The International Atomic Energy Agency organized a technical meeting at its headquarters in Vienna, Austria, in 2022 that included 17 experts representing 12 countries, whose research spanned the development and use of radiolabeled agents for imaging infection. The meeting focused largely on bacterial pathogens. The group discussed and evaluated the advantages and disadvantages of several radiopharmaceuticals, as well as the science driving various imaging approaches. The main objective was to understand why few infection-targeted radiotracers are used in clinical practice despite the urgent need to better characterize bacterial infections. This article summarizes the resulting consensus, at least among the included scientists and countries, on the current status of radiopharmaceutical development for infection imaging. Also included are opinions and recommendations regarding current research standards in this area. This and future International Atomic Energy Agency-sponsored collaborations will advance the goal of providing the medical community with innovative, practical tools for the specific image-based diagnosis of infection.

Center for Infection and Inflammation Imaging Research Johns Hopkins University School of Medicine Baltimore Maryland

College of Pharmacy and Nutrition University of Saskatchewan Saskatoon Saskatchewan Canada

Department of Nuclear Medicine Hospital Internacional de Colombia Fundación Cardiovascular de Colombia Piedecuesta Colombia

Department of Nuclear Sciences and Applications International Atomic Energy Agency Vienna Austria

Department of Radiology and Biomedical Imaging University of California San Francisco San Francisco California

Department of Small Animal Clinical Sciences Western College of Veterinary Medicine University of Saskatchewan Saskatoon Saskatchewan Canada

Institute of Molecular and Translational Medicine and Czech Advanced Technology and Research Institute Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Instituto Nacional de Investigaciones Nucleares Ocoyoacac Mexico

Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Leiden The Netherlands; and

National Nuclear Energy Agency South Tangerang Indonesia

Nuclear Medicine Unit Department of Medical Surgical Sciences and Translational Medicine Faculty of Medicine and Psychology University of Rome Sapienza Rome Italy

Nuclear Medicine University of Pretoria and Radiochemistry Applied Radiation South African Nuclear Energy Corporation Pelindaba South Africa

Radioactive Isotopes and Generator Department Hot Labs Center Egyptian Atomic Energy Authority Cairo Egypt

Radiopharmaceutical Program Board of Radiation and Isotope Technology Mumbai India

Radiopharmaceuticals Division Bhabha Atomic Research Centre Mumbai India

Werner Siemens Imaging Center Department of Preclinical Imaging and Radiopharmacy Eberhard Karls University of Tübingen Tübingen Germany

See more in PubMed

GBD 2019 Antimicrobial Resistance Collaborators. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2022;400:2221–2248. PubMed PMC

GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788. PubMed PMC

Rudd KE, Johnson SC, Agesa KM, et al. . Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200–211. PubMed PMC

O’Neill J. Tackling drug-resistant infections globally: final report and recommendations. Review on Antimicrobial Resistance website. https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf. Published May 2016. Accessed August 30, 2023.

Dadgostar P. Antimicrobial resistance: implications and costs. Infect Drug Resist. 2019;12:3903–3910. PubMed PMC

Dhesi Z, Enne VI, Brealey D, et al. . Organisms causing secondary pneumonias in COVID-19 patients at 5 UK ICUs as detected with the FilmArray test. medRxiv website. https://www.medrxiv.org/content/10.1101/2020.06.22.20131573v1. Published June 23, 2020. Accessed August 31, 2023. DOI

Cassat JE, Moore JL, Wilson KJ, et al. . Integrated molecular imaging reveals tissue heterogeneity driving host-pathogen interactions. Sci Transl Med. 2018;10:eaan6361. PubMed PMC

Ordonez AA, Tucker EW, Anderson CJ, et al. . Visualizing the dynamics of tuberculosis pathology using molecular imaging. J Clin Invest. 2021;131:e145107. PubMed PMC

Ordonez AA, Wang H, Magombedze G, et al. . Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions. Nat Med. 2020;26:529–534. PubMed PMC

Tucker EW, Guglieri-Lopez B, Ordonez AA, et al. . Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis. Sci Transl Med. 2018;10:eaau0965. PubMed PMC

Ruiz-Bedoya CA, Mota F, Tucker EW, et al. . High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis. J Clin Invest. 2022;132:e155851. PubMed PMC

Jain SK, Andronikou S, Goussard P, et al. . Advanced imaging tools for childhood tuberculosis: potential applications and research needs. Lancet Infect Dis. 2020;20:e289–e297. PubMed PMC

Strosberg J, El-Haddad G, Wolin E, et al. . Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–135. PubMed PMC

Rowe SP, Gorin MA, Pomper MG. Imaging of prostate-specific membrane antigen with small-molecule PET radiotracers: from the bench to advanced clinical applications. Annu Rev Med. 2019;70:461–477. PubMed

Romanò CL, Petrosillo N, Argento G, et al. . The role of imaging techniques to define a peri-prosthetic hip and knee joint infection: multidisciplinary consensus statements. J Clin Med. 2020;9:2548. PubMed PMC

Lauri C, Signore A, Glaudemans AWJM, et al. . Evidence-based guideline of the European Association of Nuclear Medicine (EANM) on imaging infection in vascular grafts. Eur J Nucl Med Mol Imaging. 2022;49:3430–3451. PubMed PMC

Lauri C, Tamminga M, Glaudemans AWJM, et al. . Detection of osteomyelitis in the diabetic foot by imaging techniques: a systematic review and meta-analysis comparing MRI, white blood cell scintigraphy, and FDG-PET. Diabetes Care. 2017;40:1111–1120. PubMed

Steinsträsser A, Oberhausen E. Granulocyte labelling kit BW 250/183: results of the European multicenter trial. Nuklearmedizin. 1996;35:1–11. PubMed

Jamar F, Buscombe J, Chiti A, et al. . EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med. 2013;54:647–658. PubMed

Welling M, Stokkel M, Balter J, Sarda-Mantel L, Meulemans A, Le Guludec D. The many roads to infection imaging. Eur J Nucl Med Mol Imaging. 2008;35:848–849. PubMed PMC

Polvoy I, Flavell RR, Rosenberg OS, Ohliger MA, Wilson DM. Nuclear imaging of bacterial infection: the state of the art and future directions. J Nucl Med. 2020;61:1708–1716. PubMed PMC

Langer O, Brunner M, Zeitlinger M, et al. . In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET. Eur J Nucl Med Mol Imaging. 2005;32:143–150. PubMed

Sarda L, Crémieux A-C, Lebellec Y, et al. . Inability of 99mTc-ciprofloxacin scintigraphy to discriminate between septic and sterile osteoarticular diseases. J Nucl Med. 2003;44:920–926. PubMed

Dumarey N, Blocklet D, Appelboom T, Tant L, Schoutens A. Infecton is not specific for bacterial osteo-articular infective pathology. Eur J Nucl Med Mol Imaging. 2002;29:530–535. PubMed

Pauwels EK, Welling MM, Lupetti A, Paulusma-Annema A, Nibbering PH, Balter HS. Concerns about 99mTc-labelled ciprofloxacin for infection detection. Eur J Nucl Med. 2000;27:1866. PubMed

Welling MM, Nibbering PH, Paulusma-Annema A, Hiemstra PS, Pauwels EK, Calame W. Imaging of bacterial infections with 99mTc-labeled human neutrophil peptide-1. J Nucl Med. 1999;40:2073–2080. PubMed

Auletta S, Baldoni D, Varani M, et al. . 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. Q J Nucl Med Mol Imaging. 2019;63:37–47. PubMed

Larikka MJ, Ahonen AK, Niemelä O, Junila JA, Hämäläinen MM, Syrjälä HP. Specificity of 99mTc-ciprofloxacin imaging [letter]. J Nucl Med. 2003;44:1368. PubMed

Alexander K, Drost WT, Mattoon JS, Kowalski JJ, Funk JA, Crabtree AC. Binding of ciprofloxacin labelled with technetium Tc 99m versus 99mTc-pertechnetate to a live and killed equine isolate of Escherichia coli . Can J Vet Res. 2005;69:272–277. PubMed PMC

Dutta P, Bhansali A, Mittal BR, Singh B, Masoodi SR. Instant 99mTc-ciprofloxacin scintigraphy for the diagnosis of osteomyelitis in the diabetic foot. Foot Ankle Int. 2006;27:716–722. PubMed

De Winter F, Gemmel F, Van Laere K, et al. . 99mTc-ciprofloxacin planar and tomographic imaging for the diagnosis of infection in the postoperative spine: experience in 48 patients. Eur J Nucl Med Mol Imaging. 2004;31:233–239. PubMed

Fuster D, Soriano A, Garcia S, et al. . Usefulness of 99mTc-ciprofloxacin scintigraphy in the diagnosis of prosthetic joint infections. Nucl Med Commun. 2011;32:44–51. PubMed

Gemmel F, De Winter F, Van Laere K, Vogelaers D, Uyttendaele D, Dierckx RA. 99mTc ciprofloxacin imaging for the diagnosis of infection in the postoperative spine. Nucl Med Commun. 2004;25:277–283. PubMed

Welch RA, Burland V, Plunkett G, et al. . Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli . Proc Natl Acad Sci USA. 2002;99:17020–17024. PubMed PMC

Polvoy I, Seo Y, Parker M, et al. . Imaging joint infections using D-methyl-11C-methionine PET/MRI: initial experience in humans. Eur J Nucl Med Mol Imaging. 2022;49:3761–3771. PubMed PMC

Neumann KD, Villanueva-Meyer JE, Mutch CA, et al. . Imaging active infection in vivo using D-amino acid derived PET radiotracers. Sci Rep. 2017;7:7903. PubMed PMC

Stewart MN, Parker MFL, Jivan S, et al. . High enantiomeric excess in-loop synthesis of D-[methyl-11C]methionine for use as a diagnostic positron emission tomography radiotracer in bacterial infection. ACS Infect Dis. 2020;6:43–49. PubMed PMC

Parker MFL, Luu JM, Schulte B, et al. . Sensing living bacteria in vivo using d-alanine-derived 11C radiotracers. ACS Cent Sci. 2020;6:155–165. PubMed PMC

Weinstein EA, Ordonez AA, DeMarco VP, et al. . Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Sci Transl Med. 2014;6:259ra146. PubMed PMC

Ordonez AA, Wintaco LM, Mota F, et al. . Imaging Enterobacterales infections in patients using pathogen-specific positron emission tomography. Sci Transl Med. 2021;13:eabe9805. PubMed PMC

Ordonez AA, Weinstein EA, Bambarger LE, et al. . A systematic approach for developing bacteria-specific imaging tracers. J Nucl Med. 2017;58:144–150. PubMed PMC

Webb EW, Scott PJH. Potential applications of artificial intelligence and machine learning in radiochemistry and radiochemical engineering. PET Clin. 2021;16:525–532. PubMed PMC

Mota F, Ordonez AA, Firth G, Ruiz-Bedoya CA, Ma MT, Jain SK. Radiotracer development for bacterial imaging. J Med Chem. 2020;63:1964–1977. PubMed PMC

Parker MFL, Flavell RR, Luu JM, Rosenberg OS, Ohliger MA, Wilson DM. Small molecule sensors targeting the bacterial cell wall. ACS Infect Dis. 2020;6:1587–1598. PubMed PMC

Gouws AC, Kruger HG, Gheysens O, et al. . Antibiotic-derived radiotracers for positron emission tomography: nuclear or “unclear” infection imaging? Angew Chem Int Ed. 2022;61:e202204955. PubMed PMC

Lawal I, Zeevaart J, Ebenhan T, et al. . Metabolic imaging of infection. J Nucl Med. 2017;58:1727–1732. PubMed

Vermeulen K, Vandamme M, Bormans G, Cleeren F. Design and challenges of radiopharmaceuticals. Semin Nucl Med. 2019;49:339–356. PubMed

Halouska S, Zhang B, Gaupp R, et al. . Revisiting protocols for the NMR analysis of bacterial metabolomes. J Integr OMICS. 2013;3:120–137. PubMed PMC

Bauermeister A, Mannochio-Russo H, Costa-Lotufo LV, Jarmusch AK, Dorrestein PC. Mass spectrometry-based metabolomics in microbiome investigations. Nat Rev Microbiol. 2022;20:143–160. PubMed PMC

Namavari M, Gowrishankar G, Srinivasan A, Gambhir SS, Haywood T, Beinat C. A novel synthesis of 6″-[18F]-fluoromaltotriose as a PET tracer for imaging bacterial infection. J Labelled Comp Radiopharm. 2018;61:408–414. PubMed PMC

Everitt JI, Berridge BR. The role of the IACUC in the design and conduct of animal experiments that contribute to translational success. ILAR J. 2017;58:129–134. PubMed

Signore A, Artiko V, Conserva M, et al. . Imaging bacteria with radiolabelled probes: is it feasible? J Clin Med. 2020;9:2372. PubMed PMC

Aarntzen EHJG, Noriega-Álvarez E, Artiko V, et al. . EANM recommendations based on systematic analysis of small animal radionuclide imaging in inflammatory musculoskeletal diseases. EJNMMI Res. 2021;11:85. PubMed PMC

Auletta S, Galli F, Varani M, et al. . In vitro and in vivo evaluation of 99mTc-polymyxin B for specific targeting of gram-bacteria. Biomolecules. 2021;11:232. PubMed PMC

Madeja ZE, Pawlak P, Piliszek A. Beyond the mouse: non-rodent animal models for study of early mammalian development and biomedical research. Int J Dev Biol. 2019;63:187–201. PubMed

Esteves PJ, Abrantes J, Baldauf H-M, et al. . The wide utility of rabbits as models of human diseases. Exp Mol Med. 2018;50:1–10. PubMed PMC

Via LE, Schimel D, Weiner DM, et al. . Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [18F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob Agents Chemother. 2012;56:4391–4402. PubMed PMC

Ordonez AA, Parker MF, Miller RJ, et al. . 11C-para-aminobenzoic acid PET imaging of S. aureus and MRSA infection in preclinical models and humans. JCI Insight. 2022;7:e154117. PubMed PMC

Elgazzar AH, Dannoon S, Sarikaya I, Farghali M, Junaid TA. Scintigraphic patterns of indium-111 oxine-labeled white blood cell imaging of gram-negative versus gram-positive vertebral osteomyelitis. Med Princ Pract. 2017;26:415–420. PubMed PMC

Walker RL, Eggel M. From mice to monkeys? Beyond orthodox approaches to the ethics of animal model choice. Animals (Basel). 2020;10:77. PubMed PMC

‘t Hart BA, Abbott DH, Nakamura K, Fuchs E. The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease. Drug Discov Today. 2012;17:1160–1165. PubMed PMC

Hatziioannou T, Evans DT. Animal models for HIV/AIDS research. Nat Rev Microbiol. 2012;10:852–867. PubMed PMC

Coleman MT, Maiello P, Tomko J, et al. . Early changes by 18fluorodeoxyglucose positron emission tomography coregistered with computed tomography predict outcome after Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun. 2014;82:2400–2404. PubMed PMC

Mattila JT, Maiello P, Sun T, Via LE, Flynn JL. Granzyme B-expressing neutrophils correlate with bacterial load in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques. Cell Microbiol. 2015;17:1085–1097. PubMed PMC

Toyohara J, Sakata M, Tago T, Colabufo NA, Luurtsema G. Automated synthesis, preclinical toxicity, and radiation dosimetry of [18F]MC225 for clinical use: a tracer for measuring P-glycoprotein function at the blood-brain barrier. EJNMMI Res. 2020;10:84. PubMed PMC

Prado C, Kazi A, Bennett A, MacVittie T, Prado K. Mean organ doses resulting from non-human primate whole thorax lung irradiation prescribed to mid-line tissue. Health Phys. 2015;109:367–373. PubMed PMC

Ebenhan T, Sathekge MM, Lengana T, et al. . 68Ga-NOTA-functionalized ubiquicidin: cytotoxicity, biodistribution, radiation dosimetry, and first-in-human PET/CT imaging of infections. J Nucl Med. 2018;59:334–339. PubMed

Tanner R, White AD, Boot C, et al. . A non-human primate in vitro functional assay for the early evaluation of TB vaccine candidates. NPJ Vaccines. 2021;6:3. PubMed PMC

Uno Y, Uehara S, Yamazaki H. Utility of non-human primates in drug development: comparison of non-human primate and human drug-metabolizing cytochrome P450 enzymes. Biochem Pharmacol. 2016;121:1–7. PubMed

Orsi A, Rees D, Andreini I, Venturella S, Cinelli S, Oberto G. Overview of the marmoset as a model in nonclinical development of pharmaceutical products. Regul Toxicol Pharmacol. 2011;59:19–27. PubMed PMC

Seyedmousavi S, Bosco S de MG, de Hoog S, et al. . Fungal infections in animals: a patchwork of different situations. Med Mycol. 2018;56(suppl 1):165–187. PubMed PMC

Vamathevan JJ, Hall MD, Hasan S, et al. . Minipig and beagle animal model genomes aid species selection in pharmaceutical discovery and development. Toxicol Appl Pharmacol. 2013;270:149–157. PubMed

Signore A, Casali M, Lauri C. An easy and practical guide for imaging infection/inflammation by [18F]FDG PET/CT. Clin Transl Imaging. 2021;9:283–297. PubMed PMC

Corrales-Medina VF, deKemp RA, Chirinos JA, et al. . Persistent lung inflammation after clinical resolution of community-acquired pneumonia as measured by 18FDG-PET/CT imaging. Chest. 2021;160:446–453. PubMed PMC

Baldoni D, Waibel R, Bläuenstein P, et al. . Evaluation of a novel Tc-99m labelled vitamin B12 derivative for targeting Escherichia coli and Staphylococcus aureus in vitro and in an experimental foreign-body infection model. Mol Imaging Biol. 2015;17:829–837. PubMed PMC

Aulakh GK, Brocos Duda JA, Guerrero Soler CM, Snead E, Singh J. Characterization of low-dose ozone-induced murine acute lung injury. Physiol Rep. 2020;8:e14463. PubMed PMC

Aulakh GK, Kaur M, Brown V, Ekanayake S, Khan B, Fonge H. Quantification of regional murine ozone-induced lung inflammation using [18F]F-FDG microPET/CT imaging. Sci Rep. 2020;10:15699. PubMed PMC

Duda JAB, Kaur M, Aulakh GK. Visualizing lung cellular adaptations during combined ozone and LPS induced murine acute lung injury. J Vis Exp. 2021;(169). PubMed

Henneberg S, Hasenberg A, Maurer A, et al. . Antibody-guided in vivo imaging of Aspergillus fumigatus lung infections during antifungal azole treatment. Nat Commun. 2021;12:1707. PubMed PMC

Welling MM, Duszenko N, van Willigen DM, et al. . Cyclodextrin/adamantane-mediated targeting of inoculated bacteria in mice. Bioconjug Chem. 2021;32:607–614. PubMed PMC

Cho SY, Pomper MG. Clinical translation of molecular imaging probes. In: Chen A, ed. Molecular Imaging Probes for Cancer Research. World Scientific; 2012:1041–1065.

Wester H-J. Nuclear imaging probes: from bench to bedside. Clin Cancer Res. 2007;13:3470–3481. PubMed

Liu CH, Sastre A, Conroy R, Seto B, Pettigrew RI. NIH workshop on clinical translation of molecular imaging probes and technology: meeting report. Mol Imaging Biol. 2014;16:595–604. PubMed PMC

Automated Production of [68Ga]Ga-Desferrioxamine B on Two Different Synthesis Platforms