Positron emission tomography in infections associated with immune dysfunction
Ankrah, Alfred
DOI:
10.33612/diss.144628960
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Ankrah, A. (2020). Positron emission tomography in infections associated with immune dysfunction.
University of Groningen. https://doi.org/10.33612/diss.144628960
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Chapter 3
Radiopharmaceuticals for PET Imaging of Infection
Ankrah AO and Elsinga PH
Book chapter. In: Signore A., Glaudemans A. (eds) Nuclear Medicine in Infectious Diseases. Springer, Cham 2020:19‐35Radiopharmaceuticals for
PET Imaging of Infection
Ankrah AO, Elsinga PH
Book chapter. In: Signore A., Glaudemans A. (eds) Nuclear Medicine in Infec-tious Diseases. Springer,
Cham 2020:19‐35
Abstract
Early diagnosis of infection in order to perform adequate treatment is crucial. Several radiopharmaceuticals presently available play a useful role in the diagnosis of infections, while new ones are being evaluated. In this review, we highlight tracers based on different uptake mechanisms that have been used in the evaluation infections. The performance of [18F]FDG, radiolabeled blood cells, [68Ga]Ga‐citrate, and peptides used in humans is discussed and a large group of experimental infection‐specific PET tracers (mostly bacteria‐specific) are considered.
34 35
Introduction
Fluorine‐18 fluorodeoxyglucose ([18F]FDG) is the most common PET tracer used in the evaluation of infection. [18F]FDG is used for evaluating bacterial, fungal, parasitic, and viral infections [1–3]. [18F]FDG is used for the assessment of site‐specific infections such as spondylodiscitis, infection in specialized groups such as diabetic or neutropenic patients and patients with prosthetic devices [4]. However, [18F]FDG is nonspecific and other PET tracers have been used in an attempt to overcome this limitation of [18F]FDG by taking advantage of differences in microorganisms and mammalian biochemical processes [5]. [68Ga]Gallium citrate has also been tested in some infections but it is also a nonspecific tracer accumulating in non‐infectious inflammation. Radiolabeled white blood cells (WBC) imaging is the method of choice in the evaluation of many infections in nuclear medicine imaging. SPECT‐based radiolabeled WBC is the most commonly used in clinical practice. PET imaging affords better special resolution and better ability to quantify tracer uptake that is crucial for monitoring the treatment of infection. White blood cells have been labeled with PET radioisotopes and radiopharmaceuticals to take advantage of the properties of PET imaging. Some challenges in PET labeling of WBC have not allowed PET WBC to supplant SPECT WBC in the clinical evaluation of infection. Other compounds have been labeled with 18F for infection imaging. The use of the68Ga‐based radiopharmaceuticals has been gaining prominence in the last decade. Some 68Ga‐based tracers have been used in infection imaging or have the potential to be used. Other PET radioisotopes such as 64Cu and 89Zr have been used in infection imaging especially in procedures where a longer half‐life is desirable. In this chapter, we briefly review the various PET tracers that are used or can potentially be used in infection.Clinically
Validated/Tested
and
Commercially
Available
Radiopharmaceuticals
[
18F]FDG
During infection, the human body responds with the migration and activation of immune cells to the site of infection. These activated immune cells markedly increase their glucose uptake. The glucose transporters on the membrane of immune cells transport [18F]FDG, a glucose analog into the cell. Once [18F]FDG is inside the immune cell it is phosphorylated like glucose but is unable to continue along the biochemical pathway for glucose utilization and remains trapped in the immune cell. In addition to this, some microorganisms like bacteria have been found to contribute to the [18F]FDG signal by actively taking up [18F]FDG [6]. Compared to other methods used in infection imaging, the process of imaging with FDG is relatively fast with the study complete within a few hours. Unlike white cell labeling, [18F]FDG does not require direct handling of blood and laborious labeling procedures. [18F]FDG can be used in patients with neutropenia where anatomical‐based imaging modalities or white cell imaging may be less helpful. [18F]FDG has some limitations including its non‐specificity that is particularly a problem in the early postoperative period when inflammation at the site of operation limits the ability of [18F]FDG to detect infection. [18F]FDG does not image the microorganism themselves but rather the downstream immune activation. Table 1 summarizes the targets of the radiopharmaceuticals used in infection.3
34 35Table 1: Biological process and target of currently available or potential PET tracers
Process Target Tracer example Stage
Activated immune cells Energy consumption [18F]FDG Clinical Infiltration of leucocytes Radiolabeled white blood cells Clinical
Host defense Iron availability [68Ga]citrate Clinical Iron scavenging [68Ga]siderophores Preclinical Immune response Antimicrobial peptides Ubiquicidine peptides Clinical
Bacterial cell wall Cell wall synthesis inhibition No PET tracers Preclinical
Bacterial biosynthesis Folic acid synthesis inhibition [18F]trimethoprim Preclinical Protein synthesis inhibition [68Ga]puromycin Preclinical RNA synthesis inhibition [11C]rifampicin Preclinical DNA synthesis inhibition [68Ga]ciprofloxacin Preclinical Host defense Bacterial antigens 64Cu and 89Zr-radiolabeled
Antibodies Preclinical
Bacterial metabolism Carbohydrate metabolism [18F]carbohydrates Preclinical Various other processes [18F]FLT, PET-amino acids, etc. Preclinical
[
18F]FDG and Different Microorganisms
[18F]FDG‐PET has been used in the evaluation of different microorganisms. For viruses, [18F]FDG has been used to stage the infection and assess HIV‐associated infections and malignancies [1, 7]. In bacterial imaging, [18F]FDG has been used to determine the site of infection when the site of infection is unknown or stage infection to determine the location of undiagnosed disease. In bacterial infections that require prolonged treatment like tuberculosis, [18F]FDG is useful in monitoring treatment of infection (Fig. 1) [8]. In fungal infections, [18F]FDG can be used to help diagnosis and guide therapy in a wide array of fungal infections [3, 9]. For parasitic infections, [18F]FDG has been used in the follow‐ up of treatment for alveolar echinococcosis [2]. Figure 1 18F‐FDG‐PET/CT scan before anti‐TB treatment and 2 months after initiation of treatment for interim assessment of treatment response. (a) Maximum intensity projection (MIP) image before treatment (PET images only), showing
extensive disease: pulmonary, cervical, axillary, mediastinal, abdominal, pelvic and inguinal lymph nodes, hepatic and skeletal metastasis to the lumbar spine and right humerus.
(b) MIP image after 2 months of anti‐TB treatment (PET images only): complete meta‐ bolic
response of the pulmonary and right humeral lesions and the pelvic and inguinal lymph nodes. Good metabolic response in the mediastinal, cervical, and axillary nodes. Active disease is still present in the lumber spine with progression of the hepatic lesions.
(c) Transverse scans showing axillary nodes before treatment (PET and integrated PET/CT
images). (d) Transverse scans showing response of axillary nodes after 2 month of anti‐TB therapy; nodal uptake diminished but still present
36 37
FDG Imaging of Some Site‐Specific Infections Which Have Been Validated
Osteomyelitis
[18F]FDG is useful in the diagnosis of osteomyelitis, especially chronic osteomyelitis. A meta‐analysis
found the sensitivity and specificity of [18F]FDG‐PET in chronic osteomyelitis to be 96% and 91%,
respectively [10]. [18F]FDG‐PET is particularly useful in multi‐focal osteomyelitis.
Spondylodiscitis
[18F]FDG is used for imaging spondylodiscitis where other imaging modalities may be suboptimal [11–
13]. Differentiating degenerative disease from infection is particularly challenging, and [18F]FDG‐
PET/CT is very useful for this purpose [12]. A meta‐analysis found the pooled sensitivity and specificity of [18F]FDG‐PET/CT in spondylodiscitis to be 97% and 88% [14].
Diabetic Foot
FDG‐PET is useful in diagnosing pedal osteomyelitis. One study found PET/CT had sensitivity and specificity of 81% and 93% in the diagnosis of pedal osteomyelitis in the diabetic foot [15]. Hip and Knee Prosthesis [18F]FDG‐PET has been used in the evaluation of infected prosthesis of the hip and knee joints. Several studies found [18F]FDG‐PET useful and also established interpretation criteria [16–20]. A meta‐analysis of the diagnosis of infected knee and ankle prosthesis by [18F]FDG‐PET found a pooled sensitivity of 87% and specificity of 87% [21]. Infected Vascular Graft Some studies have evaluated the role of [18F]FDG‐PET in the evaluation of infected vascular graft. The sensitivity, specificity, and accuracy of [18F]FDG‐PET in the diagnosis of infected vascular graft were 100%, 86%, and 97%%, respectively [22]. Infective Endocarditis [18F]FDG‐PET/CT is used in the evaluation of infected prosthetic heart valves and is recommended by
major international guidelines [23]. The sensitivity and specificity of [18F]FDG‐PET/CT in prosthetic
heart valves was found to be 71% and 95%, respectively, after confounders were removed the sensitivity and specificity improved to 91% and 95% [24]. [18F]FDG‐PET/CT is not recommended in the
assessment of native valve infective endocarditis; however, it is useful in detecting septic emboli from native valve endocarditis.
Cardiac Implantable Electronic Device Infectionss
[18F]FDG‐PET/CT is a useful additive tool in patients with suspected cardiac implantable electronic
device infections [25]. A meta‐analysis found [18F]FDG‐PET had a pooled sensitivity and specificity of
87% and 94% for infected implantable cardiac devices [26].
Labeled White Blood Cells
During infection, chemotactic agents attract leucocytes to the site of infection. Radiolabeled WBC provides a means of imaging infection. Leucocytes have been labeled with [18F]FDG [27, 28]. The
sensitivity and specificity per lesion were found to be 91% and 85%, respectively, and 86% for both sensitivity and specificity per patient [27]. The labeling efficiency of [18F]FDG labeled white cells are lower than SPECT‐based tracers, and the short half‐life of 18F is not ideal for delayed imaging which is essential for the diagnosis of infection by labeled WBCs. Leucocytes have also been labeled with 64Cu
3
36 37because the long half‐life of 64Cu would permit delayed imaging to distinguish infection. The labeling efficiency and viability of the labeled leucocytes were higher than 111In‐labeled leucocyte. However, there was higher leakage from 64Cu compared to SPECT‐based labeled leucocytes [29]. The radiation exposure to the long‐lived lymphocytes from PET‐based radioisotope is a concern [30].
[
68Ga]Citrate
[68Ga]citrate has been used to image osteomyelitis, tuberculosis, and soft‐tissue infections in human studies [31–33]. Iron is utilized by both mammals and microorganism for their metabolism. Gallium mimics iron, and in infection, the uptake of gallium is due to transferrin‐dependent and independent mechanisms. [68Ga]citrate like [18F]FDG lacks specificity and accumulates in sterile inflammatory process or malignancy [34]. The ease of preparation of the radiopharmaceutical and the availability of good manufacturing practice 68Ga‐generators makes the use of [68Ga]citrate appealing. The sensitivity and specificity for osteomyelitis was 100% and 76%, respectively. Larger studies with [68Ga]citrate are required to validate its use in various clinical scenarios.Peptides
AMPs are peptides produced by the immune system of the host against microorganisms. They have low toxicity and have activity against a wide range of microorganisms. Several AMPs have been labeled for imaging infection. For PET imaging, ubiquicidin fragments have been most widely investigated. Ubiquicidin (UBI) Fragments UBI, a 51 amino acid peptide that binds negatively charged moieties in the cell wall of bacteria has shown promising results for imaging infection. Several fragments of UBI have been labeled with 68Ga and 18F and tested in different animal models [35–39]. The [68Ga]UBI fragments were able to distinguish infection and inflammation and had good localization of infection (Fig.2) [36]. [68Ga]UBI fragments (UBI29‐41 and UBI31‐38) have been used in humans with promising results [36, 37]. The UBI29‐41 fragment was labeled with 18F but did not have as much success in imaging infection as the 68Ga‐labeled counterpart due to significant defluorination and the lack of specific binding to Staphylococcus aureus in vivo. Larger studies with [68Ga]UBI would be necessary to validate the use of the tracer in different clinical situations.
Figure 2
PET/CT images of healthy mouse (a),
mouse with sterile inflammation (b), and
mouse infected with S. aureus (c). Images
were acquired 2 h after injection of 68
Ga-NOTA-UBI-29-41 (1, coronal; 2, sagittal; and 3, axial). Images correspond to frame 2 of 4. Arrows indicate inflamed or infected muscle (Mónica Vilche et al. J Nucl Med 2016; 57:622–627.)
38 39
Experimental Radiopharmaceuticals
Peptides
Depsipeptide Derivative A depsipeptide derivative was labeled with 68Ga by DOTA chelation and was used for in vivo evaluation of Escherichia coli in a mouse model and Staphylococcus aureus and Mycobacterium tuberculosis in a rabbit model [40, 41]. The tracer detected these infections but was not able to differentiate infection‐ associated inflammation from bacteremia. K‐A9 Peptide K‐A9 is a peptide that binds to Staphylococcus aureus that was selected and proposed as an imagingpeptide [42]. The peptide was radiolabeled with 68Ga but was not found to be selective towards
infection probably due to some factors including vascular leakiness, hyperemia, and the peptide‐ binding epitopes in dead bacteria [43].
Antibiotics and other antimicrobials
Antibiotics have been used extensively with SPECT tracers. A few have also been labeled with PET radionuclides. Ciprofloxacin Radiolabeled ciprofloxacin is one of the earliest antibiotics used in imaging infections. The antibiotic or its conjugates have been labeled with 68Ga and 18F [44, 45]. [68Ga]ciprofloxacin conjugates were labeledby bifunctional DOTA and NOTA chelators [44]. The [68Ga]ciprofloxacin conjugates (Fig. 3) could
discriminate between Staphylococcus aureus infected sites in rat muscle from inflammation. These tracers are yet to be tested in the clinic. Ciprofloxacin was also labeled by nucleophilic 18F‐fluorination. However, the radioactivity was not retained in the infected tissue, and the clearance from infected tissue was similar to non‐infected tissue [45]. Trimethoprim
Trimethoprim inhibits the synthesis of the nucleic acid thymidine in bacteria by inhibiting tetrahydrofolic acid. Trimethoprim has been labeled with 18F by nucleophilic fluorination and was
found to show a very high uptake (>100‐fold) in live bacteria but not in other pathologies such as cancer or sterile inflammation in a mouse model. The biodistribution of this tracer has been determined in a nonhuman primate but no human studies have been carried out [46]. Puromycin Puromycin is an antibiotic that interrupts bacteria protein synthesis by terminating the translation of ribosomes. Puromycin has been labeled with 68Ga by DOTA chelation and showed promising results for uptake in Staphylococcus aureus foci compared to sterile inflammation [47]. Puromycin has also been labeled with 18F for imaging protein synthesis [48]. This labeled antibiotic has not yet been tested for infection imaging.
3
38 39Rifampicin
The anti‐mycobacterial agent rifampicin was radiolabeled with 11C. The SPECT equivalent of this radiolabeled antibiotic was evaluated as a tuberculosis imaging agent. The 11C‐labeled antibiotic was used to determine the distribution of the agent but may play a role in imaging the infection. The short half‐life of 11C however may limit its clinical application [49]. Isoniazid The anti‐mycobacterial drug isoniazid was radiolabeled with 18F by nucleophilic substitution [50]. The tracer was used to image mice infected with Mycobacterium tuberculosis and the tracer showed good uptake at infected sites. This tracer is yet to be translated to human studies. Pyrazinamide Pyrazinamide, an anti‐mycobacterial agent, was labeled with 18F by a fluoride exchange reaction. The biodistribution of the 5‐[18F]pyrazinamide compound was assessed. The pyrazinamide analog did not show significant differences in infected tissue and uninfected mice model of tuberculosis. There was rapid and extensive defluorination of [18F]pyrazinamide. As a result of this, the fluorine analog of pyrazinamide may be limited as an infection imaging agent [51]. Fluconazole Fluconazole an antifungal agent has been radiolabeled with 99mTc and was found to be an excellent tracer for detecting Candida albicans in mice [52]. The agent was also labeled with 18F. The PET tracer, however, may not be as successful in imaging candida infections as there was intense hepatic uptake due to the excretion of the [18F]fluconazole [53].
Antibody Labeling
Antibodies Against Gram‐Negative Bacteria Polyclonal antibodies against the outer membrane protein of Yersinia enterocolitica, adhesion A, were labeled with 64Cu. The radiolabeling was achieved by chelation with 1,4,7‐triazacyclononane,1‐glutaric acid‐4,7‐acetic acid (NODAGA). The 64Cu‐labeled antibody was taken up in infected tissues in a dose‐ dependent manner. The 64Cu‐labeled antibody was able to detect infection in spleens of mice with low dose infection in contrast to FDG [54]. Antibodies Against Gram‐Positive Bacteria Gram‐positive bacteria surface molecule lipoteichoic acid (LTA) was imaged with the anti‐LTA antibody SAC55 labeled with 89Zr after its conjugation with bifunctional chelate, p‐SCN‐Bn‐DFO. The tracer was tested in a mouse model of prosthetic joint infection and was able to distinguish infection prosthetic joints from inflammation non‐infected joint. The findings are yet to be translated to humans [55]. Antibody Against Simian Immunodeficiency Virus Envelope Protein A monoclonal antibody against the glycoprotein Gp120 on the surface of Simian immunodeficiency virus has been labeled with 64Cu. The radiolabeling method was DOTA chelation of the modified antibody. The tracer was used to provide the location and quantification of in vivo viral replication in a nonhuman primate [56]. Aspergillus Fumigatus‐Specific Monoclonal Antibody JF5 The JF5 monoclonal antibody binds to an extracellular mannoprotein of Aspergillus fumigatus that is produced during growth of the fungi. The JF5 monoclonal antibody was radiolabeled with 64Cu by 40 41chelating with DOTA. The tracer was tested in a neutrophil‐depleted mouse model of invasive fungal infection. The tracer was able to distinguish the growth phase of Aspergillus fumigatus from other pathology including infection with other microorganisms [57].
Imaging Targeted Molecules or Metabolism Specific to Microorganisms
Siderophores Siderophores are proteins used by microorganisms to scavenge iron in their micro‐environment. 68Ga‐ labeled siderophores have been used for imaging invasive pulmonary aspergillosis in an animal model. Two compounds triacetylfusarinine and ferrioxamine E were radiolabeled using the direct method. The 68Ga‐labeled siderophores showed high sensitivity and selectivity for rat lungs infected with Aspergillus fumigatus [58, 59]. Carbohydrate MetabolismMaltodextrins: Maltohexose was labeled with 18F by nucleophilic substitution. [18F]fluoromaltohexose
is transported into the bacteria by a maltodextrin transporter which is unique to bacteria making it a promising agent. In an in vivo study involving a rat model of an implantable cardiac device, the tracer was found to be specific and sensitive for the detection of Staphylococcus aureus [60]. The tracer had earlier been shown to be sensitive and specific for the detection of Escherichia coli in in vitro studies [61]. The tracer was found to accumulate in as few as 105 colony forming units [62]. Maltotriose: Maltotriose is also utilized by bacteria but not mammalian cells. 6‐[18F]fluoromaltotriose was radiolabeled by nucleophilic 18F‐fluorination. In preliminary in vivo studies in mice, the tracer was specifically taken up by viable Escherichia coli but not in sterile inflammation [63].
Sorbitol: Sorbitol is a substrate for Gram‐negative bacteria, Enterobacteriaceae. The tracer
[18F]fluorosorbitol ([18F]FDS). The tracer which can easily be synthesized from [18F]FDG (Fig. 4) was found to be promising as a bacteria‐specific imaging agent some studies. [18F]FDS was found to be a better biomarker than [18F]FDG, in tracking bacterial lung infection using a mouse model [64]. In another study, [18F]FDS was found to accumulate in susceptible and carbapenem‐resistant drug isolates [65]. [18F]FDS was evaluated in humans for safety and no adverseeffects were observed 24 h after administration of the tracer [66]. [18F]FDS was able to detect Enterobacteraceae in mixed infections, brain infections, and mice undergoing chemotherapy [67].
Figure 3: Chemical structure of [68Ga]‐Bz‐SCN‐ciprofloxacin Figure 4: Synthesis of [18F]FDS from clinical grade [18F]FDG
via a reduction step
[18F]Fluorodeoxyglucose‐phosphate (FDG‐P): Bacteria can utilize FDG‐P using universal hexose
phosphate transporters which are not present in mammalian cells. Unlike FDS which targeted only
3
Gram‐negative bacteria, it was hoped that FDG‐P would be useful in imaging Gram‐positive bacteria with high sensitivity and bacteria selectivity. FDG‐P uptake was higher in Staphylococcal‐infected catheter implants in mice compared to uninfected implants [68]. D‐mannitol: The ability of some bacteria to utilize d‐mannitol as a source of energy has been exploited for potential bacterial imaging. The sugar was radiolabeled with 18F. The radiolabeled d‐mannitol was rapidly taken up by Gram‐positive and Gram‐negative bacteria in a myositis model in mice. The tracer was taken up by both susceptible and resistant microorganisms [65].
Fluoroacetamide‐d‐glycopyranose (FAG): Amino sugars are important components of the
bacterial cell wall. This makes them a good target for imaging bacteria. An analog of an amino sugar was radiolabeled by microwave irradiation to [18F] FAG. The radiolabeled tracer was able to distinguish infection with Escherichia coli and sterile inflammation in an animal model [69]. Trehalose analogs: Trehalose is a disaccharide sugar that is used by plants and microorganism for some functions like stress protection and energy storage. A modified 18F‐labeled analog of trehalose has been produced by the chemoenzymatic conversion of [18F]FDG. The 18F‐labeled analog of trehalose was shown to be metabolized by Mycobacterium smegmatis but not mammalian cell in cellular uptake experiments. There are no clinical studies available [70]. Other Metabolites Fialuridine (FIAU)
Fialuridine is a nucleoside analog that is a building block of the nucleic acid of microorganisms. Fialuridine is phosphorylated by thymidine kinase and remains trapped in the microorganism allowing imaging is tagged with a radioisotope. FIAU has been radiolabeled with 18F and 124I [68, 71, 72]. The [18F]FIAU was radiolabeled by nucleophilic substitution. The synthesis of [18F]FIAU is more complex and achieves lower yields than [124I]FIAU. When [124I]FIAU was used in the evaluation of prosthetic joint prosthesis the image quality and specificity was low [73].
Para‐Aminobenzoic acid (PABA)
PABA is utilized by bacteria in the synthesis of folate. In mammals, folate is obtained from the diet and mammals cannot utilize PABA. This makes PABA a good target to image infection. PABA has been labeled with 11C and 18F [74, 75]. In an animal model, the [11C]PABA was able to distinguish between infection and sterile inflammation. The [18F]PABA was tested in an animal model where it was found to be useful in imaging Staphylococcus aureus infection.
D‐Methionine
D‐Methionine was labeled with 11C and successfully used to image bacteria. D‐amino acids are used solely by bacteria for building their cell walls. The [11C] methionine rapidly accumulated in Gram‐ positive and Gram‐negative bacteria. No human study has been done on this PET tracer [76].
Prothrombin
Some Staphylococcus sp. produce staphylocoagulase which help bacteria evade detection by the immune system of their host by covering their antigen with clotted blood from the host. An analog of prothrombin was labeled with 64Cu by chelation with DOTA. This enabled the detection of
Staphylococcus sp.‐induced endocarditis in mice [77].
Transferrin
Transferrin is a protein involved in the transport of iron. Transferrin was labeled with 68Ga as [68Ga]apotransferrin. The tracer was found to be able to detect Staphylococcus aureus infection in a rat model within an hour of injection [78].
Nonspecific Tracers Used in Infection to Discriminate Infection from Malignancy
[18F]fluorothymidine ([18F]FLT)Synthesis of DNA can be imaged by [18F]FLT. During an infection, microorganisms are constantly growing with actively synthesizing nucleic acids. The growth of Staphylococcus aureus in rabbit was imaged using [18F]FLT. However, nucleic acid formation is not limited to bacteria growth and makes the tracer just as nonspecific as [18F]FDG [79, 80]. In another study using a model with Yersinia
enterocolitica, [18F]FLT was not useful in assessing bacterial proliferation [81].
Other clinically available PET tracers have been used in the evaluation of different aspects a particular infection. In tuberculosis, for example, [18F]NaF used to evaluate calcification of tuberculous granulomas in mice, the complex lipid covering was evaluated by [11C]choline or [18F]fluoroethylcholine. The use of these tracers is limited to the pathology of a particular infection and lacked specificity for the infection [8].
Conclusion and Future Perspective
PET imaging of infection has gained prominence over the last decade. [18F]FDG has been found useful in many site‐specific infections. It is likely to be validated in more clinical situations in the future. The introduction of PET/MRI into clinical practice may open a new chapter in infection imaging, especially where soft‐tissue definition is essential. The use microorganism‐specific tracers are being explored and the presence of longer acting PET tracer such as 64Cu and 89Zr has increased the possibilities especially in the labeling of antibodies. A lot of the tracers are at the preclinical stage of development. A lot more research is needed for the clinical application of these tracers. The search for an ideal PET tracer is still ongoing. The ideal tracer should be able to distinguish infection from inflammation, cheap, easy to prepare, and not require handling of blood products. A tracer should be able to detect both resistant and susceptible species. Another major clinical hurdle is biofilm formation making bacteria not sensitive to anti‐bacterial agents as these agents are not able to penetrate into biofilm. Recent research on adaptive biofilm‐targeted agents can trigger development of a completely new class of imaging agents in the future.3
42 43References
1. Sathekge M, Maes A, Van de Wiele C. FDG‐PET imaging in HIV infection and tuberculosis. Semin Nucl Med 2013; 43:349‐66. 2. Ammann RW, Stumpe KD, Grimm F, et al. Outcome after discontinuing long‐term benzimidazole treatment in 11 patients with non‐resectable alveolar echinococcosis with negative FDG‐PET/CT and anti‐EmII/3‐10 serology. PLoS Negl Trop Dis 2015; 9:e0003964. 3. Ankrah AO, Sathekge MM, Dierckx RA, Glaudemans AW. Imaging fungal infections in children. Clin Transl Imaging 2016; 4:57–72. 4. Glaudemans AW, Signore A. FDG‐PET/CT in infections: the imaging method of choice? Eur J Nucl Med Mol Imaging 2010; 37:1986‐91. 5. Auletta S, Varani M, Horvat R, Galli F, Signore A, Hess S. PET radiopharmaceuticals for specific bacteria imaging: a systematic review. J Clin Med 2019; 8:E197. 6. Heuker M, Sijbesma JWA, Suarez RA, et al. In vitro imaging of 18F‐fluorodeoxyglucose micropositron emission tomoghraphy. Sci Rep 2017; 7:4973. 7. Ankrah AO, Glaudemans AWJM, Klein HC, Dierckx RAJO, Sathekge M. The role of nuclear medicine in the staging and management of human immune deficiency virus infection and associated diseases. Nucl Med Mol Imaging 2017; 51:127–39. 8. Ankrah AO, van der Werf TS, de Vries EF, Dierckx RA, Sathekge MM, Glaudemans AW. PET/CT imaging of mycobacterium tuberculosis infection. Clin Transl Imaging. 2016; 4:131‐44. 9. Ankrah AO, Klein HC, Span LFR, et al. The role of PET in monitoring therapy in fungal infections. Curr Pharm Des 2018; 24:795–805. 10. Termaat MF, Raijmakers PG, Scholten HJ, Bakker FC, Patka P, Haarman HJ. The accuracy of diagnostic imaging for the assessment of chronic osteomyelitis: a systematic review and meta‐analysis. J Bone Joint Surg Am 2005; 87:2464‐71.11. Stumpe KD, Zanetti M, Weishaupt D, Hodler J, Boos N, Von Schulthess GK. FDG positron emission tomography for differentiation of degenerative and infectious endplate abnormalities in the lumbar spine detected on MR imaging. AJR Am J Roentgenol 2002; 179:1151‐7.
12. Schmitz A, Risse JH, Grünwald F, Gassel F, Biersack HJ, Schmitt O. Fluorine‐18 fluorodeoxy‐glucose positron emission tomography findings in spondylodiscitis: preliminary results. Eur Spine J 2001; 10:534‐9.
13. Signore A, Jamar F, Israel O, Buscombe J, Martin‐Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti‐granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging 2018; 45:1816‐31.
14. Prodromou ML Ziakas PD, Poulou LS, Karsaliakos P, Thanos L, Mylonakis E. FDG PET is a robust tool for the diagnosis of spondylodiscitis: a meta‐analysis of diagnostic data. Clin Nucl Med 2014; 39:330‐5. 15. Navaz A, Torigian DA, Siegelman ES, Basu S, Chryssikos T, Alavi A. Diagnostic performance of FDG‐PET, MRI, and plain film radiography (PFR) for the diagnosis of osteomyelitis in the diabetic foot. Mol Imaging Biol 2010; 12:355‐ 42. 16. Chryssikos T, Parvizi J, Ghanem E, Newberg A, Zhuang H, Alavi A. FDG‐PET imaging can diagnose periprosthetic infection of the hip. Clin Orthop Relat Res 2008; 466:1338‐42. 17. Chacko TK, Zhuang H, Stevenson K, Moussavian B, Alavi A. The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses. Nucl Med Commun 2002; 23:851‐5. 44 45
18. Vanquickenborne B, Maes A, Nuyts J, et al. The value of (18)FDG‐PET for the detection of infected hip prosthesis. Eur J Nucl Med Mol Imaging 2003; 30:705‐15.
19. Mumme T, Reinartz P, Alfer J, Müller‐Rath R, Buell U, Wirtz DC. Diagnostic values of posittron emission tomography versus triple‐phase bone scan in hip arthroplasty loosening. Arch Orthop Trauma Surg. 2005;125:322– 9. 20. Basu S, Kwee TC, Saboury B, et al. FDG PET for diagnos‐ ing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined (111)In‐labeled leukocyte/(99m)Tc‐sulfur colloid bone marrow imaging in 88 prostheses. Clin Nucl Med 2014; 39:609–15. 21. Hao R, Yuan L, Kan Y, Yang J. 18F‐FDG PET for diagnosing painful arthroplasty/prosthetic joint infection. Clin Transl Imaging 2017; 5:315‐22. 22. Sah BR, Husmann L, Mayer D, et al. Diagnostic performance of 18F‐FDG‐PET/CT in vascular graft infections. Vasc Endovascular Surg 2015; 49:455‐64. 23. The 2015 ESC guidelines for the management of infective endocarditis. Eur Heart J 2015;36; 3036‐7. 24. Swart LE, Gomes A, Scholtens AM, et al. Improving the diagnostic performance of 18F‐fluorodeoxyglucose positron‐ emission tomography/computed tomography in prosthetic heart valve endocarditis. Circulation 2018; 138:1412‐ 27. 25. Scarsbrook A, Barrington S. Evidence based indications for the use of PET/CT in the United Kingdom. Clin Radiol 2016; 71:e171‐88.
26. Juneau D, Golfam M, Hazra S, et al. Positron emission tomography and single‐photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection: a systematic review and meta‐analysis. Circ Cardiovasc Imaging 2017; 10:e005772. 27. Dumarey N, Egrise D, Blocklet D, et al. Imaging infection with 18F‐FDG‐labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med 2006; 47:625‐32. 28. Bhattacharya A, Kochhar R, Sharma S, et al. PET/CT with 18F‐FDG‐labeled autologous leukocytes for the diagnosis of infected fluid collections in acute pancreatitis. J Nucl Med 2014;‐55:1267–72. 29. Bhargava KK, Gupta RK, Nichols KJ, Palestro CJ. In vitro human leukocyte labelling with 64Cu: an intraindividual
comparison with [111In]oxine and [18F]FDG. Nucl Med Biol 2009; 36:545‐9.
30. Miñana E, Roldán M, Chivato T, Martínez T, Fuente T. Quantification of the chromosomal radiation damage induced by labelling of leukocytes with [18F]FDG. Nucl Med Biol 2015; 42:720‐3.
31. Nanni C, Errani C, Boriani L, et al. 68Ga‐citrate PET/CT for evaluating patients with infections of the bone:
preliminary results. J Nucl Med 2010; 51:1932‐6.
32. Vorster M, Maes A, van de Wiele C, Sathekge M. 68Ga‐citrate PET/CT in tuberculosis: a pilot study. Q J Nucl Med
Mol Imaging 2019; 63:48‐55.
33. Salomäki SP, Kemppainen J, Hohenthal U, et al. Head‐to‐head comparison of 68Ga‐citrate and 18F‐FDG PET/CT for
detection of infectious foci in patients with Staphylococcus aureus bacteraemia. Contrast Media Mol Imaging 2017; 2017:3179607.
34. Vorster M, Maes A, Jacobs A, et al. Evaluating the possible role of 68Ga‐citrate PET/CT in the characterization of
indeterminate lung lesions. Ann Nucl Med 2014; 28:523‐30.
35. Ebenhan T, Zeevaart JR, Venter JD, et al. Preclinical evaluation of 68Ga‐labeled 1,4,7‐triazacyclononane‐1,4,7‐
triacetic acid‐ubiquicidin as a radioligand for PET infection imaging. J Nucl Med 2014; 55:308‐14.
36. Bhatt J, Mukherjee A, Shinto A, Karuppusamy KK, Korde A, Kumar M, et al. Gallium‐68 labeled Ubiquicidin derived octapeptide as a potential infection imaging agent. Nucl Med Biol 2018; 62‐63:47‐53.
3
37. 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; 59:334‐9. 38. Vilche M, Reyes AL, Vasilskis E, Oliver P, Balter H, Engler H. 68Ga‐NOTA‐UBI‐29‐41 as a PET tracer for detection of bacterial infection. J Nucl Med 2016; 57:622‐7. 39. Salber D, Gunawan J, Langen KJ, et al. Comparison of [99mTc]‐ and [18F]ubiquicidin autoradiography to anti‐ Staphylococcus aureus immunofluorescence in rat muscle abscesses. J Nucl Med 2008; 49:995‐9. 40. Ebenhan T, Mokaleng BB, Venter JD, Kruger HG, Zeevaart JR, Sathekge M. Preclinical assessment of a 68Ga‐DOTA functionalized depsipeptide as a radiodiagnostic infection imaging agent. Molecules 2017 ;22:E1403. 41. Mokaleng BB, Ebenhan T, Ramesh S, et al. Synthesis, 68Ga‐radiolabeling, and preliminary in vivo assessment of a depsipeptide‐derived compound as a potential PET/CT infection imaging agent. Biomed Res Int 2015; 2015:284354. 42. Nielsen KM, Kyneb MH, Alstrup AK, et al. (68) Ga‐labeled phage‐display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm‐associated infections: selection, radiolabelling and pre‐ liminary biological evaluation. Nucl Med Biol 2016; 43:593‐0605. 43. Nielsen KM, Jorgensen NP, Kyneb MH, et al. Preclinical evaluation of potential infection‐imaging probe [68Ga]Ga‐ DOTA‐K‐A9 in sterile and infectious inflammation. J Label Compd Radiopharm [Internet] 2018 [cited 2019. 02.26]. https://onlinelibrary.wiley.com/doi/full/10.1002/jlcr.3640. https://doi.org/10.1002/ jlcr.3640 44. Satpati D, Arjun C, Krishnamohan R, Samuel G, Banerjee S. 68Ga‐labeled ciprofloxacin con‐ jugates as radiotracers for targeting bacterial infection. Chem Biol Drug Des 2016; 87:680‐6. 45. 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; 32:143‐50. 46. Sellmyer MA, Lee I, Hou C, et al. Bacterial infection imaging with [18F]fluoropropyl‐trimethoprim. Proc Natl Acad Sci U S A 2017; 114:8372–7. 47. Eigner S, Beckford Vera D, Lebeda O, Eigner Henke K. 68Ga‐DOTA‐puromycin: in vivo imaging of bacterial infection. J Nucl Med 2013; S54:1218. 48. Betts HM, Milicevic Sephton S, et al. Synthesis, in vitro evaluation, and radiolabeling of fluorinated puromycin analogues: potential candidates for PET imaging of protein synthesis. J Med Chem 2016; 59:9422‐30. 49. DeMarco VP, Ordonez AA, Klunk M, et al. Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis‐infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemothe. 2015; 59:5768‐7.
50. Weinstein EA, Liu L, Ordonez AA, et al. Noninvasive determination of 2‐[18F]‐fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in mycobacterium tuberculosis‐infected mice. Antimicrob Agents Chemother 2012; 57:6284‐90. 51. Zhang Z, Ordonez AA, Smith‐Jones P, et al. The biodistribution of 5‐[18F]fluoropyrazinamide in Mycobacterium tuberculosis‐infected mice determined by positron emission tomography. PLoS One 2017; 12:e0170871. 52. Lupetti A, Welling MM, Pauwels EK, Nibbering PH. Detection of fungal infections using radiolabeled antifungal agents. Curr Drug Targets 2005; 6:945‐54. 53. Livni E, Fischman AJ, Ray S, et al. Synthesis of 18F‐labeled fluconazole and positron emission tomography studies in rabbits. Int J Rad Appl Instrum B. 1992;19:191‐9. 54. Wiehr S, Warnke P, Rolle AM, et al. New pathogen‐ specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection. Oncotarget 2016; 7:10990‐1001.
55. Pickett JE, Thompson JM, Sadowska A, et al. Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. Bone Res 2018; 6:13.
56. Santangelo PJ, Rogers KA, Zurla C, et al. Whole‐body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy‐treated macaques. Nat Methods 2015; 12:427‐32.
57. Rolle AM, Hasenberg M, Thornton CR, et al. ImmunoPET/ MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo. Proc Natl Acad Sci U S A 2016; 113:E1026‐33.
58. Petrik M, Franssen GM, Haas H, et al. Preclinical evaluation of two 68Ga‐siderophores as potential
radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging 2012; 39:1175‐83.
59. Petrik M, Haas H, Laverman P, et al. 68Ga‐triacetylfusarinine C and 68Ga‐ferrioxamine E for Aspergillus infection
imaging: uptake specificity in various microorganisms. Mol Imaging Biol 2014; 16:102‐8. 60. Takemiya K, Ning X, Seo W, et al. Novel PET and near infrared imaging probes for the specific detection of bacterial infections associated with cardiac devices. JACC Cardiovasc Imaging 2018; 12:875‐86 61. Ning X, Seo W, Lee S, et al. PET imaging of bacterial infections with fluorine‐18 labeled maltohexaose. Angew Chem Int Ed Engl 2014; 53:14096‐101. 62. Ning X, Lee S, Wang Z, et al. Maltodextrin‐based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat Mater 2011;10:602‐7. 63. Gowrishankar G, Namavari M, Jouannot EB, et al. Investigation of 6‐[18F]‐fluoromaltose as a novel PET tracer for imaging bacterial infection. PLoS One 2014; 9:e107951.
64. Li J, Zheng H, Fodah R, Warawa JM, Ng CK. Validation of 2‐18F‐fluorodeoxysorbitol as a potential radiopharmaceutical for imaging bacterial infection in the lung. J Nucl Med 2018; 59:134‐9.
65. Ordonez AA, Weinstein EA, Bambarger LE, et al. A systematic approach for developing bacteria‐specific imaging tracers. J Nucl Med 2017; 58:144‐50.
66. Yao S, Xing H, Zhu W, et al. Infection imaging with 18F‐FDS and first‐in‐human evaluation. Nucl Med Biol 2016;
43:206‐14.
67. 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.
68. Mills B, Awais RO, Luckett J, et al. [18F]FDG‐6‐P as a novel in vivo tool for imaging staphylococcal infections. EJNMMI Res 2015; 5:13.
69. Martìnez ME, Kiyono Y, Noriki S, et al. New radiosynthesis of 2‐deoxy‐2‐[18F]fluoroacetamido‐D‐glucopyranose and its evaluation as a bacterial infections imaging agent. Nucl Med Biol 2011; 38:807‐17.
70. Peña‐Zalbidea S, Huang AY, Kavunja HW, et al. Chemoenzymatic radiosynthesis of 2‐deoxy‐2‐[18F]fluoro‐d‐ trehalose ([18F]‐2‐FDTre): a PET radioprobe for in vivo tracing of trehalose metabolism. Carbohydr Res 2019; 472:16‐22. 71. Rajamani S, Kuszpit K, Scarff JM, Lundh L, Khan M, Brown J, et al. Bioengineering of bacterial pathogens for noninvasive imaging and in vivo evaluation of therapeutics. Sci Rep 2018; 8:12618. 72. Diaz LA, Foss CA, Thornton K, et al. Imaging of muscculoskeletal bacterial infections by [124I]FIAU‐PET/CT. PLoS One 2007; 2:e1007. 73. Zhang XM, Zhang HH, McLeroth P, et al. [124I]FIAU: human dosimetry and infection imaging in patients with suspected prosthetic joint infection. Nucl Med Biol 2016; 43:273‐9.
74. Mutch CA, Ordonez AA, Qui H, et al. [11C] Para‐aminobenzoic acid: a positron emission tomography tracer targeting bacteria‐specific metabolism. ACS Infect Dis 2018; 4:1067‐72.
75. Zhang Z, Ordonez AA, Wang H, et al. Positron emission tomography imaging with 2‐[18F]F‐p‐aminobenzoic acid detects Staphylococcus aureus infections and monitors drug response. ACS Infect Dis 2018; 4:1635‐44.
3
76. 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. 77. Panizzi P, Nahrendorf M, Figueiredo JL, et al. In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen‐specific prothrombin activation. Nat Med 2012; 17:1142‐6. 78. Kumar V, Boddeti DK, Evans SG, Roesch F, Howman‐Giles R. Potential use of 68Ga‐apo‐transferrin as a PET imaging agent for detecting Staphylococcus aureus infection. Nucl Med Biol 2011; 38:393‐8. 79. Jang SJ, Lee YJ, Lim S, et al. Imaging of a localized bacterial infection with endogenous thymidine kinase using radioisotope‐labeled nucleosides. Int J Med Microbiol 2012; 302:101‐7. 80. Tan Y, Liang J, Liu D, et al. 18F‐FLT PET/CT imaging in a Wister rabbit inflammation model. Exp Ther Med 2014; 8:69‐ 72.
81. Wiehr S, Rolle AM, Warnke P, Kohlhofer U, Quintanilla‐Martinez L, Reischl G, et al. The positron emission tomography tracer 3′‐deoxy‐3′‐[18F]Fluorothymidine ([18F]FLT) is not suitable to detect tissue proliferation induced by systemic yersinia enterocolitica infection in mice. PLoS One 2016; 11:e0164163. 48
