Evaluation of safety and efficacy outcomes of direct oral anticoagulants versus warfarin in normal and extreme body weights for the treatment of atrial fibrillation or venous thromboembolism.

Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to measure the impact of DOACs compared to warfarin on safety and efficacy outcomes in extreme body weight patients. This multi-center, health system, retrospective study examined the outcomes of patients with all body weights and extreme body weights prescribed a DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) or warfarin for atrial fibrillation or venous thromboembolism over a 9-year period. The primary outcome was a composite of thromboembolism, symptomatic recurrent VTE, or severe bleeding; analyzed by pre-determined BMI cutoffs. A total of 19,697 patients were included in the study: 11,604 in the DOAC group and in the 8093 in the warfarin group. 295 patients were underweight and 9108 patients were pre-obese to obese class 3. After adjusting for potential confounders, warfarin patients had higher odds of experiencing the composite outcome compared to DOAC patients (OR 1.337, 95% CI 1.212-1.475). Additionally, obese patients were 24.6% more likely to experience the outcome compared to normal BMI patients. Adjusted modeling showed that warfarin patients experienced higher bleed rates compared to DOAC patients (OR 1.432, 95% CI 1.266-1.620). Obese patients were less likely to be diagnosed with a bleed (OR 0.749, 95% CI 0.658-0.854), and underweight patients were more likely to be diagnosed with a bleed (OR 1.522, 95% CI 1.095-2.115) compared to normal BMI patients. In conclusion, DOACs for atrial fibrillation or VTE in patients with extreme body weights appear safe and effective when compared to warfarin.

Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients.

BACKGROUND: The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults. METHODS: Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule-based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis. RESULTS: A median (range) of 3 (2-4) blood and 3 (2-5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF Cmax and Cmin values (interquartile range [IQR]) were 2.97 (1.76-8.56) mg/L and 1.59 (0.77-2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%-10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively. CONCLUSIONS: Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic-pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.

Azole-resistant Aspergillus and Echinocandin-resistant Candida - What are the treatment options?

PURPOSE OF REVIEW: This review summarizes current treatment options for echinocandin-resistant Candida spp. (ERC) and azole-resistant Aspergillus fumigatus (ARAF), emphasizing recent in vitro/in vivo data, clinical reports, and consensus statements. RECENT FINDINGS: Advances in ERC and ARAF treatment are limited to specific antifungal combinations and dose optimization but remain reliant on amphotericin products. Although novel antifungals may provide breakthroughs in the treatment of resistant fungi, these agents are not yet available. Early identification and appropriate treatment remain a paramount, albeit elusive, task. SUMMARY: When either ERC or ARAF are suspected or proven, amphotericin products remain the cornerstone of initial therapy. For ERC, azoles are de-escalation options for susceptible isolates in stable patients to avoid amphotericin toxicities. Although combination echinocandin with high-dose salvage posaconazole or isavuconazole may be attempted in ARAF, it requires careful consideration following patient stabilization. Future research defining optimal therapies and early identification of ERC and ARAF is of extreme importance.