Gemeinschaftsklinikum Mittelrhein

Background: Cefiderocol, a siderophore cephalosporin, is approved for the treatment of infections caused by multi-drug-resistant Gram-negative bacteria (MRGN). At present, few data are available on the pharmacokinetics of this substance in critically ill patients, particularly for the treatment of central nervous system infections. Patients and Methods: Here, we reported on a 22-year-old male patient after severe open head trauma. Initial screening revealed colonization with 4MRGN A. baumannii (OXA-23) (perianal) and 4MRGN K. pneumoniae (KPC) (tracheal). Unfortunately, he developed ventriculitis (4MRGN A. baumannii). According to microbiological testing, the patient with normal renal function received 3 × 2 g/d i.v. cefiderocol as a prolonged infusion (3 h) and colistin 3 × 3 Mio. IU/d i.v. for 2 weeks. In addition to serum trough levels, drug monitoring was performed in the cerebrospinal fluid (CSF) via external ventricular drainage (24 h aliquots). Results: Serum and CSF specimens analyzed by liquid chromatography-mass spectroscopy (LC-MS) in the presence of severe meningeal inflammation yielded average CSF concentrations of cefiderocol from 5.48 to 8.40 (median 6.98) μg/mL and a concentration ratio CCSF mean/Cserum trough from 0.38 to 0.76 (median 0.48). The cefiderocol levels in the CSF were sufficient for eradication of A. baumannii. A subsequent CSF infection with K. pneumoniae (found initially in screening and resistant to cefiderocol) after completed treatment with cefiderocol was successfully treated with gentamicin (intrathecally) and ceftazidime/avibactam (i.v.). However, the patient died due to a Candida tropicalis infection detected in the CSF on day 71. Conclusions: Our results indicate that standard dosages of cefiderocol are sufficient for treatment of CNS infections in the presence of a severe disruption of the blood-CSF barrier.

Anthracyclines are an essential component of induction therapy for acute myeloid leukemia (AML), but their optimal dosing and the associated risk for cardiotoxicity remain under debate. The DaunoDouble trial compared daunorubicin at 60 (Dauno60) versus 90 mg/m2 (Dauno90) in combination with cytarabine (100 mg/m2 for 7 days) in newly diagnosed AML patients aged 18-65 years. Cardiac function was assessed by left ventricular ejection fraction (LVEF) and cardiac biomarkers (high-sensitivity troponin T [hsTnT], NT-proBNP) before treatment and on Day 15 in 317 randomized patients. Median LVEF declined significantly from 65% [IQR 60%-68.5%] to 61% [IQR 58%-67.8%] across all patients (p < 0.01), without significant differences between treatment arms. NT-proBNP levels measured after induction therapy correlated negatively with LVEF at the same time point (ρ = -0.24, p = 0.02), but did not change significantly during induction-neither between Day 1 and 15 nor between treatment arms. HsTnT levels increased significantly from 5 [IQR 4-8] to 8 ng/L [IQR 6-14] across all patients (p < 0.01), with higher post-induction values in the Dauno90 group (9.5 ng/L [IQR 7-14]) compared to Dauno60 (7 ng/L [IQR 5-14]; p < 0.01). In exploratory subgroup analyses, post-induction hsTnT levels were also significantly higher in patients with obesity and arterial hypertension. These findings provide evidence of a dose-dependent cardiotoxic effect of daunorubicin, already apparent at standard induction doses, and underscore the importance of early cardiac monitoring. Long-term follow-up will be essential to determine the clinical significance of these early changes. Trial Registration: ClinicalTrials.gov identifier: NCT02140242.

Heavy menstrual bleeding (HMB) is a common complication of anticoagulant therapy in menstruating women with venous thromboembolism (VTE). Direct oral anticoagulants (DOAC) used for VTE treatment may differ in their menstrual bleeding profiles. Therefore, the prospective multicenter noninterventional investigator-initiated HEMBLED registry (HE: avy M: enstrual BLE: eding in patients treated with D: OAC) was performed to analyze spontaneous menstrual bleeding in women treated with therapeutic DOAC doses.A modified pictorial blood assessment chart (PBAC) score was used to define the severity of menstrual bleeding. Patients were only included when they did not use hormonal or intrauterine contraception methods. The prospective follow-up was 4 months. The primary endpoint was the comparison of the PBAC scores between the individual DOAC groups.Overall, 73 patients with 213 monthly assessments of the PBAC scores were analyzed. Patients were on average 35 years old and were anticoagulated with apixaban (62%), rivaroxaban (26%), edoxaban (7%), or dabigatran (6%). The PBAC scores of the rivaroxaban group (mean: 145 points) were significantly increased by 54% compared with the apixaban group (mean: 93 points, p = 0.0193). HMB (PBAC score > 100 points) at least once was detected in 53% of the apixaban group compared with 79% of the rivaroxaban group (p = 0.0913). The duration of menstrual bleeding was numerically shorter in the apixaban group compared with the rivaroxaban group (p = 0.1894).DOAC differ in their influence on the intensity of spontaneous menstrual bleeding. This should be taken into account when advising young women with VTE who need an oral anticoagulant.

Background/Objectives: Phosphatidylinositol (PI) species are bioactive lipids implicated in liver fibrogenesis. Hepatitis C virus (HCV) relies on host lipid metabolism for infection. The relationship between serum PI profiles, chronic HCV, and liver injury remains incompletely defined. Methods: Fourteen PI species were quantified by direct flow injection–tandem mass spectrometry (FIA–MS/MS; triple quadrupole) in serum from 178 patients with chronic HCV at three time points: before treatment and at weeks 4 and 12 after starting direct-acting antiviral (DAA) therapy. Results: At baseline, PI 34:1, 36:1, and 36:3 were higher in patients with ultrasound-diagnosed cirrhosis than in those without, whereas PI 38:4, 40:5, and 40:6 were lower. In non-cirrhotic patients, PI 36:3, 36:4, 38:3, 38:4, and 38:5 increased, while PI 40:5 and 40:6 declined at weeks 4 and 12 after therapy start. In cirrhosis, viral cure was not associated with changes in PI species. By the end of therapy, cirrhotic patients showed higher PI 36:3 and lower PI 38:4 than non-cirrhotic patients. Genotype 3a was associated with lower PI 38:3, 38:4, and 38:5; the reduction in PI 38:4 persisted to the end of therapy. Across time points, most PI species did not correlate with routine markers of liver injury or inflammation. Conclusions: HCV cure remodels the serum PI profile in non-cirrhotic patients. These findings suggest that altered PI profiles are primarily linked to HCV infection, supporting a role for PI lipids in viral propagation.

PurposeThe objective of this study was to systematically review the existing literature related to adjuvant injection therapies among patients with cartilage defects of the knee joint who have undergone bone marrow stimulation procedures and ascertain their potential clinical benefits.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines, a search was conducted on PubMed and the Cochrane Library to identify articles documenting the utilization of adjuvant injection therapies after surgery for cartilage defects, with a minimum short‐term follow‐up. Animal studies, uncontrolled trials, studies lacking primary surgical intervention or those including patients with osteoarthritis were excluded.ResultsTwelve articles focusing on knee cartilage defects were analysed (531 patients). Platelet‐rich plasma was used in eight studies, mesenchymal stromal cells in four and hyaluronic acid in one. Injection frequency and timing varied, with the most common timing being during surgery. Primary outcome measures included subjective International Knee Documentation Committee (IKDC) and Visual Analogue Scale (VAS) scores. Subjective IKDC showed significant difference in five out of nine studies and VAS in three out of eight studies, favouring injection therapy groups.ConclusionThe present review demonstrates a large heterogeneity among included studies regarding surgical interventions, injection strategies and timing as well as outcome measures. While several studies suggest a potential benefit of adjuvant therapies, findings remain inconsistent. Due to the limited quality and comparability of the evidence, no definitive recommendations can be made at this time, highlighting the need for standardized protocols and high‐quality randomized controlled trials.Level of EvidenceLevel IV.