Search

Vaccination or recent exposure to infection with SARS-CoV-2 currently grants the vast majority of the population considerable immunity and thereby protection against severe disease. It is yet unknow how long this protection lasts. Continuous changes of the viral genotype and phenotype herein play an important role, in particular the variant-specific alterations of the spike protein. Protection by T-cell immunity seems to be more preserved in the event of changes in the virus as compared to antibody-mediated host defences. Furthermore, the continuous succession of virus variants also directly and indirectly affects the effectiveness of medical treatment. Regarding immune-modulating as well as anti-viral therapy, the viral characteristics of the circulating SARS-CoV-2 variant in combination with the level of host immunity will determine whether their use makes sense, and for which patients. The number of patients needed to treat to prevent a clinically negative outcome herein represents an important figure.

Up to 10% of hospitalized patients have an antibiotic allergy label in their medical file, most frequently concerning penicillins. However, the vast majority of reported allergies to antibiotics does not represent a "true" allergy but are due to drug intolerance, idiosyncratic reactions or symptoms of the concurrent infectious disease. Since antibiotic allergy labels result in deviation from first-choice antimicrobial therapy, tackling the issue of incorrect antibiotic allergy labelling, already at young age, is a core element of antibiotic stewardship. In this article, we describe the structured approach to the patient with a presumed antibiotic allergy with emphasis on key elements of allergy-specific history taking and the limited risk of cross-allergic reactions between beta-lactam subclasses.

Description of the changing patterns of antibiotic resistance in Helicobacter pylori infection in the Netherlands.Retrospective database study using the Dutch infectious disease surveillance information system-antibiotic resistance (ISIS-AR).In the ISIS-AR database antibiotic resistance data are reported by 46 microbiologic laboratories in the Netherlands. For the present study, data from 16 centres were used with a 10 year period of reporting H. pylori resistance data, from 1 January 2010 till 1 January 2020, for amoxycillin, levofloxacin, claritrhromycin, tetracyclin and metronidazole.In 2019 Antimicrobial resistance rates in the Netherlands were 1% for tetracycline, 5% for amoxycillin, 23%% for levofloxacin, 46% for metronidazole and 47% for clarithromycin. The combined resistance rate for clarithromycin and metronidazole was 29%. Significantly higher resistance rates were found in female patients for amoxycillin (8% vs 1%), clarithromycin (53% vs 38%) and metronidazole (52% vs 38%). From 2010 to 2019, a significant rise in resistance rates was found for amoxycillin (0% - 5%), clarithromycin (7% - 40%), metronidazole (14% - 45%) and for the clarithromycin and metronidazole combination (2% - 29%).There was an important rise in antibiotic resistance rates in H. pylori in the Netherlands. For optimal H. pylori treatment bismuth-based therapies should become available again in the Netherlands. Treatment of H. pylori should be based on the individual antibiotic resistance profile and be in concordance with the principles of antibiotic stewardship. Guidelines for treatment of H. pylori in the Netherlands should be adapted and have a better correlation with International guidelines and best practices.

Background as the coronavirus disease of 2019 (COVID-19) pandemic progressed diagnostics and treatment changed. Objective to investigate differences in characteristics, disease presentation and outcomes of older hospitalised COVID-19 patients between the first and second pandemic wave in The Netherlands. Methods this was a multicentre retrospective cohort study in 16 hospitals in The Netherlands including patients aged ≥ 70 years, hospitalised for COVID-19 in Spring 2020 (first wave) and Autumn 2020 (second wave). Data included Charlson comorbidity index (CCI), disease severity and Clinical Frailty Scale (CFS). Main outcome was in-hospital mortality. Results a total of 1,376 patients in the first wave (median age 78 years, 60% male) and 946 patients in the second wave (median age 79 years, 61% male) were included. There was no relevant difference in presence of comorbidity (median CCI 2) or frailty (median CFS 4). Patients in the second wave were admitted earlier in the disease course (median 6 versus 7 symptomatic days; P Conclusions compared with older patients hospitalised in the first COVID-19 wave, patients in the second wave had lower in-hospital mortality, independent of risk factors for mortality. The better prognosis likely reflects earlier diagnosis, the effect of improvement in treatment and is relevant for future guidelines and treatment decisions.

Reducing unnecessarily long antibiotic treatments is an imperative effort in the context of antibiotic stewardship. As every infectious entity shows substantial heterogeneity in the degree of severity and extent of disease, ideally the duration of antimicrobial therapy is personalized. The heterogeneity in the presentation and course of an infection is caused by variability in exposure to the causative pathogens via variables like inoculum, virulence factors and elapsed time. Simultaneously, interacting host factors, e.g. the acquired immune system, herein play an important role. Antimicrobial treatment is intended to shift the balance of the host-pathogen interaction in favor of the host and to subsequently reach a favorable outcome (cure). In this perspective it is less likely that single biomarkers like procalcitonin can always capture both the complex host-pathogen balance as well as the resulting antimicrobial treatment duration that is needed. Hence, biomarker-driven algorithms for the duration of antimicrobial therapy sometimes may seem to be an ideal solution, but will have limitations.

Background Approximately 2% of patients in primary care practice and up to 25% of hospital patients are registered as being allergic to an antibiotic. However, up to 90% of these registrations are incorrect, leading to unnecessary prescription of 2nd choice antibiotics with the attendant loss of efficacy, increased toxicity and antibiotic resistance. To improve registration, a better understanding is needed of how incorrect labels are attributed. Objective To investigate the quality of antibiotic allergy registration in primary care and identify determinants to improve registration of antibiotic allergies. Design Registration of antibiotic allergies in primary care practices were analysed for 1) completeness and 2) correctness. To identify determinants for improvement, semi-structured interviews with healthcare providers from four healthcare domains were conducted. Participants A total of 300 antibiotic allergy registrations were analysed for completeness and correctness. Thirty-four healthcare providers were interviewed. Main measures A registration was defined as complete when it included a description of all symptoms, time to onset of symptoms and the duration of symptoms. It was defined as correct when the conclusion was concordant with the Salden criteria. Determinants of correct antibiotic allergy registrations were divided into facilitators or obstructers. Key results Rates of completeness and correctness of registrations were 0% and 29.3%, respectively. The main perceived barriers for correct antibiotic allergy registration were insufficient knowledge, lack of priority, limitations of registration features in electronic medical records (EMR), fear of medical liability and patients interpreting side-effects as allergies. Conclusions The quality of antibiotic allergy registrations can be improved. Potential interventions include raising awareness of the consequences of incomplete and the importance of correct registrations, by continued education, and above all simplifying registration in an EMR by adequate ICT support.

Background and Objective In the randomized controlled trial REMAP-CAP, it was shown that next to dexamethasone, the interleukin (IL)-6 receptor antagonist tocilizumab improves outcome, including survival in intensive care unit (ICU)-admitted coronavirus disease 2019 (COVID)-19 patients. Therefore tocilizumab has been added to many COVID-19 treatment guidelines. Because obesity is a risk factor for the development of severe COVID-19, concerns have been raised about overtreatment, as well as undertreatment, through weight-based dosing of tocilizumab. The currently applied dose of 8 mg/kg is based on the use of this drug for other indications, however it has not formally been investigated for COVID-19. In this study, the pharmacokinetics and pharmacodynamics of tocilizumab were investigated in ICU-admitted COVID-19 patients. Methods This was an open-label, single-centre, observational population pharmacokinetic and descriptive pharmacodynamic evaluation study. Enrolled patients, with polymerase chain reaction-confirmed COVID-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received intravenous tocilizumab 8 mg/kg (maximum 800 mg) within 24 h after admission to the ICU and received dexamethasone 6 mg daily as concomitant therapy. For evaluation of the pharmacokinetics and pharmacodynamics of tocilizumab, all time points from day 0 to 20 days after dose administration were eligible for collection. A nonlinear mixed-effects model was developed to characterize the population pharmacokinetic parameters of tocilizumab in ICU-admitted COVID-19 patients. Covariate analysis was performed to identify potential covariates for dose individualization. For the development of alternative dosing schedules, Monte Carlo simulations using the final model were performed. Results Overall, 29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and nonlinear clearance (CL) was developed and validated. Average CL was estimated to be 0.725 L/day, average volume of distribution (Vd) was 4.34 L, maximum elimination rate (Vmax) was 4.19 μg/day, and concentration at which the elimination pathway is half saturated (Km) was 0.22 μg/mL. Interindividual variability was identified for CL (18.9%) and Vd (21%). Average area under the concentration versus time curve from time zero to infinity of the first dose (AUCinf 1st DOSE) was 938 [±190] μg/mL*days. All patients had tocilizumab exposure above 1 μg/mL for at least 15 days. Bodyweight-based dosing increases variability in exposure compared with fixed dosing. Conclusions This study provides evidence to support a fixed dose of tocilizumab 600 mg in COVID-19 patients. Fixed dosing is a safe, logistically attractive, and drug expenses saving alternative compared with the current 8 mg/kg recommendation. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01074-2.

Acute kidney injury (AKI) is a frequent complication in patients with Staphylococcus aureus bacteremia (SAB), with a significant impact on patient management and outcome. This study aimed to provide insight in the proportion of patients with SAB that develop AKI, the risk factors for developing AKI in this population, and its reversibility. In this retrospective, multicenter cohort study, adult patients with SAB were eligible for inclusion. Patient characteristics, clinical variables, and laboratory results were retrieved from the electronic patient files. Primary outcome was development of AKI, defined as 1.5 times baseline creatinine. Secondary outcomes were reversibility of AKI and risk factors for AKI. A total of 315 patients with SAB were included, of whom 115/315 (37%) developed acute kidney injury. In 68/115 (59%), the AKI was reversible. If kidney function recovered, this occurred within 7 days in 56/68 (82%) of patients. In multivariable logistic regression analyses, independent risk factors for AKI were as follows: complicated SAB, use of diuretics, and hemodynamic instability. Development of AKI was associated with 30-day mortality (OR 3.9; CI 2.2-6.9; p 0.01). Acute kidney injury is a frequent complication in patients with Staphylococcus aureus bacteremia. Considering the irreversibility in a relevant proportion of patients, future research into the underlying pathophysiology and potential interventions is warranted.

Background: The association between intraoperative bile cultures and infectious complications after pancreatoduodenectomy remains unclear. This cohort study and meta-analysis aimed to determine the predictive role of intraoperative bile cultures in abdominal infectious complications after pancreatoduodenectomy. Methods: The cohort study included 114 patients undergoing pancreatoduodenectomy. Regression analyses were used to estimate the odds to develop an organ space infection (OSI) or isolated OSI (OSIs without a simultaneous complication potentially contaminating the intraabdominal space) after a positive bile culture. A systematic review and meta-analysis was performed on abdominal infectious complications (Mantel-Haenszel fixed-effect model). Results: The positive bile culture rate was 61%, predominantly in patients after preoperative biliary drainage (98% vs 26%, p < 0.001). OSIs occurred in 35 patients (31%) and isolated OSIs in nine patients (8%) and were not associated with positive bile cultures (OSIs: odds ratio = 0.6, 95% CI = 0.25-1.23, isolated OSIs: odds ratio = 0.77, 95% CI = 0.20-3.04). In the meta-analysis, 15 studies reporting on 2047 patients showed no association between positive bile cultures and abdominal infectious complications (pooled odds ratio = 1.3, 95% CI = 0.98-1.65). Conclusion: Given the rare occurrence of isolated OSIs and similar odds for patients with positive and negative bile cultures to develop abdominal infectious complications, routine performance of bile cultures should be reconsidered.

Much has changed in the medical treatment of COVID-19 after the first patient with an infection with SARS-CoV-2 in the Netherlands was diagnosed in February 2020. On the basis of limited data, at first only off-label use of (hydroxy)chloroquine seemed to be a treatment option. However, now based on the findings of several randomized studies, other medicines have been included in the Dutch guidelines about the treatment of COVID-19. In this article, we will briefly discuss the current state of affairs with regard to the drugs (hydroxy) chloroquine, remdesivir and corticosteroids. Again, it appears that only well-executed randomized clinical trials can determine the status of various supposedly effective drugs.

Objectives: The benefit of oseltamivir treatment in patients admitted with influenza virus infection and the design of studies addressing this issue have been questioned extensively. As the burden of influenza disease is substantial and oseltamivir treatment is biologically plausible, this study assessed the clinical benefit of oseltamivir treatment in adult patients admitted with severe seasonal influenza virus infection in daily practice.Patients and methods: A multi-centre, retrospective cohort study was conducted to compare the effectiveness of treatment with and without oseltamivir Results: In total, 390 patients were included in this study, of whom 80% had comorbidities. Thirty-day mortality, as well as the composite endpoint of 30-day mortality or intensive care unit admission >48 h after admission, were reduced by 9% (P=0.04) and 11% (P=0.02), respectively. Length of hospital stay and in-hospital mortality rates all showed a trend towards reduction. The median duration between symptom onset and initiation of treatment was 3 days.Conclusions: This study supports that, in daily practice, patients admitted with influenza virus infection should be treated with oseltamivir within 48 h of admission, even if they have had complaints for >48 h.

Objective A cornerstone in the management of Staphylococcus aureus bacteraemia (SAB) is the differentiation between a complicated and an uncomplicated SAB course. The ability to early and accurately identify patients with ‐ and without ‐ complicated bacteraemia may optimise the utility of diagnostics and prevent unnecessary prolonged antibiotic therapy. Methods Development and validation of a prediction score in SAB using demographic, clinical, and laboratory data from two independent Dutch cohorts; estimating the risk of complicated disease at the time of the first positive blood culture. Models were developed using logistic regression and evaluated by c‐statistics, ie area under the ROC‐curve, and negative predictive values (NPV). Results The development‐ and validation cohorts included 150 and 183 patients, respectively. The most optimal prediction model included: mean arterial pressure, signs of metastatic infection on physical examination, leucocyte count, urea level and time to positivity of blood cultures (c‐statistic 0.82, 95% CI 0.74‐0.89). In the validation cohort, the c‐statistic of the prediction score was 0,77 (95% CI 0.69‐0.84). The NPV for complicated disease for patients with a score of ≤2 was 0.83 (95% CI 0.68‐0.92), with a negative likelihood ratio of 0.14 (95% CI 0.06‐0.31). Conclusion The early SAB risk score helps to identify patients with high probability of uncomplicated SAB. However, the risk score's lacked absolute discriminative power to guide decisions on the management of all patients with SAB on its own. The heterogenicity of the disease and inconsistency in definitions of complicated SAB are important challenges in the development of clinical rules to guide the management of SAB.

Young patients are thought to have a more severe disease course and a higher rate of recurrent diverticulitis. However, these understandings are mainly based on studies with important limitations. This review aimed to clarify the true natural history of acute diverticulitis in young patients compared to elderly patients. PubMed and MEDLINE were searched for studies reporting outcomes on disease severity or recurrences in young and elderly patients with a computed tomography-proven diagnosis of acute diverticulitis. Twenty-seven studies were included. The proportion of complicated diverticulitis at presentation (21 studies) was not different for young patients (age cut-off 40–50 years) compared to elderly patients [risk ratio (RR) 1.19; 95% confidence interval 0.94–1.50]. The need for emergency surgery (11 studies) or percutaneous abscess drainage (two studies) yielded comparable results for both groups with a RR of 0.93 (95% confidence interval 0.70–1.24) and 1.65 (95% confidence interval 0.60–4.57), respectively. Crude data on recurrent diverticulitis rates (12 studies) demonstrated a significantly higher RR of 1.47 (95% confidence interval 1.20–1.80) for young patients. Notably, no association between age and recurrent diverticulitis was found in the studies that used survival analyses, taking length of follow-up per age group into account. In conclusion, young patients do not have a more severe course of acute diverticulitis. Published data on the risk of recurrent diverticulitis in young patients are conflicting, but those with the most robust design do not demonstrate an increased risk. Therefore, young patients should not be treated more aggressively nor have a lower threshold for elective surgery just because of their age.

BackgroundAntimicrobial resistance is an increasingly serious threat to public health, and the increased occurrence of multidrug-resistant (MDR) bacteria is a concern in both high-income and low- and middle-income countries. The purpose of this systematic review was to identify and critically appraise current antimicrobial treatment options for infections with MDR Gram-negative bacteria.MethodsA literature search for treatment of MDR extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa was conducted in MEDLINE in January 2019. Relevant studies published in English, German, and French that evaluated clinical success, microbiological success, and 30-day mortality outcomes were included. The population of interest was adult patients.ResultsOf 672 studies, 43 met the inclusion criteria. Carbapenems are the most common antibiotics used for the treatment of ESBL-producing Enterobacteriaceae. The clinical and microbiological success was similar for group 1 carbapenems (imipenem, meropenem, or doripenem), group 2 carbapenems (ertapenem), and non-carbapenem antibiotics. Mortality data were contradictory for group 1 carbapenems compared to group 2 carbapenems. The most common treatment option for A. baumannii and P. aeruginosa infections was intravenous colistin, regardless of infection site. Clinical success and mortality were similar in A. baumannii infections treated with colistin combination therapy vs. colistin monotherapy, whereas heterogeneous results were found with respect to microbiological success. Monotherapy and colistin combination therapy were used against P. aeruginosa with clinical and microbiological success (70–100%) depending on the infection site and severity, and the antibiotic used. Ceftazidime-avibactam therapy for ESBL-producing Enterobacteriaceae and P. aeruginosa showed good clinical success in one study.ConclusionWe did not find robust evidence for antibiotic treatment of any infection with MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa, that would lead to a firm recommendation for one specific antibiotic over another or for monotherapy over combination therapy. The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of antibiotic resistance and the risk of severe side effects. Background: Antimicrobial resistance is an increasingly serious threat to public health, and the increased occurrence of multidrug-resistant (MDR) bacteria is a concern in both high-income and low- and middle-income countries. The purpose of this systematic review was to identify and critically appraise current antimicrobial treatment options for infections with MDR Gram-negative bacteria. Methods: A literature search for treatment of MDR extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa was conducted in MEDLINE in January 2019. Relevant studies published in English, German, and French that evaluated clinical success, microbiological success, and 30-day mortality outcomes were included. The population of interest was adult patients. Results: Of 672 studies, 43 met the inclusion criteria. Carbapenems are the most common antibiotics used for the treatment of ESBL-producing Enterobacteriaceae. The clinical and microbiological success was similar for group 1 carbapenems (imipenem, meropenem, or doripenem), group 2 carbapenems (ertapenem), and non-carbapenem antibiotics. Mortality data were contradictory for group 1 carbapenems compared to group 2 carbapenems. The most common treatment option for A. baumannii and P. aeruginosa infections was intravenous colistin, regardless of infection site. Clinical success and mortality were similar in A. baumannii infections treated with colistin combination therapy vs. colistin monotherapy, whereas heterogeneous results were found with respect to microbiological success. Monotherapy and colistin combination therapy were used against P. aeruginosa with clinical and microbiological success (70-100%) depending on the infection site and severity, and the antibiotic used. Ceftazidime-avibactam therapy for ESBL-producing Enterobacteriaceae and P. aeruginosa showed good clinical success in one study. Conclusion: We did not find robust evidence for antibiotic treatment of any infection with MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa, that would lead to a firm recommendation for one specific antibiotic over another or for monotherapy over combination therapy. The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of antibiotic resistance and the risk of severe side effects.

Prosthetic joint infection A prosthetic joint infection (PJI) is a serious complication that can lead to lengthy hospitalization, significant limitations in mobility, and a reduced quality of life. For acute PJI, the aim is to cure the infection whilst retaining the prosthesis; this can be achieved by means of thorough surgical debridement, cleaning of the artificial material, replacement of exchangeable prosthesis parts and adjuvant antibiotic therapy. In cases of chronic PJI, the prosthetic joint needs to be replaced. For patients in whom surgery is not feasible, or who refuse surgical intervention, chronic suppressive antibiotic therapy can be applied if the infection persists. In order to increase the likelihood of a favourable outcome, it is important to take a multidisciplinary approach.

Background From a stewardship perspective it is recommended that antibiotic guidelines are adjusted to the local setting, accounting for the local epidemiology of pathogens. In many settings the prevalence of Gram-negative pathogens with resistance to empiric sepsis therapy is increasing. How and when to escalate standard sepsis therapy to a reserve antimicrobial agent, is a recurrent dilemma. The study objective was to develop decision strategies for empiric sepsis therapy based on local microbiological and clinical data, and estimate the number needed to treat with a carbapenem to avoid mismatch of empiric therapy in one patient (NNTC). Methods We performed a nested case control study in patients (> 18 years) with Gram-negative bacteremia in 2013–2016. Cases were defined as patients with Gram-negative bacteremia with in vitro resistance to the combination 2nd generation cephalosporin AND aminoglycoside (C-2GC + AG). Control patients had Gram-negative bacteremia with in vitro susceptibility to cefuroxime AND/OR gentamicin, 1:2 ratio. Univariate and multivariable analysis was performed for demographic and clinical predictors of resistance. The adequacy rates of empiric therapy and the NNTC were estimated for different strategies. Results The cohort consisted of 486 episodes of Gram-negative bacteremia in 450 patients. Median age was 66 years (IQR 56–74). In vitro resistance to C-2GC + AG was present in 44 patients (8.8%). Independent predictors for resistance to empiric sepsis therapy were hematologic malignancy (adjusted OR 4.09, 95%CI 1.43–11.62, p

In at risk populations, Pneumocystis pneumonia (PCP) may occur as a solitary event as well as in a cluster- or outbreak setting due to interpatient transmission of Pneumocystis jirovecii. Despite the data and insights obtained from studies of outbreaks of PCP, the development and implementation of comprehensive recommendations for the prevention of healthcare related transmission of P. jirovecii have been delayed. Both optimization of chemoprophylaxis strategies as well as combination with prudent use of isolation precautions are warranted to achieve this goal. The rationale of the available measures for the prevention of PCP should be viewed in the context of what is currently known about the complex biology and epidemiology of P. jirovecii. From there, phased but practical prevention strategies can be deducted to balance the efforts, costs and negative consequences of chemoprophylaxis and isolation precautions with the beneficial effect of preventing healthcare related transmission of P. jirovecii and development of PCP.

We describe a case of community-acquired pneumonia due to Chlamydia caviae in a patient with no direct animal exposure, raising questions about the zoonotic reservoirs and potential transmission routes. Genotyping of Chamydia isolates that cause pneumonia should be performed for a precise diagnosis and to initiate adequate infection control measures.

OBJECTIVES Blood cultures (BCs) are essential in the evaluation of neutropenic fever. Modern BC systems have significantly reduced the time-to-positivity (TTP) of BC. This study explores the probability of bacteraemia when BCs have remained negative for different periods of time. METHODS All adult patients with neutropenia and bacteraemia were included (January 2012-February 2016). Predictive clinical factors for short (≤16 hours) and long (>24 hours) TTP were determined. The residual probability of bacteraemia was estimated for the scenario of negative BC 24 hours after collection. RESULTS The cohort consisted of 154 patients, accounting for 190 episodes of bacteraemia. Median age of 61 years, 60.5% were male. In 123 (64.7%) episodes, BC yielded a single Gram-positive micro-organism and in 49 (25.8%) a Gram-negative micro-organism (median TTP 16.7, 14.5 hours respectively, P

Background The recommended treatment of Pneumocystis jirovecii pneumonia (PCP) is high-dose trimethoprim–sulfamethoxazole (TMP–SMX) in an equivalent of TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2 or 3 weeks. High rates of adverse events are reported with this dose, which raises the question if lower doses are possible. Methods All adult patients diagnosed with PCP in various immune dysfunctions and treated with TMP–SMX between January 1, 2003 and July 1, 2013 in a tertiary university hospital were included. Per institutional protocol, patients initiated treatment on intermediate-dose TMP–SMX (TMP 10–15 mg/kg/day) and could be stepped down to low-dose TMP–SMX (TMP 4–6 mg/kg/day) during treatment. Clinical variables at presentation, relapse rate and mortality rates were compared between intermediate- and step-down treatment groups by uni- and multivariate analyses. Results A total of 104 patients were included. Twenty-four patients (23 %) were switched to low-dose TMP–SMX after a median of 4.5 days (IQR 2.8–7.0 days). One relapse (4 %) occurred in the step-down group versus none in the intermediate-dose group. The overall 30-day mortality was 13 %. There was 1 death in the step-down group (4 %) compared to 13 deaths (16 %) in the intermediate-dose group. Conclusions We observed high cure rates of PCP by treatment with intermediate-dose TMP–SMX. In addition, a step-down strategy to low-dose TMP–SMX during treatment in selected patients appears to be safe and does not compromise the outcome of treatment.

BACKGROUND Infections are a major cause of morbidity and mortality among dialysis patients. Dialysis modality has been hypothesized to be a potential immunomodulatory factor. The objective of this study was to determine the influence of the first dialysis modality on the risk for infections on dialysis. METHODS Our study was conducted utilizing the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) cohort of incident dialysis patients. Medical records of all patients from two tertiary care university hospitals and three regional hospitals were reviewed using pre-specified criteria. Information about infections was collected from the start of dialysis until death, modality switch, study withdrawal, kidney transplantation or at the end of the study. Age-standardized incidence rates for infections were calculated. Poisson regression analysis was used to calculate adjusted incidence rate ratios (IRRs). RESULTS In total, 452 patients, of whom 285 started with haemodialysis (HD) and 167 with peritoneal dialysis (PD), were included. The median follow-up time on the first dialysis modality was similar for HD and PD, 1.8 and 2.0 dialysis years, respectively. During the first 6 months, the age-standardized infection incidence rate was higher on HD compared with PD patients (P = 0.02). Overall, PD patients had a higher infection risk [adjusted IRR: 1.65, 95% confidence interval (CI): 1.34-2.03], which could be attributed to a 4-fold increased risk for dialysis technique-related infections. The risk for non-dialysis technique-related infections was lower in PD patients (adjusted IRR: 0.56, 95% CI: 0.40-0.79). CONCLUSIONS Overall, PD patients carry a higher risk for infections. Interestingly, the risk for non-dialysis technique-related infections was higher in HD patients. The links between dialysis modality and the immune system are expected to explain this difference, but future studies are needed to test these assumptions.

BackgroundBlood cultures are considered the gold standard to distinguish bacteremia from non-bacteremic systemic inflammation. In current clinical practice, bacteraemia is considered unlikely if blood cultures have been negative for 48-72 hours. Modern BC systems have reduced this time-to-positivity (TTP), questioning whether the time frame of 48-72 hrs is still valid. This study investigates the distribution of TTP, the probability of blood culture positivity after 24 hours, and identifies clinical predictors of prolonged TTP.MethodsAdult patients with monomicrobial bacteremia in an academic hospital were included retrospectively over a three-year period. Clinical data were retrieved from the medical records. Predictors of TTP >24 hours were determined by uni- and multivariate analyses. The residual probability of bacteremia was estimated for the scenario of negative BCs at 24 hours after bedside collection.ResultsThe cohort consisted of 801 patients, accounting for 897 episodes of bacteremia. Mean age was 65 years (IQR 54-73), 534 (59.5%) patients were male. Median TTP was 15.7 (IQR 13.5-19.3) hours. TTP was ≤24 hours in 85.3% of episodes. Antibiotic pre-treatment (adjusted OR 1.77; 95%CI 1.14-2.74, pConclusionWith adequate hospital logistics, the probability of positive blood cultures after 24 hours of negative cultures was low. Combined with clinical reassessment, knowledge of this low probability may contribute to prioritization of the differential diagnosis and decisions on antimicrobial therapy. As a potential antibiotic stewardship tool, this strategy warrants further prospective investigation.

OBJECTIVE Dolutegravir (DGV) is one of the preferred antiretroviral agents in first-line combination antiretroviral therapy (cART). Though considered to be a well tolerated drug, we aimed to determine the actual rate, timing and detailed motivation of stopping DGV in a real-life clinical setting. DESIGN A cohort study including all patients who started DGV in two HIV treatment centers in The Netherlands. METHODS All cART-naive and cART-experienced patients who had started DGV were identified from the institutional HIV databases. Clinical data, including motivation and timing of discontinuation of DGV, were extracted from the patient files. Factors that potentially influenced discontinuation of DGV were compared between patients who stopped or continued DGV by multivariate and Kaplan-Meier analyses. RESULTS In total, 556 patients were included, of whom 102 (18.4%) were cART-naive at initiation of DGV. Median follow-up time was 225 days. Overall, in 85 patients (15.3%), DGV was stopped. In 76 patients (13.7%), this was due to intolerability. Insomnia and sleep disturbance (5.6%), gastrointestinal complaints (4.3%) and neuropsychiatric symptoms such as anxiety, psychosis and depression (4.3%) were the predominant reasons for switching DGV. In regimens that included abacavir, DGV was switched more frequently (adjusted relative risk 1.92, 95% confidence interval 1.09-3.38, P log-rank 0.01). No virologic failures were observed. CONCLUSION A relatively high rate of preliminary discontinuation of DGV due to intolerability was detected in our patient population. In particular, DGV was stopped more frequently if the regimen included abacavir. Multiple factors may explain these unexpected postmarketing observations, which warrant further investigation.

From 1980 onwards, an increasing number of outbreaks of Pneumocystis pneumonia (PCP) among kidney transplant recipients have been reported. The cause of these outbreaks is unclear and different explanations have been provided. We performed a systematic review to provide a comprehensive overview of the epidemiologic characteristics as well as the involved clinical risk factors. A total of 15 peer-reviewed English language articles published from 1980 onward were included. Outbreak settings were all marked by absence of adequate chemoprophylaxis, frequent inter-patient contacts and lack of isolation measures taken during hospitalization of PCP cases. PCP-associated mortality rates significantly decreased from a weighted mean of 38% before 1990 to 19% and 13% in the following two decades. Clinical risk factors for PCP in outbreak settings were largely similar to non-outbreak settings. Genotyping by multilocus sequence typing (MLST) or comparison of the internal transcribed spacer (ITS) regions 1 and 2 showed that the outbreaks are most frequently caused by a predominant or a single Pneumocystis strain. Pooled epidemiological data and genotyping results strongly support the theory that interhuman transmission of Pneumocystis occurred. No seasonal trend was noted. The results emphasize the need for chemoprophylaxis in kidney transplant recipients despite a low baseline incidence of PCP in this population, and support the current CDC recommendation with regard to isolation of patients with PCP during hospitalization.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) are at risk for invasive aspergillosis (IA) even prior to the introduction of stem cell transplantation (SCT). In times of increasing triazole resistance and changing use of antifungal prophylaxis, insight into the risk factors for IA is needed to improve strategies for preventing IA in this population. Consecutive patients who received remission-induction therapy for AML or MDS at the Leiden Academic Medical Centre were included. Instead of standard antifungal prophylaxis, an assertive protocol for diagnosis of suspected fungal infection was in place. IA was classified according to the revised European Organization for Research and Treatment of Cancer criteria. Potential predisposing characteristics for IA were compared by uni- and multivariate analyses. In 45 (25%) of 184 included episodes (167 patients), IA was diagnosed prior to SCT. A multivariate Cox regression model demonstrated that relapsed AML (hazard ratio [HR] 2.4; 95% confidence interval [CI], 1.1-5.1; P = 0.02), secondary AML (HR, 5.2; 95% CI, 2.3-11.8; P < 0.001), and prolonged duration of neutropenia (HR, 2.2; 95% CI, 1.2-4.0; P = 0.01) were independently associated with IA. Use of granulocyte-colony-stimulating factor showed a trend toward a protective effect (HR, 0.37; 95% CI, 0.1-31.0; P = 0.06). Relapsed AML, secondary AML, and duration of neutropenia were independent factors for determining the risk for development of IA prior to SCT. The results provide further guidance for antifungal stewardship programs when integrating individual patient tailored decision making in antifungal prophylaxis strategies.

Contains fulltext : 98410.pdf (Publisher’s version ) (Closed access) BACKGROUND: Dectin-1 is the major receptor for fungal beta-glucans on myeloid cells. We investigated whether defective Dectin-1 receptor function, because of the early stop codon polymorphism Y238X, enhances susceptibility to invasive aspergillosis (IA) in at-risk patients. METHODS: Association of Dectin-1 Y238X polymorphism with occurrence and clinical course of IA was evaluated in 71 patients who developed IA post hematopoietic stem cell transplantation (HSCT) and in another 21 non-HSCT patients with IA. The control group consisted of 108 patients who underwent HSCT. Functional studies were performed to investigate consequences of the Y238X Dectin-1 polymorphism. RESULTS: The Y238X allele frequency was higher in non-HSCT patients with IA (19.0% vs 6.9%-7.7%; P < .05). Heterozygosity for Y238X polymorphism in HSCT recipients showed a trend toward IA susceptibility (odds ratio, 1.79; 95% CI, .77-4.19; P = .17) but did not influence clinical course of IA. Functional assays revealed that although peripheral blood mononuclear cells with defective Dectin-1 function due to Y238X responded less efficiently to Aspergillus, corresponding macrophages showed adequate response to Aspergillus. CONCLUSIONS: Dectin-1 Y238X heterozygosity has a limited influence on susceptibility to IA and may be important in susceptible non-HSCT patients. This is partly attributable to redundancy inherent in the innate immune system. Larger studies are needed to confirm these findings.

Objective: To prospectively assess the diagnostic utility of S-adenosylmethionine (AdoMet) and (1 -> 3)-beta-D-glucan (beta-D-glucan) serum markers for Pneumocystis pneumonia (PCP) in HIV-negative patients. Methods: HIV-negative, immunocompromised patients suspected of PCP based on clinical presentation and chest imaging were included. PCP was confirmed or rejected by results of direct microscopy and/or real-time PCR on broncho-alveolar lavage (BAL) fluid. Measurement of serum beta-D-glucan and AdoMet was performed on serum samples collected at enrollment and during follow-up. Both serum beta-D-glucan and AdoMet were assessed for diagnostic accuracy and correlation with clinical and laboratory parameters. Results: In 31 patients enrolled (21 PCP-positive, 10 PCP-negative), AdoMet levels did not discriminate between patients with and without PCP. Elevated serum beta-D-glucan was a reliable indicator for PCP with a sensitivity of 0.90 and specificity of 0.89 at the 60 pg/ml cut-off. In PCP-positive patients beta-D-glucan serum levels decreased during treatment and inversely correlated with Pneumocystis PCR cycle threshold values in BAL fluid. Conclusions: The level of serum beta-D-glucan-but not AdoMet - was diagnostic for PCP within the clinical context and may serve as marker for pulmonary fungal load and treatment monitoring. (C) 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Invasive fungal infections are recognized as an important cause of morbidity and mortality in the immunocompromised host. Rapid initiation of adequate antifungal treatment is often hampered by the limitations of current diagnostic methods. This review encompasses the promises and limitations of newer tracers (believed to target the infectious agents), i.e., radiolabeled antimicrobial peptides, antifungals and chitin-specific agents, for fungal infection imaging by scintigraphy. In mice (99m)Tc-labeled peptides derived from human ubiquicidin (UBI29-41) and lactoferrin (hLF1-11) distinguished local Candida albicans and Aspergillus fumigatus infections from sterile inflammatory processes, but not from bacterial infections. Clinical trials showed that (99m)Tc-UBI29-41 can distinguish infections from inflammatory lesions with 80% specificity and 100% sensitivity. (99m)Tc-hLF1-11 was able to monitor the antifungal effects of fluconazole on C. albicans infections. Moreover, (99m)Tc-fluconazole proved to be an excellent tracer for C. albicans infections as it did not accumulate in bacterial infections and inflammatory processes. However this tracer poorly detected A. fumigatus infections. Furthermore, (123)I-chitinase and (99m)Tc-HYNIC-CBP21 accumulated in both C. albicans and A. fumigatus infections in mice at later time points. In conclusion, despite the recent advances in radiolabeled imaging techniques for invasive fungal infections, the search for better tracers for fungal infection imaging should be continued.

Background. An outbreak of Pneumocystis jiroveci pneumonia (PCP) occurred among renal transplant recipients attending the outpatient department at the Leiden University Medical Centre (Leiden, The Netherlands) from 1 March 2005 through 1 February 2006. Clinical, epidemiological, and molecular data were analyzed to trace the outbreak's origin. Methods. Renal transplant recipients with a clinical suspected diagnosis of PCP were included in the study. The diagnosis had to be confirmed by direct microscopy or real-time polymerase chain reaction of the dihydropteroate synthase gene in a bronchoalveolar fluid specimen. To detect contacts between patients, a transmission map was constructed. A case-control analysis was performed to asses whether infection was associated with certain wardrooms. Genotyping of Pneumocystis isolates was performed by sequence analysis of the internal transcribed spacer (ITS) number 1 and 2 gene regions. Results. Twenty-two confirmed PCP cases were identified; approximately 0-1 would have been expected over the same time period. No risk factor was predominantly present, and standard immunosuppressive regimens had not changed. Liver transplant recipients who used the same outpatient facilities had not acquired PCP. The transmission map findings were compatible with interhuman transmission on multiple occasions. The case-control study did not point to wardrooms as a common source. Genotyping by sequencing of the ITS1 and ITS2 gene regions revealed type Ne in 12 of 16 successfully typed samples. Genotype Ne was found in only 2 of 12 reference samples. Conclusions. The clinical data and genotyping results are compatible with either interhuman transmission or an environmental source of infection. More complex models may account for PCP clusters.

Among preterm infants there is a relationship between skin blood flow and transepidermal water loss (TEWL). The aim of this study was to assess whether halogen spotlight phototherapy without significant heat stress increases TEWL and affects maintenance fluid requirements in preterm infants. TEWL was measured noninvasively before the start and after 1 h of halogen spotlight phototherapy in a group of preterm infants, nursed in double-walled incubators with moderately high relative humidity. Relative humidity and ambient temperature in the incubator were tightly controlled. Mean +/- SD birth weight of the 18 infants was 1412 +/- 256 g, gestational age 30.6 +/- 1.6 wk, and age at measurement 5 +/- 3 d. Nine infants received ventilatory assistance. Relative humidity was 40-80% (mean 52%). Average TEWL increased from 13.6 to 16.5 g/m(2)/h during phototherapy. These data show that TEWL increases by approximately 20% during phototherapy despite constant skin temperature and relative humidity. Maintenance fluids of preterm infants should be increased by 0.35 mL/kg/h during exposure to halogen spotlight phototherapy.

The innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages, may influence susceptibility to invasive aspergillosis in patients at risk. We investigated in a clinical setting whether common polymorphisms in Toll-like receptor (TLR) and cytokine genes involved in macrophage regulation are associated with susceptibility to invasive aspergillosis. Forty-four allogeneic stem cell transplantation recipients diagnosed with probable or proven IA according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group, were enrolled. The control group consisted of 64 allogeneic stem cell transplantation recipients without invasive aspergillosis. The TLR4 1063A>G single nucleotide polymorphism was associated with invasive aspergillosis when present in donors of allogeneic stem cell transplantation recipients (unadjusted OR 3.77 95%CI 1.08–13.2, p = 0.03). In a multivariate analysis, adjusted for occurrence of graft-versus-host-disease, Cytomegalovirus serostatus and duration of neutropenia, paired presence of the TLR4 1063A>G and IFNG 874T>A single nucleotide polymorphisms showed a trend towards increased susceptibility to invasive aspergillosis (p = 0.04). These findings point to the relevant immunological pathway involved in resistance to invasive aspergillosis and warrant further study of the effects of TLR and cytokine polymorphisms and their interaction, which may occur on different levels of the complex biological interplay between the immunocompromised host and Aspergillus sp.