Contrast Media & Molecular Imaging
Volume 2017 (2017), Article ID 3179607, 8 pages
https://doi.org/10.1155/2017/3179607

Clinical Study

Head-to-Head Comparison of ⁶⁸Ga-Citrate and ¹⁸F-FDG PET/CT for Detection of Infectious Foci in Patients with Staphylococcus aureus Bacteraemia

Soile P. Salomäki,1,2,3 Jukka Kemppainen,2,4,5 Ulla Hohenthal,1,3 Pauliina Luoto,² Olli Eskola,² Pirjo Nuutila,2,3,6 Marko Seppänen,2,4,5 Laura Pirilä,3,7 Jarmo Oksi,1,3 and Anne Roivainen2,4

¹Department of Infectious Diseases, Division of Medicine, Turku University Hospital, Turku, Finland
²Turku PET Centre, University of Turku, Turku, Finland
³Faculty of Medicine, University of Turku, Turku, Finland
⁴Turku PET Centre, Turku University Hospital, Turku, Finland
⁵Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
⁶Department of Endocrinology, Division of Medicine, Turku University Hospital, Turku, Finland
⁷Department of Rheumatology, Division of Medicine, Turku University Hospital, Turku, Finland

Correspondence should be addressed to Anne Roivainen; anne.roivainen@utu.fi

Received 14 June 2017; Revised 13 August 2017; Accepted 29 August 2017; Published 17 October 2017

Academic Editor: Frank Rösch

Copyright © 2017 Soile P. Salomäki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Purpose. This study evaluated the potential of ⁶⁸Ga-citrate positron emission tomography/computed tomography (PET/CT) for the detection of infectious foci in patients with Staphylococcus aureus bacteraemia by comparing it with 2-[¹⁸F]fluoro-2-deoxy--glucose (¹⁸F-FDG) PET/CT. Methods. Four patients admitted to hospital due to S. aureus bacteraemia underwent both ¹⁸F-FDG and ⁶⁸Ga-citrate whole-body PET/CT scans to detect infectious foci. Results. The time from hospital admission and the initiation of antibiotic treatment to the first PET/CT was 4–10 days. The time interval between ¹⁸F-FDG and ⁶⁸Ga-citrate PET/CT was 1–4 days. Three patients had vertebral osteomyelitis (spondylodiscitis) and one had osteomyelitis in the toe; these were detected by both ¹⁸F-FDG (maximum standardised uptake value [] ) and ⁶⁸Ga-citrate (  , ). Three patients had soft tissue infectious foci, with more intense ¹⁸F-FDG uptake () than ⁶⁸Ga-citrate uptake (, ). Conclusions. Our small cohort of patients with S. aureus bacteraemia revealed that ⁶⁸Ga-citrate PET/CT is comparable to ¹⁸F-FDG PET/CT for detection of osteomyelitis, whereas ¹⁸F-FDG resulted in a higher signal for the detection of soft tissue infectious foci.

1. Introduction

Positron emission tomography (PET) with the radiolabelled glucose analogue 2-[¹⁸F]fluoro-2-deoxy--glucose (¹⁸F-FDG) is a sensitive and widely used method to detect inflammation and infection according to the high glucose uptake of activated inflammatory cells. It has an important role in the diagnosis of fever of unknown origin when conventional imaging has failed [1]. Staphylococcus aureus bacteraemia is a life-threatening condition, and detection and eradication of deep infectious foci are crucial for successful treatment [2]. In previous studies, ¹⁸F-FDG PET/CT has proven to be a sensitive method for the detection of infectious foci in patients with gram-positive bacteraemia [2, 3].

⁶⁸Ga-citrate has also been shown to be a sensitive and specific tracer for the detection of infectious lesions [4, 5], although only a few human studies using ⁶⁸Ga-citrate PET/CT exist. The biological mechanism of ⁶⁸Ga-citrate accumulation in infectious foci is not fully understood. Once injected the Ga-citrate complex is quickly dissociated into Ga³⁺ and citrate³⁻ within the blood. Then, 99% of the gallium ions are attached to transferrin [6, 7], which accumulates in inflammatory lesions. In addition, it is assumed that some ⁶⁸Ga may attach to bacterial siderophores, lactoferrin inside neutrophils, and free lactoferrin at the site of infection [8]. According to previous studies, ⁶⁸Ga-citrate PET/CT appears to be a sensitive tool for the detection of bone infections [4, 9], although until now it has not been studied in patients with S. aureus bacteraemia.

The purpose of this study was to evaluate the potential of ⁶⁸Ga-citrate PET/CT for the detection of infectious foci in patients with S. aureus bacteraemia by comparing it with ¹⁸F-FDG in a head-to-head setting.

2. Materials and Methods

2.1. Subjects

This study evaluates four consecutive patients who were admitted to hospital due to S. aureus bacteraemia. All patients underwent both ¹⁸F-FDG and ⁶⁸Ga-citrate whole-body PET/CT to detect infectious foci. The study was approved by the institutional ethical review board and all participants signed informed consent. The study was registered as a clinical trial (NCT01878721).

2.2. PET/CT

The synthesis of ⁶⁸Ga-citrate was performed with automated synthesis device (Modular Lab, Eckert & Ziegler Eurotope GmbH, Berlin, Germany). ⁶⁸Ga was obtained from a ⁶⁸Ge/⁶⁸Ga generator (IGG-100, 1850 MBq, Eckert & Ziegler Isotope Products, Valencia, CA, USA) by eluting the generator with 6 ml of 0.1 M hydrogen chloride (HCl). ⁶⁸Ga was prepurified through a cationic exchanger (Strata X-C, Phenomenex Inc., Torrance, CA) by eluting with HCl/acetone-solution (800 μl). Acetone was then evaporated by heating at 110°C for 240 s and after cooling of ⁶⁸GaCl₃, the sterile isotonic sodium citrate solution (4 ml) was added to the reaction vial followed by 240 s reaction time. The product was transferred to the end product vial through a nonpyrogenic 0.22 μm sterile filter and diluted with saline (9 mg/ml, 6 ml). The radiochemical purity of the ⁶⁸Ga-citrate was evaluated by instant thin layer chromatography-silica-gel technique using methanol/acetic acid (9 : 1) as a mobile phase. pH of the product was tested with indicator strips (pH range 2.0–9.0) and sterile filter integrity was assessed by a bubble point test.

Whole-body ¹⁸F-FDG and ⁶⁸Ga-citrate PET/CT (Discovery VCT, GE Medical Systems) were performed in all patients within 1–4 days. All patients fasted before the ¹⁸F-FDG scan. The injected radioactivity doses of ¹⁸F-FDG and ⁶⁸Ga-citrate were  MBq (range: 227–387 MBq) and  MBq (range: 158–245 MBq), respectively. PET scanning started at  min (range: 52–67 min) after ¹⁸F-FDG injection and  min (range: 48–100 min) after ⁶⁸Ga-citrate injection. The whole-body PET acquisition (3 min/bed position) was performed following a low dose CT for anatomical reference and attenuation correction. PET images were reconstructed using a 3D maximum-likelihood reconstruction with an ordered-subsets expectation maximization algorithm (VUE Point, GE Healthcare). Visual analysis of the images was performed by an experienced nuclear medicine specialist (J. K.), with the results being reevaluated by the research team for consensus. A positive finding was defined as an abnormal accumulation of ¹⁸F-FDG or ⁶⁸Ga-citrate indicating infectious foci. ¹⁸F-FDG and ⁶⁸Ga-citrate uptake in the volumes of interest were quantified and expressed as maximum standardised uptake values () by normalising the tissue radioactivity concentration for the injected radioactivity dose and the patient’s weight. The blood background radioactivity concentration was determined from the left ventricle cavity as , and the target-to-background ratio (TBR) was calculated as .

2.3. Statistical Analysis

Results are expressed as mean ± SD and range. A paired -test was used to compare ¹⁸F-FDG and ⁶⁸Ga-citrate uptake. A value of <0.05 was considered statistically significant.

3. Results

⁶⁸Ga-citrate was prepared with high radiochemical purity (≥95%) with pH of 3.0−7.0.

Patient characteristics are presented in Table 1. All patients had a condition predisposing them to infection. In addition, Patient #3 had a cardiac pacemaker. The time interval from hospital admission and initiation of antibiotic treatment to the first PET/CT was 4–10 days, with the second PET/CT scan performed within another 1–4 days. The order of the ¹⁸F-FDG and ⁶⁸Ga-citrate scans depended on the availability of tracers, with both being performed first in two cases. The mean C-reactive protein (CRP) levels were  mg/l on the day of ¹⁸F-FDG PET/CT and  mg/l on the day of ⁶⁸Ga-citrate PET/CT (). The blood background () was for ¹⁸F-FDG and for ⁶⁸Ga-citrate ().

Table 1: Characteristics of the study patients.

Patient number
Age
(years)
Gender
Comorbidities
Time from starting antibiotics to ¹⁸F-FDG PET/CT (days)
Time from starting antibiotics to ⁶⁸Ga-citrate PET/CT (days)
CRP on ¹⁸F-FDG PET/CT
(mg/l)
CRP on ⁶⁸Ga-citrate PET/CT
(mg/l)
Complications from S. aureus bacteraemia based on routine exams, PET/CTs, and follow-up

()
66
F
Atopic eczema
10
11
92
109
Meningitis, vertebral osteomyelitis, paravertebral abscesses, multiple infectious foci in soft tissues

()
70
F
Liver cirrhosis, type 2 diabetes, generalised atherosclerosis, HTN
6
5
14
14
Vertebral osteomyelitis, pneumonia

()
66
M
Cardiomyopathy, HTN, asthma, cardiac pacemaker
5
4
105
291
Osteomyelitis in toe and feet

()
86
M
COPD, immunosuppressive medication due to chronic dermatology disease
8
12
146
83
Vertebral osteomyelitis, septic arthritis, multiple infectious foci in soft tissues

F, female; M, male; HTN, hypertension; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein.

Three patients had vertebral osteomyelitis (spondylodiscitis) and one patient had osteomyelitis of the toe. The osteomyelitic foci were detected by both PET/CT methods (Table 2, Figures 1 and 2) and magnetic resonance imaging (MRI) in the cases of vertebral osteomyelitis and X-ray in the case of osteomyelitis of the toe. In the areas of osteomyelitis (), the of ¹⁸F-FDG was (range: 5.3–7.4) and the of ⁶⁸Ga-citrate was (range: 2.7–11.1, ). The corresponding TBRs of ¹⁸F-FDG and ⁶⁸Ga-citrate were and , respectively (). Three patients had multiple infectious lesions and abscesses in soft tissue (Patients #1, #3, and #4). In these soft tissue infectious foci and abscesses (), the of ¹⁸F-FDG (, range: 3.7–10.6) was significantly higher than that of ⁶⁸Ga-citrate (, range: 2.1–6.1, ; Figure 1). The corresponding TBRs of ¹⁸F-FDG and ⁶⁸Ga-citrate were and , respectively ().

Table 2: Quantitative ¹⁸F-FDG and ⁶⁸Ga-citrate PET/CT findings.

Patient number
Visually active findings
¹⁸F-FDG
⁶⁸Ga-citrate

TBR

TBR

Infectious foci

()
Blood background
1.4
—
2.1
—

Vertebral osteomyelitis
6.1
4.4
7.3
3.5

Psoas/paravertebral abscess
10.6
7.6
6.1
2.9

Left elbow abscess
9.4
6.7
4.0
1.9

Three soft tissue infectious foci in left arm
7.3; 6.3; 5.4
5.2; 4.5; 3.9
5.0; 3.6; 3.5
2.4; 1.7; 1.7

Soft tissue infectious focus in left gluteus
3.7
2.6
2.1
0.8

()
Blood background
1.3
—
2.9
—

Vertebral osteomyelitis
7.4
5.7
11.1
3.8

Pneumonia, right lung
2.7
2.1
3.7
1.3

Pneumonia, left lung
3.9
3.0
3.1
1.1

()
Blood background
1.4
—
2.4
—

Septic arthritis and osteomyelitis, I toe
5.3
3.8
2.7
1.1

Soft tissue infectious focus, I toe
4.6
3.3
2.9
1.2

()
Blood background
1.4
—
4.1
—

Vertebral osteomyelitis
5.3
3.8
5.9
1.4

Shoulder abscess
4.5
3.2
4.2
1.0

Septic arthritis, glenohumeral joint
5.0
3.6
2.5
0.6

Septic arthritis, sternoclavicular joint
7.7
5.5
6.2
1.5

Other metabolic findings

()
Active spleen
2.9
2.1
2.7
1.3

Ascending aorta
1.6
1.1
2.0
1.0

()
Parotid, unexplained
1.8
1.4
9.4
3.2

Reactive lymph nodes, neck right side
2.5
1.9
5.6
1.9

Inferior vena cava, thrombosis
2.5
1.9
8.6
3.0

Ascending aorta
1.6
1.2
6.6
2.3

()
Caecum, unspecific uptake
12.6
9.0
1.7
0.7

Descending colon, tubular adenoma
9.7
6.9
7.8
3.3

Ascending aorta
2.1
1.5
5.4
2.3

()
Reactive lymph nodes, neck right side
6.8
4.9
4.6
1.1

Reactive lymph nodes, neck left side
6.6
4.7
3.7
0.9

Ascending aorta
1.2
0.9
4.6
1.1

Determined from heart left ventricle cavity, ; TBR, target-to-background ratio ().

Figure 1: Patient #1 was a 66-year-old woman (weight: 65 kg) who presented at the hospital because of back pain and general symptoms. Both ⁶⁸Ga-citrate (a) and ¹⁸F-FDG PET/CT (b) showed vertebral osteomyelitis (spondylodiscitis; red arrowheads) and abscesses in the iliopsoas and paravertebral area (red arrows). These were confirmed by MRI (c). ¹⁸F-FDG PET/CT also showed other multiple soft tissue infectious foci ((b), blue arrows), some of which were not detectable on ⁶⁸Ga-citrate PET/CT ((a), blue arrow). The injected radioactivity dose of ¹⁸F-FDG was 227 MBq and the PET acquisition started 54 min after injection. The injected radioactivity dose of ⁶⁸Ga-citrate was 245 MBq and the PET acquisition started 88 min after injection. MRI sequences were as follows: T2-weighted short inversion time inversion recovery (STIR) on the coronal view image (left) and T2-weighted on the sagittal view image (right).

Figure 2: Patient #2 was a 70-year-old woman (weight: 69 kg), with multiple background diseases, who was admitted to hospital because of back pain and high fever. Both ⁶⁸Ga-citrate (a, c, e) and ¹⁸F-FDG PET/CT (b, d, f) showed vertebral osteomyelitis (spondylodiscitis) in Th12 (red arrows) and pneumonia in both lungs. MRI showed oedema in Th12 (g, h). ⁶⁸Ga-citrate PET/CT also revealed uptake in the left parotid gland (unspecific; (a), blue arrow), neck lymph nodes (reactive), and inferior vena cava (thrombosis; (e), blue arrow). There was no ¹⁸F-FDG uptake in these areas. The injected radioactivity dose of ¹⁸F-FDG was 279 MBq and the PET acquisition started 50 min after injection. The injected radioactivity dose of ⁶⁸Ga-citrate was 199 MBq and the PET acquisition started 100 min after injection. MRI sequences were as follows: T2-weighted short inversion time inversion recovery (STIR) on the coronal view image (left) and T2-weighted on the sagittal view image (right).

In addition to infectious foci, all of the patients also had other metabolic findings. Three patients (Patients #2, #3, and #4) demonstrated strong uptake of ⁶⁸Ga-citrate in the larger arteries, coincidental to visible atherosclerosis on CT. In the ascending aorta (), the of ⁶⁸Ga-citrate was (range: 2.0–6.6), whereas the of ¹⁸F-FDG was (range: 1.2–2.1, ). The corresponding TBRs were for ⁶⁸Ga-citrate and for ¹⁸F-FDG (). Patient #1 showed increased splenic uptake of both tracers, which was interpreted as a normal reaction in a septic condition. Patient #2 demonstrated high uptake of ⁶⁸Ga-citrate in an enlarged parotid gland and lymph nodes in the neck (Figure 2(a)), which were not detected on ¹⁸F-FDG PET/CT. In the absence of clinical symptoms, the enlarged parotid gland was not further studied by MRI or ultrasound, so the observed ⁶⁸Ga-citrate uptake remained unexplained. Patient #2 also demonstrated ⁶⁸Ga-citrate uptake in the inferior vena cava, but not ¹⁸F-FDG uptake, with thrombosis being confirmed by ultrasonography. Patient #3 had a clear focal accumulation of both ⁶⁸Ga-citrate and ¹⁸F-FDG in the descending colon, which was subsequently confirmed as a tubular adenoma in a colonoscopy with biopsies. The same patient also demonstrated ¹⁸F-FDG but not ⁶⁸Ga-citrate accumulation in the caecum without specific findings on colonoscopy or biopsy. Patient #4 had reactive lymph nodes in the neck, which were indicated as being metabolically active by both imaging methods.

4. Discussion

We believe that this is the first study to compare ⁶⁸Ga-citrate and ¹⁸F-FDG PET/CT imaging of infectious foci in patients with S. aureus bacteraemia. Our results revealed that ⁶⁸Ga-citrate and ¹⁸F-FDG are comparable PET tracers for the detection of osteomyelitis. However, the soft tissue infectious foci were clearly better visualized with ¹⁸F-FDG than ⁶⁸Ga-citrate.

In general, two different tracers must be compared with caution and taking into account their potentially different properties, such as uptake mechanisms and flow/diffusion dependency. In animal models, both ¹⁸F-FDG and ⁶⁸Ga-chloride have shown increased accumulation in S. aureus osteomyelitis, whereas, in healing bones without infection, only ¹⁸F-FDG accumulation was observed [9]. Our results are in line with the animal studies, in that accumulation of these tracers in patients with osteomyelitis does not differ in the acute phase of S. aureus infection. Further studies are warranted to clarify whether ⁶⁸Ga-citrate PET/CT can confirm the healing of osteomyelitis and whether it is superior to ¹⁸F-FDG for the differentiation of infection from sterile bone inflammation.

We found a difference between ¹⁸F-FDG and ⁶⁸Ga-citrate PET/CT in the detection of soft tissue infection. Contrary to the clear findings of multiple small infectious foci without abscess formation in ¹⁸F-FDG PET/CT, such lesions were only slightly visible or not visible at all on ⁶⁸Ga-citrate PET/CT (Patient #1). The difference in between ¹⁸F-FDG and ⁶⁸Ga-citrate was also statistically significant. These findings were not controlled by other imaging modalities, but some were also detectable in clinical status (e.g., multiple infectious foci in Patient #1’s arm). In this study we used  MBq for ⁶⁸Ga-citrate PET and started imaging after minutes. The observed blood background 2.9 + 0.88 may be a strong contributing factor for not visualizing soft tissue infections with ⁶⁸Ga-citrate. It can be hypothesized that lowering of injected radioactivity dose to 100 MBq would reduce blood pool radioactivity and cause less background noise. In order to confirm the effect of a lower ⁶⁸Ga-citrate dose, further studies are warranted. A recent study comparing ¹⁸F-FDG, ⁶⁸Ga-citrate, and other tracers in a pig-model of hematogenously disseminated S. aureus infection reported slightly different results [10]. These findings may be due to the higher blood background radioactivity of ⁶⁸Ga-citrate (Table 2). The slight differences in the production of ⁶⁸Ga-citrate might reflect different results, too.

Owing to its high sensitivity, specificity, and accuracy in the detection of osteomyelitis, MRI is the recommended imaging modality when spondylodiscitis is suspected [11]. MRI provides higher spatial resolution of the spinal cord than PET/CT, which is important if an operation is considered. However, sometimes MRI cannot be obtained because of patient-related reasons (e.g., implanted cardiac devices, claustrophobia). In such cases, ¹⁸F-FDG PET/CT is the recommended imaging modality [11]. Traditionally, MRI is targeted to the part of the body where the patient has signs or symptoms; however, a previous study [12] showed that around one-third of infectious foci in S. aureus bacteraemia are asymptomatic. Thus, these silent infectious foci may pass unnoticed with traditional imaging, while PET/CT scanning provides information on the whole body, and as demonstrated in our cases, multiple infectious foci can be detected simultaneously.

In addition to infectious foci, both ¹⁸F-FDG and ⁶⁸Ga-citrate PET/CT also revealed other clinically significant findings. In Patient #3, PET/CT findings in the colon led to colonoscopy and the finding of a tubular adenoma. Patient #2 demonstrated an uptake of ⁶⁸Ga-citrate (but not ¹⁸F-FDG) in the inferior vena cava where thrombosis was later confirmed by ultrasound. This can be related to pooling tracer just proximal to the narrowing caused by the thrombus. More comprehensive studies are needed to explain the differences in the findings of ⁶⁸Ga-citrate and ¹⁸F-FDG, for example, whether they are ascribed due to infection versus sterile inflammation.

The accumulation of ⁶⁸Ga-citrate in atherosclerotic arteries warrants further studies to determine its importance. Previously, ⁶⁸Ga-chloride uptake has been demonstrated in atherosclerotic lesions in mice [13]. Instead, in the papers presented by Nanni and coworkers [4] as well as Vorster and coworkers [14], the relatively high vascular radioactivity was regarded as a normal biodistribution of ⁶⁸Ga-citrate. The identification of atherosclerosis in 3 patients by ⁶⁸Ga-citrate may be coincidental. One advantage of ⁶⁸Ga-citrate over ¹⁸F-FDG is that patients are not required to fast before the scan. However, for detection of metastatic endovascular infection the accumulation of ⁶⁸Ga-citrate in atherosclerotic arteries can be regarded as a limitation of ⁶⁸Ga-citrate PET/CT in patients with S. aureus bacteraemia.

In the current study, the time intervals between ¹⁸F-FDG and ⁶⁸Ga-citrate scans were short (1–4 days), and CRP remained at the same levels over these intervals. Neither surgical procedures nor changes to the antimicrobial treatment were made between the two scans. We thus consider that the infectious status of the patients did not differ markedly between ¹⁸F-FDG and ⁶⁸Ga-citrate studies. However, time interval from commencement of antibiotic treatment to the first PET/CT was 4–10 days and we are not able to exclude the possibility that due to this delay some of the infectious lesions were not detected. We also determined the TBRs, which revealed that the blood radioactivity concentration of ⁶⁸Ga-citrate was higher than that of ¹⁸F-FDG. Thus, in many foci, the TBRs of ⁶⁸Ga-citrate PET/CT were lower than in ¹⁸F-FDG PET/CT. In general, the number of patients is small, which can be regarded as a limitation of this study.

5. Conclusion

⁶⁸Ga-citrate and ¹⁸F-FDG are comparable PET tracers for the imaging of osteomyelitis in patients with S. aureus bacteraemia. Further studies are warranted to clarify whether ⁶⁸Ga-citrate PET/CT can detect osteomyelitis caused by other pathogens and whether it can assess the healing of infectious osteomyelitis. For the detection of soft tissue infectious foci, ¹⁸F-FDG PET/CT shows higher intensity than ⁶⁸Ga-citrate PET/CT but the effect of lower ⁶⁸Ga-citrate dose should be verified by further studies.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank Mia Koutu and Laura Kontto for helping with PET/CT imaging and Timo Kattelus for helping with the images. This study was conducted in the Finnish Centre of Excellence in Cardiovascular and Metabolic Diseases supported by the Academy of Finland, University of Turku, Turku University Hospital, and Åbo Akademi University. This study was also funded by Turku University Foundation and the Foundation of Rauno and Anne Puolimatka.

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