Live Biotherapeutic Products for the Prevention of Recurrent Clostridioides difficile Infection.

OBJECTIVE: To review the efficacy, safety, and role of live biotherapeutic products (LBPs) in the prevention of recurrent Clostridioides difficile infection (rCDI). DATA SOURCES: A literature search was performed using PubMed and Google Scholar (through February 2024) with search terms RBX2660, SER-109, and fecal microbiota. Other resources included abstracts presented at recent conferences, national clinical practice guidelines, and manufacturers' websites. STUDY SELECTION AND DATA EXTRACTION: All relevant studies, trial updates, conference abstracts, and guidelines in the English language were included. DATA SYNTHESIS: Two LBPs were recently approved by the Food and Drug Administration for the prevention of recurrence in adults following antibiotic treatment for rCDI. Fecal microbiota, live-jslm is administered rectally as a retention enema, whereas fecal microbiota spores, live-brpk is given orally after bowel preparation. Several phase 2 and phase 3 clinical trials have established the safety and efficacy of these LBPs in reducing rates of rCDI compared with placebo. Patients with severe immunosuppression and those with inflammatory bowel disease were largely excluded from these trials. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Live biotherapeutic products offer a similar mechanism to conventional fecal microbiota transplant (FMT) in preventing rCDI through microbiota restoration. The primary advantages of LBPs over FMT are their standardized composition and donor stool screening processes for transmissible pathogens. Bezlotoxumab is also available for the prevention of Clostridioides difficile infection; however, there are no clinical data available to compare the efficacy of LBPs with bezlotoxumab, and the benefit of simultaneous use of these preventative therapies is unclear. CONCLUSIONS: Live biotherapeutic products provide a safe and effective option for the prevention of rCDI and represent an improvement over conventional FMT. Additional studies are needed to further determine their place in therapy relative to bezlotoxumab and in the setting of immunosuppression and inflammatory bowel disease.

Community-acquired Coinfection in Coronavirus Disease 2019: A Retrospective Observational Experience.

Community-acquired coinfection in coronavirus disease 2019 (COVID-19) is not well defined. Current literature describes coinfection in 0-40% of COVID-19 patients. In this retrospective report, coinfection was identified in 3.7% of patients and 41% of patients admitted to intensive care (P < .005). Despite infrequent coinfection, antibiotics were used in 69% of patients.

Remdesivir Use in the Setting of Severe Renal Impairment: A Theoretical Concern or Real Risk?

BACKGROUND: Remdesivir (RDV) is US FDA approved for coronavirus disease 2019 (COVID-19) but not recommended in severe renal impairment (SRI, Creatinine clearance <30mL/min or requiring renal replacement therapy). Few studies have evaluated RDV in patients with SRI. METHODS: Hospitalized patients who received RDV between 1 May 2020 and 31 October 2020 were analyzed in a retrospective chart review. We compared incident adverse events (AEs) in patients with and without SRI, including hepatotoxicity, nephrotoxicity, any reported AE, mortality, and length of stay. RESULTS: Of a total of 135 patients, 20 had SRI. Patients with SRI were significantly older (70 vs 54 years, P = .0001). The incidence of possible AEs was 30% among those with SRI vs 11% without (P = .06). Liver function test (LFT) elevations occurred in 10% vs 4% (P = .28), and serum creatinine (SCr) elevations in 27% vs 6% (P = .02) of patients with SRI vs without, respectively. LFT and SCr elevations were not attributed to RDV in either group. Mortality and length of stay were consistent with historical controls. CONCLUSIONS: RDV AEs occurred infrequently and overall were not significantly different between those with and without SRI. While more of patients with SRI experienced SCr elevations, 3 (75%) patients had acute kidney injury prior to RDV. The use of RDV in this small series of patients with SRI appeared to be relatively safe, and the potential benefit outweighed the theoretical risk of liver or renal toxicity. Additional studies are needed to confirm this finding.

Late onset infectious complications and safety of tocilizumab in the management of COVID-19.

BACKGROUND: Tocilizumab (TCZ) has been used in the management of COVID-19-related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug-related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID-19 patients. METHODS: All adult inpatients with COVID-19 between 1 March and 25 April 2020 that received TCZ were included. We compared the rate of late-onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post-TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion-related reactions. RESULTS: Seventy-four patients were included in each group. Seventeen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (P = .013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, P = .03). CONCLUSION: Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ-related toxicities, 61% of patients had a possible post-TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID-19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use.

Reducing the use of empiric antibiotic therapy in COVID-19 on hospital admission.

BACKGROUND: Empiric antibiotics for community acquired bacterial pneumonia (CABP) are often prescribed to patients with COVID-19, despite a low reported incidence of co-infections. Stewardship interventions targeted at facilitating appropriate antibiotic prescribing for CABP among COVID-19 patients are needed. We developed a guideline for antibiotic initiation and discontinuation for CABP in COVID-19 patients. The purpose of this study was to assess the impact of this intervention on the duration of empiric CABP antibiotic therapy among patients with COVID-19. METHODS: This was a single-center, retrospective, quasi-experimental study of adult patients admitted between 3/1/2020 to 4/25/2020 with COVID-19 pneumonia, who were initiated on empiric CABP antibiotics. Patients were excluded if they were initiated on antibiotics > 48 h following admission or if another source of infection was identified. The primary outcome was the duration of antibiotic therapy (DOT) prior to the guideline (March 1 to March27, 2020) and after guideline implementation (March 28 to April 25, 2020). We also evaluated the clinical outcomes (mortality, readmissions, length of stay) among those initiated on empiric CABP antibiotics. RESULTS: A total of 506 patients with COVID-19 were evaluated, 102 pre-intervention and 404 post-intervention. Prior to the intervention, 74.5% (n = 76) of patients with COVID-19 received empiric antibiotics compared to only 42% of patients post-intervention (n = 170), p < 0.001. The median DOT in the post-intervention group was 1.3 days shorter (p < 0.001) than the pre-intervention group, and antibiotics directed at atypical bacteria DOT was reduced by 2.8 days (p < 0.001). More patients in the post-intervention group were initiated on antibiotics based on criteria consistent with our guideline (68% versus 87%, p = 0.001). There were no differences between groups in terms of clinical outcomes. CONCLUSION: Following the implementation of a guideline outlining recommendations for initiating and discontinuing antibiotics for CABP among COVID-19 inpatients, we observed a reduction in antibiotic prescribing and DOT. The guideline also resulted in a significant increase in the rate of guideline-congruent empiric antibiotic initiation.

The effect of delays in second-dose antibiotics on patients with severe sepsis and septic shock.

BACKGROUND: Early antibiotics are fundamental to sepsis management. Second-dose antibiotic delays were associated with increased mortality in a recent study. Study objectives include: 1) determine factors associated with delays in second-dose antibiotic administration; 2) evaluate if delays influence clinical outcomes. METHODS: ED-treated adults (≥18 years; n = 1075) with severe sepsis or septic shock receiving ≥2 doses of intravenous antibiotics were assessed, retrospectively, for second-dose antibiotic delays (dose time > 25% of recommended interval). Predictors of delay and impact on outcomes were determined, controlling for MEDS score, 30 mL/kg fluids and antibiotics within three hours of sepsis onset, lactate, and renal failure, among others. RESULTS: In total, 335 (31.2%) patients had delayed second-dose antibiotics. A total of 1864 second-dose antibiotics were included, with 354 (19.0%) delays identified by interval (delayed/total doses): 6-h (36/67) = 53.7%; 8-h (165/544) = 30.3%; 12-h (114/436) = 26.1%; 24-h (21/190) = 8.2%; 48-h (0/16) = 0%. In-hospital mortality in the timely group was 15.5% (shock-17.6%) and 13.7% in the delayed group (shock-16.9%). Increased odds of delay were observed for ED boarding (OR 2.54, 95% 1.81-3.55), shorter dosing intervals (6/8-h- OR 2.99, 95% CI 1.95-4.57; 12-h- OR 2.46, 95% CI 1.72-3.51), receiving 30 mL/kg fluids by three hours (OR 1.42, 95% CI 1.06-1.90), and renal failure (OR 2.57, 95% CI 1.50-4.39). Delays were not associated with increased mortality (OR 0.87, 95% CI 0.58-1.29) or other outcomes. CONCLUSIONS: Factors associated with delayed second-dose antibiotics include ED boarding, antibiotics requiring more frequent dosing, receiving 30 mL/kg fluid, and renal failure. Delays in second-dose administration were not associated with mortality or other outcomes.

From Etest to Vitek 2: Impact of Enterococcal Linezolid Susceptibility Testing Methodology on Time to Active Therapy.

Different linezolid antimicrobial susceptibility testing (AST) methodologies yield various results. In 2018, we transitioned our linezolid AST methodology from the Etest to Vitek 2. We sought to evaluate the impact of this change on antibiotic use among 181 inpatients with vancomycin-resistant enterococcal (VRE) infections. The transition from Etest to Vitek 2 resulted in an increase in linezolid susceptibility (38% versus 96%; P < 0.001) and a reduction in time to active antibiotic therapy (3 versus 2.6 days; P = 0.007).

Effect of IV Push Antibiotic Administration on Antibiotic Therapy Delays in Sepsis.

OBJECTIVES: Timeliness of antibiotic administration is recognized as an important factor in reducing mortality associated with sepsis. According to guidelines, antibiotics should be administered within 1 hour of sepsis presentation and the Centers for Medicare & Medicaid Services mandates administration within 3 hours. This study evaluates the difference in time from sepsis diagnosis to first-dose completion of ß-lactam antibiotics between IV push and IV piggyback administration. DESIGN: Single-center, retrospective analysis. SETTING: Urban, tertiary-care emergency department. PATIENTS: Inclusion criteria were as follows: 1) adult patients (n = 274) diagnosed with severe sepsis or septic shock per Sepsis-2 criteria from September to November 2016 and from September to November 2017 and 2) received ß-lactam antibiotic. INTERVENTIONS: Initial ß-lactam agent administered as either IV push or IV piggyback. MEASUREMENTS AND MAIN RESULTS: Median time (interquartile range) from sepsis diagnosis to administration of a ß-lactam antibiotic was 48 minutes (19-96 min) versus 72 minutes (8-180 min) and to administration of the complete broad-spectrum regimen was 108 minutes (66-144 min) versus 114 minutes (42-282 min) in the IV push (n = 143) versus IV piggyback (n = 131) groups, respectively. When controlling for time to sepsis diagnosis and other factors, IV push was associated with approximately 32-minute time savings to ß-lactam (ß = -0.60; 95% CI, -0.91 to -0.29) and approximately 32-minute time savings to broad-spectrum (ß = -0.32; 95% CI, -0.62 to -0.02) antibiotic administrations. The IV push group was less likely to fail the goal of ß-lactam antibiotics within 1 hour (44.6% vs 57.3%; odds ratio, 2.27; 95% CI, 1.34-3.86) and 3 hours (7.6% vs 24.5%; odds ratio, 4.31; 95% CI, 2.01-10.28) of sepsis diagnosis compared with IV piggyback. The IV push strategy did not affect mortality, need for ICU admission, or ICU length of stay. No adverse events, including infusion reactions, were found in either arm. CONCLUSIONS: Use of an IV push strategy may safely facilitate more rapid administration of ß-lactam antibiotics and may allow for better compliance with sepsis management guidelines.

Impact of mail order pharmacy use and travel time to pharmacy on viral suppression among people living with HIV.

This study aimed to evaluate the impact of mail order pharmacy services and travel time to pharmacy on HIV viral suppression rates among people living with HIV. For adult patients receiving HIV care from 2010 to 2015 at an urban HIV care clinic, we collected demographics, pharmacy type, viral load, and patient home and pharmacy address. We geocoded addresses and measured travel time to pharmacy by car and public transportation. No difference was observed in recent viral suppression rates based on pharmacy type (p = 0.41), distance to pharmacy (p = 0.16), or travel time to pharmacy by car (p = 0.20) or public transportation (p = 0.15). The only factors significantly associated with sustained viral suppression were number of doses per day of antiretroviral therapy, with patients prescribed twice daily regimens less likely to be virally suppressed than those prescribed once daily regimens (aOR 0.4, 95% CI, [0.1, 0.6]) and average household income in patients' zip code, with patients living in zip codes with average household income <$40,000 per year less likely to be virally suppressed than those living in zip codes with average income >$55,000 per year (aOR 0.2. 95% CI, [0.1, 0.7]).

Universal molecular Clostridioides difficile screening and overtreatment in solid organ transplant recipients.

BACKGROUND: Screening for Clostridioides difficile (CD) colonization can be performed using molecular testing to identify the presence of microbial DNA of the toxin gene. Colonization rates for hospitalized patients are as high as 20% and may be considerably higher in solid organ transplant (SOT) recipients. Treatment for CD should be based on clinical disease and not colonization, yet clinicians may misinterpret a positive CD screen resulting in overtreatment. OBJECTIVES: The objective of this analysis is to determine how often positive CD screens resulted in inappropriate treatment with oral vancomycin. METHODS: Clostridioides difficile screens were performed using the Xpert C difficile assay (Cepheid), a nucleic acid amplification testing method utilizing polymerase chain reaction (PCR), on peri-rectal swabs for newly admitted patients. This was a single-center cohort study of adult patients with CD screens hospitalized between July 2015 and November 2018. The primary outcome was the rate of inappropriate oral vancomycin treatment in all patients and in SOT recipients, defined as therapy in the absence of diarrhea. RESULTS: Of the 47 076 total CD screens reviewed, 1,921 were positive. In the SOT cohort, 58 of 329 screens were positive (4.1% vs 17.9%, P < .01). Of all patients with a positive CD screen, 20.1% (386/1921) were treated with oral vancomycin within 48 hours of swab collection. In the SOT cohort, 39.6% (23/58) with positive CD screens were treated with oral vancomycin within 48 hours. Of the SOT patients who received oral vancomycin, 39% (9/23) did not have true CD infection. CONCLUSION: Solid organ transplant recipients were more likely to have CD colonization detected by peri-rectal screening than the general inpatient population. SOT and non-SOT patients were treated with oral vancomycin at similar rates in response to the positive screen. Nearly half of the oral vancomycin use in SOT recipients was likely overtreatment, but this finding is limited by the low number of patients in this cohort.

Reducing medication errors involving antiretroviral therapy with targeted electronic medical record modifications.

Medication errors are common among HIV-infected patients on anti-retroviral therapy (ART), especially when transitioning to the inpatient setting. In previous studies, medication error rates among hospitalized patients on ART have been reported to exceed 50%. When patients receiving ART are admitted to the hospital, medication errors can be prevented through optimization of administration instructions and dosing defaults in order-entry screens in the electronic medical record (EMR). We sought to evaluate the impact of EMR modifications (defaulted doses, frequencies, and administration instructions) implemented to improve the order-entry process and reduce errors. All adult patients admitted between 10/1/2010-3/31/2012 (pre-EMR modification) and 10/1/2013-3/31/2014 (post-EMR modification) that continued on ART upon admission were included. The primary outcome was the overall rate of medication errors identified through review by the antimicrobial stewardship program (ASP). We also characterized the types of medication errors identified during the two time periods. Following EMR modifications, the medication error rate identified through ASP review was reduced from 50.2% to 28.2% (P < 0.01). The number of medication related errors relating to dosage (regimens requiring dose optimization, renal dose adjustment, and dose timing) were reduced by 22% (P < 0.01). Modifications at the anti-retroviral medication order-entry screens in the EMR significantly reduced medication errors, particularly with respect to dosing and dose timing.

Moxifloxacin versus levofloxacin for antibacterial prophylaxis in acute leukemia patients.

OBJECTIVE: The primary endpoint of this study was to determine the incidence of febrile neutropenia among patients receiving either moxifloxacin or levofloxacin for antibacterial prophylaxis. Secondary endpoints were number of documented infections and in-hospital mortality in patients who develop febrile neutropenia. METHODS: A single-center retrospective cohort analysis at a large tertiary care academic medical center was conducted. This study included adult acute leukemia patients (age ≥18 years old) who received inpatient antibacterial prophylaxis (moxifloxacin or levofloxacin) from 1 July 2012 to 1 October 2014. Patients were excluded from the study if they were treated with antimicrobial therapy in the preceding five days or admitted to the hospital with neutropenic fever. Fisher's exact test was used for categorical data and Mann-Whitney test for continuous data. Logistic regression analysis was used to determine risk factors for febrile neutropenia. RESULTS: Eighty-five patients were included in the final analysis with 40 patients who received moxifloxacin and 45 patients who received levofloxacin. Baseline characteristics were similar between the two groups. Twenty-two patients experienced febrile neutropenia requiring intravenous antibiotics in the moxifloxacin group and 30 patients in the levofloxacin group (P = 0.190). Age and duration of neutropenia appeared to predict for febrile neutropenia; however, after multivariate analysis, longer duration of neutropenia was shown to be the best predictor for febrile neutropenia with an odds ratio of 4.69 (95% CI, 1.697-12.968). Both groups had similar rates of documented infections and in-hospital morality. CONCLUSION: Moxifloxacin and levofloxacin showed similar rates of febrile neutropenia when used for neutropenic antibacterial prophylaxis in acute leukemia patients.

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.

OBJECTIVE: Studies in sepsis are limited by heterogeneity regarding what constitutes suspicion of infection. We sought to compare potential suspicion criteria using antibiotic and culture order combinations in terms of patient characteristics and outcomes. We further sought to determine the impact of differing criteria on the accuracy of sepsis screening tools and early warning scores. DESIGN: Observational cohort study. SETTING: Academic center from November 2008 to January 2016. PATIENTS: Hospitalized patients outside the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six criteria were investigated: 1) any culture, 2) blood culture, 3) any culture plus IV antibiotics, 4) blood culture plus IV antibiotics, 5) any culture plus IV antibiotics for at least 4 of 7 days, and 6) blood culture plus IV antibiotics for at least 4 of 7 days. Accuracy of the quick Sepsis-related Organ Failure Assessment score, Sepsis-related Organ Failure Assessment score, systemic inflammatory response syndrome criteria, the National and Modified Early Warning Score, and the electronic Cardiac Arrest Risk Triage score were calculated for predicting ICU transfer or death within 48 hours of meeting suspicion criteria. A total of 53,849 patients met at least one infection criteria. Mortality increased from 3% for group 1 to 9% for group 6 and percentage meeting Angus sepsis criteria increased from 20% to 40%. Across all criteria, score discrimination was lowest for systemic inflammatory response syndrome (median area under the receiver operating characteristic curve, 0.60) and Sepsis-related Organ Failure Assessment score (median area under the receiver operating characteristic curve, 0.62), intermediate for quick Sepsis-related Organ Failure Assessment (median area under the receiver operating characteristic curve, 0.65) and Modified Early Warning Score (median area under the receiver operating characteristic curve 0.67), and highest for National Early Warning Score (median area under the receiver operating characteristic curve 0.71) and electronic Cardiac Arrest Risk Triage (median area under the receiver operating characteristic curve 0.73). CONCLUSIONS: The choice of criteria to define a potentially infected population significantly impacts prevalence of mortality but has little impact on accuracy. Systemic inflammatory response syndrome was the least predictive and electronic Cardiac Arrest Risk Triage the most predictive regardless of how infection was defined.

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 [ß (SE) = -0.33 (2.2), P = 0.88], log ALT [ß (SE) = -0.02 (0.03), P = 0.63], ALK [ß (SE) = 2.2 (2.9), P = 0.46] and TBILI [ß (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.

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

Objectives Febrile neutropenia management guidelines recommend the use of vancomycin as part of an empiric antimicrobial regimen when specific criteria are met. Often, vancomycin use among patients with febrile neutropenia is not indicated and may be over utilized for this indication. We sought to evaluate the impact of implementing a febrile neutropenia clinical pathway on empiric vancomycin use for febrile neutropenia and to identify predictors of vancomycin use when not indicated. Methods Adult febrile neutropenia patients who received initial therapy with an anti-pseudomonal beta-lactam with or without vancomycin were identified before (June 2008 to November 2010) and after (June 2012 to June 2013) pathway implementation. Patients were assessed for appropriateness of therapy based on whether the patient received vancomycin consistent with guideline recommendations. Using a comorbidity index used for risk assessment in high risk hematology/oncology patients, we evaluated whether specific comorbidities are associated with inappropriate vancomycin use in the setting of febrile neutropenia. Results A total of 206 patients were included in the pre-pathway time period with 35.9% of patients receiving vancomycin therapy that was inconsistent with the pathway. A total of 131 patients were included in the post-pathway time period with 11.4% of patients receiving vancomycin inconsistent with the pathway ( p = 0.001). None of the comorbidities assessed, nor the comorbidity index score were found to be predictors of vancomycin use inconsistent with guideline recommendations. Conclusion Our study has demonstrated that implementation of a febrile neutropenia pathway can significantly improve adherence to national guideline recommendations with respect to empiric vancomycin utilization for febrile neutropenia.

Impact of Pharmacy Practice Model Expansion on Pharmacokinetic Services: Optimization of Vancomycin Dosing and Improved Patient Safety.

Background: The impact of pharmacy interventions on optimizing vancomycin therapy has been described, however interventions vary among studies and the most optimal pharmacy practice model (PPM) for pharmacokinetic (PK) services has not been established. Objective: The purpose of this study is to demonstrate the value of 24 hours a day, 7 days a week (24/7) PK services. Methods: New PK services were implemented in 2 phases with institutional PPM expansion. Phase 1 included universal monitoring by pharmacists with recommendations made to prescribers during business hours. Phase 2 expanded clinical pharmacists' coverage to 24/7 and provided an optional 24/7 pharmacist-managed PK consult service. We compared vancomycin therapeutic trough attainment, dosing, and clinical and safety outcomes between phases 1 and 2 in adult inpatients receiving therapeutic intravenous vancomycin. Results. One hundred and fifty patients were included in each phase. Phase 2 had a greater proportion of vancomycin courses with therapeutic initial trough concentrations (27.5% vs 46.1%; p = 0.002), higher initial trough concentrations (10.9 mcg/mL vs 16.4 mcg/mL; p < 0.001), and optimized initial vancomycin dosing (13.5 mg/kg vs 16.2 mg/kg; p < 0.001). Phase 2 also saw significant reduction in the incidence of vancomycin-associated nephrotoxicity (21.1% vs 11.7%; p = 0.038). Dose optimization and improvement in initial target trough attainment were most notable among intensive care unit (ICU) patients. Conclusions. Our study demonstrated that 24/7 PK services implemented with institutional PPM expansion optimized vancomycin target trough attainment and improved patient safety.

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

Severe cases of itraconazole-induced hepatotoxicity have been reported; however, these events are thought to occur very rarely. The available literature is comprised largely of individual case reports and small series that do not report the itraconazole serum concentration at the time of the severe adverse event or apply an objective scale to assess probability of the event being related to drug exposure. We report a case of severe hepatotoxicity after 6 months of itraconazole therapy for histoplasmosis, resulting in acute hepatic failure (aspartate transaminase >20× and alanine transaminase >15× upper limit normal), in the setting of therapeutic serum concentrations (5 mg/mL). Both the Naranjo probability scale and the Roussel Uclaf causality assessment method were used to assess the probability of a causality relationship showing a "probable" and "highly probable" association with itraconazole exposure, respectively. The available literature describing severe hepatotoxicity resulting in hepatic failure associated with itraconazole is also reviewed.

Impact of the FDA Warning for Azithromycin and Risk for QT Prolongation on Utilization at an Academic Medical Center.

A US Food and Drug Administration (FDA) drug safety communication was released in March 2013, warning prescribers of the risk of QT prolongation associated with azithromycin. Overall azithromycin utilization and adherence to an inpatient QTc monitoring guideline during 8-month time periods before and after the warning were assessed to evaluate the impact of this warning on inpatient azithromycin utilization and QTc monitoring. Fifty-five patients were included in the prewarning time period and 50 were included in the postwarning period. A significant reduction in utilization in days of therapy per 1,000 patient days was observed (31.2 prewarning vs 17.5 postwarning, p < .001) in these groups. No changes in QTc monitoring among patients receiving azithromycin were identified. FDA warnings of severe, life-threatening toxicities can have a profound impact on utilization and prescribing of medications, however they may not necessarily change monitoring practices.

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 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.