Development of a Model-Informed Dosing Tool to Optimise Initial Antibiotic Dosing - A Translational Example for Intensive Care Units

The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has a high potential to improve outcomes in this vulnerable patient population. This study aimed to develop a tabular dosing decision tool for initial therapy of meropenem integrating hospital-specific, thus far unexploited pathogen susceptibility information. An appropriate meropenem pharmacokinetic model was selected from the literature and evaluated using clinical data. Probability of target attainment (PTA) analysis was conducted for clinically interesting dosing regimens. To inform dosing prior to pathogen identification, the local pathogen-independent mean fraction of response (LPIFR) was calculated based on the observed minimum inhibitory concentrations distribution in the hospital. A simple, tabular, model-informed dosing decision tool was developed for initial meropenem therapy. Dosing recommendations achieving PTA > 90% or LPIFR > 90% for patients with different creatinine clearances were integrated. Based on the experiences during the development process, a generalised workflow for the development of tabular dosing decision tools was derived. The proposed workflow can support the development of model-informed dosing tools for initial therapy of various drugs and hospital-specific conditions

Preparing for patients with high-consequence infectious diseases: Example of a high-level isolation unit

Introduction: Patients with high-consequence infectious diseases (HCID) are rare in Western Europe. However, high-level isolation units (HLIU) must always be prepared for patient admission. Case fatality rates of HCID can be reduced by providing optimal intensive care management. We here describe a single centre’s preparation, its embedding in the national context and the challenges we faced during the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic. Methods: Ten team leaders organize monthly whole day trainings for a team of doctors and nurses from the HLIU focusing on intensive care medicine. Impact and relevance of training are assessed by a questionnaire and a perception survey, respectively. Furthermore, yearly exercises with several partner institutions are performed to cover different real-life scenarios. Exercises are evaluated by internal and external observers. Both training sessions and exercises are accompanied by intense feedback. Results: From May 2017 monthly training sessions were held with a two-month and a seven-month break due to the first and second wave of the SARS-CoV-2 pandemic, respectively. Agreement with the statements of the questionnaire was higher after training compared to before training indicating a positive effect of training sessions on competence. Participants rated joint trainings for nurses and doctors at regular intervals as important. Numerous issues with potential for improvement were identified during post processing of exercises. Action plans for their improvement were drafted and as of now mostly implemented. The network of the permanent working group of competence and treatment centres for HCID (Ständiger Arbeitskreis der Kompetenz- und Behandlungszentren für Krankheiten durch hochpathogene Erreger (STAKOB)) at the Robert Koch-Institute (RKI) was strengthened throughout the SARS-CoV-2 pandemic. Discussion: Adequate preparation for the admission of patients with HCID is challenging. We show that joint regular trainings of doctors and nurses are appreciated and that training sessions may improve perceived skills. We also show that real-life scenario exercises may reveal additional deficits, which cannot be easily disclosed in training sessions. Although the SARS-CoV-2 pandemic interfered with our activities the enhanced cooperation among German HLIU during the pandemic ensured constant readiness for the admission of HCID patients to our or to collaborating HLIU. This is a single centre’s experience, which may not be generalized to other centres. However, we believe that our work may address aspects that should be considered when preparing a unit for the admission of patients with HCID. These may then be adapted to the local situations.Peer Reviewe

Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients

Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment. Patients and methods: We queried our center's transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity. Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact. Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients

Severe infections of Panton-Valentine leukocidin positive Staphylococcus aureus in children

Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported.We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children.Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study.Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus n = 4) including necrotizing pneumonia (n = 4), necrotizing fasciitis (n = 2), pyomyositis (n = 2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (n = 1), preorbital cellulitis (n = 1), and recurrent deep furunculosis in an immunosuppressed patient (n = 1). Specific complications of PVL-SA infections were venous thrombosis (n = 2), sepsis (n = 5), respiratory failure (n = 5), and acute respiratory distress syndrome (n = 3). The median duration of hospital stay was 14 days (range 5-52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified.PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures

Role of genetic variants of toll like receptors (TLR) in severe malaria and analysis of the TLR ligand glykosylphosphatidylinositol (GPI)

Genetische Wirtsfaktoren spielen eine entscheidende Rolle für die Anfälligkeit gegenüber der Malaria und für den Schweregrad der Erkrankung. Die Malaria tropica infolge der Infektion mit Plasmodium falciparum verursacht jährlich eine Millionen Todesfälle. Toll-Like-Rezeptoren (TLR) sind in vitro an der Erkennung von P. falciparum beteiligt; der Glycosylphosphatidylinositol (GPI)-Anker des Parasiten induziert über TLR-2 und TLR-4 den Signalweg in den Wirtszellen. Dabei induziert die Interaktion von mikrobiellen Liganden mit dem jeweiligen TLR die Freisetzung von proinflammatorischen Zytokinen über die TLR/IL-2-Rezeptor-Domäne. Die TLR sind damit mutmaßlich zentrale Vermittler der Wirtsantwort im Sinne von Zytokinproduktion und Fieber bei der Malaria. Der parasitäre TLR-Ligand GPI induziert im Mausmodell die Symptome einer schweren Malaria. Die Wirkung des P. falciparum-GPI auf humane Immunzellen ist dagegen unklar. Im Rahmen einer Fall-Kontroll-Studie bei 870 ghanaischen Kindern wurde die Bedeutung von TLR-2- und -4-Polymorphismen hinsichtlich der Anfälligkeit für die schwere Malaria untersucht. Zudem wurden in vitro Stimulationsassays mit murinen und humanen Zelllinien durchgeführt, um die Rolle von synthetischem P. falciparum-GPI bei der pro-inflammatorischen Antwort zu untersuchen. Bei Europäern und Asiaten häufige TLR-2-Polymorphismen konnten bei den ghanaischen Kindern nicht nachgewiesen werden. Allerdings wurde eine seltene, bisher nicht vorbeschriebene Mutation (Leu658Pro) detektiert, die die Signaltransduktion via TLR-2 beeinträchtigt. Der TLR-4-Polymorphismus Asp299Gly fand sich dagegen deutlich häufiger als bei Europäern. In der gesunden Kontrollgruppe wiesen 17.6% diese Variante auf; bei Patienten mit schwerer Malaria lag eine signifikante Häufung dieses Polymorphismus vor (24.1%, P < 0.05). In ähnlicher Weise wurde der Polymorphismus TLR-4-Thr399Ile bei 2.4% der gesunden Kontrollen und bei 6.2% der Patienten mit schwerer Malaria beobachtet (P = 0.02). Das Risiko (Odds), an schwerer Malaria zu erkranken, war bei Trägern der Polymorphismen TLR-4-Asp299Gly und TLR-4-Thr399Ile 1,5- bzw. 2,6-fach erhöht. Synthetisches P. falciparum-GPI induzierte allerdings keinerlei Zytokinproduktion in den untersuchten Zelllinien. Diese Ergebnisse verweisen erstmals auf die Bedeutung des TLR-Systems für die Manifestation der Malaria in vivo und somit auf die prinzipielle Möglichkeit, den Krankheitsverlauf dementsprechend zu beeinflussen. Insbesondere erhöhen in Afrika häufige TLR-4-Varianten das Risiko einer schweren Malaria. Die ausbleibende pro-inflammatorische Antwort bei Stimulation mit synthetischem P. falciparum-GPI spricht nicht zwingend gegen die Erkennung dieses Moleküls durch das TLR-System und eine Rolle bei der Pathophysiologie der Malaria, sondern ist wahrscheinlich auf strukturelle Abweichungen des synthetischen vom natürlich vorkommenden GPI zurückzuführen.Genetic host factors play a critical role in susceptibility to malaria and its severity. Malaria tropica caused by Plasmodium falciparum results in over one million deaths annually. Toll-like-receptors have been shown in vitro to be involved in recognition of P. falciparum. The glycosylphosphatidylinositol anchor of P. falciparum induces signaling in host cells via TLR-2 und TLR-4. The interaction of the microbial ligand and the respective TLR results in the release of proinflammatory cytokines via the TLR/IL-2-receptor (TIR) domain. Thus, TLR may contribute as key host molecules to inflammatory responses including cytokine production and fever in malaria. In mice, P. falciparum GPI induces the symptoms of severe malaria while the effect of P. falciparum GPI on human immune cells remains unknown. In a case-control study among 870 Ghanaian children we examined the influence of TLR-2- and -4 polymorphisms in susceptibility to severe malaria. Additionally we examined the role of synthetic P. falciparum GPI in the proinflammatory immune response in in vitro stimulation assays using murine and human cell lines. TLR-2 polymorphisms frequently seen in Caucasians and Asians were completely absent in all Ghanaian children. However, we detected a rare and previously undescribed mutation (Leu658Pro) which impairs signaling via TLR-2 in vitro. On the contrary, the TLR-4 polymorphism Asp299Gly was observed at an extraordinarily higher rate than in Europeans. In healthy controls it was found in 17.6%; in severe malaria patients it occurred at a significantly higher frequency (24.1%, P < 0.05). The TLR-4 polymorphism Thr399Ile was found at similarly high rates, in 2.4% of healthy children and in 6.2% of patients with severe malaria (P = 0.02). The polymorphisms TLR-4 Asp299Gly and TLR-4 Thr399Ile conferred an 1.5- and 2.6-fold risk of severe malaria. Synthetic P. falciparum GPI did not induce cytokine production in the stimulated cells. These findings suggest an important role of TLR in malaria susceptibility in vivo and their potential influence on the progression of the disease. Especially in Africa common TLR-4 variants predispose to severe malaria. The absence of a proinflammatory immune response to stimulation with synthetic P. falciparum GPI observed here does not mean necessarily that TLR do not recognize P. falciparum GPI or that it does not play a role in the pathogenesis of malaria. This is more likely explained by structural differences between the synthetic P. falciparum GPI and natural GPI

Development of a Model-Informed Dosing Tool to Optimise Initial Antibiotic Dosing&mdash;A Translational Example for Intensive Care Units

The prevalence and mortality rates of severe infections are high in intensive care units (ICUs). At the same time, the high pharmacokinetic variability observed in ICU patients increases the risk of inadequate antibiotic drug exposure. Therefore, dosing tailored to specific patient characteristics has a high potential to improve outcomes in this vulnerable patient population. This study aimed to develop a tabular dosing decision tool for initial therapy of meropenem integrating hospital-specific, thus far unexploited pathogen susceptibility information. An appropriate meropenem pharmacokinetic model was selected from the literature and evaluated using clinical data. Probability of target attainment (PTA) analysis was conducted for clinically interesting dosing regimens. To inform dosing prior to pathogen identification, the local pathogen-independent mean fraction of response (LPIFR) was calculated based on the observed minimum inhibitory concentrations distribution in the hospital. A simple, tabular, model-informed dosing decision tool was developed for initial meropenem therapy. Dosing recommendations achieving PTA &gt; 90% or LPIFR &gt; 90% for patients with different creatinine clearances were integrated. Based on the experiences during the development process, a generalised workflow for the development of tabular dosing decision tools was derived. The proposed workflow can support the development of model-informed dosing tools for initial therapy of various drugs and hospital-specific conditions

Evaluation of a Meropenem and Piperacillin Monitoring Program in Intensive Care Unit Patients Calls for the Regular Assessment of Empirical Targets and Easy-to-Use Dosing Decision Tools

The drug concentrations targeted in meropenem and piperacillin/tazobactam therapy also depend on the susceptibility of the pathogen. Yet, the pathogen is often unknown, and antibiotic therapy is guided by empirical targets. To reliably achieve the targeted concentrations, dosing needs to be adjusted for renal function. We aimed to evaluate a meropenem and piperacillin/tazobactam monitoring program in intensive care unit (ICU) patients by assessing (i) the adequacy of locally selected empirical targets, (ii) if dosing is adequately adjusted for renal function and individual target, and (iii) if dosing is adjusted in target attainment (TA) failure. In a prospective, observational clinical trial of drug concentrations, relevant patient characteristics and microbiological data (pathogen, minimum inhibitory concentration (MIC)) for patients receiving meropenem or piperacillin/tazobactam treatment were collected. If the MIC value was available, a target range of 1&ndash;5 &times; MIC was selected for minimum drug concentrations of both drugs. If the MIC value was not available, 8&ndash;40 mg/L and 16&ndash;80 mg/L were selected as empirical target ranges for meropenem and piperacillin, respectively. A total of 356 meropenem and 216 piperacillin samples were collected from 108 and 96 ICU patients, respectively. The vast majority of observed MIC values was lower than the empirical target (meropenem: 90.0%, piperacillin: 93.9%), suggesting empirical target value reductions. TA was found to be low (meropenem: 35.7%, piperacillin 50.5%) with the lowest TA for severely impaired renal function (meropenem: 13.9%, piperacillin: 29.2%), and observed drug concentrations did not significantly differ between patients with different targets, indicating dosing was not adequately adjusted for renal function or target. Dosing adjustments were rare for both drugs (meropenem: 6.13%, piperacillin: 4.78%) and for meropenem irrespective of TA, revealing that concentration monitoring alone was insufficient to guide dosing adjustment. Empirical targets should regularly be assessed and adjusted based on local susceptibility data. To improve TA, scientific knowledge should be translated into easy-to-use dosing strategies guiding antibiotic dosing

Which parameters support disposition decision in suspected COVID-19 cases in the emergency department (ED): a German clinical cohort study

Objectives: One major goal of the emergency department (ED) is to decide, whether patients need to be hospitalised or can be sent home safely. We aim at providing criteria for these decisions without knowing the SARS-CoV-2 test result in suspected cases. Setting: Tertiary emergency medicine. Participants: All patients were treated at the ED of the Charite during the pandemic peak and underwent SARS-CoV-2 testing. Patients with positive test results were characterised in detail and underwent a 14-day-follow-up. Primary and secondary outcome measures: Logistic regression and classification and regression tree (CART) analyses were performed to identify predictors (primary endpoint), which confirm safe discharge. The clinical endpoint was all-cause mortality or need for mechanical ventilation during index stay or after readmission. Results: The primary test population of suspected COVID-19 consisted of n=1255 cases, 45.2% were women (n=567). Of these, n=110 tested positive for SARS-CoV-2 (8.8%). The median age of SARS-CoV-2-positive cases was 45 years (IQR: 33-66 years), whereas the median age of the group tested negative for SARS-CoV-2 was 42 years (IQR: 30-60 years) (p=0.096). 43.6% were directly admitted to hospital care. CART analysis identified the variables oxygen saturation (<95%), dyspnoea and history of cardiovascular (CV) disease to distinguish between high and low-risk groups. If all three variables were negative, most patients were discharged from ED, and the incidence of the clinical endpoint was 0%. The validation cohort confirmed the safety of discharge using these variables and revealed an incidence of the clinical endpoint from 14.3% in patients with CV disease, 9.4% in patients with dyspnoea and 18.2% in patients with O-2 satuaration below 95%. Conclusions: Based on easily available variables like dyspnoea, oxygen saturation, history of CV disease, approximately 25% of patients subsequently confirmed with COVID-19 can be identified for safe discharge

Which parameters support disposition decision in suspected COVID-19 cases in the emergency department (ED): a German clinical cohort study

Objectives One major goal of the emergency department (ED) is to decide, whether patients need to be hospitalised or can be sent home safely. We aim at providing criteria for these decisions without knowing the SARS-CoV-2 test result in suspected cases. Setting Tertiary emergency medicine. Participants All patients were treated at the ED of the Charite during the pandemic peak and underwent SARS-CoV-2 testing. Patients with positive test results were characterised in detail and underwent a 14-day-follow-up. Primary and secondary outcome measures Logistic regression and classification and regression tree (CART) analyses were performed to identify predictors (primary endpoint), which confirm safe discharge. The clinical endpoint was all-cause mortality or need for mechanical ventilation during index stay or after readmission. Results The primary test population of suspected COVID-19 consisted of n=1255 cases, 45.2% were women (n=567). Of these, n=110 tested positive for SARS-CoV-2 (8.8%). The median age of SARS-CoV-2-positive cases was 45 years (IQR: 33-66 years), whereas the median age of the group tested negative for SARS-CoV-2 was 42 years (IQR: 30-60 years) (p=0.096). 43.6% were directly admitted to hospital care. CART analysis identified the variables oxygen saturation (<95%), dyspnoea and history of cardiovascular (CV) disease to distinguish between high and low-risk groups. If all three variables were negative, most patients were discharged from ED, and the incidence of the clinical endpoint was 0%. The validation cohort confirmed the safety of discharge using these variables and revealed an incidence of the clinical endpoint from 14.3% in patients with CV disease, 9.4% in patients with dyspnoea and 18.2% in patients with O-2 satuaration below 95%. Conclusions Based on easily available variables like dyspnoea, oxygen saturation, history of CV disease, approximately 25% of patients subsequently confirmed with COVID-19 can be identified for safe discharge