Positive Impact of [18F]FDG-PET/CT on Mortality in Patients With Staphylococcus aureus Bacteremia Explained by Immortal Time Bias.

BACKGROUND: Several studies have suggested that in patients with Staphylococcus aureus bacteremia (SAB) [18F] fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) improves outcome. However, these studies often ignored possible immortal time bias. METHODS: Prospective multicenter cohort study in 2 university and 5 non-university hospitals, including all patients with SAB. [18F]FDG-PET/CT was performed on clinical indication as part of usual care. Primary outcome was 90-day all-cause mortality. Effect of [18F]FDG-PET/CT was modeled with a Cox proportional hazards model using [18F]FDG-PET/CT as a time-varying variable and corrected for confounders for mortality (age, Charlson score, positive follow-up cultures, septic shock, and endocarditis). Secondary outcome was 90-day infection-related mortality (assessed by adjudication committee) using the same analysis. In a subgroup-analysis, we determined the effect of [18F]FDG-PET/CT in patients with high risk of metastatic infection. RESULTS: Of 476 patients, 178 (37%) underwent [18F]FDG-PET/CT. Day-90 all-cause mortality was 31% (147 patients), and infection-related mortality was 17% (83 patients). The confounder adjusted hazard ratio (aHR) for all-cause mortality was 0.50 (95% confidence interval [CI]: .34-.74) in patients that underwent [18F]FDG-PET/CT. Adjustment for immortal time bias changed the aHR to 1.00 (95% CI .68-1.48). Likewise, after correction for immortal time bias, [18F]FDG-PET/CT had no effect on infection-related mortality (cause specific aHR 1.30 [95% CI .77-2.21]), on all-cause mortality in patients with high-risk SAB (aHR 1.07 (95% CI .63-1.83) or on infection-related mortality in high-risk SAB (aHR for 1.24 [95% CI .67-2.28]). CONCLUSIONS: After adjustment for immortal time bias [18F]FDG-PET/CT was not associated with day-90 all-cause or infection-related mortality in patients with SAB.

Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Use of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin. OBJECTIVE: The primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety. MATERIALS/PATIENTS: IN THIS MULTICENTER RCT PATIENTS AGED ≥ 18-YEAR-OLD WERE INCLUDED WITH CONFIRMED BRONCHIECTASIS AND ≥ 2 EXACERBATIONS IN THE PRECEDING YEAR. PATIENTS WERE ASSIGNED (1:1) TO RECEIVE TIS OR PLACEBO OD FOR 1-YEAR.: RESULTS: 58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49-1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes. CONCLUSION: Long-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease. TRAIL REGISTRATION NUMBER: The BATTLE study was registered at Clinical trials.gov number: NCT02657473 . Date: 13 august 2016.

Bacterial DNA load in Staphylococcus aureus bacteremia is significantly higher in intravascular infections.

OBJECTIVES: Determination of pathogen-specific bacterial DNA load (BDL) in blood has been shown to be directly correlated with severity of infection in patients with bacteremia. In the diagnostic work-up of patients with Staphylococcus aureus bacteremia (SAB), determination of the primary focus is imperative, because of implications for treatment duration, and ultimately prognosis. Here we investigate whether measurement of BDL in patients with SAB can distinguish between intravascular and extravascular foci of infection. METHODS: In a consecutive cohort of 43 patients with positive blood cultures with Staphylococcus aureus, we performed a quantitative PCR on whole blood to detect the bacterial DNA load. Infections were classified into 3 categories: i) soft tissue infections and phlebitis, ii) deep-seated infections and iii) endocarditis and other intravascular infections. Bacterial DNA loads and inflammatory parameters in the three categories were analyzed and compared. RESULTS: Median BDL in patients with endocarditis and other intravascular infections was 1015 cfu/ml, significantly higher than BDL in the other two categories (28 and 31 cfu/ml respectively). In contrast, CRP and leukocytes were not significantly different between the three patient categories. BDL could be detected in all patients with intravascular causes and levels were generally 10-30 times higher than in the other infection categories. Median BDL in non-survivors was 85 cfu/ml, which was higher than in survivors with a median BDL of 29 cfu/ml, although not significant. CONCLUSIONS: In Staphylococcus aureus bacteremia pathogen-specific BDL is distinctly higher in patients with intravascular infections compared to extravascular origins. As measurement of BDL by PCR can easily be implemented in routine diagnostics, it can improve the diagnostic work-up of SAB by rapidly identifying the subset of patients who need higher dosages of antibiotics and additional measures to improve outcome.

All-Cause and Infection-Related Mortality in Staphylococcus aureus Bacteremia, a Multicenter Prospective Cohort Study.

Background: Staphylococcus aureus bacteremia (SAB) is a heterogeneous disease with changing epidemiology due to changing demographics and evolving clinical management. SAB is associated with high mortality, but the current fraction of infection-related mortality is less well quantified. Methods: In a multicenter prospective cohort study of consecutive patients with SAB, we determined clinical features of SAB and determined 90-day mortality and risk factors of all-cause and infection-related mortality. Infection-related mortality was based on an adjudication committee evaluation. Results: Four hundred ninety patients with SAB were included, with community-acquired (n = 166), health care-associated (n = 163), and hospital-acquired SAB (n = 161). Endocarditis (n = 90, 18.3%), peripheral intravenous catheter infection (n = 80, 16.3%), and septic arthritis (n = 58, 11.8%) were the most frequent diagnoses, but proportions differed for community, health care, and hospital acquisition. One hundred ninety-two patients (39%) had permanent implanted prosthetic material (eg, prosthetic joint, heart valve, pacemaker). Day 90 all-cause mortality was 33% (n = 161), with 60% adjudicated as infection-related, and 90% of infection-related deaths occurring in the first 30 days post-SAB. Infection-related deaths after 30 days were rare and mainly related to endocarditis. Determinants associated with day 90 infection-related mortality were age (odds ratio [OR], 1.09; 95% CI, 1.06-1.11), Charlson comorbidity index (OR, 1.13; 95% CI, 1.01-1.26), septic shock (OR, 9.78; 95% CI, 4.56-20.95), endocarditis (OR, 3.4; 95% CI, 1.75-6.61), and persistent SAB at 48 hours (OR, 2.36; 95% CI, 1.27-4.37). Conclusions: Mortality due to S. aureus infection remains high and mainly occurs in the first 30 days, which could guide end points in future studies.

Prediction Rules for Ruling Out Endocarditis in Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is in 10% to 20% of cases complicated by infective endocarditis. Clinical prediction scores may select patients with SAB at highest risk for endocarditis, improving the diagnostic process of endocarditis. We compared the accuracy of the Prediction Of Staphylococcus aureus Infective endocarditiseTime to positivity, Iv drug use, Vascular phenomena, preExisting heart condition (POSITIVE), Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT), and VIRSTA scores for classifying the likelihood of endocarditis in patients with SAB. METHODS: Between August 2017 and September 2019, we enrolled consecutive adult patients with SAB in a prospective cohort study in 7 hospitals in the Netherlands. Using the modified Duke Criteria for definite endocarditis as reference standard, sensitivity, specificity, negative predictive (NPV), and positive predictive values were determined for the POSITIVE, PREDICT, and VIRSTA scores. An NPV of at least 98% was considered safe for excluding endocarditis. RESULTS: Of 477 SAB patients enrolled, 33% had community-acquired SAB, 8% had a prosthetic valve, and 11% a cardiac implantable electronic device. Echocardiography was performed in 87% of patients, and 42% received transesophageal echocardiography (TEE). Eighty-seven (18.2%) had definite endocarditis. Sensitivity was 77.6% (65.8%-86.9%), 85.1% (75.8%-91.8%), and 98.9% (95.7%-100%) for the POSITIVE (n = 362), PREDICT, and VIRSTA scores, respectively. NPVs were 92.5% (87.9%-95.8%), 94.5% (90.7%-97.0%), and 99.3% (94.9%-100%). For the POSITIVE, PREDICT, and VIRSTA scores, 44.5%, 50.7%, and 70.9% of patients with SAB, respectively, were classified as at high risk for endocarditis. CONCLUSIONS: Only the VIRSTA score had an NPV of at least 98%, but at the expense of a high number of patients classified as high risk and thus requiring TEE. CLINICAL TRIALS REGISTRATION: Netherlands Trial Register code 6669.

Narrow-spectrum antibiotics for community-acquired pneumonia in Dutch adults (CAP-PACT): a cross-sectional, stepped-wedge, cluster-randomised, non-inferiority, antimicrobial stewardship intervention trial.

BACKGROUND: Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. METHODS: In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov, NCT02604628. FINDINGS: Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of -1·7 days (95% CI -2·4 to -1·1) and a relative reduction of 26·6% (95% CI 18·0-35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI -2·7 to 2·4), indicating non-inferiority. INTERPRETATION: In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. FUNDING: None.

Diagnosis and management of aspergillosis in the Netherlands: a national survey.

A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B.

Evaluation of approaches to monitor Staphylococcus aureus virulence factor expression during human disease.

Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize S. aureus isolates recovered from infected patients and also to investigate approaches for examining expression of S. aureus vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed S. aureus wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage S. aureus isolates were recovered and characterized for genotypic diversity. S. aureus antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. S. aureus nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable S. aureus triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the S. aureus virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine.

[Streptococcus suis meningitis in a meat factory employee]. / Streptococcus suis-meningitis bij een medewerker van een vleesfabriek.

BACKGROUND: In the Netherlands, Streptococcus suis is a rare cause of meningitis. Over the past few years, the number of reported cases worldwide has increased. The bacterium is mainly isolated in pigs, but humans can also become infected. CASE DESCRIPTION: At the Emergency Department, a 60-year-old man presented with headache, confusion, fever and nuchal rigidity. He worked at a meat factory. Laboratory testing showed abnormalities linked to bacterial meningitis. S. suis was cultured from blood and cerebrospinal fluid. The patient was treated with dexamethasone, ceftriaxone and later benzylpenicillin intravenously. He recovered well, but had bilateral perceptive hearing loss as a sequela. CONCLUSION: Particularly people who are in close contact with pigs have an increased risk of S. suis infection. S. suis meningitis can be very severe and lead to serious complications and even death. Rapid diagnosis and adequate treatment are critical. Permanent hearing loss is the most frequent sequela.

Abiotrophia defectiva infection of a total hip arthroplasty diagnosed by 16S rRNA gene sequencing.

We describe a case of a total hip arthroplasty infection caused by Abiotrophia defectiva, identified by 16S rRNA gene sequencing. Removal of the prosthesis followed by antibiotic treatment resulted in a good clinical outcome. 16S rRNA gene sequencing can be a useful tool in diagnosing infection with this fastidious microorganism that can easily be misidentified using phenotypic identification methods.