On the impact of surveillance test strategies: a cost-benefit modelling analysis based upon real-world data from SARS-CoV-2.

OBJECTIVES: Active regular surveillance testing of asymptomatic and symptomatic individuals can reduce infection and onward transmission rates, as demonstrated for SARS-CoV-2. STUDY DESIGN: Cost-benefit analysis based on real-world data. METHODS: Two different surveillance-testing strategies using nucleic acid amplification tests (NAATs) performed in 14,177 hospital employees were compared for their costs and their effectiveness in preventing secondary infections. RESULTS: Compared to not testing, NAAT-based testing twice a week accompanied by contact tracing or testing five times a week without tracing of contacts were more effective in preventing infections through early identification of infected individuals. While expansion of the test frequency from two to five times per week increased the initial costs, importantly, a 49.6 % higher inhibitory effect on infection growth with a 11.1-fold reduction of potentially averted infections and resulting workforce loss was observed, demonstrating a substantial cost-benefit of the 5-tests-per-week strategy. CONCLUSIONS: Adaptation of the test frequency of SARS-CoV-2 and possibly of other pathogens with epidemic potential according to the prevailing incidences and reproduction rates in high-prevalence situations may not only be beneficial in averting potential infections in hospital employees and, subsequently, on a population level but may also represent the most cost-effective method.

In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model.

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy. Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma. Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min. Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Sepsis caused by multidrug-resistant klebsiella pneumoniae infection in a 23-year-old burn patient: case report and literature review.

Septic complications are a major problem in burn care. Infections caused by multidrug-resistant (MDR) Klebsiella pneumoniae strains represent a growing threat. In particular, Romania has seen rapidly increasing rates of MDR Klebsiella pneumoniae isolates in recent years. The PubMed database was searched with the terms 'Klebsiella pneumoniae', 'multiple drug resistant', 'enterobacteria', 'infection', 'sepsis or septicaemia or blood stream infection', 'surveillance', 'diagnose', 'burn', 'intensive care unit' and 'Romania or Europe'. In addition, the case of a burn patient who suffered from sepsis caused by MDR Klebsiella pneumoniae and who was treated at our burn intensive care unit (ICU) was reviewed. The 23-year-old male was initially treated in Romania, but after 48 hours he was transferred to our burn ICU. Initially, the treatment course was appropriate and sufficient wound healing was achieved by day 27. However, the patient's condition deteriorated rapidly on day 28 and blood culture analysis showed growth of MDR Klebsiella pneumoniae. Despite intensive medical therapy, the patient died as a result of multiple organ failure (MOF) on day 44. Sepsis caused by MDR Klebsiella pneumoniae represents an enormous therapeutic challenge. Burn patients who are transferred from Southeast Europe would likely benefit from an intensified screening for MDR pathogens.

Les accidents septiques sont une préoccupation majeure en brûlologie. Celles dues à Klebsiella pneumoniæ multirésistante (KP-BMR) sont en augmentation, particulièrement rapide ces dernières années en Roumanie. Nous avons effectué une recherche PubMed avec les critères « Klebsiella pneumoniæ ¼, « multirésistant ¼, « entérobactérie ¼, infection ¼, « sepsis ¼, septicémie ¼, « surveillance ¼, « diagnostic ¼, « brûlure ¼, « unité de soins intensifs ¼, « Roumanie ¼, « Europe ¼, à la suite du cas d'un patient de 23 ans, transféré dans notre service en provenance de Roumanie, à sa 48ème heure d'hospitalisation. La couverture cutanée était terminée à J27. Á J28, son état s'est rapidement dégradé et les hémocultures sont revenues positives à KP-BMR. Le patient est décédé à J44, dans un tableau de défaillance multiviscérale. Les infections à KP-BMR représentent un formidable défi. Les patients en provenance d'Europe du Sud-Est devraient bénéficier d'un screening bactériologique à la recherche de BMR.

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients.

Critically ill patients often experience acute kidney injury and the need for renal replacement therapy in the course of their treatment in an intensive care unit (ICU). These patients are at an increased risk for candidiasis. Although there have been several reports of micafungin disposition during renal replacement therapy, to this date there are no data describing the elimination of micafungin during high-dose continuous venovenous hemodiafiltration with modified AN69 membranes. The aim of this prospective open-label pharmacokinetic study was to assess whether micafungin plasma levels are affected by continuous hemodiafiltration in critical ill patients using the commonly employed AN69 membrane. A total of 10 critically ill patients with micafungin treatment due to suspected or proven candidemia were included in this trial. Prefilter/postfilter micafungin clearance was measured to be 46.0 ml/min (±21.7 ml/min; n = 75 individual time points), while hemofilter clearance calculated by the sieving coefficient was 0.0038 ml/min (±0.002 ml/min; n = 75 individual time points). Total body clearance was measured to be 14.0 ml/min (±7.0 ml/min; n = 12). The population area under the curve from 0 to 24 h (AUC0-24) was calculated as 158.5 mg · h/liter (±79.5 mg · h/liter; n = 13). In spite of high protein binding, no dose modification is necessary in patients receiving continuous venovenous hemodiafiltration with AN69 membranes. A dose elevation may, however, be justified in certain cases. (This study has been registered at ClinicalTrials.gov under identifier NCT02651038.).

Dalbavancin reduces biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE).

Activity of dalbavancin against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) in biofilm was investigated and the microbicidal biofilm concentrations (MBC) were determined. Biofilms obtained from ten MRSA and ten MRSE bloodstream isolates, collected from patients in the General Hospital of Vienna between 2012 and 2015, were incubated with dalbavancin in trypticase soy broth (TSB) in serial dilution from 0.0625 mg/l to 256 mg/l using a microtiter plate biofilm model. The plates were incubated for 24 h at 37 ° C and 50% humidity. Biofilms were fixed with 2.5% glutaraldehyde and stained with crystal violet. Subsequently the optical density (OD620) was used to measure the MBC, defined as the concentration of dalbavancin leading to a 50% reduction of biofilm. MBC for MRSA was 1 mg/l-4 mg/l (minimal inhibitory concentrations (MIC) 0.0312 mg/l-0.064 mg/l). MBC for MRSE was 2 mg/l-16 mg/l (MIC 0.023 mg/l-0.0625 mg/l). Dalbavancin successfully reduced MRSA and MRSE in biofilms, and therefore provides a promising option for the treatment of biofilm-associated infections.

Doripenem Treatment during Continuous Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Hepatosplenic Abscesses and Osteomyelitis of the Spine in an Immunocompetent Adult with Cat Scratch Disease.

We present an 18-year-old, immunocompetent Austrian military conscript with cervical lymphadenopathy, fever, back-pain, and persistent inflammation markers despite two weeks of antimicrobial therapy with ampicillin/sulbactam. All specific laboratory investigations for identification of a specific etiology, including blood cultures and autoantibodies, were inconspicuous. Abdominal computed tomography showed multiple hypodense hepatosplenic lesions and osteomyelitis of the thoracic and lumbar spine with base plate fracture. Based on the patient's history, clinical presentation, and radiological findings, serology for cat scratch disease (CSD) was performed and high B. henselae specific IgM and IgG antibodies were detected. Due to its variety of clinical presentations, diagnosis of CSD is challenging, especially in the absence of a history of specific exposure. This case report shall remind the physician that cat scratch disease is a common disease, mainly presenting with fever and lymphadenopathy in young patients. Nevertheless CSD has many different and rare forms of presentations, including hepatosplenic lesions and bone involvement as shown in this case.

[Probiotics for the prevention of antibiotic-induced diarrhea]. / Probiotika in der Prävention der Antibiotika-induzierten Diarrhö.

Between 5 and 49% of patients treated with antibiotics suffer from diarrhoea. Principally all microbial agents can cause diarrhoea, especially oral agents like cephalosporines, clindamycin, broad-spectrum penicillins, and quinolones of the 3  rd and 4th generation. Manifestations of antibiotic-associated diarrhoea range from mild self-limiting forms to severe life-threatening courses. The potentially most severe form of antibiotic-associated diarrhoea is caused by Clostridium diffcile accounting for approx. 25  % of antibiotic-associated diarrhoea. In the past two decades a broad spectrum of different probiotic strains has been evaluated for the primary prevention of antibiotic-associated diarrhoea in children and adults. Based on their efficacy and clinical data, different levels of evidence and recommendations are emerging on the preventive use of probiotics in antibiotic-associated diarrhoea.

Hepatotoxicity of antibacterials: Pathomechanisms and clinical.

Drug-induced hepatotoxicity is a frequent cause of liver disease and acute liver failure, particularly in patients treated with multiple drugs. Several antibacterial drugs have the potential to cause severe liver injury and failure. This article aims to increase the awareness and understanding of drug induced liver injury (DILI) due to antibacterial drugs. It reviews the pattern of antibacterial DILI and provides details on molecular mechanisms and toxicogenomics, as well as clinical data based on epidemiology studies. Certain antibacterial drugs are more frequently linked to hepatotoxicity than others. Therefore, the hepatotoxic potential of tetracyclines,sulfonamides, tuberculostatic agents, macrolides, quinolones,and beta-lactams are discussed in more detail. Efforts to improve the early detection of DILI and the acquisition of high-quality epidemiological data are pivotal for increased patient safety.

Intermittent administration of betalactam-antibiotics for treatment of severe infection in hemodialysis patients.

Infections are a leading cause of morbidity and mortality in hemodialysis patients. Still, due to altered pharmacokinetics and potential toxic sideeffects, safe and efficient antibiotic therapy in dialysis patients remains a major challenge. We reviewed our experience with intermittent administration of betalactam antibiotics for treatment of severe infections in hemodialysis patients. A total of 81 episodes of infection in 45 patients was assessed. All patients were treated with betalactam antibiotics (cefepime in 11 episodes, cefpirom in 33 episodes, piperacillin in 9 episodes, amoxicillin in 18 episodes, ceftazidime in 10 episodes, respectively). All antibiotics were given post hemodialysis 3x per week. Treatment was considered efficient in case of a significant decrease in CRP in addition to clinical response. Overall treatment success rate was 85% (69 episodes of infection). The decrease of CRP was 52% (6.9 +/- 5.8 to 3.3 +/- 4.9 mg/dl; p = 0.00003). The mean duration of treatment was 19 +/- 13 days. Treatment was generally well tolerated. We conclude, that severe infections in hemodialysis patients can be treated safely and efficiently with an empiric therapy with betalactam antibiotics. Intermittent administration, potentially allowing ambulatory treatment, is possible.

[Tubercular osteomyelitis of the clivus and the nasopharynx]. / Tuberkulöse Osteomyelitis des Klivus mit Beteiligung des Nasopharynx.

Involvement of the skull base is rare in tuberculosis. We report here the case of a 28-year-old female patient with an osteolytic process of the clivus with compression of the brain stem and involvement of the nasopharynx. She reported suffering from headaches for the last 6 months, and diplopia had occurred 1 week before her diagnosis as a result of paresis of the VIth cranial nerve on the right side. A biopsy was obtained endoscopically via a transnasal approach, revealing a granulomatous inflammation with acid-fast rods and thus confirming the diagnosis of a tuberculoma. When the biopsy was taken there was no evidence of any further tuberculomas in this patient. The clinical picture, diagnosis, and treatment of tuberculosis of the skull base and nasopharynx are discussed and the literature on this rare clinical entity is reviewed with reference to this patient's case report.

Pharmacokinetics of teicoplanin during continuous hemofiltration with a new and a 24-h used highly permeable membrane: rationale for therapeutic drug monitoring-guided dosage.

OBJECTIVE: Continuous venovenous hemofiltration (CVVH) is widely used in the management of critically ill patients, but only few administration guidelines for antimicrobial drugs are available. It is unclear whether the use of a filter for more than 24 hours might lead to less efficient extraction. This study describes the pharmacokinetics of teicoplanin during CVVH using a highly permeable membrane. METHODS: Pharmacokinetics of teicoplanin during continuous hemofiltration with a new (group 1) and a 24-h used (group 2), highly permeable polyamide membrane were assessed in 3 patients. RESULTS: The teicoplanin serum concentrations (44.0 +/- 18.5 mg/l vs 109.5 +/- 34.5 mg/l) and half-life of teicoplanin (4.6 +/- 1.1 h vs 5.2 +/- 0.7 h) differed significantly between the 2 groups indicating a smaller elimination of the drug on the second day. Substantial binding of teicoplanin to filter membranes could explain this observation. CONCLUSION: The results suggest that daily adjustment of the dosage is necessary to achieve sufficient teicoplanin concentrations and a fixed dosage recommendation is not suitable for this drug.

[Left ventricular dysfunction in Churg-Strauss syndrome]. / Linksventrikuläre Dysfunktion im Rahmen von Churg-Strauss-Syndrom.

Churg-Strauss syndrome is a rare disorder characterized by hypereosinophilia and a systemic vasculitis occurring inpatients with asthma and allergic rhinitis. Vasculitis commonly affects the lungs, the heart, the skin, and the peripheral nervous system. Cardiac involvement is characterized by acute and constrictive pericarditis, myocarditis and endocarditis, as well as ischemic cardiomyopathy. Endomyocardial fibrosis similar to Loeffler's syndrome has been rarely described. In the presented case, a 43 year old man with a history of allergy and asthma suffered from increasing dyspnea, fever, pulmonary infiltates and cardiomyopathy. Laboratory studies were notable for marked hypereosinophilia. In a bronchoscopic lavage and transbronchial biopsy eosinophilic infiltrates accompanied by vasculitis were found, Churg-Strauss syndrome was diagnosed. Echocardiogram showed endomyocardial deposits in the apex of the right ventricle, right ventricular function was normal particular in the basal segments. The left ventricle was slightly enlarged and left ventricular function was impaired. The diastolic mitral in-flow showed a restrictive pattern. Additionally, a pericardial effusion was observed without signs of tamponade. The patient received corticosteroids, cyclophosphamide and cardiomyopathy-specific therapy and showed a marked improvement after 4 months.

Application of blood-based polymerase chain reaction for detection of Chlamydia pneumoniae in acute respiratory tract infections.

The aim of this study was to investigate whether blood-based polymerase chain reaction could serve as a diagnostic tool to identify individuals with acute respiratory Chlamydia pneumoniae infection. Respiratory specimens and peripheral blood mononuclear cells of 58 patients were analyzed using nested polymerase chain reaction and cell culture. Fifteen patients were polymerase chain reaction-positive for Chlamydia pneumoniae. Nine patients were positive in only the respiratory specimen; two in both the respiratory and blood sample (time intervals between onset of symptoms and sample collection, 3-10 days and 3-4 weeks, respectively); and four in only the blood sample. Detection of Chlamydia pneumoniae DNA in peripheral blood mononuclear cells does not seem to be a suitable marker for acute respiratory Chlamydia pneumoniae infection.

Continuous beta-lactam antibiotic therapy in a double-lung transplanted patient with a multidrug-resistant Pseudomonas aeruginosa infection.

BACKGROUND: It is well known that the bactericidal effect of beta-lactam antibiotics is closely related to the time which the serum concentration of the antibiotic remains above the minimal inhibitory concentration of the target pathogen. Thus, the optimal administration of beta-lactam antibiotics would be the continuous infusion of the drug. METHODS: We present a case report with a critically ill double-lung transplanted patient with pneumonia due to a multidrug-resistant Pseudomonas aeruginosa who received continuously 8 g meropenem/24 hr. Based on a previous pharmacokinetic study showing that continuous infusion of meropenem is at least equivalent to intermittent administration this case report is reported to demonstrate the clinical efficacy of continuous infusion. RESULTS: C-reactive protein and pneumonia decreased rapidly when clinical conditions were improved significantly. Continuous administration of meropenem did not interfere with cyclosporine, no side effects were seen, and the patient's renal function was not impaired during the whole period of treatment. CONCLUSION: The continuous administration of beta-lactam antibiotics is a powerful application in critically ill patients to intensify antimicrobial therapy.

Single-dose pharmacokinetics of levofloxacin during continuous veno-venous haemofiltration in critically ill patients.

The present study was performed to analyse the pharmacokinetics of levofloxacin during continuous veno-venous haemofiltration (CVVH) with a high-flux polyamide membrane. Twelve patients received 500 mg levofloxacin intravenously. The mean levofloxacin concentration peak was 1.9 +/- 1.0 mg/L. The elimination half-life, haemofiltration clearance and total removal were 8.3 +/- 2.6 h, 27.6 +/- 8.4 mL/min and 56 +/- 19%, respectively. Further multiple-dose studies are required to enable dosage recommendations to be made for patients receiving renal replacement therapy with CVVH.