Citation: Singh, S.B.; Bhandari, S.; Siwakoti, S.; Bhatta, R.; Raynor, W.Y.; Werner, T.J.; Alavi, A.; Hess, S.; Revheim, M.-E. Is Imaging Bacteria with PET a Realistic Option or an Illusion? Diagnostics 2023, 13, 1231. https://doi.org/10.3390/ diagnostics13071231 Academic Editor: Alessio Imperiale Received: 24 February 2023 Revised: 14 March 2023 Accepted: 22 March 2023 Published: 24 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). diagnostics Review Is Imaging Bacteria with PET a Realistic Option or an Illusion? Shashi B. Singh 1 , Sadikshya Bhandari 2 , Shisir Siwakoti 2 , Rabi Bhatta 3 , William Y. Raynor 4 , Thomas J. Werner 1 , Abass Alavi 1 , Soren Hess 5,6 and Mona-Elisabeth Revheim 7,8,9, * 1 Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA 2 Kathmandu University School of Medical Sciences, Dhulikhel Hospital, Dhulikhel 45200, Nepal 3 Universal College of Medical Sciences, Bhairahawa 32900, Nepal 4 Department of Radiology, Rutgers Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, MEB #404, New Brunswick, NJ 08901, USA 5 Department of Radiology and Nuclear Medicine, Hospital Southwest Jutland, 6700 Esbjerg, Denmark 6 Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, 5230 Odense, Denmark 7 The Intervention Center, Division of Technology and Innovation, Oslo University Hospital, 0424 Oslo, Norway 8 Division for Radiology and Nuclear Medicine, Oslo University Hospital, 0424 Oslo, Norway 9 Norway and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0315 Oslo, Norway * Correspondence: monar@ous-hf.no or m.e.rootwelt-revheim@medisin.uio.no Abstract: The application of [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG) as a radiotracer to detect sites of inflammation (either due to bacterial infection or primary inflammation) has led to exploring the role of PET in visualizing bacteria directly at sites of infection. However, the results from such efforts are controversial and inconclusive so far. We aimed to assess the limitations of PET as an effective modality in the diagnosis of bacterial infections. Inflammation due to bacterial infections can be visualized by using [ 18 F]FDG-PET. However, the non-specificity of [ 18 F]FDG makes it undesirable to visualize bacteria as the underlying cause of inflammation. Hence, more specific radiotracers that possibly bind to or accumulate in bacteria-specific receptors or enzymes are being explored. Several radiotracers, including 2-deoxy-2-[ 18 F]fluorosorbitol ([ 18 F]FDS), 6-[ 18 F]-fluoromaltose, [ 11 C]para- aminobenzoic acid ([ 11 C]PABA), radiolabeled trimethoprim ( 11 C-TMP) and its analog fluoropropyl- trimethoprim ( 18 F-FPTMP), other radiolabeled sugars, and antimicrobial drugs have been used to image microorganisms. Unfortunately, no progress has been made in translating the results to routine human use; feasibility and other factors have constrained their success in clinical settings. In the current article, we discuss the limitations of direct bacterial visualization with PET tracers, but emphasize the important role of [ 18 F]FDG-PET as the only option for detecting evidence of infection. Keywords: PET; imaging; bacteria; infection; inflammation; [ 18 F]FDG; radiotracers 1. State of PET Imaging in Infectious Diseases In 1976, when [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG) was introduced as a radiotracer for positron emission tomography (PET), it revolutionized medical imaging, especially in the fields of neurology, oncology, and cardiology [1–3]. Later, it also gained importance in diagnosing infectious and inflammatory disorders [4,5]. [ 18 F]FDG, as an analog of glucose, accumulates in a cell with high rates of glycolysis (such as in cancer cells and inflammatory cells) by entering the cell via glucose transporters and is then phosphorylated by hexokinase to deoxyglucose phosphate, which remains locked in this state [6]. The high uptake of [ 18 F]FDG by the metabolically active inflammatory cells has played a major role in the detection of inflammatory reactions in response to microorganisms such as bacteria. Hence, [ 18 F]FDG is commonly used for detecting infectious and inflammatory disorders [7] (Figure 1). Diagnostics 2023, 13, 1231. https://doi.org/10.3390/diagnostics13071231 https://www.mdpi.com/journal/diagnostics