Therapeutic drug monitoring (TDM) aims to minimize the clinical impact of posaconazole and voriconazole pharmacokinetic variability. However, its benefits on clinical outcomes are still being defined. Additionally, TDM data are limited for posaconazole IV and delayed-release tablet formulations among specific patient populations, including critically ill. The aim of this study was to determine the percentage of therapeutic posaconazole and voriconazole drug levels across all formulations in a real-world clinical setting and elucidate factors affecting attainment of target concentrations. This study was a retrospective cohort study conducted at the University of Colorado Hospital between September 2006 and June 2015 that evaluated patients who received posaconazole or voriconazole TDM as part of routine care. Voriconazole (n = 250) and posaconazole (n = 100) levels were analyzed from 151 patients. Of these, 54% of voriconazole and 69% of posaconazole levels were therapeutic. For posaconazole, 14/38 (37%), 28/29 (97%) and 27/33 (82%) levels were therapeutic for the oral suspension, IV, and delayed-release tablet, respectively. Intravenous and delayed-release tablet posaconazole were 20 fold (p < 0.01) and sevenfold (p = 0.002) more likely than the oral suspension to achieve a therapeutic level. Subsequent levels were more likely to be therapeutic after dose adjustments (OR 3.31; 95% CI 1.3–8.6; p = 0.02), regardless of timing of initial non-therapeutic level. In a multivariable logistic regression analysis, no characteristics were independently predictive of therapeutic voriconazole levels and only absence of H2RA/PPI use was independently predictive of therapeutic posaconazole levels. There was no correlation between survival and therapeutic drug levels for either voriconazole (p = 0.67) or posaconazole (p = 0.50). A high percentage of drug levels did not achieve TDM targets for voriconazole and posaconazole oral suspension, supporting the need for routine TDM for those formulations. The utility of TDM for the IV and delayed-release tablet formulations of posaconazole is less apparent.

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.

This study evaluated the impact of dexmedetomidine (DEX) administration on benzodiazepine (BZD) requirements in intensive care unit (ICU) patients experiencing alcohol withdrawal syndrome (AWS). This trial included adults admitted to the ICU for >24 hours for AWS. Early DEX was defined as receiving DEX within 60 hours of hospital admission. The primary outcome was 12-hour BZD requirement from the inflection point or DEX initiation. Secondary outcomes included 24-hour BZD requirements, symptom control, ICU and hospital length of stay, and incidence and duration of mechanical ventilation. Safety outcomes included incidence of bradycardia and hypotension. Twenty patients receiving DEX were matched to 22 control patients. The mean 12-hour change in BZD requirement was significantly different for DEX versus control (−20 vs −8.3 mg, P = .0455) with a trend toward significance at 24 hours (−29.6 vs −11 mg, P = .06). No significant differences were noted in other secondary outcomes. Patients receiving DEX experienced significantly more bradycardia than controls (35% vs 0%, P < .01) but not hypotension. This study suggests DEX is associated with a reduction in BZD requirement when utilized as adjunctive therapy for AWS. A larger prospective trial is needed to evaluate the clinical impact of DEX for AWS.

Invasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efficacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efficacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole. This single center retrospective matched cohort study evaluated adults between January 2015 and December 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost. A total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was different between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p = 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p = 0.029) were different between the three groups. No differences in mortality, length of stay, readmission, or infection recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not different between treatments (p = 0.36). Patients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not significantly different between the treatment therapy options.

Objective: To report the successful treatment of external ventricular-drain (EVD)– associated infection due to vancomycin-resistant Enterococcus faecium (VRE) with intraventricular daptomycin and intravenous linezolid. Case Summary: A 64-year-old white male with a complicated medical history was admitted to the neurosurgical unit with Scedosporium apiospermum meningitis and hydrocephalus requiring management with a right and left EVD. On day 28, cerebrospinal fluid cultures from the right EVD grew VRE. Despite initiation of intravenous linezolid, cultures from the right EVD remained positive. Intraventricular daptomycin 5 mg daily was initiated and administered into the right EVD for 7 days. Cerebrospinal fluid was collected from EVD outputs and analyzed for daptomycin concentrations. VRE in cultures from the EVD cleared after 1 day of therapy and no adverse effects were noted. Right and left EVD daptomycin concentrations were discordant throughout therapy by at least a 3-fold difference. First-dose peak and trough daptomycin concentrations in the cerebrospinal fluid were 112.2 and 1.34 μg/mL, respectively, for the right EVD and 37.4 and 0.37 μg/mL, respectively, for the left EVD. Daptomycin accumulation was evident after 3 days of therapy. Discussion: Varying doses and frequencies of intraventricular daptomycin have been reported effective for VRE ventriculitis. Intraventricular drug distribution may not be homogeneous throughout the central nervous system. Therefore, daptomycin minimum inhibitory concentration for VRE, cerebrospinal fluid communication throughout the central nervous system, EVD output, and the potential for drug accumulation should be considered when selecting a dose and frequency. Conclusions: Intraventricular daptomycin may be an option for EVD-associated VRE infections that do not respond to conventional therapy. Intraventricular daptomycin 5 mg is a reasonable initial dose in adults with VRE ventriculitis, based on our experience in this patient.