Third-generation cephalosporin resistant gram-negative bacteraemia in patients with haematological malignancy; an 11-year multi-centre retrospective study.

OBJECTIVES: Among patients with haematological malignancy, bacteraemia is a common complication during chemotherapy-induced neutropenia. Resistance of gram-negative bacteria (GNB) to third-generation cephalosporins (3GC) is increasing. In order to explore the value of using surveillance cultures to guide empirical treatment e.g. choosing between carbapenem versus ceftazidime- we aimed to assess the distribution of pathogens causing bacteraemia in patients with haematological malignancy, and the proportion of 3GC-resistant GNB (3GC-R GNB) bacteraemia that was preceded by 3GC-R GNB colonization. METHODS: Using 11 years of data (2008-2018) from the Dutch national antimicrobial resistance surveillance system, we assessed the prevalence of 3GC-R GNB in episodes of bacteraemia, and the proportion of 3GC-R GNB bacteraemia that was preceded by 3GC-R GNB colonization. Colonization was defined as availability of any GNB surveillance isolate in the year before, independent of the causative micro-organism (time-paired isolates). RESULTS: We included 3887 patients, representing 4142 episodes of bacteraemia. GNB were identified in 715/4142 (17.3%), of which 221 (30.9%) were 3GC-R GNB. In 139 of these 221 patients a time-paired surveillance culture was available. In 76.2% (106/139) of patients these surveillance cultures already showed 3GC-R GNB isolates in the year prior to the culture date of the 3GC-R GNB positive blood isolate. CONCLUSIONS: This multi-centre study shows that in patients with haematological malignancy, the majority of 3GC-R GNB bacteraemia is preceded by 3GC-R GNB colonization. Prospective clinical studies are needed to assess the safety and benefits of the use of surveillance-cultures to guide empirical therapy to restrict the empirical use of carbapenems in this population.

Reducing the dosing frequency of selective digestive tract decontamination to three times daily provides effective decontamination of Gram-negative bacteria.

This study evaluated the effectiveness of selective digestive tract decontamination (SDD) application three times daily (t.i.d.) compared to the standard four times daily (q.i.d.). Retrospective equivalence (combined non-inferiority and non-superiority design) study with a before-and-after design on a tertiary ICU in which the SDD frequency was reduced from q.i.d. to t.i.d. All patients with ICU admissions ≥72h and with ≥2 surveillance cultures collected on different dates were included in this study. We compared successful decontamination of Gram-negative bacteria (GNB). Furthermore, time to decontamination, ICU-acquired GNB bacteraemia and 28-day mortality were compared between the two groups. In total 1958 ICU admissions (1236 q.i.d., 722 t.i.d). Decontamination was achieved during the first week of admission in 77% and 76% of patients receiving SDD q.i.d and t.i.d., respectively. Successful decontamination within 14 days (without consecutive acquisition of Gram-negative bacteria) was achieved in 69.3% of the admissions with q.i.d. versus 66.8% in t.i.d. SDD (p-value = 0.2519). The proportions of successful decontamination of GNB were equivalent in both groups (-0.025, 98% CI: -0.087; 0.037). There was no significant difference in time to decontamination between the two regimens (log-rank test p-value = 0.55). Incidence (episodes/1000 days) of ICU-acquired GNB bacteraemia was 0.9 in both groups, and OR for death at day 28 in the t.i.d. group compared to the q.i.d. group was 0.99 (95% confidence interval, 0.80-1.21). This study shows that a t.i.d. application regimen achieves similar outcomes to the standard q.i.d. regime, for both microbiological and clinical outcome measures.

The evidence base for the optimal antibiotic treatment duration of upper and lower respiratory tract infections: an umbrella review.

BACKGROUND: Many trials, reviews, and meta-analyses have been performed on the comparison of short versus long antibiotic treatment in respiratory tract infections, generally supporting shorter treatment. The aim of this umbrella review is to assess the soundness of the current evidence base for optimal antibiotic treatment duration. METHODS: A search in Ovid MEDLINE, Embase, and Clarivate Analytics Web of Science Core Collection was performed on May 1, 2024, without date and language restrictions. Systematic reviews addressing treatment durations in community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD), hospital-acquired pneumonia (HAP), acute sinusitis, and streptococcal pharyngitis, tonsillitis, or pharyngotonsillitis were included. Studies from inpatient and outpatient settings were included; reviews in paediatric populations were excluded. Outcomes of interest were clinical and bacteriological cure, microbiological eradication, mortality, relapse rate, and adverse events. The quality of the reviews was assessed using the AMSTAR 2 tool, risk of bias of all included randomised controlled trials (RCTs) using the Cochrane risk-of-bias tool (version 1), and overall quality of evidence according to GRADE. FINDINGS: We identified 30 systematic reviews meeting the criteria; they were generally of a low to critically low quality. 21 reviews conducted a meta-analysis. For CAP outside the intensive care unit (ICU; 14 reviews, of which eight did a meta-analysis) and AECOPD (eight reviews, of which five did a meta-analysis), there was sufficient evidence supporting a treatment duration of 5 days; evidence for shorter durations is scarce. Evidence on non-ventilator-associated HAP is absent, despite identifying three reviews (of which one did a meta-analysis), since no trials were conducted exclusively in this population. For sinusitis the evidence appears to support a shorter regimen, but more evidence is needed in the population who actually require antibiotic treatment. For pharyngotonsillitis (eight reviews, of which six did a meta-analysis), sufficient evidence exists to support short-course cephalosporin but not short-course penicillin when dosed three times a day. INTERPRETATION: The available evidence for non-ICU CAP and AECOPD supports a short-course treatment duration of 5 days in patients who have clinically improved. Efforts of the scientific community should be directed at implementing this evidence in daily practice. High-quality RCTs are needed to underpin even shorter treatment durations for CAP and AECOPD, to establish the optimal treatment duration of HAP and acute sinusitis, and to evaluate shorter duration using an optimal penicillin dosing schedule in patients with pharyngotonsillitis. FUNDING: None.

Identifying excessive length of antibiotic treatment duration for hospital-acquired infections: a semi-automated approach to support antimicrobial stewardship.

BACKGROUND: Avoiding excessive antibiotic treatment duration is a fundamental goal in antimicrobial stewardship. Manual collection of data is a time-consuming process, but a semi-automated approach for data extraction has been shown feasible for community-acquired infections (CAI). Extraction of data however may be more challenging in hospital-acquired infections (HAI). The aim of this study is to explore whether semi-automated data extraction of treatment duration is also feasible and accurate for HAI. METHODS: Data from a university-affiliated hospital over the period 1-6-2020 until 1-6-2022 was used for this study. From the Electronic Health Record, raw data on prescriptions, registered indications and admissions was extracted and processed to define treatment courses. In addition, clinical notes including prescription instructions were obtained for the purpose of validation. The derived treatment course was compared to the registered indication and the actual length of treatment (LOT) in the clinical notes in a random sample of 5.7% of treatment courses, to assess the accuracy of the data for both CAI and HAI. RESULTS: Included were 10.564 treatment courses of which 73.1% were CAI and 26.8% HAI. The registered indication matched the diagnosis as recorded in the clinical notes in 79% of treatment courses (79.2% CAI, 78.5% HAI). Higher error rates were seen in urinary tract infections (UTIs) (29.0%) and respiratory tract infections (RTIs) (20.5%) compared to intra-abdominal infections (7.4%), or skin or soft tissue infections (11.1%), mainly due to incorrect specification of the type of UTI or RTI. The LOT was accurately extracted in 98.5% of courses (CAI 98.2%, HAI 99.3%) when compared to prescriptions in the EHR. In 21% of cases however the LOT did not match with the clinical notes, mainly if patients received treatment from other health care providers preceding or following the present course. CONCLUSION: Semi-automatic data extraction can yield reliable information about the indication and LOT in treatment courses of hospitalized patients, for both HAI and CAI. This can provide stewardship programs with a surveillance tool for all in-hospital treated infections, which can be used to achieve stewardship goals.

Impact of Blood Culture Contamination on Antibiotic Use, Resource Utilization, and Clinical Outcomes: A Retrospective Cohort Study in Dutch and US Hospitals.

Background: Blood culture contamination (BCC) has been associated with prolonged antibiotic use (AU) and increased health care utilization; however, this has not been widely reevaluated in the era of increased attention to antibiotic stewardship. We evaluated the impact of BCC on AU, resource utilization, and length of stay in Dutch and US patients. Methods: This retrospective observational study examined adults admitted to 2 hospitals in the Netherlands and 5 hospitals in the United States undergoing ≥2 blood culture (BC) sets. Exclusion criteria included neutropenia, no hospital admission, or death within 48 hours of hospitalization. The impact of BCC on clinical outcomes-overall inpatient days of antibiotic therapy, test utilization, length of stay, and mortality-was determined via a multivariable regression model. Results: An overall 22 927 patient admissions were evaluated: 650 (4.1%) and 339 (4.8%) with BCC and 11 437 (71.8%) and 4648 (66.3%) with negative BC results from the Netherlands and the United States, respectively. Dutch and US patients with BCC had a mean ± SE 1.74 ± 0.27 (P < .001) and 1.58 ± 0.45 (P < .001) more days of antibiotic therapy than patients with negative BC results. They also had 0.6 ± 0.1 (P < .001) more BCs drawn. Dutch but not US patients with BCC had longer hospital stays (3.36 days; P < .001). There was no difference in mortality between groups in either cohort. AU remained higher in US but not Dutch patients with BCC in a subanalysis limited to BC obtained within the first 24 hours of admission. Conclusions: BCC remains associated with higher inpatient AU and health care utilization as compared with patients with negative BC results, although the impact on these outcomes differs by country.

Appropriate use of blood cultures in the emergency department through machine learning (ABC): study protocol for a randomised controlled non-inferiority trial.

INTRODUCTION: The liberal use of blood cultures in emergency departments (EDs) leads to low yields and high numbers of false-positive results. False-positive, contaminated cultures are associated with prolonged hospital stays, increased antibiotic usage and even higher hospital mortality rates. This trial aims to investigate whether a recently developed and validated machine learning model for predicting blood culture outcomes can safely and effectively guide clinicians in withholding unnecessary blood culture analysis. METHODS AND ANALYSIS: A randomised controlled, non-inferiority trial comparing current practice with a machine learning-guided approach. The primary objective is to determine whether the machine learning based approach is non-inferior to standard practice based on 30-day mortality. Secondary outcomes include hospital length-of stay and hospital admission rates. Other outcomes include model performance and antibiotic usage. Participants will be recruited in the EDs of multiple hospitals in the Netherlands. A total of 7584 participants will be included. ETHICS AND DISSEMINATION: Possible participants will receive verbal information and a paper information brochure regarding the trial. They will be given at least 1 hour consideration time before providing informed consent. Research results will be published in peer-reviewed journals. This study has been approved by the Amsterdam University Medical Centers' local medical ethics review committee (No 22.0567). The study will be conducted in concordance with the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act, General Data Privacy Regulation and Medical Device Regulation. TRIAL REGISTRATION NUMBER: NCT06163781.

Enterobacterales carrying chromosomal AmpC ß-lactamases in Europe (EuESCPM): Epidemiology and antimicrobial resistance burden from a cohort of 27 hospitals, 2020-2022.

INTRODUCTION: The ESCPM group (Enterobacter species including Klebsiella aerogenes - formerly Enterobacter aerogenes, Serratia species, Citrobacter freundii complex, Providencia species and Morganella morganii) has not yet been incorporated into systematic surveillance programs. METHODS: We conducted a multicentre retrospective observational study analysing all ESCPM strains isolated from blood cultures in 27 European hospitals over a 3-year period (2020-2022). Diagnostic approach, epidemiology, and antimicrobial susceptibility were investigated. RESULTS: Our study comprised 6,774 ESCPM isolates. MALDI-TOF coupled to mass spectrometry was the predominant technique for bacterial identification. Susceptibility to new ß-lactam/ß-lactamase inhibitor combinations and confirmation of AmpC overproduction were routinely tested in 33.3% and 29.6% of the centres, respectively. The most prevalent species were E. cloacae complex (44.8%) and S. marcescens (22.7%). Overall, third-generation cephalosporins (3GC), combined third- and fourth-generation cephalosporins (3GC + 4GC) and carbapenems resistance phenotypes were observed in 15.7%, 4.6%, and 9.5% of the isolates, respectively. AmpC overproduction was the most prevalent resistance mechanism detected (15.8%). Among carbapenemase-producers, carbapenemase type was provided in 44.4% of the isolates, VIM- (22.9%) and OXA-48-enzyme (16%) being the most frequently detected. E. cloacae complex, K. aerogenes and Providencia species exhibited the most notable cumulative antimicrobial resistance profiles, with the former displaying 3GC, combined 3GC + 4GC and carbapenems resistance phenotypes in 15.2%, 7.4%, and 12.8% of the isolates, respectively. K. aerogenes showed the highest rate of both 3GC resistant phenotype (29.8%) and AmpC overproduction (32.1%), while Providencia species those of both carbapenems resistance phenotype (42.7%) and carbapenemase production (29.4%). ESCPM isolates exhibiting both 3GC and combined 3GC + 4GC resistance phenotypes displayed high susceptibility to ceftazidime/avibactam (98.2% and 95.7%, respectively) and colistin (90.3% and 90.7%, respectively). Colistin emerged as the most active drug against ESCPM species (except those intrinsically resistant) displaying both carbapenems resistance phenotype (85.8%) and carbapenemase production (97.8%). CONCLUSIONS: This study presented a current analysis of ESCPM species epidemiology in Europe, providing insights to inform current antibiotic treatments and guide strategies for antimicrobial stewardship and diagnostics.

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.

Risk factors for readmission among patients receiving outpatient parenteral antimicrobial therapy: a retrospective cohort study.

Background In the Netherlands, home treatment with intravenous antimicrobial therapy is a relatively new concept. Although several studies have shown that outpatient parenteral antimicrobial therapy (OPAT) can be administered safely, people receiving antimicrobials at home remain at risk for adverse events, including readmission. Aim The aim of our retrospective study was to identify risk factors for readmission in patients discharged with OPAT. Method Patients who were at least 18 years or older, discharged with OPAT between January 2016-December 2018 were included. Variables that were collected consisted of baseline demographics, complications, readmission within 30 days and treatment failure. Multivariate logistic regression analysis was performed to identify risk factors for readmission. Results A total of 247 patients were included; the most common reason for OPAT was bone and joint infections (17%). Penicillin (37%), cephalosporin (26%) and vancomycin/aminoglycoside (15%) were the most commonly prescribed antimicrobials. Among patients receiving medication subject to therapeutic drug monitoring (i.e. aminoglycosides or vancomycin), 51% (19/37) received weekly therapeutic drug monitoring. Receiving aminoglycosides or vancomycin (adjusted OR 2.05; 95% CI 1.30-3.25, p < 0.05) and infection of prosthetic material (adjusted OR 2.92, 95% CI 1.11-7.65, p < 0.05) were independent risk factors associated with readmission. Conclusion Although patients receiving medication subject to therapeutic drug monitoring are at higher risk of readmission, only half of the patients discharged with aminoglycosides or vancomycin were monitored according to IDSA guidelines. A specialized team in charge of monitoring patients with OPAT is more likely to increase the rate of monitoring to prevent readmissions and complications.

Comparative analysis of IMP-4- and OXA-58-containing plasmids of three carbapenemase-producing Acinetobacter ursingii strains in the Netherlands.

OBJECTIVES: A recent occurrence of carbapenemase-producing Acinetobacter ursingii was reported in the Netherlands and comprised three unrelated strains carrying the blaIMP-4 and blaOXA-58 encoding genes. The objective was to investigate a putative common source of the carbapenemase resistance genes and plasmids in these A. ursingii strains. METHODS: Hybrid assembly of short-read and long-read sequencing data was performed using Unicycler and assembled genomes were analysed by ResFinder and PlasmidFinder. RESULTS: Hybrid assemblies of A. ursingii genomes yielded a circular chromosome, a large plasmid harboring blaIMP-4 and blaOXA-58 genes (sizes 259-317kb), and four to five other smaller plasmids. ResFinder analyses revealed 16 other acquired resistance genes on the plasmids carrying the blaIMP-4 and blaOXA-58 genes. These 18 genes encode resistance towards eight antibiotic classes. The smaller plasmids did not carry acquired resistance genes. Comparative analysis showed that the three blaIMP-4/blaOXA-58 plasmids were similar (61%-83%) and shared 13 to 17 of the 18 resistance genes. BLAST analysis showed that the blaIMP-4/blaOXA-58 plasmids were not reported before. However, a close match with a 399 kb plasmid from Acinetobacter johnsonii was found (99% similarity, 80% coverage). This A. johnsonii plasmid contains the blaOXA-58 gene, but lacks blaIMP-4, and it shares eight other resistance genes with those present on the A. ursingii blaIMP-4/blaOXA-58 plasmids. CONCLUSION: Three blaIMP-4/blaOXA-58-carrying plasmids were characterized in three carbapenemase-producing A. ursingii strains. The plasmids were highly similar, suggesting a putative common source or co-selection of resistance genes from A. johnsonii. These results provide initial insights in the dissemination of carbapenem-resistance in A. ursingii in the Netherlands.

Detecting inappropriate total duration of antimicrobial therapy using semi-automated surveillance.

OBJECTIVES: Evaluation of the appropriateness of the duration of antimicrobial treatment is a cornerstone of antibiotic stewardship programs, but it is time-consuming. Furthermore, it is often restricted to antibiotics prescribed during hospital admission. This study aimed to determine whether mandatory prescription-indication registration at the moment of prescribing antibiotics enables reliable automated assessment of the duration of antibiotic therapy, including post-discharge duration, limiting the need for manual chart review to data validation. METHODS: Antibiotic prescription and admission data, from 1-6-2020 to 31-12-2021, were electronically extracted from the Electronic Medical Record of two hospitals using mandatory indication registration. All consecutively prescribed antibiotics of adult patients who received empiric therapy in the first 24 h of admission were merged to calculate the total length of therapy (LOT) per patient, broken down per registered indication. Endpoints were the accuracy of the data, evaluated by comparing the extracted LOT and registered indication with the clinical notes in 400 randomly selected records, and guideline adherence of treatment duration. Data were analysed using a reproducible syntax, allowing semi-automated surveillance. RESULTS: A total of 3,466 antibiotic courses were analysed. LOT was accurately retrieved in 96% of the 400 evaluated antibiotic courses. The registered indication did not match chart review in 17% of antibiotic courses, of which only half affected the assessment of guideline adherence. On average, in 44% of patients treatment was continued post-discharge, accounting for 60% (± 19%) of their total LOT. Guideline adherence ranged from 26 to 75% across indications. CONCLUSIONS: Mandatory prescription-indication registration data can be used to reliably assess total treatment course duration, including post-discharge antibiotic duration, allowing semi-automated surveillance.

Guidance of empirical antimicrobial therapy by surveillance cultures in high-risk neutropenic patients: a retrospective cohort study.

BACKGROUND: In neutropenic patients, bloodstream infections (BSI) significantly contribute to morbidity and mortality. Appropriate empirical antibiotic therapy (EAT) of BSI is essential, at the same time overconsumption of very broad-spectrum antibiotics should be avoided. We investigated: (1) whether surveillance cultures can predict BSI with third-generation cephalosporin -resistant Enterobacterales and Pseudomonas aeruginosa (3GC-R), (2) the effect of inappropriate empirical antimicrobial therapy (IEAT) on clinical outcome and (3) the potential reduction of carbapenem use when using surveillance cultures to guide therapy. METHODS: Retrospective study of adult patients with haematological malignancies with febrile episodes during chemotherapy-induced high-risk neutropenia in whom surveillance cultures were collected weekly. IEAT was defined as the absence of in vitro susceptibility of blood-isolates to the administered EAT. Clinical outcome (ICU admission and death) was evaluated within 30 days. RESULTS: A total of 673 febrile episodes occurred among 372 high-risk neutropenic patients. BSI was present in 20.1% (135/673), of which 25.9% (35/135) were due to Enterobacterales and P. aeruginosa. Of these, 17/35 were 3GC-R and 70.6% (12/17) were preceded by 3GC-R colonization. Negative predictive value of surveillance cultures for 3GC-R BSI was 99.1%. IEAT due to (3GC-R) BSI was not significantly associated with clinical outcome. Using surveillance cultures to guide EAT could potentially reduce carbapenem use by 82.8%, when compared to standard EAT with carbapenem. CONCLUSIONS: This retrospective analysis shows that in patients with high-risk neutropenia, surveillance cultures can potentially reduce the use of carbapenems with infrequent IEAT for 3GC-R BSI and no negative impact on clinical outcome.

Diagnostic stewardship for blood cultures in the emergency department: A multicenter validation and prospective evaluation of a machine learning prediction tool.

BACKGROUND: Overuse of blood cultures (BCs) in emergency departments (EDs) leads to low yields and high numbers of contaminated cultures, accompanied by increased diagnostics, antibiotic usage, prolonged hospitalization, and mortality. We aimed to simplify and validate a recently developed machine learning model to help safely withhold BC testing in low-risk patients. METHODS: We extracted data from the electronic health records (EHR) for 44.123 unique ED visits with BC sampling in the Amsterdam UMC (locations VUMC and AMC; the Netherlands), Zaans Medical Center (ZMC; the Netherlands), and Beth Israel Deaconess Medical Center (BIDMC; United States) in periods between 2011 and 2021. We trained a machine learning model on the VUMC data to predict blood culture outcomes and validated it in the AMC, ZMC, and BIDMC with subsequent real-time prospective evaluation in the VUMC. FINDINGS: The model had an Area Under the Receiver Operating Characteristics curve (AUROC) of 0.81 (95%-CI = 0.78-0.83) in the VUMC test set. The most important predictors were temperature, creatinine, and C-reactive protein. The AUROCs in the validation cohorts were 0.80 (AMC; 0.78-0.82), 0.76 (ZMC; 0.74-0.78), and 0.75 (BIDMC; 0.74-0.76). During real-time prospective evaluation in the EHR of the VUMC, it reached an AUROC of 0.76 (0.71-0.81) among 590 patients with BC draws in the ED. The prospective evaluation showed that the model can be used to safely withhold blood culture analyses in at least 30% of patients in the ED. INTERPRETATION: We developed a machine learning model to predict blood culture outcomes in the ED, which retained its performance during external validation and real-time prospective evaluation. Our model can identify patients at low risk of having a positive blood culture. Using the model in practice can significantly reduce the number of blood culture analyses and thus avoid the hidden costs of false-positive culture results. FUNDING: This research project was funded by the Amsterdam Public Health - Quality of Care program and the Dutch "Doen of Laten" project (project number: 839205002).

Real-world Evidence of the Effects of Novel Treatments for COVID-19 on Mortality: A Nationwide Comparative Cohort Study of Hospitalized Patients in the First, Second, Third, and Fourth Waves in the Netherlands.

Background: Large clinical trials on drugs for hospitalized coronavirus disease 2019 (COVID-19) patients have shown significant effects on mortality. There may be a discrepancy with the observed real-world effect. We describe the clinical characteristics and outcomes of hospitalized COVID-19 patients in the Netherlands during 4 pandemic waves and analyze the association of the newly introduced treatments with mortality, intensive care unit (ICU) admission, and discharge alive. Methods: We conducted a nationwide retrospective analysis of hospitalized COVID-19 patients between February 27, 2020, and December 31, 2021. Patients were categorized into waves and into treatment groups (hydroxychloroquine, remdesivir, neutralizing severe acute respiratory syndrome coronavirus 2 monoclonal antibodies, corticosteroids, and interleukin [IL]-6 antagonists). Four types of Cox regression analyses were used: unadjusted, adjusted, propensity matched, and propensity weighted. Results: Among 5643 patients from 11 hospitals, we observed a changing epidemiology during 4 pandemic waves, with a decrease in median age (67-64 years; P < .001), in in-hospital mortality on the ward (21%-15%; P < .001), and a trend in the ICU (24%-16%; P = .148). In ward patients, hydroxychloroquine was associated with increased mortality (1.54; 95% CI, 1.22-1.96), and remdesivir was associated with a higher rate of discharge alive within 29 days (1.16; 95% CI, 1.03-1.31). Corticosteroids were associated with a decrease in mortality (0.82; 95% CI, 0.69-0.96); the results of IL-6 antagonists were inconclusive. In patients directly admitted to the ICU, hydroxychloroquine, corticosteroids, and IL-6 antagonists were not associated with decreased mortality. Conclusions: Both remdesivir and corticosteroids were associated with better outcomes in ward patients with COVID-19. Continuous evaluation of real-world treatment effects is needed.

Low frequency of community-acquired bacterial co-infection in patients hospitalized for COVID-19 based on clinical, radiological and microbiological criteria: a retrospective cohort study.

BACKGROUND: We defined the frequency of respiratory community-acquired bacterial co-infection in patients with COVID-19, i.e. patients with a positive SARS-CoV-2 PCR or a COVID-19 Reporting and Data System (CO-RADS) score ≥ 4, based on a complete clinical assessment, including prior antibiotic use, clinical characteristics, inflammatory markers, chest computed tomography (CT) results and microbiological test results. METHODS: Our retrospective study was conducted within a cohort of prospectively included patients admitted for COVID-19 in our tertiary medical centres between 1-3-2020 and 1-6-2020. A multidisciplinary study team developed a diagnostic protocol to retrospectively categorize patients as unlikely, possible or probable bacterial co-infection based on clinical, radiological and microbiological parameters in the first 72 h of admission. Within the three categories, we summarized patient characteristics and antibiotic consumption. RESULTS: Among 281 included COVID-19 patients, bacterial co-infection was classified as unlikely in 233 patients (82.9%), possible in 35 patients (12.4%) and probable in 3 patients (1.1%). Ten patients (3.6%) could not be classified due to inconclusive data. Within 72 h of hospital admission, 81% of the total study population and 78% of patients classified as unlikely bacterial co-infection received antibiotics. CONCLUSIONS: COVID-19 patients are unlikely to have a respiratory community-acquired bacterial co-infection. This study underpins recommendations for restrictive use of antibacterial drugs in patients with COVID-19.

A blaVIM-1 positive Aeromonas hydrophila strain in a near-drowning patient: evidence for interspecies plasmid transfer within the patient.

Aim: To show that a strain of Aeromonas hydrophila became resistant to carbapenems by interspecies transfer of a plasmid using long-read sequencing. Material & methods: Whole genome sequencing of the four isolates was done using Illumina Hiseq, while the plasmid was reconstructed using the MinION sequencer. The resistome was identified with ResFinder. Results: Whole genome sequencing and long-read sequencing showed that all isolates carried a blaVIM-1 gene located on a 165 kb incA/C plasmid. ResFinder confirmed that the resistome of the plasmid, comprising 13 resistance genes, was identical within all isolates. Discussion: Long-read sequencing using the MinION successfully reconstructed a plasmid that was identical in all isolates, providing evidence for horizontal gene transfer of this blaVIM-1 gene carrying plasmid within the patient.

Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis.

OBJECT: Routine microbiological and chemical analysis of cerebrospinal fluid (CSF) is often performed to diagnose external drainage-related bacterial meningitis (ED-BM) at an early stage. A cohort study was performed to investigate the value of several commonly used CSF parameters for the prediction and diagnosis of ED-BM. METHODS: In a cohort of 230 consecutive patients in whom external drains had been placed, CSF samples were collected daily, prospectively evaluated for the presence of bacteria using Gram stain and microbiological culture, and analyzed for leukocyte count, protein concentration, glucose concentration, and ratio of CSF glucose to blood glucose. In addition, the CSF concentration of interleukin-6 (IL-6) was determined. The definition of ED-BM was based on positive culture results in combination with clinical symptoms. A matched case-control study was performed to evaluate the cohort longitudinally and to control for biasing factors such as duration of external drainage. External drainage-related bacterial meningitis developed in 22 patients (9.6%). Results from analyses of 1516 CSF samples showed no significant differences between the patients in whom ED-BM developed and a control group without ED-BM during the first 3 days of infection or during the 3 days preceding the infection with regard to leukocyte count, protein concentration, glucose concentration, and CSF/blood glucose ratio. No significant difference between groups was found for the CSF IL-6 concentration during the 3 days preceding the infection. In the matched case-control study, none of the parameters had significant predictive or diagnostic value for ED-BM in analyses using absolute values, ratios, and differences between the current and previous day's values. A comparison of the results from Gram stains and CSF cultures showed that the Gram staining had a very high specificity (99.9%) but a low sensitivity (18% [four of 22 patients] on the 1st day of infection and 60% [nine of 15 patients] on the 2nd day). CONCLUSIONS: Severe disturbances in the CSF of patients with external drains limit the value of routine CSF analysis for prediction or diagnosis of ED-BM. Routine Gram stain of CSF has also limited predictive or diagnostic value due to its low sensitivity in screening for ED-BM.

Bacterial meningitis caused by the use of ventricular or lumbar cerebrospinal fluid catheters.

OBJECT: In the present study the authors compared the incidence and risk factors for external drainage-related bacterial meningitis (ED-BM) by using ventricular and lumbar catheters. METHODS: A cohort of 230 consecutive patients with ED was evaluated. Cerebrospinal fluid samples were obtained daily for microbiological culture, and ED-BM was defined based on culture results in combination with clinical symptoms. The incidence of ED-BM was 7% in lumbar and 15% in ventricular drains. Independent risk factors included site leakage, drain blockage, and most importantly duration of ED. Despite a higher infection rate, ventricular catheters did not have a significant higher risk of infection after correcting for duration of drainage. CONCLUSIONS: Analysis of data in the present study showed that the incidence of ED-associated death is low (0.45%) in patients who do not receive continuous antibiotic prophylaxis during ED.

One-stage revision in two cases of Salmonella prosthetic hip infection.

We describe two cases of prosthetic joint infection (PJI) of the hip due to Salmonella. The first patient presented with an early infection 5 d after being discharged following a total hip replacement and the second patient presented at the emergency ward with a late infection, thirteen years following a total hip replacement. Both cases occurred within one month of each other at our institution and both were successfully treated with a one-stage revision. PJI caused by Salmonella species is very rare: so far only 20 Salmonella PJIs of the hip have been described. Therefore, full consensus on the best treatment approach has not yet been reached. An aggressive two-stage approach is advised because of the virulence of Salmonella, although a limited number of successful one-stage approaches have been described as well. According to the latest guidelines, one-stage revision has comparable success rates and less morbidity compared to two-stage treatment, when selecting the right patients. In our opinion, PJI caused by Salmonella should be treated just as PJI caused by other bacteria, with consideration of the selection criteria as mentioned in several treatment guidelines. As illustrated by these two cases, one-stage revision can be successful in both early and late Salmonella PJI of the hip.