saline and serum up to 6 h. In vitro binding assay showed significant displaceable binding to Gram-negative bacteria but not to Gram-positive controls. In mice, 99mTc-HYNIC-PMB was mainly taken up by liver and kidneys. Targeting studies confirmed the specificity of 99mTc-HYNIC-PMB obtained in vitro, showing significantly higher T/B ratios for Gram-negative bacteria than Gram-positive controls. Conclusions: In vitro and in vivo results suggest that 99mTc-HYNIC-PMB has a potential for in vivo identification of Gram-negative bacteria in patients with infections of unknown etiology. However, further investigations are needed to deeply understand the mechanism of action and behavior of 99mTc-HYNIC-PMB in other animal models and in humans.
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Xiao F, Cao B, Wang C, Guo X, Li M, Xing D, Hu X. Pathogen-Specific Polymeric Antimicrobials with Significant Membrane Disruption and Enhanced Photodynamic Damage To Inhibit Highly Opportunistic Bacteria. ACS NANO 2019; 13:1511-1525. [PMID: 30632740 DOI: 10.1021/acsnano.8b07251] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Highly pathogenic Gram-negative bacteria and their drug resistance are a severe public health threat with high mortality. Gram-negative bacteria are hard to kill due to the complex cell envelopes with low permeability and extra defense mechanisms. It is challenging to treat them with current strategies, mainly including antibiotics, peptides, polymers, and some hybrid materials, which still face the issue of drug resistance, limited antibacterial selectivity, and severe side effects. Together with precise bacteria targeting, synergistic therapeutic modalities, including physical membrane damage and photodynamic eradication, are promising to combat Gram-negative bacteria. Herein, pathogen-specific polymeric antimicrobials were formulated from amphiphilic block copolymers, poly(butyl methacrylate)- b-poly(2-(dimethylamino) ethyl methacrylate- co-eosin)- b-ubiquicidin, PBMA- b-P(DMAEMA- co-EoS)-UBI, in which pathogen-targeting peptide ubiquicidin (UBI) was tethered in the hydrophilic chain terminal, and Eosin-Y was copolymerized in the hydrophilic block. The micelles could selectively adhere to bacteria instead of mammalian cells, inserting into the bacteria membrane to induce physical membrane damage and out-diffusion of intracellular milieu. Furthermore, significant in situ generation of reactive oxygen species was observed upon light irradiation, achieving further photodynamic eradication. Broad-spectrum bacterial inhibition was demonstrated for the polymeric antimicrobials, especially highly opportunistic Gram-negative bacteria, such as Pseudomona aeruginosa ( P. aeruginosa) based on the synergy of physical destruction and photodynamic therapy, without detectable resistance. In vivo P. aeruginosa-infected knife injury model and burn model both proved good potency of bacteria eradication and promoted wound healing, which was comparable with commercial antibiotics, yet no risk of drug resistance. It is promising to hurdle the infection and resistance suffered from highly opportunistic bacteria.
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Affiliation(s)
- Fengfeng Xiao
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
| | - Bing Cao
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
| | - Congyu Wang
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
| | - Xujuan Guo
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
| | - Mengge Li
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
| | - Da Xing
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
| | - Xianglong Hu
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science , South China Normal University , Guangzhou 510631 , China
- College of Biophotonics , South China Normal University , Guangzhou 510631 , China
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10
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Zoller SD, Park HY, Olafsen T, Zamilpa C, Burke ZD, Blumstein G, Sheppard WL, Hamad CD, Hori KR, Tseng JC, Czupryna J, McMannus C, Lee JT, Bispo M, Romero Pastrana F, Raineri EJ, Miller JF, Miller LS, van Dijl JM, Francis KP, Bernthal NM. Multimodal imaging guides surgical management in a preclinical spinal implant infection model. JCI Insight 2019; 4:124813. [PMID: 30728332 DOI: 10.1172/jci.insight.124813] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/09/2019] [Indexed: 01/16/2023] Open
Abstract
Spine implant infections portend disastrous outcomes, as diagnosis is challenging and surgical eradication is at odds with mechanical spinal stability. Current imaging modalities can detect anatomical alterations and anomalies but cannot differentiate between infection and aseptic loosening, diagnose specific pathogens, or delineate the extent of an infection. Herein, a fully human monoclonal antibody 1D9, recognizing the immunodominant staphylococcal antigen A on the surface of Staphylococcus aureus, was assessed as a nuclear and fluorescent imaging probe in a preclinical model of S. aureus spinal implant infection, utilizing bioluminescently labeled bacteria to confirm the specificity and sensitivity of this targeting. Postoperative mice were administered 1D9 probe dual labeled with 89-zirconium (89Zr) and a bars represent SEM dye (NIR680) (89Zr-NIR680-1D9), and PET-CT and in vivo fluorescence and bioluminescence imaging were performed. The 89Zr-NIR680-1D9 probe accurately diagnosed both acute and subacute implant infection and permitted fluorescent image-guided surgery for selective debridement of infected tissue. Therefore, a single probe could noninvasively diagnose an infection and facilitate image-guided surgery to improve the clinical management of implant infections.
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Affiliation(s)
- Stephen D Zoller
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | - Howard Y Park
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | - Tove Olafsen
- Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
| | - Charles Zamilpa
- Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
| | - Zachary Dc Burke
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | - Gideon Blumstein
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | - William L Sheppard
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
| | | | - Kellyn R Hori
- David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | | | | | | | - Jason T Lee
- Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California, USA
| | - Mafalda Bispo
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Francisco Romero Pastrana
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Elisa Jm Raineri
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jeffery F Miller
- California NanoSystems Institute, UCLA, Los Angeles, California, USA.,Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, UCLA, Los Angeles, USA
| | - Lloyd S Miller
- Department of Orthopaedic Surgery.,Department of Dermatology, and.,Division of Infectious Disease, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jan Maarten van Dijl
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Kevin P Francis
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA.,PerkinElmer, Hopkinton, Massachusetts, USA
| | - Nicholas M Bernthal
- Department of Orthopedic Surgery, David Geffen School of Medicine at UCLA, Santa Monica, California, USA
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Bargon R, Bruenke J, Carli A, Fabritius M, Goel R, Goswami K, Graf P, Groff H, Grupp T, Malchau H, Mohaddes M, Novaes de Santana C, Phillips KS, Rohde H, Rolfson O, Rondon A, Schaer T, Sculco P, Svensson K. General Assembly, Research Caveats: Proceedings of International Consensus on Orthopedic Infections. J Arthroplasty 2019; 34:S245-S253.e1. [PMID: 30348560 DOI: 10.1016/j.arth.2018.09.076] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
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12
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Mukherjee A, Bhatt J, Shinto A, Korde A, Kumar M, Kamaleshwaran K, Joseph J, Sarma HD, Dash A. 68Ga-NOTA-ubiquicidin fragment for PET imaging of infection: From bench to bedside. J Pharm Biomed Anal 2018; 159:245-251. [PMID: 29990892 DOI: 10.1016/j.jpba.2018.06.064] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 06/29/2018] [Accepted: 06/30/2018] [Indexed: 10/28/2022]
Abstract
This study explores the possibility of formulation of a cold kit for fast and easy preparation of a PET radiopharmaceutical, 68Ga-NOTA-UBI (29-41) for clinical translation. In this study, Circular dichroism (CD) spectroscopy to study conformation of NOTA-UBI (29-41) and its comparison with conformation of UBI (29-41) was done. Pharmaceutical grade cold kits of NOTA-UBI (29-41) were formulated for radiolabeling with 68Ga and necessary quality control tests were carried out. 68Ga-NOTA-UBI (29-41) could be prepared in >90% radiochemical yield and radiochemical purity using cold kits of NOTA-UBI (29-41). In vitro and in vivo evaluation of 68Ga-NOTA-UBI (29-41) was done to demonstrate specificity of the agent for imaging infection. Kits were utilized for preparation of patient dose of 68Ga-NOTA-UBI (29-41). Simple instant thin layer chromatography (ITLC) method for estimating radiolabeling yield of 68Ga-NOTA-UBI (29-41) at hospital radiopharmacy was demonstrated. Clinical evaluation was done in patients with suspected infection. 148-185 MBq of 68Ga-NOTA-UBI (29-41) was injected intravenously in three patients. 68Ga-NOTA-UBI (29-41) uptake could clearly delineate infection foci from non target normal tissues. This is the first report on formulation of a cold kit of NOTA-UBI (29-41) for preparation of 68Ga labeled NOTA-UBI(29-41) at hospital radiopharmacy for infection imaging. Initial clinical evaluation reveal it to be a prospective agent for imaging infection.
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Affiliation(s)
- Archana Mukherjee
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC), Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India.
| | - Jyotsna Bhatt
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC), Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Ajit Shinto
- Kovai Medical Center and Hospital Limited, Coimbatore, India
| | - Aruna Korde
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC), Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - Mukesh Kumar
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre (BARC), Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
| | - K Kamaleshwaran
- Kovai Medical Center and Hospital Limited, Coimbatore, India
| | - Jephy Joseph
- Kovai Medical Center and Hospital Limited, Coimbatore, India
| | - Haladhar Dev Sarma
- Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre (BARC), Mumbai 400085, India
| | - Ashutosh Dash
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre (BARC), Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India
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Nielsen KM, Jørgensen NP, Kyneb MH, Borghammer P, Meyer RL, Thomsen TR, Bender D, Jensen SB, Nielsen OL, Alstrup AKO. Preclinical evaluation of potential infection-imaging probe [ 68 Ga]Ga-DOTA-K-A9 in sterile and infectious inflammation. J Labelled Comp Radiopharm 2018; 61:780-795. [PMID: 29790580 DOI: 10.1002/jlcr.3640] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 04/21/2018] [Accepted: 05/13/2018] [Indexed: 12/25/2022]
Abstract
The development of bacteria-specific infection radiotracers is of considerable interest to improve diagnostic accuracy and enabling therapy monitoring. The aim of this study was to determine if the previously reported radiolabelled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated peptide [68 Ga]Ga-DOTA-K-A9 could detect a staphylococcal infection in vivo and distinguish it from aseptic inflammation. An optimized [68 Ga]Ga-DOTA-K-A9 synthesis omitting the use of acetone was developed, yielding 93 ± 0.9% radiochemical purity. The in vivo infection binding specificity of [68 Ga]Ga-DOTA-K-A9 was evaluated by micro positron emission tomography/magnetic resonance imaging of 15 mice with either subcutaneous Staphylococcus aureus infection or turpentine-induced inflammation and compared with 2-deoxy-2-[18 F]fluoro-D-glucose ([18 F]FDG). The scans showed that [68 Ga]Ga-DOTA-K-A9 accumulated in all the infected mice at injected doses ≥3.6 MBq. However, the tracer was not found to be selective towards infection, since the [68 Ga]Ga-DOTA-K-A9 also accumulated in mice with inflammation. In a concurrent in vitro binding evaluation performed with a 5-carboxytetramethylrhodamine (TAMRA) fluorescence analogue of the peptide, TAMRA-K-A9, the microscopy results suggested that TAMRA-K-A9 bound to an intracellular epitope and therefore preferentially targeted dead bacteria. Thus, the [68 Ga]Ga-DOTA-K-A9 uptake observed in vivo is presumably a combination of local hyperemia, vascular leakiness and/or binding to an epitope present in dead bacteria.
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Affiliation(s)
- Karin M Nielsen
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Herlev, Denmark
- Department of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nis P Jørgensen
- Department of Infectious Diseases and Department of Clinical Microbiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Majbritt H Kyneb
- Biotech, Life Science, Danish Technological Institute, Aarhus, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Rikke L Meyer
- Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark
| | - Trine R Thomsen
- Biotech, Life Science, Danish Technological Institute, Aarhus, Denmark
- Department of Biotechnology, Aalborg University, Aalborg, Denmark
| | - Dirk Bender
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Svend B Jensen
- Department of Nuclear Medicine, Aalborg University Hospital, Aalborg, Denmark
- Department of Chemistry and Biochemistry, Aalborg University, Aalborg, Denmark
| | - Ole L Nielsen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Aage K O Alstrup
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark
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14
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Rozenblum-Beddok L, Verillaud B, Paycha F, Vironneau P, Abulizi M, Benada A, Cross T, El-Deeb G, Vodovar N, Peretti I, Herman P, Sarda-Mantel L. 99mTc-HMPAO-leukocyte scintigraphy for diagnosis and therapy monitoring of skull base osteomyelitis. Laryngoscope Investig Otolaryngol 2018; 3:218-224. [PMID: 30062138 PMCID: PMC6057221 DOI: 10.1002/lio2.159] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 03/05/2018] [Accepted: 03/17/2018] [Indexed: 11/06/2022] Open
Abstract
Objective Skull base osteomyelitis (SBO) is a rare but life‐threatening disease observed in elderly diabetic patients, with high risk of recurrence and difficult therapeutic management. The diagnosis is ascertained from a set of clinical, biological, and imaging findings. CT and MRI allow initial diagnosis, but are not accurate to affirm healing at the end of therapy. 99mTc‐HMPAO‐Leucocyte Scintigraphy (LS) is highly sensitive and specific for the detection of infection. The aim of this study was to evaluate LS i) for initial diagnosis, and ii) to confirm healing at the end of antibiotherapy in SBO. Study design We retrospectively reviewed from November 2011 to September 2015 all patients with confirmed SBO who underwent LS twice, at diagnosis and at the end of antibiotic therapy in our nuclear medicine department (n = 27). Methods Clinical, biological, CT, LS, and follow‐up data were recorded in all patients. LS images (planar and tomographic performed 4 hours and 24 hours after intravenous injection of autologous Tc‐99m‐HMPAO‐leucocytes) were visually assessed and quantified. Results At initial diagnosis, 25 of 27 patients had a positive LS. At the end of antibiotic therapy (3 ± 1 months duration), 26 of 27 patients had a negative LS. During subsequent follow‐up (= or >6 months), the disease recurred in four patients including three with a negative postantibiotherapy LS scan. Conclusion In this retrospective study, LS was powerful for initial diagnostic of SBO and for healing assessment at the end of antibiotic therapy. We conclude it is a useful technique for therapeutic monitoring of SBO. Level of Evidence 4
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Affiliation(s)
| | | | - Frédéric Paycha
- Service de Médecine Nucléaire, Hôpital Lariboisière Paris France.,Service d'Otorhinolaryngologie, Hôpital Lariboisière Paris France.,Paris Diderot Université Paris France
| | - Pierre Vironneau
- Service d'Otorhinolaryngologie, Hôpital Lariboisière Paris France
| | | | - Abdel Benada
- Service de Médecine Nucléaire, Hôpital Lariboisière Paris France
| | - Tumatarii Cross
- Service de Médecine Nucléaire, Hôpital Lariboisière Paris France.,Radiopharmacie, Hôpital Lariboisière Paris France
| | - Ghada El-Deeb
- Service de Médecine Nucléaire, Hôpital Lariboisière Paris France.,Radiopharmacie, Hôpital Lariboisière Paris France
| | | | - Ilana Peretti
- Service de Médecine Nucléaire, Hôpital Lariboisière Paris France.,Paris Diderot Université Paris France
| | - Philippe Herman
- Service d'Otorhinolaryngologie, Hôpital Lariboisière Paris France.,Paris Diderot Université Paris France
| | - Laure Sarda-Mantel
- Service de Médecine Nucléaire, Hôpital Lariboisière Paris France.,Inserm UMR-S942, Hôpital Lariboisière Paris France.,Paris Diderot Université Paris France
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15
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Auletta S, Baldoni D, Varani M, Galli F, Hajar IA, Duatti A, Ferro-Flores G, Trampuz A, Signore A. Comparison of 99mTc-UBI 29-41, 99mTc-ciprofloxacin, 99mTc-ciprofloxacin dithiocarbamate and 111In-biotin for targeting experimental Staphylococcus aureus and Escherichia coli foreign-body infections: an ex-vivo study. THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING : OFFICIAL PUBLICATION OF THE ITALIAN ASSOCIATION OF NUCLEAR MEDICINE (AIMN) [AND] THE INTERNATIONAL ASSOCIATION OF RADIOPHARMACOLOGY (IAR), [AND] SECTION OF THE SOCIETY OF RADIOPHARMACEUTICAL CHEMISTRY AND BIOLOGY 2017; 63:37-47. [PMID: 28849632 DOI: 10.23736/s1824-4785.17.02975-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335). METHODS Stability controls were performed with the labelled radiopharmaceuticals during 6 hours in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 °C and 4 °C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues. RESULTS Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 hours for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 hours for both E. coli and at 4 hours for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages. CONCLUSIONS 99mTc-UBI, 99mTcN-CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated.
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Affiliation(s)
- Sveva Auletta
- Unit of Nuclear Medicine, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy
| | - Daniela Baldoni
- Infectious Diseases Research Laboratory, Department of Biomedicine, University Hospital, Basel, Switzerland
| | - Michela Varani
- Unit of Nuclear Medicine, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy
| | - Filippo Galli
- Unit of Nuclear Medicine, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy
| | - Iman A Hajar
- Laboratory of Nuclear Medicine, Department of Radiological Sciences, University of Ferrara, Ferrara, Italy
| | - Adriano Duatti
- Laboratory of Nuclear Medicine, Department of Radiological Sciences, University of Ferrara, Ferrara, Italy
| | - Guillermina Ferro-Flores
- Department of Radioactive Material, National Institute of Nuclear Investigations, Center of Nuclear Applications on Health, Ocoyoacac, Mexico
| | - Andrej Trampuz
- Unit of Septic Surgery, Center for Musculoskeletal Surgery, Charité, University of Medicine, Berlin, Germany
| | - Alberto Signore
- Unit of Nuclear Medicine, Department of Medical-Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy -
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16
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Li H, Shen XF, Zhou XE, Shi YE, Deng LX, Ma Y, Wang XY, Li JY, Huang N. Antibacterial mechanism of high-mobility group nucleosomal-binding domain 2 on the Gram-negative bacteria Escherichia coli. J Zhejiang Univ Sci B 2017; 18:410-420. [PMID: 28471113 DOI: 10.1631/jzus.b1600139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To investigate the antibacterial mechanism of high-mobility group nucleosomal-binding domain 2 (HMGN2) on Escherichia coli K12, focusing on the antibacterial and antibiofilm formation effects. Its chemotactic activity on human neutrophils was also investigated. METHODS Human tissue-derived HMGN2 (tHMGN2) was extracted from fresh uterus fiber cystadenoma and purified by HP1100 reversed-phase high-performance liquid chromatography (RP-HPLC). Recombinant human HMGN2 (rHMGN2) was generated in E. coli DE3 carrying PET-32a-c(+)-HMGN2. Antibacterial activity of HMGN2 was determined using an agarose diffusion assay and minimum inhibitory concentration (MIC) of HMGN2 was determined by the microdilution broth method. Bacterial membrane permeability assay and DNA binding assay were performed. The antibiofilm effect of HMGN2 was investigated using a crystal violet assay and electron microscopy scanning. The activating effect and chemotactic activity of HMGN2 on neutrophils were determined using a nitroblue tetrazolium (NBT) reduction assay and Transwell chamber cell migration assay, respectively. RESULTS HMGN2 showed a relatively high potency against Gram-negative bacteria E. coli and the MIC of HMGN2 was 16.25 μg/ml. Elevated bacterial membrane permeability was observed in HMGN2-treated E. coli K12. HMGN2 could also bind the bacterial plasmid and genomic DNA in a dose-dependent manner. The antibiofilm effect of HMGN2 on E. coli K12 was confirmed by crystal violet staining and scanning electron microscopy. However, the activating effects and chemotactic effects of HMGN2 on human neutrophils were not observed. CONCLUSIONS As an antimicrobial peptide (AMP), HMGN2 possessed a good capacity for antibacterial and antibiofilm activities on E. coli K12. This capacity might be associated with disruption of the bacterial membrane and combination of DNA, which might affect the growth and viability of E. coli.
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Affiliation(s)
- Heng Li
- Research Unit of Infection and Immunity, Sichuan University, Chengdu 610041, China.,Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Xiao-Fei Shen
- Research Unit of Infection and Immunity, Sichuan University, Chengdu 610041, China.,Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Xin-E Zhou
- Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Yan-E Shi
- Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Lu-Xia Deng
- Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Yi Ma
- Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Xiao-Ying Wang
- Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Jing-Yu Li
- Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Ning Huang
- Research Unit of Infection and Immunity, Sichuan University, Chengdu 610041, China.,Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu 610041, China.,Sichuan University "985 Project Science and Technology Innovation Platform for Novel Drug Development", Sichuan University, Chengdu 610041, China
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17
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Clinical utility of 99mTc-ubiquicidin (29–41) as an adjunct to bone scan in differentiating infected versus noninfected loosening of prosthesis before revision surgery. Nucl Med Commun 2017; 38:285-290. [DOI: 10.1097/mnm.0000000000000648] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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18
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Kniess T, Laube M, Wüst F, Pietzsch J. Technetium-99m based small molecule radiopharmaceuticals and radiotracers targeting inflammation and infection. Dalton Trans 2017; 46:14435-14451. [DOI: 10.1039/c7dt01735a] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
99mTc-labeled antibiotics, antifungal drugs, antimicrobial peptides and COX-2 inhibitors are comprehensively reviewed.
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Affiliation(s)
- Torsten Kniess
- Helmholtz-Zentrum Dresden-Rossendorf
- Institute of Radiopharmaceutical Cancer Research
- 01328 Dresden
- Germany
| | - Markus Laube
- Helmholtz-Zentrum Dresden-Rossendorf
- Institute of Radiopharmaceutical Cancer Research
- 01328 Dresden
- Germany
| | - Frank Wüst
- University of Alberta
- Department of Oncology
- 11560 University Avenue
- Edmonton
- Canada
| | - Jens Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf
- Institute of Radiopharmaceutical Cancer Research
- 01328 Dresden
- Germany
- Technische Universität Dresden
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19
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Bhatt J, Mukherjee A, Korde A, Kumar M, Sarma HD, Dash A. Radiolabeling and Preliminary Evaluation of Ga-68 Labeled NODAGA-Ubiquicidin Fragments for Prospective Infection Imaging. Mol Imaging Biol 2016; 19:59-67. [DOI: 10.1007/s11307-016-0983-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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20
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Nielsen KM, Kyneb MH, Alstrup AKO, Jensen JJ, Bender D, Schønheyder HC, Afzelius P, Nielsen OL, Jensen SB. (68)Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: Selection, radiolabelling and preliminary biological evaluation. Nucl Med Biol 2016; 43:593-605. [PMID: 27474962 DOI: 10.1016/j.nucmedbio.2016.07.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 06/06/2016] [Accepted: 07/04/2016] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and (68)Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. METHODS Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine-serine-glycine spacer (GSG). The (68)Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA. Stability of (68)Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of (68)Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. RESULTS The (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA remained stable in product formulation, whereas (68)Ga-A8-K-DOTA was unstable. The S. aureus binding of (68)Ga-A11-GSGK-DOTA and (68)Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The (68)Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the (68)Ga-A9-K-DOTA. CONCLUSION The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected (68)Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.
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Affiliation(s)
- Karin M Nielsen
- Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Copenhagen, Denmark.
| | - Majbritt H Kyneb
- Section for Medical Biotechnology, Danish Technological Institute, DK-8000 Aarhus, Denmark
| | - Aage K O Alstrup
- Department of Nuclear Medicine and PET-centre, Aarhus University Hospital, DK-8000 Aarhus, Denmark
| | - Jakob J Jensen
- Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Section for Medical Biotechnology, Danish Technological Institute, DK-8000 Aarhus, Denmark
| | - Dirk Bender
- Department of Nuclear Medicine and PET-centre, Aarhus University Hospital, DK-8000 Aarhus, Denmark
| | - Henrik C Schønheyder
- Department of Clinical Microbiology, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, DK-9000 Aalborg, Denmark
| | - Pia Afzelius
- Department of Diagnostic Imaging, Section of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, North Zealand, DK-3400 Hillerød, Denmark
| | - Ole L Nielsen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Copenhagen, Denmark
| | - Svend B Jensen
- Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Department of Chemistry and Biochemistry, Aalborg University, DK-9000 Aalborg, Denmark
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21
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Love C, Palestro CJ. Nuclear medicine imaging of bone infections. Clin Radiol 2016; 71:632-46. [PMID: 26897336 DOI: 10.1016/j.crad.2016.01.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 12/24/2015] [Accepted: 01/04/2016] [Indexed: 02/08/2023]
Abstract
Osteomyelitis is a broad group of infectious diseases that involve the bone and/or bone marrow. It can arise haematogenously, via extension from a contiguous infection, or by direct inoculation during surgery or trauma. The diagnosis is not always obvious and imaging tests are frequently performed as part of the diagnostic work-up. Commonly performed radionuclide tests include technetium-99m ((99m)Tc)-diphosphonate bone scintigraphy (bone), and gallium-67 ((67)Ga) and in vitro labelled leukocyte (white blood cell; WBC) imaging. Although they are useful, each of these tests has limitations. Bone scintigraphy is sensitive but not specific, especially when underlying osseous abnormalities are present. (67)Ga accumulates in tumour, trauma, and in aseptic inflammation; furthermore, there is typically an interval of 1-3 days between radiopharmaceutical injection of and imaging. Currently, this agent is used primarily for spinal infections. Except for the spine, WBC imaging is the nuclear medicine test of choice for diagnosing complicating osteomyelitis. The in vitro leukocyte labelling process requires skilled personnel, is laborious, and is not always available. Complementary marrow imaging is usually required to maximise accuracy. Not surprisingly, alternative radiopharmaceuticals are continuously being investigated. Radiolabelled anti-granulocyte antibodies and antibody fragments, investigated as in vivo leukocyte labelling agents, have their own limitations and are not widely available. (111)In-biotin is useful for diagnosing spinal infections. Radiolabelled synthetic fragments of ubiquicidin, a naturally occurring human antimicrobial peptide that targets bacteria, have shown promise as infection specific radiopharmaceuticals. 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) with or without computed tomography (CT) is very useful in musculoskeletal infection. Sensitivities of more than 95% and specificities ranging from 75-99% have been reported in acute and subacute bone and soft-tissue infection. FDG is the radionuclide test of choice for spinal infection. It is sensitive, has a high negative predictive value, and can differentiate degenerative from infectious vertebral body end-plate abnormalities. Data on the accuracy of FDG for diagnosing diabetic pedal osteomyelitis and prosthetic joint infection are inconclusive and its role for these indications remains to be determined. Other PET radiopharmaceuticals that are under investigation as infection imaging agents include gallium-68 citrate ((68)Ga) and iodine-124 fialuridine ((124)I -FIAU).
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Affiliation(s)
- C Love
- Division of Nuclear Medicine, PET/CT Center, Montefiore Medical Center, 1695A Eastchester Road, Bronx, NY 11755, USA.
| | - C J Palestro
- Division of Nuclear Medicine & Molecular Imaging, Northwell Health, Manhasset & New Hyde Park, NY, USA
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22
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Arjun C, Mukherjee A, Bhatt J, Chaudhari P, Repaka KM, Venkatesh M, Samuel G. Studies on batch formulation of a kit for the preparation of the 99m Tc-Ubiquicidin (29-41): An infection imaging agent. Appl Radiat Isot 2016; 107:8-12. [DOI: 10.1016/j.apradiso.2015.09.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 08/01/2015] [Accepted: 09/07/2015] [Indexed: 10/23/2022]
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Gatin L, Saleh-Mghir A, Massin P, Crémieux AC. Critical analysis of experimental models of periprosthetic joint infection. Orthop Traumatol Surg Res 2015; 101:851-5. [PMID: 26454411 DOI: 10.1016/j.otsr.2015.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 08/01/2015] [Accepted: 08/25/2015] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Because the extreme diversity of clinical situations makes formal clinical trials difficult to carry out, animal models of periprosthetic infection in orthopaedics are needed to understand the aetiology and pathology of these infections, and to test new treatment methods. These experimental models must reproduce the features of the infections encountered in clinical practice. One of the model variables is the method of inoculation: local (intra-articular), intravenous or intra-arterial. Another is the timing of the inoculation: intra-operative or postoperative. Together, these options simulate the different contamination methods: direct, by proximity or blood-borne. However, the chosen inoculation route can also affect the infection rate and severity in the various models, and in some cases do not accurately reproduce the postoperative infections encountered clinically. HYPOTHESIS The direct inoculation method is the most effective for inducing a local infection on a foreign body in a joint, and the least iatrogenic. METHODS A critical analysis of published studies was carried out to evaluate each model against three endpoints, according to the type of inoculation. The primary endpoint was the infection rate, which should be as close as possible to 100%. The secondary endpoints were the mortality rate and rate of spontaneous healing, both of which should be as low as possible. Twenty-one articles were reviewed. RESULTS Intra-articular and intra-medullary inoculations had induction rates between 70 and 100%; intra-arterial inoculations had an induction rate of 100%, while intravenous inoculation had a rate of 47 to 77%. The mortality rates were lower with the intra-articular and intramedullary inoculations (5 to 23%) than for the intra-arterial inoculations (37%) and intravenous inoculations (28 to 56%). The spontaneous healing rate was 0 to 30% for intra-articular and intramedullary inoculations, 30 to 53% for intravenous inoculations and 0% for intra-arterial inoculations. CONCLUSION Direct inoculation methods are most effective at reproducing chronic periprosthetic joints infections, without putting the animal's life at risk or allowing for spontaneous healing. The simulation of blood-borne infections is more random.
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Affiliation(s)
- L Gatin
- EA 3647, université de Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France.
| | - A Saleh-Mghir
- EA 3647, université de Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France; Service de maladies infectieuses, hôpital Raymond-Poincaré, 92380 Garches, France
| | - P Massin
- Département de chirurgie orthopédique et traumatologique, hôpitaux universitaires Paris Nord-Val-de-Seine, 46, rue Henri-Huchard, 75877 Paris cedex 18, France; EA 7334 REMES (recherche clinique coordonnée Ville, hôpital, méthodologies et société), université Paris-Diderot, Sorbonne Paris Cité, 75010 Paris, France
| | - A-C Crémieux
- EA 3647, université de Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France; Service de maladies infectieuses, hôpital Raymond-Poincaré, 92380 Garches, France
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Abstract
Radionuclide procedures frequently are performed as part of the diagnostic workup of osteomyelitis. Bone scintigraphy accurately diagnoses osteomyelitis in bones not affected by underlying conditions. Degenerative joint disease, fracture, and orthopedic hardware decrease the specificity of the bone scan, making it less useful in these situations. Gallium-67 scintigraphy was often used as an adjunct to bone scintigraphy for diagnosing osteomyelitis. However, now it is used primarily for spinal infections when (18)F-FDG imaging cannot be performed. Except for the spine, in vitro-labeled leukocyte imaging is the nuclear medicine test of choice for diagnosing complicating osteomyelitis. Leukocytes accumulate in bone marrow as well as in infection. Performing complementary bone marrow imaging with (99m)Tc-sulfur colloid facilitates the differentiation between osteomyelitis and normal marrow and improves test overall accuracy. Antigranulocyte antibodies and antibody fragments, such as (99m)Tc-besilesomab and (99m)Tc-sulesomab, were developed to eliminate the disadvantages associated with in vitro-labeled leukocytes. These agents, however, have their own shortcomings and are not widely available. As biotin is used as a growth factor by certain bacteria, (111)In-biotin is useful to diagnose spinal infections. Radiolabeled synthetic fragments of ubiquicidin, a naturally occurring human antimicrobial peptide that targets bacteria, can differentiate infection from sterile inflammation and may be useful to monitor response to treatment. (18)F-FDG is extremely useful in the diagnostic workup of osteomyelitis. Sensitivity in excess of 95% and specificity ranging from 75%-99% have been reported. (18)F-FDG is the radionuclide test of choice for spinal infection. The test is sensitive, with a high negative predictive value, and reliably differentiates degenerative from infectious vertebral body end-plate abnormalities. Data on the accuracy of (18)F-FDG for diagnosing diabetic pedal osteomyelitis are contradictory, and its role for this indication remains to be determined. Initial investigations suggested that (18)F-FDG accurately diagnoses prosthetic joint infection; more recent data indicate that it cannot differentiate infection from other causes of prosthetic failure. Preliminary data on the PET agents gallium-68 and iodine-124 fialuridine indicate that these agents may have a role in diagnosing osteomyelitis.
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Affiliation(s)
- Christopher J Palestro
- Department of Radiology Hofstra, NorthShore-LIJ School of Medicine, Hempstead, NY; Division of Nuclear Medicine and Molecular Imaging, North Shore Long Island Jewish Health System, Manhasset & New Hyde Park, NY.
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Kamaleshwaran KK, Rajkumar N, Mohanan V, Kalarikal R, Shinto AS. 99m-Tc-ubiquicidin scintigraphy in diagnosis of knee prosthesis infection and comparison with F-18 fluorodeoxy-glucose positron emission tomography/computed tomography. Indian J Nucl Med 2015; 30:259-62. [PMID: 26170572 PMCID: PMC4479918 DOI: 10.4103/0972-3919.158540] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Total knee arthroplasty has witnessed a significant increase in recent years. Despite the advantages of this surgical procedure, it has some complications, the most serious of which is prosthetic infection. The discrimination of bacterial infections from sterile inflammatory processes is of great importance in the management of periprosthetic infection (PPI). Ubiquicidin (UBI) is a synthetic antimicrobial peptide fragment reported to be highly infection-specific. Tc99m-UBI has recently been reported to be a promising radiotracer for infection imaging. We report a case of left knee PPI diagnosed using 99mTc-UBI scintigraphy and compared with F-18 fluorodeoxy-glucose positron emission tomography.
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Affiliation(s)
| | - N Rajkumar
- Department of Orthopedics, Ganga Medical Centre and Hospitals Private Limited, Coimbatore, Tamil Nadu, India
| | - Vyshak Mohanan
- Department of Nuclear Medicine, PET/CT and Radionuclide Therapy, Kovai Medical Center and Hospital Limited, Coimbatore, Tamil Nadu, India
| | - Radhakrishnan Kalarikal
- Department of Nuclear Medicine, PET/CT and Radionuclide Therapy, Kovai Medical Center and Hospital Limited, Coimbatore, Tamil Nadu, India
| | - Ajit Sugunan Shinto
- Department of Nuclear Medicine, PET/CT and Radionuclide Therapy, Kovai Medical Center and Hospital Limited, Coimbatore, Tamil Nadu, India
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26
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van Oosten M, Hahn M, Crane LMA, Pleijhuis RG, Francis KP, van Dijl JM, van Dam GM. Targeted imaging of bacterial infections: advances, hurdles and hopes. FEMS Microbiol Rev 2015; 39:892-916. [PMID: 26109599 DOI: 10.1093/femsre/fuv029] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2015] [Indexed: 02/06/2023] Open
Abstract
Bacterial infections represent an increasing problem in modern health care, in particular due to ageing populations and accumulating bacterial resistance to antibiotics. Diagnosis is rarely straightforward and consequently treatment is often delayed or indefinite. Therefore, novel tools that can be clinically implemented are urgently needed to accurately and swiftly diagnose infections. Especially, the direct imaging of infections is an attractive option. The challenge of specifically imaging bacterial infections in vivo can be met by targeting bacteria with an imaging agent. Here we review the current status of targeted imaging of bacterial infections, and we discuss advantages and disadvantages of the different approaches. Indeed, significant progress has been made in this field and the clinical implementation of targeted imaging of bacterial infections seems highly feasible. This was recently highlighted by the use of so-called smart activatable probes and a fluorescently labelled derivative of the antibiotic vancomycin. A major challenge remains the selection of the best imaging probes, and we therefore present a set of target selection criteria for clinical implementation of targeted bacterial imaging. Altogether, we conclude that the spectrum of potential applications for targeted bacterial imaging is enormous, ranging from fundamental research on infectious diseases to diagnostic and therapeutic applications.
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Affiliation(s)
- Marleen van Oosten
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands
| | - Markus Hahn
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands
| | - Lucia M A Crane
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands
| | - Rick G Pleijhuis
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands
| | | | - Jan Maarten van Dijl
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands
| | - Gooitzen M van Dam
- Department of Surgery, Division of Surgical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen, the Netherlands
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Tang C, Wang F, Hou Y, Lu S, Tian W, Xu Y, Jin C, Wang L. Technetium-99m-labeled annexin V imaging for detecting prosthetic joint infection in a rabbit model. J Biomed Res 2015; 29:224-31. [PMID: 26060446 PMCID: PMC4449490 DOI: 10.7555/jbr.29.20130113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 09/03/2013] [Accepted: 05/07/2014] [Indexed: 02/01/2023] Open
Abstract
Accurate and timely diagnosis of prosthetic joint infection is essential to initiate early treatment and achieve a favorable outcome. In this study, we used a rabbit model to assess the feasibility of technetium-99m-labeled annexin V for detecting prosthetic joint infection. Right knee arthroplasty was performed on 24 New Zealand rabbits. After surgery, methicillin-susceptible Staphylococcus aureus was intra-articularly injected to create a model of prosthetic joint infection (the infected group, n = 12). Rabbits in the control group were injected with sterile saline (n = 12). Seven and 21 days after surgery, technetium-99m-labeled annexin V imaging was performed in 6 rabbits of each group. Images were acquired 1 and 4 hours after injection of technetium-99m-labeled annexin V (150 MBq). The operated-to-normal-knee activity ratios were calculated for quantitative analysis. Seven days after surgery, increased technetium-99m-labeled annexin V uptake was observed in all cases. However, at 21 days a notable decrease was found in the control group, but not in the infected group. The operated-to-normal-knee activity ratios of the infected group were 1.84 ± 0.29 in the early phase and 2.19 ± 0.34 in the delay phase, both of which were significantly higher than those of the control group (P = 0.03 and P = 0.02). The receiver operator characteristic curve analysis showed that the operated-to-normal-knee activity ratios of the delay phase at 21 days was the best indicator, with an accuracy of 80%. In conclusion, technetium-99m-labeled annexin V imaging could effectively distinguish an infected prosthetic joint from an uninfected prosthetic joint in a rabbit model.
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Affiliation(s)
- Cheng Tang
- Department of Orthopedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Feng Wang
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Yanjie Hou
- Department of Radiation Oncology, the First Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Shanshan Lu
- Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Wei Tian
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Yan Xu
- Department of Orthopedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Chengzhe Jin
- Department of Orthopedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
| | - Liming Wang
- Department of Orthopedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, China
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Welling MM, Bunschoten A, Kuil J, Nelissen RGHH, Beekman FJ, Buckle T, van Leeuwen FWB. Development of a Hybrid Tracer for SPECT and Optical Imaging of Bacterial Infections. Bioconjug Chem 2015; 26:839-849. [PMID: 25853214 DOI: 10.1021/acs.bioconjchem.5b00062] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In trauma and orthopedic surgery, infection of implants has a major impact on the outcome for patients. Infections may develop either during the initial implantation or during the lifetime of an implant. Both infections, as well as aseptic loosening of the implant, are reasons for revision of the implants. Therefore, discrimination between aseptic-mechanical-loosening and septic-bacterial-loosening of implants is critical during selection of a patient-tailored treatment policy. Specific detection and visualization of infections is a challenge because it is difficult to discriminate infections from inflammation. An imaging tracer that facilitates bacterial identification in a pre- and intraoperative setting may aid the workup for patients suspicious of bacterial infections. In this study we evaluated an antimicrobial peptide conjugated to a hybrid label, which contains both a radioisotope and a fluorescent dye. After synthesis of DTPA-Cy5-UBI29-41 and-when necessary-radiolabeling with (111)In (yield 96.3 ± 2.7%), in vitro binding to various bacterial strains was evaluated using radioactivity counting and confocal fluorescence microscopy. Intramuscular bacterial infections (S. aureus or K. pneumoniae) were also visualized in vivo using a combined nuclear and fluorescence imaging system. The indium-111 was chosen as label as it has a well-defined coordination chemistry, and in pilot studies labeling DTPA-Cy5-UBI29-41 with technetium-99m, we encountered damage to the Cy5 dye after the reduction with SnCl2. As a reference, we used the validated tracer (99m)Tc-UBI29-41. Fast renal excretion of (111)In-DTPA-Cy5-UBI29-41 was observed. Target to nontarget (T/NT) ratios were highest at 2 h post injection: radioactivity counting yielded T/NT ratios of 2.82 ± 0.32 for S. aureus and 2.37 ± 0.05 for K. pneumoniae. Comparable T/NT ratios with fluorescence imaging of 2.38 ± 0.09 for S. aureus and 3.55 ± 0.31 for K. pneumoniae were calculated. Ex vivo confocal microscopy of excised infected tissues showed specific binding of the tracer to bacteria. Using a combination of nuclear and fluorescence imaging techniques, the hybrid antimicrobial peptide conjugate DTPA-Cy5-UBI29-41 was shown to specifically accumulate in bacterial infections. This hybrid tracer may facilitate integration of noninvasive identification of infections and their extent as well as real-time fluorescence guidance during surgical resection of infected areas.
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Affiliation(s)
| | | | | | | | - Freek J Beekman
- §Delft University of Technology, 2628 CD Delft, The Netherlands
- ∥MILabs, 3584 CX Utrecht, The Netherlands
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29
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The use of nuclear imaging for the diagnosis of periprosthetic infection after knee and hip arthroplasties. Nucl Med Commun 2015; 36:305-11. [DOI: 10.1097/mnm.0000000000000266] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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30
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Chest wall osteomyelitis after breast cancer surgery. A case series. Enferm Infecc Microbiol Clin 2014; 33:210-1. [PMID: 25200215 DOI: 10.1016/j.eimc.2014.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 04/21/2014] [Accepted: 05/12/2014] [Indexed: 11/24/2022]
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31
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Palestro CJ. Nuclear medicine and the failed joint replacement: Past, present, and future. World J Radiol 2014; 6:446-458. [PMID: 25071885 PMCID: PMC4109096 DOI: 10.4329/wjr.v6.i7.446] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Revised: 02/26/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Soon after the introduction of the modern prosthetic joint, it was recognized that radionuclide imaging provides useful information about these devices. The bone scan was used extensively to identify causes of prosthetic joint failure. It became apparent, however, that although sensitive, regardless of how the images were analyzed or how it was performed, the test was not specific and could not distinguish among the causes of prosthetic failure. Advances in anatomic imaging, notably cross sectional modalities, have facilitated the diagnosis of many, if not most, causes of prosthetic failure, with the important exception of infection. This has led to a shift in the diagnostic paradigm, in which nuclear medicine investigations increasingly have focused on diagnosing infection. The recognition that bone scintigraphy could not reliably diagnose infection led to the development of combined studies, first bone/gallium and subsequently leukocyte/bone and leukocyte/marrow imaging. Labeled leukocyte imaging, combined with bone marrow imaging is the most accurate (about 90%) imaging test for diagnosing joint arthroplasty infection. Its value not withstanding, there are significant disadvantages to this test. In-vivo techniques for labeling leukocytes, using antigranulocyte antibodies have been explored, but have their own limitations and the results have been inconsistent. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) has been extensively investigated for more than a decade but its role in diagnosing the infected prosthesis has yet to be established. Antimicrobial peptides bind to bacterial cell membranes and are infection specific. Data suggest that these agents may be useful for diagnosing prosthetic joint infection, but large scale studies have yet to be undertaken. Although for many years nuclear medicine has focused on diagnosing prosthetic joint infection, the advent of hybrid imaging with single-photon emission computed tomography(SPECT)/electronic computer X-ray tomography technique (CT) and the availability of fluorine-18 fluoride PET suggests that the diagnostic paradigm may be shifting again. By providing the anatomic information lacking in conventional radionuclide studies, there is renewed interest in bone scintigraphy, performed as a SPECT/CT procedure, for detecting joint instability, mechanical loosening and component malpositioning. Fluoride-PET may provide new insights into periprosthetic bone metabolism. The objective of this manuscript is to provide a comprehensive review of the evolution of nuclear medicine imaging of joint replacements.
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Kahrom M, Mehrabi Bahar M, Jangjoo A, Erfani M, Sadeghi R, Zakavi SR. Poor sensitivity of 99mTc-labeled ubiquicidin scintigraphy in diagnosis of acute appendicitis. Eur Surg 2014. [DOI: 10.1007/s10353-014-0278-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Liu GD, Yu HJ, Ou S, Luo X, Ni WD, Huang XK, Chen JY, Wang Y, Javard P, Fei J. Human beta-defensin-3 for the diagnosis of periprosthetic joint infection and loosening. Orthopedics 2014; 37:e384-90. [PMID: 24762845 DOI: 10.3928/01477447-20140401-61] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 11/22/2013] [Indexed: 02/03/2023]
Abstract
In this study, the difference in expression of human beta-defensin-3 in periprosthetic tissue and cancellous bone was observed in the periprosthetic tissue and cancellous bone of patients in the periprosthetic joint infection group, the aseptic loosening group, and the spacer treatment group as well as the synovial membrane and ilium of the normal control group. Hematoxylin and eosin staining of the synovial tissue showed different levels of neutrophil infiltration in all groups except for the normal control group. Immunofluorescence staining of periprosthetic tissue and cancellous bone showed the most positive cells expressing human beta-defensin-3 and the largest mean optical density in the periprosthetic joint infection group, followed by the aseptic loosening group, the spacer treatment group, and the normal control group, with a significant difference in comparison between the periprosthetic joint infection group and the other 3 groups (P<.01). White blood cell count, erythrocyte sedimentation rate, and C-reactive protein level were highest in the periprosthetic joint infection group, whereas no difference was found between the other 3 groups. Taken together, high levels of human beta-defensin-3 protein expression were found in the periprosthetic tissue and cancellous bone of patients with periprosthetic joint infection and aseptic loosening, but there are differential expressions of human beta-defensin-3, and this may provide a new marker for the differential diagnosis of infection and loosening of the artificial joint.
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34
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Bunschoten A, Welling MM, Termaat MF, Sathekge M, van Leeuwen FWB. Development and prospects of dedicated tracers for the molecular imaging of bacterial infections. Bioconjug Chem 2013; 24:1971-1989. [PMID: 24200346 DOI: 10.1021/bc4003037] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Bacterial infections have always been, and still are, a major global healthcare problem. For accurate treatment it is of upmost importance that the location(s), severity, type of bacteria, and therapeutic response can be accurately staged. Similar to the recent successes in oncology, tracers specific for molecular imaging of the disease may help advance patient management. Chemical design and bacterial targeting mechanisms are the basis for the specificity of such tracers. The aim of this review is to provide a comprehensive overview of the molecular imaging tracers developed for optical and nuclear identification of bacteria and bacterial infections. Hereby we envision that such tracers can be used to diagnose infections and aid their clinical management. From these compounds we have set out to identify promising targeting mechanisms and select the most promising candidates for further development.
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Affiliation(s)
- A Bunschoten
- Department of Radiology, Interventional Molecular Imaging Laboratory, Leiden University Medical Center , Leiden, The Netherlands
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35
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Palestro CJ, Glaudemans AWJM, Dierckx RAJO. Multiagent imaging of inflammation and infection with radionuclides. Clin Transl Imaging 2013; 1:385-396. [PMID: 32289033 PMCID: PMC7102491 DOI: 10.1007/s40336-013-0041-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 11/13/2013] [Indexed: 11/26/2022]
Abstract
Molecular imaging with single photon- and positron-emitting tracers plays an important role in the evaluation of inflammation and infection. Although supplanted by labeled leukocyte imaging for most indications, gallium-67 remains useful for opportunistic infections, pulmonary inflammation and interstitial nephritis and, when [18F]FDG is not available, spinal infection and fever of unknown origin. In vitro labeled leukocyte imaging is the radionuclide procedure of choice for most infections in immunocompetent patients. When performed for musculoskeletal infection, complementary bone marrow imaging usually is necessary. Recent data suggest that dual time point imaging might be an alternative to marrow imaging. Several methods of labeling leukocytes in vivo, with agents including antigranulocyte antibodies and antibody fragments, peptides and cytokines, have been investigated, with variable results. These agents are not widely available and none of them are available in the USA. Radiolabeled antibiotics have been investigated as “infection-specific” tracers, but the results to date have been disappointing. Conversely, radiolabeled antimicrobial peptides do hold promise as infection-specific tracers. The use of positron-emitting tracers for diagnosing inflammation and infection has generated considerable interest. [18F]FDG is useful in fever of unknown origin, spinal osteomyelitis, vasculitis and sarcoidosis. Other positron-emitting tracers that have been investigated include [18F]FDG-labeled leukocytes, copper-64-labeled leukocytes, gallium-68 citrate and iodine-124 FIAU. Although radiolabeled tracers are used primarily for diagnosis, they also offer objective biomarkers for assessing response to therapeutic interventions in inflammatory diseases. They could also potentially be used to target cells and molecules with specific receptor expression for histological characterization, select patients for receptor-targeted therapy and predict response to treatment.
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Affiliation(s)
- Christopher J. Palestro
- Department of Radiology, Hofstra North Shore-LIJ, School of Medicine, Hempstead, NY USA
- Division of Nuclear Medicine and Molecular Imaging, North Shore-Long Island Jewish Health System, Manhasset, NY USA
- Division of Nuclear Medicine and Molecular Imaging, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY 11040 USA
| | - Andor W. J. M. Glaudemans
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rudi A. J. O. Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Functional Imaging in Diagnostic of Orthopedic Implant-Associated Infections. Diagnostics (Basel) 2013; 3:356-71. [PMID: 26824928 PMCID: PMC4665528 DOI: 10.3390/diagnostics3040356] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 09/10/2013] [Accepted: 09/22/2013] [Indexed: 12/11/2022] Open
Abstract
Surgeries’ sterile conditions and perioperative antibiotic therapies decrease implant associated infections rates significantly. However, up to 10% of orthopedic devices still fail due to infections. An implant infection generates a high socio-economic burden. An early diagnosis of an infection would significantly improve patients’ outcomes. There are numerous clinical tests to diagnose infections. The “Gold Standard” is a microbiological culture, which requires an invasive sampling and lasts up to several weeks. None of the existing tests in clinics alone is sufficient for a conclusive diagnosis of an infection. Meanwhile, there are functional imaging modalities, which hold the promise of a non-invasive, quick, and specific infection diagnostic. This review focuses on orthopedic implant-associated infections, their pathogenicity, diagnosis and functional imaging.
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Abstract
BACKGROUND Nanoparticles are increasingly being incorporated into the design of diagnostic imaging agents. Significant research efforts have been conducted with one class of lipid nanoparticle (liposomes) radiolabeled with gamma-emitting radionuclides as radiopharmaceuticals for scintigraphic imaging of cancer, inflammation/infection and sentinel lymph node detection. OBJECTIVE This article reviews the current literature with special emphasis on the clinical studies performed with liposome radiopharmaceuticals for detection of tumors, infectious/inflammatory sites or metastatic lymph nodes. Future uses of liposome radiopharmaceuticals are also described. METHODS Characteristics required of the radionuclide, liposome formulation and radiolabeling method for an effective radiopharmaceutical are discussed. A description of the procedures and instrumentation for conducting an imaging study with liposome radiopharmaceutical is included. Clinical studies using liposome radiopharmaceuticals are summarized. Future imaging applications of first- and second-generation radiolabeled liposomes for chemodosimetry and the specific targeting of a disease process are also described. RESULTS/CONCLUSION The choice of radionuclide, liposome formulation and radiolabeling method must be carefully considered during the design of a liposome radiopharmaceutical for a given application. After-loading and surface chelation methods are the most efficient and practical. Clinical studies with liposome radiopharmaceuticals demonstrated that a wide variety of tumors could be detected with good sensitivity and specificity. Liposome radiopharmaceuticals could also clearly detect various soft tissue and bone inflammatory/infectious lesions, and performed equal to or better than infection imaging agents that are approved at present. Yet, despite these favorable results, no liposome radiopharmaceutical has been approved for any indication. Some of the reasons for this can be attributed to reports of an unexpected infusion-related adverse reaction in two studies, the requirement of more complex liposome manufacturing procedures, and the adoption of other competing imaging procedures. Continued research of liposome radiopharmaceutical design based on a better understanding of liposome biology, improved radiolabeling methodologies and advances in gamma camera technology is warranted.
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Affiliation(s)
- Beth A Goins
- The University of Texas Health Science Center at San Antonio, TX Department of Radiology, Mail Code 7800, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA +1 210 567 5575 ; +1 210 567 5549 ;
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38
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A Pooled Analysis of Diagnostic Value of 99mTc-Ubiquicidin (UBI) Scintigraphy in Detection of an Infectious Process. Clin Nucl Med 2013; 38:413-6. [DOI: 10.1097/rlu.0b013e3182867d56] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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39
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Kakkar D, Tiwari AK, Singh H, Mishra AK. Past and Present Scenario of Imaging Infection and Inflammation: A Nuclear Medicine Perspective. Mol Imaging 2012. [DOI: 10.2310/7290.2011.00051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Nuclear medicine techniques provide potential non-invasive tools for imaging infections and inflammations in the body in a precise way. These techniques are further exploited by the use of radiopharmaceuticals in conjunction with imaging tests such as scintigraphy and positron emission tomography. Improved agents for targeting infection exploit the specific accumulation of radiolabeled compounds to understand the pathophysiologic changes involved in the inflammatory process and correlate them with other chronic illnesses. In the recent past, a wide variety of radiopharmaceuticals have been developed, broadly classified as specific radiopharmaceuticals and nonspecific radiopharmaceuticals. New developments in positron emission (leveraging 18F and 18fluorodeoxyglucose) and heterocyclic/peptide chemistry and radiochemistry are resulting in unique agents with high specific activity. Various approaches to visualizing infection and inflammation are presented in this review, in an integral manner, that give a clear view of the existing radiopharmaceuticals in clinical practice and those under development.
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Affiliation(s)
- Dipti Kakkar
- From the Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, and the Centre for Biomedical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India
| | - Anjani K. Tiwari
- From the Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, and the Centre for Biomedical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India
| | - Harpal Singh
- From the Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, and the Centre for Biomedical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India
| | - Anil K. Mishra
- From the Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, and the Centre for Biomedical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India
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Antimicrobial peptides as infection imaging agents: better than radiolabeled antibiotics. INTERNATIONAL JOURNAL OF PEPTIDES 2012; 2012:965238. [PMID: 22675369 PMCID: PMC3362861 DOI: 10.1155/2012/965238] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Revised: 02/09/2012] [Accepted: 03/11/2012] [Indexed: 11/17/2022]
Abstract
Nuclear medicine imaging techniques offer whole body imaging for localization of number and site of infective foci inspite of limitation of spatial resolution. The innate human immune system contains a large member of important elements including antimicrobial peptides to combat any form of infection. However, development of antibiotics against bacteria progressed rapidly and gained popularity over antimicrobial peptides but even powerful antimicrobials failed to reduce morbidity and mortality due to emergence of mutant strains of bacteria resulting in antimicrobial resistance. Differentiation between infection and inflammation using radiolabeled compounds with nuclear medicine techniques has always been a dilemma which is still to be resolved. Starting from nonspecific tracers to specific radiolabeled tracers, the question is still unanswered. Specific radiolabeled tracers included antibiotics and antimicrobial peptides which bind directly to the bacteria for efficient localization with advanced nuclear medicine equipments. However, there are merits and demerits attributed to each. In the current paper, radiolabeled antibiotics and radiolabeled peptides for infection localization have been discussed starting with the background of primitive nonspecific tracers. Radiolabeled antimicrobial peptides have certain merits compared with labeled antibiotics which make them superior agents for localization of infective focus.
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Gemmel F, Van den Wyngaert H, Love C, Welling MM, Gemmel P, Palestro CJ. Prosthetic joint infections: radionuclide state-of-the-art imaging. Eur J Nucl Med Mol Imaging 2012; 39:892-909. [PMID: 22361912 DOI: 10.1007/s00259-012-2062-7] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Accepted: 01/02/2012] [Indexed: 12/27/2022]
Abstract
Prosthetic joint replacement surgery is performed with increasing frequency. Overall the incidence of prosthetic joint infection (PJI) and subsequently prosthesis revision failure is estimated to be between 1 and 3%. Differentiating infection from aseptic mechanical loosening, which is the most common cause of prosthetic failure, is especially important because of different types of therapeutic management. Despite a thorough patient history, physical examination, multiple diagnostic tests and complex algorithms, differentiating PJI from aseptic loosening remains challenging. Among imaging modalities, radiographs are neither sensitive nor specific and cross-sectional imaging techniques, such as computed tomography and magnetic resonance imaging, are limited by hardware-induced artefacts. Radionuclide imaging reflects functional rather than anatomical changes and is not hampered by the presence of a metallic joint prosthesis. As a result scintigraphy is currently the modality of choice in the investigation of suspected PJI. Unfortunately, there is no true consensus about the gold standard technique since there are several drawbacks and limitations inherent to each modality. Bone scintigraphy (BS) is sensitive for identifying the failed joint replacement, but cannot differentiate between infection and aseptic loosening. Combined bone/gallium scintigraphy (BS/GS) offers modest improvement over BS alone for diagnosing PJI. However, due to a number of drawbacks, BS/GS has generally been superseded by other techniques but it still may have a role in neutropenic patients. Radiolabelled leucocyte scintigraphy remains the gold standard technique for diagnosing neutrophil-mediated processes. It seems to be that combined in vitro labelled leucocyte/bone marrow scintigraphy (LS/BMS), with an accuracy of about 90%, is currently the imaging modality of choice for diagnosing PJI. There are, however, significant limitations using in vitro labelled leucocytes and considerable effort has been devoted to developing alternative radiotracers, such as radiolabelled HIGs, liposomes, antigranulocyte antibodies and fragments, as well as more investigational tracers such as radiolabelled antibiotics, antimicrobial peptides, bacteriophages and thymidine kinase. On the other hand, positron emission tomography (PET) is still growing in the field of PJI imaging with radiotracers such as (18)F-fluorodeoxyglucose (FDG), (18)F-FDG white blood cells and (18)F-fluoride. But unfortunately this superb tomographic technique will only receive full acceptance when specific PET uptake patterns can be successfully developed. The emergence of hybrid modality imaging using integrated single photon emission computed tomography (SPECT) and PET with computed tomography (SPECT/CT and PET/CT) may also have a contributing role for more accurate assessment of joint replacement complications, especially combined with new radiotracers such as (68)Ga and (64)Cu. Finally, in searching for infection-specific tracers, currently there is no such diagnostic agent available.
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Affiliation(s)
- Filip Gemmel
- Department of Nuclear Medicine, AZ Alma Campus Sijsele, Gentse Steenweg 132, 8340 Sijsele-Damme, Belgium.
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Shriver-Lake LC, North SH, Dean SN, Taitt CR. Antimicrobial Peptides for Detection and Diagnostic Assays. SPRINGER SERIES ON CHEMICAL SENSORS AND BIOSENSORS 2012. [DOI: 10.1007/5346_2012_19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Specificity of 99mTc-UBI for detecting infection foci in patients with fever in study. Nucl Med Commun 2010; 31:889-95. [DOI: 10.1097/mnm.0b013e32833d96d1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Meléndez-Alafort L, Nadali A, Pasut G, Zangoni E, De Caro R, Cariolato L, Giron MC, Castagliuolo I, Veronese FM, Mazzi U. Detection of sites of infection in mice using 99mTc-labeled PN(2)S-PEG conjugated to UBI and 99mTc-UBI: a comparative biodistribution study. Nucl Med Biol 2009; 36:57-64. [PMID: 19181269 DOI: 10.1016/j.nucmedbio.2008.10.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Revised: 10/15/2008] [Accepted: 10/25/2008] [Indexed: 11/29/2022]
Abstract
UNLABELLED The antimicrobial peptide ubiquicidin (UBI) directly labeled with technetium-99m ((99m)Tc) has recently been shown to be specifically taken up at sites of infection; however, its chemical structure is not well defined. To address this problem, the aim of the present study was to label UBI using poly(ethyleneglycol)-N-(N-(3-diphenylphosphinopropionyl)glycyl)-S-tritylcysteine ligand (PEG-PN(2)S) in order to compare its ability to detect infection sites with that of (99m)Tc-UBI. METHODS The PN(2)S-PEG-UBI conjugate was prepared and labeled with (99m)Tc, and its radiochemical purity was subsequently assessed. The stability of the conjugate to cysteine challenge and dilution with both saline solution and phosphate buffer was determined and serum stability and protein binding were also assessed. In vivo studies were carried out in healthy mice to study the biodistribution of (99m)Tc-PN(2)S-PEG-UBI and its precursor (99m)Tc-PN(2)S-PEG and in infected mice to compare the uptakes of (99m)Tc-UBI and (99m)Tc-PN(2)S-PEG-UBI at the site of infection using scintigraphic imaging and ex vivo tissue counting. RESULTS (99m)Tc-PN(2)S-PEG-UBI was obtained with high radiochemical purity (98+/-1%) and high stability. The amphiphilic nature of the conjugate leads to a tendency to form micellar aggregates that explain the high protein binding values obtained. Biodistribution studies in mice showed low renal clearance followed by a predominant reticuloendothelial system clearance that limits its application in the abdominal area. Statistical analysis revealed no significant difference between (99m)Tc-UBI and (99m)Tc-PN(2)S-PEG-UBI uptake in infected mouse thigh, and the site of infection was clearly visualized using scintigraphic imaging. CONCLUSIONS (99m)Tc-PN(2)S-PEG-UBI proved to be as effective as (99m)Tc-UBI in detecting sites of infection; however, the well-defined chemical structure of (99m)Tc-PN(2)S-PEG-UBI makes it a better candidate for clinical imaging of infection.
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Abstract
Timely and specific diagnosis of infectious diseases can be clinically challenging but essential for the patient's outcome. Laboratory tests, such as a blood culture or urine specimen, can detect the responsible micro-organism but cannot discriminate between sterile inflammatory disease and truly infectious disease. Imaging tests, like scintigraphic techniques, can pinpoint the infection in the body. There are a number of clinical scintigraphic tests from which to choose, and no single test is optimal for the various presentations of clinical infectious disease. The currently available radiopharmaceuticals often are not capable of distinguishing between sterile inflammation, and bacterial or fungal infections. Neutrophil-mediated processes, characteristic for both inflammatory and infectious processes, can be targeted in situ by radiolabeled leukocytes, antibodies or fragments, or even by cytokines and (18)F-fluorodeoxyglucose. Unfortunately those techniques are not infection-specific markers, and ongoing research is in progress to tackle this problem. The most promising option in this respect is directly targeting bacteria or fungi with radiolabeled antibiotics or antimicrobial peptides. These theoretically highly infection-specific radiopharmaceuticals could be used for monitoring the success of antimicrobial therapy of infectious disease. Although results from preclinical experiments and pilot studies in patients are promising, radiolabeled anti-infective agents are not currently in routine clinical use and studies are continuing to prove their effectiveness for diagnostic imaging of infections in the future.
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Affiliation(s)
- Filip Gemmel
- Department of Nuclear Medicine, KCL, Medical Center, Leeuwarden, The Netherlands.
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Salber D, Gunawan J, Langen KJ, Fricke E, Klauth P, Burchert W, Zijlstra S. Comparison of 99mTc- and 18F-ubiquicidin autoradiography to anti-Staphylococcus aureus immunofluorescence in rat muscle abscesses. J Nucl Med 2008; 49:995-9. [PMID: 18483088 DOI: 10.2967/jnumed.108.050880] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
UNLABELLED 99mTc-ubiquicidin (UBI) 29-41 is under clinical evaluation for discrimination between bacterial infection and unspecific inflammation. We compared the distribution of 99mTc-UBI 29-41, the potential PET tracers 18F-UBI 29-41 and 18F-UBI 28-41, and 3H-deoxyglucose (DG) in rat muscle abscesses to that of anti-Staphylococcus aureus immunofluorescent imaging. METHODS Calf abscesses were induced in 15 CDF-Fischer rats after inoculation of Staphylococcus aureus. One to 6 d later, either 18F-UBI 29-41 and 3H-DG (n = 5) or 18F-UBI 28-41 and 3H-DG (n = 6) or 99mTc-UBI 29-41 and 3H-DG (n = 4) were injected simultaneously. Dual-tracer autoradiography of the abscess area was compared with the distribution of bacteria and macrophages. RESULTS The UBI derivates exhibited increased uptake in the abscess area that partly matched 3H-DG uptake and macrophage infiltration but showed no congruity with areas that were highly positive for bacteria. CONCLUSION A specific binding of UBI derivatives to Staphylococcus aureus in vivo could not be confirmed in this study.
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Affiliation(s)
- Dagmar Salber
- C. & O. Vogt Institute of Brain Research, University Hospital Düsseldorf, Düsseldorf, Germany
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Walker RC, Jones-Jackson LB, Martin W, Habibian MR, Delbeke D. New imaging tools for the diagnosis of infection. Future Microbiol 2007; 2:527-54. [DOI: 10.2217/17460913.2.5.527] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Infection imaging became widespread in 1971 with the release of 67Ga citrate. Multiphase skeletal scintigraphy and radiolabeled white blood cells (WBCs) have since become the most widespread clinically used agents for the imaging of infection. A wide variety of other radiolabeled probes are under investigation, based on antibodies, cytokines, assorted proteins and other molecules, alone or in various combinations. However, these latter agents, with a few exceptions, are not routinely used clinically. Radiolabeled ciprofloxacin represents the first attempt to develop an infection-specific imaging agent (most infection-imaging probes localized nonspecifically to inflammation as well), but it has not proven superior to radiolabeled WBCs or 18F-fluoro-deoxy-glucose (FDG) PET. Because of the ability to combine exquisite anatomic detail with focal uptake of 18F-FDG, PET–computed tomography has achieved great success in the detection and localization of infection, including in clinically adverse conditions. Despite these advances, at this time an infection-specific imaging agent does not exist.
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Affiliation(s)
- Ronald C Walker
- Associate Professor Vanderbilt University Medical Center, Department of Radiology & Radiological Sciences, 1161 21st Avenue South, CCC-1121 MCN, Nashville, TN 37232-2675, USA
| | - Laurie B Jones-Jackson
- Associate Professor Vanderbilt University Medical Center, Department of Radiology & Radiological Sciences, 1161 21st Avenue South, CCC-1121 MCN, Nashville, TN 37232-2675, USA
| | - William Martin
- Associate Professor Vanderbilt University Medical Center, Department of Radiology & Radiological Sciences, 1161 21st Avenue South, CCC-1121 MCN, Nashville, TN 37232-2675, USA
| | - M Reza Habibian
- Associate Professor Vanderbilt University Medical Center, Department of Radiology & Radiological Sciences, 1161 21st Avenue South, CCC-1121 MCN, Nashville, TN 37232-2675, USA
| | - Dominique Delbeke
- Professor Vanderbilt University Medical Center, Department of Radiology & Radiological Sciences, 1161 21st Avenue South, CCC-1121 MCN, Nashville, TN 37232-2675, USA
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