Introduction
Staphylococcus aureus bacteremia (SAB) is one of the most common severe bacterial infections and has a 30-day overall mortality of around 20% [
1,
2]. SAB is notorious for causing metastatic infection through hematogenous spread, including endocarditis, osteomyelitis, and abscesses [
1,
3]. Risk factors for metastatic infections include community acquisition of bacteremia, a delayed start of adequate antibiotic treatment, positive blood cultures 24 h after start of adequate antibiotic treatment, and persistent fever 72 h after the initial positive blood culture [
3,
4].
Accurate and timely diagnosis of metastatic foci of infection is essential in SAB management for multiple reasons. First, current guidelines recommend treating SAB presenting with metastatic infections with a prolonged course of antibiotics, i.e. 4–6 weeks [
5]. Moreover, metastatic infections often require specific treatment, and source control of metastatic abscesses is associated with improved outcomes [
1,
5]. Early detection of metastatic infections, however, is challenging since patients often do not present with clinical signs or symptoms [
6,
7]. Finally, mortality in SAB patients has plateaued over the last decades emphasizing the need for improved diagnostic and therapeutic strategies [
1].
2-[
18F]fluoro-2-deoxy-D-glucose positron emission tomography with combined computed tomography ([18F]FDG-PET/CT) is an imaging modality with potentially broad applications in the field of infectious diseases [
8]. Globally, the use of [18F]FDG-PET/CT in the diagnostic workup of infectious diseases varies greatly because of local differences in availability of scanners, costs, and reimbursement for infectious diseases indications [
9‐
11]. For diagnosis of prosthetic valve endocarditis and cardiac implantable electronic device (CIED) infections use of [18F]FDG-PET/CT has been incorporated in international guidelines [
12]. In SAB patients, [18F]FDG-PET/CT offers potential for detection of metastatic infections, with subsequent adjustment of antibiotic therapy and source control interventions. Recently, several studies have investigated its use in patients with SAB. In the current study, we performed a systematic review to summarize the effects of [18F]FDG-PET/CT on clinical outcomes in hospitalized adult patients with SAB.
Discussion
In our systematic review we found low certainty evidence that [18F]FDG-PET/CT is associated with lower mortality and very low certainty evidence that it leads to more SAB-related diagnostic findings in patients with SAB. A limited number of studies investigated this research question and all included studies were non-randomized, which makes them inherently at risk of bias. Nevertheless, the studies fairly consistently showed that performing [18F]FDG-PET/CT is associated with a large reduction in mortality.
Since
18F-FDG PET/CT is an imaging modality without therapeutic effects, its association with improved survival in SAB must be mediated by therapeutic interventions, especially modifications in antibiotic treatment and source control interventions. Up to a third of patients with gram-positive bacteremia and metastatic infection does not have guiding signs or symptoms [
7]. Therefore, a diagnostic work-up strategy guided by clinical presentation alone is at high risk for missing relevant metastatic infections. Our review yielded only one study that reported on these treatment modifications following [18F]FDG-PET/CT as compared to patients that did not undergo [18F]FDG-PET/CT [
15]. Based on this study, there is very low certainty evidence for a longer duration of appropriate antibiotic treatment (42 vs. 19 days) and more frequent performance of interventions (22 vs. 12%) in patients undergoing [18F]FDG-PET/CT [
15]. Other studies in our review also reported a high incidence of new SAB-related diagnostic findings and subsequent treatment modifications in patients undergoing
18F-FDG PET/CT [
18,
20]. However, these latter studies did not report on these outcomes in the control group without [18F]FDG-PET/CT, precluding a comparison between groups.
An important question for clinical practice is which subgroup of patients would benefit most from performing [18F]FDG-PET/CT. SAB is a very heterogeneous disease and its clinical course can range from mild to extremely severe, which warrants patient tailored clinical management [
1]. A strategy of performing [18F]FDG-PET/CT in all patients with SAB is at risk for over-testing, unnecessary radiation burden, and expenditure of scarce recourses. In clinical practice, [18F]FDG-PET/CT is most often performed in patients with risk factors for metastatic infections, since these patients are supposed to have a higher prior probability of finding relevant findings. Most studies in our review included patients with a high frequency of these risk factors in the intervention group. Therefore we were not able to identify which subgroups of SAB patients would benefit most from [18F]FDG-PET/CT. Scarce evidence exists to support its use in patients without risk factors for metastatic infection. One study reported a stronger association between [18F]FDG-PET/CT and lower mortality in low-risk SAB than in high-risk SAB (unadjusted OR 0.27 (95% CI 0.10–0.72) versus 0.44 (95% CI 0.20–0.98)) [
15]. The group of 67 patients with low-risk SAB had a comparable frequency of SAB-related diagnostic findings (61.2%) as the 84 patients with high-risk SAB (66.7%). Further studies must investigate whether this beneficial effect of [18F]FDG-PET/CT in low-risk SAB is robust.
Besides diagnosing metastatic infections that generally warrant prolongation of antibiotic treatment, [18F]FDG-PET/CT also has the potential to justify shorter antibiotic treatment in selected patients. The Infectious Diseases Society of America (IDSA) guideline states that patients with positive follow-up blood cultures performed 48–96 h after the initial culture and persistent fever after 72 h of adequate antibiotic therapy must be classified as having complicated bacteremia and should be treated with an extended antibiotic course, i.e. 4–6 weeks [
5]. One study in our review showed that patients with risk factors for metastatic infections but normal [18F]FDG-PET/CT and echocardiography results received similar antibiotic treatment duration and had similar outcomes as patients with uncomplicated bacteremia who did not undergo [18F]FDG-PET/CT [
20]. This finding suggests that these patients could be “reclassified” as having uncomplicated bacteremia by performing
18F-FDG PET/CT and possibly be treated with a shorter course of antibiotics. However, this study was underpowered to detect a statistically significant difference between both groups. Moreover, certain risk factors yield higher risk of metastatic complications than others, making it unclear whether this strategy is equally safe in all patients in this subgroup [
3].
Strengths of our systematic review include the prospectively registered study protocol, rigorous systematic bibliographic search, and extensive assessment of bias using the ROBINS-I tool. Our study also has several important limitations. First, only a limited number of studies were identified which addressed the research question and three out of five studies were performed in The Netherlands [
17,
19,
20]. Second, performing a meaningful meta-analysis was not possible since studies were not sufficiently homogeneous. Lastly, all included studies were non-randomized and therefore prone to bias, especially confounding by indication and immortal time bias. Confounding by indication could lead to a biased effect estimate if [18F]FDG-PET/CT was less likely to be performed in patients with certain characteristics. For example, not performing [18F]FDG-PET/CT in patients with severe disease because they were too sick to undergo [18F]FDG-PET/CT would lead to a bias towards [18F]FDG-PET/CT being beneficial. Another important potential form of bias in the included studies was immortal time bias. Immortal time bias could occur by including patients that died before [18F]FDG-PET/CT could be performed. These patients would be classified in the group that did not receive [18F]FDG-PET/CT, leading to a biased effect estimate in favor of undergoing PET-CT.
The findings of our systematic review warrant further research directed at the effects of performing [18F]FDG-PET/CT in SAB. Ultimately, a randomized controlled trial (RCT) could provide higher-quality evidence. Currently, a RCT is being performed in France which randomizes adult SAB patients without infective endocarditis to [18F]FDG-PET/CT or to a control group with routine care 14 days after the SAB diagnosis [
16]. Primary outcome is presence of deep foci of infection and secondary outcomes include 3- and 6 month survival and cost-effectiveness. This study, however, does not use frequency and clinical consequences of non-infection related accidental findings on [18F]FDG-PET/CT as an outcome, which is necessary to enable an informed cost–benefit analysis. Non-infection related accidental findings could lead to unnecessary and potentially harmful diagnostic and therapeutic interventions. Other potential disadvantages of [18F]FDG-PET/CT include the harmful effects of radiation and the associated monetary costs.
In summary, our systematic review showed that based on limited evidence of very low to low certainty, [18F]FDG-PET/CT leads to lower mortality in patients with SAB and a higher frequency of SAB-related diagnostic findings. Its effect on other clinical outcomes is yet unclear. Future studies should further define subgroups of SAB patients that benefit most from [18F]FDG-PET/CT.
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