BACKGROUND:In adult patients with sepsis or septic shock admitted to the emergency department, a single intravenous 15 mg/kg amikacin dose provides inadequate pharmacokinetic-pharmacodynamic target attainment at the locally reported minimum inhibitory concentration (MIC) of 2 mg/L and the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint for Enterobacterales of 8 mg/L. OBJECTIVES:To provide an amikacin dosing strategy with a clinically acceptable probability of target attainment (PTA) for all patients. METHODS:Stochastic simulations were performed using a two-compartment population pharmacokinetics model of amikacin (NONMEM 7.5). PTA was evaluated for various dosing strategies across a range of virtual patients' body weight, body mass index, serum total protein, serum sodium, fluid balance, and estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI), at the locally reported MIC of 2 mg/L and the clinical breakpoint of 8 mg/L. The pharmacokinetic-pharmacodynamic targets were a 24-hour area under the concentration-time curve (AUC24h)/MIC of ≥80 and a 24-hour postdose concentration (C24h) of < 3 mg/L for efficacy and safety, respectively. RESULTS:The PTA for the clinical breakpoint of 8 mg/L was <90% with standard 15 mg/kg dosing, across all patient characteristics. A flat 1500-mg dose achieved ≥90% PTA for the entire population at a MIC of 2 mg/L. However, at the clinical breakpoint of 8 mg/L, a flat 3500-mg dose provided ≥90% PTA only when the eGFRCKD-EPI was <96 mL/min/1.73 m2. The C24h was similar for 1500 mg and 15 mg/kg dosing, whereas 3500 mg resulted in a higher C24h. CONCLUSIONS:A flat dose is recommended over weight-based dosing. However, selecting a 1500-mg or 3500-mg dose may compromise either efficacy (MIC 2 mg/L) or safety (clinical breakpoint 8 mg/L), posing a dilemma. Clinical validation is warranted.

We aimed to develop and implement dosing recommendations for antimicrobials in obese and underweight patients within an academic hospital, and assess their impact on antibiotic prescribing. A multi-step approach project was performed. First, obese and underweight patient prevalence and antimicrobial prescription frequency was determined in a point prevalence study. Second and third, a literature review and e-survey provided dosing evidence. Fourth, a consensus meeting was organized to formulate dosing recommendations. Fifth, these were implemented in our clinical validation service as six clinical rules continuously screening patients’ records for potentially inappropriate prescriptions (PIPs). Uptake was evaluated by documenting the number of advices and acceptance rate. Last, an interrupted time series analysis (ITS) compared pre- and post-implementation periods to measure the impact of the intervention on residual PIPs/day. A residual PIP was defined as a PIP which persisted up to 48 h. First, 41

ObjectiveWe evaluated the histamine 1 receptor antagonist ebastine as a potential treatment for patients with non-constipated irritable bowel syndrome (IBS) in a randomised, placebo-controlled phase 2 study.MethodsNon-constipated patients with IBS fulfilling the Rome III criteria were randomly assigned to 20 mg ebastine or placebo for 12 weeks. Subjects scored global relief of symptoms (GRS) and abdominal pain intensity (API). A subject was considered a weekly responder for GRS if total or obvious relief was reported and a responder for API if the weekly average pain score was reduced by at least 30% vs baseline. The primary endpoints were the proportion of subjects who were weekly responders for at least 6 out of the 12 treatment weeks for both GRS and API ('GRS+API', composite endpoint) and for GRS and API separately.Results202 participants (32 +/- 11 years, 68% female) were randomly allocated to receive ebastine (n=101) or placebo (n=101). Treatment with ebastine resulted in significantly more responders (12%, 12/92) for GRS+API compared with placebo (4%, 4/87, p=0.047) while the proportion of responders for GRS and API separately was higher for ebastine compared with placebo, although not statistically significant (placebo vs ebastine, GRS: 7% (6/87) vs 15% (14/91), p=0.072; API: 25% (20/85) vs 37% (34/92), p=0.081).ConclusionsOur study shows that ebastine is superior to placebo and should be further evaluated as novel treatment for patients with non-constipated IBS.Trial registration numberThe study protocol was approved by the local ethics committee of each study site (EudraCT number: 2013-001199-39; ClinicalTrials.gov identifier: NCT01908465).

According to the latest reports from WHO, the incidence of antibiotic-resistant bacterial infections is increasing worldwide, resulting in increased morbidity and mortality and a rising pressure on health-care systems. However, the development of new antibiotics is an expensive and time-consuming process, urging scientists to seek alternative antimicrobial strategies. Over the past few decades, the concept of therapeutic administration of bacteriophages (also known as phages) has gained popularity worldwide. Although conceptually promising, the widespread implementation of phage therapy in routine clinical practice is restricted by the scarcity of safety and efficacy data obtained according to the strict standards of the applicable clinical trial regulations. In this systematic review, we list clinical data published between Jan 1, 2000 and Aug 14, 2021 on the safety and efficacy of phage therapy for difficult-to-treat bacterial infections, and provide an overview of trials and case studies on the use of phage therapy in several medical disciplines.

Three-dimensional distribution gradients of intracerebrally injected tritiated dopamine were calculated on the basis of concentrations in multiple punch-samples from sequential sections of Macaca fascicularis brain tissue. The monkey was pretreated systemically with a monoamine oxidase inhibitor to retard elimination. Gradients were best fit by cubic exponential equations relating concentration to distance from the center of the site. The concentration at the center, total amount of label, and total extent of the site injected just before perfusion were consistent with initial distribution in the extracellular space, if the volume fraction of the latter is estimated at 20%. The extent of distribution was distinctly greater in the mediolateral and dorsoventral dimensions than in the anteroposterior dimension. The total amount of label near the site decreased rapidly in the first few minutes after injection, then much more slowly, reaching about 30% of the injected amount after 2 h. Its distribution within the site changed steadily, the outer boundary gradually expanding and the peak at the center gradually decreasing. This pattern was consistent with an initial rapid dispersion by injection pressure and an initial loss of tritiated dopamine due to disruption of the blood-brain barrier at the center of the site, followed by a steady expansion of the site driven by diffusion and bulk flow.

Background Adverse drug events following inappropriate prescribing in the hospital cause a substantial and avoidable medical and economic burden to hospitals, payers and patients alike. A clinical rule-based, pharmacist-led medication-review service, the 'Check of Medication Appropriateness' (CMA) was implemented in the University Hospitals Leuven. The CMA is shown to be effective in reducing potentially inappropriate prescriptions. Aim This study investigated whether this centralised clinical pharmacy service is cost-effective. Method We performed a cost-effectiveness analysis of three clinical rules of the CMA, targeting adverse drug events at three levels of severity: A) persistent opioid-induced constipation, B) ketorolac-induced gastrointestinal bleeding and C) drug-induced Torsade de Pointes. A decision tree was developed for each clinical rule. Both intervention costs as well as total costs associated with the occurrence of an adverse drug event were considered. The outcomes were reported in the form of an incremental cost-effectiveness ratio, expressed as an incremental cost per adverse drug event avoided. Results Applying clinical rules to avoid persistent opioid-induced constipation and ketorolac-induced gastrointestinal bleeding were cost-saving. Implementation of a medication check to avoid drug-induced Torsade de Pointes costed €8,846 per Torsade de Pointes avoided. Conclusion Our study provides strong indications that the CMA is worth its investment for clinical rules targeting (very) common adverse drug events, that can be avoided with limited expenses. Further research is required to assess the full CMA. The proposed model may be useful to perform cost-effectiveness analyses of other centralised clinical pharmacy services targeting inappropriate prescribing, at the level of individual adverse drug events.

After switching from 13-valent to 10-valent pneumococcal conjugate vaccine (PCV10) (2015–2016) for children in Belgium, we observed rapid reemergence of serotype 19A invasive pneumococcal disease (IPD). Whole-genome sequencing of 166 serotype 19A IPD isolates from children (n = 54) and older adults (n = 56) and carriage isolates from healthy children (n = 56) collected after the vaccine switch (2017–2018) showed 24 sequence types (STs). ST416 (global pneumococcal sequence cluster [GPSC] 4) and ST994 (GPSC146) accounted for 75.9% of IPD strains from children and 65.7% of IPD (children and older adults) and carriage isolates in the PCV10 period (2017–2018). These STs differed from predominant 19A IPD STs after introduction of PCV7 (2011) in Belgium (ST193 [GPSC11] and ST276 [GPSC10]), which indicates that prediction of emerging strains cannot be based solely on historical emerging strains. Despite their susceptible antimicrobial drug profiles, these clones spread in carriage and IPD during PCV10 use.

Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR(CKD-EPI)) and free cefepime trough concentration were 101 (85-112) mL/min/1.73m(2) and 8.6 (4.9-16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P < 0.001). This study provides real-world clinical data showing that high cefepime dosage is efficacious and safe in FN patients. Routine TDM does not appear to be needed in FN patients with preserved renal function. However, TDM might be reserved for FN patients at high risk of cefepime-induced neurotoxicity or when intended to cover pathogens with a minimum inhibitory concentration >1 mg/L. (C) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

ObjectivesEarly switch from intravenous to oral therapy of bioequivalent drugs has major advantages but remains challenging. At our hospital, a basic clinical rule was designed to automatically alert the physician to review potential intravenous to oral switch (IVOS). A rather low acceptance rate was observed. In this study, we aimed to develop, validate and investigate the effect of more advanced clinical rules for IVOS, as part of a centralised pharmacist-led medication review service.Design and settingA quasi-experimental study was performed in a large teaching hospital in Belgium using an interrupted time series design.InterventionA definite set of 13 criteria for IVOS, focusing on the ability of oral absorption and type of infection, was obtained by literature search and validated by a multidisciplinary expert panel. Based on these criteria, we developed a clinical rule for paracetamol and one for ten bioequivalent antibiotics to identify patients with potentially inappropriate intravenous prescriptions (PIVs). Postintervention, the clinical rule alerts were reviewed by pharmacists, who provided recommendations to switch in case of eligibility.Primary and secondary outcome measuresA regression model was used to assess the impact of the intervention on the number of persistent PIVs between the preintervention and the postintervention period. The total number of recommendations, acceptance rate and financial impact were recorded for the 8-month postintervention period.ResultsAt baseline, a median number of 11 (range: 7–16) persistent PIVs per day was observed. After the intervention, the number reduced to 3 (range: 1–7) per day. The advanced IVOS clinical rules showed an immediate relative reduction of 79% (incidence rate ratio=0.21, 95% CI 0.13 to 0.32; p<0.01) in the proportion of persistent PIVs. No significant underlying time trends were observed during the study. Postintervention, 1091 recommendations were provided, of which 74.1% were accepted, resulting in a total 1-day cost saving of €4648.35.ConclusionsWe showed the efficacy of advanced clinical rules combined with a pharmacist-led medication review for IVOS of bioequivalent drugs.

AimsInappropriate anticoagulant use increases the risk of bleeding and thrombotic events. We implemented clinical decision rules to promote judicious medication use, as part of the ‘Check of Medication Appropriateness’ (CMA). The CMA is a pharmacist‐led review service, targeting potentially inappropriate prescriptions (PIPs). In this analysis, we aimed to evaluate the impact of the CMA on anticoagulant prescribing.MethodsThe number of anticoagulant‐related PIPs was evaluated before and after implementation of the intervention in a quasi‐experimental interrupted time series analysis. The pre‐implementation cohort received usual care. The anticoagulant‐focused CMA, comprising 13 clinical rules pertaining to anticoagulation therapies, was implemented in the post‐implementation cohort. Segmented regression analysis was used to assess the impact of the intervention on the number of residual PIPs. A residual PIP was defined as a PIP which persisted up to 48 hours after the CMA intervention. Total number of recommendations and acceptance rate were documented for the 2‐year post‐implementation period.ResultsPre‐implementation, we observed 501 PIPs in 466 inpatients on 36 days, with a median proportion of 78.5% (range: 46.2%–100%) residual PIPs per day. Post‐implementation, 538 PIPs were detected in 485 patients over the same number of days. The CMA intervention reduced the median proportion to 18.2% (range: 0–100%) per day. The effect coincided with an immediate relative reduction of 70% (95%CI 0.19–0.46) in anticoagulant‐related residual PIPs. Post‐implementation, 2778 recommendations were provided and 75.1% were accepted.ConclusionOur CMA approach significantly reduced anticoagulant‐related PIPs. Implementing a pharmacist‐led intervention, based on clinical rules, may support safer prescribing of anticoagulants.

We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or continuous vancomycin infusions. Each patient provided two randomly selected pairs of two consecutive vancomycin concentrations. A web-based precision dosing software, TDMx, was used to evaluate the model-based approaches. In total, 154 patients contributed 308 pairs. With standard TDM-based dosing, only 48.1% (148/308) of all of the second concentrations were within the therapeutic range. Across the model-based approaches we investigated, the mean relative bias and relative root mean square error varied from −5.36% to 3.18% and from 24.8% to 28.1%, respectively. The model averaging approach according to the squared prediction errors showed an acceptable bias and was the most precise. According to this approach, the median (interquartile range) differences between the model-predicted and prescribed doses, expressed as mg every 12 h, were 113 [−69; 427] mg, −70 [−208; 120], mg and 40 [−84; 197] mg in the case of subtherapeutic, supratherapeutic, and therapeutic exposure at the second concentration, respectively. These dose differences, along with poor target attainment, suggest a large window of opportunity for the model-based TDM compared with the standard TDM-based vancomycin dosing. Implementation studies of model-based TDM in routine care are warranted.

Vancomycin is commonly used in outpatient parenteral antimicrobial therapy (OPAT) of Gram-positive infections. Therapeutic drug monitoring and adverse event monitoring pose a challenge. Outcome data of vancomycin in OPAT (vOPAT) are limited. The study aim was to report the safety and efficacy of a structured vOPAT program implemented in the University Hospitals Leuven. The program provides continuous elastomeric infusion of vancomycin at home with biweekly follow-up at the outpatient clinic. Demographics, clinical, biochemical and treatment parameters, target attainment parameters and clinical outcomes were recorded. An e-survey was conducted to assess patient satisfaction. Thirty-five vOPAT episodes in 32 patients were included. During 206 follow-up consultations, 203 plasma concentration measurements were registered with a median vancomycin plasma concentration of 22.5 mg/L (range 6.6–32.0). The majority of concentrations (68.5%) were within the therapeutic range (20.0–25.0 mg/L). Adverse event rates, including drug- (5.7%) and catheter-related (5.7%) events, were low. For 32 vOPAT episodes, a clinical cure rate of 100% was observed. All patients who completed the e-survey were satisfied with their vOPAT course. These findings show that a structured vOPAT program with rigorous follow-up provides safe and effective ambulatory treatment of patients with vancomycin in continuous infusion.

Objectives: Inappropriate prescribing of antimicrobials in hospitals contributes to the emergence of resistance and adverse drug events. To support antimicrobial stewardship (AMS), clinical decision rules focusing on antimicrobial therapy were implemented in the 'Check of Medication Appropriateness' (CMA). The CMA is a hospital-wide pharmacist-led medication review service consisting of a clinical rule-based screening for potentially inappropriate prescriptions (PIPs). We aimed to investigate the impact of the CMA on antimicrobial prescribing. Methods: An interrupted time series study was performed at the University Hospitals Leuven. The pre-implementation cohort was exposed to standard-of-care AMS. Afterwards, an AMS-focused CMA comprising 41 specific clinical rules, targeting six AMS objectives, was implemented in the post-implementation period. A regression model was used to assess the impact of the intervention on the number of AMS-related residual PIPs between both periods. The total number of recommendations and acceptance rate was recorded for the 2 year post-implementation period. Results: Pre-implementation, a median proportion of 75% (range: 33%-100%) residual PIPs per day was observed. After the CMA intervention, the proportion was reduced to 8% (range: 0%-33%) per day. Use of clinical rules resulted in an immediate relative reduction of 86.70% (P < 0.0001) in AMS-related residual PIPs. No significant underlying time trends were observed during the study period. Post-implementation, 2790 recommendations were provided of which 81.32% were accepted. Conclusions: We proved that the CMA approach reduced the number of AMS-related residual PIPs in a highly significant and sustained manner, with the potential to further expand the service to other AMS objectives.

In 2020, EUCAST introduced breakpoints for temocillin. Based on these guidelines, reporting of temocillin susceptibility of Enterobacterales in the context of complicated urinary tract infections (cUTI) implicates the use of a high dose of temocillin (2 g q8h) constantly. We aimed to evaluate the clinical outcome of patients treated with the standard dose (4 g/day) of temocillin in outpatient parenteral antimicrobial therapy (tOPAT). Demographics, clinical and treatment parameters, and late clinical cure (at day 30 after tOPAT completion) were recorded. Univariate generalised estimating equation analyses, with clinical cure as outcome variable, were performed to evaluate covariate associations. Fifty-seven tOPAT episodes in 50 patients were included with a median antimicrobial treatment duration of 21 (range 10–228) days, and cUTI was the main indication (87.7%). Late clinical cure was achieved in 85.7% of the tOPAT episodes. Non-disseminated infections and minimal inhibitory concentrations (MIC) values ≤ 8 mg/L were associated with good late clinical outcome. In conclusion, a standard temocillin dose (4 g/day) results in good clinical outcomes in the treatment of cUTIs in tOPAT patients. Therefore, our centre concluded that the use of standard temocillin dosing should be continued instead of the high dose for cUTI in non-critically ill patients infected with Enterobacterales with an MIC ≤ 4 mg/L.

AllergyAccepted Articles LETTER Non-invasive delabeling and refining of beta-lactam allergy labels in inpatients to optimize antimicrobial stewardship Greet Van De Sijpe, Corresponding Author Greet Van De Sijpe greet.vandesijpe@uzleuven.be orcid.org/0000-0003-1475-6178 Pharmacy Department, University Hospitals Leuven, Leuven, Belgium Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium Correspondence Greet Van De Sijpe, Herestraat 49; 3000 Leuven; Belgium Email: greet.vandesijpe@uzleuven.beSearch for more papers by this authorLiesbeth Gilissen, Liesbeth Gilissen Department of Public Health and Primary Care, Centre for Environment and Health, KU Leuven, Leuven, Belgium KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research group, KU Leuven, Leuven, BelgiumSearch for more papers by this authorMartijn Vandebotermet, Martijn Vandebotermet Department of General Internal Medicine, University Hospitals Leuven, Leuven, BelgiumSearch for more papers by this authorWilly E. Peetermans, Willy E. Peetermans KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research group, KU Leuven, Leuven, Belgium Department of General Internal Medicine, University Hospitals Leuven, Leuven, BelgiumSearch for more papers by this authorIsabel Spriet, Isabel Spriet Pharmacy Department, University Hospitals Leuven, Leuven, Belgium Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium Shared last authorship: Isabel Spriet and Rik Schrijvers contributed equally to this manuscriptSearch for more papers by this authorRik Schrijvers, Rik Schrijvers KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research group, KU Leuven, Leuven, Belgium Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium Shared last authorship: Isabel Spriet and Rik Schrijvers contributed equally to this manuscriptSearch for more papers by this author Greet Van De Sijpe, Corresponding Author Greet Van De Sijpe greet.vandesijpe@uzleuven.be orcid.org/0000-0003-1475-6178 Pharmacy Department, University Hospitals Leuven, Leuven, Belgium Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium Correspondence Greet Van De Sijpe, Herestraat 49; 3000 Leuven; Belgium Email: greet.vandesijpe@uzleuven.beSearch for more papers by this authorLiesbeth Gilissen, Liesbeth Gilissen Department of Public Health and Primary Care, Centre for Environment and Health, KU Leuven, Leuven, Belgium KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research group, KU Leuven, Leuven, BelgiumSearch for more papers by this authorMartijn Vandebotermet, Martijn Vandebotermet Department of General Internal Medicine, University Hospitals Leuven, Leuven, BelgiumSearch for more papers by this authorWilly E. Peetermans, Willy E. Peetermans KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research group, KU Leuven, Leuven, Belgium Department of General Internal Medicine, University Hospitals Leuven, Leuven, BelgiumSearch for more papers by this authorIsabel Spriet, Isabel Spriet Pharmacy Department, University Hospitals Leuven, Leuven, Belgium Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium Shared last authorship: Isabel Spriet and Rik Schrijvers contributed equally to this manuscriptSearch for more papers by this authorRik Schrijvers, Rik Schrijvers KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research group, KU Leuven, Leuven, Belgium Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium Shared last authorship: Isabel Spriet and Rik Schrijvers contributed equally to this manuscriptSearch for more papers by this author First published: 25 July 2022 https://doi.org/10.1111/all.15453 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/all.15453 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Supporting Information Filename Description all15453-sup-0001-Supinfo.docxWord 2007 document , 69.9 KB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Accepted ArticlesAccepted, unedited articles published online and citable. 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Objectives Currently existing pneumococcal vaccines have contributed to a major reduction in pneumococcal disease. However, there remains an unmet need for vaccine coverage of serotypes not included in PCV13 to further reduce the burden of disease. The objective of this review is to assess the potential impact of implementation of the investigational 20-valent pneumococcal conjugate vaccine (PCV20) in the childhood and adult immunization programme in Belgium and Europe. Methods A literature search was conducted to identify publications and surveillance reports concerning the effectiveness and safety of pneumococcal vaccines, epidemiological data on pneumococcal disease or serotype distribution dynamics after introduction of systematic vaccination. Results Serotypes included in PCV20 currently account for the majority of pneumococcal disease in Belgium and Europe. In Belgium, PCV20-serotypes accounted for 71.4% of invasive pneumococcal disease (IPD) cases across all age groups in 2019, of which 39.2% were caused by PCV20-non-PCV13-serotypes. In Europe, these seven serotypes accounted for 37,6% of IPD cases in 2018. PCV20 has proven to be well tolerated in vaccine-naive adults and elicits a substantial immune response against all serotypes included. Conclusion Due to serotype replacement following the introduction of PCV7 and PCV13, a considerable proportion of pneumococcal disease is currently caused by PCV20-serotypes. PCV20 has the potential of preventing more pneumococcal disease in children and the adult population at risk than the existing conjugate vaccines. The available evidence on safety and immunogenicity of PCV20 is promising, but further research is needed to provide data about vaccine effectiveness, immune response duration and replacement phenomenon after introduction of PCV20.

Background: Infective endocarditis (IE) remains a severe disease with high mortality. Most studies report on short-term outcome while real world long-term outcome data are scarce. This study reports reinfection rates and mortality data during long-term follow-up. Methods: A total of 270 patients meeting the modified Duke criteria for definite IE admitted to a tertiary care center between July 2000 and June 2007 were analyzed retrospectively. Early reinfection was defined as a new 10 episode within 6 months; late reinfection as a new IE episode beyond 6 months follow-up. Results: Median follow-up was 85 years. Early reinfection occurred in 10 patients (3.7%), late reinfection in 18 patients (6.7%). Staphylococci (39.7%) were the most frequent causative microorganisms, followed by Streptococci (30.0%) and Enterococci ( 17.8%). Independent predictors of any reinfection were heart failure (HR 3.02, 95% CI 1.42-6.41), peripheral embolization (HR 4.00, 95% CI 1.58-10.17) and implanted pacemakers (HR 3.43, 95% CI 1.25-9.36). Survival rates were 71.1%, 552% and 433% at respectively 1-, 5- and 10-years follow-up. Independent predictors for mortality were age (HR 1.03, 95% CI 1.01-1.04), diabetes mellitus (HR 224, 95% CI 1.46-3.45), hemodialysis (HR 2.70, 95% CI 1.37-5.29), heart failure (HR 1.64, 95% CI 1.19-226), stroke (HR 1.73, 95% CI 1.18-2.52), antimicrobial treatment despite surgical indication (HR 5.53, 95% CI 3.59-8.49) and non-Streptococci causative microorganisms (HR 1.84, 95% CI 128-2.64). Conclusions: Contemporary mortality rates of infective endocarditis remain high, irrespective of reinfection. Heart failure, peripheral embolization and presence of a pacemaker were predictors of reinfection. (C) 2021 Elsevier B.V. All rights reserved.

In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts.

In their Article, Stefanie Desmet and colleagues1Desmet S Lagrou K Wyndham-Thomas C et al.Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study.Lancet Infect Dis. 2021; 21: 127-136Summary Full Text Full Text PDF Scopus (20) Google Scholar describe changes in paediatric invasive pneumococcal disease in Belgium following sequential use of the seven-valent, 13-valent, and ten-valent (also known as pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine [PHiD-CV]) pneumococcal conjugate vaccines (PCV7, PCV13, and PCV10, respectively). The authors cautiously hypothesise that the observed rise in invasive pneumococcal disease in children (mostly due to serotype 19A) might be linked to the PCV13-to-PCV10 switch. We would like to highlight an aspect of the Belgian setting to help contextualise these findings. Sequential use of PCVs in a national immunisation programme is not unique to Belgium. Other countries or regions (eg, New Zealand, Sweden, Quebec in Canada, Piedmont in Italy, and Morocco) have implemented a PCV13-to-PCV10 switch, mainly driven by cost-effectiveness and the similar effects of both PCVs on reducing the overall pneumococcal disease burden—the ultimate goal of a PCV programme. The limited data available from some of these countries or regions indicate that dynamics as seen in Belgium were not observed.2Nieto Guevara J Borys D DeAntonio R Guzman-Holst A Hoet B Interchangeability between pneumococcal conjugate vaccines for pediatric use: a systematic literature review.Expert Rev Vaccines. 2020; 19: 1011-1022Crossref Scopus (2) Google Scholar Unique to Belgium is that, despite 11 years of universal PCV use and high vaccination coverage, the overall incidence of invasive pneumococcal disease in children younger than 2 years remains three to four times higher than in other European countries with similarly mature PCV programmes and reliable surveillance (appendix).1Desmet S Lagrou K Wyndham-Thomas C et al.Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study.Lancet Infect Dis. 2021; 21: 127-136Summary Full Text Full Text PDF Scopus (20) Google Scholar, 3Batah J Varon E Rapport d'activité 2018: epidémiologie.https://cnr-pneumo.com/docman/rapports/39-2018-epidemiologie-2017/fileDate: 2017Date accessed: August 11, 2020Google Scholar, 4Finnish Institute for Health and WelfareIncidence of invasive pneumococcal disease in Finland.https://thl.fi/en/web/thlfi-en/research-and-expertwork/projects-and-programmes/monitoring-the-population-effectiveness-of-pneumococcal-conjugate-vaccination-in-the-finnish-national-vaccination-programme/incidence-of-invasive-pneumococcal-disease-in-finlandDate accessed: August 11, 2020Google Scholar, 5Ladhani SN Collins S Djennad A et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000–17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Summary Full Text Full Text PDF PubMed Scopus (249) Google Scholar Possible explanations for this high incidence are Belgium's high population density (among the highest in Europe) and widespread day-care attendance, which favour high pneumococcal transmission and disease pressure. This hypothesis is also supported by the observation of fast replacement disease by non-PCV13 serotypes in children younger than 2 years following PCV13 implementation in Belgium.1Desmet S Lagrou K Wyndham-Thomas C et al.Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study.Lancet Infect Dis. 2021; 21: 127-136Summary Full Text Full Text PDF Scopus (20) Google Scholar After the PCV13-to-PCV10 switch, the increasing trend in non-PCV13 serotypes no longer continued and was replaced by an increase in non-PCV10 serotypes, particularly 19A.1Desmet S Lagrou K Wyndham-Thomas C et al.Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational study.Lancet Infect Dis. 2021; 21: 127-136Summary Full Text Full Text PDF Scopus (20) Google Scholar Ultimately, local disease biology might be the key factor to understanding invasive pneumococcal disease dynamics following vaccine implementation. Given the high number of potentially pathogenic pneumococcal serotypes, the effect of PCVs on overall invasive pneumococcal disease might be more affected by transmission and disease pressure than by the vaccines' effects on specific serotypes. Which serotypes have a selective advantage might depend on vaccine composition, but the dynamics of replacement by non-vaccine serotypes—which determine overall disease impact—largely depend on local disease and transmission patterns, as observed in this high disease-incidence setting in Belgium. Therefore, the invasive pneumococcal disease dynamics following PCV changes in Belgium cannot be transposed to other countries. Further monitoring of invasive pneumococcal disease epidemiology is important, but future interpretation of the dynamics of invasive pneumococcal disease following the recent PCV10-to-PCV13 switch in Belgium might be obscured by COVID-19 measures, such as physical distancing. PI, MS, and VV are employed by, and hold shares in, the GlaxoSmithKline group of companies. GlaxoSmithKline Biologicals funded all costs associated with the development of this Correspondence. Editorial support was provided by Natalie Denef and publication coordination by Stéphanie Deroo (both from Modis on behalf of GlaxoSmithKline). Download .pdf (.23 MB) Help with pdf files Supplementary appendix Underlying factors in paediatric invasive pneumococcal disease in Belgium – Authors' replyWe agree with Patricia Izurieta and colleagues that the high disease incidence observed in Belgium might result in more pronounced epidemiological changes, whereas these changes might be less apparent in countries with a lower reported incidence of invasive pneumococcal disease. This fact can be well illustrated by comparing the evolution of serotype replacement in England and Wales with that in Belgium after introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). Although a similar, rapid, and proportional increase in non-PCV13 invasive pneumococcal disease incidence (about 50% over 5–6 years) in children younger than 2 years was detected in both places, the variation in terms of absolute number of cases of invasive pneumococcal disease was much higher in Belgium than in England and Wales. Full-Text PDF Dynamic changes in paediatric invasive pneumococcal disease after sequential switches of conjugate vaccine in Belgium: a national retrospective observational studyAfter a significant decrease during the PCV13 period, paediatric invasive pneumococcal disease incidence increased again during the PCV10 period. This observation mainly resulted from a significant increase of serotype 19A cases. During the PCV10 period, dominant serotype 19A clones differed from those detected during previous vaccine periods. Whether changes in epidemiology resulted from the vaccine switch or also from natural evolution remains to be further elucidated. 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Background: Voriconazole is an antifungal drug used as one of the first-line treatments for invasive aspergillosis. This drug is extensively metabolized, predominantly via cytochrome P450 enzymes. An interaction between flucloxacillin and voriconazole, leading to subtherapeutic voriconazole concentrations, has previously been reported. We aimed to demonstrate that flucloxacillin independently influences voriconazole exposure. Methods: Patients from three Belgian hospitals, treated with a combination of voriconazole and flucloxacillin, were included in this retrospective study. Voriconazole concentrations were collected both in a timeframe with and without flucloxacillin co-treatment. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. Results: Thirty-three patients were included in this study and 145 trough concentrations (51 with, and 94 without concomitant flucloxacillin treatment) were analyzed. The median (IQR) voriconazole trough concentration sampled during flucloxacillin co-treatment was 0.5 (0–1.8) mg/L, whereas samples without flucloxacillin co-treatment had a median (IQR) voriconazole trough concentration of 3.5 (1.7–5.1) mg/L (p = 0.002), while receiving similar voriconazole doses. Subtherapeutic concentrations (<1 mg/L) were observed in 69% and 7% of the samples with flucloxacillin co-treatment versus samples without flucloxacillin co-treatment, respectively. Conclusion: This study shows that flucloxacillin co-treatment independently decreases voriconazole exposure. Caution is needed when these two drugs are administered simultaneously.