Natasha Pettit

Isavuconazole: A New Option for the Management of Invasive Fungal Infections

OBJECTIVE To review the pharmacology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of isavuconazole, a triazole antifungal agent. DATA SOURCES Studies and reviews were identified through an English language MEDLINE search (1978 to March 2015) and from http://www.clinicaltrials.gov, Food and Drug Administration (FDA) briefing documents, program abstracts from international symposia, and the manufacturers Web site. STUDY SELECTION AND DATA EXTRACTION All published and unpublished trials, abstracts, in vitro and preclinical studies, and FDA briefing documents were reviewed. DATA SYNTHESIS Isavuconazole has activity against a number of clinically important yeasts and molds, including Candida spp, Aspergillus spp, Cryptococcus neoformans, and Trichosporon spp and variable activity against the Mucorales. Isavuconazole, available for both oral and intravenous administration, is characterized by slow elimination allowing once-daily dosing, extensive tissue distribution, and high (>99%) protein binding. The most commonly reported adverse events, which are mild and limited in nature, include nausea, diarrhea, and elevated liver function tests. Its drug interaction potential appears to be similar to other azole antifungals but less than those observed with voriconazole. Comparative trials are under way or have been recently completed for the treatment of candidemia, invasive candidiasis and aspergillosis, and rare mold infections. CONCLUSIONS Isavuconazole has a broad spectrum of activity and favorable pharmacokinetic properties, providing an advantage over other currently available broad-spectrum azole antifungals and a clinically useful alternative to voriconazole for the treatment of invasive aspergillosis. It may also prove useful for the treatment of candidemia and invasive mold infections; however, these indications await the results of clinical trials.Objective: To review the pharmacology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of isavuconazole, a triazole antifungal agent. Data Sources: Studies and reviews were identified through an English language MEDLINE search (1978 to March 2015) and from http://www.clinicaltrials.gov, Food and Drug Administration (FDA) briefing documents, program abstracts from international symposia, and the manufacturer’s Web site. Study Selection and Data Extraction: All published and unpublished trials, abstracts, in vitro and preclinical studies, and FDA briefing documents were reviewed. Data Synthesis: Isavuconazole has activity against a number of clinically important yeasts and molds, including Candida spp, Aspergillus spp, Cryptococcus neoformans, and Trichosporon spp and variable activity against the Mucorales. Isavuconazole, available for both oral and intravenous administration, is characterized by slow elimination allowing once-daily dosing, extensive tissue distribution, and high (>99%) protein binding. The most commonly reported adverse events, which are mild and limited in nature, include nausea, diarrhea, and elevated liver function tests. Its drug interaction potential appears to be similar to other azole antifungals but less than those observed with voriconazole. Comparative trials are under way or have been recently completed for the treatment of candidemia, invasive candidiasis and aspergillosis, and rare mold infections. Conclusions: Isavuconazole has a broad spectrum of activity and favorable pharmacokinetic properties, providing an advantage over other currently available broad-spectrum azole antifungals and a clinically useful alternative to voriconazole for the treatment of invasive aspergillosis. It may also prove useful for the treatment of candidemia and invasive mold infections; however, these indications await the results of clinical trials.

Documenting Penicillin Allergy: The Impact of Inconsistency.

Background Allergy documentation is frequently inconsistent and incomplete. The impact of this variability on subsequent treatment is not well described. Objective To determine how allergy documentation affects subsequent antibiotic choice. Design Retrospective, cohort study. Participants 232,616 adult patients seen by 199 primary care providers (PCPs) between January 1, 2009 and January 1, 2014 at an academic medical system. Main Measures Inter-physician variation in beta-lactam allergy documentation; antibiotic treatment following beta-lactam allergy documentation. Key Results 15.6% of patients had a reported beta-lactam allergy. Of those patients, 39.8% had a specific allergen identified and 22.7% had allergic reaction characteristics documented. Variation between PCPs was greater than would be expected by chance (all p<0.001) in the percentage of their patients with a documented beta-lactam allergy (7.9% to 24.8%), identification of a specific allergen (e.g. amoxicillin as opposed to “penicillins”) (24.0% to 58.2%) and documentation of the reaction characteristics (5.4% to 51.9%). After beta-lactam allergy documentation, patients were less likely to receive penicillins (Relative Risk [RR] 0.16 [95% Confidence Interval: 0.15–0.17]) and cephalosporins (RR 0.28 [95% CI 0.27–0.30]) and more likely to receive fluoroquinolones (RR 1.5 [95% CI 1.5–1.6]), clindamycin (RR 3.8 [95% CI 3.6–4.0]) and vancomycin (RR 5.0 [95% CI 4.3–5.8]). Among patients with beta-lactam allergy, rechallenge was more likely when a specific allergen was identified (RR 1.6 [95% CI 1.5–1.8]) and when reaction characteristics were documented (RR 2.0 [95% CI 1.8–2.2]). Conclusions Provider documentation of beta-lactam allergy is highly variable, and details of the allergy are infrequently documented. Classification of a patient as beta-lactam allergic and incomplete documentation regarding the details of the allergy lead to beta-lactam avoidance and use of other antimicrobial agents, behaviors that may adversely impact care quality and cost.

Evaluation of risk factors for vancomycin-resistant Enterococcus bacteremia among previously colonized hematopoietic stem cell transplant patients

Hematopoietic stem cell transplantation (HSCT) recipients colonized with vancomycin‐resistant Enterococcus (VRE) may have an increased risk of developing VRE bacteremia. Identification of risk factors for the development of subsequent VRE bacteremia among colonized HSCT recipients is necessary to predict which patients may benefit the most from receiving anti‐VRE antibiotic therapy as part of an initial antimicrobial regimen when gram‐positive bacteremia is suspected.

Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation

Objectives The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken. Methods This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression. Results One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220) ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P  <   0.001), ALT ( P  <   0.001), alkaline phosphatase (ALK) ( P  <   0.001), total bilirubin (TBILI) ( P  <   0.001) and QTc ( P  =   0.05) from baseline. Posaconazole levels were not associated with increases in AST [β (SE) = -0.33 (2.2), P  =   0.88], log ALT [β (SE) = -0.02 (0.03), P  =   0.63], ALK [β (SE) = 2.2 (2.9), P  =   0.46] and TBILI [β (SE) = -0.01 (0.04), P  =   0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL ( P  =   0.02) and ALK of 7.1 U/L ( P  =   0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found. Conclusions We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Comparison of turnaround time and time to oseltamivir discontinuation between two respiratory viral panel testing methodologies

Respiratory infections contribute to many Emergency Department visits and hospitalizations, resulting in a high healthcare burden (Neuzil et al., 2003; Schull et al., 2005). Rapid detection of respiratory pathogens in patients presenting with symptoms of an upper respiratory tract infection is crucial for timely determination of optimal antimicrobial management, avoidance of unnecessary evaluations and implementation of transmission-reducing infection control practices. Rapid viral testing can also result in cost savings to the healthcare system through reduction in Emergency Department boarding time and decreased duration of empiric antiviral therapy (Schull et al., 2005). With increased emphasis on antimicrobial stewardship in hospitals to facilitate improved clinical and economic outcomes with antimicrobial therapy, the implementation of rapid diagnostics for laboratory identification of pathogens is of great interest (Bauer et al., 2014). Multiplex PCR is a highly sensitive molecular method for accurate detection of respiratory pathogens and provides a more rapid turnaround time (TAT) compared with other respiratory viral testing methodologies. Our microbiology laboratory switched from the Luminex xTAG respiratory viral panel (RVP) (http://www.luminexcorp.com), which detects 12 respiratory viruses with an assay time of 8.5 h, performed two to three times per week to the Biofire Diagnostics FilmArray respiratory panel (RP) (http://filmarray.com), which detects 17 respiratory viral and three bacterial targets with an assay time of 1.2 h, performed 24 h a day/7 days per week. We compared the TAT between the two RVPs performed at different frequencies and determined the time to discontinuation of empiric oseltamivir among patients testing negative for influenza. All adult patients with an RVP test result reported between 1 December 2011 and 28 February 2012 performed on Luminex xTAG RVP (two to three times per week) and 1 December 2012 and 28 February 2013 performed on FilmArray RP (24 h a day/7 days per week) were evaluated for mean TAT. The mean TAT for the Luminex xTAG RVP (two to three times per week) between 1 December 2011 and 28 February 2012 (n = 230 assays) was 46.4 h compared with a mean TAT of 3.1 h (P<0.001) for FilmArray RP (24 h a day/7 days per week) between 1 December 2012 and 28 February 2013 (n = 872 assays) (Fig. 1). The mean time to discontinuation of empiric oseltamivir amongst patients with an RVP negative for influenza was 4 and 2 days for the Luminex xTAG RVP (n = 42) and FilmArray RP (n = 75) groups, respectively (P<0.001). The reduction in mean time to discontinuation of empiric oseltamivir resulted in cost savings of ~US

Investigating the Impact of Different Suspicion of Infection Criteria on the Accuracy of Quick Sepsis-related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores*

34.16 per patient (using a wholesale acquisition cost for oseltamivir of US

Guideline compliance and clinical outcomes among patients with Staphylococcus aureus bacteremia with infectious diseases consultation in addition to antimicrobial stewardship-directed review

8.54 per dose), which during the 2012–2013 peak influenza season would be an overall cost saving of US

Impact of a clinical pathway on appropriate empiric vancomycin use in cancer patients with febrile neutropenia.

2527.84. The amount of oseltamivir utilized after we began using the FilmArray RP (24 h a day/7 days per week) would cost US

Hepatic Failure in a Patient Receiving Itraconazole for Pulmonary Histoplasmosis-Case Report and Literature Review.

9564.80 (if all 112 influenza-positive patients received the standard 75 mg every 12 h dose for a duration of 5 days), in addition to US

Survey of institutions with multiple pharmacy residency programs

2527.84 for those that would have received empiric therapy for a duration of 2 days prior to discontinuation following a negative influenza result, totalling US