Rapid Development of Cefiderocol Resistance in Carbapenem-resistant Enterobacter cloacae During Therapy Is Associated With Heterogeneous Mutations in the Catecholate Siderophore Receptor cirA.

We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

The Problem of Appetite Loss After Major Abdominal Surgery: A Systematic Review.

OBJECTIVE: To systematically review the problem of appetite loss after major abdominal surgery. SUMMARY OF BACKGROUND DATA: Appetite loss is a common problem after major abdominal surgery. Understanding of etiology and treatment options is limited. METHODS: We searched Medline, Cochrane Central Register of Controlled Trials, and Web of Science for studies describing postoperative appetite loss. Data were extracted to clarify definition, etiology, measurement, surgical influence, pharmacological, and nonpharmacological treatment. PROSPERO registration ID: CRD42021224489. RESULTS: Out of 6144 articles, we included 165 studies, 121 of which were also analyzed quantitatively. A total of 19.8% were randomized, controlled trials (n = 24) and 80.2% were nonrandomized studies (n = 97). The studies included 20,506 patients undergoing the following surgeries: esophageal (n = 33 studies), gastric (n = 48), small bowel (n = 6), colon (n = 27), rectal (n = 20), hepatobiliary (n = 6), and pancreatic (n = 13). Appetite was mostly measured with the Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer (EORTC QLQ C30, n = 54). In a meta-analysis of 4 randomized controlled trials gum chewing reduced time to first hunger by 21.2 hours among patients who had bowel surgery. Other reported treatment options with positive effects on appetite but lower levels of evidence include, among others, intravenous ghrelin administration, the oral Japanese herbal medicine Rikkunshito, oral mosapride citrate, multidisciplin-ary-counseling, and watching cooking shows. No studies investigated the effect of well-known appetite stimulants such as cannabinoids, steroids, or megestrol acetate on surgical patients. CONCLUSIONS: Appetite loss after major abdominal surgery is common and associated with increased morbidity and reduced quality of life. Recent studies demonstrate the influence of reduced gastric volume and ghrelin secretion, and increased satiety hormone secretion. There are various treatment options available including level IA evidence for postoperative gum chewing. In the future, surgical trials should include the assessment of appetite loss as a relevant outcome measure.

Plasma concentrations of posaconazole administered via nasogastric tube in patients in a surgical intensive care unit.

Abdominal surgery may affect intestinal absorption and the resulting levels of posaconazole in the blood. We measured plasma posaconazole levels in surgical intensive care unit (SICU) patients and tried to develop a predictive population pharmacokinetics model. A total of 270 samples from 15 patients receiving posaconazole via nasogastric tube were measured by high-performance liquid chromatography (HPLC). SICU patients showed lower plasma drug concentrations, a higher apparent clearance, and a higher volume of distribution than those in hematology patients, possibly due to poor absorption.

Posaconazole as part of the antifungal armamentarium in the intensive care unit--case reports from a surgical ICU.

The authors describe two cases of successful and safe posaconazole use in patients of a surgical intensive care unit of a university hospital.

Implementation of practice guidelines for antifungal therapy in a surgical intensive care unit and its impact on use and costs.

BACKGROUND: Considering the complexity of diagnosis, high costs of therapy and high morbidity and mortality of systemic fungal infections, antifungal therapy of intensive care patients should follow clearly defined guidelines. We outline the impact of a standardised practice of antifungal treatment in an interdisciplinary surgical intensive care unit of a university hospital. METHODS: Therapy was intended to be optimised by implementation of standardised practice guidelines supported by the clinical pharmacist. Costs for antifungal agents during a period of 18 months before and after implementation of the practice guidelines were compared, respectively. RESULTS: The intervention was associated with a significant decrease in use of antifungal agents. Analysis of data revealed a reduction in costs by 50%. This could substantially be attributed to the implementation of the practice guidelines. CONCLUSION: The implementation of standardised practice guidelines for antifungal therapy in intensive care units decreased the use of selected antifungal agents and resulted in substantial reduction in expenditure on antifungal agents.

Substandard anti-malarial drugs in Burkina Faso.

BACKGROUND: There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. METHODS: A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers) and illicit (market and street vendors, shops) sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. RESULTS: Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50%) chloroquine, 10/77 (13%) pyrimethamine-sulphadoxine, 9/77 (12%) quinine, 6/77 (8%) amodiaquine, 9/77 (12%) artesunate, and 4/77 (5%) artemether-lumefantrine. 32/77 (42%) drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6%) and 27/30 (90.0%) samples of substandard drugs respectively. CONCLUSION: These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the now wider available and substantially more costly artemisinin-based combination therapies.

Posaconazole in intensive care patients I: invasive fungal infections in surgical intensive care and case presentation.

Critically ill patients after extended surgical procedures are at high risk for postoperative infections. Fungal infections play a substantial role for immunocompromised patients, e.g. after solid organ transplantation or under chronic corticoid therapy. Posaconazole, a new broad-spectrum triazole effective against Aspergillus and Candida species as well as many fungi that are resistant to other antifungals, is well tolerated and can be used as an alternative in salvage therapy. Posaconazole can be administered via gavage so that antifungal therapy can be switched from an expensive intravenously applied antifungal to oral posaconazole at an early stage. Two case reports are presented, which show that posaconazole was efficacious and well tolerated following antifungal therapy with another azole. It was administered without difficulty via gavage to a patient receiving artificial respiration and dialysis.

Best practice strategies to safeguard drug prescribing and drug administration: an anthology of expert views and opinions.

BACKGROUND: While evidence on implementation of medication safety strategies is increasing, reasons for selecting and relinquishing distinct strategies and details on implementation are typically not shared in published literature. OBJECTIVE: We aimed to collect and structure expert information resulting from implementing medication safety strategies to provide advice for decision-makers. SETTING: Medication safety experts with clinical expertise from thirteen hospitals throughout twelve European and North American countries shared their experience in workshop meetings, on-site-visits and remote structured interviews. METHODS: We performed an expert-based, in-depth assessment of implementation of best-practice strategies to improve drug prescribing and drug administration. MAIN OUTCOME MEASURES: Workflow, variability and recommended medication safety strategies in drug prescribing and drug administration processes. RESULTS: According to the experts, institutions chose strategies that targeted process steps known to be particularly error-prone in the respective setting. Often, the selection was channeled by local constraints such as the e-health equipment and critically modulated by national context factors. In our study, the experts favored electronic prescribing with clinical decision support and medication reconciliation as most promising interventions. They agreed that self-assessment and introduction of medication safety boards were crucial to satisfy the setting-specific differences and foster successful implementation. CONCLUSION: While general evidence for implementation of strategies to improve medication safety exists, successful selection and adaptation of a distinct strategy requires a thorough knowledge of the institute-specific constraints and an ongoing monitoring and adjustment of the implemented measures.

Intracranial haemorrhage in patients treated with direct oral anticoagulants.

INTRODUCTION: Direct oral anticoagulants (DOAC) are increasingly used for the prevention and treatment of thromboembolic events. However, only little evidence is available regarding the management of patients who are treated with DOAC and present with potentially life-threatening intracranial haemorrhage. Herein, we describe our experience with respective patients treated at our institution. METHODS: We retrospectively analysed all consecutive patients with DOAC intake and intracranial haemorrhage treated at our institution from 09/2011 to 03/2015. Patient characteristics were analysed with specific focus on results of laboratory studies, treatment modalities and patient outcomes. Findings were compared between survivors (SV) and non-survivors (NSV) on day 30 after admission. RESULTS: A total of 55 patients were identified. The 30-day mortality rate in this patient cohort was 20.0%. Neurosurgical procedures were carried out in 37 patients (67%). Median values of international normalized ratio (INR) did not differ significantly between SV (1.11) and NSV (1.09). Renal function was significantly lower in NSV (median serum creatinine: 115µmol/l) than in SV (median serum creatinine: 69µmol/l; p<0.05) and all patients with serum creatinine levels >125µmol/l died during in-hospital treatment. Pro-haemostatic therapy with prothrombin complex concentrates (PCC) had no effect on INR in repeated measurements. CONCLUSION: Our experience demonstrates that successful neurosurgical management of patients with intracranial haemorrhage and DOAC intake is feasible. However, drastic deterioration was observed in some patients, particularly when impaired renal function was present. The role of pro-haemostatic therapy with PCC is unclear. These findings underscore the urgent need of improving treatment modalities for these patients.

Development and validation of a high-performance liquid chromatography assay for posaconazole utilizing solid-phase extraction.

BACKGROUND: Posaconazole is a new broad-spectrum triazole antifungal drug that is used in prophylaxis and therapy of opportunistic fungal infections in immunocompromised patients. Up to now, it is available as an oral suspension only. Due to variable systemic availability known from other azoles, such as itraconazole, it is important to measure blood levels, especially in patients undergoing abdominal surgery which may influence the intestinal resorption. METHODS: A sensitive and selective high-performance liquid chromatography method for the precise determination of posaconazole and the internal standard clotrimazole in human plasma was developed and validated. Samples were extracted using solid-phase extraction and separated on a reversed-phase C8 column (150 x 4.6 mm, 5 microm) using phosphate buffer (pH 6.7, 0.04 M):acetonitrile:methanol (43:49:8, v/v/v) as mobile phase. UV detection was performed at 260 nm. RESULTS: This method showed that a lower limit of quantification was 50 ng/mL and the limit of detection 3 ng/mL. Linearity was tested in the range from 50 to 5000 ng/mL (r(2)=0.9998). Mean recovery was 86%. CONCLUSIONS: The method proved to be a useful tool for therapeutic drug monitoring. It is specific, precise and showed excellent reproducibility as well as a favourable accuracy.