Enteral feeding tube administration with therapeutic drug monitoring of crushed posaconazole tablets and opened isavuconazonium sulfate capsules.

BACKGROUND: Isavuconazole and posaconazole are commonly used for both prophylaxis and treatment of invasive fungal infections. These agents are formulated for oral administration as a capsule and delayed release (DR) tablet or suspension, respectively. In patients unable to swallow, alternative means of administration, such as crushing posaconazole DR tablets and opening isavuconazole capsules, may be used to avoid IV administration or use of posaconazole suspension, which often produces subtherapeutic concentrations. OBJECTIVES: To assess the feasibility of achieving target plasma drug concentrations with enteral feeding tube (EFT) administration of crushed posaconazole DR tablets and opened isavuconazole capsules. METHODS: We retrospectively reviewed pharmacy records to identify patients receiving EFT administration of posaconazole or isavuconazole with concurrent therapeutic drug monitoring from October 2019 to June 2021. Plasma concentrations of either agent as well as clinical outcomes were documented. RESULTS: We identified 37 patients receiving 38 courses of EFT isavuconazole or posaconazole. The majority of patients received primary prophylaxis following lung transplantation (64.9%). Plasma concentrations upon first assessment were therapeutic in the majority of patients (posaconazole 71.5%, isavuconazole 83.3%) with a mean level of 1.61 ± 0.77 mg/L for posaconazole and 2.07 ± 1.1 mg/L for isavuconazole. Of those that were subtherapeutic on initial assessment, all but one subsequently achieved target levels upon dose titration. Standard maintenance doses were used in all isavuconazole and most posaconazole patients. CONCLUSIONS: Our case series demonstrates that isavuconazole and posaconazole can be administered via EFT with concurrent therapeutic drug monitoring to achieve target plasma concentrations in the majority of patients.

Inpatient antibiotic utilization in the Veterans' Health Administration during the coronavirus disease 2019 (COVID-19) pandemic.

Antibiotic prescribing practices across the Veterans' Health Administration (VA) experienced significant shifts during the coronavirus disease 2019 (COVID-19) pandemic. From 2015 to 2019, antibiotic use between January and May decreased from 638 to 602 days of therapy (DOT) per 1,000 days present (DP), while the corresponding months in 2020 saw antibiotic utilization rise to 628 DOT per 1,000 DP.

Evaluation of antibiotic escalation in response to nurse-driven inpatient sepsis screen.

Objective: To determine the frequency and predictors of antibiotic escalation in response to the inpatient sepsis screen at our institution. Design: Retrospective cohort study. Setting: Two affiliated academic medical centers in Los Angeles, California. Patients: Hospitalized patients aged 18 years and older who had their first positive sepsis screen between January 1, 2019, and December 31, 2019, on acute-care wards. Methods: We described the rate and etiology of antibiotic escalation, and we conducted multivariable regression analyses of predictors of antibiotic escalation. Results: Of the 576 cases with a positive sepsis screen, antibiotic escalation occurred in 131 cases (22.7%). New infection was the most documented etiology of escalation, with 76 cases (13.2%), followed by known pre-existing infection, with 26 cases (4.5%). Antibiotics were continued past 3 days in 17 cases (3.0%) in which new or existing infection was not apparent. Abnormal temperature (adjusted odds ratio [aOR], 3.00; 95% confidence interval [CI], 1.91-4.70) and abnormal lactate (aOR, 2.04; 95% CI, 1.28-3.27) were significant predictors of antibiotic escalation. The patient already being on antibiotics (aOR, 0.54; 95% CI, 0.34-0.89) and the positive screen occurred during a nursing shift change (aOR, 0.36; 95% CI, 0.22-0.57) were negative predictors. Pneumonia was the most documented new infection, but only 19 (50%) of 38 pneumonia cases met full clinical diagnostic criteria. Conclusions: Inpatient sepsis screening led to a new infectious diagnosis in 13.2% of all positive sepsis screens, and the risk of prolonged antibiotic exposure without a clear infectious source was low. Pneumonia diagnostics and lactate testing are potential targets for future stewardship efforts.

Essential Staphylococcus aureus toxin export system.

Widespread antibiotic resistance among important bacterial pathogens such as Staphylococcus aureus calls for alternative routes of drug development. Interfering with crucial virulence determinants is considered a promising new approach to control bacterial infection. Phenol-soluble modulins (PSMs) are peptide toxins with multiple key roles in pathogenesis and have a major impact on the ability of highly virulent S. aureus to cause disease. However, targeting PSMs for therapeutic intervention is hampered by their multitude and diversity. Here we report that an ATP-binding cassette transporter with previously unknown function is responsible for the export of all PSMs, thus representing a single target for complete obstruction of PSM production. The transporter had a strong effect on virulence phenotypes, such as neutrophil lysis, and the extent of its effect on the development of S. aureus infection was similar to that of the sum of all PSMs. Notably, the transporter was essential for bacterial growth. Furthermore, it contributed to producer immunity toward secreted PSMs and defense against PSM-mediated bacterial interference. Our study reveals a noncanonical, dedicated secretion mechanism for an important class of toxins and identifies this mechanism as a comprehensive potential target for the development of drugs to efficiently inhibit the growth and virulence of pathogenic staphylococci.