¹⁸F-FDG PET/CT for Detection of Metastatic Infection in Gram-Positive Bacteremia

Study Design and Patients

From November 2005 to January 2008, patients were prospectively recruited from the Radboud University Nijmegen Medical Centre, a 950-bed university hospital. All nonneutropenic (neutrophil count ≥ 0.5 × 10⁹) adult patients (age, ≥18 y) were eligible when at least 1 of the following known risk factors for the presence of complicating infectious foci was present: community acquisition, signs of infection more than 48 h before initiation of appropriate treatment, fever more than 72 h after initiation of appropriate treatment, and positive blood cultures more than 48 h after initiation of appropriate treatment (3,5,12). Patients primarily admitted to the intensive care unit were included only when transferred to regular patient wards within 14 d after the first positive blood culture. Exclusion criteria were polymicrobial infection and pregnancy. The records of all patients with positive blood cultures growing S. aureus, Streptococcus species (excluding S. pneumoniae), or Enterococcus species were reviewed for eligibility as soon as blood culture results were available. The protocol was approved by the institutional review board. Written informed consent was obtained from all patients. The study has been registered in the ISRCTN database (no. 76425553).

A historical control group was defined using the electronic database of the Department of Microbiology, in which all culture results of clinical specimens are available. A pool of 456 patients diagnosed with gram-positive bacteremia between January 2000 and December 2004 in whom ¹⁸F-FDG PET/CT was not performed was identified. Patients having at least 1 of the known risk factors for developing complicating infectious foci were eligible for inclusion in the control group. For every prospectively included patient, 2 control patients were matched for the type of microorganism, site of acquisition of the infection, and the presence or absence of additional risk factors (treatment delay, persistent fever, or both). Because blood cultures had not been obtained in a standardized way in the retrospective cohort, the presence of persistently positive blood cultures more than 48 h after the initiation of treatment was not included as a risk factor in the matching strategy.

Clinical Features

The portal of entry was defined as a localized site of infection preceding bacteremia. A central venous catheter was considered a portal of entry if there was evidence of inflammation at the insertion site or if culture of the catheter tip grew the same microorganism as the blood culture in the absence of evidence for another source of infection. Respiratory or urinary tract infections were diagnosed as portals of entry only when specific symptoms and signs were present in addition to positive culture results. Phlebitis due to peripheral intravascular catheters and cellulitis, categorized as skin infections, were considered portals of entry.

Bacteremia was considered to be nosocomial if only blood cultures taken after more than 48 h of hospitalization were positive and clinical signs of the infection were absent at the time of admission. All other infections were considered community-acquired. Both infectious foci without anatomic relation to the portal of entry and direct extension of the infection beyond the primary focus of infection were defined as complicating infectious foci. Endocarditis was defined according to the Duke criteria (7).

Metastatic infectious foci not diagnosed during the first period of infection, or a second period of bacteremia with the same microorganism—either occurring within 3 mo of the first positive blood culture—was defined as relapse of infection. Patients were considered cured if no symptoms or signs of infection were present at 3 mo after the discontinuation of antibiotic treatment. Infection was considered contributory to death using the criteria described elsewhere (12,13). The outcome was assessed in a masked fashion, independent of the predicting variables and imaging results.

Diagnostic Work-up

¹⁸F-FDG PET/CT was performed as soon as possible after inclusion. The maximum time between the first positive blood culture and ¹⁸F-FDG PET/CT was 2 wk. Because antibiotic treatment can be stopped after 2 wk in uncomplicated bacteremia, the decision to prolong treatment because of infectious complications should be made within those 14 d.

An integrated PET/CT scanner (Biograph; Siemens) was used for data acquisition. Before ¹⁸F-FDG injection, patients fasted, and glucose or insulin-containing intravenous infusions were discontinued for at least 6 h. In all diabetic patients at the time of ¹⁸F-FDG injection, glucose was below 12.0 mmol/L. One hour after intravenous injection of 200–220 MBq of ¹⁸F-FDG (Covidien), a low-dose CT scan, without contrast enhancement, of the area between the proximal femora and base of the skull was acquired for anatomic correlation and attenuation correction of the PET data. Subsequently, emission images of the same area were acquired. ¹⁸F-FDG PET/CT images were evaluated by physicians without knowledge of prior clinical evaluation and imaging results. When ¹⁸F-FDG uptake was abnormal, conventional radiologic, microbiologic, or pathologic studies were performed when possible, to confirm the diagnosis. All confirmed infectious foci were reported to the attending physician.

Except for ¹⁸F-FDG PET/CT and the diagnostic procedures needed for confirmation of abnormal ¹⁸F-FDG PET/CT results, standard diagnostic and therapeutic procedures were followed. Conventional radiologic techniques before ¹⁸F-FDG PET/CT were performed only at the discretion of the attending physician. Transthoracic echocardiography, followed by transesophageal echocardiography, was to be performed in all patients. In the study group, additional blood cultures were taken at 24, 48, and 72 h after the first positive blood culture and 48 h thereafter when subsequent blood cultures were positive. C-reactive protein and leukocyte counts were ordered twice weekly. ¹⁸F-FDG PET/CT results were considered abnormal if focal accumulation of ¹⁸F-FDG was detected. Results were considered to be true-positive when abnormal ¹⁸F-FDG uptake pointed to the organ or tissue in which infection was eventually diagnosed. Abnormal results were categorized as false-positive when the abnormality could not be confirmed. Normal test results were true-negative when no complicating infectious foci were diagnosed within 2 wk after ¹⁸F-FDG PET/CT. Abnormal test results not related to metastatic infection that were caused by a confirmed alternative diagnosis (i.e., cancer) were also considered true-negative. Antibiotic treatment was not influenced by these foci. Normal test results were considered false-negative when a localized infectious focus was diagnosed. Because of the high physiologic ¹⁸F-FDG uptake within the brain, heart, and kidneys, ¹⁸F-FDG PET/CT was unsuitable for the detection of infectious foci and was not evaluated for metastatic foci in these organs. Within the study period (2000–2008), the diagnostic work-up or treatment of patients with gram-positive bacteremia remained unchanged in our hospital. If no complicating infectious foci were detected, the standard duration of treatment was 14 d. Treatment was prolonged to 6–12 wk in patients with complicating infectious foci, depending on the site of infection and clinical response according to clinical practice. Endocarditis was treated according to international guidelines (14).

Diagnosis and Patient Follow-up

The final diagnosis served as a standard of reference and was based on microbiologic and pathologic results. If these results were not available, the probable final diagnosis was based on conventional radiologic procedures and clinical follow-up. The final diagnosis was never based on the results of the ¹⁸F-FDG PET/CT scan alone. Patient follow-up was performed for 6 mo after the first positive blood culture. Epidemiologic data, number, type, and results of all diagnostic tests and treatment data were registered in a structured database (Access; Microsoft). Mortality data were obtained for all patients at 3 and 6 mo after diagnosis.

Outcome Parameters

The primary outcome parameter was relapse of infection. Secondary outcome measures were overall and attributable mortality after 3 and 6 mo, duration of antibiotic treatment, and number of diagnostic procedures performed to confirm ¹⁸F-FDG PET/CT results.

Statistical Analysis

The study was designed to detect a statistically significant difference of 10% between the study group and a historic control group (α, 0.05; power, 0.80; 2-group χ² test, 2-sided). This design required 115 evaluable study patients and 230 patients in the historic control group. An intention-to-treat analysis was performed. Differences between groups were tested with Fisher exact tests for categoric variables. Differences were considered to be statistically significant at a P value less than 0.05 (2-sided). Cox proportional hazard models were used to analyze the relationship between durations (survival, duration of therapy) and exploratory variables after adjustment for potential confounding variables. When no statistically significant confounding variables were detected, Kaplan–Meier curves were estimated. We used SPSS (version 16.0; SPSS, Inc.) for the analyses.