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EJNMMI Research
Published in: EJNMMI Research 1/2015

Open Access 01-12-2015 | Original research

[18F]FDG-6-P as a novel in vivo tool for imaging staphylococcal infections

Authors: Bethany Mills, Ramla O Awais, Jeni Luckett, Dave Turton, Paul Williams, Alan C Perkins, Philip J Hill

Published in: EJNMMI Research | Issue 1/2015

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Abstract

Background

Management of infection is a major clinical problem. Staphylococcus aureus is a Gram-positive bacterium which colonises approximately one third of the adult human population. Staphylococcal infections can be life-threatening and are frequently complicated by multi-antibiotic resistant strains including methicillin-resistant S. aureus (MRSA). Fluorodeoxyglucose ([18F]FDG) imaging has been used to identify infection sites; however, it is unable to distinguish between sterile inflammation and bacterial load. We have modified [18F]FDG by phosphorylation, producing [18F]FDG-6-P to facilitate specific uptake and accumulation by S. aureus through hexose phosphate transporters, which are not present in mammalian cell membranes. This approach leads to the specific uptake of the radiopharmaceutical into the bacteria and not the sites of sterile inflammation.

Methods

[18F]FDG-6-P was synthesised from [18F]FDG. Yield, purity and stability were confirmed by RP-HPLC and iTLC. The specificity of [18F]FDG-6-P for the bacterial universal hexose phosphate transporter (UHPT) was confirmed with S. aureus and mammalian cell assays in vitro. Whole body biodistribution and accumulation of [18F]FDG-6-P at the sites of bioluminescent staphylococcal infection were established in a murine foreign body infection model.

Results

In vitro validation assays demonstrated that [18F]FDG-6-P was stable and specifically transported into S. aureus but not mammalian cells. [18F]FDG-6-P was elevated at the sites of S. aureus infection in vivo compared to uninfected controls; however, the increase in signal was not significant and unexpectedly, the whole-body biodistribution of [18F]FDG-6-P was similar to that of [18F]FDG.

Conclusions

Despite conclusive in vitro validation, [18F]FDG-6-P did not behave as predicted in vivo. However at the site of known infection, [18F]FDG-6-P levels were elevated compared with uninfected controls, providing a higher signal-to-noise ratio. The bacterial UHPT can transport hexose phosphates other than glucose, and therefore alternative sugars may show differential biodistribution and provide a means for specific bacterial detection.
Literature
1.
Dumarey N, Egrise D, Blocklet D, Stallenberg B, Remmelink M, del Marmol V, et al. Imaging infection with F-18-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med. 2006;47:625–32.PubMed
2.
Signore A, Glaudemans AW. The molecular imaging approach to image infections and inflammation by nuclear medicine techniques. Ann Nucl Med. 2011;25:681–700. doi: 10.1007/s12149-011-0521-z.CrossRefPubMed
3.
Palestro CJ, Love C, Bhargava KK. Labeled leukocyte imaging: current status and future directions. Q J Nucl Med Mol Imaging. 2009;53:105–23.PubMed
4.
Kumar V. Radiolabeled white blood cells and direct targeting of micro-organisms for infection imaging. Q J Nucl Med Mol Imaging. 2005;49:325–38.PubMed
5.
Basu S, Chryssikos T, Moghadam-Kia S, Zhuang H, Torigian DA, Alavi A. Positron emission tomography as a diagnostic tool in infection: present role and future possibilities. Semin Nucl Med. 2009;39:36–51. doi:10.1053/j.semnuclmed.2008.08.004.CrossRefPubMed
6.
Love C, Palestro CJ. Radionuclide imaging of infection. J Nucl Med Technol. 2004;32:47–57. quiz 8–9.PubMed
7.
Becker W, Meller J. The role of nuclear medicine in infection and inflammation. Lancet Infect Dis. 2001;1:326–33. doi: 10.1016/S1473-3099(01)00146-3.CrossRefPubMed
8.
Wang Z, Ning X. Clinical diagnosis of bacterial infection via FDG-PET imaging. 2013.
9.
Zoccali C, Teori G, Salducca N. The role of FDG-PET in distinguishing between septic and aseptic loosening in hip prosthesis: a review of literature. Int Orthop. 2009;33:1–5. doi: 10.1007/s00264-008-0575-2.CrossRefPubMedCentralPubMed
10.
Aksoy SY, Asa S, Ozhan M, Ocak M, Sager MS, Erkan ME, et al. FDG and FDG-labelled leucocyte PET/CT in the imaging of prosthetic joint infection. Eur J Nucl Med Mol Imaging. 2014;41:556–64. doi: 10.1007/s00259-013-2597-2.CrossRefPubMed
11.
Stumpe KD, Dazzi H, Schaffner A, von Schulthess GK. Infection imaging using whole-body FDG-PET. Eur J Nucl Med. 2000;27:822–32.CrossRefPubMed
12.
Chacko TK, Zhuang H, Nakhoda KZ, Moussavian B, Alavi A. Applications of fluorodeoxyglucose positron emission tomography in the diagnosis of infection. Nucl Med Commun. 2003;24:615–24. doi: 10.1097/01.mnm.0000075189.60210.df.CrossRefPubMed
13.
Rosenbaum SJ, Lind T, Antoch G, Bockisch A. False-positive FDG PET uptake–the role of PET/CT. Eur Radiol. 2006;16:1054–65. doi: 10.1007/s00330-005-0088-y.CrossRefPubMed
14.
Moberg L, Karawajczyk M, Venge P. 99mTc-HMPAO (Ceretec) is stored in and released from the granules of eosinophil granulocytes. Br J Haematol. 2001;114:185–90. doi: 10.1046/j.1365-2141.2001.02889.x.CrossRefPubMed
15.
Lukawska JJ, Livieratos L, Sawyer BM, Lee T, O’Doherty M, Blower PJ, et al. Real-time differential tracking of human neutrophil and eosinophil migration in vivo. J Allergy Clin Immunol. 2014;133:233–9. e1. doi:10.1016/j.jaci.2013.06.031.CrossRefPubMed
16.
Bunschoten A, Welling MM, Termaat MF, Sathekge M, van Leeuwen FW. Development and prospects of dedicated tracers for the molecular imaging of bacterial infections. Bioconjug Chem. 2013;24:1971–89. doi:10.1021/bc4003037.CrossRefPubMed
17.
Sasser TA, Van Avermaete AE, White A, Chapman S, Johnson JR, Van Avermaete T, et al. Bacterial infection probes and imaging strategies in clinical nuclear medicine and preclinical molecular imaging. Curr Top Med Chem. 2013;13:479–87. doi: CTMC-EPUB-20130207-8.CrossRefPubMed
18.
Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev. 1997;10:505–20.PubMedCentralPubMed
19.
Dall’Antonia M, Coen PG, Wilks M, Whiley A, Millar M. Competition between methicillin-sensitive and -resistant Staphylococcus aureus in the anterior nares. J Hosp Infect. 2005;61:62–7. doi: 10.1016/j.jhin.2005.01.008.CrossRefPubMed
20.
ECDC. Antimicrobial resistance surveillance in Europe 2011. Eur Centre Dis Prev Control. 2012;1:55–7.
21.
ECDC. Antimicrobial resistance surveillance in Europe 2012. Eur Centre Dis Prev Control. 2013;1:59–62.
22.
Lowy FD. Staphylococcus aureus infections. N Engl J Med. 1998;339:520–32. doi: 10.1056/NEJM199808203390806.CrossRefPubMed
23.
WHO. Antimicrobial resistance: global report on surveillance 2014. WHO. 2014;1:9–12. 19–21.
24.
Beceiro A, Tomás M, Bou G. Antimicrobial resistance and virulence: a successful or deleterious association in the bacterial world? Clin Microbiol Rev. 2013;26:185–230. doi: 10.1128/cmr. 00059-12.CrossRefPubMedCentralPubMed
25.
Gorak EJ, Yamada SM, Brown JD. Community-acquired methicillin-resistant Staphylococcus aureus in hospitalized adults and children without known risk factors. Clin Infect Dis. 1999;29:797–800. doi: 10.1086/520437.CrossRefPubMed
26.
Charlebois ED, Bangsberg DR, Moss NJ, Moore MR, Moss AR, Chambers HF, et al. Population-based community prevalence of methicillin-resistant Staphylococcus aureus in the urban poor of San Francisco. Clin Infect Dis. 2002;34:425–33. doi: 10.1086/338069.CrossRefPubMed
27.
Carleton HA, Diep BA, Charlebois ED, Sensabaugh GF, Perdreau-Remington F. Community-adapted methicillin-resistant Staphylococcus aureus (MRSA): population dynamics of an expanding community reservoir of MRSA. J Infect Dis. 2004;190:1730–8. doi: 10.1086/425019.CrossRefPubMed
28.
Diederen BM, Kluytmans JA. The emergence of infections with community-associated methicillin resistant Staphylococcus aureus. J Infect. 2006;52:157–68. doi: 10.1016/j.jinf.2005.09.001.CrossRefPubMed
29.
Kluytmans-Vandenbergh MF, Kluytmans JA. Community-acquired methicillin-resistant Staphylococcus aureus: current perspectives. Clin Microbiol Infect. 2006;12 Suppl 1:9–15. doi: 10.1111/j.1469-0691.2006.01341.x.CrossRefPubMed
30.
Winkler HH. Distribution of an inducible hexose-phosphate transport-system among various bacteria. J Bacteriol. 1973;116:1079–81.PubMedCentralPubMed
31.
Kaarstad K, Bender D, Bentzen L, Munk OL, Keiding S. Metabolic fate of 18F-FDG in mice bearing either SCCVII squamous cell carcinoma or C3H mammary carcinoma. J Nucl Med. 2002;43:940–7.PubMed
32.
Kuklin NA, Pancari GD, Tobery TW, Cope L, Jackson J, Gill C, et al. Real-time monitoring of bacterial infection in vivo: development of bioluminescent staphylococcal foreign-body and deep-thigh-wound mouse infection models. Antimicrob Agents Chemother. 2003;47:2740–8.CrossRefPubMedCentralPubMed
33.
Hook AL, Chang CY, Yang J, Luckett J, Cockayne A, Atkinson S, et al. Combinatorial discovery of polymers resistant to bacterial attachment. Nat Biotechnol. 2012;30:868–75. doi: 10.1038/nbt.2316.CrossRefPubMedCentralPubMed
34.
Gowrishankar G, Namavari M, Jouannot EB, Hoehne A, Reeves R, Hardy J, et al. Investigation of 6-[18F]-fluoromaltose as a novel PET tracer for imaging bacterial infection. PLoS One. 2014;9:e107951. doi: 10.1371/journal.pone.0107951 PONE-D-14-25942.CrossRefPubMedCentralPubMed
35.
Weinstein EA, Ordonez AA, DeMarco VP, Murawski AM, Pokkali S, MacDonald EM, et al. Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Sci Transl Med. 2014;6:259ra146. doi: 10.1126/scitranslmed.3009815.CrossRefPubMed
36.
Archer NK, Mazaitis MJ, Costerton JW, Leid JG, Powers ME, Shirtliff ME. Staphylococcus aureus biofilms: properties, regulation, and roles in human disease. Virulence. 2011;2:445–59. doi: 10.4161/viru.2.5.17724.CrossRefPubMedCentralPubMed
37.
38.
Etzioni DA, Liu JH, Maggard MA, Ko CY. The aging population and its impact on the surgery workforce. Ann Surg. 2003;238:170–7. doi:10.1097/01.SLA.0000081085.98792.3d 00000658-200308000-00003.PubMedCentralPubMed
39.
Thurlow LR, Hanke ML, Fritz T, Angle A, Aldrich A, Williams SH, et al. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J Immunol. 2011;186:6585–96. doi: jimmunol.1002794.CrossRefPubMedCentralPubMed
40.
Kadurugamuwa JL, Sin LV, Yu J, Francis KP, Purchio TF, Contag PR. Noninvasive optical imaging method to evaluate postantibiotic effects on biofilm infection in vivo. Antimicrob Agents Chemother. 2004;48:2283–7. doi: 10.1128/AAC.48.6.2283-2287.2004 48/6/2283.CrossRefPubMedCentralPubMed
41.
Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, et al. Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med. 2006;47:999–1006. doi: 47/6/999.PubMed
42.
Kim C, Kim IH, Kim SI, Kim YS, Kang SH, Moon SH, et al. Comparison of the Intraperitoneal, retroorbital and per oral routes for F-18 FDG administration as effective alternatives to intravenous administration in mouse tumor models using small animal PET/CT studies. Nucl Med Mol Imaging. 2011;45:169–76. doi:10.1007/s13139-011-0087-7 87.CrossRefPubMedCentralPubMed
43.
Watanabe M, Goto H, Matsushima M, Shimono R, Kihara T. Distribution of glucose-6-phosphatase activity in mice studied by in vitro whole-body autoradiography. J Histochem Cytochem. 1983;31:1426–9.CrossRefPubMed
44.
Burns RL, Rosenberger PG, Klebe RJ. Carbohydrate preferences of mammalian cells. J Cell Physiol. 1976;88:307–16. doi:10.1002/jcp.1040880306.CrossRefPubMed
45.
Jamar F, Buscombe J, Chiti A, Christian PE, Delbeke D, Donohoe KJ, et al. EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med. 2013;54:647–58. doi: 10.2967/jnumed.112.112524.CrossRefPubMed
Metadata
Title
[18F]FDG-6-P as a novel in vivo tool for imaging staphylococcal infections
Authors
Bethany Mills
Ramla O Awais
Jeni Luckett
Dave Turton
Paul Williams
Alan C Perkins
Philip J Hill
Publication date
01-12-2015
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2015
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-015-0095-1

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