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Antimicrobial stewardship is advocated to improve the quality of antimicrobial use. We did a systematic review and meta-analysis to assess whether antimicrobial stewardship objectives had any effects in hospitals and long-term care facilities on four predefined patients' outcomes: clinical outcomes, adverse events, costs, and bacterial resistance rates. We identified 14 stewardship objectives and did a separate systematic search for articles relating to each one in Embase, Ovid MEDLINE, and PubMed. Studies were included if they reported data on any of the four predefined outcomes in patients in whom the specific antimicrobial stewardship objective was assessed and compared the findings in patients in whom the objective was or was not met. We used a random-effects model to calculate relative risk reductions with relative risks and 95% CIs. We identified 145 unique studies with data on nine stewardship objectives. Overall, the quality of evidence was generally low and heterogeneity between studies was mostly moderate to high. For the objectives empirical therapy according to guidelines, de-escalation of therapy, switch from intravenous to oral treatment, therapeutic drug monitoring, use of a list of restricted antibiotics, and bedside consultation the overall evidence showed significant benefits for one or more of the four outcomes. Guideline-adherent empirical therapy was associated with a relative risk reduction for mortality of 35% (relative risk 0·65, 95% CI 0·54–0·80, p<0·0001) and for de-escalation of 56% (0·44, 0·30–0·66, p<0·0001). Evidence of effects was less clear for adjusting therapy according to renal function, discontinuing therapy based on lack of clinical or microbiological evidence of infection, and having a local antibiotic guide. We found no reports for the remaining five stewardship objectives or for long-term care facilities. Our findings of beneficial effects on outcomes with nine antimicrobial stewardship objectives suggest they can guide stewardship teams in their efforts to improve the quality of antibiotic use in hospitals. Dutch Working Party on Antibiotic Policy and Netherlands National Institute for Public Health and the Environment.

In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82–1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

To curb increasing resistance rates, responsible antimicrobial use (AMU) is needed, both in human and veterinary medicine. In human healthcare, antimicrobial stewardship programmes (ASPs) have been implemented worldwide to improve appropriate AMU. No ASPs have been developed for and implemented in companion animal clinics yet. The objective of the present study was to implement and evaluate the effectiveness of an ASP in 44 Dutch companion animal clinics. The objectives of the ASP were to increase awareness on AMU, to decrease total AMU whenever possible and to shift AMU towards 1st choice antimicrobials, according to Dutch guidelines on veterinary AMU. The study was designed as a prospective, stepped-wedge, intervention study, which was performed from March 2016 until March 2018. The multifaceted intervention was developed using previous qualitative and quantitative research on current prescribing behaviour in Dutch companion animal clinics. The number of Defined Daily Doses for Animal (DDDAs) per clinic (total, 1st, 2nd and 3rd choice AMU) was used to quantify systemic AMU. Monthly AMU data were described using a mixed effect time series model with auto-regression. The effect of the ASP was modelled using a step function and a change in the (linear) time trend. A statistically significant decrease of 15% (7%-22%) in total AMU, 15% (5%-24%) in 1st choice AMU and 26% (17%-34%) in 2nd choice AMU was attributed to participation in the ASP, on top of the already ongoing time trends. Use of 3rd choice AMs did not significantly decrease by participation in the ASP. The change in total AMU became more prominent over time, with a 16% (4%-26%) decrease in (linear) time trend per year. This study shows that, although AMU in Dutch companion animal clinics was already decreasing and changing, AMU could be further optimised by participation in an antimicrobial stewardship programme.

Background Migrants often face barriers to accessing healthcare. We examined disparities in access to and use of HIV-related health services between migrant and non-migrant people recently diagnosed with HIV living in the Netherlands, taken into account sexual orientation. Also, we examined differences in experiences in living with HIV between these groups. Methods We used a questionnaire and clinical data collected between July 2013 and June 2015 among migrant and non-migrant participants of the European cross-sectional aMASE (Advancing Migrant Access to health Services in Europe) study in the Netherlands. Using univariable logistic regression analyses, we compared outcomes on between migrants and non-migrants, stratified by sexual orientation (with non-migrant men having sex with men [MSM] as the reference group). Results We included 77 migrant MSM, 115 non-migrant MSM, 21 migrant heterosexual men, 14 non-migrant heterosexual men and 20 migrant women. In univariable analyses, all heterosexual groups were less likely to ever have had an HIV-negative test before their diagnosis and were more likely to be diagnosed late than non-migrant MSM. All migrant groups were more likely to have experienced difficulties accessing general healthcare in the Netherlands and were less likely to have heard of post-exposure prophylaxis than non-migrant MSM. Migrants frequently reported uncertainty about their rights to healthcare and language barriers. Most (93%) participants visited a healthcare facility in the 2 years before HIV diagnosis but only in 41% an HIV test was discussed during that visit (no statistical difference between groups). Migrant heterosexuals were more likely to have missed appointments at their HIV clinic due to the travel costs than non-migrant MSM. Migrant MSM and women were more likely to have experienced HIV discrimination in the Netherlands than non-migrant MSM. Conclusion Disparities in access to and use of HIV-related health services and experiences exist by migrant status but also by sexual orientation. Our data suggests heterosexual men and women may particularly benefit from improved access to HIV testing (e.g., through provider-initiated testing), while migrant MSM may benefit from improved access to HIV prevention interventions (e.g., pre-exposure prophylaxis).

To assess differences in socio-demographics, HIV testing and healthcare seeking behavior between individuals diagnosed late and those diagnosed early after HIV-acquisition. Cross-sectional study among recently HIV-diagnosed migrant and non-migrant individuals living in the Netherlands. Participants self-completed a questionnaire on socio-demographics, HIV-testing and healthcare seeking behavior preceding HIV diagnosis between 2013-2015. Using multivariable logistic regression, socio-demographic determinants of late diagnosis were explored. Variables on HIV-infection, testing and access to care preceding HIV diagnosis were compared between those diagnosed early and those diagnosed late using descriptive statistics. We included 143 individuals with early and 101 with late diagnosis, of whom respectively 59/143 (41%) and 54/101 (53%) were migrants. Late diagnosis was significantly associated with older age and being heterosexual. Before HIV diagnosis, 89% of those with early and 62% of those with late diagnosis had ever been tested for HIV-infection (p<0.001), and respectively 99% and 97% reported healthcare usage in the Netherlands in the two years preceding HIV diagnosis (p = 0.79). Individuals diagnosed late most frequently visited a general practitioner (72%) or dentist (62%), and 20% had been hospitalized preceding diagnosis. In these settings, only in respectively 20%, 2%, and 6% HIV-testing was discussed. A large proportion of people diagnosed late had previously tested for HIV and had high levels of healthcare usage. For earlier-case finding of HIV it therefore seems feasible to successfully roll out interventions within the existing healthcare system. Simultaneously, efforts should be made to encourage future repeated or routine HIV testing among individuals whenever they undergo an HIV test.

Initiation of antiretroviral therapy (ART) during primary HIV-1 infection (PHI) has been proposed to limit the formation of HIV-1 reservoirs. However, it remains unknown whether temporary ART initiated during PHI has a long-term effect on viral persistence. Here, we longitudinally quantify HIV-1 persistence markers and immunological parameters in the participants ( n  = 64) of a randomized controlled trial comparing 24 or 60 weeks of temporary ART vs. no treatment during PHI, who subsequently (re)initiated ART during chronic HIV-1 infection (CHI) after a median period of 116 weeks without treatment (ISRCTN59497461). Levels of several HIV-1 persistence markers (cell-associated unspliced RNA, total DNA, and intact DNA) do not significantly differ and strongly positively correlate between early and CHI ART periods in the same participants. Early ART is associated with lower HIV-1 proviral sequence diversity and superior restoration of the CD4/CD8 ratio, as well as lower levels of monocyte activation markers, compared to CHI ART, in the same participants. At CHI ART, intact HIV-1 DNA negatively correlates with HIV-specific T-cell responses. Finally, levels of HIV-1 persistence markers during CHI ART are lower in participants who had been pre-treated during PHI, indicating a long-term suppressive effect of temporary early ART on the persistence of HIV-1 reservoir. Initiating antiretroviral therapy (ART) during primary HIV-1 infection (PHI) may influence long-term viral persistence, yet its enduring effects remain unclear. Here, Pasternak and colleagues demonstrate that temporary ART started early in infection reduces HIV-1 proviral diversity and monocyte activation, and sustains lower levels of viral persistence markers, suggesting a lasting suppressive impact on the HIV-1 reservoir.

Anal cancer is an increasing issue in HIV-positive men who have sex with men (MSM). Screening for its precursor, anal intraepithelial neoplasia (AIN), is subject of discussion. Current treatment options are suboptimum and have not been compared in a prospective trial. We compared efficacy and side-effects of imiquimod, topical fluorouracil, and electrocautery for the treatment of AIN. In this open-label randomised trial, we included HIV-positive MSM older than 18 years visiting the HIV outpatient clinic of the Academic Medical Center, Amsterdam, Netherlands. Patients with histologically confirmed AIN were randomly assigned to receive either 16 weeks of imiquimod (three times a week), 16 weeks of topical fluorouracil (twice a week), or monthly electrocautery for 4 months. Randomisation was done with random block sizes of three and six, stratified for AIN grade (AIN grades 1, 2, or 3) and AIN location (peri-anal or intra-anal). Participants were assessed by high-resolution anoscopy 4 weeks after treatment. Responding patients returned for follow-up 24 weeks, 48 weeks, and 72 weeks after treatment. The primary endpoint was histological resolution of AIN measured 4 weeks after treatment and AIN recurrence at week 24, week 48, and week 72 after treatment. The primary analysis was done in a modified intention-to-treat population, including all patients who had received their assigned treatment at least once. The trial is registered at the Netherlands Trial Register, number NTR1236. Between Aug 12, 2008, and Dec 1, 2010, we screened 388 HIV-positive MSM for AIN by high resolution anoscopy. Of the 246 (63%) patients who had AIN, 156 (63%) were randomly assigned to either receive imiquimod (54 patients), topical fluorouracil (48 patients), or electrocautery (46 patients) following withdrawing of consent by eight patients. Modified intention-to-treat analysis showed a complete response in 13 (24%, 95% CI 15–37) patients in the imiquimod group, eight (17%, 8–30) of patients in the fluorouracil group, and 18 (39%, 26–54) of patients in the electrocautery group (p=0·027). At week 24, 11 (22%) of 50 responders had recurrence; at week 48, 22 (46%) of 48 had recurred; and at week 72, 30 (67%) of 45 had recurred. Recurrence was observed at 72 weeks in 10 (71%) of 14 patients treated with imiquimod, seven (58%) of 12 patients treated with fluorouracil, and 13 (68%) of 19 patients treated with electrocautery. Grade 3–4 side-effects were noted in 23 (43%) of 53 patients in the imiquimod group, 13 (27%) of 48 patients in the fluorouracil group, and eight (18%) patients in the electrocautery group (p=0·019). The most common side-effects were pain, bleeding, and itching. Seven serious adverse events occurred, all not related to the study. Electrocautery is better than imiquimod and fluorouracil in the treatment of AIN, but recurrence rates are substantial. Anna Maurits de Cock foundation provided funding for the video colposcope.

PurposeInitiation of combination antiretroviral therapy (cART) during acute or early HIV-infection (AEHI) limits the size of the viral reservoir and preserves immune function. This renders individuals who started cART during AEHI promising participants in HIV-cure trials. Therefore, we established a multicentre prospective cohort study in the Netherlands that enrols people with AEHI. In anticipation of future cure trials, we will longitudinally investigate the properties of the viral reservoir size and HIV-specific immune responses among cohort participants.ParticipantsParticipants immediately initiate intensified cART: dolutegravir, emtricitabine/tenofovir and darunavir/ritonavir (DRV/r). After 4 weeks, once baseline resistance data are available, DRV/r is discontinued. Three study groups are assembled based on the preparedness of individuals to participate in the extensiveness of sampling. Participants accepting immediate treatment and follow-up but declining additional sampling are included in study group 1 (‘standard’) and routine diagnostic procedures are performed. Participants willing to undergo blood, leukapheresis and semen sampling are included in study group 2 (‘less invasive’). In study group 3 (‘extended’), additional tissue (gut-associated lymphoid tissue, peripheral lymph node) and cerebrospinal fluid sampling are performed.Findings to dateBetween 2015 and 2020, 140 individuals with AEHI have been enrolled at nine study sites. At enrolment, median age was 36 (IQR 28–47) years, and 134 (95.7%) participants were men. Distribution of Fiebig stages was as follows: Fiebig I, 3 (2.1%); II, 20 (14.3%); III, 7 (5.0%); IV, 49 (35.0%); V, 39 (27.9%); VI, 22 (15.7%). Median plasma HIV RNA was 5.9 (IQR 4.7–6.7) log10 copies/mL and CD4 count 510 (IQR 370–700) cells/mm3. Median time from cART initiation to viral suppression was 8.0 (IQR 4.0–16.0) weeks.Future plansThe Netherlands Cohort Study on Acute HIV infection remains open for participant enrolment and for additional sites to join the network. This cohort provides a unique nationwide platform for conducting future in-depth virological, immunological, host genetic and interventional studies investigating HIV-cure strategies.

A protective vaccine will be the most powerful instrument to reduce HIV-1 infections worldwide and help bring about a lasting end to the AIDS epidemic. The single centre, randomised, open-label, uncontrolled, phase 1 ACTHIVE-001 clinical trial (NCT03961438) aims to assess the safety and immunogenicity of the ConM SOSIP.v7 native-like trimer protein vaccine, based on an HIV-1 group M consensus sequence, in HIV-negative adults. Twenty-four individuals were enrolled to receive three dosages of ConM SOSIP.v7 protein vaccine in a liposome formulation containing a high dose of the TLR4-agonist MPLA. The primary outcome is vaccine reactogenicity, whereas the main secondary outcome is binding and neutralising antibody responses. Overall, the vaccine is safe and well-tolerated. Furthermore, the vaccine elicits robust strain-specific binding and neutralising antibody responses in nearly all vaccinees. Post-hoc exploratory analyses demonstrate that female-born participants have 22- and 6-fold higher neutralisation titres after the second and third vaccination, respectively. The vaccine adjuvant induces higher levels of IL-6 secretion from in vitro cultured monocytes from female compared to male participants, providing a possible mechanistic explanation for the sex-based differences. Our study highlights the need to take sex-based differences into consideration when assessing HIV-1 vaccine candidates and adjuvants. There is still a need for effective HIV vaccines. In this phase I clinical trial, the authors show that an HIV-1 vaccine candidate, ConM SOSIP.v7, is well-tolerated in HIV-negative adults and that it elicits a strain-specific neutralising antibody response that differed between female and male participants.

Extensive antibiotic use makes the intensive care unit (ICU) an important focus for antibiotic stewardship programs. The aim of this study was to develop a set of actionable quality indicators for appropriate antibiotic use at ICUs and an implementation toolbox, which can be used to assess and improve the appropriateness of antibiotic use in the treatment of adult patients at an ICU. A four round modified-RAND Delphi procedure was used. Potential indicators were identified by a multidisciplinary panel of 15 Dutch experts, from international literature and guidelines. Using an online survey, the identified indicators were rated on three criteria: relevance, actionability and feasibility. Experts discussed and rated the indicators for the second time during a face-to-face consensus meeting. During a final consensus meeting the toolbox was developed, containing potential barriers and improvement strategies which were identified using a validated checklist by Flottorp et al., and if available also containing supporting material. The first round resulted in 24 potential indicators. After the final meeting a set of three process indicators, one structure indicator and one quantity metric remained: 1) perform at least two sets of blood cultures before start of empirical systemic therapy; 2) perform therapeutic drug monitoring in patients treated with vancomycin or aminoglycosides; 3) perform surveillance cultures if selective digestive or oropharyngeal decontamination is applied at the ICU; 4) biannual face-to-face meetings between ICU and microbiology staff in which local resistance rates are discussed; and 5) quantitative antibiotic use at the ICU expressed in days of therapy (DOT). The toolbox contains 24 unique barriers and 37 improvement strategies. Our study identified a set of four actionable quality indicators and one quantity metric, together with an implementation toolbox, to improve appropriate antibiotic use at ICUs.