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.

Lymphopenia is associated with broad host response aberrations in community-acquired pneumonia.

OBJECTIVES: Lymphopenia at hospital admission occurs in over one-third of patients with community-acquired pneumonia (CAP), yet its clinical relevance and pathophysiological implications remain underexplored. We evaluated outcomes and immune features of patients with lymphopenic CAP (L-CAP), a previously described immunophenotype characterized by admission lymphocyte count <0.724 × 109 cells/L. METHODS: Observational study in 149 patients admitted to a general ward for CAP. We measured 34 plasma biomarkers reflective of inflammation, endothelial cell responses, coagulation, and immune checkpoints. We characterized lymphocyte phenotypes in 29 patients using spectral flow cytometry. RESULTS: L-CAP occurred in 45 patients (30.2%) and was associated with prolonged time-to-clinical-stability (median 5 versus 3 days), also when we accounted for competing events for reaching clinical stability and adjusted for baseline covariates (subdistribution hazard ratio 0.63; 95% confidence interval 0.45-0.88). L-CAP patients demonstrated a proportional depletion of CD4 T follicular helper cells, CD4 T effector memory cells, naïve CD8 T cells and IgG+ B cells. Plasma biomarker analyses indicated increased activation of the cytokine network and the vascular endothelium in L-CAP. CONCLUSIONS: L-CAP patients have a protracted clinical recovery course and a more broadly dysregulated host response. These findings highlight the prognostic and pathophysiological relevance of admission lymphopenia in patients with CAP.

Virological failure after switch to long-acting cabotegravir and rilpivirine injectable therapy: an in-depth analysis.

BACKGROUND: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for HIV-1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merits further evaluation. METHODS: We performed an in-depth clinical, virological and pharmacokinetic analysis on the reasons behind, and the impact of VF during LA CAB/RPV therapy in five cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cut-off (

The Utility of Risk Factors to Define Complicated Staphylococcus aureus Bacteremia in a Setting With Low Methicillin-Resistant S. aureus Prevalence.

INTRODUCTION: Recommended duration of antibiotic treatment of Staphylococcus aureus bacteremia (SAB) is frequently based on distinguishing uncomplicated and complicated SAB, and several risk factors at the onset of infection have been proposed to define complicated SAB. Predictive values of risk factors for complicated SAB have not been validated, and consequences of their use on antibiotic prescriptions are unknown. METHODS: In a prospective cohort, patients with SAB were categorized as complicated or uncomplicated through adjudication (reference definition). Associations and predictive values of 9 risk factors were determined, compared with the reference definition, as was accuracy of Infectious Diseases Society of America (IDSA) criteria that include 4 risk factors, and the projected consequences of applying IDSA criteria on antibiotic use. RESULTS: Among 490 patients, 296 (60%) had complicated SAB. In multivariable analysis, persistent bacteremia (odds ratio [OR], 6.8; 95% confidence interval [CI], 3.9-12.0), community acquisition of SAB (OR, 2.9; 95% CI, 1.9-4.7) and presence of prosthetic material (OR, 2.3; 95% CI, 1.5-3.6) were associated with complicated SAB. Presence of any of the 4 risk factors in the IDSA definition of complicated SAB had a positive predictive value of 70.9% (95% CI, 65.5-75.9) and a negative predictive value of 57.5% (95% CI, 49.1-64.8). Compared with the reference, IDSA criteria yielded 24 (5%) false-negative and 90 (18%) false-positive classifications of complicated SAB. Median duration of antibiotic treatment of these 90 patients was 16 days (interquartile range, 14-19), all with favorable clinical outcome. CONCLUSIONS: Risk factors have low to moderate predictive value to identify complicated SAB and their use may lead to unnecessary prolonged antibiotic use.

A national antimicrobial guide with local, customizable versions: how is it used? A two-year analysis.

Objectives: Guideline adherence is one of the most important objectives for antibiotic stewardship. The Dutch Working Party on Antibiotic Policy (SWAB) developed an online national guide (SWAB-ID) in 2006. Every Dutch hospital is offered the opportunity to customize the national version to their local context and distribute it through an independent website. We studied user data to see how often the guidelines on therapy, prophylaxis and medication are used. Methods: Data on usage between 19 June 2020 and 30 June 2022 were extracted through Google Analytics for the national site and the 53 hospitals using a customized version of the national guide. User data were divided into three main groups: users of the national guide SWAB-ID, and users of the sites of general hospitals and university hospitals. Results: A total of 1 837 126 searches were analysed, of which 1 393 681 (75.9%) concerned therapy, 111 774 (6.1%) prophylaxis and 331 671 (18%) medication. Of these searches, 456 854 (24.9%) were performed on the national site, 950 887 (51.8%) by general hospitals and 429 385 (23.4%) by university hospitals. The most commonly searched tracts among all user groups were lower respiratory tract (21.8%), kidney and urinary tract (16.6%) and skin and soft tissues (11.8%). The most commonly searched conditions were community-acquired pneumonia (15.3%), cystitis (13.5%) and sepsis (11.3%). The top ranked pages on medication differed for the three categories of users. Conclusions: The SWAB-ID antimicrobial guide is used extensively by both general and university hospitals. The online guide can help in prescribing therapy according to the guideline.

Analytical validation and diagnostic performance of the ASCL1/ZNF582 methylation test for detection of high-grade anal intraepithelial neoplasia and anal cancer.

DNA methylation testing on biopsies can detect high-grade anal intraepithelial neoplasia (HGAIN) in need of treatment and anal cancer. This study aimed to analytically validate and determine the diagnostic performance of a newly developed multiplex quantitative methylation-specific PCR, PreCursor-M AnoGYN (RUO), combining ASCL1, ZNF582 and a reference (ACTB) in one assay. Analytical validation was performed on two qPCR devices using predefined quality criteria. Diagnostic performance was determined on a cross-sectional series of 111 anal biopsies covering all stages of anal disease. Differences in methylation levels were assessed using the Kruskal-Wallis test. Area under the curve was determined using logistic regression analysis. Detection rates were calculated at predefined specificities for the cross-sectional and an additional longitudinal series of 23 HGAIN biopsies preceding anal cancer (i.e., progressive HGAIN). For both devices analytical quality criteria were met. ASCL1 and ZNF582 methylation levels increased with increasing severity of disease (p < 6*10-8). Diagnostic performance for AIN3+ was 0.81. All cancers and virtually all progressive HGAIN were detected at 70% and 80% specificity. In conclusion, the ASCL1/ZNF582 methylation test (PreCursor-M AnoGYN (RUO)) was demonstrated to be highly robust and reproducible. Moreover, it had excellent diagnostic accuracy to detect AIN3+ and can potentially be used to guide HGAIN management.

Perceptions of Rapid Antiretroviral Therapy Initiation Among Participants of The Netherlands Cohort Study on Acute HIV Infection.

Starting antiretroviral therapy (ART) same-day, or as soon as possible after HIV diagnosis is advised in guidelines worldwide. Especially during acute HIV infection (AHI), rapid ART start may be more urgent because of a higher risk of transmission or symptoms of acute retroviral syndrome. During this phase, rapid ART start may have additional benefits for viral reservoir size and host immunity. We explored perceptions of rapid ART start among participants of The Netherlands Cohort Study on Acute HIV infection (NOVA study), who started ART rapidly after diagnosis of AHI. We conducted 20 in-depth qualitative interviews with NOVA study participants between October and December 2018. Data were analyzed thematically, using inductive and iterative coding techniques. Roughly half of the participants stated they felt well-informed about the importance of (rapid) ART. Starting ART rapidly was perceived positively by almost all participants, mostly because of the expected benefits on their health, and to prevent HIV transmission. Rapid ART start was seen as a way to cope with the diagnosis. However, a more negative perception was that rapid ART start confronted participants with their diagnosis, when they were still adjusting to a new situation. Our results show that among people diagnosed during AHI, rapid ART is well-accepted. These results should be encouraging to HIV care providers who encounter people with AHI in their clinical practice and to researchers who carry out cure-related studies, in which early ART is often included. The Clinical Trial Registration number is NCT05728996.

Virological and immunological correlates of HIV posttreatment control after temporal antiretroviral therapy during acute HIV infection.

OBJECTIVE: People with HIV rarely control viral replication after cessation of antiretroviral therapy (ART). We present a person with HIV with extraordinary posttreatment control (PTC) for over 23 years after temporary ART during acute HIV infection (AHI) leading to a new insight in factors contributing to PTC. DESIGN/METHODS: Viral reservoir was determined by HIV qPCR, Intact Proviral DNA Assay, and quantitative viral outgrowth assay. Viral replication kinetics were determined in autologous and donor PBMC. IgG levels directed against HIV envelope and neutralizing antibodies were measured. Immune phenotyping of T cells and HIV-specific T-cell responses were analyzed by flow cytometry. RESULTS: The case presented with AHI and a plasma viral load of 2.7 million copies/ml. ART was initiated 2 weeks after diagnosis and interrupted after 26 months. Replicating virus was isolated shortly after start ART. At 18 years after treatment interruption, HIV-DNA in CD4 + T cells and low levels of HIV-RNA in plasma (<5 copies/ml) were detectable. Stable HIV envelope glycoprotein-directed IgG was present during follow-up, but lacked neutralizing activity. Strong antiviral CD8 + T-cell responses, in particular targeting HIV-gag, were detected during 25 years follow-up. Moreover, we found a P255A mutation in an HLA-B∗44 : 02 restricted gag-epitope, which was associated with decreased replication. CONCLUSION: We describe an exceptional case of PTC, which is likely associated with sustained potent gag-specific CD8 + T-cell responses in combination with a replication attenuating escape mutation in gag. Understanding the initiation and preservation of the HIV-specific T-cell responses could guide the development of strategies to induce HIV control.

Pneumonia pattern recognition on ultra-low-dose CT does not allow for a reliable differentiation between viral and bacterial pneumonia: A multicentre observer study.

PURPOSE: While a reliable differentiation between viral and bacterial pneumonia is not possible with chest X-ray, this study investigates whether ultra-low-dose chest-CT (ULDCT) could be used for this purpose. METHODS: In the OPTIMACT trial 281 patients had a final diagnosis of pneumonia, and 96/281 (34%) had one or more positive microbiology results: 60 patients viral pathogens, 48 patients bacterial pathogens. These 96 ULDCT's were blindly and independently evaluated by two chest radiologists, who reported CT findings, pneumonia pattern, and most likely type of pathogen. Differences between groups were analysed for each radiologist separately, diagnostic accuracy was evaluated by calculating sensitivity. RESULTS: The dominant CT finding significantly differed between the viral and bacterial pathogen groups (p = 0.04; p = 0.04). Consolidation was the most frequent dominant CT finding in both patients with viral and bacterial pathogens, but was observed significantly more often in those with a bacterial pathogen: 32/60 and 22/60 versus 38/48 and 31/48 (p = 0.005; p = 0.004). The lobar pneumonia pattern was more frequently observed in patients with a bacterial pathogen: 23/48 and 18/48, versus 10/60 and 8/60 for viral pathogens (p < 0.001; p = 0.004). For the bronchopneumonia and interstitial pneumonia patterns the proportions of viral and bacterial pathogens were not significantly different. Both radiologists suggested a viral pathogen correctly (sensitivity) in 6/60 (10%), for a bacterial pathogen this was 34/48 (71%). CONCLUSION: Reliable differentiation between viral and bacterial pneumonia could not be made by pattern recognition on ULDCT, although a lobar pneumonia pattern was significantly more often observed in bacterial infection.

Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of High-Grade Anal Intraepithelial Neoplasia in HIV+ Men.

PURPOSE: Anal cancer is increasing in HIV+ men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I to II dose-finding study, we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01) in HIV+ MSM with HPV16-positive HGAIN. PATIENTS AND METHODS: Four dosage schedules (1-5-10; 5-10-20; 10-20-40; and 40-40-40-40 µg) of SLP-HPV-01 were administered intradermally with a 3-week interval in 10 patients per dose level (DL). In each dose group, 5 patients also received 1 µg/kg pegylated IFNα-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3, 6, and 12 months. RESULTS: Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFNα groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histologic response and one had a partial response (in total 9/38, 23.7%). At the highest dosage level, the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders. CONCLUSIONS: The highest DL is safe, immunogenic, and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN.

Population pharmacokinetic/pharmacodynamic target attainment of ceftriaxone 2 g once daily in non-critically ill hospitalized adult patients during the acute phase of infection.

AIMS: Pharmacokinetic/pharmacodynamic target attainment of ceftriaxone is compromised in intensive care unit (ICU) patients and non-ICU hospitalized patients in Beira, Mozambique. Whether this also accounts for non-ICU patients in a high-income setting is unknown. We therefore assessed the probability of target attainment (PTA) of the currently recommended dosing regimen of 2 g every 24 h (q24h) in this patient group. METHODS: We performed a multicentre population pharmacokinetic study in hospitalized non-ICU adult patients empirically treated with intravenous ceftriaxone. During both the acute phase of infection (i.e. first 24 h of treatment) and convalescence, a maximum of 4 random blood samples were obtained per patient for ceftriaxone total and unbound concentration measurements. PTA was calculated using NONMEM and was defined as the percentage of patients of which the unbound ceftriaxone concentration exceeded the minimum inhibitory concentration (MIC) for >50% of the first dosing interval of 24 h. Monte Carlo simulations were performed to determine PTA for different estimated glomerular filtration rates (eGFR; CKD-EPI) and MICs. PTA >90% was considered adequate. RESULTS: Forty-one patients provided 252 ceftriaxone total and 253 unbound concentrations. The median eGFR was 65 mL/min/1.73 m2 (5th to 95th percentile 36-122). With the recommended dose of 2 g q24h, PTA >90% was achieved for bacteria with an MIC ≤2 mg/L. Simulations showed that PTA was insufficient for an MIC of 4 mg/L in case the eGFR was 122 mL/min/1.73 m2 (PTA 56.9%) and for an MIC of 8 mg/L regardless of eGFR. CONCLUSION: The PTA of 2 g q24h ceftriaxone dosing is adequate for common pathogens during the acute phase of infection in non-ICU patients.

Limited Clinical Impact of Ultralow-Dose Computed Tomography in Suspected Community-Acquired Pneumonia.

Patients clinically suspected of community-acquired pneumonia (CAP) were randomized between ultralow-dose chest computed tomography ([ULDCT] 261 patients) and chest radiograph ([CXR] 231 patients). We did not find evidence that performing ULDCT instead of CXR affects antibiotic treatment policy or patient outcomes. However, in a subgroup of afebrile patients, there were more patients diagnosed with CAP in the ULDCT group (ULDCT, 106 of 608 patients; CXR, 71 of 654 patients; P = .001).

The yield of chest X-ray or ultra-low-dose chest-CT in emergency department patients suspected of pulmonary infection without respiratory symptoms or signs.

OBJECTIVE: The yield of pulmonary imaging in patients with suspected infection but no respiratory symptoms or signs is probably limited, ultra-low-dose CT (ULDCT) is known to have a higher sensitivity than Chest X-ray (CXR). Our objective was to describe the yield of ULDCT and CXR in patients clinically suspected of infection, but without respiratory symptoms or signs, and to compare the diagnostic accuracy of ULDCT and CXR. METHODS: In the OPTIMACT trial, patients suspected of non-traumatic pulmonary disease at the emergency department (ED) were randomly allocated to undergo CXR (1210 patients) or ULDCT (1208 patients). We identified 227 patients in the study group with fever, hypothermia, and/or elevated C-reactive protein (CRP) but no respiratory symptoms or signs, and estimated ULDCT and CXR sensitivity and specificity in detecting pneumonia. The final day-28 diagnosis served as the clinical reference standard. RESULTS: In the ULDCT group, 14/116 (12%) received a final diagnosis of pneumonia, versus 8/111 (7%) in the CXR group. ULDCT sensitivity was significantly higher than that of CXR: 13/14 (93%) versus 4/8 (50%), a difference of 43% (95% CI: 6 to 80%). ULDCT specificity was 91/102 (89%) versus 97/103 (94%) for CXR, a difference of - 5% (95% CI: - 12 to 3%). PPV was 54% (13/24) for ULDCT versus 40% (4/10) for CXR, NPV 99% (91/92) versus 96% (97/101). CONCLUSION: Pneumonia can be present in ED patients without respiratory symptoms or signs who have a fever, hypothermia, and/or elevated CRP. ULDCT's sensitivity is a significant advantage over CXR when pneumonia has to be excluded. CLINICAL RELEVANCE STATEMENT: Pulmonary imaging in patients with suspected infection but no respiratory symptoms or signs can result in the detection of clinically significant pneumonia. The increased sensitivity of ultra-low-dose chest CT compared to CXR is of added value in vulnerable and immunocompromised patients. KEY POINTS: • Clinical significant pneumonia does occur in patients who have a fever, low core body temperature, or elevated CRP without respiratory symptoms or signs. • Pulmonary imaging should be considered in patients with unexplained symptoms or signs of infections. • To exclude pneumonia in this patient group, ULDCT's improved sensitivity is a significant advantage over CXR.

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.

Effect of the introduction of screening for cancer precursor lesions on anal cancer incidence over time in people living with HIV: a nationwide cohort study.

BACKGROUND: Incidence of anal cancer is high in people living with HIV, particularly in men who have sex with men (MSM). Screening for and treatment of precursor lesions might prevent progression to anal cancer in people living with HIV. We examined trends in incidence of and mortality after anal cancer diagnosis in people living with HIV, including the effect of screening from 2007 onwards, in the Netherlands. METHODS: In this observational cohort study, we analysed data from the ongoing open nationwide Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. We included all consenting adults living with HIV and identified all primary anal squamous cell carcinoma. We reported temporal trends in incident anal cancer cases from Jan 1, 1996, to Dec 31, 2020, and all-cause and anal cancer-related mortality in individuals diagnosed with anal cancer. Multivariable Poisson regression was used to explore risk factors for incident anal cancer and multivariable Cox regression was used to explore risk factors for anal cancer-related mortality. FINDINGS: Among 28 175 individuals in HIV care (59·7% MSM), 227 primary anal cancer cases were diagnosed. Despite the increasing average age of the cohort, crude incidence rates of anal cancer in MSM declined slowly over time, from 107·0 (95% CI 75·7-147·0) per 100 000 person-years in 1996-2005 to 93·7 (75·3-115·0) per 100 000 person-years in 2013-20 (p=0·49). Crude incidence rates in men who do not have sex with men (non-MSM) and women were generally lower than in MSM, but increased slightly over time, from 51·08 (95% CI 20·54-105·25) to 67·82 (40·83-105·91; p=0·52) per 100 000 person-years in non-MSM and from 8·09 (0·20-45·06) to 24·95 (10·03-51·40; p=0·29) per 100 000 person-years in women. The age-adjusted incidence rate in MSM in 2013-20 was significantly lower (rate ratio 0·62 [95% CI 0·41-0·92]) compared with in 1996-2005. Changes in risk factors (less smoking, cumulative exposure to CD4 count of <200 cells per µL, and plasma HIV-1 RNA of >1000 copies per mL) mostly explained the decrease in anal cancer risk over time in MSM. 3866 (23·0%) of 16 819 MSM participated in anal cancer screening at least once. TNM tumour staging was more favourable (Cochrane-Armitage test for trend p=0·033) in individuals diagnosed during screening. Crude anal cancer-associated 5-year mortality in people living with HIV decreased from 30·4% (1996-2005) to 18·3% (2013-20; odds ratio 0·48; p=0·070). Anal cancer-related mortality was 3·7% (95% CI 0·5-23·5) in all men who had been screened and 24·0% (95% CI 18·1-31·3) in men who had not been screened (p=0·023). In men, screening participation (hazard ratio [HR] 0·31, p=0·051) and cumulative exposure to CD4 counts of less than 200 cells per µL (HR 1·11 per year; p=0·0022) were independently associated with anal cancer-related mortality. INTERPRETATION: As anal cancer incidence is slowly declining in MSM but not in non-MSM and women, health-care professionals should not focus only on MSM for anal cancer prevention. Men diagnosed with anal cancer during screening had improved survival, probably because they were diagnosed at an earlier disease stage. Next to preventing anal cancer, these data are an important justification to screen those most at risk of anal cancer. FUNDING: None.

Value of diagnosing immunological phenomena in patients with suspected endocarditis.

PURPOSE: Immunological phenomena are a minor criteria in the modified Duke Criteria for endocarditis. Given the changes in epidemiology and diagnostics, the added value of determining these phenomena in today's patients with suspected endocarditis is unknown. METHODS: In a retrospective cohort study of all patients with suspected endocarditis admitted to our hospital and discussed in our endocarditis team, we determined the proportion of patients classified as definite endocarditis because of either positive IgM rheumatoid factor (IgM RF), haematuria, or Roth's spots on ophthalmology consultation. We also determined diagnostic accuracy of each of these immunological phenomena separately and combined. RESULTS: Of 285 patients included, 138 (48%) had definite endocarditis and at least one immunological test was performed in 222 patients (78%). Elevated IgM RF was found in 22 of 126 patients tested (17%), haematuria in 78 of 196 tested (40%) and Roth's spots in six of 120 tested (5%). Eighteen of 138 patients with definite IE (13%) were classified as such because of a positive IgM RF, haematuria or Roth's spots. Haematuria had the highest sensitivity: 50.5% (95% CI 40.4-60.6) and Roth's spots the highest specificity: 98.3% (95% CI 90.8-99.9). The diagnostic accuracy results were robust in a sensitivity analysis aimed at avoiding incorporation bias. CONCLUSION: Among patients with a clinical suspicion of endocarditis, recommended systematic testing for immunological phenomena helped classify more patients as definite IE and is useful to confirm the diagnosis of endocarditis.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.

HIV transmission among acutely infected participants of a Dutch cohort study 2015-2021 is not associated with large, clustered outbreaks.

OBJECTIVE: Timely identification of acute or early HIV infection (AEHI) is important to help prevent onward transmission, and understanding the number of secondary infections resulting from individuals with AEHI is key to planning HIV prevention services and case finding. DESIGN: We performed a phylogenetic investigation of a dense sample of individuals with AEHI who took part in the Netherlands Cohort Study on Acute HIV infection (NOVA) in the Netherlands during 2015-2021. METHODS: Transmission clusters were identified using phylogenetic analyses based on HIV pol sequences. The Tamura-Nei model was used to estimate genetic distance. A number of 1000 bootstraps was used to check the reliability of clustering using maximum likelihood. A cluster was defined as having a bootstrap value of at least 95% and a genetic distance of at most 1.5%. Sensitivity analyses using different values for the bootstrap and genetic distance were performed to study the reproducibility of the clustering. RESULTS: Of the 156 participants included in NOVA between July 2015 and April 2021, 134 individuals for whom baseline characteristics and genotypic resistance data at baseline were available could be included. We identified 10 clusters, but the majority of persons (111/134) were not part of a cluster, suggesting mainly independent transmission events. CONCLUSION: Mainly independent transmission events among a study population consisting predominantly of MSM in a low-incidence high-resource setting is likely the result of active AEHI case finding and direct start of treatment, and the roll-out over recent years of preventive measures such as preexposure prophylaxis.

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.

The 2021 Dutch Working Party on Antibiotic Policy (SWAB) guidelines for empirical antibacterial therapy of sepsis in adults.

BACKGROUND: The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. METHODS: Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). RESULTS: Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. CONCLUSIONS: Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.