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BackgroundIn critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population.ObjectivesTo assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime.MethodsAdult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207.ResultsTwenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission.ConclusionsThese results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

Infections pose a major threat to intensive care (ICU) patients, with considerable mortality and long-term sequelae in survivors.In this thesis, three major subjects regarding infections in ICU patients are discussed. The aim of included studies is the improvement of prevention and treatment of such infections.The first part describes the incidence of highly resistant microorganisms (HRMOs), comparing characteristics and outcome of ICU-patients with versus those without HRMO. In this cohort, a small but relevant proportion of patients was HRMO-positive, with most HRMOs imported to as opposed to acquired in the ICU. Most HRMOs were Gram-negatives. The clinical outcome was worse in those with HRMO compared to those without HRMO.The second part describes the pharmacokinetics of beta-lactam antibiotics. First, plasma concentrations of continuously dosed piperacillin in ICU-patients were evaluated, followed by evaluation of plasma concentrations of cefotaxime in a randomised trial. In this trial, one group was treated by intermittent, the other group by continuous dosing of cefotaxime. In both trials, continuous dosing did not guarantee the attainment of target concentrations, but in the cefotaxime-trial continuous dosing led to adequate plasma concentrations more often compared to intermittent dosing.The third part describes the dynamics of fecal microbiota in ICU-patients admitted for planned cardiosurgery. Bacterial diversity decreased during admission compared to baseline. Also, the relative abundance of anaerobes, considered part of a ‘healthy’ gut microbiota decreased, whereas the relative abundance of some pathobionts increased. In most patients the change in microbiota during hospital stay reverted to the original composition post-discharge.

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Optimal dosing of β-lactam antibiotics in critically ill patients is a challenge given the unpredictable pharmacokinetic profile of this patient population. Several studies have shown intermittent dosing to often yield inadequate drug concentrations. Continuous dosing is an attractive alternative from a pharmacodynamic point of view. This study evaluated whether, during continuous dosing, piperacillin concentrations reached and maintained a pre-defined target in critically ill patients. Adult patients treated with piperacillin by continuous dosing in the intensive care unit of a university medical centre in The Netherlands were prospectively studied. Total and unbound piperacillin concentrations drawn at fixed time points throughout the entire treatment course were determined by liquid chromatography-tandem mass spectrometry. A pharmacokinetic combined target of a piperacillin concentration ≥80 mg/L, reached within 1 h of starting study treatment AND maintained throughout the treatment course, was set. Eighteen patients were analysed. The median duration of monitored piperacillin treatment was 60 h (interquartile range, 33-96 h). Of the 18 patients, 5 (27.8 %) reached the combined target; 15 (83.3%) reached and maintained a less strict target of >16 mg/L. In this patient cohort, this dosing schedule was insufficient to reach the pre-defined target. Depending on which target is to be met, a larger initial cumulative dose is desirable, combined with therapeutic drug monitoring.

Background: Virtually no studies on the dynamics of the intestinal microbiota in patients admitted to the intensive care unit (ICU) are published, despite the increasingly recognized important role of microbiota on human physiology. Critical care patients undergo treatments that are known to influence the microbiota. However, dynamics and extent of such changes are not yet fully understood. To address this topic, we analyzed the microbiota before, during and after planned major cardio surgery that, for the first time, allowed us to follow the microbial dynamics of critical care patients. In this prospective, observational, longitudinal, single center study, we analyzed the fecal microbiota using 16S rRNA gene sequencing. Results: Samples of 97 patients admitted between April 2015 and November 2016 were included. In 32 patients, data of all three time points (before, during and after admission) were available for analysis. We found a large intra-individual variation in composition of gut microbiota. During admission, a significant change in microbial composition occurred in most patients, with a significant increase in pathobionts combined with a decrease in strictly anaerobic gut bacteria, typically beneficial for health. A lower bacterial diversity during admission was associated with longer hospitalization. In most patients analyzed at all three time points, the change in microbiota during hospital stay reverted to the original composition post-discharge. Conclusions: Our study shows that, even with a short ICU stay, patients present a significant change in microbial composition shortly after admission. The unique longitudinal setup of this study displayed a restoration of the microbiota in most patients to baseline composition post-discharge, which demonstrated its great restorative capacity. A relative decrease in benign or even beneficial bacteria and increase of pathobionts shifts the microbial balance in the gut, which could have clinical relevance. In future studies, the microbiota of ICU patients should be considered a good target for optimisation.

Background Although the important role of intestinal microbiota on human physiology is increasingly recognised, few studies on its dynamics in patients admitted to the intensive care unit (ICU) have been published. Disturbance of microbiota (dysbiosis) has been reported, but clinical consequences are unclear. We assessed the dynamics of intestinal microbiota before, during and after hospital admission in planned cardio-surgical patients admitted to the ICU. Methods In this prospective, observational, longitudinal, single centre study, we analysed the microbiota at three time points in patients scheduled for surgery using 16SrRNA-gene sequencing. Findings Samples of 97 patients admitted between April 2015 and November 2016 to our institution were included. We found a large inter-individual variation in gut microbiota. At baseline, some patients' microbiota appeared to be in a state of dysbiosis, others showed a profile consistent with that of healthy individuals. Most displayed a significant change from baseline towards a composition with a relative preponderance of potentially pathogenic species, to restore post-discharge. Interpretation Our study shows that even patients with a short ICU stay present a marked change in microbial composition shortly after admission, to restore post-discharge, while some patients' microbiota are in a state of dysbiosis before any intervention. Consequently, a relative decrease in benign or even beneficial bacteria and increase of pathobionts shifts the microbial balance in the gut, which could have clinical relevance. In future studies, the microbiota of ICU patients should be considered a good target for optimisation. Funding University Medical Center Groningen Healthy Ageing Committee, Marie SkA‚odowska-Curie Actions. Conflict of Interest: All authors declare no competing interests. Ethical Approval Statement: Ethical approval by the Medical Ethics Committee of our institution was received (approval number METc2014/206) and all research was conducted in accordance with the Declaration of Helsinki.

Virus-associated hemophagocytic syndrome (VAHS) is a severe complication of various viral infections often resulting in multiorgan failure and death. The purpose of this study was to describe baseline characteristics, development of VAHS, related treatments and associated mortality rate of consecutive critically ill patients with confirmed 2009 influenza A (H1N1) infection and respiratory failure.We conducted a prospective observational study of 25 critically ill patients with 2009 influenza A (H1N1) infection at a single-center intensive care unit in Germany between 5 October 2009 and 4 January 2010. Demographic data, comorbidities, diagnosis of VAHS, illness progression, treatments and survival data were collected. The primary outcome measure was the development of VAHS and related mortality. Secondary outcome variables included duration of mechanical ventilation, support of extracorporeal membrane oxygenation and duration of viral shedding.VAHS developed in 9 (36%) of 25 critically ill patients with confirmed 2009 influenza A (H1N1) infection, and 8 (89%) of them died. In contrast, the mortality rate in the remaining 16 patients without VAHS was 25% (P = 0.004 for the survival difference in patients with or without VAHS by log-rank analysis). The patients were relatively young (median age, 45 years; interquartile range (IQR), 35 to 56 years of age); however, 18 patients (72%) presented with one or more risk factors for a severe course of illness. All 25 patients received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia, with a median duration of mechanical ventilation of 19 days (IQR, 13 to 26 days). An additional 17 patients (68%) required extracorporeal membrane oxygenation for a median of 10 days (IQR, 6 to 19 days).The findings of this study raise the possibility that VAHS may be a frequent complication of severe 2009 influenza A (H1N1) infection and represents an important contributor to multiorgan failure and death.

A 58-year-old man was submitted to our intensive care ward with respiratory failure due to pneumonitis. He had previously been treated for non-Hodgkin lymphoma by autologous stem cell transplantation, as a result of which bone marrow function was reduced. Further analysis showed infection with new influenza A(H1N1); typing revealed an oseltamivir-resistant subpopulation (H275Y). The patient was treated with oseltamivir and intravenously with zanamivir, but died of respiratory disease progression. This is the first published case of oseltamivir-resistant new influenza A(H1N1) infection in the Netherlands.

Awareness of the importance of quality assurance in the ICU is growing but the methodology is still under development and subject to debate [1-3]. Ventilatorassociated pneumonia (VAP) seemed to come close to being an important, valid, reliable, responsive, interpretable and feasible outcome parameter [3]. We therefore decided to measure VAP incidence on a regular basis. A prospective study was carried out with yearly assessment of the incidence of VAP during a 3-month period. Defi nition of VAP was based on the recommendations of the Centers for Disease Control and Prevention [4]. Overall, out of 550 patients ventilated for >48 hours, only two cases of defi nite VAP were observed [5]. Because no further improvement could be achieved in this fi eld, we turned our attention to other outcome parameters. A perceived rise in incidence of VAP led us to repeat our evaluation, despite growing concern about the importance, validity and reliability of VAP as a quality indicator [2].

A 46-year-old woman had a swollen tongue due to amyloid light chain (AL) amyloidosis caused by multiple myeloma.

A transplant recipient presented with fever and pancytopenia. Bone marrow biopsy showed Leishmania parasites. Travel history revealed a trip to Greece 17 months prior to admission. This case illustrates the importance of considering leishmaniasis as a cause of pancytopenia, especially in the immunocompromised, even in the absence of recent travel to an endemic area. Acknowledgment of this infection is vital as the outcome can be fatal if left untreated.