The ONTAI study - a survey on antimicrobial dosing and the practice of therapeutic drug monitoring in German intensive care units.

PURPOSE: Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays. METHODS: Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire. RESULTS: The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly. CONCLUSION: German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

Higher procoagulatory potential but lower DIC score in COVID-19 ARDS patients compared to non-COVID-19 ARDS patients.

BACKGROUND: COVID-19 is a novel viral disease. Severe courses may present as ARDS. Several publications report a high incidence of coagulation abnormalities in these patients. We aimed to compare coagulation and inflammation parameters in patients with ARDS due to SARS-CoV-2 infection versus patients with ARDS due to other causes. METHODS: This retrospective study included intubated patients admitted with the diagnosis of ARDS to the ICU at Munich university hospital. 22 patients had confirmed SARS-CoV2-infection (COVID-19 group), 14 patients had bacterial or other viral pneumonia (control group). Demographic, clinical parameters and laboratory tests including coagulation parameters and thromboelastometry were analysed. RESULTS: No differences were found in gender ratios, BMI, Horovitz quotients and haemoglobin values. The median SOFA score, serum lactate levels, renal function parameters (creatinine, urea) and all inflammation markers (IL-6, PCT, CRP) were lower in the COVID-19 group (all: p < 0.05). INR (p < 0.001) and antithrombin (p < 0.001) were higher in COVID-19 patients. D-dimer levels (p = 0.004) and consecutively the DIC score (p = 0.003) were lower in this group. In ExTEM®, Time-to-Twenty (TT20) was shorter in the COVID-19 group (p = 0.047), these patients also had higher FibTEM® MCF (p = 0.005). Further, these patients presented with elevated antigen and activity levels of von-Willebrand-Factor (VWF). CONCLUSION: COVID-19 patients presented with higher coagulatory potential (shortened global clotting tests, increased viscoelastic and VWF parameters), while DIC scores were lower. An intensified anticoagulation regimen based on an individual risk assessment is advisable to avoid thromboembolic complications.

[Is the discipline associated with self-confidence in handling rational antibiotic prescription? : Results from the MR2 study in German hospitals]. / Ist die Fachrichtung assoziiert mit der Selbstsicherheit im Umgang mit rationaler Antibiotikaverordnung? : Ergebnisse der MR2-Studien an deutschen Kliniken.

BACKGROUND: Besides public awareness and specialist knowledge and training of physicians, their self-confidence plays a key role for clinical decision-making in the respective area. OBJECTIVE: This exploratory study investigated the influence of the discipline on differences in self-confidence in dealing with antibiotics and in the self-rated knowledge. METHODS: In 2015 the multi-institutional reconnaissance of practice with multiresistant bacteria (MR2) questionnaire containing items on antibiotic prescription and multiresistant pathogens was sent out to 1061 physicians working in departments for internal medicine, general surgery, gynecology and obstetrics and urology. In 2017 a similar MR2 survey was sent to 1268 specialist and assistant physicians in anesthesiology in Germany. Besides demographic data 4 items on self-confidence in the use of antibiotic treatment and 11 items concerning self-rated knowledge about rational antibiotic therapy and multiresistant pathogens were included in the present analysis. Logistic regression analysis, the χ2-test and the Kruskal-Wallis test were used for statistical analysis of the influence of the discipline on these items. RESULTS: The response rates were 43% (456 out of 1061) from the non-anesthetists and 56% (705 out of 1268) from the anesthetists. Of the non-anesthetists 44% and 57% of the anesthetists had had no advanced training on antibiotic stewardship during the year before the study. In the overall analysis anesthetists (mean±SD: 2.53±0.54) were significantly less self-confident about antibiotics than colleagues from other departments (internal medicine: 3.10±0.50, general surgery: 2.97±0.44, gynecology and obstetrics: 3.12±0.42 and urology: 3.15±0.44) in the unadjusted (all p<0.001) and adjusted comparison. The analysis of self-rated knowledge about rational antibiotic prescription showed similar results. Senior consultant status and advanced training in infectiology were significantly associated with self-confidence and self-rated knowledge about antibiotics. CONCLUSION: Anesthetists showed significantly less self-confidence in dealing with antibiotics than colleagues from other disciplines. Advanced training on a rational prescription of antibiotics was associated with a greater self-confidence, so that the implementation of compulsory courses on rational antibiotic stewardship in the respective residency curriculum needs to be considered.

Therapeutic drug monitoring-guided high dose meropenem therapy of a multidrug resistant Acinetobacter baumannii - A case report.

BACKGROUND: Infections with multidrug resistant Acinetobacter baumannii in immunocompromised patients are life-threatening. Therapeutic options are rare in this context, but patients are dependent on an effective antibiotic therapy. Thus, new antibiotic strategies are deemed necessary. CASE PRESENTATION: This case report recounts the therapeutic drug monitoring-guided meropenem therapy of a 32 years old patient admitted with acute exacerbation of cystic fibrosis. Veno-venous extracorporeal membrane oxygenation was initiated on the first day of admission to the intensive care unit. The patient showed insufficient serum trough levels of meropenem despite the maximum approved dose (2g every 8h) was administered which was due to augmented renal clearance. Through continuous infusion of the same cumulative dose, target levels were reached. On day 17 of admission, the patient underwent successful double-lung-transplant surgery and extracorporeal membrane oxygenation was ended. Unfortunately, the donor's lung was colonized with a multidrug resistant Acinetobacter baumannii that was positive for OXA-23 carbapenemase. Hence a combination therapy of intravenous sulbactam, tigecycline, meropenem and inhalative colistin was established, with a known minimal inhibitory concentration for meropenem of 32 mg/l. Under continuous infusion of 8 g meropenem/day, serum levels exceeded 32 mg/l over 12 days. The patient was transferred from the intensive care unit to a general ward without any signs of infection. CONCLUSIONS: Therapeutic drug monitoring-guided meropenem may be a sound new therapeutic option in eradicating multidrug resistant Acinetobacter and offer a novel therapeutic option in the field of personalized medicine.

Current clinical use of intravenous fosfomycin in ICU patients in two European countries.

PURPOSE: In Europe, intravenous fosfomycin (IV) is used particularly in difficult-to-treat or complex infections, caused by both Gram-positive and Gram-negative pathogens including multidrug-resistant strains. Here, we investigated the efficacy and safety of intravenous fosfomycin under real-life conditions. METHODS: Prospective, multi-center, and non-interventional study in patients with bacterial infections from 20 intensive care units (ICU) in Germany and Austria (NCT01173575). RESULTS: Overall, 209 patients were included (77 females, 132 males, mean age: 59 ± 16 years), 194 of which were treated in intensive care (APACHE II score at the beginning of fosfomycin therapy: 23 ± 8). Main indications (± bacteremia or sepsis) were infections of the CNS (21.5%), community- (CAP) and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP, 15.3%), bone and joint infections (BJI, 11%), abdominal infections (11%), and bacteremia (10.5%). Most frequently identified pathogens were S. aureus (22.3%), S. epidermidis (14.2%), Enterococcus spp. (10.8%), E. coli (12.3%) and Klebsiella spp. (7.7%). At least one multidrug-resistant (MDR) pathogen was isolated from 51 patients (24.4%). Fosfomycin was administered with an average daily dose of 13.7 ± 3.5 g over 12.4 ± 8.6 days, almost exclusively (99%) in combination with other antibiotics. The overall clinical success was favorable in 81.3% (148/182) of cases, and in 84.8% (39/46) of patients with ≥ 1 MDR pathogen. Noteworthy, 16.3% (34/209) of patients developed at least one, in the majority of cases non-serious, adverse drug reaction during fosfomycin therapy. CONCLUSION: Our data suggest that IV fosfomycin is an effective and safe combination partner for the treatment of a broad spectrum of severe bacterial infections in critically ill patients.

Simultaneous quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin in human serum using an isotope-dilution HPLC-MS/MS method.

The aim of the current study was to develop and validate a robust multi-analyte high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for simultaneous quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin, which are the most commonly used antibiotics in intensive care units. Sample clean-up included a protein precipitation protocol, followed by chromatographic separation on a C8 reverse phase HPLC column within 4 min, using a formic acid-ammonium formiate methanol step-elution gradient. All compounds were detected with electrospray ionization (ESI+) mass spectrometry in multiple reaction time monitoring. The method was validated according to the protocol from the European Medicines Agency and was thoroughly evaluated for interferences and quantification linearity. Linear relationships between peak area responses and drug concentrations were obtained in the range of 0.25-200 mg/l for cefepime, 0.25-120 mg/l for meropenem, 0.05-10 mg/l for ciprofloxacin, 0.125-10 mg/l for moxifloxacin, 0.125-50 mg/l for linezolid and 0.5-400 mg/l for piperacillin with an R2 > 0.997. Imprecision and inaccuracy values (both intra- and inter-assay) were ≤ 6.8% and ≤10.9% for all analytes in quality control samples, respectively. The assay proved to be selective for the study antibiotics, and the internal standards consistently compensated for matrix effects. The described simple and reliable HPLC-MS/MS assay is a powerful tool for routine TDM of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin in human serum in clinical laboratories. With a total process time of approximately 30 min, it allows for accurate and selective quantification up to the expected pharmacokinetic peak concentrations.

Posaconazole liquid vs tablet formulation in lung transplant recipients.

Posaconazole is an extended-spectrum triazole antifungal used in the treatment and prophylaxis of Aspergillus infections. It is available as oral suspension (POS-Liq) and delayed-release tablets (POS-Tab). The aim of this longitudinal, retrospective study was to compare the clinical effectiveness, toxicity and pharmacokinetics of POS-Liq vs POS-Tab in lung transplant recipients (LTx-recipients), who were treated with both formulations subsequently. Twenty-four consecutive LTx-recipients with 191 documented posaconazole trough levels (PTLs) for POS-Liq or POS-Tab were included. The administered daily doses were 300 mg for POS-Tab and 600 mg (prophylaxis) or 800 mg (therapy) for POS-Liq. Target PTLs were ≥700 ng/mL (prophylaxis) and ≥1250 ng/mL (therapy). The overall prophylactic and therapeutic response rates were 78% and 67%, respectively. No cases of hepatotoxicity or QT-prolongation were observed with either formulation. The achieved target PTLs were tripled under POS-Tab compared to POS-Liq with fewer risk factors for sub-therapeutic PTLs. Concomitant administration of POS-Tab significantly reduced the tacrolimus concentration-to-dose ratio (P = .001). We suggest the use of POS-Tab is appropriate for prophylaxis and therapy of Aspergillus infections in LTx-recipients, since POS-Tab displayed more reliable PTLs with no added adverse events. However, we recommend regular drug monitoring for POS-Liq and for therapy with POS-Tab and that immunosuppressant levels are monitored closely when the posaconazole formulation is switched.

[Analysis of workplace health promotion and its effect on work ability and health-related quality of life in a medium-sized business]. / Analyse der Arbeitsfähigkeit und gesundheitsbezogenen Lebensqualität im Rahmen bewegungsbezogener Maßnahmen der betrieblichen Gesundheitsförderung in einem mittelständischen Unternehmen.

This study analyses the effect of workplace health promotion on work ability and health-related quality of life in white-collar and blue-collar workers in a medium-sized business. The intervention group contains 75 subjects with a mean age of 36.6±10.63 years (55 men, 20 women). The participation rate is 47%. White-collar workers show improvement in their health-related quality of life regarding physical and psychological aspects and work ability. Physically inactive employees show improvement in their health-related quality of life regarding physical and psychological aspects as well as context. Active employees only show significant improvement in terms of work ability. In conclusion, the promotion of exercise in the context of occupational health promotion has a positive effect on quality of life and work ability of employees and, thus, is a benefit for both the individual as well as the business itself.

PET imaging in a case of the semantic variant of primary progressive aphasia.

A 64-year-old right-handed Caucasian presented with a four-year history of word-finding deficits and otherwise fluent speech production. Neurological examination remained unremarkable apart from the word finding impairment. Likewise, neuropsychological evaluation confirmed significantly reduced semantic word fluency. While brain MRI depicted only discrete anterior temporal atrophy, 18-fluorodeoxyglucose PET showed clear hypometabolism of the anterior temporal pole bilaterally with left predominance. An imaging-supported diagnosis of the semantic variant of primary progressive aphasia was established in close accordance to recently published diagnostic criteria.The PET findings can be regarded as typical for this condition and PET imaging proved helpful to delineate other variants (non-fluent and logopenic) of primary progressive aphasia.

Mucocutaneous candidiasis in a mandrill (Mandrillus sphinx).

An adult male mandrill (Mandrillus sphinx) suffered from chronic ulceration of the facial and gluteal skin and the oral and nasal mucosa. The ulcers were resistant to therapy and led to deterioration in the general condition of the animal. Microscopical examination revealed a severe, chronic, multifocal, granulomatous and eosinophilic dermatitis and panniculitis. There was also stomatitis and rhinitis with numerous intralesional fungal elements. These organisms were identified by immunohistochemistry, transmission electron microscopy, polymerase chain reaction and fungal culture as Candida albicans. Species identification was confirmed by MALDI-TOF mass spectrometry. A specific predisposing immunosuppressive factor for the deep chronic mucocutaneous candidiasis was not identified; however, social stress and/or a primary defect in cell-mediated immunity could not be excluded as possible causes for a predisposing immunodeficiency in the animal.

[Vocational training of future GPs in Swiss hospitals: the view of chief physicians]. / Weiterbildung von angehenden Hausärzten an stationären Weiterbildungsstellen: Sicht der Chefärzte.

BACKGROUND: We sought to assess the way future general practitioners are promoted by their chief physicians. METHODS: Semi quantitative questionnaires sent to 54 chief physicians (hospitals in cantons Zurich and Berne). RESULTS: 42 (77.8%) questionnaires were returned. 41 (97.6%) chief physicians asked the assistant physicians about their intended career. 23 (54.8%) discussed with future general practitioners (GPs) specific learning objectives. 32 (76.2%) chief physicians would have appreciated an official catalogue of learning objectives for future GPs. A GP-specific traineeship was lacking in most of the hospitals. CONCLUSIONS: The upcoming shortage of future GPs could be inhibited by an appropriate GP curriculum during the vocational training.

Bronchoconstriction in nonhuman primates: a species comparison.

Bronchoconstriction is a characteristic symptom of various chronic obstructive respiratory diseases such as chronic obstructive pulmonary disease and asthma. Precision-cut lung slices (PCLS) are a suitable ex vivo model to study physiological mechanisms of bronchoconstriction in different species. In the present study, we established an ex vivo model of bronchoconstriction in nonhuman primates (NHPs). PCLS prepared from common marmosets, cynomolgus macaques, rhesus macaques, and anubis baboons were stimulated with increasing concentrations of representative bronchoconstrictors: methacholine, histamine, serotonin, leukotriene D4 (LTD4), U46619, and endothelin-1. Alterations in the airway caliber were measured and compared with previously published data from rodents, guinea pigs, and humans. Methacholine induced maximal airway constriction, varying between 74 and 88% in all NHP species, whereas serotonin was ineffective. Histamine induced maximal bronchoconstriction of 77 to 90% in rhesus macaques, cynomolgus macaques, and baboons and a lesser constriction of 53% in marmosets. LTD4 was ineffective in marmosets and rhesus macaques but induced a maximum constriction of 44 to 49% in cynomolgus macaques and baboons. U46619 and endothelin-1 caused airway constriction in all NHP species, with maximum constrictions of 65 to 91% and 70 to 81%, respectively. In conclusion, PCLS from NHPs represent a valuable ex vivo model for studying bronchoconstriction. All NHPs respond to mediators relevant to human airway disorders such as methacholine, histamine, U46619, and endothelin-1 and are insensitive to the rodent mast cell product serotonin. Only PCLS from cynomolgus macaques and baboons, however, responded also to leukotrienes, suggesting that among all compared species, these two NHPs resemble the human airway mechanisms best.

[Vocational training of future GPs in Swiss hospitals: the view of assistant physicians]. / Weiterbildung von angehenden Hausärzten an stationären Weiterbildungsstellen: Sicht der Assistenzärzte.

BACKGROUND: We sought to assess views of young physicians, performing vocational training in hospitals, regarding primary care. METHODS: Semi quantitative questionnaires sent to 535 assistant physicians (hospitals in cantons Zurich and Berne). RESULTS: 318 (62.4%) questionnaires were returned. 143 (45.0%) of the assistant physicians considered becoming a general practitioner (GP). There from, 58 (40.3%) decided in their undergraduate phase, 56 (38.9%) decided postgraduate. They felt generally supported by supervisors. A lack of specific learning objectives and hospital GP-traineeships were revealed. CONCLUSIONS: Our study shows that the decision for a career in primary care is made in equal parts undergraduate and postgraduate. These future and potential GPs should be attracted by an appropriate GP curriculum during their vocational training.

Testicular and epididymal appendages in the cynomolgus macaque (Macaca fascicularis).

BACKGROUND: Vestigial remnants of the mesonephric duct and paramesonephric duct are well-known developmental abnormalities of the human testis and epididymis. METHODS AND RESULTS: During routine macroscopic and histological examination of four cynomolgus macaques, three different forms of testicular and epididymal appendages were observed, namely a unilateral appendix testis, a bilateral appendix epididymidis, and several vasa aberrantia. By histological and immunohistochemical examinations it could be demonstrated that both the appendix testis and the appendix epididymidis consisted of a central fibromuscular core and a pseudostratified columnar epithelium at the outer surface. The vasa aberrantia were attached to the connective tissue sheaths of the epididymis/testis and were represented by small duct-like or cystic structures internally lined with a simple cuboidal to columnar, partly ciliated epithelium. CONCLUSION: Awareness of these rudimental tissues in non-human primates is necessary to determine actual incidence rates in non-human primate species used in toxicological research and avoids misdiagnosing during routine necropsy and histological examinations.

Malignant nephroblastoma in a common marmoset (Callithrix jacchus).

Necropsy of a 17-month-old male common marmoset (Callithrix jacchus) with a history of increased abdominal girth resulted in the finding of a unilateral polycystic renal neoplasm. Detailed histopathologic and immunohistochemical investigations revealed different tissue types within the tumor including stromal connective tissue and fusiform mesenchymal cell formations surrounding blastemal cells as well as different developmental stages of organ-specific epithelial cells accompanied by extensive cyst formation. Metastases were not observed. In consideration of the macroscopic, histologic, and immunohistochemical findings, the tumor was classified as a nephroblastoma closely resembling the so-called Wilms' tumor, a malignant embryonic renal tumor frequently observed in humans, especially in young children. In contrast, this tumor entity has rarely been observed in nonhuman primates. This report represents the first documented case of a cystic variant of nephroblastoma in a nonhuman primate.