¹⁸F-FDG PET/CT Optimizes Treatment in Staphylococcus Aureus Bacteremia and Is Associated with Reduced Mortality

Study Design and Patients

This retrospective cohort study was performed at Radboud University Medical Center, Nijmegen, The Netherlands. All consecutive adult SAB cases between January 2013 and April 2016 were included. SAB was defined as 1 or more blood cultures positive for S. aureus. SAB cases were designated hospital-acquired if patients had been admitted for at least 48 h before the first positive blood culture, or as community-acquired in all other cases. Exclusion criteria were pregnancy and death within 48 h after the first positive blood culture with S. aureus. According to the Dutch law, this study was exempt from approval by an ethics committee, because of the retrospective character of this study and the anonymous processing of data. The regional institutional review board approved this retrospective study, and the requirement to obtain informed consent was waived.

Data Collection

We reviewed the medical records of all patients and collected data on patient demographic characteristics; estimated prognosis of preexisting underlying disease and comorbidity according to the Charlson comorbidity score (12); and determined onset of bacteremia, presence of intravascular catheters or foreign body material, resistance of S. aureus to methicillin, foci of infection, and clinical parameters at SAB onset, diagnostic investigations, antimicrobial therapy, and outcomes. The data were retrieved electronically from clinical charts and reports of diagnostic studies (including laboratory, microbiologic, and imaging data).

Diagnostic Workup

According to definitions established previously (3,8), cases were designated high-risk SAB if one of the following criteria for increased risk of metastatic infection was met: community acquisition of the bacteremia, signs of infection for more than 48 h before initiation of appropriate antibiotic treatment, fever more than 72 h after initiation of appropriate antibiotic treatment, positive blood cultures more than 48 h after initiation of appropriate antibiotic treatment, or already confirmed metastatic foci at the moment of presentation. For all patients with high-risk SAB, echocardiography and ¹⁸F-FDG PET/CT were recommended.

An integrated PET/CT scanner (Biograph 40 mCT; Siemens Healthcare) was used. Before ¹⁸F-FDG injection, patients fasted and any glucose- or insulin-containing infusions were discontinued for at least 6 h. In 66.7% of patients, a low-carbohydrate fat-allowed diet was followed 24 h before ¹⁸F-FDG PET/CT. Blood glucose samples were taken from all patients before ¹⁸F-FDG administration. At the time of ¹⁸F-FDG injection, glucose was below 12 mmol/L in all patients, including diabetic patients. One hour after intravenous injection of an average dosage of 3.3 MBq × body weight (kg)/min/bed position of ¹⁸F-FDG (Mallinckrodt Pharmaceuticals or IBA Molecular), a whole-body low-dose CT was acquired for anatomic correlation and attenuation correction of the PET data. Emission images of the same area were acquired. ¹⁸F-FDG PET/CT scans were considered abnormal if focal accumulation of ¹⁸F-FDG was detected. Normal test results were considered true-negative when no complicating infectious foci were diagnosed within 2 wk after ¹⁸F-FDG PET/CT was performed. Normal test results were considered false-negative when a localized infectious focus was diagnosed but not reported on ¹⁸F-FDG PET/CT. Abnormal test results not related to metastatic infection that were caused by a confirmed alternative diagnosis (i.e., cancer) were categorized as noninfectious relevant.

In all patients with SAB, the local antimicrobial stewardship program recommends bedside consultation by an ID specialist as well as echocardiography. Transthoracic echocardiography was used as a first-line screening technique, except for those patients with prosthetic valves, in whom transesophageal echocardiography was the first-line technique. Transesophageal echocardiography was recommended in all patients in whom transthoracic echocardiography was negative for endocarditis, especially when imaging was hampered by technical or anatomic problems. Endocarditis was defined according to the modified Duke criteria (13).

Patients were treated according to the national guideline for SAB, which is concordant with the Infectious Diseases Society of America guideline (14). However, for patients with risk factors for metastatic foci but without evidence of endocarditis after echocardiography and without signs of metastatic infection on ¹⁸F-FDG PET/CT, the institutional guideline recommends antimicrobial therapy for 2 wk. These patients were considered as having uncomplicated bacteremia instead of complicated bacteremia.

Diagnosis and Patient Follow-up

Patient outcome and recurrent infection were assessed by reviewing patients’ medical records. Patient follow-up after the end of antimicrobial therapy was at least 3 mo to capture SAB relapse, mortality, and cause of death. Patients were considered to be cured if no symptoms or signs of infection were present 3 mo after the discontinuation of antibiotic treatment. Relapse of SAB was defined as a second episode of SAB within 3 mo after the end of treatment.

¹⁸F-FDG PET/CT and Treatment Modifications

The impact of ¹⁸F-FDG PET/CT on treatment was determined by the investigators for all cases in a 2-step approach. First, treatment duration was determined on the basis of all clinical information available before ¹⁸F-FDG PET/CT was performed. Second, the results of the ¹⁸F-FDG PET/CT were provided, and the modifications of therapy based on these results were noted. During a weekly multidisciplinary meeting, all results of ¹⁸F-FDG PET/CT scans obtained in patients with SAB were discussed with a panel of ID specialists and nuclear medicine physicians and treatment modifications based on these results were also noted in the patient’s chart.

The impact of ¹⁸F-FDG PET/CT on treatment was classified as follows. The first was extension of antibiotic treatment including prolonged intravenous antibiotic therapy, for example, instead of oral antibiotic therapy; addition of a second antimicrobial drug, for example, rifampin, in patients with foreign body material infection; or extension of total treatment duration, for example, in the case of joint or vascular prosthesis infection. The second classification was surgical or radiologic intervention, for example, abscess drainage, removal of foreign body material. The third classification was shortening of treatment duration. If the results of the ¹⁸F-FDG PET/CT did not result in any intervention, this was also reported. To prevent interpretation bias, 2 independent physician observers reviewed hospitalization records and determined treatment modification before and after ¹⁸F-FDG PET/CT results. If there was no consensus, a third independent ID specialist with broad experience in SAB and ¹⁸F-FDG PET/CT made the final judgment. In patients with high-risk SAB, a comparison was made between patients who underwent ¹⁸F-FDG PET/CT and patients who did not.

Statistical Analysis

SPSS (version 22.0; SPSS, Inc.) was used for analyzing data. Descriptive statistics for continuous variables were represented as median ± SD. Unpaired Student t tests were used to compare continuous variables. Categoric variables were compared by use of the χ² test or Fisher exact test when the χ² test was not appropriate. Differences were considered to be statistically significant at a 2-sided P value of less than 0.05. To determine independent predictors of 3-mo mortality in the high-risk bacteremia group, we performed a multivariate analysis, including prognostic factors associated with a P value of less than 0.20 in univariate analysis. To limit the amount of variables in the model, the Charlson comorbidity score was used as a composite variable for age and comorbidity. As a composite variable for risk factors for metastatic infection, a risk score previously described by Fowler et al. (3) was used; community-acquisition, persistent fever longer than 72 h, and skin findings suggesting the presence of metastatic infection were separately scored as 1 point, and positive follow-up blood culture results were scored as 2 points.