Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease.

BACKGROUND: The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment. METHODS: In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease--either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi--to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed. RESULTS: Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin-hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, -2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, -1.6 to 3.3] in the clarithromycin-hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P<0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event occurred during the 12-week randomized phase. CONCLUSIONS: In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment. (Funded by the Netherlands Organization for Health Research and Development ZonMw; PLEASE ClinicalTrials.gov number, NCT01207739.).

Cognitive impairments in patients with persistent symptoms attributed to Lyme disease.

BACKGROUND: Persistent symptoms attributed to Lyme borreliosis often include self-reported cognitive impairment. However, it remains unclear whether these symptoms can be substantiated by objective cognitive testing. METHODS: For this observational study, cognitive performance was assessed in 280 adults with persistent symptoms attributed to Lyme borreliosis (as part of baseline data collected for the Dutch PLEASE study). Cognitive testing covered the five major domains: episodic memory, working memory / attention, verbal fluency, information-processing speed and executive function. Patients' profiles of test scores were compared to a large age-, education- and sex-adjusted normative sample using multivariate normative comparison. Performance validity was assessed to detect suboptimal effort, and questionnaires were administered to measure self-reported cognitive complaints, fatigue, anxiety, depressive symptoms and several other psychological factors. RESULTS: Of 280 patients, one was excluded as the test battery could not be completed. Of the remaining 279 patients, 239 (85.4%) displayed sufficient performance validity. Patients with insufficient performance validity felt significantly more helpless and physically fatigued, and less orientated. Furthermore, they had a lower education level and less often paid work. Of the total study cohort 5.7% (n = 16) performed in the impaired range. Among the 239 patients who displayed sufficient performance validity, 2.9% (n = 7) were classified as cognitively impaired. No association between subjective cognitive symptoms and objective impairment was found. CONCLUSIONS: Only a small percentage of patients with borreliosis-attributed persistent symptoms have objective cognitive impairment. Performance validity should be taken into account in neuropsychological examinations of these patients. Self-report questionnaires are insufficiently valid to diagnose cognitive impairment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207739 . Registered 23 September 2010.

Clinical application of FDG-PET/CT in metastatic infections.

FDG-PET/CT has proven its clinical value and cost-effectiveness in diagnosing metastatic infections in patients with Gram-positive bacteremia. In identification of metastatic foci, FDG-PET/CT is useful as a screening method when localizing symptoms are absent because it provides whole-body coverage. FDG-PET/CT detects early metabolic activity rather than the late anatomical changes as visualized by computed tomography and magnetic resonance imaging. FDG-PET/CT allows more precise localization of infection within a shorter time span between injection and diagnosis as compared to conventional nuclear imaging. This review focuses on the clinical application of imaging of metastatic infectious diseases, with an emphasis on FDG-PET/CT putting it in perspective with other imaging modalities.

A comparison of the diagnostic value of MRI and 18F-FDG-PET/CT in suspected spondylodiscitis.

PURPOSE: The purpose of this study was to evaluate the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT scan) and magnetic resonance imaging (MRI) in diagnosing spondylodiscitis and its complications, such as epidural and paraspinal abscesses. METHODS: From January 2006 to August 2013 patients with a clinical suspicion of spondylodiscitis, with an infection, or with fever of unknown origin were retrospectively included if 18F-FDG-PET/CT and MRI of the spine were performed within a 2-week time span. Imaging results were compared to the final clinical diagnosis and follow-up data were collected. RESULTS: Sixty-eight patients were included of whom 49 patients were diagnosed with spondylodiscitis. MRI showed an overall sensitivity of 67 % and specificity of 84 %. Diagnostic accuracy was 58 %, when MRI was performed within 2 weeks after the start of symptoms and improved to 82 %, when performed more than 2 weeks after onset of symptoms. 18F-FDG-PET/CT showed a sensitivity of 96 % and a specificity of 95 %, with no relation to the interval between the scan and the start of symptoms. CONCLUSIONS: As compared to MRI, 18F-FDG-PET/CT has superior diagnostic value for detecting early spondylodiscitis. After 2 weeks both techniques perform similarly.

Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)--design of a randomized controlled trial of prolonged antibiotic treatment in patients with persistent symptoms attributed to Lyme borreliosis.

BACKGROUND: Lyme borreliosis, a potentially severe tick-borne infection caused by Borrelia burgdorferi, can cause multi-system inflammatory disease. The incidence has been increasing, as has the number of patients with persistent symptoms attributed to Borrelia. These symptoms, also referred to as post-Lyme disease syndrome, may follow an erythema migrans or other Lyme manifestations, and include pain, fatigue, and cognitive disturbances. The optimal duration of treatment for these symptoms is a subject of controversy. The PLEASE study is designed to determine whether prolonged antibiotic treatment leads to better patient outcome than standard treatment. METHODS/DESIGN: The PLEASE study is a double-blind, randomized, placebo-controlled trial. Based on power analysis and compensating for possible loss to follow-up, a minimum of 255 patients with borreliosis-attributed persistent symptoms are included. These symptoms are either (a) temporally related to an erythema migrans or otherwise proven symptomatic borreliosis, or (b) accompanied by a positive B. burgdorferi IgG or IgM immunoblot. All patients receive open-label ceftriaxone for two weeks. Patients are then randomized (ratio 1:1:1) to blinded oral follow-up treatment for 12 weeks with (I) doxycycline, (II) clarithromycin combined with hydroxychloroquine, or (III) placebo. The primary outcome is the physical component summary score (PCS) of the RAND-36 Health Status Inventory (RAND SF-36) at week 14. Secondary outcomes include physical and mental aspects of health-related quality of life (assessed by the subscales of the RAND SF-36), fatigue, neuropsychological evaluation, physical activity, and cost-effectiveness. DISCUSSION: This article describes the background and design issues of the PLEASE study protocol. The results of this study may provide evidence for prescribing or withholding prolonged antibiotic treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01207739 , Netherlands Trial Register: NTR2469.

The value of 18F-FDG PET/CT in diagnosing infectious endocarditis.

PURPOSE: Early detection of infectious endocarditis is challenging. For diagnosing infectious endocarditis, the revised Duke criteria are the gold standard. Evidence of endocardial involvement on echocardiography is a major criterion, but sensitivity and specificity of echocardiography are not optimal. Here we investigated the utility of (18)F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) to diagnose infectious endocarditis in patients with gram-positive bacteraemia. METHODS: Seventy-two patients with gram-positive bacteraemia were prospectively included. Patients with a positive blood culture growing Staphylococcus aureus, Streptococcus species or Enterococcus species were eligible when a risk factor for developing metastatic infectious foci was present. Infectious endocarditis was defined according to the revised Duke criteria. All patients underwent (18)F-FDG PET/CT and echocardiography. (18)F-FDG uptake in or around the heart valves was evaluated independently by two nuclear medicine physicians. RESULTS: Sensitivity for diagnosing infectious endocarditis with (18)F-FDG PET/CT was 39% and specificity was 93%. The positive predictive value was 64% and negative predictive value was 82%. The mortality rate in patients without infectious endocarditis and without increased (18)F-FDG uptake in or around the heart valves was 18%, and in patients without infectious endocarditis but with high (18)F-FDG uptake in or around the heart valves the mortality rate was 50% (p = 0.181). CONCLUSION: (18)F-FDG PET/CT is currently not sufficiently adequate for the diagnosis of infectious endocarditis because of its low sensitivity. Improvements such as patient preparation with low carbohydrate-fat allowed diet and technical advances in the newest PET/CT scanners may increase sensitivity in future studies.

18F-FDG PET/CT for diagnosing infectious complications in patients with severe neutropenia after intensive chemotherapy for haematological malignancy or stem cell transplantation.

PURPOSE: Between 30 and 50% of febrile neutropenic episodes are accounted for by infection. C-reactive protein (CRP) is a nonspecific parameter for infection and inflammation but might be employed as a trigger for diagnosis. The aim of the study was to evaluate whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT can be used to detect inflammatory foci in neutropenic patients with elevated CRP and whether it helps to direct treatment. METHODS: Twenty-eight consecutive patients with neutropenia as a result of intensive chemotherapy for haematological malignancies or myeloablative therapy for haematopoietic stem cell transplantation were prospectively included. (18)F-FDG PET/CT was added to the regular diagnostic workup once the CRP level rose above 50 mg/l. RESULTS: Pathological FDG uptake was found in 26 of 28 cases despite peripheral neutrophil counts less than 0.1 × 10(-9)/l in 26 patients: in the digestive tract in 18 cases, around the tract of the central venous catheter (CVC) in 9 and in the lungs in 7 cases. FDG uptake in the CVC tract was associated with coagulase-negative staphylococcal bacteraemia (p < 0.001) and deep venous thrombosis (p = 0.002). The number of patients having Streptococcus mitis bacteraemia appeared to be higher in patients with grade 3 oesophageal FDG uptake (p = 0.08). Pulmonary FDG uptake was associated with the presence of invasive fungal disease (p = 0.04). CONCLUSION: (18)F-FDG PET/CT scanning during chemotherapy-induced febrile neutropenia and increased CRP is able to detect localized foci of infection and inflammation despite the absence of circulating neutrophils. Besides its potential role in detecting CVC-related infection during febrile neutropenia, the high negative predictive value of (18)F-FDG PET/CT is important for avoiding unnecessary diagnostic tests and therapy.

Nuclear medicine imaging of infection in cancer patients (with emphasis on FDG-PET).

Infections are a common cause of death and an even more common cause of morbidity in cancer patients. Timely and adequate diagnosis of infection is very important. This article provides clinicians as well as nuclear medicine specialists with a concise summary of the most important and widely available nuclear medicine imaging techniques for infectious and inflammatory diseases in cancer patients with an emphasis on fluorodeoxyglucose positron emission tomography (FDG-PET). 67Ga-citrate has many unfavorable characteristics, and the development of newer radiopharmaceuticals has resulted in the replacement of 67Ga-citrate scintigraphy by scintigraphy with labeled leukocytes or FDG-PET for the majority of conditions. The sensitivity of labeled leukocyte scintigraphy in non-neutropenic cancer patients is comparable with that in patients without malignancy. The specificity, however, is lower because of the uptake of labeled leukocytes in many primary tumors and metastases, most probably as a result of their inflammatory component. In addition, labeled leukocyte scintigraphy cannot be used for febrile neutropenia because of the inability to harvest sufficient peripheral leukocytes for in vitro labeling. FDG-PET has several advantages over these conventional scintigraphic techniques. FDG-PET has shown its usefulness in diagnosing septic thrombophlebitis in cancer patients. It has also been shown that imaging of infectious processes using FDG-PET is possible in patients with severe neutropenia. Although larger prospective studies examining the value of FDG-PET in cancer patients suspected of infection, especially in those with febrile neutropenia, are needed, FDG-PET appears to be the most promising scintigraphic technique for the diagnosis of infection in this patient group.

Clinical impact of preincubation of blood cultures at 37°C.

The effect of immediate incubation of blood cultures at 37°C on the turnaround time and the impact of Gram stain results on antimicrobial management were investigated. During a 6-month period, blood cultures collected at the emergency department outside laboratory operating hours were preincubated at 37°C until transportation to the laboratory. Upon the arrival of blood cultures at the laboratory, Gram stains and subcultures were made from all bottles prior to further incubation in the automated system (Bactec 9240). Data from 1 year earlier, when all blood cultures were stored at room temperature, were used for comparison. In the study period, 79 episodes of bacteremia were detected for 75 patients, compared to 70 episodes for 67 patients in the control period. Preincubation of blood cultures at 37°C resulted in a 15-h reduction in the median time to reporting of Gram stain results, from 34 to 19 h (P, <0.001). With preincubation, 3 episodes (4%) of bacteremia were not detected by the Bactec 9240 system. Based on the reporting of the Gram stain results, appropriate antimicrobial therapy was initiated for 12% of all patients with positive blood cultures, while for 24% the therapy was streamlined. Thus, immediate incubation of blood cultures reduced the time to reporting of Gram stain results. However, not all episodes of bacteremia were detected by the Bactec 9240 system after preincubation at 37°C. Blood culture results contributed importantly to appropriate antimicrobial management.

Expectancies as predictors of symptom improvement after antimicrobial therapy for persistent symptoms attributed to Lyme disease.

INTRODUCTION/OBJECTIVE: Expectancies about symptom improvement or deterioration are reliable predictors of symptom progression and treatment outcomes (symptom resolution or symptomatic improvement) in many (non-)pharmacological studies and treatments. This study examined predictors of symptom improvement after antimicrobial therapy for persistent symptoms attributed to Lyme disease, hypothesizing particularly pre-treatment expectancies regarding symptom improvement to be predictive. METHODS: A predictive study was performed on pre-treatment and post-treatment individual characteristics, including expectancies, and physical and mental health-related quality of life (HRQoL) from the PLEASE-trial comparing randomized 12-weeks of doxycycline, clarithromycin-hydroxychloroquine, or placebo following 2 weeks of intravenous ceftriaxone. At end-of-treatment (14 weeks after trial start) and follow-up (52 weeks), complete data of 231 and 170 (of initial 280) patients with persistent symptoms temporally related to a history of erythema migrans or otherwise confirmed symptomatic Lyme disease, or accompanied by B. burgdorferi IgG or IgM antibodies, were examined through hierarchical regression analyses. RESULTS: In addition to pre-treatment HRQoL, pre-treatment expectancies regarding symptom improvement were consistently associated with stronger physical and mental HRQoL improvements at both end-of-treatment and follow-up (95% CI range: .09;.54, p < .01 to .27;.92, p < .001). Post-treatment expectancies regarding having received antibiotics vs. placebo was associated with more HRQoL improvement at end-of-treatment, but not at follow-up (95% CI-range 1.00;4.75, p = .003 to -7.34; -2.22, p < .001). CONCLUSIONS: The present study shows that, next to pre-treatment functioning, patients' pre-treatment and post-treatment expectancies regarding improvement of persistent symptoms attributed to Lyme disease relate to a more beneficial symptom course. Expectancies of patients may be relevant to explain and potentially improve patient outcomes (e.g., by optimized communication about treatment success). TRIAL REGISTRATION: ClinicalTrials.gov, NCT01207739 (Registration date: 23-09-2010) Key Points • As there is currently no sufficient symptom resolution or symptomatic improvement for many patients with persistent symptoms attributed to Lyme disease, it is relevant to know which factors determine symptom progression and predict heterogeneity in treatment response. • Next to pre-treatment functioning, expectancies regarding symptom improvement and having received antimicrobial study medication are associated with a more beneficial symptom course after both shorter-term and longer-term antimicrobial treatment. • Expectancies are relevant to consider in treatment studies and may be useful in clinical settings to improve symptom course and treatment outcome (e.g., by optimized communication about treatment success).

Effect of prolonged antibiotic treatment on cognition in patients with Lyme borreliosis.

OBJECTIVE: To investigate whether longer-term antibiotic treatment improves cognitive performance in patients with persistent symptoms attributed to Lyme borreliosis. METHODS: Data were collected during the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) trial, a randomized, placebo-controlled study. Study participants passed performance-validity testing (measure for detecting suboptimal effort) and had persistent symptoms attributed to Lyme borreliosis. All patients received a 2-week open-label regimen of intravenous ceftriaxone before the 12-week blinded oral regimen (doxycycline, clarithromycin/hydroxychloroquine, or placebo). Cognitive performance was assessed at baseline and after 14, 26, and 40 weeks with neuropsychological tests covering the cognitive domains of episodic memory, attention/working memory, verbal fluency, speed of information processing, and executive function. RESULTS: Baseline characteristics of patients enrolled (n = 239) were comparable in all treatment groups. After 14 weeks, performance on none of the cognitive domains differed significantly between the treatment arms (p = 0.49-0.82). At follow-up, no additional treatment effect (p = 0.35-0.98) or difference between groups (p = 0.37-0.93) was found at any time point. Patients performed significantly better in several cognitive domains at weeks 14, 26, and 40 compared to baseline, but this was not specific to a treatment group. CONCLUSIONS: A 2-week treatment with ceftriaxone followed by a 12-week regimen of doxycycline or clarithromycin/hydroxychloroquine did not lead to better cognitive performance compared to a 2-week regimen of ceftriaxone in patients with Lyme disease-attributed persistent symptoms. CLINICALTRIALSGOV IDENTIFIER: NCT01207739. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that longer-term antibiotics in patients with borreliosis-attributed persistent symptoms does not increase cognitive performance compared to shorter-term antibiotics.

Cost-effectiveness of longer-term versus shorter-term provision of antibiotics in patients with persistent symptoms attributed to Lyme disease.

BACKGROUND: The treatment of persistent symptoms attributed to Lyme disease remains controversial. Recently, the PLEASE study did not demonstrate any additional clinical benefit of longer-term versus shorter-term antibiotic treatment. However, the economic impact of the antibiotic strategies has not been investigated. METHODS: This prospective economic evaluation, adhering a societal perspective, was performed alongside the PLEASE study, a multicenter, placebo-controlled, double-blind 1:1:1 randomized clinical trial in which all patients received open-label intravenous ceftriaxone for two weeks before the 12-week randomized blinded oral antibiotic regimen (doxycycline, clarithromycin plus hydroxychloroquine, or placebo). Between 2010 and 2013, patients (n = 271) with borreliosis-attributed persistent symptoms were enrolled and followed for one year. Main outcomes were costs, quality-adjusted life years, and incremental net monetary benefit of longer-term versus shorter-term antibiotic therapy. RESULTS: Mean quality-adjusted life years (95% CI) were not significantly different (p = 0.96): 0.82 (0.77-0.88) for ceftriaxone/doxycycline (n = 82), 0.81 (0.76-0.88) for ceftriaxone/clarithromycin-hydroxychloroquine (n = 93), and 0.81 (0.76-0.86) for ceftriaxone/placebo (n = 96). Total societal costs per patient (95% CI) were not significantly different either (p = 0.35): €11,995 (€8,823-€15,670) for ceftriaxone/doxycycline, €12,202 (€9,572-€15,253) for ceftriaxone/clarithromycin-hydroxychloroquine, and €15,249 (€11,294-€19,781) for ceftriaxone/placebo. Incremental net monetary benefit (95% CI) for ceftriaxone/doxycycline compared to ceftriaxone/placebo varied from €3,317 (-€2,199-€8,998) to €4,285 (-€6,085-€14,524) over the willingness-to-pay range, and that of ceftriaxone/clarithromycin-hydroxychloroquine compared to ceftriaxone/placebo from €3,098 (-€888-€7,172) to €3,710 (-€4,254-€11,651). For every willingness-to-pay threshold, the incremental net monetary benefits did not significantly differ from zero. CONCLUSION: The longer-term treatments were similar with regard to costs, effectiveness and cost-effectiveness compared to shorter-term treatment in patients with borreliosis-attributed persistent symptoms after one year of follow-up. Given the results of this study, and taking into account the external costs associated with antibiotic resistance, the shorter-term treatment is the antibiotic regimen of first choice.

A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol.

We conducted a prospective study to update our knowledge of fever of unknown origin (FUO) and to explore the utility of a structured diagnostic protocol. From December 2003 to July 2005, 73 patients with FUO were recruited from 1 university hospital (n = 40) and 5 community hospitals (n = 33) in the same region in The Netherlands. FUO was defined as a febrile illness of >3 weeks' duration, a temperature of >38.3 degrees C on several occasions, without a diagnosis after standardized history-taking, physical examination, and certain obligatory investigations. Immunocompromised patients were excluded. A structured diagnostic protocol was used. Patients from the university hospital were characterized by more secondary referrals and a higher percentage of periodic fever than those referred to community hospitals. Infection was the cause in 16%, a neoplasm in 7%, noninfectious inflammatory diseases in 22%, miscellaneous causes in 4%, and in 51%, the cause of fever was not found (no differences between university and community hospitals). There were no differences regarding the number and type of investigations between university and community hospitals. Significant predictors for reaching a diagnosis included continuous fever; fever present for <180 days; elevated erythrocyte sedimentation rate, C-reactive protein, or lactate dehydrogenase; leukopenia; thrombocytosis; abnormal chest computed tomography (CT); and abnormal F-fluorodeoxyglucose positron emission tomography (FDG-PET). For future FUO studies, inclusion of outpatients and the use of a set of obligated investigations instead of a time-related criterion are recommended. Except for tests from the obligatory part of our protocol and cryoglobulins in an early stage, followed by FDG-PET, and in a later stage by abdominal and chest CT, temporal artery biopsy in patients aged 55 years or older, and possibly bone marrow biopsy, other tests should not be used as screening investigations.

18F-FDG PET in detecting metastatic infectious disease.

UNLABELLED: Timely identification of metastatic complications of bloodstream infections due to spreading of the microorganisms to distant sites, although critical, is often difficult. As 18F-FDG accumulates in activated leukocytes in infectious lesions, 18F-FDG PET represents a promising imaging technique in these patients. The aim of this study was to assess the value of 18F-FDG PET in detecting infectious foci in patients at high risk of metastatic complications. METHODS: The results of all 18F-FDG PET scans ordered because of suspected metastatic infection from October 1998 to September 2004 were analyzed retrospectively. These results were compared with conventional investigation techniques and the final clinical diagnosis. RESULTS: The results of 40 18F-FDG PET scans were evaluated. In 60% of all episodes, Gram-positive bacteria were cultured, in 18% Gram-negative bacteria, in 20% Candida spp., and in 3% the infection was polymicrobial. Metastatic complications were diagnosed in 75% of all episodes. A median number of 4 diagnostic procedures to search for metastatic infection had been performed before 18F-FDG PET was ordered. 18F-FDG PET diagnosed a clinically relevant new focus in 45% of cases and confirmed abnormalities already diagnosed in 30% of cases. The positive predictive value of 18F-FDG PET was 91% and the negative predictive value was 100%. CONCLUSION: 18F-FDG PET is a valuable imaging technique in patients at high risk of metastatic infectious disease, even when the results of other diagnostic procedures are normal.

[FDG-PET/CT: a valuable technique in Staphylococcus aureus bacteraemia]. / FDG-PET/CT waardevol bij S. aureus-bacteriëmie.

Staphylococcus aureus bacteraemia is often complicated by metastatic infectious foci. Some of these metastatic foci do not cause any localizing symptoms, which complicates early detection and adequate treatment. Where localizing symptoms are absent FDG-PET/CT is highly useful as a screening method for the identification of metastatic foci as it provides whole-body coverage. Furthermore, it detects early metabolic activity rather than the late anatomical changes needed for detection with CT or MRI. FDG-PET/CT has proven its clinical value and cost-effectiveness in diagnosing metastatic infections in patients with Gram positive bacteraemia, including S. aureus. Therefore, we firmly believe that all patients with a community-acquired S. aureus bacteraemia infection, with a time span longer than 48 h between the first symptoms and initiation of antibiotic therapy, fever that still persists after 72 h, or positive follow-up blood cultures at 48 h after the start of treatment would benefit from an FDG-PET/CT scan for timely detection of metastatic infection and optimal treatment.

The use of FDG-PET/CT in patients with febrile neutropenia.

Fever is a frequent complication of neutropenia induced by the treatment of various neoplasms. This is referred to as febrile neutropenia, which is considered to be a sign of a potentially life-threatening infectious complication until proven otherwise. However, most infectious foci do not have localizing signs and symptoms owing to the lack of inflammatory infiltrates during neutropenia. At the same time, recent studies also showed that febrile neutropenia is not a specific indicator for infection. An increase in C-reactive protein and fever may initially be caused by inflammation of the digestive tract mucosa due to cytotoxic treatment of hematologic malignancies. Infectious foci can be found in various organ systems, such as the respiratory tract including invasive fungal disease, septic thrombophlebitis in those patients with central venous catheters, metastatic infection including soft tissue abscesses, and the digestive tract, for example, colitis and esophagitis probably associated with mucosal barrier injury. A growing number of studies focus on the use of FDG-PET/CT to detect infection in patients with febrile neutropenia. Studies show that FDG uptake in inflammatory foci seems not to be hampered by the lack of circulating neutrophils. At the same time, the very high negative predictive value of FDG-PET/CT excluding localized infectious foci might facilitate guidance of antimicrobial treatment. However, larger prospective studies are needed before FDG-PET/CT would be embedded in diagnostic guidelines in patients with febrile neutropenia.

Metastatic infectious disease and clinical outcome in Staphylococcus aureus and Streptococcus species bacteremia.

Early detection of metastatic infection in patients with Gram-positive bacteremia is important as morbidity and mortality are higher in the presence of these foci, probably due to incomplete eradication of clinically silent foci during initial treatment. We performed a prospective study in 115 patients with Staphylococcus aureus or Streptococcus species bacteremia with at least 1 risk factor for the development of metastatic foci, such as community acquisition, treatment delay, persistently positive blood cultures for >48 hours, and persistent fever >72 hours after initiation of treatment. An intensive search for metastatic infectious foci was performed including ¹8F-fluorodeoxyglucose-positron emission tomography in combination with low-dose computed tomography scanning for optimizing anatomical correlation (FDG-PET/CT) and echocardiography in the first 2 weeks of admission. Metastatic infectious foci were detected in 84 of 115 (73%) patients. Endocarditis (22 cases), endovascular infections (19 cases), pulmonary abscesses (16 cases), and spondylodiscitis (11 cases) were diagnosed most frequently. The incidence of metastatic infection was similar in patients with Streptococcus species and patients with S. aureus bacteremia. Signs and symptoms guiding the attending physician in the diagnostic workup were present in only a minority of cases (41%). An unknown portal of entry, treatment delay >48 hours, and the presence of foreign body material were significant risk factors for developing metastatic foci. Mean C-reactive protein levels on admission were significantly higher in patients with metastatic infectious foci (74 vs. 160 mg/L). FDG-PET/CT was the first technique to localize metastatic infectious foci in 35 of 115 (30%) patients. As only a minority of foci were accompanied by guiding signs or symptoms, the number of foci revealed by symptom-guided CT, ultrasound, and magnetic resonance imaging remained low. Mortality tended to be lower in patients without complicated infection compared to those with metastatic foci (16% vs. 25%, respectively). Five of 31 patients (16%) without proven metastatic foci died. In retrospect, 3 of these 5 patients likely had metastatic foci that could not be diagnosed while alive. In patients with Gram-positive bacteremia and a high risk of developing complicated infection, a structured protocol including echocardiography and FDG-PET/CT aimed at detecting metastatic infectious foci can contribute to improved outcome.

Cost-effectiveness of routine (18)F-FDG PET/CT in high-risk patients with gram-positive bacteremia.

UNLABELLED: Gram-positive bacteremia has a high morbidity and mortality rate of approximately 30%. Delayed diagnosis of clinically silent metastatic infectious foci is an important indicator for a complicated outcome. (18)F-FDG PET/CT allows detection of focal infection, resulting in lower relapse rates and mortality. Here, we present a cost-effectiveness analysis associated with introduction of (18)F-FDG PET/CT for patients with gram-positive bacteremia. METHODS: A cost-effectiveness analysis in a prospective (18)F-FDG PET/CT group (n = 115) and matched control group (n = 230) was performed alongside a clinical study, the results of which were previously published. Mortality at 6 mo was considered the final effect outcome and was used in the denominator of the incremental cost-effectiveness ratio. RESULTS: Mortality in the (18)F-FDG PET/CT group was 19%, compared with 32% in the control group (P < 0.01). Incremental costs of (18)F-FDG PET/CT were $9,454 (95% confidence interval [CI], $3,963-$14,947), mainly because of admission (mean, $6,631; 95% CI, $1,449-$11,814). Additional costs were related to echocardiography (P < 0.01), not to (18)F-FDG PET/CT (P = 0.8). The mean incremental costs of the (18)F-FDG PET/CT strategy estimated by stratification for endocarditis were $5,277 per patient (95% CI, $429-$10,123; P = 0.03). The point estimate of the incremental cost-effectiveness ratio is $72,487 per prevented death (95% CI, $11,388-$323,379). CONCLUSION: Introduction of a diagnostic regimen including routine (18)F-FDG PET/CT decreases morbidity and mortality. The cost increase is due to in-hospital treatment of metastatic infectious foci. Costs per prevented death, $72,487, are within the range that is considered to be efficient by Dutch guidelines. Patients with high-risk gram-positive bacteremia therefore should have easy access to (18)F-FDG PET/CT to enable early detection of metastatic infectious disease.